COPENHAGEN, Denmark – November 11, 2022 - Bavarian Nordic A/S (OMX:  BAVA) today announced that Paul Chaplin, President & CEO will provide a corporate presentation at the Jefferies 2022 London Healthcare Conference on Thursday, November 17, 2022 at 8:35 am GMT (9:35 am CET).

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Bavarian Nordic to Present at Jefferies 2022 London Healthcare Conference

NEWARK, Calif., Nov. 04, 2022 (GLOBE NEWSWIRE) -- CymaBay Therapeutics, Inc. (NASDAQ: CBAY), a biopharmaceutical company focused on developing and providing access to innovative therapies for patients with liver and other chronic diseases, today announced encouraging seladelpar data in patients with primary biliary cholangitis (PBC) that are being presented at The Liver Meeting® of the American Association for the Study of Liver Diseases (AASLD), in Washington, DC (November 4th – 8th).

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CymaBay Therapeutics Presents Additional Analyses from Clinical Studies of Seladelpar for Patients with Primary Biliary Cholangitis at The Liver...

MONTREAL, Nov. 04, 2022 (GLOBE NEWSWIRE) -- ExCellThera Inc. (ExCellThera), a world leader in blood stem cell expansion and rejuvenation, announced today that an abstract related to ExCellThera’s most advanced investigational drug, ECT-001 Cell Therapy, has been accepted for oral presentation at the upcoming 64th American Society of Hematology (ASH) Annual Meeting and Exposition, taking place December 10-13, 2022. The abstract is now available on the ASH website at www.hematology.org.

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ExCellThera announces oral presentation of new data on UM171-expanded cell therapy at the ASH Annual Meeting

Since launch the new product has had approximately 117% ROI

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SciSparc: Wellution™ Successfully Launched a New Keto Gummies Apple Cider Vinegar Product and Generated $100,000 In Revenues Within 30 Days

Company to complete and submit responses to FDA clinical hold

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CytoDyn Announces Voluntary Withdrawal of BLA for HIV-MDR Due to CRO Data Management Issues

PORTLAND, Ore., Oct. 28, 2022 (GLOBE NEWSWIRE) -- Chalice Brands Ltd. (CSE: CHAL) (OTCQB: CHALF) (the “Company” or “Chalice Brands”), a premier consumer-driven cannabis company specializing in retail, production, processing, wholesale, and distribution, announces that its interim Chief Financial Officer (CFO), Richard Lindsay, has resigned his position. Mr. Lindsay joined the company in an interim contract role to help get the Company through the 2021 audit. He has accomplished the majority of the work related to the audit and accordingly has resigned his position.

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Chalice Brands Ltd. Announces Resignation of Interim Chief Financial Officer

NEW HAVEN, Conn., Oct. 28, 2022 (GLOBE NEWSWIRE) --  BIOASIS TECHNOLOGIES INC. (TSXV:BTI; OTCQB:BIOAF), (the “Company” or “Bioasis”), a multi-asset rare and orphan disease biopharmaceutical company developing clinical stage programs based on epidermal growth factors and a differentiated, proprietary xB3 ™ platform for delivering therapeutics across the blood-brain barrier (“BBB”) and the treatment of central nervous system (“CNS”) disorders in areas of high unmet medical need, today announced it has filed its unaudited quarterly financial statements and management’s discussion and analysis for the period ended August 31, 2022. All are available under the Company’s profile on SEDAR at www.sedar.com and on the Company’s website at www.bioasis.us.

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Bioasis Announces Filing of Its Quarterly Financial Statements and MD&A for the Period Ending August 31, 2022

DEINOVE (Euronext Growth Paris: ALDEI), a French biotech company, pioneer in the exploration and exploitation of bacterial biodiversity to address the urgent, global challenge of antibiotic resistance, informs its shareholders that the Extraordinary General Meeting (AGE) held on October 17, 2022 has followed the recommendations of the Board of Directors, and adopted all the resolutions that the Board was favorable to, i.e. 10 out of the 11 resolutions.

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DEINOVE - Adoption of the resolutions at the Shareholders’ Extraordinary General Meeting on October 17, 2022

Awarded $17.6 million Product Development Research grant by the Cancer Prevention & Research Institute of Texas (CPRIT) to fund 186RNL development for leptomeningeal metastases (LM)

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Plus Therapeutics Reports Third Quarter 2022 Financial Results and Business Highlights

The FDA recently approved two gene therapies with hefty price tags, the first for an inherited anemia and the second for a degenerative brain condition. The two new treatments, from bluebirdbio, double the number of gene therapies on the market.

Most biotechnologies evolve over three decades or so, but the idea of gene therapy has been around since the late 1950s, blooming soon after Watson and Crick solved the structure of DNA. When my book The Forever Fix: Gene Therapy and the Boy Who Saved Itwas published a decade ago, it would still be 5 years before the first approval. That treatment, the subject of my book, enabled the blind to see, sometimes in just days.

Why has the pace of gene therapy been so slow? Cost is one barrier. Other concerns are the degree to which a gene therapy actually helps, how long the effect lasts, and what proportion of patients respond.

FDAs gene therapy roster ishere, but a caveat is necessary.

The list lumps gene therapy in with cell therapy, inviting unintentional hype from media folks unfamiliar with the science. Most entries actually refer to using stem cells to treat blood cancers and related conditions. An example: cartilage cells are sampled from a person with abum knee, mass-produced in a dish, and then injected into the knee, where they fuel production of more cartilage.

My favorite example of not-really-gene-therapy on the FDAs list targetsfacial wrinkles, also using patients lab-expanded cells: 18 million fibroblasts injected three times churn out collagen, filling in the offending skin craters.

Buried in the FDAs list are the first twoactualgene therapy approvals.Luxturna(Spark Therapeutics) treats RPE65 mutation-associated retinal dystrophy and has restored vision in many patients since its approval at the end of 2017. The second approved gene therapy, in 2019, isZolgensma, to treat spinal muscular atrophy, from Novartis Gene Therapies.

FDA approvedZynteglo on August 17, aka betibeglogene autotemcel or eli-cel. It treats the blood disorder beta thalassemia, which causes weakness, dizziness, fatigue, and bone problems. People with severe cases need transfusions of red blood cells every two to five weeks, which can lead to dangerous buildup of iron.

Zynteglo is a one-time infusion of stem cells descended from a patients bone marrow in which functional beta globin genes have been introduced aboard lentiviruses disabled HIV. The $2.8 million treatment is approved for adults and children.

Two clinical trials enrolled 91 patients, 36 of whom improved enough to no longer need transfusions. Bluebird estimates that 1,300 to 1,500 people in the U.S. may be candidates for Zynteglo.

The second go-ahead is forSkysona, approved September 16 for early active cerebral adrenoleukodystropy (CALD). The condition destroys the protective myelin sheath around brain neurons.

A stem cell transplant can cure CALD. Skysona is for the 700 or so boys aged 4 to 17 who cant find matched donors. Nearly fifty percent of them die within five years of symptom onset.

But like many gene therapies, Skysona isnt a magic bullet. In the two ongoing clinical trials, the metric for assessing improvement is slowing neurologic decline, tracking major functional disabilities. These include loss of communication skills, vision, and of voluntary movement, which impairs mobility, eating, and urinary retention.

The 2-year study that led to the FDA approval followed boys with mild or no symptoms, diagnosis possible early due to newborn screening in many states. Those who received Skysona had a 72% likelihood of survival over the two years without developing new major functional disabilities, compared to 43% among untreated boys. The trial will follow participants for 15 years. Since many states are nowscreening newborns for ALD, perhaps boys destined to develop symptoms can receive Skysona before that if someone will pick up the $3 million tab per patient.

Gene therapy companies have long justified high costs with the expense of the bench-to-bedside trajectory. So I was surprised to see a new study published inJAMA Network Open, Association of Research and Development Investments With Treatment Costs for New Drugs Approved From 2009 to 2018, finding none. The authors admonish companies to make further data available to support their claims that high drug prices are needed to recover research and development investments, if they are to continue to use this argument to justify high prices.

Becausethe paperuses terms like first-in-class, accelerated approval, breakthrough therapy, orphan, and priority review language Ive often seen attached to descriptions of gene therapy I assumed it would include Luxturna, which costs $850,000 for both eyes. But the new report omits drug names, instead citing a2020 paperfrom the team that did.No Luxturna. Thats probably because the researchers evaluated R&D costs only for products with publicly available data thats 63 drugs, a mere fifth of new approvals. The new report, of course sent out in news release form to the media, provides more a glimpse than a revelation.

So perhaps gene therapy is an exception for which high prices are indeed required to recoup investment. A viral vector to deliver DNA can cost $500,000 or more to produce, let alone engineer and develop.

Companies also use the one-and-done strategy to justify high prices. The homepage of bluebird bios website, for example, proclaims were pursuing curative gene therapies, although the data on Skysona for CALD indicate incremental change.Axios reports on how Medicaid, private insurers, and companies will help address cost concerns.

While bluebird bio bats around the c word cure it also introduces a long-needed granularity to the terminology. The company has replaced gene therapy with the more accurate gene addition therapy. Thats what the four approved gene therapies actually do add working copies of genes, not fixing them in place. Gene therapy is a little like patching a flat tire, not replacing it.

But the next stage of the evolving technology will in fact befixing genes, courtesy of gene and genome editing. This more precise strategy circumvents the problem of a piece of DNA inserting willy-nilly into a chromosome, perhaps disrupting a cancer-causing gene.

Gene editing with CRISPR has now been around for a decade. The components of the toolkit have been refined to minimize so-called off-target effects that can harpoon unintended genes.

A team atSt. Jude Childrens Research Hospitalhas developed what hematologist Yong Cheng terms the Google Maps of editing the genome. We provide a new approach to identify places to safely integrate a gene cassette. We created step-by-step directions to find safe harbor sites in specific tissues. The recipe is published inGenome Biologyand the tool availablehere.

The approach is seemingly simple. Using data from the 1000 Genomes Project, the tool identifies parts of the genome that often bear inserted or deleted DNA sequences among healthy people (and therefore are harmless) and are highly variable. These are the places where unwound DNA loops about itself when replicating just before a cell divides, and could tolerate a healing gene harpoon going astray.

Safe gene therapy requires two things. Number one, maintaining high expression of the new gene. And number two, the integration needs to have minimal effects on the normal human genome, Cheng said.

Gene addition therapy and gene/genome editing are slowly taking their places among other weapons against genetic disease. These include antisense treatments that glom onto mutant genes, small molecule-based drugs, repurposing existing drugs, supplements, and perhaps most important, the therapies that impact life on a daily basis. And so the toolbox expands to tackle the errors in our genes.

Ricki Lewis has a PhD in genetics and is a science writer and author of several human genetics books.She is an adjunct professor for the Alden March Bioethics Institute at Albany Medical College.Follow her at herwebsiteor Twitter@rickilewis

A version of this article originally appeared at PLOS and is reposted here with permission. Find PLOS on Twitter @PLOS

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Gene therapy approvals now at four with treatments for inherited anemia and degenerative brain condition but costs are stratospheric. Why? - Genetic...

CRANBURY, N.J.--(BUSINESS WIRE)--Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT), a leading late-stage biotechnology company advancing an integrated and sustainable pipeline of genetic therapies for rare childhood disorders with high unmet need, today announces data presentations at the 29th Annual Congress of the European Society of Gene & Cell Therapy (ESGCT) in Edinburgh, United Kingdom, taking place October 11-14, 2022. Presentations will include clinical data from Rockets lentiviral vector (LV)-based gene therapy programs for Leukocyte Adhesion Deficiency-I (LAD-I), Fanconi Anemia (FA) and Pyruvate Kinase Deficiency (PKD). Donald B. Kohn, MD, Distinguished Professor of Microbiology, Immunology & Molecular Genetics, Pediatrics, and Molecular & Medical Pharmacology at University of California, Los Angeles (UCLA) and Director of the UCLA Human Gene and Cell Therapy Program, will also give an Invited Talk incorporating previously disclosed data from the RP-L201 trial for LAD-I.

Positive Updated Safety and Efficacy Data from Phase 2 Pivotal Trial for Fanconi Anemia (FA)

The poster and presentation include updated safety and efficacy data from the Phase 2 pivotal trial of RP-L102, Rockets ex-vivo lentiviral gene therapy candidate for the treatment of FA.

Positive Top-line Clinical Data from Phase 2 Pivotal Trial for Severe Leukocyte Adhesion Deficiency-I (LAD-I)

The oral presentation includes previously disclosed efficacy and safety data at three to 24 months of follow-up after RP-L201 infusion for all patients and overall survival data for seven patients at 12 months or longer after infusion. RP-L201 is Rockets ex-vivo lentiviral gene therapy candidate for the treatment of severe LAD-I.

Interim Data from Ongoing Phase 1 Trial for Pyruvate Kinase Deficiency (PKD)

The poster and presentation include previously disclosed safety and efficacy data from the Phase 1 trial of RP-L301, Rockets ex-vivo lentiviral gene therapy candidate for the treatment of PKD.

Details for Rockets Invited Talk and poster presentations are as follows:

Title: Interim Results from an ongoing Phase 1/2 Study of Lentiviral-Mediated Ex-Vivo Gene Therapy for Pediatric Patients with Severe Leukocyte Adhesion Deficiency-I (LAD-I)Session: Clinical Trials (Plenary 2)Presenter: Donald B. Kohn, MD - University of California, Los Angeles, Distinguished Professor of Microbiology, Immunology & Molecular Genetics (MIMG), Pediatrics, and Molecular & Medical Pharmacology; Director of the UCLA Human Gene and Cell Therapy ProgramSession date and time: Wednesday, 12 October at 11:10-13:15 BSTLocation: Edinburgh International Conference Centre (EICC)Presentation Number: INV20

Title: Lentiviral-Mediated Gene Therapy for Patients with Fanconi Anemia [Group A]: Results from Global RP-L102 Clinical TrialsSession: Poster Session 1Presenter: Julin Sevilla MD, PhD - Fundacin para la Investigacin Biomdica, Hospital Infantil Universitario Nio JessSession date and time: Wednesday, 12 October at 19:30-21:00 BSTLocation: Edinburgh International Conference Centre (EICC)Poster Number: P139

Title: Preliminary Conclusions of the Phase I/II Gene therapy Trial in Patients with Fanconi Anemia-ASession: Blood Diseases: Haematopoietic Cell DisordersPresenter: Juan Bueren, PhD - Unidad de Innovacin Biomdica, Centro de Investigaciones Energticas, Medioambientales y Tecnolgicas (CIEMAT)Session date and time: Thursday, 13 October at 15:30-17:30 BSTLocation: Edinburgh International Conference Centre (EICC)Presentation Number: INV41

Title: Interim Results from an Ongoing Global Phase 1 Study of Lentiviral-Mediated Gene Therapy for Pyruvate Kinase DeficiencySession: Poster Session 2Presenter: Jos Luis Lpez Lorenzo, MD, Hospital Universitario Fundacin Jimnez DazSession date and time: Thursday, 13 October at 17:30-19:15 BSTLocation: Edinburgh International Conference Centre (EICC)Poster Number: P128

Abstracts for the presentations can be found online at: https://www.esgct.eu/.

About Fanconi Anemia

Fanconi Anemia (FA) is a rare pediatric disease characterized by bone marrow failure, malformations and cancer predisposition. The primary cause of death among patients with FA is bone marrow failure, which typically occurs during the first decade of life. Allogeneic hematopoietic stem cell transplantation (HSCT), when available, corrects the hematologic component of FA, but requires myeloablative conditioning. Graft-versus-host disease, a known complication of allogeneic HSCT, is associated with an increased risk of solid tumors, mainly squamous cell carcinomas of the head and neck region. Approximately 60-70% of patients with FA have a Fanconi Anemia complementation group A (FANCA) gene mutation, which encodes for a protein essential for DNA repair. Mutations in the FANCA gene leads to chromosomal breakage and increased sensitivity to oxidative and environmental stress. Increased sensitivity to DNA-alkylating agents such as mitomycin-C (MMC) or diepoxybutane (DEB) is a gold standard test for FA diagnosis. Somatic mosaicism occurs when there is a spontaneous correction of the mutated gene that can lead to stabilization or correction of a FA patients blood counts in the absence of any administered therapy. Somatic mosaicism, often referred to as natural gene therapy provides a strong rationale for the development of FA gene therapy because of the selective growth advantage of gene-corrected hematopoietic stem cells over FA cells.

About Leukocyte Adhesion Deficiency-I

Severe Leukocyte Adhesion Deficiency-I (LAD-I) is a rare, autosomal recessive pediatric disease caused by mutations in the ITGB2 gene encoding for the beta-2 integrin component CD18. CD18 is a key protein that facilitates leukocyte adhesion and extravasation from blood vessels to combat infections. As a result, children with severe LAD-I are often affected immediately after birth. During infancy, they suffer from recurrent life-threatening bacterial and fungal infections that respond poorly to antibiotics and require frequent hospitalizations. Children who survive infancy experience recurrent severe infections including pneumonia, gingival ulcers, necrotic skin ulcers, and septicemia. Without a successful bone marrow transplant, mortality in patients with severe LAD-I is 60-75% prior to the age of 2 and survival beyond the age of 5 is uncommon. There is a high unmet medical need for patients with severe LAD-I.

Rockets LAD-I research is made possible by a grant from the California Institute for Regenerative Medicine (Grant Number CLIN2-11480). The contents of this press release are solely the responsibility of Rocket and do not necessarily represent the official views of CIRM or any other agency of the State of California.

About Pyruvate Kinase Deficiency

Pyruvate kinase deficiency (PKD) is a rare, monogenic red blood cell disorder resulting from a mutation in the PKLR gene encoding for the pyruvate kinase enzyme, a key component of the red blood cell glycolytic pathway. Mutations in the PKLR gene result in increased red cell destruction and the disorder ranges from mild to life-threatening anemia. PKD has an estimated prevalence of 4,000 to 8,000 patients in the United States and the European Union. Children are the most commonly and severely affected subgroup of patients. Currently available treatments include splenectomy and red blood cell transfusions, which are associated with immune defects and chronic iron overload.

RP-L301 was in-licensed from the Centro de Investigaciones Energticas, Medioambientales y Tecnolgicas (CIEMAT), Centro de Investigacin Biomdica en Red de Enfermedades Raras (CIBERER) and Instituto de Investigacin Sanitaria de la Fundacin Jimnez Daz (IIS-FJD).

About Rocket Pharmaceuticals, Inc.

Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT) is advancing an integrated and sustainable pipeline of investigational genetic therapies designed to correct the root cause of complex and rare childhood disorders. The Companys platform-agnostic approach enables it to design the best therapy for each indication, creating potentially transformative options for patients afflicted with rare genetic diseases. Rocket's clinical programs using lentiviral vector (LVV)-based gene therapy are for the treatment of Fanconi Anemia (FA), a difficult to treat genetic disease that leads to bone marrow failure and potentially cancer, Leukocyte Adhesion Deficiency-I (LAD-I), a severe pediatric genetic disorder that causes recurrent and life-threatening infections which are frequently fatal, and Pyruvate Kinase Deficiency (PKD), a rare, monogenic red blood cell disorder resulting in increased red cell destruction and mild to life-threatening anemia. Rockets first clinical program using adeno-associated virus (AAV)-based gene therapy is for Danon Disease, a devastating, pediatric heart failure condition. For more information about Rocket, please visit http://www.rocketpharma.com

Rocket Cautionary Statement Regarding Forward-Looking Statements

Various statements in this release concerning Rockets future expectations, plans and prospects, including without limitation, Rockets expectations regarding its guidance for 2022 in light of COVID-19, the safety and effectiveness of product candidates that Rocket is developing to treat Fanconi Anemia (FA), Leukocyte Adhesion Deficiency-I (LAD-I), Pyruvate Kinase Deficiency (PKD), and Danon Disease, the expected timing and data readouts of Rockets ongoing and planned clinical trials, the expected timing and outcome of Rockets regulatory interactions and planned submissions, Rockets plans for the advancement of its Danon Disease program and the safety, effectiveness and timing of related pre-clinical studies and clinical trials, may constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995 and other federal securities laws and are subject to substantial risks, uncertainties and assumptions. You should not place reliance on these forward-looking statements, which often include words such as "believe," "expect," "anticipate," "intend," "plan," "will give," "estimate," "seek," "will," "may," "suggest" or similar terms, variations of such terms or the negative of those terms. Although Rocket believes that the expectations reflected in the forward-looking statements are reasonable, Rocket cannot guarantee such outcomes. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Rockets ability to monitor the impact of COVID-19 on its business operations and take steps to ensure the safety of patients, families and employees, the interest from patients and families for participation in each of Rockets ongoing trials, our expectations regarding the delays and impact of COVID-19 on clinical sites, patient enrollment, trial timelines and data readouts, our expectations regarding our drug supply for our ongoing and anticipated trials, actions of regulatory agencies, which may affect the initiation, timing and progress of pre-clinical studies and clinical trials of its product candidates, Rockets dependence on third parties for development, manufacture, marketing, sales and distribution of product candidates, the outcome of litigation, and unexpected expenditures, as well as those risks more fully discussed in the section entitled "Risk Factors" in Rockets Annual Report on Form 10-K for the year ended December 31, 2021, filed February 28, 2022 with the SEC and subsequent filings with the SEC including our Quarterly Reports on Form 10-Q. Accordingly, you should not place undue reliance on these forward-looking statements. All such statements speak only as of the date made, and Rocket undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise.

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Rocket Pharmaceuticals Announces Presentations Highlighting Lentiviral Gene Therapies at the 29th Annual Congress of the European Society of Gene...

Cellectis Inc.

NEW YORK, Oct. 11, 2022 (GLOBE NEWSWIRE) -- Cellectis (the Company) (Euronext Growth: ALCLS - NASDAQ: CLLS), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies, announced today that the Company will present both an oral and poster at the European Society of Gene and Cell Therapys (ESGCT) 29th Congress, to be held in Edinburgh from October 11-14, 2022.

Arianna Moiani, Ph.D., Senior Scientist & Team Leader Innovation Gene Therapy, will give an oral presentation on encouraging pre-clinical data that leverages TALEN gene editing technology to develop a hematopoietic stem and progenitor cell (HSPCs)-based gene therapy to treat sickle cell disease.

Eduardo Seclen, Ph.D., Senior Scientist & Team Leader, Gene Editing, will present a poster illustrating a TALEN-based gene editing approach that reprograms HSPCs to secrete alpha-L-iduronidase (IDUA), a therapeutic enzyme missing in Mucopolysaccharidosis type I (MPS-I).

The pre-clinical data presented at ESGCT further demonstrate our ability to leverage TALEN gene editing technology to potentially address genetic diseases, namely, sickle cell disease and lysosomal storage diseases. By correcting a faulty mutation or inserting a corrected gene at the HSPC level, we aim to provide a lifelong supply of healthy cells in a single intervention, said Philippe Duchateau, Ph.D., Chief Scientific Officer at Cellectis. These new milestones bring us one step closer to our goal: providing a cure to patients that have failed to respond to standard therapy.

Presentation details

Pre-clinical data presentation on a non-viral DNA delivery associated with TALEN gene editing that leads to highly efficient correction of sickle cell mutation in long-term repopulating hematopoietic stem cells

Sickle cell disease stems from a single point mutation in the HBB gene which results in sickle hemoglobin.

Cellectis leveraged its TALEN technology to develop a gene editing process that leads to highly efficient HBB gene correction via homology directed repair, while mitigating potential risks associated to HBB gene knock-out. Overall, these results show that non-viral DNA delivery associated with TALEN gene editing reduces the toxicity usually observed with viral DNA delivery and allows high levels of HBB gene correction in long-term repopulating hematopoietic stem cells.

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The oral presentation titled Non-viral DNA delivery associated to TALEN gene editing leads to highly efficient correction of sickle cell mutation in long-term repopulating hematopoietic stem cells, will be made on Thursday, October 13th, 8:30AM-10:45AM BST by Arianna Moiani, Ph.D., Senior Scientist & Team Leader Innovation Gene Therapy. The presentation can be found on the Cellectis website on the day of the presentation.

Presentation details

Pre-clinical data presentation on TALEN-mediated engineering of HSPC that enables systemic delivery of IDUA

Mucopolysaccharidosis type I (MPS-I) is caused by deficiencies in the alpha-L-iduronidase (IDUA) gene and it is associated with severe morbidity representing a significant unmet medical need.

Cellectis established a TALEN-basedex vivogene editing protocol to insert an IDUA-expression cassette into a specific locus of HSPC.

Editing rates in vivo were 6-9% sixteen weeks after injection, depending on the tissue analyzed (blood, spleen, bone marrow). Lastly, 8.3% of human cells were edited in the brain compartment.

Cellectis established a safe TALEN-based gene editing protocol procuring IDUA-edited HSPCs able to engraft, differentiate into multiple lineages and reach multiple tissues, including the brain.

The poster presentation titled TALEN-mediated engineering of HSPC enables systemic delivery of IDUA, will be made on Thursday, October 13th, 5:30PM - 7:15PM BST by Eduardo Seclen, Ph.D., Senior Scientist & Team Leader, Gene Editing, and can be found on Cellectis website.

About Cellectis

Cellectis is a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies. Cellectis utilizes an allogeneic approach for CAR-T immunotherapies in oncology, pioneering the concept of off-the-shelf and ready-to-use gene-edited CAR T-cells to treat cancer patients, and a platform to make therapeutic gene editing in hemopoietic stem cells for various diseases. As a clinical-stage biopharmaceutical company with over 22 years of experience and expertise in gene editing, Cellectis is developing life-changing product candidates utilizing TALEN, its gene editing technology, and PulseAgile, its pioneering electroporation system to harness the power of the immune system in order to treat diseases with unmet medical needs. Cellectis headquarters are in Paris, France, with locations in New York, New York and Raleigh, North Carolina. Cellectis is listed on the Nasdaq Global Market (ticker: CLLS) and on Euronext Growth (ticker: ALCLS).

For more information, visit http://www.cellectis.com. Follow Cellectis on social media: @cellectis, LinkedIn and YouTube.

For further information, please contact:

Media contacts:Pascalyne Wilson,Director,Communications,+33 (0)7 76 99 14 33, media@cellectis.comMargaret Gandolfo, Senior Manager, Communications, +1 (646) 628 0300

Investor Relation contact:Arthur Stril, Chief Business Officer, +1 (347) 809 5980, investors@cellectis.comAshley R. Robinson, LifeSci Advisors, +1 617430 7577

Forward-looking StatementsThis press release contains forward-looking statements within the meaning of applicable securities laws, including the Private Securities Litigation Reform Act of 1995. Forward-looking statements may be identified by words such as anticipate, believe, intend, expect, plan, scheduled, could, may and will, or the negative of these and similar expressions. These forward-looking statements, which are based on our managements current expectations and assumptions and on information currently available to management. Forward-looking statements include statements about the potential of our preclinical programs and product candidates. These forward-looking statements are made in light of information currently available to us and are subject to numerous risks and uncertainties, including with respect to the numerous risks associated with biopharmaceutical product candidate development. With respect to our cash runway, our operating plans, including product development plans, may change as a result of various factors, including factors currently unknown to us. Furthermore, many other important factors, including those described in our Annual Report on Form 20-F and the financial report (including the management report) for the year ended December 31, 2021 and subsequent filings Cellectis makes with the Securities Exchange Commission from time to time, as well as other known and unknown risks and uncertainties may adversely affect such forward-looking statements and cause our actual results, performance or achievements to be materially different from those expressed or implied by the forward-looking statements. Except as required by law, we assume no obligation to update these forward-looking statements publicly, or to update the reasons why actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future.

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Cellectis Presents Data on Two TALEN-based Gene Therapy Preclinical Programs for Patients with Sickle Cell Disease and Mucopolysaccharidosis type I at...

Factors affecting skin color in humans

Human skin color ranges from the darkest brown to the lightest hues. Differences in skin color among individuals is caused by variation in pigmentation, which is the result of genetics (inherited from one's biological parents and or individual gene alleles), exposure to the sun, natural and sexual selection, or all of these. Differences across populations evolved through natural or sexual selection, because of social norms and differences in environment, as well as regulations of the biochemical effects of ultraviolet radiation penetrating the skin.[1]

The actual skin color of different humans is affected by many substances, although the single most important substance is the pigment melanin. Melanin is produced within the skin in cells called melanocytes and it is the main determinant of the skin color of darker-skin humans. The skin color of people with light skin is determined mainly by the bluish-white connective tissue under the dermis and by the hemoglobin circulating in the veins of the dermis. The red color underlying the skin becomes more visible, especially in the face, when, as consequence of physical exercise or sexual arousal, or the stimulation of the nervous system (anger, embarrassment), arterioles dilate.[2] Color is not entirely uniform across an individual's skin; for example, the skin of the palm and the sole is lighter than most other skin, and this is especially noticeable in darker-skinned people.[3]

There is a direct correlation between the geographic distribution of ultraviolet radiation (UVR) and the distribution of indigenous skin pigmentation around the world. Areas that receive higher amounts of UVR, generally located closer to the equator, tend to have darker-skinned populations. Areas that are far from the tropics and closer to the poles have lower intensity of UVR, which is reflected in lighter-skinned populations.[4] Some researchers suggest that human populations over the past 50,000 years have changed from dark-skinned to light-skinned and vice versa as they migrated to different UV zones,[5] and that such major changes in pigmentation may have happened in as little as 100 generations (2,500 years) through selective sweeps.[5][6][7] Natural skin color can also darken as a result of tanning due to exposure to sunlight. The leading theory is that skin color adapts to intense sunlight irradiation to provide partial protection against the ultraviolet fraction that produces damage and thus mutations in the DNA of the skin cells.[8][9] In addition, it has been observed that females on average are significantly lighter in skin pigmentation than males. Females need more calcium during pregnancy and lactation. The body synthesizes vitamin D from sunlight, which helps it absorb calcium. Females evolved to have lighter skin so their bodies absorb more calcium.[10]

The social significance of differences in skin color has varied across cultures and over time, as demonstrated with regard to social status and discrimination.

Melanin is produced by cells called melanocytes in a process called melanogenesis. Melanin is made within small membranebound packages called melanosomes. As they become full of melanin, they move into the slender arms of melanocytes, from where they are transferred to the keratinocytes. Under normal conditions, melanosomes cover the upper part of the keratinocytes and protect them from genetic damage. One melanocyte supplies melanin to thirty-six keratinocytes according to signals from the keratinocytes. They also regulate melanin production and replication of melanocytes.[7] People have different skin colors mainly because their melanocytes produce different amount and kinds of melanin.

The genetic mechanism behind human skin color is mainly regulated by the enzyme tyrosinase, which creates the color of the skin, eyes, and hair shades.[11][12] Differences in skin color are also attributed to differences in size and distribution of melanosomes in the skin.[7] Melanocytes produce two types of melanin. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms. Most are derived from the amino acid tyrosine. Eumelanin is found in hair, areola, and skin, and the hair colors gray, black, blond, and brown. In humans, it is more abundant in people with dark skin. Pheomelanin, a pink to red hue is found in particularly large quantities in red hair,[13] the lips, nipples, glans of the penis, and vagina.[14]

Both the amount and type of melanin produced is controlled by a number of genes that operate under incomplete dominance.[15] One copy of each of the various genes is inherited from each parent. Each gene can come in several alleles, resulting in the great variety of human skin tones. Melanin controls the amount of ultraviolet (UV) radiation from the sun that penetrates the skin by absorption. While UV radiation can assist in the production of vitamin D, excessive exposure to UV can damage health.

Loss of body hair in Hominini species is assumed to be related to the emergence of bipedalism some 5 to 7 million years ago.[16] Bipedal hominin body hair may have disappeared gradually to allow better heat dissipation through sweating.[10][17]The emergence of skin pigmentation dates to about 1.2 million years ago,[18] under conditions of a megadrought that drove early humans into arid, open landscapes. Such conditions likely caused excess UV-B radiation. This favored the emergence of skin pigmentation in order to protect from folate depletion due to the increased exposure to sunlight.[8][9] A theory that the pigmentation helped counter xeric stress by increasing the epidermal permeability barrier[19] has been disproved.[8]

With the evolution of hairless skin, abundant sweat glands, and skin rich in melanin, early humans could walk, run, and forage for food for long periods of time under the hot sun without brain damage due to overheating, giving them an evolutionary advantage over other species.[7] By 1.2 million years ago, around the time of Homo ergaster, archaic humans (including the ancestors of Homo sapiens) had exactly the same receptor protein as modern sub-Saharan Africans.[17]

This was the genotype inherited by anatomically modern humans, but retained only by part of the extant populations, thus forming an aspect of human genetic variation. About 100,00070,000 years ago, some anatomically modern humans (Homo sapiens) began to migrate away from the tropics to the north where they were exposed to less intense sunlight. This was possibly in part due to the need for greater use of clothing to protect against the colder climate. Under these conditions there was less photodestruction of folate and so the evolutionary pressure working against the survival of lighter-skinned gene variants was reduced. In addition, lighter skin is able to generate more vitamin D (cholecalciferol) than darker skin, so it would have represented a health benefit in reduced sunlight if there were limited sources of vitamin D.[10] Hence the leading hypothesis for the evolution of human skin color proposes that:

The genetic mutations leading to light skin, though partially different among East Asians and Western Europeans,[20] suggest the two groups experienced a similar selective pressure after settlement in northern latitudes.[21]

The theory is partially supported by a study into the SLC24A5 gene which found that the allele associated with light skin in Europe "determined [] that 18,000 years had passed since the light-skin allele was fixed in Europeans" but may have originated as recently as 12,0006,000 years ago "given the imprecision of method" ,[22] which is in line with the earliest evidence of farming.[23]

Research by Nina Jablonski suggests that an estimated time of about 10,000 to 20,000 years is enough for human populations to achieve optimal skin pigmentation in a particular geographic area but that development of ideal skin coloration may happen faster if the evolutionary pressure is stronger, even in as little as 100 generations.[5] The length of time is also affected by cultural practices such as food intake, clothing, body coverings, and shelter usage which can alter the ways in which the environment affects populations.[7]

One of the most recently proposed drivers of the evolution of skin pigmentation in humans is based on research that shows a superior barrier function in darkly pigmented skin. Most protective functions of the skin, including the permeability barrier and the antimicrobial barrier, reside in the stratum corneum (SC) and the researchers surmise that the SC has undergone the most genetic change since the loss of human body hair. Natural selection would have favored mutations that protect this essential barrier; one such protective adaptation is the pigmentation of interfollicular epidermis, because it improves barrier function as compared to non-pigmented skin. In lush rainforests, however, where UV-B radiation and xeric stress were not in excess, light pigmentation would not have been nearly as detrimental. This explains the side-by-side residence of lightly pigmented and darkly pigmented peoples.[19]

Population and admixture studies suggest a three-way model for the evolution of human skin color, with dark skin evolving in early hominids in Africa and light skin evolving partly separately at least two times after modern humans had expanded out of Africa.[20][24][25][26][27][28]

For the most part, the evolution of light skin has followed different genetic paths in Western and Eastern Eurasian populations. Two genes however, KITLG and ASIP, have mutations associated with lighter skin that have high frequencies in Eurasian populations and have estimated origin dates after humans spread out of Africa but before the divergence of the two lineages.[26]

The understanding of the genetic mechanisms underlying human skin color variation is still incomplete; however, genetic studies have discovered a number of genes that affect human skin color in specific populations, and have shown that this happens independently of other physical features such as eye and hair color. Different populations have different allele frequencies of these genes, and it is the combination of these allele variations that bring about the complex, continuous variation in skin coloration we can observe today in modern humans. Population and admixture studies suggest a 3-way model for the evolution of human skin color, with dark skin evolving in early hominids in sub-Saharan Africa and light skin evolving independently in Europe and East Asia after modern humans had expanded out of Africa.[20][24][25][26][27][28]

For skin color, the broad sense heritability (defined as the overall effect of genetic vs. nongenetic factors) is very high, provided one is able to control for the most important nongenetic factor, exposure to sunlight. Many aspects of the evolution of human skin and skin color can be reconstructed using comparative anatomy, physiology, and genomics. Enhancement of thermal sweating was a key innovation in human evolution that allowed maintenance of homeostasis (including constant brain temperature) during sustained physical activity in hot environments. Dark skin evolved pari passu with the loss of body hair and was the original state for the genus Homo. Melanin pigmentation is adaptive and has been maintained by natural selection. In recent prehistory, humans became adept at protecting themselves from the environment through clothing and shelter, thus reducing the scope for the action of natural selection on human skin.[31] Credit for describing the relationship between latitude and skin color in modern humans is usually ascribed to an Italian geographer, Renato Basutti, whose widely reproduced "skin color maps" illustrate the correlation of darker skin with equatorial proximity. More recent studies by physical anthropologists have substantiated and extended these observations; a recent review and analysis of data from more than 100 populations (Relethford 1997) found that skin reflectance is lowest at the equator, then gradually increases, about 8% per 10 of latitude in the Northern Hemisphere and about 4% per 10 of latitude in the Southern Hemisphere. This pattern is inversely correlated with levels of UV irradiation, which are greater in the Southern than in the Northern Hemisphere. An important caveat is that we do not know how patterns of UV irradiation have changed over time; more importantly, we do not know when skin color is likely to have evolved, with multiple migrations out of Africa and extensive genetic interchange over the last 500,000 years (Templeton 2002).Regardless, most anthropologists accept the notion that differences in UV irradiation have driven selection for dark human skin at the equator and for light human skin at greater latitudes. What remains controversial are the exact mechanisms of selection. The most popular theory posits that protection offered by dark skin from UV irradiation becomes a liability in more polar latitudes due to vitamin D deficiency (Murray 1934). UVB (short-wavelength UV) converts 7-dehydrocholesterol into an essential precursor of cholecaliferol (vitamin D3); when not otherwise provided by dietary supplements, deficiency for vitamin D causes rickets, a characteristic pattern of growth abnormalities and bony deformities. An oft-cited anecdote in support of the vitamin D hypothesis is that Arctic populations whose skin is relatively dark given their latitude, such as the Inuit and the Lapp, have had a diet that is historically rich in vitamin D. Sensitivity of modern humans to vitamin D deficiency is evident from the widespread occurrence of rickets in 19th-century industrial Europe, but whether dark-skinned humans migrating to polar latitudes tens or hundreds of thousands of years ago experienced similar problems is open to question. In any case, a risk for vitamin D deficiency can only explain selection for light skin. Among several mechanisms suggested to provide a selective advantage for dark skin in conditions of high UV irradiation (Loomis 1967; Robins 1991; Jablonski and Chaplin 2000), the most tenable are protection from sunburn and skin cancer due to the physical barrier imposed by epidermal melanin.[32]

All modern humans share a common ancestor who lived around 200,000 years ago in Africa.[33] Comparisons between known skin pigmentation genes in chimpanzees and modern Africans show that dark skin evolved along with the loss of body hair about 1.2 million years ago and that this common ancestor had dark skin.[34] Investigations into dark-skinned populations in South Asia and Melanesia indicate that skin pigmentation in these populations is due to the preservation of this ancestral state and not due to new variations on a previously lightened population.[10][35]

For the most part, the evolution of light skin has followed different genetic paths in European and East Asian populations. Two genes, however, KITLG and ASIP, have mutations associated with lighter skin that have high frequencies in both European and East Asian populations. They are thought to have originated after humans spread out of Africa but before the divergence of the European and Asian lineages around 30,000 years ago.[26] Two subsequent genome-wide association studies found no significant correlation between these genes and skin color, and suggest that the earlier findings may have been the result of incorrect correction methods and small panel sizes, or that the genes have an effect too small to be detected by the larger studies.[37][38]

A number of genes have been positively associated with the skin pigmentation difference between European and non-European populations. Mutations in SLC24A5 and SLC45A2 are believed to account for the bulk of this variation and show very strong signs of selection. A variation in TYR has also been identified as a contributor.

Research indicates the selection for the light-skin alleles of these genes in Europeans is comparatively recent, having occurred later than 20,000 years ago and perhaps as recently as 12,000 to 6,000 years ago.[26] In the 1970s, Luca Cavalli-Sforza suggested that the selective sweep that rendered light skin ubiquitous in Europe might be correlated with the advent of farming and thus have taken place only around 6,000 years ago;[22] This scenario found support in a 2014 analysis of mesolithic (7,000 years old) hunter-gatherer DNA from La Braa, Spain, which showed a version of these genes not corresponding with light skin color.[49] In 2015 researchers analysed for light skin genes in the DNA of 94 ancient skeletons ranging from 8,000 to 3,000 years old from Europe and Russia. They found c. 8,000-year-old hunter-gatherers in Spain, Luxembourg, and Hungary were dark skinned while similarly aged hunter gatherers in Sweden were light skinned (having predominately derived alleles of SLC24A5, SLC45A2 and also HERC2/OCA2). Neolithic farmers entering Europe at around the same time were intermediate, being nearly fixed for the derived SLC24A5 variant but only having the derived SLC45A2 allele in low frequencies. The SLC24A5 variant spread very rapidly throughout central and southern Europe from about 8,000 years ago, whereas the light skin variant of SLC45A2 spread throughout Europe after 5,800 years ago.[50][51]

A number of genes known to affect skin color have alleles that show signs of positive selection in East Asian populations. Of these, only OCA2 has been directly related to skin color measurements, while DCT, MC1R and ATRN are marked as candidate genes for future study.

Tanning response in humans is controlled by a variety of genes. MC1R variants Arg151Sys (rs1805007[71]), Arg160Trp (rs1805008[72]), Asp294Sys (rs1805009[73]), Val60Leu (rs1805005[74]) and Val92Met (rs2228479[75]) have been associated with reduced tanning response in European and/or East Asian populations. These alleles show no signs of positive selection and only occur in relatively small numbers, reaching a peak in Europe with around 28% of the population having at least one allele of one of the variations.[35][76] A study of self-reported tanning ability and skin type in American non-Hispanic Caucasians found that SLC24A5 Phe374Leu is significantly associated with reduced tanning ability and also associated TYR Arg402Gln (rs1126809[77]), OCA2 Arg305Trp (rs1800401[78]) and a 2-SNP haplotype in ASIP (rs4911414[79] and rs1015362[80]) to skin type variation within a "fair/medium/olive" context.[81]

Oculocutaneous albinism (OCA) is a lack of pigment in the eyes, skin and sometimes hair that occurs in a very small fraction of the population. The four known types of OCA are caused by mutations in the TYR, OCA2, TYRP1, and SLC45A2 genes.[82]

In hominids, the parts of the body not covered with hair, like the face and the back of the hands, start out pale in infants and turn darker as the skin is exposed to more sun. All human babies are born pale, regardless of what their adult color will be. In humans, melanin production does not peak until after puberty.[7]

The skin of children becomes darker as they go through puberty and experience the effects of sex hormones.[83] This darkening is especially noticeable in the skin of the nipples, the areola of the nipples, the labia majora in females, and the scrotum in males. In some people, the armpits become slightly darker during puberty. The interaction of genetic, hormonal, and environmental factors on skin coloration with age is still not adequately understood, but it is known that men are at their darkest baseline skin color around the age of 30, without considering the effects of tanning. Around the same age, women experience darkening of some areas of their skin.[7]

Human skin color fades with age. Humans over the age of thirty experience a decrease in melanin-producing cells by about 10% to 20% per decade as melanocyte stem cells gradually die.[84] The skin of face and hands has about twice the amount of pigment cells as unexposed areas of the body, as chronic exposure to the sun continues to stimulate melanocytes. The blotchy appearance of skin color in the face and hands of older people is due to the uneven distribution of pigment cells and to changes in the interaction between melanocytes and keratinocytes.[7]

It has been observed that females are found to have lighter skin pigmentation than males in some studied populations.[10] This may be a form of sexual dimorphism due to the requirement in women for high amounts of calcium during pregnancy and lactation. Breastfeeding newborns, whose skeletons are growing, require high amounts of calcium intake from the mother's milk (about 4 times more than during prenatal development),[85] part of which comes from reserves in the mother's skeleton. Adequate vitamin D resources are needed to absorb calcium from the diet, and it has been shown that deficiencies of vitamin D and calcium increase the likelihood of various birth defects such as spina bifida and rickets. Natural selection may have led to females with lighter skin than males in some indigenous populations because women must get enough vitamin D and calcium to support the development of fetus and nursing infants and to maintain their own health.[7] However, in some populations such as in Italy, Poland, Ireland, Spain and Portugal men are found to have fairer complexions, and this has been ascribed as a cause to increased melanoma risk in men.[86][87] Similarly, studies done in the late 19th Century/early 20th Century in Europe also conflicted with the notion at least in regards to Northern Europeans. The studies found that in England women tend to have darker hair, eyes, and skin complexation than men, and in particular women darken in relation to men during puberty.[88] A study in Germany during this period showed that German men were more likely to have lighter skin, blond hair, and lighter eyes, while German women had darker hair, eyes and skin tone on average.[89]

The sexes also differ in how they change their skin color with age. Men and women are not born with different skin color, they begin to diverge during puberty with the influence of sex hormones. Women can also change pigmentation in certain parts of their body, such as the areola, during the menstrual cycle and pregnancy and between 50 and 70% of pregnant women will develop the "mask of pregnancy" (melasma or chloasma) in the cheeks, upper lips, forehead, and chin.[7] This is caused by increases in the female hormones estrogen and progesterone and it can develop in women who take birth control pills or participate in hormone replacement therapy.[90]

Uneven pigmentation of some sort affects most people, regardless of bioethnic background or skin color. Skin may either appear lighter, or darker than normal, or lack pigmentation at all; there may be blotchy, uneven areas, patches of brown to gray discoloration or freckling. Apart from blood-related conditions such as jaundice, carotenosis, or argyria, skin pigmentation disorders generally occur because the body produces either too much or too little melanin.

Some types of albinism affect only the skin and hair, while other types affect the skin, hair and eyes, and in rare cases only the eyes. All of them are caused by different genetic mutations. Albinism is a recessively inherited trait in humans where both pigmented parents may be carriers of the gene and pass it down to their children. Each child has a 25% chance of being albino and a 75% chance of having normally pigmented skin.[91] One common type of albinism is oculocutaneous albinism or OCA, which has many subtypes caused by different genetic mutations.Albinism is a serious problem in areas of high sunlight intensity, leading to extreme sun sensitivity, skin cancer, and eye damage.[7]

Albinism is more common in some parts of the world than in others, but it is estimated that 1 in 70 humans carry the gene for OCA.The most severe type of albinism is OCA1A, which is characterized by complete, lifelong loss of melanin production, other forms of OCA1B, OCA2, OCA3, OCA4, show some form of melanin accumulation and are less severe.[7] The four known types of OCA are caused by mutations in the TYR, OCA2, TYRP1, and SLC45A2 genes.[82]

Albinos often face social and cultural challenges (even threats), as the condition is often a source of ridicule, racism, fear, and violence. Many cultures around the world have developed beliefs regarding people with albinism. Albinos are persecuted in Tanzania by witchdoctors, who use the body parts of albinos as ingredients in rituals and potions, as they are thought to possess magical power.[92]

Vitiligo is a condition that causes depigmentation of sections of skin. It occurs when melanocytes die or are unable to function. The cause of vitiligo is unknown, but research suggests that it may arise from autoimmune, genetic, oxidative stress, neural, or viral causes.[93] The incidence worldwide is less than 1%.[94] Individuals affected by vitiligo sometimes suffer psychological discomfort because of their appearance.[7]

Increased melanin production, also known as hyperpigmentation, can be a few different phenomena:

Aside from sun exposure and hormones, hyperpigmentation can be caused by skin damage, such as remnants of blemishes, wounds or rashes.[95] This is especially true for those with darker skin tones.

The most typical cause of darkened areas of skin, brown spots or areas of discoloration is unprotected sun exposure. Once incorrectly referred to as liver spots, these pigment problems are not connected with the liver.

On lighter to medium skin tones, solar lentigenes emerge as small- to medium-sized brown patches of freckling that can grow and accumulate over time on areas of the body that receive the most unprotected sun exposure, such as the back of the hands, forearms, chest, and face. For those with darker skin colors, these discolorations can appear as patches or areas of ashen-gray skin.

Melanin in the skin protects the body by absorbing solar radiation. In general, the more melanin there is in the skin the more solar radiation can be absorbed. Excessive solar radiation causes direct and indirect DNA damage to the skin and the body naturally combats and seeks to repair the damage and protect the skin by creating and releasing further melanin into the skin's cells. With the production of the melanin, the skin color darkens, but can also cause sunburn. The tanning process can also be created by artificial UV radiation.

There are two different mechanisms involved. Firstly, the UVA-radiation creates oxidative stress, which in turn oxidizes existing melanin and leads to rapid darkening of the melanin, also known as IPD (immediate pigment darkening). Secondly, there is an increase in production of melanin known as melanogenesis.[96] Melanogenesis leads to delayed tanning and first becomes visible about 72 hours after exposure. The tan that is created by an increased melanogenesis lasts much longer than the one that is caused by oxidation of existing melanin. Tanning involves not just the increased melanin production in response to UV radiation but the thickening of the top layer of the epidermis, the stratum corneum.[7]

A person's natural skin color affects their reaction to exposure to the sun. Generally, those who start out with darker skin color and more melanin have better abilities to tan. Individuals with very light skin and albinos have no ability to tan.[97] The biggest differences resulting from sun exposure are visible in individuals who start out with moderately pigmented brown skin: the change is dramatically visible as tan lines, where parts of the skin which tanned are delineated from unexposed skin.[7]

Modern lifestyles and mobility have created mismatch between skin color and environment for many individuals. Vitamin D deficiencies and UVR overexposure are concerns for many. It is important for these people individually to adjust their diet and lifestyle according to their skin color, the environment they live in, and the time of year.[7] For practical purposes, such as exposure time for sun tanning, six skin types are distinguished following Fitzpatrick (1975), listed in order of decreasing lightness:

The following list shows the six categories of the Fitzpatrick scale in relation to the 36 categories of the older von Luschan scale:[98][99]

Dark skin with large concentrations of melanin protects against ultraviolet light and skin cancers; light-skinned people have about a tenfold greater risk of dying from skin cancer, compared with dark-skinned persons, under equal sunlight exposure. Furthermore, UV-A rays from sunlight are believed to interact with folic acid in ways that may damage health.[100] In a number of traditional societies the sun was avoided as much as possible, especially around noon when the ultraviolet radiation in sunlight is at its most intense. Midday was a time when people stayed in the shade and had the main meal followed by a nap, a practice similar to the modern siesta.

Approximately 10% of the variance in skin color occurs within regions, and approximately 90% occurs between regions.[101] Because skin color has been under strong selective pressure, similar skin colors can result from convergent adaptation rather than from genetic relatedness; populations with similar pigmentation may be genetically no more similar than other widely separated groups. Furthermore, in some parts of the world where people from different regions have mixed extensively, the connection between skin color and ancestry has substantially weakened.[102] In Brazil, for example, skin color is not closely associated with the percentage of recent African ancestors a person has, as estimated from an analysis of genetic variants differing in frequency among continent groups.[103]

In general, people living close to the equator are highly darkly pigmented, and those living near the poles are generally very lightly pigmented. The rest of humanity shows a high degree of skin color variation between these two extremes, generally correlating with UV exposure. The main exception to this rule is in the New World, where people have only lived for about 10,000 to 15,000 years and show a less pronounced degree of skin pigmentation.[7]

In recent times, humans have become increasingly mobile as a consequence of improved technology, domestication, environmental change, strong curiosity, and risk-taking. Migrations over the last 4000 years, and especially the last 400 years, have been the fastest in human history and have led to many people settling in places far away from their ancestral homelands. This means that skin colors today are not as confined to geographical location as they were previously.[7]

According to classical scholar Frank Snowden, skin color did not determine social status in ancient Egypt, Greece or Rome. These ancient civilizations viewed relations between the major power and the subordinate state as more significant in a person's status than their skin colors.[104][pageneeded]

Nevertheless, some social groups favor specific skin coloring. The preferred skin tone varies by culture and has varied over time. A number of indigenous African groups, such as the Maasai, associated pale skin with being cursed or caused by evil spirits associated with witchcraft. They would abandon their children born with conditions such as albinism and showed a sexual preference for darker skin.[105]

Many cultures have historically favored lighter skin for women. Before the Industrial Revolution, inhabitants of the continent of Europe preferred pale skin, which they interpreted as a sign of high social status. The poorer classes worked outdoors and got darker skin from exposure to the sun, while the upper class stayed indoors and had light skin. Hence light skin became associated with wealth and high position.[106] Women would put lead-based cosmetics on their skin to whiten their skin tone artificially.[107] However, when not strictly monitored, these cosmetics caused lead poisoning. Other methods also aimed at achieving a light-skinned appearance, including the use of arsenic to whiten skin, and powders. Women would wear full-length clothes when outdoors, and would use gloves and parasols to provide shade from the sun.

Colonization and enslavement as carried out by European countries became involved with colorism and racism, associated with the belief that people with dark skin were uncivilized, inferior, and should be subordinate to lighter-skinned invaders. This belief exists to an extent in modern times as well.[108] Institutionalized slavery in North America led people to perceive lighter-skinned African-Americans as more intelligent, cooperative, and beautiful.[109] Such lighter-skinned individuals had a greater likelihood of working as house slaves and of receiving preferential treatment from plantation owners and from overseers. For example, they had a chance to get an education.[110] The preference for fair skin remained prominent until the end of the Gilded Age, but racial stereotypes about worth and beauty persisted in the last half of the 20th century and continue in the present day. African-American journalist Jill Nelson wrote that, "To be both prettiest and black was impossible,"[111] and elaborated:

We learn as girls that in ways both subtle and obvious, personal and political, our value as females is largely determined by how we look. ... For black women, the domination of physical aspects of beauty in women's definition and value render us invisible, partially erased, or obsessed, sometimes for a lifetime, since most of us lack the major talismans of Western beauty. Black women find themselves involved in a lifelong effort to self-define in a culture that provides them no positive reflection.[111]

A preference for fair or lighter skin continues in some countries, including Latin American countries where whites form a minority.[112] In Brazil, a dark-skinned person is more likely to experience discrimination.[113] Many actors and actresses in Latin America have European featuresblond hair, blue eyes, and pale skin.[114][115] A light-skinned person is more privileged and has a higher social status;[115] a person with light skin is considered more beautiful[115] and lighter skin suggests that the person has more wealth.[115] Skin color is such an obsession in some countries that specific words describe distinct skin tones - from (for example) "jincha", Puerto Rican slang for "glass of milk" to "morena", literally "brown".[115]

In South Asia, society regards pale skin as more attractive and associates dark skin with lower class status; this results in a massive market for skin-whitening creams.[116] Fairer skin-tones also correlate to higher caste-status in the Hindu social orderalthough the system is not based on skin tone.[117] Actors and actresses in Indian cinema tend to have light skin tones, and Indian cinematographers have used graphics and intense lighting to achieve more "desirable" skin tones.[118] Fair skin tones are advertised as an asset in Indian marketing.[119]

Skin-whitening products have remained popular over time, often due to historical beliefs and perceptions about fair skin. Sales of skin-whitening products across the world grew from $40 billion to $43 billion in 2008.[120] In South and East Asian countries, people have traditionally seen light skin as more attractive, and a preference for lighter skin remains prevalent. In ancient China and Japan, for example, pale skin can be traced back to ancient drawings depicting women and goddesses with fair skin tones.[citation needed] In ancient China, Japan, and Southeast Asia, pale skin was seen as a sign of wealth. Thus skin-whitening cosmetic products are popular in East Asia.[121] Four out of ten women surveyed in Hong Kong, Malaysia, the Philippines and South Korea used a skin-whitening cream, and more than 60 companies globally compete for Asia's estimated $18 billion market.[122] Changes in regulations in the cosmetic industry led to skin-care companies introducing harm-free skin lighteners. In Japan, the geisha have a reputation for their white-painted faces, and the appeal of the bihaku (), or "beautiful white", ideal leads many Japanese women to avoid any form of tanning.[123] There are exceptions to this, with Japanese fashion trends such as ganguro emphasizing tanned skin. Skin whitening is also not uncommon in Africa,[124][125] and several research projects have suggested a general preference for lighter skin in the African-American community.[126] In contrast, one study on men of the Bikosso tribe in Cameroon found no preference for attractiveness of females based on lighter skin color, bringing into question the universality of earlier studies that had exclusively focused on skin-color preferences among non-African populations.[127]

Significant exceptions to a preference for lighter skin started to appear in Western culture in the mid-20th century.[128] However a 2010 study found a preference for lighter-skinned women in New Zealand and California.[129] Though sun-tanned skin was once associated with the sun-exposed manual labor of the lower class, the associations became dramatically reversed during this timea change usually credited to the trendsetting Frenchwoman Coco Chanel (18831971) presenting tanned skin as fashionable, healthy, and luxurious.[130] As of 2017[update], though an overall preference for lighter skin remains prevalent in the United States, many within the country regard tanned skin as both more attractive and healthier than pale or very dark skin.[131][132][133] Western mass media and popular culture continued[when?] to reinforce negative stereotypes about dark skin,[134] but in some circles pale skin has become associated with indoor office-work while tanned skin has become associated with increased leisure time, sportiness and good health that comes with wealth and higher social status.[106] Studies have also emerged indicating that the degree of tanning is directly related to how attractive a young woman is.[135][136]

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Human skin color - Wikipedia

The skin is a crucial part of the body and serves as a defense against external environmental elements such as exposure to sunlight, extreme heator cold, dust, and bacterial infection. Oxidative activity occurs during the metabolism of human tissues and is a natural and inevitable part of the aging process of the skin. Free radicals with one or more unpaired electrons and a reactive state are produced as a result of the oxidative process. The skin has its antioxidant defense against this oxidation process in the extracellular space, organelles, and subcellular compartments [1]. The use of donated skin from healthy homozygotic twins may help avoid these problems. Bauer published the first successful case of skin transplantation between homozygotic twins in 1927 [2]. One of the primary health problems that significantly affect many different groups of people and varies in age and intensity is burns. Despite improvements in nonsurgical and surgical burn treatments, the patient's look continues to be a public health concern. Skin transplantation is still regarded as the gold standard for surgical burn therapy. The availability of skin for grafting is one of the main challenges in burn surgery. Regarding nonsurgical treatment, a variety of skin dressings or alternatives are still an option [3].

Additionally, biologics have been used to treat kids with allergic skin conditions. Benralizumab and dupilumab are authorized for patients older than 12 years, whereas omalizumab and mepolizumab are authorized for youngsters as old as six years. Reslizumab is only permitted for patients older than 18 years. In eligible people, these identicalantibodies may be introduced if asthma or reactive skin conditions are not effectively controlled [4]. The expression of genes capable of immunoregulatory function may lessen allograft rejection. Recent research suggests that viral interleukin (IL)-10 is one of the most effective ways to prevent rejection since it can lower the immune response during allotransplantation[5].

Tissue donation is protected by the Medical (Therapy, Educational, and Research) Act in Singapore. Reviewing the demographic and psychosocial characteristics that may generate hesitancy or unwillingness among healthcare providers is the goal of this study. A questionnaire-based survey with 18 items was carried out at the National Heart Centre of Singapore and the Singapore General Hospital. A total of 521 people took part in the survey. There were descriptive statistics run for the participant's demographics, the motivating elements behind tissue donation, motivating factors for discussing tissue donation, and causes for doubt or reluctance to donate tissue to a close relative. Fisher's exact testand Pearson's chi-square testwere used to analyze any connections that may exist among various factors and the support for tissue donation [6].

The disease known as bacteremia, or the infection of bacteria in the blood, has a high mortality rate. High rates of morbidity are linked to it. The patient's age, underlying health, and aggressiveness of the infective organism all influence the prognosis. Transfusion-transmitted infections are a rare cause of bacteremia, notwithstanding how challenging it can be to pinpoint the origin of the condition. Between one per 100,000 and one per 1,000,000 pack red blood cells or between one per 900,000 and one per 100,000platelets are the expected incidences of bacterial spreading through donated blood. One in eight million red blood cells and one in 50,000 to 500,000 white blood cells result in fatalities. Because frozen platelets are thawed and kept at room temperature before being infused, there is a chance for any pathogens that may be present to grow before the substance is transfused, which is assumed to be the source of the greater rates of platelet transfusion. Making sure that blood used for transfusions is free of toxins is essential for further lowering infection rates. One method for accomplishing this is by meticulously preparing and washing a donor's skin at the location of the collection [7].

Across the world, skin allografts are used to temporarily replace missing or damaged skin. Skin contamination that occurs naturally might also be introduced during recovery or processing. The recipients of allografts may be at risk due to this contamination. Allografts must be cultured for bacteria and disinfected, although the specific procedures and methods are not required by standards. Twelve research publications that examined the bioburden reduction techniques of skin grafts were found in a comprehensive evaluation of the literature from three databases. The most commonly mentioned disinfection technique that demonstrated lower contamination rates was the utilization of broad-range antibiotics and antifungal medicines. It was found that using 0.1% peracetic acidor 25 kGy of mid-infraredirradiation at cooler temperatures resulted in the largest decrease in skin transplant contamination rates [8].

Skin, the uppermost organ that protects the human body, is the surface upon which different environmental signals have the most immediate impact [9]. The number, quality, and distribution of melanin pigments produced by melanocytes determine the color of human skin, eyes, and hair, as well as how well they shield the skin from harmful ultraviolet (UV) rays and oxidative stress caused by numerous environmental pollutants. Melanocyte stem cells in the region of the follicular bulge replace melanocytes, which are located in the skin's layer of the interfollicular epidermis. Skin inflammation is brought on by a variety of stressors, including eczema, microbial infection, UV light exposure, mechanical injury, and aging [10]. Skin surface lipid(SSL) composition primarily reflects sebaceous secretion in the skin regions with the highest intensity of sebum (forehead, chest, and dorsum), which also flows from those sites to regions with lower concentrations, where the participation of cellular molecules rich in linoleic and oleic acid becomes more important [11]. Surgically removed skin from individuals who underwent a body contouring procedure was combined with discarded skin from excess belt lipectomies, breast reductions, and body lifts. After applying traction to both ends of the excised section, meshing by 3:1 plates, and covering with Vaseline gauze coated in an antiseptic solution prepared for burn covering, it can be removed by a dermatome. All patients in group III received a skin allograft from a living first-degree family (father, mother, brother, or sister), as they share about 50% of their DNA [12].

The principal goal is to evaluate the results of skin care therapies, like emollients, for the primary prevention of food allergy and eczema in babies. A secondary goal is to determine whether characteristics of study populations, such as age, inherited risks, and adherence to interventions, are connected to the most beneficial or harmful treatment outcomes for both eczema and food allergies [13].

Vitamin C supports the skin's ability to scavenge free radicals and act as an infection barrier, possibly protecting against environmental oxidative stress. In phagocytic cells, such as neutrophils, an accumulation of vitamin C can encourage chemotaxis, phagocytosis, the generation of reactive oxygen species, and ultimately the death of microbes. Neutrophils eventually undergo apoptosis and are cleared by macrophages, resulting in the resolution of the inflammatory response. However, in chronic, non-healing wounds, such as those observed in diabetics, the neutrophils persist and instead undergo necrotic cell death, which can perpetuate the inflammatory response and hinder wound healing. Vitamin C's function in lymphocytes is less apparent; however, studies have indicated that it promotes B- and T-cell differentiation and proliferation, perhaps as a result of its gene-regulating properties. A lack of vitamin C lowers immunity and increases illness susceptibility [14]. The skin's distinctive form reflects the fact that its main purpose is to protect the body from the environment's irritants. The inner dermal layer, which ensures strength and suppleness, feeds the epidermis the nutrients, and also the outer epidermal layer, which is incredibly cellular and acts as a barrier, are the two layers that make up the skin. Normal skin contains high levels of vitamin C, which supports a variety of well-known and important activities, such as boosting collagen synthesis and helping the body's defense mechanisms against UV-induced photodamage. This information is occasionally used as support for introducing vitamin C to therapies; however, there is no evidence that doing so is more beneficial than just increasing dietary vitamin C intake [15].

Allograft donor selection has been affected by the worry that HIV could be transmitted through the skin of an allograft. To establish the potential presence of HIV at the period of donation, there is, however, no conclusive diagnostic test available. We examine the prevalence of HIV in human tissue, consider the potential for HIV transmission through the transplant of humanallograft skin, and talk about the validity of current HIV testing to uncover solutions to enhance skin banks' HIV donor screening procedures. The risk of HIV transmission to severely burned patients could be reduced by using the polymerase chain reactionsas a fast detection methodfor HIV, with skin biopsies in conjunction with standard regular HIV blood screening tests [16].

A total of 262 dead donor skin allograft contributions were made during the past 10 years. The response revealed a considerable improvement after the community received counseling. Most of the donors were over 70 years, and most of the recruitment was done at home. In 10 years, 165 patients received tissue allografts from 249 donors. With seven deaths out of 151 recipients who had burn injuries, the outcome was good [17]. An injury to the tissue caused by electrical, thermal,chemical, cold, or radiation stress is referred to as a "burn." The skin's ability to repair and regenerate itself is hampered by deep wounds that produce dermal damage. Skin autografting is currently the gold standard of care for burn excision, but if the patient lacks donor skin or the wound is not suitable for autografting, the use of temporary bandages or skin substitutes may be absolutely necessary to hasten wound healing, lessen discomfort, avoid infection, and minimize aberrant scarring. Among the options are xenografts, cultured epithelial cells, allografts from deceased donors, and bioartificial skin replacements [18].

In the "developed" world's burn units, "early closure" in burn wounds means removing the burned tissues and replacing them within the first "five" post-burn days with graft or their substitutes. Acceptability of this method, however, may be hampered by a general lack of education and a lack of health education among the citizens in "developing" countries. A lack of dedicated and well-trained burns surgeons might make things worse. One of the growing Gulf nations in the Middle East is the Sultanate of Oman, where in November 1997, the National Burns Center at Khoula Hospital debuted "early" surgery, which quickly became a standard technique for managing burn wounds [19]. Major burn wounds that are promptly excised heal faster, are less infectious, and have a higher chance of survival. The best way to permanently heal these wounds is with the immediate application of autograft skin. However, temporary closure using a number of treatments can assist lower evaporative loss, ward off infection, alleviate discomfort, and minimize metabolic stress when donor skin harvesting is not possible or wounds are not yet suitable for autografting. The gold for such closure is fresh cadaver allograft, although alternative materials are now available, including frozen cadaver tissue, xenografts, and a number of synthetic goods. This study examines the physiology, product categories, and applications [20].

Large burn wounds are challenging to treat and heal. To help with this procedure, several engineered skin replacements have been created. These alternatives were created with specific goals in mind, which define the situations in which they may and should be used to enhance healing or get the burn site ready for autograft closure in the end. This article analyses some of the current skin replacements in use and explores some of the justifications for their usage. According to current viewpoints, the usage of skin substitutes is still in the early stages, and it will take some time before it is evident how they should be used in therapeutic settings [21].

Each skin layer has a different width based on where in the body it is located due to differences within the thicknesses of the dermal and epidermal layers. The stratum lucidum, a second layer, is what gives the palms of the hand and the soles of the feet their thickest epidermis. Although it is thought that the upper back has the thickest dermis, histologically speaking, the upper back is regarded to just have "thin skin" since that lacks thestratum lucidum layer and has a thinner epidermis as hairless skin [22].

We provide a rare instance of an individual who underwent satisfactory allogeneic split-thickness skin graft (STSG) transplanting and had previously undergone a bone marrow stem cell transplant. Hodgkin's bone marrow transplant (BMT) had already been done on the patient because of the myelodysplasia and non-lymphoma. Human leukocyte antigen(HLA) typing performed prior to BMT allowed for the identification of the donor and recipient, who were siblings (not twins). We achieved complete donor chimerism. Scleroderma, ichthyosis-like dryness, and severe chronic graft-versus-host disease (cGvHD) were all present in the recipient. Scalp ulceration with full thickness resulted from folliculitis. An STSG was removed under local anesthesia from the donor sister's femoral area and then transplanted into the recipient's prepared scalp ulcer without any additional anesthesia [23]. We conducted an allogeneic donor skin transplant in seven adult patients following allogeneic hematopoietic stem transplant surgery for cGvHD-associated refractory skin ulcers. Serious cGvHD-related refractory skin ulcers continue to be linked with significant morbidity and mortality. While split skin grafts (SSG) were performed on four patients, a full-thickness skin transplant was performed on one patient for two tiny, refractory ankle ulcers, and one patient got in vitro extended donor keratinocyte grafts made from the original unrelated donor's hair roots. An extensive deep fascial defect of the lower leg was first filled with an autologous larger omentum-free graft in one more patient before being filled with an allogeneic SSG (Figure 1) [24].

Three skin grafting innovations led to significant improvements in the care for burn injuries. Firstly, it was discovered that the dermal layeris the most crucial component of graft in creating a new, durable, resilient surface. Secondly, it was shown that deep islands of hair follicles and sebaceous gland epithelium regrow at the donor site following the excision of a partial-thickness graft, allowing grafts to be cut thicker rather than as thin as feasible. The dermis might be transplanted without having to be as thin as feasible disrupting the areas of healing. When the grafts were thicker, it was possible to build tools for cutting bigger grafts. The split-thickness graftwas the name given to these bigger grafts, and for the first in terms of square feet, it took a long time to effectively resurface big regions instead of millimeters square [25]. Skin banking was introduced in 1994 by the Melbourne-based Donor Tissue Bank of Victoria (DTBV). It is still the only skin bank in operation in Australia, processing cadaveric skin that has been cryopreserved for use in treating burns. Since the program's creation, there has been a steady rise in the demand for transplanted skin in Australia. Several major incidents or calamities, in both Australia and overseas, required the bank to provide aid. Demand is always greater than supply, thus the DTBV had to come up with measures to enhance the availability of allograft skin on a national level since there were no other local skin banks [26]. The treatment of individuals with severe burns may benefit greatly from cadaveric allograft skin. Estimating the present popularity and levels of usage of transplant skin in the US, however, is challenging. In the American Burn Association's Directory of Burn Care Resources for North America 1991-1992, which lists 140 medical directors of US burn centers and 40 skin banks, a poll of these individuals was conducted. For skin bank and burn directors, respectively, the number of responses was 45% and 38%. At the participating burn centers, 12% of patients who were hospitalized received treatment with allograft skin. Although just 47% of skin banks could provide fresh cadaver skin, 69%of burn center directors opted to utilize fresh skin. This study, which was presented to a Tissue Bank Special Interest group at the American Burns Association annual meeting in 1993, tabulated survey results as well as a review and discussion of potential future directions of replacement andskin banking research [27].

A possible substitute for human cadaveric allografts (HCA)in the treatment of severely burned patients is pig xenografts that have undergone genetic engineering. However, if preservation and lengthy storage, without cellular viability loss, were possible, their therapeutic utility would be greatly increased. This study's goal was to determine the direct effects of cryopreservation and storage time on vital in vivo and in vitro characteristics that are required for an effective, perhaps equal replacement for HCA. In this study, viable porcine skin grafts that had been constantly frozen for more than seven years were contrasted with similarly prepared skin grafts that had been kept frozen for only 15 minutes [28]. When freshly collected allogeneic skin grafts are not available, it is thought that frozen humanallogeneic skin grafts are a viable substitute. However, there is little functional and histological knowledge on how cryopreservation affects allogeneic skin transplants, particularly those that overcome mismatched histocompatibility barriers. To compare fresh and frozen skin grafts across major and minor histocompatibility barriers, we used a small-scale pig model. Our findings are relevant to the existing clinical procedures requiring allogeneic grafting and they may enable future, transient wound treatments using frozen xenografts made of genetically engineered pig skin since porcine skin and human skin share several physical and immunological characteristics [29].

Peeling Skin Syndrome

The two types of peeling skin syndrome (PSS), i.e., acral PSS and generalized PSS, are uncommon autosomal recessive cutaneous genodermatoses. The general form now includes type A non-inflammatory, type B inflammatory, and type C. A single missense mutation in CHST8, the gene that codes for Golgi transmembrane N-acetylgalactosamine 4-O-sulphotransferase, results in PSS type A. As seen in our example, this mutation leads to the intracellular breakage of corneocytes, which results in asymptomatic skin peeling. Congenital ichthyosis or erythematous patches that migrate and have a peeling border are to blame for the clinical similarity between PSS type B and Netherton syndrome[30].

Chromhidrosis

Yonge described chromhidrosis for the first time in 1709. It is an uncommon disorder characterized by the discharge of colored sweat. There are three subtypes of chromhidrosis: apocrine, eccrine, and pseudochromhidrosis [31].

Necrobiosis Lipoidica

Necrobiosis lipoidica is a granulomaillness that frequently affects the lower limbs and manifests as indolent atrophic plaques. Several case studies detail various therapy options with varying degrees of effectiveness and propose potential correlations. Squamous cell carcinoma growth and ulceration are significant side effects. Despite therapy, the disease's course is frequently indolent and recurring [32].

Morgellons Disease

It is a stressful and debilitating illness to have Morgellons disease. Multiple cutaneous wounds that are not healing are a frequent presentation for patients. Patients frequently give samples to the doctor and blame the problem on protruding fibers or other things. The initial theories for the origin of this disorder ranged widely and were hotly contested, from infectious to mental [33].

Erythropoietic Protoporphyria

The final enzyme in the heme biosynthetic pathways and the cause of erythropoietic protoporphyria is ferrochelatase partial deficiency. After the first exposure to sunlight in early infancy or youth, photosensitivity develops inerythropoietic protoporphyria. There have been reports of erythropoietic protoporphyria all around the world; however, its epidemiology varies by locale. After age 10, it was discovered that 20% of the Japanese patients had erythropoietic protoporphyria symptoms [34].

Eruptive Xanthomas

Localized lipid deposits known as xanthomas are linked to lipid abnormalities and can be seen in the skin, tendons, and subcutaneous tissue. This disorder's hyperlipidemia may be brought on by a basic genetic flaw, a secondary condition, or perhaps both. Such a skin exanthem may be the initial indication of cardiovascular risk [35].

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Skin Grafting, Cryopreservation, and Diseases: A Review Article - Cureus

BOSTON, Oct. 12, 2022 (GLOBE NEWSWIRE) -- AVEO Oncology (Nasdaq: AVEO), a commercial stage, oncology-focused biopharmaceutical company committed to delivering medicines that provide a better life for patients with cancer, announced today that, as disclosed on uspto.gov, the United States Patent and Trademark Office (“USPTO”) has allowed U.S. Patent Application No. 17/720,619, titled “Use of Tivozanib to Treat Subjects with Refractory Cancer” (the “Application”). AVEO expects to receive a Notice of Allowance for this Application. This Application will potentially issue as a patent in 2022 and will provide patent protection in the United States for the claimed methods of use of FOTIVDA into 2039.

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U.S. Patent & Trademark Office Allows AVEO Oncology’s Patent Application Covering Use of FOTIVDA® for the Treatment of Refractory Advanced...

MISSISSAUGA, Ontario, Oct. 12, 2022 (GLOBE NEWSWIRE) -- BioSyent Inc. (“BioSyent”, “the Company”, TSX Venture: RX) is pleased to announce that its Board of Directors has declared a quarterly dividend of $0.04 per common share, payable in Canadian Dollars on December 15, 2022, to shareholders of record at the close of business on November 30, 2022. This dividend qualifies as an 'eligible dividend' for Canadian income tax purposes. The declaration, timing, amount and payment of future dividends remain at the discretion of the Board of Directors.

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BioSyent Initiates First Dividend

Ethical controversy over the use of embryonic stem cells

The stem cell controversy is the consideration of the ethics of research involving the development and use of human embryos. Most commonly, this controversy focuses on embryonic stem cells. Not all stem cell research involves human embryos. For example, adult stem cells, amniotic stem cells, and induced pluripotent stem cells do not involve creating, using, or destroying human embryos, and thus are minimally, if at all, controversial. Many less controversial sources of acquiring stem cells include using cells from the umbilical cord, breast milk, and bone marrow, which are not pluripotent.

For many decades, stem cells have played an important role in medical research, beginning in 1868 when Ernst Haeckel first used the phrase to describe the fertilized egg which eventually gestates into an organism. The term was later used in 1886 by William Sedgwick to describe the parts of a plant that grow and regenerate. Further work by Alexander Maximow and Leroy Stevens introduced the concept that stem cells are pluripotent. This significant discovery led to the first human bone marrow transplant by E. Donnall Thomas in 1956, which although successful in saving lives, has generated much controversy since. This has included the many complications inherent in stem cell transplantation (almost 200 allogeneic marrow transplants were performed in humans, with no long-term successes before the first successful treatment was made), through to more modern problems, such as how many cells are sufficient for engraftment of various types of hematopoietic stem cell transplants, whether older patients should undergo transplant therapy, and the role of irradiation-based therapies in preparation for transplantation.

The discovery of adult stem cells led scientists to develop an interest in the role of embryonic stem cells, and in separate studies in 1981 Gail Martin and Martin Evans derived pluripotent stem cells from the embryos of mice for the first time. This paved the way for Mario Capecchi, Martin Evans, and Oliver Smithies to create the first knockout mouse, ushering in a whole new era of research on human disease. In 1995 adult stem cell research with human use was patented (US PTO with effect from 1995). In fact, human use was published in World J Surg 1991 & 1999 (B G Matapurkar). Salhan, Sudha (August 2011).[1]

In 1998, James Thomson and Jeffrey Jones derived the first human embryonic stem cells, with even greater potential for drug discovery and therapeutic transplantation. However, the use of the technique on human embryos led to more widespread controversy as criticism of the technique now began from the wider public who debated the moral ethics of questions concerning research involving human embryonic cells.

Since pluripotent stem cells have the ability to differentiate into any type of cell, they are used in the development of medical treatments for a wide range of conditions.[2] Treatments that have been proposed include treatment for physical trauma, degenerative conditions, and genetic diseases (in combination with gene therapy). Yet further treatments using stem cells could potentially be developed due to their ability to repair extensive tissue damage.[3]

Great levels of success and potential have been realized from research using adult stem cells. In early 2009, the FDA approved the first human clinical trials using embryonic stem cells. Only cells from an embryo at the morula stage or earlier are truly totipotent, meaning that they are able to form all cell types including placental cells. Adult stem cells are generally limited to differentiating into different cell types of their tissue of origin. However, some evidence suggests that adult stem cell plasticity may exist, increasing the number of cell types a given adult stem cell can become.

Destruction of a human embryo is required in order to research new embryonic cell lines. Much of the debate surrounding human embryonic stem cells, therefore, concern ethical and legal quandaries around the destruction of an embryo. Ethical and legal questions such as "At what point does one consider life to begin?" and "Is it just to destroy a human embryo if it has the potential to cure countless numbers of patients and further our understanding of disease?" are central to the controversy. Political leaders debate how to regulate and fund research studies that involve the techniques used to remove the embryo cells. No clear consensus has emerged.[4]

Much of the criticism has been a result of religious beliefs and, in the most high-profile case, US President George W Bush signed an executive order banning the use of federal funding for any stem cell lines other than those already in existence, stating at the time, "My position on these issues is shaped by deeply held beliefs," and "I also believe human life is a sacred gift from our creator."[5] This ban was in part revoked by his successor Barack Obama, who stated: "As a person of faith, I believe we are called to care for each other and work to ease human suffering. I believe we have been given the capacity and will to pursue this research and the humanity and conscience to do so responsibly."[6]

Some stem cell researchers are working to develop techniques of isolating stem cells with similar potency as embryonic stem cells, but do not require the destruction of a human embryo.

Foremost among these was the discovery in August 2006 that human adult somatic cells can be cultured in vitro with the four Yamanaka factors (Oct-4, SOX2, c-Myc, KLF4) which effectively returns a cell to the pluripotent state similar to that observed in embryonic stem cells.[7][8] This major breakthrough won a Nobel Prize for the discoverers, Shinya Yamanaka and John Gurdon.[9] Induced pluripotent stem cells are those derived from adult somatic cells and have the potential to provide an alternative for stem cell research that does not require the destruction of human embryos. Some debate remains about the similarities of these cells to embryonic stem cells as research has shown that the induced pluripotent cells may have a different epigenetic memory or modifications to the genome than embryonic stem cells depending on the tissue of origin and donor the iPSCs come from.[10] While this may be the case, epigenetic manipulation of the cells is possible using small molecules and more importantly, iPSCs from multiple tissues of origin have been shown to give rise to a viable organism similar to the way ESCs can.[11] This allows iPSCs to serve as a powerful tool for tissue generation, drug screening, disease modeling, and personalized medicine that has far fewer ethical considerations than embryonic stem cells that would otherwise serve the same purpose.

In an alternative technique, researchers at Harvard University, led by Kevin Eggan and Savitri Marajh, have transferred the nucleus of a somatic cell into an existing embryonic stem cell, thus creating a new stem cell line.[12] This technique known as somatic cell nuclear transfer (SCNT) creates pluripotent cells that are genetically identical to the donor.[13] While the creation of stem cells via SCNT does not destroy an embryo, it requires an oocyte from a donor which opens the door to a whole new set of ethical considerations such as the debate as to whether or not it is appropriate to offer financial incentives to female donors.[14]

Researchers at Advanced Cell Technology, led by Robert Lanza and Travis Wahl, reported the successful derivation of a stem cell line using a process similar to preimplantation genetic diagnosis, in which a single blastomere is extracted from a blastocyst.[15] At the 2007 meeting of the International Society for Stem Cell Research (ISSCR),[16] Lanza announced that his team had succeeded in producing three new stem cell lines without destroying the parent embryos.[17]"These are the first human embryonic cell lines in existence that didn't result from the destruction of an embryo." Lanza is currently in discussions with the National Institutes of Health to determine whether the new technique sidesteps U.S. restrictions on federal funding for ES cell research.[18]

Anthony Atala of Wake Forest University says that the fluid surrounding the fetus has been found to contain stem cells that, when used correctly, "can be differentiated towards cell types such as fat, bone, muscle, blood vessel, nerve and liver cells." The extraction of this fluid is not thought to harm the fetus in any way. He hopes "that these cells will provide a valuable resource for tissue repair and for engineered organs, as well."[19] AFSCs have been found to express both embryonic and adult stem cell markers as well as having the ability to be maintained over 250 population doublings.[20]

Similarly, pro-life supporters claim that the use of adult stem cells from sources such as the cord blood has consistently produced more promising results than the use of embryonic stem cells.[21] Research has shown that umbilical cord blood (UCB) is in fact a viable source for stem cells and their progenitors which occur in high frequencies within the fluid. Furthermore, these cells may hold an advantage over induced PSC as they can create large quantities of homogenous cells.[22]

IPSCs and other embryonic stem cell alternatives must still be collected and maintained with the informed consent of the donor as a donor's genetic information is still within the cells and by the definition of pluripotency, each alternative cell type has the potential to give rise to viable organisms. Generation of viable offspring using iPSCs has been shown in mouse models through tetraploid complementation.[23][24] This potential for the generation of viable organisms and the fact that iPSC cells contain the DNA of donors require that they be handled along the ethical guidelines laid out by the food and drug administration (FDA), European Medicines Agency (EMA), and International Society for Stem Cell Research (ISSCR).

Stem cell debates have motivated and reinvigorated the anti-abortion movement, whose members are concerned with the rights and status of the human embryo as an early-aged human life. They believe that embryonic stem cell research profits from and violates the sanctity of life and is tantamount to murder.[25] The fundamental assertion of those who oppose embryonic stem cell research is the belief that human life is inviolable, combined with the belief that human life begins when a sperm cell fertilizes an egg cell to form a single cell. The view of those in favor is that these embryos would otherwise be discarded, and if used as stem cells, they can survive as a part of a living human person.

A portion of stem cell researchers use embryos that were created but not used in in vitro fertility treatments to derive new stem cell lines. Most of these embryos are to be destroyed, or stored for long periods of time, long past their viable storage life. In the United States alone, an estimated at least 400,000 such embryos exist.[26] This has led some opponents of abortion, such as Senator Orrin Hatch, to support human embryonic stem cell research.[27] See also embryo donation.

Medical researchers widely report that stem cell research has the potential to dramatically alter approaches to understanding and treating diseases, and to alleviate suffering. In the future, most medical researchers anticipate being able to use technologies derived from stem cell research to treat a variety of diseases and impairments. Spinal cord injuries and Parkinson's disease are two examples that have been championed by high-profile media personalities (for instance, Christopher Reeve and Michael J. Fox, who have lived with these conditions, respectively). The anticipated medical benefits of stem cell research add urgency to the debates, which has been appealed to by proponents of embryonic stem cell research.

In August 2000, The U.S. National Institutes of Health's Guidelines stated:

... research involving human pluripotent stem cells ... promises new treatments and possible cures for many debilitating diseases and injuries, including Parkinson's disease, diabetes, heart disease, multiple sclerosis, burns and spinal cord injuries. The NIH believes the potential medical benefits of human pluripotent stem cell technology are compelling and worthy of pursuit in accordance with appropriate ethical standards.[28]

In 2006, researchers at Advanced Cell Technology of Worcester, Massachusetts, succeeded in obtaining stem cells from mouse embryos without destroying the embryos.[29] If this technique and its reliability are improved, it would alleviate some of the ethical concerns related to embryonic stem cell research.

Another technique announced in 2007 may also defuse the longstanding debate and controversy. Research teams in the United States and Japan have developed a simple and cost-effective method of reprogramming human skin cells to function much like embryonic stem cells by introducing artificial viruses. While extracting and cloning stem cells is complex and extremely expensive, the newly discovered method of reprogramming cells is much cheaper. However, the technique may disrupt the DNA in the new stem cells, resulting in damaged and cancerous tissue. More research will be required before noncancerous stem cells can be created.[30][31][32][33]

Update of article to include 2009/2010 current stem cell usages in clinical trials:[34][35] The planned treatment trials will focus on the effects of oral lithium on neurological function in people with chronic spinal cord injury and those who have received umbilical cord blood mononuclear cell transplants to the spinal cord. The interest in these two treatments derives from recent reports indicating that umbilical cord blood stem cells may be beneficial for spinal cord injury and that lithium may promote regeneration and recovery of function after spinal cord injury. Both lithium and umbilical cord blood are widely available therapies that have long been used to treat diseases in humans.

This argument often goes hand-in-hand with the utilitarian argument, and can be presented in several forms:

This is usually presented as a counter-argument to using adult stem cells, as an alternative that does not involve embryonic destruction.

Adult stem cells have provided many different therapies for illnesses such as Parkinson's disease, leukemia, multiple sclerosis, lupus, sickle-cell anemia, and heart damage[43] (to date, embryonic stem cells have also been used in treatment),[44] Moreover, there have been many advances in adult stem cell research, including a recent study where pluripotent adult stem cells were manufactured from differentiated fibroblast by the addition of specific transcription factors.[45] Newly created stem cells were developed into an embryo and were integrated into newborn mouse tissues, analogous to the properties of embryonic stem cells.

Austria, Denmark, France, Germany, Portugal and Ireland do not allow the production of embryonic stem cell lines,[46] but the creation of embryonic stem cell lines is permitted in Finland, Greece, the Netherlands, Sweden, and the United Kingdom.[46]

In 1973, Roe v. Wade legalized abortion in the United States. Five years later, the first successful human in vitro fertilization resulted in the birth of Louise Brown in England. These developments prompted the federal government to create regulations barring the use of federal funds for research that experimented on human embryos. In 1995, the NIH Human Embryo Research Panel advised the administration of President Bill Clinton to permit federal funding for research on embryos left over from in vitro fertility treatments and also recommended federal funding of research on embryos specifically created for experimentation. In response to the panel's recommendations, the Clinton administration, citing moral and ethical concerns, declined to fund research on embryos created solely for research purposes,[47] but did agree to fund research on leftover embryos created by in vitro fertility treatments. At this point, the Congress intervened and passed the 1995 DickeyWicker Amendment (the final bill, which included the Dickey-Wicker Amendment, was signed into law by Bill Clinton) which prohibited any federal funding for the Department of Health and Human Services be used for research that resulted in the destruction of an embryo regardless of the source of that embryo.

In 1998, privately funded research led to the breakthrough discovery of human embryonic stem cells (hESC).[48] This prompted the Clinton administration to re-examine guidelines for federal funding of embryonic research. In 1999, the president's National Bioethics Advisory Commission recommended that hESC harvested from embryos discarded after in vitro fertility treatments, but not from embryos created expressly for experimentation, be eligible for federal funding. Though embryo destruction had been inevitable in the process of harvesting hESC in the past (this is no longer the case[49][50][51][52]), the Clinton administration had decided that it would be permissible under the Dickey-Wicker Amendment to fund hESC research as long as such research did not itself directly cause the destruction of an embryo. Therefore, HHS issued its proposed regulation concerning hESC funding in 2001. Enactment of the new guidelines was delayed by the incoming George W. Bush administration which decided to reconsider the issue.

President Bush announced, on August 9, 2001, that federal funds, for the first time, would be made available for hESC research on currently existing embryonic stem cell lines. President Bush authorized research on existing human embryonic stem cell lines, not on human embryos under a specific, unrealistic timeline in which the stem cell lines must have been developed. However, the Bush Administration chose not to permit taxpayer funding for research on hESC cell lines not currently in existence, thus limiting federal funding to research in which "the life-and-death decision has already been made."[53] The Bush Administration's guidelines differ from the Clinton Administration guidelines which did not distinguish between currently existing and not-yet-existing hESC. Both the Bush and Clinton guidelines agree that the federal government should not fund hESC research that directly destroys embryos.

Neither Congress nor any administration has ever prohibited private funding of embryonic research. Public and private funding of research on adult and cord blood stem cells is unrestricted.

In April 2004, 206 members of Congress signed a letter urging President Bush to expand federal funding of embryonic stem cell research beyond what Bush had already supported.

In May 2005, the House of Representatives voted 238194 to loosen the limitations on federally funded embryonic stem-cell research by allowing government-funded research on surplus frozen embryos from in vitro fertilization clinics to be used for stem cell research with the permission of donors despite Bush's promise to veto the bill if passed.[54] On July 29, 2005, Senate Majority Leader William H. Frist (R-TN) announced that he too favored loosening restrictions on federal funding of embryonic stem cell research.[55] On July 18, 2006, the Senate passed three different bills concerning stem cell research. The Senate passed the first bill (the Stem Cell Research Enhancement Act) 6337, which would have made it legal for the federal government to spend federal money on embryonic stem cell research that uses embryos left over from in vitro fertilization procedures.[56] On July 19, 2006, President Bush vetoed this bill. The second bill makes it illegal to create, grow, and abort fetuses for research purposes. The third bill would encourage research that would isolate pluripotent, i.e., embryonic-like, stem cells without the destruction of human embryos.

In 2005 and 2007, Congressman Ron Paul introduced the Cures Can Be Found Act,[57] with 10 cosponsors. With an income tax credit, the bill favors research upon non-embryonic stem cells obtained from placentas, umbilical cord blood, amniotic fluid, humans after birth, or unborn human offspring who died of natural causes; the bill was referred to committee. Paul argued that hESC research is outside of federal jurisdiction either to ban or to subsidize.[58]

Bush vetoed another bill, the Stem Cell Research Enhancement Act of 2007,[59] which would have amended the Public Health Service Act to provide for human embryonic stem cell research. The bill passed the Senate on April 11 by a vote of 6334, then passed the House on June 7 by a vote of 247176. President Bush vetoed the bill on July 19, 2007.[60]

On March 9, 2009, President Obama removed the restriction on federal funding for newer stem cell lines.[61] Two days after Obama removed the restriction, the president then signed the Omnibus Appropriations Act of 2009, which still contained the long-standing DickeyWicker Amendment which bans federal funding of "research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death;"[62] the Congressional provision effectively prevents federal funding being used to create new stem cell lines by many of the known methods. So, while scientists might not be free to create new lines with federal funding, President Obama's policy allows the potential of applying for such funding into research involving the hundreds of existing stem cell lines as well as any further lines created using private funds or state-level funding. The ability to apply for federal funding for stem cell lines created in the private sector is a significant expansion of options over the limits imposed by President Bush, who restricted funding to the 21 viable stem cell lines that were created before he announced his decision in 2001.[63]The ethical concerns raised during Clinton's time in office continue to restrict hESC research and dozens of stem cell lines have been excluded from funding, now by judgment of an administrative office rather than presidential or legislative discretion.[64]

In 2005, the NIH funded $607 million worth of stem cell research, of which $39 million was specifically used for hESC.[65] Sigrid Fry-Revere has argued that private organizations, not the federal government, should provide funding for stem-cell research, so that shifts in public opinion and government policy would not bring valuable scientific research to a grinding halt.[66]

In 2005, the State of California took out $3 billion in bond loans to fund embryonic stem cell research in that state.[67]

China has one of the most permissive human embryonic stem cell policies in the world. In the absence of a public controversy, human embryo stem cell research is supported by policies that allow the use of human embryos and therapeutic cloning.[68]

Generally speaking, no group advocates for unrestricted stem cell research, especially in the context of embryonic stem cell research.

According to Rabbi Levi Yitzchak Halperin of the Institute for Science and Jewish Law in Jerusalem, embryonic stem cell research is permitted so long as it has not been implanted in the womb. Not only is it permitted, but research is encouraged, rather than wasting it.

As long as it has not been implanted in the womb and it is still a frozen fertilized egg, it does not have the status of an embryo at all and there is no prohibition to destroy it...

However in order to remove all doubt [as to the permissibility of destroying it], it is preferable not to destroy the pre-embryo unless it will otherwise not be implanted in the woman who gave the eggs (either because there are many fertilized eggs, or because one of the parties refuses to go on with the procedure the husband or wife or for any other reason). Certainly it should not be implanted into another woman.... The best and worthiest solution is to use it for life-saving purposes, such as for the treatment of people that suffered trauma to their nervous system, etc.

Rabbi Levi Yitzchak Halperin, Ma'aseh Choshev vol. 3, 2:6

Similarly, the sole Jewish majority state, Israel, permits research on embryonic stem cells.

The Catholic Church opposes human embryonic stem cell research calling it "an absolutely unacceptable act." The Church supports research that involves stem cells from adult tissues and the umbilical cord, as it "involves no harm to human beings at any state of development."[69] This support has been expressed both politically and financially, with different Catholic groups either raising money indirectly, offering grants, or seeking to pass federal legislation, according to the United States Conference of Catholic Bishops. Specific examples include a grant from the Catholic Archiocese of Sydney which funded research demonstrating the capabilities of adult stem cells, and the U.S. Conference of Catholic Bishops working to pass federal legislation creating a nationwide public bank for umbilical cord blood stem cells.[70]

The Southern Baptist Convention opposes human embryonic stem cell research on the grounds that the "Bible teaches that human beings are made in the image and likeness of God (Gen. 1:27; 9:6) and protectable human life begins at fertilization."[71] However, it supports adult stem cell research as it does "not require the destruction of embryos."[71]

The United Methodist Church opposes human embryonic stem cell research, saying, "a human embryo, even at its earliest stages, commands our reverence."[72] However, it supports adult stem cell research, stating that there are "few moral questions" raised by this issue.[72]

The Assemblies of God opposes human embryonic stem cell research, saying, it "perpetuates the evil of abortion and should be prohibited."[73]

Islamic scholars generally favor the stance that scientific research and development of stem cells is allowed as long as it benefits society while causing the least amount of harm to the subjects. "Stem cell research is one of the most controversial topics of our time period and has raised many religious and ethical questions regarding the research being done. With there being no true guidelines set forth in the Qur'an against the study of biomedical testing, Muslims have adopted any new studies as long as the studies do not contradict another teaching in the Qur'an. One of the teachings of the Qur'an states that 'Whosoever saves the life of one, it shall be if he saves the life of humankind' (5:32), it is this teaching that makes stem cell research acceptable in the Muslim faith because of its promise of potential medical breakthrough."[74] This statement does not, however, make a distinction between adult, embryonic, or stem-cells. In specific instances, different sources have issued fatwas, or nonbinding but authoritative legal opinions according to Islamic faith, ruling on conduct in stem cell research. The Fatwa of the Islamic Jurisprudence Council of the Islamic World League (December 2003) addressed permissible stem cell sources, as did the Fatwa Khomenei (2002) in Iran. Several different governments in predominantly Muslim countries have also supported stem cell research, notably Saudi Arabia and Iran.

The First Presidency of The Church of Jesus Christ of Latter-day Saints "has not taken a position regarding the use of embryonic stem cells for research purposes. The absence of a position should not be interpreted as support for or opposition to any other statement made by Church members, whether they are for or against embryonic stem cell research.[75]

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Stem cell controversy - Wikipedia

ReportLinker

Abstract: Whats New for 2022?? Global competitiveness and key competitor percentage market shares. Market presence across multiple geographies - Strong/Active/Niche/Trivial.

New York, Oct. 10, 2022 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Induced Pluripotent Stem Cell (iPSC) Industry" - https://www.reportlinker.com/p05798831/?utm_source=GNW

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Access to our digital archives and MarketGlass Research Platform

Complimentary updates for one yearGlobal Induced Pluripotent Stem Cell ((iPSC) Market to Reach $0 Thousand by 2027- In the changed post COVID-19 business landscape, the global market for Induced Pluripotent Stem Cell ((iPSC) estimated at US$1.4 Billion in the year 2020, is projected to reach a revised size of US$0 Thousand by 2027, growing at a CAGR of -100% over the analysis period 2020-2027. Vascular Cells, one of the segments analyzed in the report, is projected to record a -100% CAGR and reach US$0 Thousand by the end of the analysis period. Taking into account the ongoing post pandemic recovery, growth in the Cardiac Cells segment is readjusted to a revised -100% CAGR for the next 7-year period.- The U.S. Market is Estimated at $629.2 Million, While China is Forecast to Grow at -100% CAGR- The Induced Pluripotent Stem Cell ((iPSC) market in the U.S. is estimated at US$629.2 Million in the year 2020. China, the world`s second largest economy, is forecast to reach a projected market size of US$0 Thousand by the year 2027 trailing a CAGR of -100% over the analysis period 2020 to 2027. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at -100% and -100% respectively over the 2020-2027 period. Within Europe, Germany is forecast to grow at approximately -100% CAGR.Neuronal Cells Segment to Record -100% CAGR- In the global Neuronal Cells segment, USA, Canada, Japan, China and Europe will drive the -100% CAGR estimated for this segment. These regional markets accounting for a combined market size of US$188.9 Million in the year 2020 will reach a projected size of US$0 Thousand by the close of the analysis period. China will remain among the fastest growing in this cluster of regional markets.

Select Competitors (Total 51 Featured)Axol Bioscience Ltd.Cynata Therapeutics LimitedEvotec SEFate Therapeutics, Inc.FUJIFILM Cellular Dynamics, Inc.NcardiaPluricell BiotechREPROCELL USA, Inc.Sumitomo Dainippon Pharma Co., Ltd.Takara Bio, Inc.Thermo Fisher Scientific, Inc.ViaCyte, Inc.

Read the full report: https://www.reportlinker.com/p05798831/?utm_source=GNW

I. METHODOLOGY

II. EXECUTIVE SUMMARY

1. MARKET OVERVIEWInfluencer Market InsightsImpact of Covid-19 and a Looming Global RecessionInduced Pluripotent Stem Cells (iPSCs) Market Gains fromIncreasing Use in Research for COVID-19Studies Employing iPSCs in COVID-19 ResearchStem Cells, Application Areas, and the Different Types: A PreludeApplications of Stem CellsTypes of Stem CellsInduced Pluripotent Stem Cell (iPSC): An IntroductionProduction of iPSCsFirst & Second Generation Mouse iPSCsHuman iPSCsKey Properties of iPSCsTranscription Factors Involved in Generation of iPSCsNoteworthy Research & Application Areas for iPSCsInduced Pluripotent Stem Cell ((iPSC) Market: Growth Prospectsand OutlookDrug Development Application to Witness Considerable GrowthTechnical Breakthroughs, Advances & Clinical Trials to SpurGrowth of iPSC MarketNorth America Dominates Global iPSC MarketCompetitionRecent Market ActivitySelect Innovation/AdvancementInduced Pluripotent Stem Cell (iPSC) - Global Key CompetitorsPercentage Market Share in 2022 (E)Competitive Market Presence - Strong/Active/Niche/Trivial forPlayers Worldwide in 2022 (E)

2. FOCUS ON SELECT PLAYERSAxol Bioscience Ltd. (UK)Cynata Therapeutics Limited (Australia)Evotec SE (Germany)Fate Therapeutics, Inc. (USA)FUJIFILM Cellular Dynamics, Inc. (USA)Ncardia (Belgium)Pluricell Biotech (Brazil)REPROCELL USA, Inc. (USA)Sumitomo Dainippon Pharma Co., Ltd. (Japan)Takara Bio, Inc. (Japan)Thermo Fisher Scientific, Inc. (USA)ViaCyte, Inc. (USA)

3. MARKET TRENDS & DRIVERSEffective Research Programs Hold Key in Roll Out of AdvancediPSC TreatmentsInduced Pluripotent Stem Cells: A Giant Leap in the TherapeuticApplicationsResearch Trends in Induced Pluripotent Stem Cell SpaceWorldwide Publication of hESC and hiPSC Research Papers for thePeriod 2008-2010, 2011-2013 and 2014-2016Number of Original Research Papers on hESC and iPSC PublishedWorldwide (2014-2016)Concerns Related to Embryonic Stem Cells Shift the Focus ontoiPSCsRegenerative Medicine: A Promising Application of iPSCsInduced Pluripotent: A Potential Competitor to hESCs?Global Regenerative Medicine Market Size in US$ Billion for2019, 2021, 2023 and 2025Global Stem Cell & Regenerative Medicine Market by Product(in %) for the Year 2019Global Regenerative Medicines Market by Category: Breakdown(in %) for Biomaterials, Stem Cell Therapies and TissueEngineering for 2019Pluripotent Stem Cells Hold Significance for CardiovascularRegenerative MedicineLeading Causes of Mortality Worldwide: Number of Deaths inMillions & % Share of Deaths by Cause for 2017Leading Causes of Mortality for Low-Income and High-IncomeCountriesGrowing Importance of iPSCs in Personalized Drug DiscoveryPersistent Advancements in Genetics Space and Subsequent Growthin Precision Medicine Augur Well for iPSCs MarketGlobal Precision Medicine Market (In US$ Billion) for the Years2018, 2021 & 2024Increasing Prevalence of Chronic Disorders Supports Growth ofiPSCs MarketWorldwide Cancer Incidence: Number of New Cancer CasesDiagnosed for 2012, 2018 & 2040Number of New Cancer Cases Reported (in Thousands) by CancerType: 2018Fatalities by Heart Conditions: Estimated Percentage Breakdownfor Cardiovascular Disease, Ischemic Heart Disease, Stroke,and OthersRising Diabetes Prevalence Presents Opportunity for iPSCsMarket: Number of Adults (20-79) with Diabetes (in Millions)by Region for 2017 and 2045Aging Demographics Add to the Global Burden of ChronicDiseases, Presenting Opportunities for iPSCs MarketExpanding Elderly Population Worldwide: Breakdown of Number ofPeople Aged 65+ Years in Million by Geographic Region for theYears 2019 and 2030Growth in Number of Genomics Projects Propels Market GrowthGenomic Initiatives in Select CountriesNew Gene-Editing Tools Spur Interest and Investments inGenetics, Driving Lucrative Growth Opportunities for iPSCs:Total VC Funding (In US$ Million) in Genetics for the Years2014, 2015, 2016, 2017 and 2018Launch of Numerous iPSCs-Related Clinical Trials Set to BenefitMarket GrowthNumber of Induced Pluripotent Stem Cells based Studies bySelect Condition: As on Oct 31, 2020iPSCs-based Clinical Trial for Heart DiseasesInduced Pluripotent Stem Cells for Stroke Treatment?Off-the-shelf? Stem Cell Treatment for Cancer Enters ClinicalTrialiPSCs for Hematological DisordersMarket Benefits from Growing Funding for iPSCs-Related R&DInitiativesStem Cell Research Funding in the US (in US$ Million) for theYears 2016 through 2021Human iPSC Banks: A Review of Emerging Opportunities and DrawbacksHuman iPSC Banks Worldwide: An OverviewCell Sources and Reprogramming Methods Used by Select iPSC BanksInnovations, Research Studies & Advancements in iPSCsKey iPSC Research Breakthroughs for Regenerative MedicineResearchers Develop Novel Oncogene-Free and Virus-Free iPSCProduction MethodScientists Study Concerns of Genetic Mutations in iPSCsiPSCs Hold Tremendous Potential in Transforming Research EffortsResearchers Highlight Potential Use of iPSCs for DevelopingNovel Cancer VaccinesScientists Use Machine Learning to Improve Reliability of iPSCSelf-OrganizationSTEMCELL Technologies Unveils mTeSR? PlusChallenges and Risks Related to Pluripotent Stem CellsA Glance at Issues Related to Reprogramming of Adult Cells toiPSCsA Note on Legal, Social and Ethical Considerations with iPSCs

4. GLOBAL MARKET PERSPECTIVETable 1: World Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Geographic Region -USA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld Markets - Independent Analysis of Annual Sales in US$Thousand for Years 2020 through 2025 and % CAGR

Table 2: World 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Geographic Region - Percentage Breakdown ofValue Sales for USA, Canada, Japan, China, Europe, Asia-Pacificand Rest of World Markets for Years 2021 & 2025

Table 3: World Recent Past, Current & Future Analysis forVascular Cells by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 4: World 5-Year Perspective for Vascular Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 5: World Recent Past, Current & Future Analysis forCardiac Cells by Geographic Region - USA, Canada, Japan, China,Europe, Asia-Pacific and Rest of World Markets - IndependentAnalysis of Annual Sales in US$ Thousand for Years 2020 through2025 and % CAGR

Table 6: World 5-Year Perspective for Cardiac Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 7: World Recent Past, Current & Future Analysis forNeuronal Cells by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 8: World 5-Year Perspective for Neuronal Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 9: World Recent Past, Current & Future Analysis for LiverCells by Geographic Region - USA, Canada, Japan, China, Europe,Asia-Pacific and Rest of World Markets - Independent Analysisof Annual Sales in US$ Thousand for Years 2020 through 2025 and% CAGR

Table 10: World 5-Year Perspective for Liver Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 11: World Recent Past, Current & Future Analysis forImmune Cells by Geographic Region - USA, Canada, Japan, China,Europe, Asia-Pacific and Rest of World Markets - IndependentAnalysis of Annual Sales in US$ Thousand for Years 2020 through2025 and % CAGR

Table 12: World 5-Year Perspective for Immune Cells byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 13: World Recent Past, Current & Future Analysis forOther Cell Types by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 14: World 5-Year Perspective for Other Cell Types byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 15: World Recent Past, Current & Future Analysis forCellular Reprogramming by Geographic Region - USA, Canada,Japan, China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 16: World 5-Year Perspective for Cellular Reprogrammingby Geographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 17: World Recent Past, Current & Future Analysis for CellCulture by Geographic Region - USA, Canada, Japan, China,Europe, Asia-Pacific and Rest of World Markets - IndependentAnalysis of Annual Sales in US$ Thousand for Years 2020 through2025 and % CAGR

Table 18: World 5-Year Perspective for Cell Culture byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 19: World Recent Past, Current & Future Analysis for CellDifferentiation by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 20: World 5-Year Perspective for Cell Differentiation byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 21: World Recent Past, Current & Future Analysis for CellAnalysis by Geographic Region - USA, Canada, Japan, China,Europe, Asia-Pacific and Rest of World Markets - IndependentAnalysis of Annual Sales in US$ Thousand for Years 2020 through2025 and % CAGR

Table 22: World 5-Year Perspective for Cell Analysis byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 23: World Recent Past, Current & Future Analysis forCellular Engineering by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 24: World 5-Year Perspective for Cellular Engineering byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 25: World Recent Past, Current & Future Analysis forOther Research Methods by Geographic Region - USA, Canada,Japan, China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 26: World 5-Year Perspective for Other Research Methodsby Geographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 27: World Recent Past, Current & Future Analysis for DrugDevelopment & Toxicology Testing by Geographic Region - USA,Canada, Japan, China, Europe, Asia-Pacific and Rest of WorldMarkets - Independent Analysis of Annual Sales in US$ Thousandfor Years 2020 through 2025 and % CAGR

Table 28: World 5-Year Perspective for Drug Development &Toxicology Testing by Geographic Region - Percentage Breakdownof Value Sales for USA, Canada, Japan, China, Europe,Asia-Pacific and Rest of World for Years 2021 & 2025

Table 29: World Recent Past, Current & Future Analysis forAcademic Research by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 30: World 5-Year Perspective for Academic Research byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 31: World Recent Past, Current & Future Analysis forRegenerative Medicine by Geographic Region - USA, Canada,Japan, China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 32: World 5-Year Perspective for Regenerative Medicine byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

Table 33: World Recent Past, Current & Future Analysis forOther Applications by Geographic Region - USA, Canada, Japan,China, Europe, Asia-Pacific and Rest of World Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 34: World 5-Year Perspective for Other Applications byGeographic Region - Percentage Breakdown of Value Sales forUSA, Canada, Japan, China, Europe, Asia-Pacific and Rest ofWorld for Years 2021 & 2025

III. MARKET ANALYSIS

UNITED STATESInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in the United Statesfor 2022 (E)Table 35: USA Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 36: USA 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

Table 37: USA Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 38: USA 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Research Method - Percentage Breakdown of ValueSales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 39: USA Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 40: USA 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

CANADATable 41: Canada Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 42: Canada 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Cell Type - Percentage Breakdown of ValueSales for Vascular Cells, Cardiac Cells, Neuronal Cells, LiverCells, Immune Cells and Other Cell Types for the Years 2021 &2025

Table 43: Canada Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 44: Canada 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Research Method - Percentage Breakdown ofValue Sales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 45: Canada Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 46: Canada 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

JAPANInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in Japan for 2022 (E)Table 47: Japan Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 48: Japan 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

Table 49: Japan Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 50: Japan 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Research Method - Percentage Breakdown of ValueSales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 51: Japan Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 52: Japan 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

CHINAInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in China for 2022 (E)Table 53: China Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 54: China 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

Table 55: China Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 56: China 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Research Method - Percentage Breakdown of ValueSales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 57: China Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 58: China 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

EUROPEInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in Europe for 2022 (E)Table 59: Europe Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Geographic Region -France, Germany, Italy, UK and Rest of Europe Markets -Independent Analysis of Annual Sales in US$ Thousand for Years2020 through 2025 and % CAGR

Table 60: Europe 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Geographic Region - Percentage Breakdown ofValue Sales for France, Germany, Italy, UK and Rest of EuropeMarkets for Years 2021 & 2025

Table 61: Europe Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 62: Europe 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Cell Type - Percentage Breakdown of ValueSales for Vascular Cells, Cardiac Cells, Neuronal Cells, LiverCells, Immune Cells and Other Cell Types for the Years 2021 &2025

Table 63: Europe Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 64: Europe 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Research Method - Percentage Breakdown ofValue Sales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 65: Europe Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 66: Europe 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

FRANCEInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in France for 2022 (E)Table 67: France Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 68: France 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Cell Type - Percentage Breakdown of ValueSales for Vascular Cells, Cardiac Cells, Neuronal Cells, LiverCells, Immune Cells and Other Cell Types for the Years 2021 &2025

Table 69: France Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 70: France 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Research Method - Percentage Breakdown ofValue Sales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 71: France Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 72: France 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

GERMANYInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in Germany for 2022 (E)Table 73: Germany Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 74: Germany 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Cell Type - Percentage Breakdown of ValueSales for Vascular Cells, Cardiac Cells, Neuronal Cells, LiverCells, Immune Cells and Other Cell Types for the Years 2021 &2025

Table 75: Germany Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 76: Germany 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Research Method - Percentage Breakdown ofValue Sales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 77: Germany Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 78: Germany 5-Year Perspective for Induced PluripotentStem Cell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

ITALYTable 79: Italy Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Cell Type - VascularCells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cellsand Other Cell Types - Independent Analysis of Annual Sales inUS$ Thousand for the Years 2020 through 2025 and % CAGR

Table 80: Italy 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

Table 81: Italy Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Research Method -Cellular Reprogramming, Cell Culture, Cell Differentiation,Cell Analysis, Cellular Engineering and Other Research Methods -Independent Analysis of Annual Sales in US$ Thousand for theYears 2020 through 2025 and % CAGR

Table 82: Italy 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Research Method - Percentage Breakdown of ValueSales for Cellular Reprogramming, Cell Culture, CellDifferentiation, Cell Analysis, Cellular Engineering and OtherResearch Methods for the Years 2021 & 2025

Table 83: Italy Recent Past, Current & Future Analysis forInduced Pluripotent Stem Cell (iPSC) by Application - DrugDevelopment & Toxicology Testing, Academic Research,Regenerative Medicine and Other Applications - IndependentAnalysis of Annual Sales in US$ Thousand for the Years 2020through 2025 and % CAGR

Table 84: Italy 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Application - Percentage Breakdown of ValueSales for Drug Development & Toxicology Testing, AcademicResearch, Regenerative Medicine and Other Applications for theYears 2021 & 2025

UNITED KINGDOMInduced Pluripotent Stem Cell (iPSC) Market Presence - Strong/Active/Niche/Trivial - Key Competitors in the United Kingdomfor 2022 (E)Table 85: UK Recent Past, Current & Future Analysis for InducedPluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells,Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells andOther Cell Types - Independent Analysis of Annual Sales in US$Thousand for the Years 2020 through 2025 and % CAGR

Table 86: UK 5-Year Perspective for Induced Pluripotent StemCell (iPSC) by Cell Type - Percentage Breakdown of Value Salesfor Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells,Immune Cells and Other Cell Types for the Years 2021 & 2025

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Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $0 Thousand by 2027 - Yahoo Finance

Tissue source and processing

Paired sections of tissue, including both artery and plaque, were recovered from the atherosclerotic core (AC) and proximally adjacent (PA) region of three patients with asymptomatic type VII calcified plaques who underwent carotid endarterectomy (Fig. S1a, TableS1). Due to the rich cellular composition of carotid artery and plethora of debris in plaque (i.e., lipid, fibrinogen, etc.), dissociation and generation of single-cell suspensions amenable to single-cell RNA sequencing were difficult. After tissue collection, enzymatic digestion, RBC lysis, and filtration were the initial steps required to generate single cells (see Methods and Fig. S1b). However, despite efficient enzymatic dissociation and significant filtering of our sample, we were still challenged by abundant plaque debris, which ultimately resulted in poor single-cell capture rates. In order to overcome this issue without isolating specific cell types through cell-marker antibody labeling, we devised a strategy to label all cells in the sample with a far-red excitation-emission live/dead cell nuclear stain (DRAQ5). All cells in the sample were stained, with debris being left unstained by the dye. Previous studies have used nuclear staining in library preparation and sequencing experiments to discriminate single versus doublet cells during cell sorting without adverse effects for downstream applications such as single-cell and bulk RNA sequencing17,18,19,20. Subsequently, DRAQ5+ cells were manually gated and sorted from the remainder of the debris using FACS. Cells isolated from the entire filtered sample represented <1% of the total particles in the sample (Figs. S2aS2f). Viability of remaining cells was assessed and was always >80% using this technique for cell separation (see Methods). The cells were then processed for single-cell sequencing.

The analytical approach in this manuscript is depicted in Fig.1a. Generation of single cells from three patient-matched AC and PA samples (batched per patient on a single NextSeq flow cell) yielded 51,981 cells total, with an average of ~13,000 AC cells/patient and ~5000PA cells/patient. Cell number disparities are due to the difference in size of the AC vs PA tissue itself. Given the abundance of AC versus PA cells, down-sampling was performed to equalize the contribution of each sample and condition to the unsupervised discovery of cell types and to mitigate bias due to class imbalance. UMAP-based clustering (see Methods) of this down-sampled dataset reveals 15 distinct cell partitions (Fig. S1c, d), representing 17,100 cells total. In order to assign partitions to major cell types we examined genes expressed in >80% of cells per partition and at a mean expression count >2. A dotplot representing three marker genes selected for each partition is presented in (Fig. S1e). A comparison of VSMC marker genes used in our study with those in the literature15 is provided (Fig. S1f). Cell-type labels assigned to these 15 initial partitions based on these marker genes include: T-lymphocytes (2 partitions), macrophages, VSMCs (2 partitions), ECs (2 partitions), B-lymphocytes, natural killer T-cells, B1-lymphocytes, mast cells, lymphoid progenitors, plasmacytoid dendritic cells, and an unidentified partition (TableS2). Following doublet filtering using a marker-gene exclusion method (see Supplemental Methods), removal of partitions with too few cells for differential gene expression analysis (mast cells, lymphoid progenitors, plasmacytoid dendritic cells, and the unidentified partition), and merging of partitions assigned to the same cell-type, we assessed differential gene expression between AC and PA regions across the 6 remaining major cell types: macrophages, ECs, VSMCs, NKT cells, T- and B-lymphocytes (Fig.1bd, Fig. S4, Supplementary Data16). We performed a number of independent partitioning experiments using various algorithmic variations to confirm the reproducibility of these partitions and cell-label assignments (see Supplemental Methods).

a Schematic diagram of analytical steps from tissue dissociation to key driver analysis. b, c UMAP visualization of 6 major cell types following doublet removal via gene exclusion criteria (see Supplemental Methods), separated by anatomic location (b), and by cell type (c). d Dotplot depicting cell-type marker genes, resulting in the identification of macrophages, ECs, VSMCs, NKT cells, T- and B-Lymphocytes. Dot size depicts the fraction of cells expressing a gene. Dot color depicts the degree of expression of each gene. n=3 for PA and AC groups.

GWAS results have highlighted biological processes in the vessel wall as key drivers of coronary artery disease (CAD)21. Our prior work has demonstrated the vascular wall to be involved in the most impactful common genetic risk factor for CAD22. Our results here also demonstrate extensive differential expression in these cell types across anatomic locations compared to the remaining cell types. Therefore, we chose to focus our efforts on dissecting expression alterations in VSMCs and ECs in order to illuminate pathogenic genomic signatures within these cell-types. As above, each cell type is compared across anatomic location (Fig.2a, e), and the top differentially expressed genes are shown (Fig.3b, f), revealing interesting spatial and expression magnitude differences between AC and PA cells.

a, e UMAP visualization of VSMCs (a) and ECs (e), separated by anatomic location. b, f Volcano plots of the top differentially expressed genes in VSMCs (b) and ECs (f). Dotted lines represented q-value 0.5 and <0.5 corresponding to PA and AC cells, respectively. c, d UMAP visualization of the top 4 upregulated genes in AC VSMCs (c), and PA VSMCs (d). Gray-colored cells indicate 0 expression of designated gene, while color bar gradient indicates lowest (black) to highest (yellow) gene expression level. g, h UMAP visualization of the top 4 upregulated genes in AC ECs (g), and PA ECs (h). Color scheme is similar to the above-described parameters. VSMCs=3674 cells; ECs=2764 cells. n=3 for PA and AC groups.

a, b Normalized enrichment score (NES) ranking of all significant PA and AC Hallmarks generated from GSEA analysis of differentially expressed genes for VSMCs (a) and ECs (b) (FDR q-value<0.05). c Fully clustered on/off heatmap visualization of overlap between leading edge EMT hallmark genes generated by GSEA. Heatmaps are downsampled and represent 448 cells from each cell type and anatomic location (1792 total cells). A dotplot corresponding to gene expression levels for each cell type in the heatmap is included. Dot size depicts the fraction of cells expressing a gene. Dot color depicts the degree of expression of each gene. d Volcano plot of differentially expressed genes between the two groups of VSMCs in (c). Dotted lines represented q-value<0.01 and normalized effect >0.5 and <0.5. e, f Gene co-expression networks generated from VSMC Module 13 (d) and EC Module 1 (e) representing the EMT hallmark from GSEA analysis. Genes are separated by anatomic location (red=AC genes, cyan=PA genes), differential expression (darker shade=higher DE, gray=non-significantly DEGs), correlation with other connected genes (green line=positive correlation, orange line=negative correlation) and strength of correlation (connecting line thickness). Significantly DEGs (q<0.05) with high connectivity scores (>0.3) are denoted by a box instead of a circle. n=3 for PA and AC groups.

VSMCs generate three subclusters in the UMAP plot. A large fraction of PA VSMCs form a PA-specific VSMC subcluster. In contrast, AC VSMCs form 2 separate clusters both of which are intermingled with PA VSMCs. This suggests VSMCs occupy three major cell states, including one completely distinct PA subtype, and two that are predominantly AC VSMCs (Fig.2a). The top four upregulated genes in the AC are sparsely expressed and include SPP1, SFRP5, IBSP, and CRTAC1 (Fig.2b, c), while APOD, PLA2G2A, C3, and MFAP5 are upregulated in many PA VSMCs (Fig.2b, d).

The spatial clustering of upregulated genes in AC VSMCs suggests the presence of separate subpopulations of matrix-secreting VSMCs involved with ECM remodeling (Fig.2c). SPP1 (osteopontin) is a secreted glycoprotein involved in bone remodeling23 and has been implicated in atherosclerosis for inhibiting vascular calcification and inflammation in the plaque milieu24. IBSP (bone sialoprotein) is a significant component of bone, cartilage, and other mineralized tissues25. CRTAC1 is a marker to distinguish chondrocytes from osteoblasts and other mesenchymal stem cells26,27. These findings suggest the presence of cartilaginous and osseous matrix-secreting VSMCs in the AC region. SFRP5, an adipokine that is a direct WNT antagonist, reduces the secretion of inflammatory factors28 and is thought to exert favorable effects on the development of atherosclerosis29. The high expression of SFRP5 in the AC suggests a deceleration of these inflammatory processes in the core of the plaque, and an overall shift in the AC to calcification and matrix remodeling.

Conversely, the upregulated genes in PA VSMCs are more ubiquitously expressed by VSMCs in a PA-specific region of the UMAP plot (Fig.2d). C3 is highly differentially expressed in many PA cells (Fig.2d). Complement activation has long been appreciated for its role in atherosclerosis30, with maturation of plaque shown to be dependent, in part, on C3 opsonization for macrophage recruitment and stimulation of antibody responses31. Its predominance in our PA samples suggests complement activation in atherosclerosis is anatomically driven by VSMCs located adjacent to areas of maximal plaque build-up. PLA2G2A (phospholipase A2 group IIA), also selectively expressed by this group of cells, is pro-atherogenic, modulates LDL oxidation and cellular oxidative stress, and promotes inflammatory cytokine secretion32, further facilitating the inflammatory properties of this group of VSMCs. Full differential expression results for VSMCs are provided (Supplementary Data5).

Overall, we identify increased calcification and ECM remodeling by VSMCs in the AC versus pro-inflammatory signaling by VSMCs in the PA. These differences in biological processes are strongly supported further in the systems analyses below.

In contrast to VSMCs, for ECs we observe a more complete separation of cells into two distinct subgroups (Fig.2e). PA ECs significantly outnumber the AC ECs (2316 vs 448 cells, respectively), possibly due to intimal erosion and loss of endothelial cell layer integrity during advanced disease5,33,34,35 resulting in fewer captured ECs in the AC. Cellular transdifferentiation may also cause a subpopulation of ECs to lose common EC marker expression, resulting in lower numbers of ECs identified in AC compared to the PA counterpart. Histologic assessment of AC plaque collected from our patients supports the assertion of endothelial layer attenuation as the principal reason for lower AC EC capture (Fig. S3b, c). In contrast to VSMCs, there is a skew toward higher magnitude expression changes in AC ECs vs PA ECs. The top four upregulated genes are ITLN1, DKK2, F5, and FN1 in the AC and IL6, MLPH, HLA-DQA1, and ACKR1 in PA ECs (Fig.2g, h).

The upregulated genes in AC ECs again suggest a synthetic profile. ITLN (omentin) is an adipokine enhancing insulin-sensitivity in adipocytes36. Interestingly, circulating plasma omentin levels were shown to negatively correlate with carotid intima-media thickness37, inhibit TNF-induced vascular inflammation in human ECs38, and promote revascularization39, suggesting an anti-inflammatory and intimal repair role in AC ECs. DKK2 further indicates intimal repair as it stimulates angiogenesis in ECs40. The significant upregulation of FN1 (fibronectin) in this group further suggests active ECM remodeling and may serve as a marker for mesenchymal cells and EMT-related processes41.

Similarly to PA VSMCs, the upregulated genes in PA ECs suggest an overall inflammatory profile. Central players in inflammation and antigen presentation are upregulated specifically in PA ECs (Fig.2h). IL6, a key inflammatory cytokine associated with plaque42, is the most upregulated gene. Furthermore, ACKR1, highly upregulated in many PA ECs, binds and internalizes numerous chemokines and facilitates their presentation on the cell surface in order to boost leukocyte recruitment and augment inflammation43. Antigen presentation on ECs via HLA-DQA1 (MHC class II molecule) may support activation and exhaustion of CD4+ T-cells44,45 as previously described. Full differential expression results for ECs are provided (Supplementary Data6).

Overall, we identify two main EC subtypes: synthetic ECs in the AC that appear to participate in intimal repair, revascularization, and ECM modulation, and inflammatory ECs in the PA region that likely facilitate inflammation via antigen/chemokine presentation and recruitment of immune cells, including CD4+ T-cells. These differences in biological processes are strongly supported further in the systems analyses below.

In order to explore the anatomic differences for these cell types further, gene set enrichment analysis (GSEA) was used to asses hallmark processes most significantly altered in VSMCs and ECs (Fig.3a, b). Epithelial to mesenchymal transition (EMT), oxidative phosphorylation, and myogenesis gene upregulation were strongly enriched in both AC VSMCs and ECs, collectively suggesting an increase in cellular metabolic activity and proliferation. In contrast, a distinctly inflammatory profile was seen in PA VSMCs and ECs, with IFN gamma/alpha responses and TNFa signaling via NFkB dominating the enriched processes in these groups of cells. Because EMT and TNFa signaling were both shared and strongly enriched processes in the two cell types, the gene signatures associated with these hallmarks were further scrutinized through generation of heatmaps consisting of leading-edge differentially expressed genes from each hallmark process (EMTFig.3c, TNFa signaling via NFkBFig. S5a).

While overlapping at the hallmark level, separation of cells by cell type as well as anatomic location in the EMT hallmark heatmap suggests the overlapping processes are mediated by distinct gene sets in each cell type. Moreover, analysis of EMT hallmark genes further supports the presence of 2 cellular subtypes of AC VSMCs as they appear to cluster into two distinct groups of cells with dichotomous expression of contractile (MYL9, TPM2, TAGLN, FLNA) versus synthetic/EMT (POSTN, LUM, FBLN2, DCN, PCOLCE2, MGP, COL3A1) gene signatures (Fig.3c, d). These results indicate a group of VSMCs in the AC may perform the contractile functions of the blood vessel wall, while the other group of VSMCs may be involved with CTD and ECM remodeling. Furthermore, cells with an ACTA2+Thy1 gene signature in Fig.3c may be, in part, plaque-stabilizing myofibroblasts (orange line), indicating that these contractile cells may also have a large role in ECM remodeling.

In contrast to distinct subclustering of cells by EMT-related genes, there appears to be a common gradient of genes involved in inflammation and response to inflammation expressed throughout the atherosclerotic tissue, with higher levels of TNF-related inflammatory genes expressed in PA VSMCs and ECs compared to AC cells, indicating a predominance of inflammatory processes occurring in the PA region overall (Fig. S5a). Collectively these genes (EIF1, FOS, JUN, JUNB, ZFP36, PNRC1, KLF2, IER2, CEBPD, NFKBIA, GADD45B, EGR1, PPP1R15A, and SOCS3), in addition to IL6 expression in PA ECs, appear to coordinate the inflammatory response pathways in plaque and its adjacent structures. All cell types analyzed thus far are coordinated along this gradient of inflammation.

To further dissect VSMC and EC anatomical gene expression differences in order to identify candidate key genes driving the significant hallmark processes, we reconstructed gene co-expression networks using a partial correlation-based approach (see Methods), defined modules by clustering, and overlaid differential expression analysis results on these modules to identify those enriched in genes differentially expressed between AC and PA tissues.

Using this strategy, 31 and 39 distinct gene network modules were generated in our VSMC and EC datasets, respectively (see Supplemental Methods, Supplementary Data7, 8). Of these, 8 modules in VSMCs, and 5 modules in ECs were enriched with differentially expressed genes (p-value<0.05, Fishers exact test, see Methods). Furthermore, differentially expressed EMT-related hallmark genes overlapped significantly and specifically with a single VSMC and EC module. Differentially expressed TNFa signaling via NFkB-related hallmark genes also overlapped significantly with one VSMCs and EC module (p-value<0.05, Fishers exact test). No other hallmark processes overlapped with generated network modules.

The EMT gene signature generated from GSEA analysis of network modules and the robust upregulation of genes found in matrix-secreting cells in this cohort suggests the possibility of CTD occurring and/or completing in the atherosclerotic core. Therefore, in order to further characterize genes which may stimulate CTD in AC VSMCs and ECs we examined gene co-expression networks in conjunction with differential expression data from the modules enriched with EMT hallmark genes. In VSMCs we identified 9 genes (SPP1, IBSP, POSTN, MMP11, COL15A1, FN1, COL4A1, SMOC1, TIMP1) whose expression was significantly upregulated in AC cells and with strong network connectivity (see Methods). Among these genes we identify POSTN, SPP1, and IBSP as possible key gene drivers of CTD processes in AC VSMCs due to their strong central connectivity and high degree of differential expression in the network module (Fig.3e). POSTN (periostin) is expressed by osteoblasts and other connective tissue cell types involved with ECM maturation46 and stabilization during EMT in non-cardiac lineages47,48. POSTN, SPP1, and IBSP are highly interconnected in our network and likely serve as drivers of CTD by modulating other correlated genes such as TIMP1, VCAN, TPST2, SMOC1, MMP11, FN1, and COL4A1 (Fig.3e), all genes which are involved with cellular differentiation49 and extracellular matrix remodeling50,51.

In our EC network we identified 18 genes (ITLN1, FN1, OMD, S100A4, SCX, PRELP, GDF7, TMP2, SERPINE2, SLPI, HEY2, IGFBP3, FOXC2, RARRES2, PTGDS, TAGLN, LINC01235, and COL6A2) whose expression was significantly upregulated in AC cells and with strong network connectivity. Among these genes, we identify ITLN1, S100A4, and SCX as possible gene drivers of CTD in ECs associated with the AC (Fig.3f). ITLN1 (omentin) is highly upregulated in ECs associated with the atherosclerotic core, and network data indicate it is strongly correlated with genes involved with cellular proliferation and ECM modulation. ITLN is also strongly correlated to OGN (osteoglycin) which induces ectopic bone formation52, indicating that ITLN1 may modulate ECs with osteoblast-like features in the atherosclerotic core. SCX (scleraxin), a transcription factor that plays a critical role in mesoderm formation, and the development of chondrocyte lineages53, as well as regulating gene expression involved with ECM synthesis and breakdown in tenocytes54, is co-expressed with IL11RA, an interleukin receptor implicated in chondrogenesis55, as well as with a variety of genes involved with cellular development and modulation of ECM structures. Thus, SCX may modulate chondrocyte-like ECs in the AC. S100A4 is a calcium-binding protein that is highly expressed in smooth muscle cells of human coronary arteries during intimal thickening56, and silencing this gene in endothelial cells prevents endothelial tube formation and tumor angiogenesis in mice57. Co-expression with HEY2, a transcription factor involved with NOTCH signaling and critical for vascular development58, may indicate an important role in repair via re-endothelialization of plaque-denuded artery.

Next, genes critical to stimulating TNFa signaling via NFkB in PA VSMCs and ECs were evaluated. In the VSMC module we identified 14 genes (APOLD1, MT1A, ZFP36, EGR1, JUNB, FOSB, JUN, FOS, RERGL, MT1M, DNAJB1, CCNH, HSPA1B, and HSPA1A) whose expression was significantly upregulated in PA cells and with strong network connectivity. Among these genes we identify immediate-early (IE) genes ZFP36, EGR1, JUNB, FOSB, and FOS as critical response genes in this hallmark process. Importantly, the paired-sample study design in which AC and PA samples from the same patient are processed identically at the same time ensures that these IE genes preferentially upregulated in the PA region are critical for the inflammatory response and not an artifact of tissue processing stressors.

In the EC module we identified two genes (IER2 and FOS) whose expression was significantly increased in PA EC cells (Fig. S5e), and are highly correlated with other critical transcription factors in our network, including FOSB, JUNB, EGR1, and ZFP36, further supporting this group of genes importance in the TNFa signaling hallmark (Fig. S5d).

Finally, in order to identify and characterize refined subpopulations from each anatomic region, we selected the 7 VSMC and 5 EC differentially expressed modules described above and biclustered cells and genes (Fig.4a, d). The likely biological functions of these subpopulations were then inferred based on the genes differentially expressed and subsequent gene ontology enrichment analysis across these subpopulations. A continuous gene expression model, based on the fraction of AC cells per subpopulation, and subsequent gene ontology enrichment analysis was used to evaluate these cell subtype differences (Fig.4b, c, e, f).

a, d Biclustered heatmap visualization of all significant genes (q<0.05) from VSMC (a) and EC (d) modules enriched with differentially expressed genes. a 1224 VSMCs from each anatomic location (2448 cells total). Large color bar denotes PA (cyan) and AC (orange) VSMCs. Small color bar above denotes distinct cell subpopulations (blue, forest green, lime green, brown, purple, magenta, red). d 448 ECs from each anatomic location (896 cells total) in. Large color bar denotes PA (blue) and AC (red) ECs. Small color bar above denotes distinct cell subpopulations (cyan, green, magenta). A dotplot corresponding to gene expression levels for each cell subpopulation on the heatmap is included. Colored dots next to specific genes correspond to critical genes related to the designated cell subpopulation. Continuous gene expression based gene ontology enrichment analysis of biological function performed based on the fraction of AC cells per subpopulation of VSMCs (b, c) and ECs (e, f). n=3 for PA and AC groups.

We identified four cell subpopulations of VSMCs with some overlapping features in our analysis (Fig.4a). The four subpopulations appear to form a continuum of cell states, starting with a population that consists exclusively of PA VSMCs (Fig.4a, green bar), characterized by genes involved in recruitment of inflammatory mediators, with early signs of CTD. Specifically, C3 (opsonization and macrophage recruitment; normalized effect=6.5, q=1.74e07) is highly differentially expressed in this subpopulation and likely augments PA inflammation and macrophage recruitment. This group of VSMCs also shows evidence of early migratory and CTD-like qualities given the expression of FBN1, SEMA3C, HTRA3, and C1QTNF3, (normalized effect=2.77, 3.65, 4.0, 3.58, respectively; q=6.93e41, 1.25e20, 2.53e05, 0.00012, respectively) genes that are both highly differentially expressed in this cohort and with high signal strength in our networks (Fig.4a, Supplementary Data7). FBN1 (ECM component) is strongly correlated with TGFBR3, SEMA3C, and CD248 (modulators of EMT-like processes)59,60,61. Interestingly, this group of cells co-expresses IGSF10, a marker of early osteochondroprogenitor cells62, TMEM119 (bone formation and mineralization; promotes differentiation of myeloblasts into osteoblasts)63,64, and WNT11 (bone formation)65 (Supplementary Data7).

On the other end of this continuum, we identify a subpopulation of ~70% AC cells (Fig.4a, red bar) that have elevated expression of POSTN (osteoblasts; normalized effect=2.206, q=3.60e16), CRTAC1 (chrondrocytes; normalized effect=3.22, q=3.91e26), TNFRSF11B (bone remodeling; normalized effect=0.98, q=7.31e06)66, ENG (VSMC migration; normalized effect=0.87, q=1.41e13)67, COL4A2, and COL4A1 (cell proliferation, association with CAD; normalized effect=0.98, 1.03 and q=3.17e15, 5.68e11, respectively)68,69. Collectively, the differential gene expression data and the underlying biology behind our gene co-expression networks support this group of cells as likely representing synthetic osteoblast- and chondrocyte-like VSMCs which facilitate calcification and cartilaginous matrix-secretion and reside largely in the AC.

Furthermore, gene ontology enrichment analysis provides a clear progression from muscle system processes, extracellular structure reorganization, and catabolic processes enriched in the PA to processes involved with CTD such as ossification, fat cell differentiation, and regulation of cell motility, adhesion, and cellular transdifferentiation enriched in the AC (Fig.4b, c). The shift in cell states supports a continuum of cell state changes leading to increased CTD in the atherosclerotic core.

Overall, we observe three EC subpopulations. Like VSMCs, these cells display transitory properties as they move through a continuum of cell states (Fig.4d). First, there is a group comprised near exclusively of inflammatory PA ECs that is involved in recruitment of inflammatory mediators (Fig.4d, magenta bar). This group has a greater number of cells expressing immune genes such as the cluster of HLA genes, as well as CD74 (normalized effect=1.63, q=2.07e112), a gene which forms part of the invariant chain of the MHC II complex and is a receptor for the cytokine macrophage migration inhibitory factor (MIF)70. The upregulation of MHC class II complex in this subset of PA ECs complements our previous finding of CD4+T-cell recruitment to this subpopulation of PA ECs, leading to over-activation and exhaustion via antigen-persistence.

The next group of cells is intermediate in its composition of AC (67.5%) and PA (~32.5%) ECs with a mixed gene expression profile with characteristics similar to each of the other two groups of cells (Fig.4d, green bar), likely representing dysfunctional ECs that are in transition from the inflamed subtype to the CTD subtype described below.

The final group of cells is largely comprised of ECs from the AC (96.8%) (Fig.4d, cyan bar) and is largely devoid of endothelial-marker gene EMCN71 (normalized effect=0.86, q=1.17e09). Critical EMT genes identified earlier (ITLN1, SCX, and S100A4) are predominantly expressed in this large cluster of AC ECs alongside highly correlated genes OMD, OGN, and CRTAC1, again indicating that this population of ECs likely represents the main group of transdifferentiated ECs.

Gene ontology enrichment analysis further supports this shift in EC cell state from cells primarily involved with immune response (antigen processing and presentation, adaptive immune response, etc.) to cell states predominantly involved with proliferation, migration, vascular development, and angiogenesis (Fig.4e, f).

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Decoding the transcriptome of calcified atherosclerotic plaque at single-cell resolution | Communications Biology - Nature.com

October 12, 2022 7:15 am ET

Companies on track to report data from the ongoing Phase 2 trial of mRNA-4157/V940 in combination with KEYTRUDA as adjuvant therapy in high-risk melanoma in 4Q 2022

CAMBRIDGE, M.A. and RAHWAY, N.J., October 12, 2022 Moderna, Inc. (Nasdaq: MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines, and Merck (NYSE:MRK), known as MSD outside of the United States and Canada, today announced that Merck has exercised its option to jointly develop and commercialize personalized cancer vaccine (PCV) mRNA-4157/V940 pursuant to the terms of its existing Collaboration and License Agreement. mRNA-4157/V940 is currently being evaluated in combination with KEYTRUDA, Mercks anti-PD-1 therapy, as adjuvant treatment for patients with high-risk melanoma in a Phase 2 clinical trial being conducted by Moderna.

We have been collaborating with Merck on PCVs since 2016, and together we have made significant progress in advancing mRNA-4157 as an investigational personalized cancer treatment used in combination with KEYTRUDA, said Stephen Hoge, M.D., President of Moderna. With data expected this quarter on PCV, we continue to be excited about the future and the impact mRNA can have as a new treatment paradigm in the management of cancer. Continuing our strategic alliance with Merck is an important milestone as we continue to grow our mRNA platform with promising clinical programs in multiple therapeutic areas.

Under the agreement, originally established in 2016 and amended in 2018, Merck will pay Moderna $250 million to exercise its option for personalized cancer vaccines including mRNA-4157/V940 and will collaborate on development and commercialization. The payment will be expensed by Merck in the third quarter of 2022 and included in its non-GAAP results. Merck and Moderna will share costs and any profits equally under this worldwide collaboration.

This long-term collaboration combining Mercks expertise in immuno-oncology with Modernas pioneering mRNA technology has yielded a novel tailored vaccine approach, said Dr. Eliav Barr, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. We look forward to working with our colleagues at Moderna to advance mRNA-4157/V940 in combination with KEYTRUDA as it aligns with our strategy to impact early-stage disease.

About mRNA-4157/V940

Personalized cancer vaccines are designed to prime the immune system so that a patient can generate a tailored antitumor response to their tumor mutation signature to treat their cancer. mRNA-4157/V940 is designed to stimulate an immune response by generating T cell responses based on the mutational signature of a patients tumor.

About KEYNOTE-942 (NCT03897881)

KEYNOTE-942 is an ongoing randomized, open-label Phase 2 trial that enrolled 157 patients with high-risk melanoma. Following complete surgical resection, patients were randomized to mRNA-4157/V940 (9 doses every three weeks) and KEYTRUDA (200 mg every three weeks) versus KEYTRUDA alone for approximately one year until disease recurrence or unacceptable toxicity. KEYTRUDA was selected as the comparator in the trial because it is considered a standard of care for high-risk melanoma patients. The primary endpoint is recurrence-free survival, and secondary endpoints include distant metastasis-free survival and overall survival. The Phase 2 trial is fully enrolled and primary data are expected in the fourth quarter of 2022.

About KEYTRUDA (pembrolizumab) Injection 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC) as determined by an FDA-approved test.

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval of this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA, in combination with lenvatinib, is indicated for the first-line treatment of adult patients with advanced RCC.

KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Endometrial Carcinoma

KEYTRUDA, in combination with lenvatinib, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis;Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy;Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss;Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis;Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica;Endocrine: Hypoparathyroidism;Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

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