Mitalipov successfully repairs genes in human embryos

A ground breaking discovery by Shoukhrat Mitalipov, Ph.D.,was reported in Nature the successful removal of a lethal geneticdefect in human embryos. The breakthrough is the initial confirmation that adangerous genetic defect can in theory be erased.

Scientific success in embryo editing re-opens reg debate. BioWorld

Study in Nature demonstrates method for repairing genes in human embryos that prevents inherited diseases. OHSU News

Gene Editing Breakthrough. Charlie Rose Show

A Promising And Still Uncertain Future For Human Gene Editing. Science Friday

In Breakthrough, Scientists Edit a Dangerous Mutation From Genes in Human Embryos. NY Times

First human embryo editing experiment in U.S.'corrects' gene for heart condition. The Washington Post.

Scientists Precisely Edit DNA In Human Embryos To Fix A Disease Gene. NPR

Human embryos edited to stop disease. BBC

A Gene Editing Breakthrough. On Point with Tom Ashbrook.

First U.S.-based group to edit human embryos brings practice closer to clinic. Science

In breakthrough, OHSU corrects defective gene in embryo. Oregonlive.

First Safe Repair of Gene in Human Embryos. Associated Press.

A new discovery may unlock the answer to a vexing scientificquestion: How to conduct mitochondrial replacement therapy, a new gene-therapytechnique, in such a way that safely prevents the transmission of harmful mitochondrialgene mutations from mothers to their children.

For women with mitochondrial diseases, a step closer to preventing transmission. STAT

Human embryo experiment shows progress toward 'three-parent' babies. The Washington Post

Families struggling with infertility or a genetic predisposition for debilitating mitochondrial diseases may someday benefit from a new breakthrough led by scientists at OHSU and the Salk Institute for Biological Studies.

Egg 'nobbles' can be used to create embryos, say scientists in fertility breakthrough

Fertility success may get boost from new research

First he pioneered a new way of making life. Now he wants to try it in people

Shoukhrat Mitalipov: The cloning chief.

Researchers announced they had derived stem cells fromcloned human embryos, a long-awaited research coup that Science's editors choseas a runner-up for Breakthrough of the Year.Read the article on Science

#4. Finally, We're Just Like Dolly

#5. Functioning Organs Made From Stem Cells

#2. Human embryonic stem cells cloned

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Center for Embryonic Cell and Gene Therapy | Center for ...

Social security expenditures keep rising endlessly as the aging of Japans population accelerates with the low birthrate. Yet, little is known about the way huge sums of taxpayer money are being poured into wasteful projects tied to vested interests in the name of saving human lives.

The Japan Agency for Medical Research and Development (AMED), which Prime Minister Shinzo Abe created with much fanfare in 2015 as a counterpart to the U.S. National Institute of Health, has an annual budget in excess of 140 billion. But the National Cancer Center (NCC), which is supposed to be a major recipient of the AMED fund, is in trouble because excessive sums have been spent on construction of buildings and facilities in the name of life science research.

A glance at the NCCs financial statements shows that its retained earnings plummeted from 5.6 billion in fiscal 2010 to 762 million in 2015. The steep fall in the retained earnings is not due to cuts in grants from the Health, Labor and Welfare Ministry, as a high-ranking NCC official claims. The NCC earned 31.4 billion from medical services and 4.3 billion from research projects in fiscal 2010, and these earnings rose by 41 percent to 44.4 billion and 14 percent to 9.2 billion, respectively, unequivocally showing that the rise in earnings far exceeded the cut in government grants.

Then why have its retained earnings fallen so rapidly? The answer is that excessive investments in construction of new facilities have eaten into its funds. For example, it cost 5.4 billion to build a new research center on next-generation surgery and endoscopy, which was completed in May, and another 16.7 billion to build a new research laboratory that began operating in July. The question here is not the sheer sum spent on these projects, but their balance with the institutes earnings. During the 2010-16 period, money spent on such construction projects exceeded the NCCs operating income by 44.3 billion. It seems clear that the NCC is investing beyond its means even as construction costs surge ahead of the 2020 Tokyo Olympic Games.

Cases of advanced medicine becoming an arena for big spending like public works projects are also found in the field of heavy particle therapy. Japan has five institutions specializing in this field, the pioneer among them being the National Institute of Radiological Sciences in Chiba Prefecture. The number in Japan represents nearly half of the 11 such facilities now operating worldwide.

The five heavy particle therapy facilities are located in Chiba, Hyogo, Gunma, Saga and Kanagawa prefectures, with one more being planned in Yamagata. And oddly enough, though, the NCC supposedly the control tower of cancer therapy in Japan has no such institute. That is said to be because those institutes were located in facilities with close links to the Education, Culture, Sports, Science and Technology Ministry which took the lead in the development of heavy particle therapy instead of the health ministry.

One reason why Gunma University has one of those institutes is not because the university excelled in cancer treatment but, according to a source familiar with the decision, because of the influence of former education minister Hirofumi Nakasone, an Upper House member elected from the Gunma constituency and a powerful member of the Liberal Democratic Partys education lobby. Gunma Prefecture was eager to have the facility established there because that involved heavy initial investments about 7 billion each for the buildings and radiation equipment providing huge economic benefits to local construction and other related industries.

Haphazard ways in which money is being spent on advanced medical research are also found in the projects for biobanks, institutions that collect and preserve biospecimens of people such as blood, urine and DNA samples. Through followup research on the registered people and linking with their clinical information, their activities are expected to contribute to identifying the causes of illnesses and developing new medicines.

Of a number of biobanks set up in Japan, the Tohoku Medical Megabank Organization at Tohoku University is by far the largest. It started operating in fiscal 2011 as part of a series of government projects for recontruction from the Great East Japan Earthquake and tsunami that hit the regions Pacific coast. In its initial year of operation, more than 10 billion from the government budget was poured into the Tohoku Medical Megabank. A total of 5.1 billion was spent on the construction and design of a seven-story complex and another 7.5 billion on its facilities and equipment in the years through fiscal 2013. While spending was scaled back in subsequent years, 4.5 billion has been set aside for the project in fiscal 2017 a sum equivalent to the funding allocated to Kyoto University for its research on iPS (induced pluripotent stem) cells.

Tohoku Medical Megabank is staffed with 32 professors, 10 associate professors and 25 instructors. However, some of the staff are deemed not necessarily fit for the types of work assigned to the institute, leading some students to comment sarcastically that those who have failed to be promoted to full professorship at Tohoku University have been given new jobs at the biobank. Moreover, the quality of some of the work performed by the institute has been called into question.

The value of biobank is determined by the quality of the data obtained by its research. If the quality is poor, such an institute would not be trusted by researchers in pharmaceutical companies or other institutes. Six years after its creation, Tohoku Medical Megabanks achievement remains poor in terms of significant research that would have lured pharmaceutical firms and others to collaborate with the institute. The head of the biobank is not deterred, however, as he says his institutes research projects take time before tangible results can be produced, and the institute keeps asking for more funding from the AMED.

As funding for Tohoku Medical Megabank gets prioritized, budgetary allocations for the more prestigious BioBank Japan, which has been jointly established by the government-affiliated Riken research institute and the University of Tokyos Institute of Medical Science, has been significantly reduced. The budget cut by AMED is about to deal a fatal blow to the institute that has played a leading role in genome research in Japan.

Given Japans dire fiscal conditions, government funding on scientific research cannot be an exception to budget cuts. Time will come sooner or later for the generous funding for Tohoku Medical Megabank to be curtailed. Today, however, huge sums of taxpayer money are being poured on the institute despite its poor records of significant achievements in the name of the reconstruction of the areas ravaged by the 2011 disasters. Along with the spending of taxpayer money, new positions are being created for post-retirement jobs for government bureaucrats.

The circumstances surrounding those advanced medical research institutes look similar to those involving the governments public works projects: Securing funding from taxpayer money becomes more important than the outcome of projects. Unless the structure is fixed, there will be no hope of medical science becoming a core of the governments growth strategy.

This is an abridged translation of an article from the August issue of Sentaku, a monthly magazine covering political, social and economic scenes. More English articles can be read at http://www.sentaku-en.com

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Wasteful spending on medical public works - The Japan Times

Theres a lot to be said for being in the right place at the right time, but could Air Supplys long-time success be the result or a chance meeting or was the cosmos working overtime on a little something called destiny? Maybe, but one thing is for surenone of it would have been possible at all without their hard work and tenacity to make it happen.The two Russells, Graham Russell and Russell Hitchcock, happened to be cast in the same Sydney, Australian production of Jesus Christ Superstar in 1975, and everything changed after that.

Many an audience member has probably asked himself if a fine looking group of ladies about to take the stage could possibly do justice to one of the most popular rock bands in the world. Its a legitimate question considering its not easy music to play, so a person cant help but wonder if the music will be taken as seriously as the people in the audience do. However, once the guitars are plugged in and the girls dig into those first few chords, the obvious answer to that question is, oh, hell, yes.

Many a cook tries their hand at duplicating foods they love in restaurants and specialty shops, telling themselves, it cant be that difficult. Often times, theyre right. It can be doneand its pretty simple. However, sometimes, its not as easy as it looks.Mexican food for example looks easy because ingredients are simple, sauces are often slow-cooked and meat is marinated, making this comfort food one of Americas favorite. Recipes are often handed down and each time theyre prepared, a spice might be tweaked or flavor added, depending on taste and preference.

Its been 40 years since Elvis Presley died (August 16, 1977) and millions of people still have the date circled in red on their calendars. People still remember and they still mourn. Some internet sites have gone to the extent of estimating what he would look like now, if he were still here in the physical.This time of year Memphis fills up with more people than usual as crowds in large numbers make their pilgrimages to Graceland for visits to his home while tribute shows pop up all around the country to remember the huge icon that he was.

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For Immune System Stem Cell Studies, Mice Aren't Enough Science 2.0 Stem cell therapy is all the rage, with suspect companies sprouting up like supplement stores, claiming to be a benefit for this and that. Often all they have are mouse studies and FDA disclaimers on ... The authors found that two varieties of ... and more »

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For Immune System Stem Cell Studies, Mice Aren't Enough - Science 2.0

Yaron Ramati, Director of Regulatory Affairs at Pluristem Therapeutics

Over the past few years, the regulatory landscape for cell therapy development has grown increasingly complex. There are now accelerated pathways for advanced therapy medicinal products (ATMPs) in several countries worldwide, including the U.S., Japan, and South Korea. While the possibility for accelerated commercialization has resulted from these changes, substantial complexity has also been introduced, making it a more elaborate process to move cell therapy products from bench to bedside.

In the interview with Yaron Ramati, Director of Regulatory Affairs at Pluristem Therapeutics, we get an experts perspective on how the regulatory environment has changed and new opportunities that exist for bringing cell therapy products through the clinical trial process and into the global marketplace.

Yaron Ramati: I have 10 years of experience in regulatory affairs in biotechnology companies in Israel.

I have a PhD in Philosophy of Biology from the London School of Economics and an M.Sc. from the Technion in Neurobiology

Yaron Ramati:The United States, Japan, and South Korea are countries that have accelerated pathways that are unique for cell and gene therapies. Legislation took effect in Japan in late 2014, in South Korea in 2016, and in the United States in 2017.

Additionally, the EU has a program for product acceleration the Adaptive Pathways. Although it is not explicitly for cell and gene therapies, these have been given a lot of attention by the group.

Yaron Ramati:

In the United States: Regenerative medicine advanced therapy (RMAT) designation.Cell therapies that aim to treat serious medical conditions with high unmet need, and have preliminary favorable clinical data, can get the designation. It allows for accelerated approval (i.e., the use of biomarkers and intermediate endpoints for BLA, priority review).

In Japan: Conditional time-limited marketing authorization.This program allows for regenerative therapies (cell, gene and tissue therapies) to receive conditional marketing authorization for up to 7 years, following confirmation of safety and an initial proof of efficacy in Japan in diseases that are serious and have a high unmet need.

In South Korea: Conditional marketing authorization for cell therapy.As in Japan, this program allows for cell therapies to receive conditional marketing authorization for a limited time, following an initial proof of efficacy in serious diseases.

In EU: Adaptive Pathways pilot program. This program is a pilot program established by the EMA to explore ways in which the EMA can assist the streamlining the development of new promising therapies for serious conditions with high unmet need. Although this program is not explicitly for cell or gene therapy, it is the main focus of the group.

Yaron Ramati: All EU countries have a joint definition for ATMPs as set by EU regulation. Other countries have separate definitions that only partially overlap.

Yaron Ramati: Only few countries in the world are willing to be the first to provide marketing authorization for novel therapies. For ATMPs, European regulation does not allow individual countries in the union to provide marketing authorization, and so the EMA is the only gateway for ATMPs in Europe.

The U.S. FDA, Japan PMDA, and South Korea KFDA are the only others that are willing to be first to approve ATMPs.

Yaron Ramati: Currently, the EMA and PMDA are leading with four marketing approvals of cell and gene therapies each. RMAT designation procedure in the U.S. is expecting to give a boost to the products that are being developed for the U.S. market.

Yaron Ramati: Pluristem is very active in the field of accelerated development of its products. PLX-PAD of Pluristem has been accepted to the Japan conditional time-limited marketing authorization scheme by PMD, as well as to the adaptive pathways program of the EMA. It is active in both programs.

In addition, Pluristem intends to make use of the accelerated pathways offered for regenerative therapies in both the U.S. and in South Korea.

Yaron Ramati: The focus of Pluristem in these programs is the advancement of PLX-PAD. Pluristem had achieved understandings with EMA and PMDA regarding the accelerated approval of PLX-PAD for the treatment of critical limb ischemia (CLI).

It is the intention of Pluristem to achieve similar understandings with FDA, EMA, PMDA and KFDA regarding the development of PLX-PAD for the treatment of patients following hip fractures.

Yaron Ramati: PLX-PAD was accepted into the EMA adaptive pathways pilot program in 2015. Since then, Pluristem has taken advantage of this program in coming to an understanding with the EMA on the desired regulatory path of PLX-PAD in CLI. In addition, Pluristem undertook parallel scientific advice with the EMA and leading health technology assessment (HTA) bodies in Europe.

In this meeting, Pluristem received valuable feedback on the expectations that these bodies have for purposes of reimbursement in Europe. Pluristem has designed the Phase 3 PACE study in CLI patients in view of the feedback received from both the EMA and the HTA bodies, with the purpose of addressing their respective expectations.

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An Experts Perspective on Accelerated Pathways for Cell ...

Stem cell science involves many technical terms. This glossary covers many of the common terms you will encounter in reading about stem cells.

Adult stem cellsA commonly used term for tissue-specific stem cells, cells that can give rise to the specialized cells in specific tissues. Includes all stem cells other than pluripotent stem cells such as embryonic and induced pluripotent stem cells.

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AutologousCells or tissues from the same individual; an autologous bone marrow transplant involves one individual as both donor and recipient.

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Basic researchResearch designed to increase knowledge and understanding (as opposed to research designed with the primary goal to solve a problem).

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BlastocystA transient, hollow ball of 150 to 200 cells formed in early embryonic development that contains the inner cell mass, from which the embryo develops, and an outer layer of cell called the trophoblast, which forms the placenta.

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Bone marrow stromal cellsA general term for non-blood cells in the bone marrow, such as fibroblasts, adipocytes (fat cells) and bone- and cartilage-forming cells that provide support for blood cells. Contained within this population of cells are multipotent bone marrow stromal stem cells that can self-renew and give rise to bone, cartilage, adipocytes and fibroblasts.

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CardiomyocytesThe functional muscle cells of the heart that allow it to beat continuously and rhythmically.

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Clinical translationThe process of using scientific knowledge to design, develop and apply new ways to diagnose, stop or fix what goes wrong in a particular disease or injury; the process by which basic scientific research becomes medicine.

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Clinical trialTests on human subjects designed to evaluate the safety and/or effectiveness of new medical treatments.

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Cord bloodThe blood in the umbilical cord and placenta after child birth. Cord blood contains hematopoietic stem cells, also known as cord blood stem cells, which can regenerate the blood and immune system and can be used to treat some blood disorders such as leukemia or anemia. Cord blood can be stored long-term in blood banks for either public or private use. Also called umbilical cord blood.

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CytoplasmFluid inside a cell, but outside the nucleus.

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DifferentiationThe process by which cells become increasingly specialized to carry out specific functions in tissues and organs.

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Drug discoveryThe systematic process of discovering new drugs.

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Drug screeningThe process of testing large numbers of potential drug candidates for activity, function and/or toxicity in defined assays.

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EmbryoGenerally used to describe the stage of development between fertilization and the fetal stage; the embryonic stage ends 7-8 weeks after fertilization in humans.

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Embryonic stem cells (ESCs)Undifferentiated cells derived from the inner cell mass of the blastocyst; these cells have the potential to give rise to all cell types in the fully formed organism and undergo self-renewal.

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FibroblastA common connective or support cell found within most tissues of the body.

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GlucoseA simple sugar that cells use for energy.

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HematopoieticBlood-forming; hematopoietic stem cells give rise to all the cell types in the blood.

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ImmunomodulatoryThe ability to modify the immune system or an immune response.

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Induced pluripotent stem cells (iPSCs)Embryonic-like stem cells that are derived from reprogrammed, adult cells, such as skin cells. Like ESCs, iPS cells are pluripotent and can self-renew.

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In vitroLatin for in glass. In biomedical research this refers to experiments that are done outside the body in an artificial environment, such as the study of isolated cells in controlled laboratory conditions (also known as cell culture).

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In vivoLatin for within the living. In biomedical research this refers to experiments that are done in a living organism. Experiments in model systems such as mice or fruit flies are an example of in vivo research.

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Islets of LangerhansClusters in the pancreas where insulin-producing beta cells live.

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MaculaA small spot at the back of the retina, densely packed with the rods and cones that receive light, which is responsible for high-resolution central vision.

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Mesenchymal stem cells (MSCs)A term used to describe cells isolated from the connective tissue that surrounds other tissues and organs. MSCs were first isolated from the bone marrow and shown to be capable of making bone, cartilage and fat cells. MSCs are now grown from other tissues, such as fat and cord blood. Not all MSCs are the same and their characteristics depend on where in the body they come from and how they are isolated and grown. May also be called mesenchymal stromal cells.

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Multipotent stem cellsStem cells that can give rise to several different types of specialized cells in specific tissues; for example, blood stem cells can produce the different types of cells that make up the blood, but not the cells of other organs such as the liver or the brain.

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NeuronAn electrically excitable cell that processes and transmits information through electrical and chemical signals in the central and peripheral nervous systems.

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Pancreatic beta cellsCells responsible for making and releasing insulin, the hormone responsible for regulating blood sugar levels. Type I diabetes occurs when these cells are attacked and destroyed by the body's immune system.

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PhotoreceptorsRod or cone cells in the retina that receive light and send signals to the optic nerve, which passes along these signals to the brain.

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PlaceboA pill, injection or other treatment that has no therapeutic benefit; often used as a control in clinical trials to see whether new treatments work better than no treatment.

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Placebo effectPerceived or actual improvement in symptoms that cannot be attributed to the placebo itself and therefore must be the result of the patient's (or other interested person's) belief in the treatment's effectiveness.

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Pluripotent stem cellsStem cells that can become all the cell types that are found in an embryo, fetus or adult, such as embryonic stem cells or induced pluripotent (iPS) cells.

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Preclinical researchLaboratory research on cells, tissues and/or animals for the purpose of discovering new drugs or therapies.

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Precursor cellsAn intermediate cell type between stem cells and differentiated cells. Precursor cells have the potential to give rise to a limited number or type of specialized cells. Also called progenitor cells.

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Progenitor cellsAn intermediate cell type between stem cells and differentiated cells. Progenitor cells have the potential to give rise to a limited number or type of specialized cells and have a reduced capacity for self-renewal. Also called precursor cells.

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Regenerative MedicineAn interdisciplinary branch of medicine with the goal of replacing, regenerating or repairing damaged tissue to restore normal function. Regenerative treatments can include cellular therapy, gene therapy and tissue engineering approaches.

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ReprogrammingIn the context of stem cell biology, this refers to the conversion of differentiated cells, such as fibroblasts, into embryonic-like iPS cells by artificially altering the expression of key genes.

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Retinal pigment epitheliumA single-cell layer behind the rods and cones in the retina that provide support functions for the rods and cones.

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RNARibonucleic acid; it "reads" DNA and acts as a messenger for carrying out genetic instructions.

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Scientific methodA systematic process designed to understand a specific observation through the collection of measurable, empirical evidence; emphasis on measurable and repeatable experiments and results that test a specific hypothesis.

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Self-renewalA special type of cell division in stem cells by which they make copies of themselves.

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Somatic stem cellsScientific term for tissue-specific or adult stem cells.

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Stem cellsCells that have both the capacity to self-renew (make more stem cells by cell division) and to differentiate into mature, specialized cells.

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Stem cell tourismThe travel to another state, region or country specifically for the purpose of undergoing a stem cell treatment available at that location. This phrase is also used to refer to the pursuit of untested and unregulated stem cell treatments.

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TeratomaA benign tumor that usually consists of several types of tissue cells that are foreign to the tissue in which the tumor is located.

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TissueA group of cells with a similar function or embryological origin. Tissues organize further to become organs.

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Tissue-specific stem cellsStem cells that can give rise to the specialized cells in specific tissues; blood stem cells, for example, can produce the different types of cells that make up the blood, but not the cells of other organs such as the liver or the brain. Includes all stem cells other than pluripotent stem cells such as embryonic and induced pluripotent cells. Also called adult or somatic stem cells.

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TotipotentThe ability to give rise to all the cells of the body and cells that arent part of the body but support embryonic development, such as the placenta and umbilical cord.

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Translational researchResearch that focuses on how to use knowledge gleaned from basic research to develop new drugs, treatments or therapies.

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ZygoteThe single cell formed when a sperm cell fuses with an egg cell.

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Stem Cell Glossary

Cuorips, a Japan-based cardiac therapy developer spun out from Osaka University, has secured an undisclosed amount from pharmaceutical firm Daiichi Sankyo.

The investment was made as part of an agreement that gives the corporate an option right for the worldwide commercialisation of Cuorips technology, called iPS-derived cardiomyocyte sheet, a cell therapy for patients suffering from severe heart failure.

The treatment uses induced pluripotent stem (iPS) cells, which can be generated directly from a donors mature cells and differentiated into any organ. It offers an alternative to patients who would otherwise require a heart or artificial heart transplant.

The technology is based on research led by Yoshiki Sawa, professor at the Graduate School of Medicines Department of Cardiovascular Surgery.

Sawa developed the therapy through his participation in the Research Center Network for Realization of Regenerative Medicine, operated by the research organisation Japan Agency for Medical Research and Development.

Cuorips is currently gearing up for clinical research and an investigator-initiated clinical trial.

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Daiichi Sankyo hearts Cuorips - Global University Venturing

Daiichi Sankyo Company has signed an investment contract with Cuorips Inc., an Osaka University spin-off venture to receive an option right concerning the worldwide commercialization of iPS-derived cardiomyocyte (iPS-CM) sheet developed by Cuorips.

The iPS-CM sheet is an allogeneic cell therapy product consisting of cardiomyocyte derived from human iPS cells. Its transplantation is expected to provide improvement of cardiac function and amelioration of heart failure and become a new treatment option for patients with severe heart failure, who have no remedies other than heart transplantation or artificial heart implantation.

Based on the cutting-edge cell therapy research targeting heart diseases, the team at the Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, led by Professor Yoshiki Sawa, has been working on the iPS-CM research and development by participating in the Research Center Network for Realization of Regenerative Medicine, which is run by the Japan Agency for Medical Research and Development (AMED). They are currently preparing for clinical research as well as investigator initiated clinical study.

Cuorips is an Osaka University spin-off venture founded to develop and commercialize iPS-CM sheets based on the research data and technologies developed by the university.

Daiichi Sankyo Group has been conducting research on iPS cell-derived cardiomyocyte and their production, and is currently working on the efficient production process capable for commercial supply.

Daiichi Sankyo and Cuorips are aiming to commercialize iPS-CM sheets as a pioneering treatment for severe heart failure. iPS cells are capable of almost unlimited proliferation and differentiation into any organ, and are expected to be used in the field of cell therapy. There are two types of cell therapy: autologous therapy where the patients own cells are collected, cultured and processed, and allogeneic therapy where a donors cells are collected, cultured and processed.

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Daiichi Sankyo signs Investment contract with Cuorips to commercialize iPS-derived cardiomyocyte sheet - pharmabiz.com

Japanese pharma major Daiichi Sankyo (TYO: 4568) revealed this morning that it has signed an investment contract with Cuorips Inc, an Osaka University spin-off venture to receive an option right concerning the worldwide commercialization of iPS-derived cardiomyocyte (iPS-CM) sheet developed by Cuorips.

The iPS-CM sheet is an allogeneic cell therapy product consisting of cardiomyocyte derived from human iPS cells. Its transplantation is expected to provide improvement of cardiac function and amelioration of heart failure and become a new treatment option for patients with severe heart failure, who have no remedies other than heart transplantation or artificial heart implantation.

Based on the cutting-edge cell therapy research targeting heart diseases, the team at the Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, led by Professor Yoshiki Sawa, has been working on the iPS-CM research and development by participating in the Research Center Network for Realization of Regenerative Medicine, which is run by the Japan Agency for Medical Research and Development (AMED). They are currently preparing for clinical research as well as investigator initiated clinical study.

Cuorips was founded to develop and commercialize iPS-CM sheets based on the research data and technologies developed by the university.

Daiichi Sankyo has been conducting research on iPS cell-derived cardiomyocyte and their production, and is currently working on the efficient production process capable for commercial supply. Daiichi Sankyo and Cuorips are aiming to commercialize iPS-CM sheets as a pioneering treatment for severe heart failure.

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Daiichi Sankyo invests in Osaka University spin-off - The Pharma Letter (registration)

Affimed Therapeutics (NASDAQ:AFMD)

Q2 2017 Earnings Conference Call

August 1, 2017 8:30 AM ET

Executives

Anca Alexandru Head of Communications

Adi Hoess Chief Executive Officer

Florian Fischer Chief Financial Officer

Analysts

Maury Raycroft Jefferies

Do Kim BMO Capital Markets

Michael Schmidt Leerink

Peter Lawson SunTrust

Operator

Good day and welcome to the Affimed Second Quarter 2017 Financial Results and Corporate Update Conference Call. Todays conference is being recorded. At this time, I would like to turn the conference over to Anca Alexandru. Please go ahead.

Anca Alexandru

Thanks. I would like to welcome you to our investor and analyst call on the results for the second quarter of 2017. On the call with me today are Adi Hoess, CEO of Affimed, who will present the corporate update; and Florian Fischer, Affimeds CFO, who will walk you through the financials.

Slide 2, before we start, please note that this call and the Q&A session contains forward-looking statements, including statements regarding our future financial condition, business strategy, and our plans and objectives for our future operations.

These statements represent our beliefs and assumptions only as of the date of this discussion. 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.

These forward-looking statements are subject to risks and uncertainties and actual results may differ materially from those expressed or implied in the forward-looking statements due to various factors including, but not limited to those identified under the section entitled risk Factors in our filings with the SEC and those identified under the section entitled cautionary statements regarding forward-looking statements in our Form 6-K filed with the SEC earlier today.

Thank you for your understanding. I will now hand the call over to our CEO, Adi Hoess, who will provide the corporate update.

Adi Hoess

Thanks a lot, Anca. Affimed has developed an immune cell engager and our clinical and preclinical pipeline based on tetravalent bi and trispecificantibody formats. Were an industry leader in NK cell engagement and our lead product candidate AFM13 is to our knowledge, the most advanced NK-cell engager in clinical development.

We also have a well-differentiated T-cell based approach, which includes our clinical candidate AFM11 and well provide an update on these clinical programs as well as our pre-clinical programs today. We employ about 75 full time equivalents with our headquarter located in Heidelberg, Germany, and affiliate offices in the U.S., that is Affimed Inc., as well as our subsidiary AbCheck in Plze, in the Czech Republic.

Slide 4. We have an unencumbered clinical and pre-clinical pipeline of NK and T-cell engagers, with our NK-cell engagers being developed in hematological diseases and solid tumors. Based on our NK-cell platform, we have one clinical and two pre-clinical programs in developments. And based on our T-cell platform, we have one program in our own clinical development. And second T-cell engager program based on our platform called AMV564 is being developed by Amphivena, a company of which we own about 18.5% fully diluted. AMV564 has recently entered clinical development.

Slide 5 summarizes our second quarter updates for our NK cell engager program. For AFM13, we have completed the dose escalation part of our Phase 1b combination study with Mercks Keytruda in Hodgkin Lymphoma and initiated the expansion phase. The AFM13 Phase 2a monotherapy trial in Hodgkin Lymphoma sponsored by the German Hodgkin Study Group is open to recruit under new study design, which includes patients pre-treated with both brentuximab vedotin and anti-PD1.

Columbia University has recently initiated a translational study of AFM13 in CD30-positive lymphoma with cutaneous manifestation and I will provide more detail later. We made further progress in our collaboration with MD Anderson Cancer Center to evaluate AFM13 in combination with MD Andersons NK cell product. In June, we presented new data for our NK cell engagers AFM24 and AFM26 at two conferences and I will go into detail later on this.

Slide 6 summarizes the progress, we have made with our T-cell engager. Two Phase 1 dose-escalation studies are ongoing with AFM11, which offer a significant opportunity to address the high unmet medical need in diffuse large B-Cell lymphoma and mantle cell lymphoma. We believe that both the properties of AFM11 and the design of our studies can attract, specifically, mutations of other drugs in development.

Both dose escalation studies, which are conducted in ALL and in NHL respectively are designed with accelerated titration followed by a classical 3+3 design. In both studies, AFM11 was overall well tolerated with no dose limits and toxicity observed to date. In the AFM11 study in relapsed refractory ALL, which was initiated in September 2016, patients are currently being recruited into the fourth dose cohort. 12 sites are open and recruiting in the Czech Republic, Poland, Russia, Austria and Israel.

As mentioned, no DLTs were observed in particular no AFM11 related grade 3 or grade 4 neurotoxicity or side effects are frequently observed with T-cell engaging antibody agents observed. In our study of AFM11 in relapsed refractory NHL, patients are currently being recruited into the third dose cohort. Recall that this study has been amended in the past to enroll patients under a new revised study design.

We believe that we have addressed this lower than effective recruitment by opening further trial sites. A total of 10 sites are now opened in the Czech Republic, Poland, Germany as well as the U.S. Like in our ALL trial, no AFM11 related grade 3 or grade 4 neurotoxicity was observed to date under their revised study design. We intend to provide regular update on both the AFM11 studies in the future.

A second T-cell engager program based on our platform is AMV564, a bispecific tetravalent CD33/CD3 antibody developed by Amphivena in AML. A Phase 1 study is recruiting. However, no further updates have been provided by Amphivena.

Slide 7 shows our platform, which is very distinguished from others as, in contrast, the most comparatives were developing tetravalent bispecific molecules. The bivalent binding of two receptors on two different cells enables high-affinity binding through the avidity effect, which is advantageous to maintain high specificity at very high affinity.

We believe that this is very important in order to obtain a favorable safety profile. Furthermore, our platform allows multi-specificity in the tailored PK. Further differentiating Affimed, while most immune cell engaging approaches to date focus on T cells, our technology platform reliably generates both T and NK-cell engagers.

While increasingly NK-cells are becoming a cornerstone of cancer immunotherapy, and we're excited to be pioneering this development. There are a number of reasons why NK-cell-based approaches are very attractive and one of the reasons is that there seems to be a positive correlation between NK-cell infiltration and clinical outcome in patients.

In this context, it has been described that a low cytotoxicity is associated with higher incidence of cancer. In addition, recent clinical data show improved anti-tumor responses of ex vivo expanded and activated NK-cell populations. NK-cell-based immunotherapy has recently advanced with different treatment approaches, including engagers, check points, cytokines and adoptive cellular transfer.

To-date, it seems that NK-cell-based approaches have this strong advantage of controlling a well manageable favorable safety profile. This creates an opportunity for NK-cell redirection to address the lack of recognition of cancer cells and also allows for potential combination of NK-cells with other approaches to enhance efficacy.

A common theme in all different cancer types is the ability of the tumor cell to evade recognition by the immune system and, specifically, by NK-cells as shown on Slide 9. Normally, NK-cells are capable of killing foreign or aberrant cells, like tumor cells, have acquired mechanisms to escape the so-called immune surveillance.

As a result, such NK-cells cannot recognize tumor cells as foreign or aberrant and, therefore, cannot fight them. We believe that our platform has the potential to overcome these limitations by disabling the tumor evasion mechanisms, and I will explain on the next slide what this belief is based on.

Our expertise and leadership in natural-killer cell-based approaches is one of our key assets. As we can see here, there are a multitude of activating and inhibitory NK-cell receptors being discovered that CD16A, a dominant activating receptor on innate immune cells, is the only activating receptor that triggers the cytotoxic activity of nave human NK cells, even in the absence of costimulatory signals.

Based on these properties and on our preclinical and clinical data generated to date, we believe that targeting CD16A is key for efficient recruitment of and killing by NK cells and macrophages. We have secured a solid IP position around CD16A targets.

Slide 10. We believe that through targeting CD16A with high affinity and specificity, the significant limitations of IgGs can differ. With our tetravalent bispecific immune cell engagers, we can restore NK-cell killing in tumor immune control, and this is depicted here.

Let me explain in more detail why we believe that our approach is superior compared to IgG-based approaches. The human body is not using NK-cell engagement by IgG to eliminate cancer cells. However, this mechanism is used for cells infected by viruses or bacteria.

In this situation, the human immune system generates a collagen antibody response that highly decorates such infected cells or organisms.

Highly decorated means that many different proteins are expressed on the cell surface, which can then be found bound by antibodies. This polyclonal and high-density binding leads to NK-cells killing upon high avidity XP binding, plus antibodies for CD16A on the NK-cell and other XP gamma receptors, for example, CD32 and CD64.

In the setting of targetable cancer cells, however, with IgG, the situation is very different. Firstly, the therapeutic molecule targets a single epitope. Hence, it confers ammonia killing response. And secondly, there are cancer cells which express only very low numbers of the desired target.

The consequence of this very low target density is an insufficient amount of IgG, decorating the cancer cells and thereby not being able to efficiently recruit immune cells. This is shown in the middle picture. Interesting, most therapeutic monoclonal antibodies are target-modulating antibodies, such as cetuximab, polatuzumab, gevokizumab, just to mention a few of them.

We are addressing this limitation by targeting CD16A with high affinity and specificity, as shown. Indeed, our immune cell engagers has the potential to elicit a robust NK-cell killing and immune control due to multivalent and apparent high-affinity binding to CD16A even at limiting antigen densities on the target.

Slide 11, furthermore, CD16A in confers additional superior engager features. The binding of immune cells through CD16A with high affinity and specificity induces NK-cell activation, which triggers an integrated immune response that can be mediated by both innate and adaptive immune cells. In particular, our NK-cell engagers do not bind to CD16B and neutrophils, which avoids the sync effect. Their affinity has been demonstrated to be over 1,000 fold higher than that of monoclonal antibodies and our engagers bind independently of the 158 valine phenylalanine polymorphism.

Most importantly, theres virtually no competition with plasma IgG, which is shown here. In the ground stage, CD16A on innate immune cells is occupied by polyclonal plasma IgG. But there is a huge excess of plasma IgG versus therapeutic antibodies, this creates a significant threshold for FC-based therapeutic antibodies, however, not for CD16A target enhancement.

Our tetravalent and bispecific molecules, which recognize a different epitope from CD16A, are virtually unaffected by plasma IgG. All these unique features result in overall increased potency and efficacy of NK-cell engagers.

Slide 12. Our lead candidate, CD30/CD16A-specific NK-cell engager, AFM13 is a first-in-class antibody suitable for mono and combination therapy. This has demonstrated safety and clinical activity in heavily pretreated Hodgkin lymphoma patients in a Phase 1 study. In this Phase 1 study, tumor shrinkage and potential responses were observed in patients treated with four weekly doses of at least 1.5 mg/kg of AFM13. In 62% of patients, which was eight out of thirteen patients, we observed tumor shrinkage in 23% of patients, which was a total of three out of thirteen experienced partial response. None of the patients experiencing a PR had been previously treated with brentuximab vedotin.

Recall, that in our investigation the Phase 2a trial for AFM13 in relapsed and refractory Hodgkin lymphoma, which is led by the German Hodgkin Study Group, we have previously guided to change the study protocol to ensure a recruitment of a homogeneous patient population pre-treated with both BV and anti-PD1 antibodies. The study is now open to recruit under the new study design.

We had also provided some preliminary data from patients enrolled under the original study protocol, where partial responses were observed in two of seven evaluated patients who had been pre-treated with brentuximab vedotin, but were anti-PD1 naive. This suggests, now, for the first time that AFM13 is active as a single agent in this heavily pre-treated group of patients and, in particular, that AFM13 is active post brentuximab vedotin. We have learned from the study sponsor that both after-responders had failed BV as the most recent treatment prior to AFM13 therapy, with one patient experiencing stable disease and the other one partial in the progressive disease under the BV treatment.

As previously guided, full data from the ongoing study will be presented upon its anticipated completion in 2019. And prior to that, a decision of data publication time points will be made together with the German Hodgkin Study Group.

We are further developing AFM13 as a combination therapy. Preclinical affinity has been demonstrated in combination with anti-PD1 in vivo in a PDX model. This has been the basis of our Phase 1b trial in relapsed refractory Hodgkin lymphoma in combination with Mercks Keytruda. And here, we have completed the dose escalation part of the trial. In detail, three patients were enrolled into dose levels one and two, respectively, and six patients were enrolled into dose level three. While no grade three or four adverse events related to the study treatment were observed, one DLT was observed in cohort 3, which was a repeated grade two infusion-related reaction, leading to discontinuation of AFM13 treatment. This event is classified as a DLT according to the protocol definition. No further DLTs occurred.

The dose expansion cohort has been initiated with the highest dose explored during dose escalation. Data readout is ongoing in the treated cohort and we intend to present data from the dose escalation at a scientific medical conference in the second half of 2017.

Another update this quarter is that Columbia University has initiated a translational Phase 1b/2a study to evaluate the validity of activity of AFM13 in patients with relapsed and refractory CD30-positive lymphoma with cutaneous manifestation. Affirmed is supporting this trial which is designed to allow for serial biopsies, thereby enabling assessment of NK-cell biology and tumor cell killing within the tumor environment. The first patient was enrolled into the study in July 2017. In general, we view CD30-positive lymphoma as an attractive indication that may broaden the potential of AFM13. In terms of further guidance, we will work together with Columbia University to provide update on this study.

Slide 13. Additional opportunities for our NK-cell engagers include combinations with adoptive NK-cell transfer. Patients on NK cells can be stimulated by monotherapy using NK-cell engagers to overcome tumor immune evasion and immunosuppression. Ex vivo expansion and stimulation of autologous NK-cells followed by reinfusion alone or in combination with NK cell engager, is a viable therapeutic approach providing increased numbers of activated NK cells. Alternatively, NK cells can be derived from peripheral blood, cord blood or IPS cells from healthy donors, which is an allogeneic setting, or from immortalized cells. After ex vivo stimulation and expansion, the NK cells are infused into the patients in combination with NK cell engagers.

We are investigating this approach with our partner MD Anderson. Initially, we plan to investigate AFM13 with MDACCs NK-cell product in the transplant setting. Preclinical research activities are on track and these are intended to be followed by Phase 1 clinical trial. Proof-of-concept for this combination would also pave the way for combinations of other pipeline product such as for AFM23.

Affimed holds an option to exclusive worldwide rights to develop and commercialize any product developed under the collaboration. In addition to our clinical product candidates, we have created a strong preclinical pipeline. Over the last quarter we have further characterized our most advanced preclinical candidates, AFM24 and AFM26, which we are developing for three solid tumors and multiple myeloma respectively.

Despite several marketed agents such as cetuximab and tyrosine kinase inhibitor or TKIs, there is a significant medical need for a novel approach to treat EGF receptor-positive tumor. Both efficacy and toxicity can be addressed. EGFR-blocking drugs have been described to have side-effects including serious skin toxicity which might impact physicians willingness to prescribe a drug. In terms of efficacy, there is a need to overcome intrinsic or acquired resistance. For example, there is no clear indication of efficacy of EGFR-blocking antibodies in patients with RAS mutation.

We are developing a first-in-class NK cell engager designed to overcome the limitations of conventional therapy. AFM24 is designed to effectively treat EGFR-expressing solid tumors, such as lung and neck, or colon cancers. It is an EGFR/CD16A targeting tetravalent bispecific antibody that is well differentiated from cetuximab, it is more potent cytotoxicity in vitro and in vivo including a potential to kill RAS-mutant cell lines. There is novel mechanism of action in safety profile and it has the potential to overcome intrinsic or acquired resistance, which is described by many patients with EGFR positive tumors.

AFM24s potent NK cell recruitment may enable the shift of the validated target EGF receptor, primary receptor block toward immuno-oncology. We have identified several development candidates for which we have initiated IND-enabling studies.

Slide 15, there are several factors which differentiate AFM24 from other therapy. Firstly, AFM24 is differentiated through its efficacy. Here you can see that in vitro, our NK cell engager which is highly potent tumor cell killing independent of RAS mutational status. In vivo, we have demonstrated efficacy in tumors resistant to EGFR targeting agents. Importantly, as shown in the graphs on the right hand side, AFM24 was similarly efficacious in a cetuximab-sensitive model.

Secondly, AFM24 is differentiated through safety, Slide 16. We have completed pilot toxicity studies in cynomolgus monkeys with no major safety findings. At the EACR-AACR-SIC Special Conference, we presented data on a dose-range binder study in which AFM24 was dosed up to 93.75 mg/kg and a repeated dose study in which AFM24 was dosed up to 30 mg/kg in 4 weeks.

No AFM24-related macro or microscopic changes were seen in tissues including vital organs, skin and injection site. Importantly, there was no evidence of skin toxicity in those studies. Also no signs of delayed toxicity was observed in the repeated dose study recovery animals. On a molecular level, we learned from in vitro toxicology studies but there was no cytokine release or NK cell proliferation in the absence of target cells. This further substantiates AFM24s potential beneficial safety profile.

Slide 17, like for EGFR targeted tumors, there is a significant need for a novel approach to treat multiple myeloma. Even though, new therapies have significant improved outcomes, cure still remains elusive and the medical need to achieve minimal residual disease negativity is not yet addressed.

MRD positivity is associated with a poorer prognosis, and it has been recorded that persistent MRD by predictive marker of unsustained complete response. A particular hurdle for therapeutics aimed at immune cell engagement are very high M-protein serum levels up to 170mg/mL. Indeed the competition by serum IgG is known to strongly impair antibody-dependent cell-mediated cytotoxicity, the activity of monoclonal antibodies.

We are developing AFM26 to overcome the limitations of conventional therapies in multiple myeloma. AFM26 is a first-in-class tetravalent bispecific antibody targeting BCMA/CD16A. Targeting BCMA and employing NK cell engagement offers the potential to achieve MRD-negativity. For AFM26, NK cell binding is largely unaffected by circulating IgG, which creates the potential of NK cell activation in the presence of M-protein.

Indeed, the high affinity binding to both target and NK cells leads to a prolonged cell retention. This is shown on the right on the slide on the right bottom. AFM26 shows high cytotoxicity cytotoxic activity towards both low and high BCMA-expressing myeloma cells. AFM26 may be potentially safer than T cell-based approaches, which would allow for faster development timelines. Based on these characteristics, AFM26 might be positioned in first line of combination with adoptive NK-cell transfer during ASCT or in a salvage setting.

AFM26 binds the B-cell maturation antigen, which is an antigen ubiquitously expressed on malignant plasma cells. Its expression on healthy tissues is limited to plasma cells and peripheral dendritic cells. We believe the BCMA is an ideal target for immunotherapy of multiple myeloma.

At ASCO and at the EACR-AACR-SIC, both in June, well present the data on AFM26 NK-cell binding properties and activity. As shown here, these data underscore that compared to native and FC-enhanced IgG. AFM26 shows improved binding and cell surface retention.

Slide 20, we also show that AFM26 is well differentiated through target cell binding in potent NK-cell mediated tumor cell lysis. And this is shown here in comparison with two marketed agents, daratumumab and anti-CD38 antibody and elotuzumab, which targets PS1. Importantly, other than described for daratumumab and elotuzumab, AFM26 did not induce NK-cell mutation.

Slide 21, like our other NK-cell engagers, AFM26 is also well differentiated for other agents [indiscernible] safety. Here you can see that compared to a T-cell engager, AFM26 is similarly potent that shows a reduced cytokine release pattern. This point is going to improve safety profile, making AFM26 uniquely suited to engage NK-cells with multiple myeloma.

I will now hand over the call to our CFO, Florian Fischer, who will provide further details on the financial figures.

Florian Fischer

Thank you, Adi. Affimeds consolidated financial statements have been prepared in accordance with IFRS as issued by the International Accounting Standards Board or IASB. The consolidated financial statements are presented in euro, which is the companys functional and presentation currency. Therefore, all financial numbers that I will present here in this call unless otherwise noted will be in euros. Any numbers referring to Q2 2017 and Q2 2016 are unaudited.

Cash and cash equivalents and financial assets totaled 48.9 million as of June 2017 compared to 44.9 million as of December 31, 2016. The increase was primarily attributable to the net proceeds of 16.4 million from a public offering of common shares in the first quarter, and of 2.5 million from the drawdown of the second tranche of the loan from Silicon Valley Bank, largely offset by operational expenses.

Net cash used in operating activities was 13.1 million for the six months ended June 30, 2017compared to 17 million for the six months ended June 30, 2016. The decrease was primarily related to lower cash expenditure for research and development in connection with Affimeds development and collaboration programs and to the expiration of the Amphivena collaboration.

Affimed expects to have cash to fund our operations at least until the end of 2018. This provides runway for the planned development of our clinical programs, as well as for product discovery and early development activity.

Revenue for the second quarter of 2017 was 0.5 million compared to 2.1 million for the second quarter 2016. Revenue in the 2017 period was primarily derived from AbCheck services, while revenue in 2016 period predominantly to Affimeds collaboration with Amphivena.

R&D expenses for the second quarter of 2017 were 5.4 million compared to 8.6 million for the second quarter of 2016. The decrease was primarily related to lower expenses for AFM13 and our discovery and early stage development activities and the expiration of the Amphivena collaboration.

G&A expenses for the second quarter of 2017 were unchanged at 2.0 million compared to the second quarter of 2016. Net loss for the second quarter of 2017 was 7.9 million, or 0.18 per common share, compared to a net loss of 8 million or 0.24 per common share for the second quarter of 2016.

The decrease of operating expenses was offset by lower revenue. In addition, the result was affected by finance costs of 1.2 million in the second quarter of 2017, whereas finance income of 0.5 million was shown in the second quarter of 2016.

I will now turn the call back over to Adi for a summary of our two clinical programs and our pipeline. Adi?

Adi Hoess

Thanks a lot Florian. Our strategy is to maximize the value of our unencumbered clinical and preclinical pipeline of NK-cell and T-cell engagers, as well as from our platform. Were leveraging our lead product, AFM13, for CD30-positive lymphoma initially focusing on the Hodgkin Lymphoma salvage setting enabling a fast development path and allowing the establishment of a cost efficient marketing and sales structure.

In addition, we believe investigating AFM13, both as monotherapy and in combination with Keytruda, reduces its development. Overall, our preclinical and clinical strategy is designed from the scientific leadership of our NK-cell platform with CD16A as proprietary target. We are expanding the preclinical and clinical activities of our tetravalent and bispecific NK-cell engager platform in solid tumors with our preclinical candidate AFM24 and in hematologic diseases, where we intend to leverage additional opportunities for AFM13 and AFM26, for example, in combination with adoptive NK-cells. We also develop T-cell engagers and our lead T-cell engager, AFM11, is being investigated in two ongoing ALL and NHL trials. BMV564, a T-cell engager derived from our technology platform, is in clinical development through Amphivena to treat AML.

In addition, as mentioned earlier, moving beyond our standard format, we are developing different tetravalent bispecific antibody formats tailored to specific indications and patient populations. And as outlined in previous earnings calls, we have more projects ongoing at the discovery stage and preclinically, including molecules developed from our MHD type complex targeting platform.

Thank you very much for your interest. The call is now open for questions.

Question-and-Answer Session

Operator

Thank you. [Operator Instructions] Our first question now comes from Maury Raycroft from Jefferies. Please go ahead.

Maury Raycroft

Good morning. Thanks for taking my questions. So I was wondering if you can mention what the AFM13 dose was that the DLT patient received in the combo trial? And then what youre going to use in the expansion cohort? And then is this dose higher, lower or in line with your predictions?

Adi Hoess

Hi, Maury, this is Adi. What we have done is we have used or given a PD-1 as its active dose and have dosed up AFM13 under the following strategy, under the following regime. We always are initially giving AFM13 three times per week for two weeks. Then, we give AFM13 once weekly for six weeks and, subsequently, we dose AFM13 every three weeks. The starting dose was 0.15 mg/kg and then switching to 0.5 mg/kg, the next one was 0.5 mg/kg going to 1.5 mg/kg, and the highest dose was 3 mg/kg going then to 7 mg/kg. So the three is always three times per week, and the seven is the weekly or every three weeks. We have seen 1 DLT in the highest dose. So at three times 3 mg/kg and once 7 mg/kg then have included an additional three patients and have not observed another DLT. So thats why we decided to go with the highest dose of 3 mg/kg three times per week subsequently given and then subsequently followed by 7 mg/kg.

Maury Raycroft

Got it, okay. And you also mentioned earlier about the two PRs generated with the monotherapy treatment? And I think you said there is a stable disease, but I missed some of the additional context, and I was just wondering if you can recap that for me?

Adi Hoess

Originally posted here:
Affimed Therapeutics' (AFMD) CEO Adi Hoess on Q2 2017 Results - Earnings Call Transcript - Seeking Alpha

Cataracts are the single leading cause of blindness worldwide, afflicting roughly 42 percent of the global population, including more than 22 million Americans. The disease, which causes cloudy patches to form on the eye's normally clear lens, can require surgery if left untreated. That's why Google's DeepMind AI division has teamed with the UK's National Health Service (NHS) and Moorfields Eye Hospital to train a neural network that will help doctors diagnose early stage cataracts.

The neural network is being trained on a million anonymized optical coherence tomography (OCT) scans (think of a sonogram, but using light instead of sound waves) in the hopes it will eventually be able to supplement human doctors' analyses, increasing both the efficiency and accuracy of individual diagnoses.

"OCT has totally revolutionized the field of ophthalmology. It's an imaging system for translucent structures that utilizes coherent light," Dr. Julie Schallhorn, an assistant professor of ophthalmology at UC San Francisco, said. "It was first described in 1998 and it gives near-cell resolution of the cornea, retina and optic nerve.

"The optic nerve is only about 200 microns thick, but you can see every cell in it. It's given us a much-improved understanding of the pathogenesis of diseases and also their response to treatments." The new iteration of OCT also measures the phase-shift of refracted light, allowing doctors to resolve images down to the capillary level and observe the internal structures in unprecedented detail.

"We're great at correcting refractive errors in the eyes so we can give you good vision far away pretty reliably, or up close pretty reliably," Schallhorn continued. "But the act of shifting focus from distance to near requires different optical powers inside the eye. The way the eye handles this when you're young is through a process called 'accommodation.'" There's a muscle that contracts and changes the shape of the lens to help you focus on close objects. When you get older, even before you typically develop cataracts, the lens will stiffen and reduce the eye's ability to change its shape.

"The lenses that we have been putting in during cataract surgery are not able to mimic that [shapeshifting] ability, so people have to wind up wearing reading glasses," Schallhorn said. There's a lot of work in the field to find solutions for this issue and help restore the eye's accommodation.

There are two front-runners for that: Accommodating lenses, which use the same ciliary muscle to shift focus, and multifocal lenses, which work just like your parents' multifocal reading glasses except that they sit directly on the eye itself. The multifocals have been on the market for about a decade, though their design and construction has been refined over that time.

To ensure the lenses that doctors are implanting are just as accurate as the diseased ones they're removing, surgeons are beginning to use optiwave refractive analysis. Traditionally, doctors relied on measurements taken before the surgery to know how to shape the replacement lenses and combined those with nomograms to estimate how powerful the new lens should be.

The key word there is "estimate." "They especially have problems in patients who have already had refractive surgery like LASIK," Schallhorn explained. The ORA system, however, performs a wavefront measurement of the cornea after the cataract has been removed to help surgeons more accurately pick the right replacement lens for the job.

Corneal inlays are also being used. These devices resemble miniature contact lenses but sit in a pocket on the cornea that's been etched out with a LASIK laser to mimic the process of accommodation and provide a greater depth of focus. They essentially serve the same function as camera apertures. The Kamra lens from AcuFocus and the Raindrop Near Vision Inlay from Revision Optics are the only inlays approved by the FDA for use in the US.

Glaucoma afflicts more than 70 million people annually. This disease causes fluid pressure within the eye to gradually increase, eventually damaging the optic nerve that carries electrical signals from the eye to the brain. Normally, detecting the early stages of glaucoma requires a comprehensive eye exam by a trained medical professional -- folks who are often in short supply in rural and underserved communities. However, the Cambridge Consultants' Viewi headset allows anyone to diagnose the disease -- so long as they have a smartphone and 10 minutes to spare.

The Viewi works much like the Daydream View, wherein the phone provides the processing power for a VR headset shell -- except, of course, that instead of watching 360 degree YouTube videos, the screen displays the flashing light patterns used to test for glaucoma. The results are reportedly good enough to share with you eye doctor and take only about five minutes per eye. Best of all, the procedure costs only about $25, which makes it ideal for use in developing nations.

And while there is no known cure for glaucoma, a team of researchers from Stanford University may soon have one. Last July, the team managed to partially restore the vision of mice suffering from a glaucoma-like condition.

Normally, when light hits your eye, specialized cells in the retina convert that light into electrical signals. These signals are then transmitted via retinal ganglion cells, whose long appendages run along the optic nerve and spread out to various parts of the brain's visual-processing bits. But if the optic nerve or the ganglion cells have been damaged through injury or illness, they stay damaged. They won't just grow back like your olfactory sensory nerve.

However, the Stanford team found that subjecting mice to a few weeks of high-contrast visual stimulation after giving them drugs to reactivate the mTOR pathway, which has been shown to instigate new growth in ganglion cells, resulted in "substantial numbers" of new axons. The results are promising, though the team will need to further boost the rate and scope of axon growth before the technique can be applied to humans.

Researchers from Japan have recently taken this idea of cajoling the retina into healing itself and applied it to age-related macular degeneration cases. AMD primarily affects people aged 60 and over (hence the name). It slowly kills cells in the macula, the part of the eye that processes sharp detail, and causes the central focal point of their field of vision to deteriorate, leaving only the peripheral.

The research team from Kyoto University and the RIKEN Center for Developmental Biology first took a skin sample from a human donor, then converted it into induced pluripotent stem (IPS) cells. These IPS cells are effectively blank slates and can be coerced into redeveloping into any kind of cell you need. By injecting these cells into the back of the patient's eye, they should regrow into retinal cells.

In March of this year, the team implanted a batch of these cells into a Japanese sexagenarian who suffers from AMD in the hope that the stem cells would take hold and halt, if not begin to reverse, the damage to his macula. The team has not yet been able to measure the efficacy of this treatment but, should it work out, the researchers will look into creating a stem-cell bank where patients could immediately obtain IPS cells for their treatment rather than wait months for donor samples to be converted.

And while there isn't a reliable treatment for dry-AMD, wherein fatty protein deposits damage the Bruchs membrane, a potent solution for wet-AMD, which involves blood leaking into the eyeball, has been discovered in a most unlikely place: cancer medication. "Genentech started developing a new drug when an ophthalmologist in Florida just decided to inject the commercially available drug into patients eyes," Schallhorn explained.

"Generally this is not a great idea because sometimes things will go terribly wrong," she continued, "but this worked super-well. It basically stops and reverses the growth of these blood vessels." The only problem is that the drugs don't last, requiring patients to receive injections into their eyeballs every four to eight weeks. Genentech and other pharma companies are working to reformulate the drug -- or at least develop a mechanical "reservoir" -- so it has to be injected only once or twice a year.

Stem-cell treatments like those used in the Kyoto University trial have already proved potentially effective against a wide range of genomic diseases, so why shouldn't it work on the rare genetic condition known as choroideremia? This disease is caused by a single faulty gene and primarily affects young men. Similar to AMD, choroideremia causes light-sensitive cells at the back of the eye to slowly wither and die, resulting in partial to complete blindness.

In April of 2016, a team of researchers from Oxford University performed an experimental surgery on a 24-year-old man suffering from the disease. They first injected a small amount of liquid into the back of the eye to lift a section of the retina away from the interior cellular wall. The team then injected functional copies of the gene into that same cavity, replacing the faulty copies and not only halting the process of cellular death but actually restoring a bit of the patient's vision.

Gene therapy may be "surely the most efficient way of treating a disease," lead author of the study, Oxford professor Robert MacLaren, told BBC News, but its widespread use is still a number of years away. Until then, good old-fashioned gadgetry will have to suffice. Take the Argus II, for example.

The Argus II bionic eye from Second Sight has been in circulation since 2013, when the FDA approved its use in treating retinitis pigmentosa. It has since gotten the go-ahead for use with AMD in 2015. The system leverages a wireless implant which sits on the retina and receives image data from an external camera that's mounted on a pair of glasses. The implant converts that data into an electrical signal which stimulates the remaining retinal cells to generate a visual image.

The Argus isn't the only implantable eyepiece. French startup Pixium Vision developed a similar system, the IRIS II, back in 2015 and implanted it in a person last November after receiving clearance from the European Union. The company is already in talks with the FDA to bring its IRIS II successor, a miniaturized wireless subretinal photovoltaic implant called PRIMA, to US clinical trials by the end of this year.

Ultimately, the goal is to be able to replace a damaged or diseased eye entirely, if necessary, using a robotic prosthetic. However, there are still a number of technological hurdles that must be overcome before that happens, as Schallhorn explained.

"The big thing that's holding us back from a fully functional artificial eye is that we need to find a way to interface with the optic nerve and the brain in a way that we transmit signals," she said. "That's the same problem we're facing with prosthetic limbs right now. But there are a lot of smart people in the field working on that, and I'm sure they'll come up with something soon."

Read more from the original source:
High-tech solutions top the list in the fight against eye disease - Engadget

VW independent/submitted information

DELPHOS A Delphos couple were injured in a home invasion assault that occurred Saturday morning.

David and Dianna Allemeier of 209 S. Pierce St. in Delphos were both taken to St. Ritas Medical Center in Lima for treatment of injuries received when a man gained entry to their home and reportedly assaulted them.

Delphos Police were first called out at 6:05 a.m. Saturday on a report of a suspicious person in the 300 block of Jackson Street who was knocking on doors and then walking away. However, while en route to that call, officers were informed that a man had been injured and was bleeding in the 200 block of Pierce Street.

When officers arrived on the scene, they found Allemeier bleeding from an injury to his neck. The Delphos resident said he received the injury from a man who had gained entry into his home.

Officers approached the residence and found the back door unlocked and a lot of blood at the scene. The home was secured and a K-9 and Crime Scene Unit sought from the Allen County Sheriffs Office.

Allemeier then said his wife was still in the house and officers then entered and found Mrs. Allemeier, who was also injured, in the bedroom area of the residence.

After the Allemeiers were transported to the hospital, a K-9 search was made of the area, and the house was processed by an Allen County sheriffs deputy.

No information was released on whether items were taken from the Allemeier house.

Police are currently seeking a young, skinny white male with black hair, possibly wearing cutoff shorts. Anyone with information is asked to contact the Delphos Police Department or Allen County Sheriffs Office.

The investigation is continuing, with no further information forthcoming at this time.

Read more from the original source:
Ventolin proair - Rsv breathing treatments albuterol - Van Wert independent

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LIMA Employers in the greater West Central Ohio region will collect $33 million in rebates from the Ohio Bureau of Workers Compensation in checks that will be mailed beginning next week.

BWC Administrator/CEO Sarah Morrison, in Lima to present a ceremonial check to local business leaders, said employers are free to spend their rebates as they wish, but she hopes they will consider investing in workplace safety.

We work with employers all over Ohio to prevent injuries and illness in the workplace, and they will tell you that investing in safety is a wise business decision, said Morrison, speaking at a press conference at the Lima/Allen County Chamber of Commerce. Safe workplaces mean fewer injuries, fewer medical claims and a stable workforce, all of which leads to a healthy bottom line for a business.

Morrison was joined by chamber President/CEO Jed Metzger and Tony Daley of Limas Spallinger Millwright Services Inc. Metzger and Daley accepted the check on behalf of employers in the entire region, which includes Allen, Auglaize, Shelby, Hancock, Putnam, and Van Wert counties.

Ohio Gov. John Kasich proposed the rebate in March. Its the third such rebate in the last four years, made possible by an improving safety climate, prudent fiscal management and strong investment returns. The plan to distribute rebates to more than 200,000 Ohio employers during the month of July was approved by BWCs Board of Directors in April. Visitbwc.ohio.govfor more details and eligibility requirements.

The plan also includes a $44 million investment innew health and safety initiativesto promote a healthy workforce and a culture of safety in every Ohio workplace. This includes a new wellness program for small employers, funding for programs to help firefighters and those who work with children and adults with disabilities, and an education campaign to address common injuries at work and in the home.

A healthy economy depends on a strong and healthy workforce, Morrison continued. And when the economy is healthy, we all benefit.

Rebate checks will be mailed in phases starting July 10.

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Antabuse doctors - Antabuse interactions with perfume - Van Wert independent

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By Lieutenant D. Bittner #3252, Antioch Police Investigations Division

On Monday, July 3, 2017 at approximately 8:26 PM, a robbery and homicide occurred at the corner of Hillcrest Avenue and E. 18th Street. An officer involved shooting by an Antioch Police Department patrol officer occurred at the scene of the robbery and homicide. The homicide was not a result of the officer involved shooting. The Antioch Police Department and the Contra Costa County Office of the District Attorney are currently investigating the incident. The investigation is in its early stages and no further information will be released, at this time.

Anyone with information is asked to call the Antioch Police Department non-emergency line at (925) 778-2441. You may also text-a-tip to 274637 (CRIMES) using the key word ANTIOCH.

Publisher @ July 4, 2017

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A copy of the Declaration of Independence.

Following is the text of the Declaration of Independence in celebration of Independence Day, July 4th, 2017:

IN CONGRESS, July 4, 1776.

The unanimous Declaration of the thirteen united States of America,

When in the Course of human events, it becomes necessary for one people to dissolve the political bands which have connected them with another, and to assume among the powers of the earth, the separate and equal station to which the Laws of Nature and of Natures God entitle them, a decent respect to the opinions of mankind requires that they should declare the causes which impel them to the separation.

We hold these truths to be self-evident, that all men are created equal, that they are endowed by their Creator with certain unalienable Rights, that among these are Life, Liberty and the pursuit of Happiness.That to secure these rights, Governments are instituted among Men, deriving their just powers from the consent of the governed, That whenever any Form of Government becomes destructive of these ends, it is the Right of the People to alter or to abolish it, and to institute new Government, laying its foundation on such principles and organizing its powers in such form, as to them shall seem most likely to effect their Safety and Happiness. Prudence, indeed, will dictate that Governments long established should not be changed for light and transient causes; and accordingly all experience hath shewn, that mankind are more disposed to suffer, while evils are sufferable, than to right themselves by abolishing the forms to which they are accustomed. But when a long train of abuses and usurpations, pursuing invariably the same Object evinces a design to reduce them under absolute Despotism, it is their right, it is their duty, to throw off such Government, and to provide new Guards for their future security.Such has been the patient sufferance of these Colonies; and such is now the necessity which constrains them to alter their former Systems of Government. The history of the present King of Great Britain is a history of repeated injuries and usurpations, all having in direct object the establishment of an absolute Tyranny over these States. To prove this, let Facts be submitted to a candid world.

He has refused his Assent to Laws, the most wholesome and necessary for the public good.

He has forbidden his Governors to pass Laws of immediate and pressing importance, unless suspended in their operation till his Assent should be obtained; and when so suspended, he has utterly neglected to attend to them.

He has refused to pass other Laws for the accommodation of large districts of people, unless those people would relinquish the right of Representation in the Legislature, a right inestimable to them and formidable to tyrants only.

He has called together legislative bodies at places unusual, uncomfortable, and distant from the depository of their public Records, for the sole purpose of fatiguing them into compliance with his measures.

He has dissolved Representative Houses repeatedly, for opposing with manly firmness his invasions on the rights of the people.

He has refused for a long time, after such dissolutions, to cause others to be elected; whereby the Legislative powers, incapable of Annihilation, have returned to the People at large for their exercise; the State remaining in the mean time exposed to all the dangers of invasion from without, and convulsions within.

He has endeavoured to prevent the population of these States; for that purpose obstructing the Laws for Naturalization of Foreigners; refusing to pass others to encourage their migrations hither, and raising the conditions of new Appropriations of Lands.

He has obstructed the Administration of Justice, by refusing his Assent to Laws for establishing Judiciary powers.

He has made Judges dependent on his Will alone, for the tenure of their offices, and the amount and payment of their salaries.

He has erected a multitude of New Offices, and sent hither swarms of Officers to harrass our people, and eat out their substance.

He has kept among us, in times of peace, Standing Armies without the Consent of our legislatures.

He has affected to render the Military independent of and superior to the Civil power.

He has combined with others to subject us to a jurisdiction foreign to our constitution, and unacknowledged by our laws; giving his Assent to their Acts of pretended Legislation:

For Quartering large bodies of armed troops among us:

For protecting them, by a mock Trial, from punishment for any Murders which they should commit on the Inhabitants of these States:

For cutting off our Trade with all parts of the world:

For imposing Taxes on us without our Consent:

For depriving us in many cases, of the benefits of Trial by Jury:

For transporting us beyond Seas to be tried for pretended offences

For abolishing the free System of English Laws in a neighbouring Province, establishing therein an Arbitrary government, and enlarging its Boundaries so as to render it at once an example and fit instrument for introducing the same absolute rule into these Colonies:

For taking away our Charters, abolishing our most valuable Laws, and altering fundamentally the Forms of our Governments:

For suspending our own Legislatures, and declaring themselves invested with power to legislate for us in all cases whatsoever.

He has abdicated Government here, by declaring us out of his Protection and waging War against us.

He has plundered our seas, ravaged our Coasts, burnt our towns, and destroyed the lives of our people.

He is at this time transporting large Armies of foreign Mercenaries to compleat the works of death, desolation and tyranny, already begun with circumstances of Cruelty & perfidy scarcely paralleled in the most barbarous ages, and totally unworthy the Head of a civilized nation. He has constrained our fellow Citizens taken Captive on the high Seas to bear Arms against their Country, to become the executioners of their friends and Brethren, or to fall themselves by their Hands. He has excited domestic insurrections amongst us, and has endeavoured to bring on the inhabitants of our frontiers, the merciless Indian Savages, whose known rule of warfare, is an undistinguished destruction of all ages, sexes and conditions.

In every stage of these Oppressions We have Petitioned for Redress in the most humble terms: Our repeated Petitions have been answered only by repeated injury. A Prince whose character is thus marked by every act which may define a Tyrant, is unfit to be the ruler of a free people.

Nor have We been wanting in attentions to our Brittish brethren. We have warned them from time to time of attempts by their legislature to extend an unwarrantable jurisdiction over us. We have reminded them of the circumstances of our emigration and settlement here. We have appealed to their native justice and magnanimity, and we have conjured them by the ties of our common kindred to disavow these usurpations, which, would inevitably interrupt our connections and correspondence. They too have been deaf to the voice of justice and of consanguinity. We must, therefore, acquiesce in the necessity, which denounces our Separation, and hold them, as we hold the rest of mankind, Enemies in War, in Peace Friends.

We, therefore, the Representatives of the united States of America, in General Congress, Assembled, appealing to the Supreme Judge of the world for the rectitude of our intentions, do, in the Name, and by Authority of the good People of these Colonies, solemnly publish and declare, That these United Colonies are, and of Right ought to be Free and Independent States; that they are Absolved from all Allegiance to the British Crown, and that all political connection between them and the State of Great Britain, is and ought to be totally dissolved; and that as Free and Independent States, they have full Power to levy War, conclude Peace, contract Alliances, establish Commerce, and to do all other Acts and Things which Independent States may of right do. And for the support of this Declaration, with a firm reliance on the protection of divine Providence, we mutually pledge to each other our Lives, our Fortunes and our sacred Honor.

The 56 signatures on the Declaration appear in the positions indicated:

Column 1

Georgia:

Button Gwinnett

Lyman Hall

George Walton

Column 2

North Carolina:

William Hooper

Joseph Hewes

John Penn

South Carolina:

Edward Rutledge

Thomas Heyward, Jr.

Thomas Lynch, Jr.

Arthur Middleton

Column 3

Massachusetts:

John Hancock

Maryland:

Samuel Chase

William Paca

Thomas Stone

Charles Carroll of Carrollton

Virginia:

George Wythe

Richard Henry Lee

Thomas Jefferson

Benjamin Harrison

Thomas Nelson, Jr.

Francis Lightfoot Lee

Carter Braxton

Column 4

Pennsylvania: Robert Morris

Benjamin Rush

Benjamin Franklin

John Morton

George Clymer

James Smith

George Taylor

James Wilson

George Ross

Delaware: Caesar Rodney

George Read

Thomas McKean

Column 5

New York:

William Floyd

Philip Livingston

Francis Lewis

Lewis Morris

New Jersey:

Richard Stockton

John Witherspoon

Francis Hopkinson

John Hart

Abraham Clark

Column 6

New Hampshire:

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Nortriptyline hcl - What is nortriptyline generic for - Antioch Herald

By RENEE WEBB rwebb@catholicglobe.org

As the use of stem cell research and therapy continues to expand, one medical research institute located in Iowa strives to uphold Catholic teachings in bioethics.

The John Paul II Medical Research Institute (JP2MRI), a non-profit of Iowa City, was founded by Dr. Alan Moy in 2007 to address a shortcoming when it came to pro-life values being upheld concerning a variety of medical practices and issues. The doctor also is co-founder and CEO of Cellular Engineering Technologies (CET), a for-profit biotechnology company that manufactures commercial adult stem cells and other biotechnology products.

He explained that JP2MRI was founded a year after starting CET to advance the application of adult stem technology to clinical applications in the area of neurodegenerative disease, rare disease, cancer and chronic diseases of unmet needs or in underperformed diseased areas. His concern was that the United States was falling behind other countries in the area of adult stem cell research.

Recently, through collaborative research by JP2MRI and CET, a new method for creating safer induced pluripotent stem cells, or iPSC, for clinical use was discovered.

We started work in traditional adult stem cells over a decade ago, Moy explained. The controversy was that among the secular scientific community, adult stem cells were viewed as inferior to embryonic stem cells because they could not convert or differentiate into the variety of cells that embryonic stem cells could.

When iPSC technology was discovered by a Japanese Nobel laureate scientist about 10 years ago, it was an ethical alternative to embryonic stem cells. iPSC are noncontroversial adult stem cells that are genetically reprogrammed into embryonic-like stem cells without using human embryos.

But that technology had inherent safety issues just like embryonic stem cells. Most embryonic stem cells and iPS cells have the risk of causing tumors because of their genetic instability, Moy said. What we worked on was trying to reduce the tumor risk.

Building on the original iPSC technology, JP2MRI and CET developed a method by using a variety of chemicals to replace known cancer-causing genes in the process.

Now we have an iPS technology that is safer, said Moy, who noted an added benefit is potential reduced cost in drug development.

Potential applications

He spoke about practical applications of this technology such as expanding the use of stored cord blood stem cells for future medical treatment if a disease develops in the child.

We have a means where we can take the cord blood and make an iPS cell which can have lifelong utility and diversity, Moy added.

For those who do not have stored cord blood, he said all is not lost as blood can be drawn and stored for people to create their own iPS cell for future use.

This technology can also provide a viable alternative to embryonic stem cells and aborted fetal tissue that are currently used by the pharmaceutical industry, noted Moy, to produce vaccines, gene therapy, cell therapy and protein therapeutics.

Right now with protein manufacturing, half of it is done using animal cells to produce human proteins, he explained. The problem is some of the human proteins that are produced have some minor animal characteristics and they are not entirely human so there is a push to produce purely human proteins out of human cells. Unfortunately, the vast majority of human cell lines used in protein manufacturing or in vaccine development are derived from aborted fetal tissue.

Moy anticipates there will increasingly be a movement to shift toward human cell manufacturing, and if we dont come up with non-controversial human cells, we are going to have a lot of controversial human protein therapeutics, gene therapies and vaccines that will be distributed at hospitals that must be administered by doctors.

Morals and ethics

This can create moral and ethical problems. Catholic hospitals and/or Catholic doctors will be forced to decide if they will use that type of product made with illicit cells.

We have to have alternative products that are equal or better than the products that are currently out there, said Moy.

The Catholic Church, as well as the average person, may not always be aware of the unethical nature of many of these products. Moy said he has been trying to communicate areas of concern to the Catholic community for years.

The evolution of biotechnology over decades has become secularized and the power is in the secularists, he said. Advancement of illicit-cell treatment and therapy is a serious potential threat to the Catholic health care system including Catholic hospitals and Catholics who are healthcare providers.

Moy feels strongly about Catholics and the church being pro-active in the bioethics arena.

The only way in which we can influence the biotechnology field is through innovation, he said. Through innovation, if you produce something they want that has technical advantage, then one can influence the direction of biotechnology. Pro-life individuals need to move from a passive bystander to an activist role.

That is part of the reason he founded the JP2MRI, which is grounded in a pro-life bioethics that respects the dignity of every human life. While more than 300 non-profit institutes and organizations engage in and support human embryonic stem cell research, JP2MRI seeks to find cures and therapies exclusively using a variety of adult stem cells and specifically the iPSC, which are derived from adult cells.

Moy said they are not only looking for ways to produce a variety of products using the safer iPS cells, but plan to license them so other scientists, companies and industries can take advantage of these cells to pursue more ethical biotechnology.

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Stem cells: JP2MRI, CET discover safer, more ethical biotechnology - Sioux City Catholic Globe

The research studies carried out by John B. Gurdon (Anglo-Saxon) and Shinya Yamanaka (Japanese) were awarded the Nobel Prize in Medicine. These two scientists are considered of being the fathers of cellular reprogramming. They have achieved to create cells that behave identically to embryonic cells, however, without having to destroy human embryos. The Swiss Academy declared that both Gurdon and Yamanaka have revolutionized the current knowledge of how cells and organisms are developed, which has led to the perfection of the absurd methods of diagnosis and therapy.

Jhon Bertrand Gurdon, professor of the Zoology Department of the University of Cambridge, admitted of feeling extremely honored for such a spectacular privilege.

Moreover, Shinya Yamanaka discovered the so called induced pluripotent stem cells (iPS), which have the same proprieties of the embryonic ones and are able to turn into whatever other type of body cell. He asserted that he will continue to conduct research in order to contribute to society and medicine. For him that is a duty.

Yamanaka created four types of genes that supply cells with their pluripotentiality, in other words, the same capacity that embryonic stem cells have. If implanted in differentiated cells, for example of skin, they become pluripotent stem cells. The iPS supply a vast amount of plasticity just as embryonic stem cells do, however, without requiring the extermination or cloning of human embryos, since the initial cells can be obtained from the same patient. In this aspect, these cells have the same status as adult stem cells do, with the advantage of their versatility.

The dilema that has been stirred by the iPS is being resolved due to recent studies carried out by Leisuke Kaji (Universidad de Edimburgo) and Andreas Nagy (Samuel Lunenfeld Research Institute of Mount Sinai Hospital of Toronto).

The created iPS perennially retain their pluripotentiality. There is still the need of research to be conducted concerning the control of the difference between these cells in order for them to create the tissue that is necessary for each case. As Kaji affirms in The Guardian, it is a step towards the practical use of reprogrammed cells in the field of medicine, which could eventually lead to eliminating the need of counting on human embryos as the main source of stem cells.

The Episcopal Subcommittee for the Family and Defense of Life of the Episcopal Conference, beliefs that no Catholic could support practices such as abortion, euthanasia or the production, freezing and/or manipulation of human embryos.

Clement Ferrer

Independent Forum of Opinion

http://indeforum.wordpress.com/

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Hurray for Gurdon and Yamanaka, Nobel Prize Winners for Pro-life Medicine - Gilmer Mirror

The research studies carried out by John B. Gurdon (Anglo-Saxon) and Shinya Yamanaka (Japanese) were awarded the Nobel Prize in Medicine. These two scientists are considered of being the fathers of cellular reprogramming. They have achieved to create cells that behave identically to embryonic cells, however, without having to destroy human embryos. The Swiss Academy declared that both Gurdon and Yamanaka have revolutionized the current knowledge of how cells and organisms are developed, which has led to the perfection of the absurd methods of diagnosis and therapy.

Jhon Bertrand Gurdon, professor of the Zoology Department of the University of Cambridge, admitted of feeling extremely honored for such a spectacular privilege.

Moreover, Shinya Yamanaka discovered the so called induced pluripotent stem cells (iPS), which have the same proprieties of the embryonic ones and are able to turn into whatever other type of body cell. He asserted that he will continue to conduct research in order to contribute to society and medicine. For him that is a duty.

Yamanaka created four types of genes that supply cells with their pluripotentiality, in other words, the same capacity that embryonic stem cells have. If implanted in differentiated cells, for example of skin, they become pluripotent stem cells. The iPS supply a vast amount of plasticity just as embryonic stem cells do, however, without requiring the extermination or cloning of human embryos, since the initial cells can be obtained from the same patient. In this aspect, these cells have the same status as adult stem cells do, with the advantage of their versatility.

The dilema that has been stirred by the iPS is being resolved due to recent studies carried out by Leisuke Kaji (Universidad de Edimburgo) and Andreas Nagy (Samuel Lunenfeld Research Institute of Mount Sinai Hospital of Toronto).

The created iPS perennially retain their pluripotentiality. There is still the need of research to be conducted concerning the control of the difference between these cells in order for them to create the tissue that is necessary for each case. As Kaji affirms in The Guardian, it is a step towards the practical use of reprogrammed cells in the field of medicine, which could eventually lead to eliminating the need of counting on human embryos as the main source of stem cells.

The Episcopal Subcommittee for the Family and Defense of Life of the Episcopal Conference, beliefs that no Catholic could support practices such as abortion, euthanasia or the production, freezing and/or manipulation of human embryos.

Clement Ferrer

Independent Forum of Opinion

http://indeforum.wordpress.com/

Read more from the original source:
The Gilmer Mirror - Hurray for Gurdon and Yamanaka Nobel Prize ... - Gilmer Mirror

Minneapolis, MN, June 26, 2017 (GLOBE NEWSWIRE) -- BioSig Technologies, Inc.(OTCQB:BSGM), a medical device company developing a proprietary platform designed to address an unmet technology need for the $4+ billion electrophysiology (EP) marketplace, today announced that the American Heart Associations 13thAnnualBasic Cardiovascular Sciences (BCVS) 2017 Scientific Sessions: Pathways to Cardiovascular Therapeuticshas accepted two abstracts for presentation that feature novel preclinical findings with BioSigs PURE EP System. The conference will be held July 10-13 in Portland, Oregon and includes the next best thing in cardiovascular research.

The abstracts, entitled, Use of a Novel Electrogram Filter to Visualize the Conduction Tissue Signals in the Ventricle in Sinus Rhythm and Arrhythmia: Canine Studies and "Assessment of Catheter Position Above or Below the Aortic Valve by Evaluation of Characteristics of the Electrogram: An Acute Canine Study", werewritten in collaboration with electrophysiologists from Mayo Clinic and will be presented during scientific poster sessions from 4:30pm 7pm on July 10 and 12, respectively.

BioSig is extremely pleased to have two abstracts, featuring our PURE EP System, accepted into the Basic Cardiovascular Sciences Conference sponsored by the American Heart Association, stated Mr. Ken Londoner, Chief Executive Officer and Chairman of BioSig Technologies. Our collaboration with Mayo Clinic physicians has resulted in seven publications to date featuring BioSigs platform technology. And, we intend to strive towards improving visualization of cardiac signal information during EP procedures to help bring benefits to those patients who suffer with, and doctors who treat, arrhythmia.

About the Basic Cardiovascular Sciences Conference

The 13th Annual BCVS 2017 Scientific Sessions: Pathways to Cardiovascular Therapeutics has become the premier conference for molecular cardiovascular biology and disease. Sponsored by the American Heart Association Basic Cardiovascular Sciences Council, the worlds leading organization of cardiovascular scientists, this conference strives to improve basic cardiovascular regulation through new therapies and insights in cardiovascular disease, as well as research in fields like microRNAs, cardiac gene and cell therapy, cardiac development, as well as tissue engineering and iPS cells.

BCVS 2017 convenes basic and translational cardiovascular scientists from around the world with the common goal to discover pathways to cardiovascular therapeutics and promoting cardiovascular health. This meeting has become the go to meeting for intra- and interdisciplinary cross-fertilization of ideas and incorporation of new approaches from the general scientific community and plays a pivotal role in the training of junior scientists and trainees. The program includes a diversity of speakers representing the best cardiovascular scientists from around the world.

About BioSig Technologies

BioSig Technologies is a medical device company developing a proprietary technology platform designed to improve the $4+ billion electrophysiology (EP) marketplace ( http://www.biosigtech.com). Led by a proven management team and a veteran, independent Board of Directors, Minneapolis-based BioSig Technologies is preparing to commercialize its PURE EP(TM) System. The technology has been developed to address an unmet need in a large and growing market.

The PURE EP System is a novel cardiac signal acquisition and display system which is engineered to assist electrophysiologists in clinical decision making during procedures to diagnose and treat patients with abnormal heart rates and rhythms. BioSigs main goal is to deliver technology to improve upon catheter ablation treatments for prevalent and deadly arrhythmias. BioSig has partnered with Minnetronix on technology development and is working toward FDA 510(k) clearance and CE Mark for the PURE EP System.

Forward-looking Statements

This press release contains forward-looking statements. Such statements may be preceded by the words intends, may, will, plans, expects, anticipates, projects, predicts, estimates, aims, believes, hopes, potential or similar words. Forward-looking statements are not guarantees of future performance, are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Companys control, and cannot be predicted or quantified

Read more from the original source:
Novel Findings Obtained with the PURE EP System to be Presented at American Heart Association's BCVS Scientific ... - Cardiovascular Business

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Stem Cell Research is an amazing field right now, and promises to be a powerful and potent tool to help us live longer and healthier lives. Just last month, for example, Stem Cell Therapy was used to restore sight in patients with severe retinal deterioration, allowing them to see clearer than they had in years, or even decades.

Now, there is another form of Stem Cell Treatment on the horizonthis one of a very different form. Stem Cells have now been used as a mechanism to deliver medical treatment designed to eliminate cancer cells, even in hard to reach places. One issue with current cancer treatments is that, treatments that are effective at treating tumors on the surface of the brain cannot be performed safely when the tumor is deeper within the brains tissues.

Stem Cells have the fantastic ability to transform into any other kind of cell within the human body, given the appropriate stimulation. As of today, most of these cells come from Embryonic Lines, but researchers are learning how to backwards engineer cells in the human body, reverting them back to their embryonic state. These cells are known as Induced Pluripotent Stem Cells.

How Does This Stem Cell Cancer Treatment Work?

Using genetic engineering, it is possible to create stem cells that are designed to release a chemical known as Pseudomonas Exotoxin, which has the ability to destroy certain tumor cells in the human brain.

What is Pseudomonas Exotoxin?

Pseudomonas Exotoxin is a compound that is naturally released by a form of bacteria known as Pseudomonas Aeruginosa. This chemical is toxic to brain tumor cells because it prevents polypeptides from growing longer, essentially preventing the polypeptides from growing and reproducing. When used in a specific manner, this toxin has the ability to destroy cancerous and malignant tissue without negatively impacting healthy tissue. In addition to its potential as a cancer treatment, there is also evidence that the therapy could be used for the treatment of Hepatitis B.

PE and Similar Toxins Have been Used Therapeutically in the Past

As of now, this chemical, which we will refer to for the rest of the article as PE, has been used as a cancer treatment before, but there are major limitations regarding the use of PE for particular cancers, not because of the risks of the treatment, but because of the lack of an effective method to deliver the medication to where it is needed.

For example, similar chemicals have been highly effective in the treatment of a large number of blood cancers, but havent been nearly as effective in larger, more inaccessible tumors. The chemicals break down or become metabolized before they can fully do their job.

How do Stem Cells Increase the Effectiveness of PE Cancer Treatment

Right now, PE has to be created in a laboratory before it is administered, which is not very effective for these embedded cancers. By using Stem Cells as an intermediary, it is possible to deliver the medication to deeper areas of the brain more effectively, theoretically highly increasing the efficacy of the treatment.

The leader of this Stem Cell Research is Harvard researcher Dr. Khalis Shah. His goal was to find an effective means to treat these deep brain tumors which are not easily treated by methods available today. In utilizing Stem Cells, Dr. Shah has potentially found a means by which the stem cells can constantly deliver this Cancer Toxin to the tumor area. The cells remain active and are fed by the body, which allows them to provide a steady stream of treatment that is impossible to provide via any other known method.

This research is still in its early stages, and has not yet reached human trials, but in mice, the PE Toxin worked exactly as hypothesized and was able to starve out tumors by preventing them from replicating effectively.

Perhaps this might seem a bit less complicated than it actually is. One of the major hurdles that had to be overcome was that this Toxin would normally be strong enough to kill the cell that hosted it. In order for the Stem Cells to release the cancer, they had to be able to withstand the effects of PE, themselves. Using genetic engineering, Dr. Shah and his associates were able to create a cell that is capable of both producing and withstanding the effects of the toxin.

Stem Cell delivered medical therapy is a 21st century form of medical treatment that researchers are just beginning to learn how to effectively utilize. Essentially, this treatment takes a stem cell and converts it into a unique symbiotic tool capable of feeding off of the host for energy in order to perform a potentially life-saving function. Its really quite fascinating.

How Does PE Not Damage or Kill Brain Cells Indiscriminately?

You might be concerned about the idea of a patient having a toxin injected into the brain to cure a disease. It sounds almost like a dangerous, tribal, homeopathic remedy. In reality, the researchers have been able to harness the destructive power of the toxin and re-engineer it so that it directly targets cancer cells while having limited negative effects on healthy, non-cancerous tissue.

The toxin does its damage after it has been absorbed by a cell. By retooling the toxin so that it does not readily absorb into healthy cells, the dangers associated with having such a potentially dangerous toxin in the brain are seriously and significantly mitigated.

Beyond that, Dr. Shah and his associates have been able to take steps to effectively turn off PE while it is inside the host stem cell, and only activates when it has entered the cancerous tissue. Dr. Shah explains that, although this research has only been conducted in animal subjects, there is no known reason why the effectiveness and safety of the treatment would not be applicable to human patients.

In this treatment, surgeons remove as much of the tumor as possible from the brain, and insert the engineered Stem Cells submerged in a sterile gel in the area where the tumor was removed or partially still exists. Researchers found that, when they used this treatment on laboratory rats, they could tell through imaging and analysis that the modified PE toxin effectively killed the cancer cells, and that this cancer treatment effectively lengthened the life of the rat, as compared to control subjects.

Whats the Next Step?

Of course, cancer treatment is far more complex than a single treatment, no matter how effective that treatment may be. Because human cancer treatment is a comprehensive therapy approach, the end goal of this research is to create a form of therapy in which the method used in animal subjects is combined with other existing approaches, increasing and maximizing the effectiveness of the comprehensive treatment.

Featured post

A recent change in how well we understand stem cells may make it easier for scientists and researchers to gather stem cells for use in scientific research as well as medical application. A new study was released in the research publication, Cell, which was performed by representatives from the University of California San Francisco.

One of the issues which hinder the use of stem cells as a more widespread treatment or field of research is that researchers and patients have a bottleneck of available healthy stem cell lines which can be used for research. Researchers hope that this new discovery will allow future scientific discoveries and applications in the areas of creating new and healthy tissue for patients with kidney failure or any other form of organ tissue failure. The future of medical therapy lies with Stem Cell Research, but many other forms of treatment, including Hormone Replacement Therapy, are already in practice today.

Researchers have discovered that it is possible to essentially flip a switch in an adult cell, reverting it back to the preliminary state at which cells existed in one of the earliest stages of developmentthe embryonic stem cell. Medical researchers hypothesize that Stem Cell treatments could be used for a variety of medical health issues which plague the world today, including kidney failure, liver disease, and Type-1 and Type-2 Diabetes.

Use of Embryonic Stem Cells Contentious

There is an ethical issue in Stem Cell Research today. Many Pro-Life Advocates are vociferously against the use of Embryonic Stem Cells harvested from procedures such as fertility treatments designed for conception. They believe that the use of embryonic stem cells harvested from donors and couples looking to conceive is unethical.

Using current research, it may be possible to bypass this ethical quandary completely by using adult cells and converting them into embryonic stem cells. Furthermore, because these stem cells are genetic derivatives of the patient from which the adult cells were harvested, this potentially paves the way for patient-specific medical treatments using stem cells.

After adult cells have been converted back into Embryonic Stem Cells, it will be possible to convert them into any possible cell that the patient needs or would benefit from.

Hijacking the Blueprint of the Cell Allows Scientists to Revert Adult Cells to their Earliest State

Researchers have increased the capacity to produce Embryonic Stem Cells by identifying previously unrecognized biochemical processes which tell human cells how to develop. In essence, researchers have discovered how the body blueprints cells, and can change the blueprints so that a new cell is made.

By utilizing these newly recognized pathways, it is possible to create new stem cells more quickly than ever before. One of the researchers explains the implications of this research. Dr. Miguel Ramalho-Santos is an associate professor of obstetrics, medicine, and cancer research at the University of California San Francisco. Dr. Ramalho-Santos is also a member of the Broad Center of Regenerative Medicine and Stem Cell Research.

He explains that these stem cell discoveries have the ability to alter the way that the medical sciences can take advantage of stem cells with regard to both cancer research and regenerative medicine. Dr. Ramalho-Santos was the lead researcher for this study, and the research was largely funded by the Director of the National Institutes of Health New Innovator Award, granted to promising young researchers which are leading highly innovative and promising medical research studies.

Dr. Ramalho-Santos research builds off of earlier research which discovered that it was possible to take adult cells and turn them back into embryonic stem cells. These stem cells dont have any inherent aging processes, and they can be turned into any other kind of tissue. In the process of this conversion, the adult cells lose all of their unique characteristics, leaving them in an ultimately immature and malleable state.

This earlier research was conducted by researchers from UC San Francisco in partnership with Dr. Shinya Yamanaka from Kyoto University and Gladstone Institutes. These entities all gained a piece of the Nobel Prize in Physiology or Medicine from their part in the study.

Pluripotent Stem Cells vs. Embryonic Stem Cells

Thus far, weve described these cells as Embryonic Stem Cells, but in fact, the more accurate term for these cells are Induced Pluripotent Stem Cells (IPS). These cells are biologically and functionally similar to Embryonic Stem Cells, but have a different name because they are sourced from adult cells. The difference between Induced Pluripotent Stem Cells and Embryonic Stem Cells is that Induced Pluripotent Stem Cells do seem to retain some of the characteristics of their previous state, which appears to limit their ability to convert into any other type of cell. This new research identifies new pathways by which it may be possible to increase the number of cells that an individual IPS Cell can turn into, perhaps allowing them to convert into any other kind of human cell.

Induced Pluripotent Stem Cells are not explicitly considered an alternative to Embryonic Stem Cells, but are considered a different approach to produce similar cells. If researchers fully uncover the mechanisms of how to reprogram these cells, it will lower many barriers to stem cell research and the availability of stem cell treatments.

As of today, researchers have figured out how to make these Induced Pluripotent Stem Cells, but the percentage of adult cells which are reverted successfully is quite low, and frequently, these cells still show some aspects of specialization, which limits their use.

How Do Scientists Make Stem Cells From Adult Cells?

There are genes within every cell which have the ability to induce pluripotency, reverting the cell to an earlier stage of specialization. The initial stage of this process is the result of activating Yamanaka Factors, specific genes that initiate this reversion process.

As of today, this process of de-maturation is not completely understood, and researchers realized from the start that the cells they created were not truly identical to Embryonic Stem Cells, because they still showed signs of their former lives, which often prevented them from being successfully reprogrammed.

The new research conducted by Dr. Ramalho-Santos appears to increase our knowledge regarding how these cells work, and how to program them more effectively. Dr. Ramalho-Santos and his team discovered more genes associated with these programming/reprogramming processes, and by manipulating them, they have increased the viability and range of particular stem cells.

It appears that these genetic impulses are constantly at play to maintain the structure and function of a cell, and that by systematically removing these safeguards, it is possible to increase the ability to alter these cells.

This research increases researchers ability to produce these stem cells, by increasing the ability of medical scientists to produce adequate numbers of stem cells, while also increasing the range of potential treatment options by more effectively inducing the total pluripotency which is available in Embryonic Stem Cells. This research may also help scientists treat certain forms of cancer which are the result of malfunctions of these genes.

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The genetics of skin cancer is an extremely broad topic. There are more than 100 types of tumors that are clinically apparent on the skin; many of these are known to have familial components, either in isolation or as part of a syndrome with other features. This is, in part, because the skin itself is a complex organ made up of multiple cell types. Furthermore, many of these cell types can undergo malignant transformation at various points in their differentiation, leading to tumors with distinct histology and dramatically different biological behaviors, such as squamous cell carcinoma (SCC) and basal cell cancer (BCC). These have been called nonmelanoma skin cancers or keratinocytic cancers.

Figure 1 is a simple diagram of normal skin structure. It also indicates the major cell types that are normally found in each compartment. Broadly speaking, there are two large compartmentsthe avascular cellular epidermis and the vascular dermiswith many cell types distributed in a largely acellular matrix.[1]

Figure 1. Schematic representation of normal skin. The relatively avascular epidermis houses basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for BCC and SCC, respectively. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

The outer layer or epidermis is made primarily of keratinocytes but has several other minor cell populations. The bottom layer is formed of basal keratinocytes abutting the basement membrane. The basement membrane is formed from products of keratinocytes and dermal fibroblasts, such as collagen and laminin, and is an important anatomical and functional structure. As the basal keratinocytes divide and differentiate, they lose contact with the basement membrane and form the spinous cell layer, the granular cell layer, and the keratinized outer layer or stratum corneum.

The true cytologic origin of BCC remains in question. BCC and basal cell keratinocytes share many histologic similarities, as is reflected in the name. Alternatively, the outer root sheath cells of the hair follicle have also been proposed as the cell of origin for BCC.[2] This is suggested by the fact that BCCs occur predominantly on hair-bearing skin. BCCs rarely metastasize but can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name rodent ulcer.[3]

Some debate remains about the origin of SCC; however, these cancers are likely derived from epidermal stem cells associated with the hair follicle.[4] A variety of tissues, such as lung and uterine cervix, can give rise to SCC, and this cancer has somewhat differing behavior depending on its source. Even in cancer derived from the skin, SCC from different anatomic locations can have moderately differing aggressiveness; for example, SCC from glabrous (smooth, hairless) skin has a lower metastatic rate than SCC arising from the vermillion border of the lip or from scars.[3]

Additionally, in the epidermal compartment, melanocytes distribute singly along the basement membrane and can transform into melanoma. Melanocytes are derived from neural crest cells and migrate to the epidermal compartment near the eighth week of gestational age. Langerhans cells, or dendritic cells, are a third cell type in the epidermis and have a primary function of antigen presentation. These cells reside in the skin for an extended time and respond to different stimuli, such as ultraviolet radiation or topical steroids, which cause them to migrate out of the skin.[5]

The dermis is largely composed of an extracellular matrix. Prominent cell types in this compartment are fibroblasts, endothelial cells, and transient immune system cells. When transformed, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma, and other vascular tumors. There are a number of immune cell types that move in and out of the skin to blood vessels and lymphatics; these include mast cells, lymphocytes, mononuclear cells, histiocytes, and granulocytes. These cells can increase in number in inflammatory diseases and can form tumors within the skin. For example, urticaria pigmentosa is a condition that arises from mast cells and is occasionally associated with mast cell leukemia; cutaneous T-cell lymphoma is often confined to the skin throughout its course. Overall, 10% of leukemias and lymphomas have prominent expression in the skin.[6]

Epidermal appendages are also found in the dermal compartment. These are derivatives of the epidermal keratinocytes, such as hair follicles, sweat glands, and the sebaceous glands associated with the hair follicles. These structures are generally formed in the first and second trimesters of fetal development. These can form a large variety of benign or malignant tumors with diverse biological behaviors. Several of these tumors are associated with familial syndromes. Overall, there are dozens of different histological subtypes of these tumors associated with individual components of the adnexal structures.[7]

Finally, the subcutis is a layer that extends below the dermis with varying depth, depending on the anatomic location. This deeper boundary can include muscle, fascia, bone, or cartilage. The subcutis can be affected by inflammatory conditions such as panniculitis and malignancies such as liposarcoma.[8]

These compartments give rise to their own malignancies but are also the region of immediate adjacent spread of localized skin cancers from other compartments. The boundaries of each skin compartment are used to define the staging of skin cancers. For example, an in situ melanoma is confined to the epidermis. Once the cancer crosses the basement membrane into the dermis, it is invasive. Internal malignancies also commonly metastasize to the skin. The dermis and subcutis are the most common locations, but the epidermis can also be involved in conditions such as Pagetoid breast cancer.

The skin has a wide variety of functions. First, the skin is an important barrier preventing extensive water and temperature loss and providing protection against minor abrasions. These functions can be aberrantly regulated in cancer. For example, in the erythroderma associated with advanced cutaneous T-cell lymphoma, alterations in the regulations of body temperature can result in profound heat loss. Second, the skin has important adaptive and innate immunity functions. In adaptive immunity, antigen-presenting cells engender a TH1, TH2, and TH17 response.[9] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Consequently, even small breaks in the skin can lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system. It may also be important in immune surveillance against cancer. Immunosuppression, which occurs during organ transplant, is a significant risk factor for skin cancer. The skin is significant for communication through facial expression and hand movements. Unfortunately, areas of specialized function, such as the area around the eyes and ears, are common places for cancer to occur. Even small cancers in these areas can lead to reconstructive challenges and have significant cosmetic and social ramifications.[1]

While the appearance of any one skin cancer can vary, there are general physical presentations that can be used in screening. BCCs most commonly have a pearly rim (see Figure 3) or can appear somewhat eczematous. They often ulcerate (see Figure 3). SCCs frequently have a thick keratin top layer (see Figure 4). Both BCCs and SCCs are associated with a history of sun-damaged skin. Melanomas are characterized by asymmetry, border irregularity, color variation, a diameter of more than 6 mm, and evolution (ABCDE criteria). (Refer to What Does Melanoma Look Like? on NCIs website for more information about the ABCDE criteria.) Photographs representing typical clinical presentations of these cancers are shown below.

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Figure 2. Superficial basal cell carcinoma (left panel) and nodular basal cell carcinoma (right panel).

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Figure 3. Ulcerated basal cell carcinoma (left panel) and ulcerated basal cell carcinoma with characteristic pearly rim (right panel).

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Figure 4. Squamous cell carcinoma on the face with thick keratin top layer (left panel) and squamous cell carcinoma on the leg (right panel).

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Figure 5. Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.

Basal cell carcinoma (BCC) is the most common malignancy in people of European descent, with an associated lifetime risk of 30%.[1] While exposure to ultraviolet (UV) radiation is the risk factor most closely linked to the development of BCC, other environmental factors (such as ionizing radiation, chronic arsenic ingestion, and immunosuppression) and genetic factors (such as family history, skin type, and genetic syndromes) also potentially contribute to carcinogenesis. In contrast to melanoma, metastatic spread of BCC is very rare and typically arises from large tumors that have evaded medical treatment for extended periods of time. BCCs can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name rodent ulcer. With early detection, the prognosis for BCC is excellent.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types. There are different patterns of sun exposure associated with each major type of skin cancer (BCC, squamous cell carcinoma [SCC], and melanoma).

While there is no standard measure, sun exposure can be generally classified as intermittent or chronic, and the effects may be considered acute or cumulative. Intermittent sun exposure is obtained sporadically, usually during recreational activities, and particularly by indoor workers who have only weekends or vacations to be outdoors and whose skin has not adapted to the sun. Chronic sun exposure is incurred by consistent, repetitive sun exposure, during outdoor work or recreation. Acute sun exposure is obtained over a short time period on skin that has not adapted to the sun. Depending on the time of day and a persons skin type, acute sun exposure may result in sunburn. In epidemiology studies, sunburn is usually defined as burn with pain and/or blistering that lasts for 2 or more days. Cumulative sun exposure is the additive amount of sun exposure that one receives over a lifetime. Cumulative sun exposure may reflect the additive effects of intermittent sun exposure, chronic sun exposure, or both.

Specific patterns of sun exposure appear to lead to different types of skin cancer among susceptible individuals. Intense intermittent recreational sun exposure has been associated with melanoma and BCC,[2,3] while chronic occupational sun exposure has been associated with SCC. Given these data, dermatologists routinely counsel patients to protect their skin from the sun by avoiding mid-day sun exposure, seeking shade, and wearing sun-protective clothing, although evidence-based data for these practices are lacking. The data regarding skin cancer risk reduction by regular sunscreen use are variable. One randomized trial of sunscreen efficacy demonstrated statistically significant protection for the development of SCC but no protection for BCC,[4] while another randomized study demonstrated a trend for reduction in multiple occurrences of BCC among sunscreen users [5] but no significant reduction in BCC or SCC incidence.[6]

Level of evidence (sun-protective clothing, avoidance of sun exposure): 4aii

Level of evidence (sunscreen): 1aii

Tanning bed use has also been associated with an increased risk of BCC. A study of 376 individuals with BCC and 390 control subjects found a 69% increased risk of BCC in individuals who had ever used indoor tanning.[7] The risk of BCC was more pronounced in females and individuals with higher use of indoor tanning.[8]

Environmental factors other than sun exposure may also contribute to the formation of BCC and SCC. Petroleum byproducts (e.g., asphalt, tar, soot, paraffin, and pitch), organophosphate compounds, and arsenic are all occupational exposures associated with cutaneous nonmelanoma cancers.[9-11]

Arsenic exposure may occur through contact with contaminated food, water, or air. While arsenic is ubiquitous in the environment, its ambient concentration in both food and water may be increased near smelting, mining, or coal-burning establishments. Arsenic levels in the U.S. municipal water supply are tightly regulated; however, control is lacking for potable water obtained through private wells. As it percolates through rock formations with naturally occurring arsenic, well water may acquire hazardous concentrations of this material. In many parts of the world, wells providing drinking water are contaminated by high levels of arsenic in the ground water. The populations in Bangladesh, Taiwan, and many other locations have high levels of skin cancer associated with elevated levels of arsenic in the drinking water.[12-16] Medicinal arsenical solutions (e.g., Fowlers solution and Bells asthma medication) were once used to treat common chronic conditions such as psoriasis, syphilis, and asthma, resulting in associated late-onset cutaneous malignancies.[17,18] Current potential iatrogenic sources of arsenic exposure include poorly regulated Chinese traditional/herbal medications and intravenous arsenic trioxide utilized to induce remission in acute promyelocytic leukemia.[19,20]

Aerosolized particulate matter produced by combustion of arsenic-containing materials is another source of environmental exposure. Arsenic-rich coal, animal dung from arsenic-rich regions, and chromated copper arsenatetreated wood produce airborne arsenical particles when burned.[21-23] Burning of these products in enclosed unventilated settings (such as for heat generation) is particularly hazardous.[24]

Clinically, arsenic-induced skin cancers are characterized by multiple recurring SCCs and BCCs occurring in areas of the skin that are usually protected from the sun. A range of cutaneous findings are associated with chronic or severe arsenic exposure, including pigmentary variation (poikiloderma of the skin) and Bowen disease (SCC in situ).[25]

However, the effect of arsenic on skin cancer risk may be more complex than previously thought. Evidence from in vivo models indicate that arsenic, alone or in combination with itraconazole, can inhibit the hedgehog pathway in cells with wild-type or mutated Smoothened by binding to GLI2 proteins; in this way, these drugs demonstrated inhibition of BCC growth in these animal models.[26,27] Additionally, the effect of arsenic on skin cancer risk may be modified by certain variants in nucleotide excision repair genes (xeroderma pigmentosum [XP] types A and D).[28]

The high-risk phenotype consists of individuals with the following physical characteristics:

Specifically, people with more highly pigmented skin demonstrate lower incidence of BCC than do people with lighter pigmented skin. Individuals with Fitzpatrick skin types I or II were shown to have a twofold increased risk of BCC in a small case-control study.[29] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) Blond or red hair color was associated with increased risk of BCC in two large cohorts: the Nurses Health Study and the Health Professionals Follow-Up Study.[30]

Immunosuppression also contributes to the formation of nonmelanoma (keratinocyte) skin cancers. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than in the general population.[31-33] Nonmelanoma skin cancers in high-risk patients (i.e., solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age and are more common, more aggressive, and have a higher risk of recurrence and metastatic spread than nonmelanoma skin cancers in the general population.[34,35] Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

This increased risk has been linked to the level of immunosuppression and UV exposure. As the duration and dosage of immunosuppressive agents increases, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[31,36] The risk appears to be highest in geographic areas of high UV radiation exposure: when comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC.[37] This speaks to the importance of rigorous sun avoidance among high-risk immunosuppressed individuals.

Individuals with BCCs and/or SCCs report a higher frequency of these cancers in their family members than do controls. The importance of this finding is unclear. Apart from defined genetic disorders with an increased risk of BCC, a positive family history of any skin cancer is a strong predictor of the development of BCC.

A personal history of BCC or SCC is strongly associated with subsequent BCC or SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these nonmelanoma skin cancers is the mid-60s.[38-43] In addition, several studies have found that individuals with a history of skin cancer have an increased risk of a subsequent diagnosis of a noncutaneous cancer;[44-47] however, other studies have contradicted this finding.[48-51] In the absence of other risk factors or evidence of a defined cancer susceptibility syndrome, as discussed below, skin cancer patients are encouraged to follow screening recommendations for the general population for sites other than the skin.

Mutations in the gene coding for the transmembrane receptor protein PTCH1, or PTCH, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. PTCH1, the human homolog of the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway, which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation) and regulatory (maintenance of stem cells) roles.

In the resting state, the transmembrane receptor protein PTCH1 acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction.[52] Stoichiometric binding of the hedgehog ligand to PTCH1 releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[53,54] Thus, the balance of PTCH1 (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH1 or gain-of-function mutations of Smo tip this balance toward constitutive activation, a key event in potential neoplastic transformation.

Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[55,56] Further investigation identified a mutation in PTCH1 that localized to the area of allelic loss.[57] Up to 30% of sporadic BCCs demonstrate PTCH1 mutations.[58] In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other tumors, have been associated with PTCH1 mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH1 mutations, predominantly truncation in type.[59]

Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, have been demonstrated in both BCC and medulloblastoma.[60,61] PTCH2 displays 57% homology to PTCH1, differing in the conformation of the hydrophilic region between transmembrane portions 6 and 7, and the absence of C-terminal extension.[62] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[60,63]

BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals.[64] The syndrome is notable for complete penetrance and extremely variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[59,65] The clinical features of BCNS differ more among families than within families.[66] BCNS is primarily associated with germline mutations in PTCH1, but families with this phenotype have also been associated with alterations in PTCH2 and SUFU.[67-69]

As detailed above, PTCH1 provides both developmental and regulatory guidance; spontaneous or inherited germline mutations of PTCH1 in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS mutation has been localized to chromosome 9q22.3-q31, with a maximum logarithm of the odd (LOD) score of 3.597 and 6.457 at markers D9S12 and D9S53.[64] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH1.[70] The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH1 mutation as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[71-75] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[76]

The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (refer to Table 1 for a comparison of these criteria).[77-80] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying mutation carriers. The BCNS Colloquium Group proposed criteria in 2011 that required 1 major criterion with molecular diagnosis, two major criteria without molecular diagnosis, or one major and two minor criteria without molecular diagnosis.[80] PTCH1 mutations are found in 60% to 85% of patients who meet clinical criteria.[81,82] Most notably, BCNS is associated with the formation of both benign and malignant neoplasms. The strongest benign neoplasm association is with ovarian fibromas, diagnosed in 14% to 24% of females affected by BCNS.[74,78,83] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[84] Ameloblastomas, aggressive tumors of the odontogenic epithelium, have also been proposed as a diagnostic criterion for BCNS, but most groups do not include it at this time.[85]

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