Cardiovascular diseases represent the world's leading cause of death. In this heterogeneous group of diseases, ischemic cardiomyopathies are the most devastating and prevalent, estimated to cause 17.9 million deaths per year. Despite all biomedical efforts, there are no effective treatments that can replace the myocytes lost during an ischemic event or progression of the disease to heart failure. In this context, cell therapy is an emerging therapeutic alternative to treat cardiovascular diseases by cell administration, aimed at cardiac regeneration and repair. In this review, we will cover more than 30 years of cell therapy in cardiology, presenting the main milestones and drawbacks in the field and signaling future challenges and perspectives. The outcomes of cardiac cell therapies are discussed in three distinct aspects: The search for remuscularization by replacement of lost cells by exogenous adult cells, the endogenous stem cell era, which pursued the isolation of a progenitor with the ability to induce heart repair, and the utilization of pluripotent stem cells as a rich and reliable source of cardiomyocytes. Acellular therapies using cell derivatives, such as microvesicles and exosomes, are presented as a promising cell-free therapeutic alternative.

Keywords: Cardiac stem cell; Cardiovascular diseases; Cell therapy; Pluripotent stem cells; Progenitor cardiac cells; Stem cell.

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Stem cell therapies in cardiac diseases: Current status and future ...

The limited regenerative capacity of the heart is a major factor in heart failure and death. Once cardiac cells are diseased, its hard for them to heal like your body would with a cut. Studying how the heart forms in fetuses and then matures is a natural step for researchers interested in generating and regenerating heart cells. Theyre also investigating the effect of stem cell-derived cardiac cells on repairing damaged hearts and their potential to treat heart muscle diseases.

Cardiovascular progenitor cells (CPCs), a type of heart cell, are called building blocks because theyre used to form the heart during fetal development. They hold tremendous therapeutic potential because of their unique ability to develop into several different heart cell types. Researchers are studying how CPC cells can renew themselves in mice. Theyre studying whether this renewal also occurs in humans and whether this is useful for repairing damaged hearts.

Because CPCs regenerate, scientists may be able to grow them in a dish. Its not as easy to grow cells in a lab as it is in the body they often have developmental arrest and dont mature. However, a recent discovery of the pathways that lead a fetal cell into an adult cell will enable researchers to recreate adult heart tissue in the lab, which holds tremendous potential for new heart disease treatment.

Videos Heart tissue grown in a dish

Heart tissue grown in a dish from mouse cardiac progenitor cells (CPCs). The CPCs, and the tissue they built, were engineered to produce a red protein.

View labs and centersAdult Cardiac Catheterization LabCiccarone CenterChulan Kwon LabHeart and Vascular InstituteCardiovascular Stem Cell Program

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Stem Cell and Regenerative Biology | Johns Hopkins Heart and Vascular ...

Reparative stem cells have the capability to restore function to damaged tissue by renewing cell growth (shown in green) in cardiac cells destroyed by heart disease.

Approximately 28 million Americans have been diagnosed with heart disease. Traditional medical therapies are not able to fully address the burden of disease, and the shortage of organs for transplantation remains a key barrier more than 117,000 people are on the national transplant list.

This unmet need drives Mayo Clinic researchers to make new discoveries to accelerate regenerative solutions into clinical trials and rapidly provide new hope to patients who can't currently be treated.

Cardiac regeneration is a broad effort that aims to repair irreversibly damaged heart tissue with cutting-edge science, including stem cell and cell-free therapy. Reparative tools have been engineered to restore damaged heart tissue and function using the body's natural ability to regenerate. Working together, patients and providers are finding regenerative solutions that restore, renew and recycle patients' own reparative capacity. Through the vision and generous support of Russ and Kathy Van Cleve, strong efforts are underway to develop discoveries that will have a global impact on ischemic heart disease.

Mayo Clinic researchers are leading efforts in translating new knowledge into applicable therapeutics through a multidisciplinary community of practice. As technology evolves, it offers the potential to regenerate cardiac tissue from noncardiac sources and ultimately provide personalized products and services to people with cardiovascular disease.

The overarching vision for the cardiac regeneration program at Mayo Clinic is to develop new therapies to cure ischemic heart disease. Mayo researchers are developing products for clinical testing that span the disease spectrum, including the following areas:

More information about cardiac regenerative medicine research at Mayo Clinic is on the Van Cleve Cardiac Regenerative Medicine Program website.

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Center for Regenerative Biotherapeutics - Cardiac Regeneration

Hypoimmune human islet cells normalized glucose in diabetic humanized immunocompetent mouse model and avoided allogeneic and autoimmune rejection by the immune system

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Sana Biotechnology Announces Preclinical Data Published in Science Translational Medicine Showing its Hypoimmune Pancreatic Islet Cells Evaded...

The body is always in a state of change. In particular, the cells in your skin are constantly replacing themselves.

The skin does this through the process of regeneration and repair.

On a cellular level, the skin cells are constantly shedding, revealing fresh, newly grown skin cells underneath. This is why scars and blemishes may fade a bit with time.

Understanding the science behind your skins life cycle can help you to take care of your skin as it goes through the regeneration process. It can also help you boost your skins natural regeneration process and give you a fresh glow.

Heres what the skin care experts have to say about how to speed up skin regeneration.

According to 2015 research, skin regeneration refers to the complete replacement of damaged tissue with new tissue. Skin repair refers to the continued healing process of existing tissue. Skin regeneration isnt usually associated with scar tissue.

The research goes on to say that skin regeneration can happen in two ways:

Skin regeneration is a natural physical process that occurs on a cellular level.

The epidermis cells, or top layers of skin, continuously replace themselves, explains Laura Chacon-Garbato, a licensed esthetician and director of education at Herbalife. This process of renewal is the process of shedding the epidermis.

In other words, skin regeneration is a constant renewal of cells.

According to a 2010 review, the epidermis is maintained by stem cells in the lowest layer of the skin. These epidermal stem cells generate daughter cells that move upward toward the surface of the skin.

During this journey, cells that produce keratin undergo a series of biochemical and morphological changes that result in the formation of the various layers of the skin.

This gives skin a young, healthy glow, adds Jennifer Hurtikant, chief science officer at Prime Matter Labs.

The same study mentioned above estimated that the epidermis turns over every 40 to 56 days on average.

When were young, the process of exfoliation happens naturally, but as we age this process is altered and slows down, Chacon-Garbato says.

An older 2006 study notes that the usual 28-day turnover time for skin increases approximately 30 percent to 50 percent by age 80.

For people over 50 years old, Chacon-Garbato says, the process can take as long as 84 days.

The effects of the slowdown cause buildup and an excess of dead skin cells that can make the skin look tired, dull, and opaque, she says.

Throughout this process, several things occur on a cellular level.

First, new skin cells are formed deep in the epidermis.

Then, as the skin cells mature and die on the upper layer of the epidermis, they naturally fall away.

If you have a cut or burn, you may be left with a scar.

This is because fibroblasts in scar tissue form collagen differently than in regular tissue. As a result, its thicker and less flexible than regular skin tissue.

However, by improving skin regeneration, you may notice that scars gradually fade away as fresh, healthy skin tissue forms beneath them.

As you get older, skin regeneration slows down. This leaves an accumulation of dead skin cells on the upper layer of the skin.

By boosting the natural regeneration process, you can help the skin look fresh and feel elastic, even as you age.

Making healthy choices can help to keep the skin regeneration process functioning optimally.

Hurtikant suggests:

There are two types of aging, cellular or intrinsic aging and environmental or extrinsic aging.

Intrinsic aging is a genetically predetermined process that occurs naturally, but may increase with stress. Extrinsic aging is a result of outside factors, like where you live and your lifestyle habits.

Stress causes intrinsic aging and the environment causes extrinsic aging, Hurtikant says.

Chacon-Garbato recommends eating plenty of protein, such as:

Proteins are essential for tissue repair and the construction of new tissue, she says. Cells need protein to maintain their life, so the body uses protein to replace worn-out or dead skin cells.

In addition, favor foods that are high in antioxidants, like:

Including antioxidants in your diet may help improve the glow and luster of the skin.

Specific skin care products can also help improve the natural cell turnover process, hydrate the skin, and get rid of built-up dead skin cells. Look for ingredients like:

Use products with vitamin B3, Chacon-Garbato suggests. Its a necessary component of cell metabolism, also known as niacinamide, and is required for many skin processes that help maintain healthy-looking skin.

She also suggests using antioxidants such as vitamin C and E to prevent cellular damage from free radicals.

Try Swisse Beauty Skin Regeneration+, an oral supplement with ALA, and Musely FaceRx Anti-Aging Night Cream with tretinoin, hyaluronic acid, and niacinamide.

These natural remedies may help boost your skins health and promote the skin regeneration process:

A 2022 study found that several plant extracts, including papaya, showed antioxidant, and antiwrinkle effects. Extracts that used ethanol as a cosolvent showed greater effects.

A 2018 review found that jojoba, rosehip, and coconut oil may help with skin barrier repair, wound healing, antioxidant effects, and antiaging.

A 2010 study noted that orange peel extract could provide useful protection against or alleviation of UV damage.

You can look for natural skin care products that contain these ingredients.

Citrus can increase photosensitivity, or sensitivity to light. Use caution when applying citrus in any form to the skin by avoiding direct sun exposure and using sun protection. Never apply citrus oils directly to the skin.

If you want to exfoliate a little deeper, a dermatologist may be able to offer a more intensive skin resurfacing procedure to kick-start skin rejuvenation. Make sure you find a dermatologist who is board certified.

Chacon-Garbato suggests:

However, she notes, theres no one-size-fits-all for the skin, so its important to check with your dermatologist to help define the best approach for the results you want to achieve.

Want to know more? Get the FAQs below.

Aloe vera encourages cell diversity and helps keep the skin well hydrated and protected.

According to a 2020 study, it also boasts natural antioxidant and anti-inflammatory properties.

Aloe vera is an excellent ingredient to use daily because its well known for its revitalizing and calming properties, Chacon-Garbato says. Its also a hugely effective hydrator and helps to minimize skin dryness.

She notes that its been used for centuries for beauty because of its many benefits, including delivering moisture directly to the tissue and helping prevent water loss due to evaporation.

Hurtikant adds that while aloe vera is great for boosting regeneration, there are other ingredients to try too.

Trending ingredients for skin regeneration are derivatives of algae and mushrooms, and hyaluronic acid, she says.

There are plenty of skin care products that have been shown to improve the appearance of aging in the skin by speeding up the natural skin regeneration process.

One highly rated product is Musely FaceRx Anti-Aging Night Cream, which includes active ingredients such as tretinoin (Retin-A), niacinamide, and hyaluronic acid.

These three ingredients are all excellent for encouraging exfoliation. Keep an eye out for them on the ingredients list when youre looking for good creams to promote regeneration.

For most adults under 50 years old, the cycle lasts between 28 and 42 days. For adults over 50 years old, this may increase to up to 84 days, though the number varies.

The time it takes for your skin to complete the skin regeneration cycle depends on a range of factors, including:

There are a range of ways to improve skin regeneration.

Simple lifestyle changes like exercise and increased hydration can keep the process working properly.

Skin creams that include exfoliating ingredients can also help to get rid of excess dead skin.

Some procedures can also encourage faster growth of new skin cells to speed up the regeneration process.

Aging slows down the skin regeneration process, but it doesnt ever stop it completely.

However, because the process becomes much slower as we age, the skin can appear thicker, less flexible, and more wrinkled or textured.

This is because the slower the regeneration, the more dead skin cells remain on the face.

Skin regeneration is a natural cycle that occurs as the skin cells turn over. In other words, dead skin cells on the top layer of the epidermis fall away, revealing fresh, newly created cells beneath.

By supporting this cycle with a healthy lifestyle and skin care routine, you can encourage a lustrous glow even as you get older.

Just remember: while boosting skin regeneration is possible, its natural for the cycle to slow down as you age. A few wrinkles and some texture are nothing to be ashamed of.

You can even think of them as signs of wisdom and experience.

Meg is a freelance journalist and features writer who covers culture, entertainment, lifestyle and health. Her writing has appeared in Cosmopolitan, Shondaland, Healthline, HelloGiggles, Readers Digest, Apartment Therapy, and more. T: @wordsbyMeg W: megwalters.co.uk

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Skin Regeneration: The Science and How to Boost It - Healthline

HS-001 consists of clusters of purified heart muscle cells derived from induced pluripotent stem cells (iPSCs).

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Heartseed and Novo Nordisk announce first patient dosed in clinical study with HS-001 – a cell therapy designed to restore heart function in people...

Overview The three layers of skin on top of muscle tissue.What is the skin?

The skin is the bodys largest organ, made of water, protein, fats and minerals. Your skin protects your body from germs and regulates body temperature. Nerves in the skin help you feel sensations like hot and cold.

Your skin, along with your hair, nails, oil glands and sweat glands, is part of the integumentary (in-TEG-you-MEINT-a-ree) system. Integumentary means a bodys outer covering.

Three layers of tissue make up the skin:

Your epidermis is the top layer of the skin that you can see and touch. Keratin, a protein inside skin cells, makes up the skin cells and, along with other proteins, sticks together to form this layer. The epidermis:

The dermis makes up 90% of skins thickness. This middle layer of skin:

The bottom layer of skin, or hypodermis, is the fatty layer. The hypodermis:

One inch of your skin has approximately 19 million skin cells and 60,000 melanocytes (cells that make melanin or skin pigment). It also contains 1,000 nerve endings and 20 blood vessels.

As the bodys external protection system, your skin is at risk for various problems. These include:

You lose collagen and elastin as you age. This causes the skins middle layer (dermis) to get thinner. As a result, the skin may sag and develop wrinkles.

While you cant stop the aging process, these actions can help maintain healthier skin:

You should call your healthcare provider if you experience:

A note from Cleveland Clinic

As the bodys largest organ, your skin plays a vital role in protecting your body from germs and the elements. It keeps your body at a comfortable temperature, and nerves beneath the skin provide the sense of touch. This external body covering can have serious problems like skin cancer, as well as more common issues like acne and skin rashes. Your healthcare provider can offer tips to help keep skin healthy.

Read more here:
Skin: Layers, Structure and Function - Cleveland Clinic

Top Questions

What is bone made of?

The two principal components of bone are collagen and calcium phosphate, which distinguish it from other hard tissues such as chitin, enamel, and shell.

What are the major functions of bone tissue?

Bone tissue makes up the individual bones of the skeletons of vertebrates. The other roles of bone include structural support for the mechanical action of soft tissues, protection of soft organs and tissues, provision of a protective site for specialized tissues such as the blood-forming system (bone marrow), and a mineral reservoir.

Do bones contain calcium?

Bone contains 99 percent of the calcium in the body and can behave as an adequate buffer for maintaining a constant level of freely moving calcium in soft tissues, extracellular fluid, and blood.

Why is calcium important for bone health?

The mechanical strength of bone is proportional to its mineral content. The Food and Nutrition Board of the U.S. National Academy of Sciences has recommended 1,0001,300 mg of calcium daily for adults and 7001,300 mg for children.

How does vitamin D deficiency affect bones in humans?

A deficiency in vitamin D results in poor mineralization of the bones of the skeleton, causing rickets in children and osteomalacia in adults.

Summary

bone, rigid body tissue consisting of cells embedded in an abundant hard intercellular material. The two principal components of this material, collagen and calcium phosphate, distinguish bone from such other hard tissues as chitin, enamel, and shell. Bone tissue makes up the individual bones of the human skeletal system and the skeletons of other vertebrates.

The functions of bone include (1) structural support for the mechanical action of soft tissues, such as the contraction of muscles and the expansion of lungs, (2) protection of soft organs and tissues, as by the skull, (3) provision of a protective site for specialized tissues such as the blood-forming system (bone marrow), and (4) a mineral reservoir, whereby the endocrine system regulates the level of calcium and phosphate in the circulating body fluids.

Bone is found only in vertebrates, and, among modern vertebrates, it is found only in bony fish and higher classes. Although ancestors of the cyclostomes and elasmobranchs had armoured headcases, which served largely a protective function and appear to have been true bone, modern cyclostomes have only an endoskeleton, or inner skeleton, of noncalcified cartilage and elasmobranchs a skeleton of calcified cartilage. Although a rigid endoskeleton performs obvious body supportive functions for land-living vertebrates, it is doubtful that bone offered any such mechanical advantage to the teleost (bony fish) in which it first appeared, for in a supporting aquatic environment great structural rigidity is not essential for maintaining body configuration. The sharks and rays are superb examples of mechanical engineering efficiency, and their perseverance from the Devonian Period attests to the suitability of their nonbony endoskeleton.

In modern vertebrates, true bone is found only in animals capable of controlling the osmotic and ionic composition of their internal fluid environment. Marine invertebrates exhibit interstitial fluid compositions essentially the same as that of the surrounding seawater. Early signs of regulability are seen in cyclostomes and elasmobranchs, but only at or above the level of true bone fishes does the composition of the internal body fluids become constant. The mechanisms involved in this regulation are numerous and complex and include both the kidney and the gills. Fresh and marine waters provide abundant calcium but only traces of phosphate; because relatively high levels of phosphate are characteristic of the body fluids of higher vertebrates, it seems likely that a large, readily available internal phosphate reservoir would confer significant independence of external environment on bony vertebrates. With the emergence of terrestrial forms, the availability of calcium regulation became equally significant. Along with the kidney and the various component glands of the endocrine system, bone has contributed to development of internal fluid homeostasisthe maintenance of a constant chemical composition. This was a necessary step for the emergence of terrestrial vertebrates. Furthermore, out of the buoyancy of water, structural rigidity of bone afforded mechanical advantages that are the most obvious features of the modern vertebrate skeleton.

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Bone | Definition, Anatomy, & Composition | Britannica

GAITHERSBURG, Md., Jan. 18, 2023 (GLOBE NEWSWIRE) -- NexImmune, Inc. (Nasdaq: NEXI), a biotechnology company developing a novel approach to immunotherapy designed to orchestrate a targeted immune response by directing the function of antigen-specific T cells, today announced the publication of an article highlighting the Company’s AIM platform as a new immunotherapy approach for viral diseases in Frontiers in Medicine. The article, titled “AIM Platform: A New Immunotherapy Approach for Viral Diseases,” focuses on the ability of AIM nanoparticles, which direct T cell response by mimicking the dendritic cell function, to consistently expand T cell populations with effector memory, central memory and self-renewing stem like memory phenotype directed at peptide-antigens from Epstein-Barr virus (EBV), human T-lymphotropic virus type 1 (HTLV-1) and human papillomavirus (HPV). Furthermore, T cells generated with the AIM platform are highly polyfunctional and display substantial in vitro cytotoxic activity against respective targeted antigens.

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NexImmune Announces Publication in Frontiers in Medicine Highlighting the Company’s AIM Platform to Treat Viral Diseases

Stem cells have been the object of much excitement and controversy amongst both scientists and the general population. Surprisingly, though, not everybody understands the basic properties of stem cells, let alone the fact that there is more than one type of cell that falls within the stem cell category. Here, Ill lay out the basic concepts of stem cell biology as a background for understanding the stem cell research field, where it is headed, and the enormous promise it offers for regenerative medicine.

Fertilization of an egg cell by a sperm cell results in the generation of a zygote, the single cell that, upon a myriad of divisions, gives rise to our whole body. Because of this amazing developmental potential, the zygote is said to be totipotent. Along the way, the zygote develops into the blastocyst, which implants into the mothers uterus. The blastocyst is a structure comprising about 300 cells that contains two main regions: the inner cell mass (ICM) and the trophoblast. The ICM is made of embryonic stem cells (ES cells), which are referred to as pluripotent. They are able to give rise to all the cells in an embryo proper, but not to extra-embryonic tissues, such as the placenta. The latter originate from the trophoblast [].

Even though it is hard to pinpoint exactly when or by whom what we now call stem cells were first discovered, the consensus is that the first scientists to rigorously define the key properties of a stem cell were Ernest McCulloch and James Till. In their pioneering work in mice in the 1960s, they discovered the blood-forming stem cell, the hematopoietic stem cell (HSC) [2, 3]. By definition, a stem cell must be capable of both self-renewal (undergoing cell division to make more stem cells) and differentiation into mature cell types. HSCs are said to be multipotent, as they can still give rise to multiple cell types, but only to other types of blood cells (see Figure 1, left column). They are one of many examples of adult stem cells, which are tissue-specific stem cells that are essential for organ maintenance and repair in the adult body. Muscle, for instance, also possesses a population of adult stem cells. Called satellite cells, these muscle cells are unipotent, as they can give rise to just one cell type, muscle cells.

Therefore, the foundations of stem cell research lie not with the famous (or infamous) human embryonic stem cells, but with HSCs, which have been used in human therapy (such as bone marrow transplants) for decades. Still, what ultimately fueled the enormous impact that the stem cell research field has today is undoubtedly the isolation and generation of pluripotent stem cells, which will be the main focus of the remainder of the text.

Figure 1: Varying degrees of stem cell potency. Left: The fertilized egg (totipotent) develops into a 300-cell structure, the blastocyst, which contains embryonic stem cells (ES cells) at the inner cell mass (ICM). ES cells are pluripotent and can thus give rise to all cell types in our body, including adult stem cells, which range from multipotent to unipotent. Right: An alternative route to obtain pluripotent stem cells is the generation of induced pluripotent stem cells (iPS cells) from patients. Cell types obtained by differentiation of either ES cell (Left) or iPS cells (Right) can then be studied in the dish or used for transplantation into patients. Figure drawn by Hannah Somhegyi.

Martin Evans (Nobel Prize, 2007) and Matt Kauffman were the first to identify, isolate and successfully culture ES cells using mouse blastocysts in 1981 []. This discovery opened the doors to the creation of murine genetic models, which are mice that have had one or several of their genes deleted or otherwise modified to study their function in disease []. This is possible because scientists can modify the genome of a mouse in its ES cells and then inject those modified cells into mouse blastocysts. This means that when the blastocyst develops into an adult mouse, every cell its body will have the modification of interest.

The desire to use stem cells unique properties in medicine was greatly intensified when James Thomson and collaborators first isolated ES cells from human blastocysts []. For the first time, scientists could, in theory, generate all the building blocks of our body in unlimited amounts. It was possible to have cell types for testing new therapeutics and perhaps even new transplantation methods that were previously not possible. Yet, destroying human embryos to isolate cells presented ethical and technical hurdles. How could one circumvent that procedure? Sir John Gurdon showed in the early 1960s that, contrary to the prevalent belief back then, cells are not locked in their differentiation state and can be reverted to a more primitive state with a higher developmental potential. He demonstrated this principle by injecting the nucleus of a differentiated frog cell into an egg cell from which the nucleus had been removed. (This is commonly known as reproductive cloning, which was used to generate Dolly the Sheep.) When allowed to develop, this egg gave rise to a fertile adult frog, proving that differentiated cells retain the information required to give rise to all cell types in the body. More than forty years later, Shinya Yamanaka and colleagues shocked the world when they were able to convert skin cells called fibroblasts into pluripotent stem cells by altering the expression of just four genes []. This represented the birth of induced pluripotent stem cells, or iPS cells (see Figure 1, right column). The enormous importance of these findings is hard to overstate, and is perhaps best illustrated by the fact that, merely six years later, Gurdon and Yamanaka shared the Nobel Prize in Physiology or Medicine 2012 [].

Since the generation of iPS cells was first reported, the stem cell eld has expanded at an unparalleled pace. Today, these cells are the hope of personalized medicine, as they allow one to capture the unique genome of each individual in a cell type that can be used to generate, in principle, all cell types in our body, as illustrated on the right panel of Figure 1. The replacement of diseased tissues or organs without facing the barrier of immune rejection due to donor incompatibility thus becomes approachable in this era of iPS cells and is the object of intense research [].

The first proof-of-principle study showing that iPS cells can potentially be used to correct genetic diseases was carried out in the laboratory of Rudolf Jaenisch. In brief, tail tip cells from mice with a mutation causing sickle cell anemia were harvested and reprogrammed into iPS cells. The mutation was then corrected in these iPS cells, which were then differentiated into blood progenitor cells and transplanted back into the original mice, curing them []. Even though iPS cells have been found not to completely match ES cells in some instances, detailed studies have failed to find consistent differences between iPS and ES cells []. This similarity, together with the constant improvements in the efficiency and robustness of generating iPS cells, provides bright prospects for the future of stem cell research and stem cell-based treatments for degenerative diseases unapproachable with more conventional methods.

Leonardo M. R. Ferreira is a graduate student in Harvard Universitys Department of Molecular and Cellular Biology

[] Stem Cell Basics: http://stemcells.nih.gov/info/basics/Pages/Default.aspx

[] Becker, A. J., McCulloch, E.A., Till, J.E. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 1963. 197: 452-4

[] Siminovitch, L., McCulloch, E.A., Till, J.E. The distribution of colony-forming cells among spleen colonies. J Cell Comp Physiol 1963, 62(3): 327-336

[] Evans, M. J. and Kaufman, M. Establishment in culture of pluripotential stem cells from mouse embryos. Nature 1981, 292: 151156

[] Simmons, D. The Use of Animal Models in Studying Genetic Disease: Transgenesis and Induced Mutation. Nature Education 2008,1(1):70

[] Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 1998, 282(5391): 1145-1147

[] Takahashi, K. and Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006. 126(4): 663-76

[] The Nobel Prize in Physiology or Medicine 2012:

[] Ferreira, L.M.R. and Mostajo-Radji, M.A. How induced pluripotent stem cells are redefining personalized medicine. Gene 2013. 520(1): 1-6 [] Hanna J. et al. Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 2007. 318: 1920-1923

[] Yee,J.Turning Somatic Cells into Pluripotent Stem Cells.Nature Education 2010.3(9):25

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Stem cells: a brief history and outlook - Science in the News

If you were to see the phrase Advanced Therapy Medicinal Product (ATMP) you might guess, an advanced treatment that is a medicine? but you will not get much more from this without doing a lot more homework.

Whoever decided that cell and gene therapy products should be described as Advanced Therapies was a little short sighted as to how this phrase would age and strangely so, once the phrase was coined and used by the FDA (note that the FDA has RMAT designation) it has been picked up and used all over the world. This is a bit of a disaster from a communications perspective for a society familiar with terms including stem cells, gene therapy, cell therapy, tissue engineering, all now being lumped to some extent under the banner Advanced Therapies. But, so it is and so we go forward. Now our focus is just to understand what Advanced Therapy Medicinal Products are and what they can offer!

ATMPs are next generation pharmaceuticals based on cells, gene therapy or tissue replacement. These pharmaceuticals offer novel technologies for new options for disease treatments. Where no treatment or no cure was available for a disease ATMPs may open new doors to enable:

You can find a more technology based classification at the end of this article.

You may have heard of some ATMPs CAR T (Yescarta, Kymriah), Luxturna gene therapy for blindness, Strimvelis gene therapy against bubble boy syndrome. These cell or recombinant (cut-paste) gene-based pharmaceuticals are revolutionizing treatments around the world and it is only early days. Patients who had no treatment options or patients who had exhausted all treatment options are finding new hope in ATMPs and many lives have been saved or transformed already. This field is moving incredibly fast; all of the major pharmaceutical companies have programs in ATMP. Interestingly, the COVID19 vaccines developed by AstraZeneca/Oxford, Pfizer/BioNTech, Moderna and Janssen are based on delivery of the same recombinant (cut-paste) gene technologies as some gene therapy ATMPs but the recombinant genes delivered for ATMPs introduce disease free human gene sequences to patients instead of coronavirus spike proteins.

The coronavirus pandemic is greatly accelerating capabilities of National healthcare agencies and clinics to be able to handle ATMP type technologies and treatment of basically the entire world population with such technologies is going to create unprecedented data on their safety. The Coronavirus pandemic is no doubt accelerating the ability to treat patients with untreatable or uncurable disease by at least 10 years.

Around the world promising initiatives to address the challenges of developing these complex gene and/or cell based pharmaceuticals have been popping up and rapidly developing in the last 10 years. Some well known examples include the British Cell and Gene Therapy Catapult, the Centre for Commercialization of Regenerative Medicine (CCRM) and the ATMP Sweden National Initiative. The breadth of need is extensive and unprecedented interactions required between pharmaceutical companies, hospitals, researchers and national authorities mean that technology is arguably right now not always the greatest challenge. There are many potential therapies trying to make their way to patients but the foundations for inclusion of these therapies in our society need to be worked out. How will we pay for an ungodly expensive therapy today that cures a patient in one treatment instead of treating this patient with a relatively cheap (or expensive) pill that they need to take every day for the rest of their life? In the end the curative therapy will be cheaper for society but the models on which our healthcare is based are not built with this type of opportunity in mind. A nice summary of the non-tech challenges in ATMP development can be seen in the program of the ATMP world tour April 26-30, 2021, where world leaders are coming together to discuss their approach to solutions. ATMP ATMP world tour 2021 (atmpsweden.se).

You may also find a video by the European Medicines Agency on ATMPs to be useful (below).

For those who want to go deeper into this topic of what ATMPs are from a technology or regulatory perspective this resource may also be useful ATMP What are ATMPs? (atmpsweden.se), including the Q&A to clarify what therapies are and are not regulated as ATMPs.

It is important to understand that ATMPs are pharmaceuticals or drugs, not all cell therapies are ATMPs. For example, a blood transfusion is a cell therapy but it is not a pharmaceutical so it is not an ATMP. Why is it not a pharmaceutical? The cells used for a blood transfusion have not been modified and will do the same job they did in the donor, thus this is just a transplant and the treating doctor is responsible for ensuring the safety and efficacy of the treatment is sufficiently risk free to benefit the patient. For more complex cell therapies , where manufacture is required or where cells are transplanted to a different organ, external and independent oversight is needed to ensure that these treatments have suitably low risk and sufficient benefit to the patient. These complex treatments are regarded as pharmaceuticals (i.e. drugs) and regulated by National/Regional public health agencies (FDA/EMA) who ensure the safety, efficacy, and security of these drug products. These treatments are now obliged to comply with Good Manufacturing Practice and undergo clinical trials towards market approval. This is EXPENSIVE and thus why many cowboys are trying to get around their treatments being classified as an ATMP as they do not want to spend their profits on proving it works or is safe if they can just buy a boat instead. Even if it did work, cowboys may treat a few thousand patients in their lifetime but a product that can be industrially produced and proven to be safe and efficacious could effectively treat millions.

We are imagining a healthcare future where we can modify a patients genome, replace diseased cells or tissues and/or selectively attack and remove defective cells. This is not a game. This is the reality of patients lives. Opportunities need to be brought forward ethically and safely. Today we can give a functional immune system to a baby born without one, and bring a terminally ill cancer patient into remission, but the potential in this industry to specifically target defective cells and genes, instead of pumping the whole body with drugs or radiation, means that in the next 10-20 years we will be looking at a very different approach to healthcare. Everyone is pepped for this, the patients, the doctors, the nurses, the caretakers. There are so many opportunities for new patient treatments that industry are working together to get this moving.

This is truly an exciting space to watch!

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Learning Objectives

By the end of this section, you will be able to:

The brain and the spinal cord are the central nervous system, and they represent the main organs of the nervous system. The spinal cord is a single structure, whereas the adult brain is described in terms of four major regions: the cerebrum, the diencephalon, the brain stem, and the cerebellum. A persons conscious experiences are based on neural activity in the brain. The regulation of homeostasis is governed by a specialized region in the brain. The coordination of reflexes depends on the integration of sensory and motor pathways in the spinal cord.

The iconic gray mantle of the human brain, which appears to make up most of the mass of the brain, is the cerebrum (Figure 14.3.1). The wrinkled portion is the cerebral cortex, and the rest of the structure is beneath that outer covering. There is a large separation between the two sides of the cerebrum called the longitudinal fissure. It separates the cerebrum into two distinct halves, a right and left cerebral hemisphere. Deep within the cerebrum, the white matter of the corpus callosum provides the major pathway for communication between the two hemispheres of the cerebral cortex.

Many of the higher neurological functions, such as memory, emotion, and consciousness, are the result of cerebral function. The complexity of the cerebrum is different across vertebrate species. The cerebrum of the most primitive vertebrates is not much more than the connection for the sense of smell. In mammals, the cerebrum comprises the outer gray matter that is the cortex (from the Latin word meaning bark of a tree) and several deep nuclei that belong to three important functional groups. The basal nuclei are responsible for cognitive processing, the most important function being that associated with planning movements. The basal forebrain contains nuclei that are important in learning and memory. The limbic cortex is the region of the cerebral cortex that is part of the limbic system, a collection of structures involved in emotion, memory, and behavior.

The cerebrum is covered by a continuous layer of gray matter that wraps around either side of the forebrainthe cerebral cortex. This thin, extensive region of wrinkled gray matter is responsible for the higher functions of the nervous system. A gyrus (plural = gyri) is the ridge of one of those wrinkles, and a sulcus (plural = sulci) is the groove between two gyri. The pattern of these folds of tissue indicates specific regions of the cerebral cortex.

The head is limited by the size of the birth canal, and the brain must fit inside the cranial cavity of the skull. Extensive folding in the cerebral cortex enables more gray matter to fit into this limited space. If the gray matter of the cortex were peeled off of the cerebrum and laid out flat, its surface area would be roughly equal to one square meter.

The folding of the cortex maximizes the amount of gray matter in the cranial cavity. During embryonic development, as the telencephalon expands within the skull, the brain goes through a regular course of growth that results in everyones brain having a similar pattern of folds. The surface of the brain can be mapped on the basis of the locations of large gyri and sulci. Using these landmarks, the cortex can be separated into four major regions, or lobes (Figure 14.3.2). The lateral sulcus that separates the temporal lobe from the other regions is one such landmark. Superior to the lateral sulcus are the parietal lobe and frontal lobe, which are separated from each other by the central sulcus. The posterior region of the cortex is the occipital lobe, which has no obvious anatomical border between it and the parietal or temporal lobes on the lateral surface of the brain. From the medial surface, an obvious landmark separating the parietal and occipital lobes is called the parieto-occipital sulcus. The fact that there is no obvious anatomical border between these lobes is consistent with the functions of these regions being interrelated.

Different regions of the cerebral cortex can be associated with particular functions, a concept known as localization of function. In the early 1900s, a German neuroscientist named Korbinian Brodmann performed an extensive study of the microscopic anatomythe cytoarchitectureof the cerebral cortex and divided the cortex into 52 separate regions on the basis of the histology of the cortex. His work resulted in a system of classification known as Brodmanns areas, which is still used today to describe the anatomical distinctions within the cortex (Figure 14.3.3). The results from Brodmanns work on the anatomy align very well with the functional differences within the cortex. Areas 17 and 18 in the occipital lobe are responsible for primary visual perception. That visual information is complex, so it is processed in the temporal and parietal lobes as well.

The temporal lobe is associated with primary auditory sensation, known as Brodmanns areas 41 and 42 in the superior temporal lobe. Because regions of the temporal lobe are part of the limbic system, memory is an important function associated with that lobe. Memory is essentially a sensory function; memories are recalled sensations such as the smell of Moms baking or the sound of a barking dog. Even memories of movement are really the memory of sensory feedback from those movements, such as stretching muscles or the movement of the skin around a joint. Structures in the temporal lobe are responsible for establishing long-term memory, but the ultimate location of those memories is usually in the region in which the sensory perception was processed.

The main sensation associated with the parietal lobe is somatosensation, meaning the general sensations associated with the body. Posterior to the central sulcus is the postcentral gyrus, the primary somatosensory cortex, which is identified as Brodmanns areas 1, 2, and 3. All of the tactile senses are processed in this area, including touch, pressure, tickle, pain, itch, and vibration, as well as more general senses of the body such as proprioception and kinesthesia, which are the senses of body position and movement, respectively.

Anterior to the central sulcus is the frontal lobe, which is primarily associated with motor functions. The precentral gyrus is the primary motor cortex. Cells from this region of the cerebral cortex are the upper motor neurons that instruct cells in the spinal cord and brain stem (lower motor neurons) to move skeletal muscles. Anterior to this region are a few areas that are associated with planned movements. The premotor area is responsible for storing learned movement algorithms which are instructions for complex movements. Different algorithmsactivate the upper motor neurons in the correct sequence when a complex motor activity is performed.The frontal eye fields are important in eliciting scanning eye movements and in attending to visual stimuli. Brocas area is responsible for the production of language, or controlling movements responsible for speech; in the vast majority of people, it is located only on the left side. Anterior to these regions is the prefrontal lobe, which serves cognitive functions that can be the basis of personality, short-term memory, and consciousness. The prefrontal lobotomy is an outdated mode of treatment for personality disorders (psychiatric conditions) that profoundly affected the personality of the patient.

Area 17, as Brodmann described it, is also known as the primary visual cortex. Adjacent to that are areas 18 and 19, which constitute subsequent regions of visual processing. Area 22 is the primary auditory cortex, and it is followed by area 23, which further processes auditory information. Area 4 is the primary motor cortex in the precentral gyrus, whereas area 6 is the premotor cortex. These areas suggest some specialization within the cortex for functional processing, both in sensory and motor regions. The fact that Brodmanns areas correlate so closely to functional localization in the cerebral cortex demonstrates the strong link between structure and function in these regions.

Areas 1, 2, 3, 4, 17, and 22 are each described as primary cortical areas. The adjoining regions are each referred to as association areas. Primary areas are where sensory information is initially received from the thalamus for conscious perception, orin the case of the primary motor cortexwhere descending commands are sent down to the brain stem or spinal cord to execute movements (Figure 14.3.4).

The cerebrum is the seat of many of the higher mental functions, such as memory and learning, language, and conscious perception, which are the subjects of subtests of the mental status exam. The cerebral cortex is the thin layer of gray matter on the outside of the cerebrum. It is approximately a millimeter thick in most regions and highly folded to fit within the limited space of the cranial vault. These higher functions are distributed across various regions of the cortex, and specific locations can be said to be responsible for particular functions. There is a limited set of regions, for example, that are involved in language function, and they can be subdivided on the basis of the particular part of language function that each governs.

A number of other regions, which extend beyond these primary or association areas of the cortex, are referred to as integrative areas. These areas are found in the spaces between the domains for particular sensory or motor functions, and they integrate multisensory information, or process sensory or motor information in more complex ways. Consider, for example, the posterior parietal cortex that lies between the somatosensory cortex and visual cortex regions. This has been ascribed to the coordination of visual and motor functions, such as reaching to pick up a glass. The somatosensory function that would be part of this is the proprioceptive feedback from moving the arm and hand. The weight of the glass, based on what it contains, will influence how those movements are executed.

Assessment of cerebral functions is directed at cognitive abilities. The abilities assessed through the mental status exam can be separated into four groups: orientation and memory, language and speech, sensorium, and judgment and abstract reasoning.

Orientation is the patients awareness of his or her immediate circumstances. It is awareness of time, not in terms of the clock, but of the date and what is occurring around the patient. It is awareness of place, such that a patient should know where he or she is and why. It is also awareness of who the patient isrecognizing personal identity and being able to relate that to the examiner. The initial tests of orientation are based on the questions, Do you know what the date is? or Do you know where you are? or What is your name? Further understanding of a patients awareness of orientation can come from questions that address remote memory, such as Who is the President of the United States?, or asking what happened on a specific date.

There are also specific tasks to address memory. One is the three-word recall test. The patient is given three words to recall, such as book, clock, and shovel. After a short interval, during which other parts of the interview continue, the patient is asked to recall the three words. Other tasks that assess memoryaside from those related to orientationhave the patient recite the months of the year in reverse order to avoid the overlearned sequence and focus on the memory of the months in an order, or to spell common words backwards, or to recite a list of numbers back.

Memory is largely a function of the temporal lobe, along with structures beneath the cerebral cortex such as the hippocampus and the amygdala. The storage of memory requires these structures of the medial temporal lobe. A famous case of a man who had both medial temporal lobes removed to treat intractable epilepsy provided insight into the relationship between the structures of the brain and the function of memory.

Henry Molaison, who was referred to as patient HM when he was alive, had epilepsy localized to both of his medial temporal lobes. In 1953, a bilateral lobectomy was performed that alleviated the epilepsy but resulted in the inability for HM to form new memoriesa condition called anterograde amnesia. HM was able to recall most events from before his surgery, although there was a partial loss of earlier memories, which is referred to as retrograde amnesia. HM became the subject of extensive studies into how memory works. What he was unable to do was form new memories of what happened to him, what are now called episodic memory. Episodic memory is autobiographical in nature, such as remembering riding a bicycle as a child around the neighborhood, as opposed to the procedural memory of how to ride a bike. HM also retained his short-term memory, such as what is tested by the three-word task described above. After a brief period, those memories would dissipate or decay and not be stored in the long-term because the medial temporal lobe structures were removed.

The difference in short-term, procedural, and episodic memory, as evidenced by patient HM, suggests that there are different parts of the brain responsible for those functions. The long-term storage of episodic memory requires the hippocampus and related medial temporal structures, and the location of those memories is in the multimodal integration areas of the cerebral cortex. However, short-term memoryalso called working or active memoryis localized to the prefrontal lobe. Because patient HM had only lost his medial temporal lobeand lost very little of his previous memories, and did not lose the ability to form new short-term memoriesit was concluded that the function of the hippocampus, and adjacent structures in the medial temporal lobe, is to move (or consolidate) short-term memories (in the pre-frontal lobe) to long-term memory (in the temporal lobe).

The prefrontal cortex can also be tested for the ability to organize information. In one subtest of the mental status exam called set generation, the patient is asked to generate a list of words that all start with the same letter, but not to include proper nouns or names. The expectation is that a person can generate such a list of at least 10 words within 1 minute. Many people can likely do this much more quickly, but the standard separates the accepted normal from those with compromised prefrontal cortices.

Read this article to learn about a young man who texts his fiance in a panic as he finds that he is having trouble remembering things. At the hospital, a neurologist administers the mental status exam, which is mostly normal except for the three-word recall test. The young man could not recall them even 30 seconds after hearing them and repeating them back to the doctor. An undiscovered mass in the mediastinum region was found to be Hodgkins lymphoma, a type of cancer that affects the immune system and likely caused antibodies to attack the nervous system. The patient eventually regained his ability to remember, though the events in the hospital were always elusive. Considering that the effects on memory were temporary, but resulted in the loss of the specific events of the hospital stay, what regions of the brain were likely to have been affected by the antibodies and what type of memory does that represent?

Language is, arguably, a very human aspect of neurological function. There are certainly strides being made in understanding communication in other species, but much of what makes the human experience seemingly unique is its basis in language. Any understanding of our species is necessarily reflective, as suggested by the question What am I? And the fundamental answer to this question is suggested by the famous quote by Ren Descartes: Cogito Ergo Sum (translated from Latin as I think, therefore I am). Formulating an understanding of yourself is largely describing who you are to yourself. It is a confusing topic to delve into, but language is certainly at the core of what it means to be self-aware.

The neurological exam has two specific subtests that address language. One measures the ability of the patient to understand language by asking them to follow a set of instructions to perform an action, such as touch your right finger to your left elbow and then to your right knee. Another subtest assesses the fluency and coherency of language by having the patient generate descriptions of objects or scenes depicted in drawings, and by reciting sentences or explaining a written passage. Language, however, is important in so many ways in the neurological exam. The patient needs to know what to do, whether it is as simple as explaining how the knee-jerk reflex is going to be performed, or asking a question such as What is your name? Often, language deficits can be determined without specific subtests; if a person cannot reply to a question properly, there may be a problem with the reception of language.

An important example of multimodal integrative areas is associated with language function (Figure 14.3.5). Adjacent to the auditory association cortex, at the end of the lateral sulcus just anterior to the visual cortex, is Wernickes area. In the lateral aspect of the frontal lobe, just anterior to the region of the motor cortex associated with the head and neck, is Brocas area. Both regions were originally described on the basis of losses of speech and language, which is called aphasia. The aphasia associated with Brocas area is known as an expressive aphasia, which means that speech production is compromised. This type of aphasia is often described as non-fluency because the ability to say some words leads to broken or halting speech. Grammar can also appear to be lost. The aphasia associated with Wernickes area is known as a receptive aphasia, which is not a loss of speech production, but a loss of understanding of content. Patients, after recovering from acute forms of this aphasia, report not being able to understand what is said to them or what they are saying themselves, but they often cannot keep from talking.

The two regions are connected by white matter tracts that run between the posterior temporal lobe and the lateral aspect of the frontal lobe. Conduction aphasia associated with damage to this connection refers to the problem of connecting the understanding of language to the production of speech. This is a very rare condition, but is likely to present as an inability to faithfully repeat spoken language.

Those parts of the brain involved in the reception and interpretation of sensory stimuli are referred to collectively as the sensorium. The cerebral cortex has several regions that are necessary for sensory perception. From the primary cortical areas of the somatosensory, visual, auditory, and gustatory senses to the association areas that process information in these modalities, the cerebral cortex is the seat of conscious sensory perception. In contrast, sensory information can also be processed by deeper brain regions, which we may vaguely describe as subconsciousfor instance, we are not constantly aware of the proprioceptive information that the cerebellum uses to maintain balance. Several of the subtests can reveal activity associated with these sensory modalities, such as being able to hear a question or see a picture. Two subtests assess specific functions of these cortical areas.

The first is praxis, a practical exercise in which the patient performs a task completely on the basis of verbal description without any demonstration from the examiner. For example, the patient can be told to take their left hand and place it palm down on their left thigh, then flip it over so the palm is facing up, and then repeat this four times. The examiner describes the activity without any movements on their part to suggest how the movements are to be performed. The patient needs to understand the instructions, transform them into movements, and use sensory feedback, both visual and proprioceptive, to perform the movements correctly.

The second subtest for sensory perception is gnosis, which involves two tasks. The first task, known as stereognosis, involves the naming of objects strictly on the basis of the somatosensory information that comes from manipulating them. The patient keeps their eyes closed and is given a common object, such as a coin, that they have to identify. The patient should be able to indicate the particular type of coin, such as a dime versus a penny, or a nickel versus a quarter, on the basis of the sensory cues involved. For example, the size, thickness, or weight of the coin may be an indication, or to differentiate the pairs of coins suggested here, the smooth or corrugated edge of the coin will correspond to the particular denomination. The second task, graphesthesia, is to recognize numbers or letters written on the palm of the hand with a dull pointer, such as a pen cap.

Praxis and gnosis are related to the conscious perception and cortical processing of sensory information. Being able to transform verbal commands into a sequence of motor responses, or to manipulate and recognize a common object and associate it with a name for that object. Both subtests have language components because language function is integral to these functions. The relationship between the words that describe actions, or the nouns that represent objects, and the cerebral location of these concepts is suggested to be localized to particular cortical areas. Certain aphasias can be characterized by a deficit of verbs or nouns, known as V impairment or N impairment, or may be classified as VN dissociation. Patients have difficulty using one type of word over the other. To describe what is happening in a photograph as part of the expressive language subtest, a patient will use active- or image-based language. The lack of one or the other of these components of language can relate to the ability to use verbs or nouns. Damage to the region at which the frontal and temporal lobes meet, including the region known as the insula, is associated with V impairment; damage to the middle and inferior temporal lobe is associated with N impairment.

Planning and producing responses requires an ability to make sense of the world around us. Making judgments and reasoning in the abstract are necessary to produce movements as part of larger responses. For example, when your alarm goes off, do you hit the snooze button or jump out of bed? Is 10 extra minutes in bed worth the extra rush to get ready for your day? Will hitting the snooze button multiple times lead to feeling more rested or result in a panic as you run late? How you mentally process these questions can affect your whole day.

The prefrontal cortex is responsible for the functions responsible for planning and making decisions. In the mental status exam, the subtest that assesses judgment and reasoning is directed at three aspects of frontal lobe function. First, the examiner asks questions about problem solving, such as If you see a house on fire, what would you do? The patient is also asked to interpret common proverbs, such as Dont look a gift horse in the mouth. Additionally, pairs of words are compared for similarities, such as apple and orange, or lamp and cabinet.

The prefrontal cortex is composed of the regions of the frontal lobe that are not directly related to specific motor functions. The most posterior region of the frontal lobe, the precentral gyrus, is the primary motor cortex. Anterior to that are the premotor cortex, Brocas area, and the frontal eye fields, which are all related to planning certain types of movements. Anterior to what could be described as motor association areas are the regions of the prefrontal cortex. They are the regions in which judgment, abstract reasoning, and working memory are localized. The antecedents to planning certain movements are judging whether those movements should be made, as in the example of deciding whether to hit the snooze button.

To an extent, the prefrontal cortex may be related to personality. The neurological exam does not necessarily assess personality, but it can be within the realm of neurology or psychiatry. A clinical situation that suggests this link between the prefrontal cortex and personality comes from the story of Phineas Gage, the railroad worker from the mid-1800s who had a metal spike impale his prefrontal cortex. There are suggestions that the steel rod led to changes in his personality. A man who was a quiet, dependable railroad worker became a raucous, irritable drunkard. Later anecdotal evidence from his life suggests that he was able to support himself, although he had to relocate and take on a different career as a stagecoach driver.

A psychiatric practice to deal with various disorders was the prefrontal lobotomy. This procedure was common in the 1940s and early 1950s, until antipsychotic drugs became available. The connections between the prefrontal cortex and other regions of the brain were severed. The disorders associated with this procedure included some aspects of what are now referred to as personality disorders, but also included mood disorders and psychoses. Depictions of lobotomies in popular media suggest a link between cutting the white matter of the prefrontal cortex and changes in a patients mood and personality, though this correlation is not well understood.

Popular media often refer to right-brained and left-brained people, as if the brain were two independent halves that work differently for different people. This is a popular misinterpretation of an important neurological phenomenon. As an extreme measure to deal with a debilitating condition, the corpus callosum may be sectioned to overcome intractable epilepsy. When the connections between the two cerebral hemispheres are cut, interesting effects can be observed.

If a person with an intact corpus callosum is asked to put their hands in their pockets and describe what is there on the basis of what their hands feel, they might say that they have keys in their right pocket and loose change in the left. They may even be able to count the coins in their pocket and say if they can afford to buy a candy bar from the vending machine. If a person with a sectioned corpus callosum is given the same instructions, they will do something quite peculiar. They will only put their right hand in their pocket and say they have keys there. They will not even move their left hand, much less report that there is loose change in the left pocket.

The reason for this is that the language functions of the cerebral cortex are localized to the left hemisphere in 95 percent of the population. Additionally, the left hemisphere is connected to the right side of the body through the corticospinal tract and the ascending tracts of the spinal cord. Motor commands from the precentral gyrus control the opposite side of the body, whereas sensory information processed by the postcentral gyrus is received from the opposite side of the body. For a verbal command to initiate movement of the right arm and hand, the left side of the brain needs to be connected by the corpus callosum. Language is processed in the left side of the brain and directly influences the left brain and right arm motor functions, but is sent to influence the right brain and left arm motor functions through the corpus callosum. Likewise, the left-handed sensory perception of what is in the left pocket travels across the corpus callosum from the right brain, so no verbal report on those contents would be possible if the hand happened to be in the pocket.

Watch the video titled The Man With Two Brains to see the neuroscientist Michael Gazzaniga introduce a patient he has worked with for years who has had his corpus callosum cut, separating his two cerebral hemispheres. A few tests are run to demonstrate how this manifests in tests of cerebral function. Unlike normal people, this patient can perform two independent tasks at the same time because the lines of communication between the right and left sides of his brain have been removed. Whereas a person with an intact corpus callosum cannot overcome the dominance of one hemisphere over the other, this patient can. If the left cerebral hemisphere is dominant in the majority of people, why would right-handedness be most common?

The cerebrum, particularly the cerebral cortex, is the location of important cognitive functions that are the focus of the mental status exam. The regionalization of the cortex, initially described on the basis of anatomical evidence of cytoarchitecture, reveals the distribution of functionally distinct areas. Cortical regions can be described as primary sensory or motor areas, association areas, or multimodal integration areas. The functions attributed to these regions include attention, memory, language, speech, sensation, judgment, and abstract reasoning.

The mental status exam addresses these cognitive abilities through a series of subtests designed to elicit particular behaviors ascribed to these functions. The loss of neurological function can illustrate the location of damage to the cerebrum. Memory functions are attributed to the temporal lobe, particularly the medial temporal lobe structures known as the hippocampus and amygdala, along with the adjacent cortex. Evidence of the importance of these structures comes from the side effects of a bilateral temporal lobectomy that were studied in detail in patient HM.

Losses of language and speech functions, known as aphasias, are associated with damage to the important integration areas in the left hemisphere known as Brocas or Wernickes areas, as well as the connections in the white matter between them. Different types of aphasia are named for the particular structures that are damaged. Assessment of the functions of the sensorium includes praxis and gnosis. The subtests related to these functions depend on multimodal integration, as well as language-dependent processing.

The prefrontal cortex contains structures important for planning, judgment, reasoning, and working memory. Damage to these areas can result in changes to personality, mood, and behavior. The famous case of Phineas Gage suggests a role for this cortex in personality, as does the outdated practice of prefrontal lobectomy.

Beneath the cerebral cortex are sets of nuclei known as subcortical nuclei that augment cortical processes. The nuclei of the basal forebrain serve as the primary location for acetylcholine production, which modulates the overall activity of the cortex, possibly leading to greater attention to sensory stimuli. Alzheimers disease is associated with a loss of neurons in the basal forebrain. The hippocampus and amygdala are medial-lobe structures that, along with the adjacent cortex, are involved in long-term memory formation and emotional responses. The basal nuclei are a set of nuclei in the cerebrum responsible for comparing cortical processing with the general state of activity in the nervous system to influence the likelihood of movement taking place. For example, while a student is sitting in a classroom listening to a lecture, the basal nuclei will keep the urge to jump up and scream from actually happening. (The basal nuclei are also referred to as the basal ganglia, although that is potentially confusing because the term ganglia is typically used for peripheral structures.)

The major structures of the basal nuclei that control movement are the caudate, putamen, and globus pallidus, which are located deep in the cerebrum. The caudate is a long nucleus that follows the basic C-shape of the cerebrum from the frontal lobe, through the parietal and occipital lobes, into the temporal lobe. The putamen is mostly deep in the anterior regions of the frontal and parietal lobes. Together, the caudate and putamen are called the striatum. The globus pallidus is a layered nucleus that lies just medial to the putamen; they are called the lenticular nuclei because they look like curved pieces fitting together like lenses. The globus pallidus has two subdivisions, the external and internal segments, which are lateral and medial, respectively. These nuclei are depicted in a frontal section of the brain in Figure 14.3.6.

The basal nuclei in the cerebrum are connected with a few more nuclei in the brain stem that together act as a functional group that forms a motor pathway. Two streams of information processing take place in the basal nuclei. All input to the basal nuclei is from the cortex into the striatum (Figure 14.3.7). The direct pathway is the projection of axons from the striatum to the globus pallidus internal segment (GPi) and the substantia nigra pars reticulata (SNr). The GPi/SNr then projects to the thalamus, which projects back to the cortex. The indirect pathway is the projection of axons from the striatum to the globus pallidus external segment (GPe), then to the subthalamic nucleus (STN), and finally to GPi/SNr. The two streams both target the GPi/SNr, but one has a direct projection and the other goes through a few intervening nuclei. The direct pathway causes the disinhibition of the thalamus (inhibition of one cell on a target cell that then inhibits the first cell), whereas the indirect pathway causes, or reinforces, the normal inhibition of the thalamus. The thalamus then can either excite the cortex (as a result of the direct pathway) or fail to excite the cortex (as a result of the indirect pathway).

The switch between the two pathways is the substantia nigra pars compacta, which projects to the striatum and releases the neurotransmitter dopamine. Dopamine receptors are either excitatory (D1-type receptors) or inhibitory (D2-type receptors). The direct pathway is activated by dopamine, and the indirect pathway is inhibited by dopamine. When the substantia nigra pars compacta is firing, it signals to the basal nuclei that the body is in an active state, and movement will be more likely. When the substantia nigra pars compacta is silent, the body is in a passive state, and movement is inhibited. To illustrate this situation, while a student is sitting listening to a lecture, the substantia nigra pars compacta would be silent and the student less likely to get up and walk around. Likewise, while the professor is lecturing, and walking around at the front of the classroom, the professors substantia nigra pars compacta would be active, in keeping with his or her activity level.

Watch this video to learn about the basal nuclei (also known as the basal ganglia), which have two pathways that process information within the cerebrum. As shown in this video, the direct pathway is the shorter pathway through the system that results in increased activity in the cerebral cortex and increased motor activity. The direct pathway is described as resulting in disinhibition of the thalamus. What does disinhibition mean? What are the two neurons doing individually to cause this?

Watch this video to learn about the basal nuclei (also known as the basal ganglia), which have two pathways that process information within the cerebrum. As shown in this video, the indirect pathway is the longer pathway through the system that results in decreased activity in the cerebral cortex, and therefore less motor activity. The indirect pathway has an extra couple of connections in it, including disinhibition of the subthalamic nucleus. What is the end result on the thalamus, and therefore on movement initiated by the cerebral cortex?

There is a persistent myth that people are right-brained or left-brained, which is an oversimplification of an important concept about the cerebral hemispheres. There is some lateralization of function, in which the left side of the brain is devoted to language function and the right side is devoted to spatial and nonverbal reasoning. Whereas these functions are predominantly associated with those sides of the brain, there is no monopoly by either side on these functions. Many pervasive functions, such as language, are distributed globally around the cerebrum.

Some of the support for this misconception has come from studies of split brains. A drastic way to deal with a rare and devastating neurological condition (intractable epilepsy) is to separate the two hemispheres of the brain. After sectioning the corpus callosum, a split-brained patient will have trouble producing verbal responses on the basis of sensory information processed on the right side of the cerebrum, leading to the idea that the left side is responsible for language function.

However, there are well-documented cases of language functions lost from damage to the right side of the brain. The deficits seen in damage to the left side of the brain are classified as aphasia, a loss of speech function; damage on the right side can affect the use of language. Right-side damage can result in a loss of ability to understand figurative aspects of speech, such as jokes, irony, or metaphors. Nonverbal aspects of speech can be affected by damage to the right side, such as facial expression or body language, and right-side damage can lead to a flat affect in speech, or a loss of emotional expression in speechsounding like a robot when talking. Damage to language areas on the right side causes a condition called aprosodia where the patient has difficulty understanding or expressing the figurative part of speech.

The diencephalon is the one region of the adult brain that retains its name from embryologic development. The etymology of the word diencephalon translates to through brain. It is the connection between the cerebrum and the rest of the nervous system, with one exception. The rest of the brain, the spinal cord, and the PNS all send information to the cerebrum through the diencephalon. Output from the cerebrum passes through the diencephalon. The single exception is the system associated with olfaction, or the sense of smell, which connects directly with the cerebrum. In the earliest vertebrate species, the cerebrum was not much more than olfactory bulbs that received peripheral information about the chemical environment (to call it smell in these organisms is imprecise because they lived in the ocean).

The diencephalon is deep beneath the cerebrum and constitutes the walls of the third ventricle. The diencephalon can be described as any region of the brain with thalamus in its name. The two major regions of the diencephalon are the thalamus itself and the hypothalamus (Figure 14.3.8). There are other structures, such as the epithalamus, which contains the pineal gland, or the subthalamus, which includes the subthalamic nucleus that is part of the basal nuclei.

The thalamus is a collection of nuclei that relay information between the cerebral cortex and the periphery, spinal cord, or brain stem. All sensory information, except for the sense of smell, passes through the thalamus before processing by the cortex. Axons from the peripheral sensory organs, or intermediate nuclei, synapse in the thalamus, and thalamic neurons project directly to the cerebrum. It is a requisite synapse in any sensory pathway, except for olfaction. The thalamus does not just pass the information on, it also processes that information. For example, the portion of the thalamus that receives visual information will influence what visual stimuli are important, or what receives attention.

The cerebrum also sends information down to the thalamus, which usually communicates motor commands. This involves interactions with the cerebellum and other nuclei in the brain stem. The cerebrum interacts with the basal nuclei, which involves connections with the thalamus. The primary output of the basal nuclei is to the thalamus, which relays that output to the cerebral cortex. The cortex also sends information to the thalamus that will then influence the effects of the basal nuclei.

Inferior and slightly anterior to the thalamus is the hypothalamus, the other major region of the diencephalon. The hypothalamus is a collection of nuclei that are largely involved in regulating homeostasis. The hypothalamus is the executive region in charge of the autonomic nervous system and the endocrine system through its regulation of the anterior pituitary gland. Other parts of the hypothalamus are involved in memory and emotion as part of the limbic system.

The midbrain and the pons and medulla of the hindbrainare collectively referred to as the brain stem (Figure 14.3.9). The structure emerges from the ventral surface of the forebrain as a tapering cone that connects the brain to the spinal cord. Attached to the brain stem, but considered a separate region of the adult brain, is the cerebellum. The midbrain coordinates sensory representations of the visual, auditory, and somatosensory perceptual spaces. The pons is the main connection with the cerebellum. The pons and the medulla regulate several crucial functions, including the cardiovascular and respiratory systems.

The cranial nerves connect through the brain stem and provide the brain with the sensory input and motor output associated with the head and neck, including most of the special senses. The major ascending and descending pathways between the spinal cord and brain, specifically the cerebrum, pass through the brain stem.

One of the original regions of the embryonic brain, the midbrain is a small region between the thalamus and pons. It is separated into the tectum and tegmentum, from the Latin words for roof and floor, respectively. The cerebral aqueduct passes through the center of the midbrain, such that these regions are the roof and floor of that canal.

The tectum is composed of four bumps known as the colliculi (singular = colliculus), which means little hill in Latin. The inferior colliculus is the inferior pair of these enlargements and is part of the auditory brain stem pathway. Neurons of the inferior colliculus project to the thalamus, which then sends auditory information to the cerebrum for the conscious perception of sound. The superior colliculus is the superior pair and combines sensory information about visual space, auditory space, and somatosensory space. Activity in the superior colliculus is related to orienting the eyes to a sound or touch stimulus. If you are walking along the sidewalk on campus and you hear chirping, the superior colliculus coordinates that information with your awareness of the visual location of the tree right above you. That is the correlation of auditory and visual maps. If you suddenly feel something wet fall on your head, your superior colliculus integrates that with the auditory and visual maps and you know that the chirping bird just relieved itself on you. You want to look up to see the culprit, but do not.

The tegmentum is continuous with the gray matter of the rest of the brain stem. Throughout the midbrain, pons, and medulla, the tegmentum contains the nuclei that receive and send information through the cranial nerves, as well as regions that regulate important functions such as those of the cardiovascular and respiratory systems.

The word pons comes from the Latin word for bridge. It is visible on the anterior surface of the brain stem as the thick bundle of white matter attached to the cerebellum. The pons is the main connection between the cerebellum and the brain stem. The bridge-like white matter is only the anterior surface of the pons; the gray matter beneath that is a continuation of the tegmentum from the midbrain. Gray matter in the tegmentum region of the pons contains neurons receiving descending input from the forebrain that is sent to the cerebellum.

The medulla is the region known as the myelencephalon in the embryonic brain. The initial portion of the name, myel, refers to the significant white matter found in this regionespecially on its exterior, which is continuous with the white matter of the spinal cord. The tegmentum of the midbrain and pons continues into the medulla because this gray matter is responsible for processing cranial nerve information. A diffuse region of gray matter throughout the brain stem, known as the reticular formation, is related to sleep and wakefulness, such as general brain activity and attention.

The cerebellum, as the name suggests, is the little brain. It is covered in gyri and sulci like the cerebrum, and looks like a miniature version of that part of the brain (Figure 14.3.10). The cerebellum is largely responsible for comparing information from the cerebrum with sensory feedback from the periphery through the spinal cord. It accounts for approximately 10 percent of the mass of the brain.

Descending fibers from the cerebrum have branches that connect to neurons in the pons. Those neurons project into the cerebellum, providing a copy of motor commands sent to the spinal cord. Sensory information from the periphery, which enters through spinal or cranial nerves, is copied to a nucleus in the medulla known as the inferior olive. Fibers from this nucleus enter the cerebellum and are compared with the descending commands from the cerebrum. If the primary motor cortex of the frontal lobe sends a command down to the spinal cord to initiate walking, a copy of that instruction is sent to the cerebellum. Sensory feedback from the muscles and joints, proprioceptive information about the movements of walking, and sensations of balance are sent to the cerebellum through the inferior olive and the cerebellum compares them. If walking is not coordinated, perhaps because the ground is uneven or a strong wind is blowing, then the cerebellum sends out a corrective command to compensate for the difference between the original cortical command and the sensory feedback. The output of the cerebellum is into the midbrain, which then sends a descending input to the spinal cord to correct the messages going to skeletal muscles.

The description of the CNS is concentrated on the structures of the brain, but the spinal cord is another major organ of the system. Whereas the brain develops out of expansions of the neural tube into primary and then secondary vesicles, the spinal cord maintains the tube structure and is only specialized into certain regions. As the spinal cord continues to develop in the newborn, anatomical features mark its surface. The anterior midline is marked by the anterior median fissure, and the posterior midline is marked by the posterior median sulcus. Axons enter the posterior side through the dorsal (posterior) nerve root, which marks the posterolateral sulcus on either side. The axons emerging from the anterior side do so through the ventral (anterior) nerve root. Note that it is common to see the terms dorsal (dorsal = back) and ventral (ventral = belly) used interchangeably with posterior and anterior, particularly in reference to nerves and the structures of the spinal cord. You should learn to be comfortable with both.

On the whole, the posterior regions are responsible for sensory functions and the anterior regions are associated with motor functions. This comes from the initial development of the spinal cord, which is divided into the basal plate and the alar plate. The basal plate is closest to the ventral midline of the neural tube, which will become the anterior face of the spinal cord and gives rise to motor neurons. The alar plate is on the dorsal side of the neural tube and gives rise to neurons that will receive sensory input from the periphery.

The length of the spinal cord is divided into regions that correspond to the regions of the vertebral column. The name of a spinal cord region corresponds to the level at which spinal nerves pass through the intervertebral foramina. Immediately adjacent to the brain stem is the cervical region, followed by the thoracic, then the lumbar, and finally the sacral region. The spinal cord is not the full length of the vertebral column because the spinal cord does not grow significantly longer after the first or second year, but the skeleton continues to grow. The nerves that emerge from the spinal cord pass through the intervertebral formina at the respective levels. As the vertebral column grows, these nerves grow with it and result in a long bundle of nerves that resembles a horses tail and is named the cauda equina. The sacral spinal cord is at the level of the upper lumbar vertebral bones. The spinal nerves extend from their various levels to the proper level of the vertebral column.

In cross-section, the gray matter of the spinal cord has the appearance of an ink-blot test, with the spread of the gray matter on one side replicated on the othera shape reminiscent of a bulbous capital H. As shown in Figure 14.3.11, the gray matter is subdivided into regions that are referred to as horns. The posterior horn is responsible for sensory processing. The anterior horn sends out motor signals to the skeletal muscles. The lateral horn, which is only found in the thoracic, upper lumbar, and sacral regions, is the central component of the sympathetic division of the autonomic nervous system.

Some of the largest neurons of the spinal cord are the multipolar motor neurons in the anterior horn. The fibers that cause contraction of skeletal muscles are the axons of these neurons. The motor neuron that causes contraction of the big toe, for example, is located in the sacral spinal cord. The axon that has to reach all the way to the belly of that muscle may be a meter in length. The neuronal cell body that maintains that long fiber must be quite large, possibly several hundred micrometers in diameter, making it one of the largest cells in the body.

Just as the gray matter is separated into horns, the white matter of the spinal cord is separated into columns. Ascending tracts of nervous system fibers in these columns carry sensory information up to the brain, whereas descending tracts carry motor commands from the brain. Looking at the spinal cord longitudinally, the columns extend along its length as continuous bands of white matter. Between the two posterior horns of gray matter are the posterior columns. Between the two anterior horns, and bounded by the axons of motor neurons emerging from that gray matter area, are the anterior columns. The white matter on either side of the spinal cord, between the posterior horn and the axons of the anterior horn neurons, are the lateral columns. The posterior columns are composed of axons of ascending tracts. The anterior and lateral columns are composed of many different groups of axons of both ascending and descending tractsthe latter carrying motor commands down from the brain to the spinal cord to control output to the periphery.

Watch this video to learn about the gray matter of the spinal cord that receives input from fibers of the dorsal (posterior) root and sends information out through the fibers of the ventral (anterior) root. As discussed in this video, these connections represent the interactions of the CNS with peripheral structures for both sensory and motor functions. The cervical and lumbar spinal cords have enlargements as a result of larger populations of neurons. What are these enlargements responsible for?

Parkinsons disease is neurodegenerative, meaning that neurons die that cannot be replaced, so there is no cure for the disorder. Treatments for Parkinsons disease are aimed at increasing dopamine levels in the striatum. Currently, the most common way of doing that is by providing the amino acid L-DOPA, which is a precursor to the neurotransmitter dopamine and can cross the blood-brain barrier. With levels of the precursor elevated, the remaining cells of the substantia nigra pars compacta can make more neurotransmitter and have a greater effect. Unfortunately, the patient will become less responsive to L-DOPA treatment as time progresses, and it can cause increased dopamine levels elsewhere in the brain, which are associated with psychosis or schizophrenia.

Visit this site for a thorough explanation of Parkinsons disease.

Compared with the nearest evolutionary relative, the chimpanzee, the human has a brain that is huge. At a point in the past, a common ancestor gave rise to the two species of humans and chimpanzees. That evolutionary history is long and is still an area of intense study. But something happened to increase the size of the human brain relative to the chimpanzee. Read this article in which the author explores the current understanding of why this happened.

According to one hypothesis about the expansion of brain size, what tissue might have been sacrificed so energy was available to grow our larger brain? Based on what you know about that tissue and nervous tissue, why would there be a trade-off between them in terms of energy use?

Have you ever heard the claim that humans only use 10 percent of their brains? Maybe you have seen an advertisement on a website saying that there is a secret to unlocking the full potential of your mindas if there were 90 percent of your brain sitting idle, just waiting for you to use it. If you see an ad like that, dont click. It isnt true.

An easy way to see how much of the brain a person uses is to take measurements of brain activity while performing a task. An example of this kind of measurement is functional magnetic resonance imaging (fMRI), which generates a map of the most active areas and can be generated and presented in three dimensions (Figure 14.3.12). This procedure is different from the standard MRI technique because it is measuring changes in the tissue in time with an experimental condition or event.

The underlying assumption is that active nervous tissue will have greater blood flow. By having the subject perform a visual task, activity all over the brain can be measured. Consider this possible experiment: the subject is told to look at a screen with a black dot in the middle (a fixation point). A photograph of a face is projected on the screen away from the center. The subject has to look at the photograph and decipher what it is. The subject has been instructed to push a button if the photograph is of someone they recognize. The photograph might be of a celebrity, so the subject would press the button, or it might be of a random person unknown to the subject, so the subject would not press the button.

In this task, visual sensory areas would be active, integrating areas would be active, motor areas responsible for moving the eyes would be active, and motor areas for pressing the button with a finger would be active. Those areas are distributed all around the brain and the fMRI images would show activity in more than just 10 percent of the brain (some evidence suggests that about 80 percent of the brain is using energybased on blood flow to the tissueduring well-defined tasks similar to the one suggested above). This task does not even include all of the functions the brain performs. There is no language response, the body is mostly lying still in the MRI machine, and it does not consider the autonomic functions that would be ongoing in the background.

Considering the anatomical regions of the nervous system, there are specific names for the structures within each division. A localized collection of neuron cell bodies is referred to as a nucleus in the CNS and as a ganglion in the PNS. A bundle of axons is referred to as a tract in the CNS and as a nerve in the PNS. Whereas nuclei and ganglia are specifically in the central or peripheral divisions, axons can cross the boundary between the two. A single axon can be part of a nerve and a tract. The name for that specific structure depends on its location.

Nervous tissue can also be described as gray matter and white matter on the basis of its appearance in unstained tissue. These descriptions are more often used in the CNS. Gray matter is where nuclei are found and white matter is where tracts are found. In the PNS, ganglia are basically gray matter and nerves are white matter.

The adult brain is separated into four major regions: the cerebrum, the diencephalon, the brain stem, and the cerebellum. The cerebrum is the largest portion and contains the cerebral cortex and subcortical nuclei. It is divided into two halves by the longitudinal fissure.

The cortex is separated into the frontal, parietal, temporal, and occipital lobes. The frontal lobe is responsible for motor functions, from planning movements through executing commands to be sent to the spinal cord and periphery. The most anterior portion of the frontal lobe is the prefrontal cortex, which is associated with aspects of personality through its influence on motor responses in decision-making.

The other lobes are responsible for sensory functions. The parietal lobe is where somatosensation is processed. The occipital lobe is where visual processing begins, although the other parts of the brain can contribute to visual function. The temporal lobe contains the cortical area for auditory processing, but also has regions crucial for memory formation.

Nuclei beneath the cerebral cortex, known as the subcortical nuclei, are responsible for augmenting cortical functions. The basal nuclei receive input from cortical areas and compare it with the general state of the individual through the activity of a dopamine-releasing nucleus. The output influences the activity of part of the thalamus that can then increase or decrease cortical activity that often results in changes to motor commands. The basal forebrain is responsible for modulating cortical activity in attention and memory. The limbic system includes deep cerebral nuclei that are responsible for emotion and memory.

The diencephalon includes the thalamus and the hypothalamus, along with some other structures. The thalamus is a relay between the cerebrum and the rest of the nervous system. The hypothalamus coordinates homeostatic functions through the autonomic and endocrine systems.

The brain stem is composed of the midbrain, pons, and medulla. It controls the head and neck region of the body through the cranial nerves. There are control centers in the brain stem that regulate the cardiovascular and respiratory systems.

The cerebellum is connected to the brain stem, primarily at the pons, where it receives a copy of the descending input from the cerebrum to the spinal cord. It can compare this with sensory feedback input through the medulla and send output through the midbrain that can correct motor commands for coordination.

Watch this video to learn about the basal nuclei (also known as the basal ganglia), which have two pathways that process information within the cerebrum. As shown in this video, the direct pathway is the shorter pathway through the system that results in increased activity in the cerebral cortex and increased motor activity. The direct pathway is described as resulting in disinhibition of the thalamus. What does disinhibition mean? What are the two neurons doing individually to cause this?

Both cells are inhibitory. The first cell inhibits the second one. Therefore, the second cell can no longer inhibit its target. This is disinhibition of that target across two synapses.

Watch this video to learn about the basal nuclei (also known as the basal ganglia), which have two pathways that process information within the cerebrum. As shown in this video, the indirect pathway is the longer pathway through the system that results in decreased activity in the cerebral cortex, and therefore less motor activity. The indirect pathway has an extra couple of connections in it, including disinhibition of the subthalamic nucleus. What is the end result on the thalamus, and therefore on movement initiated by the cerebral cortex?

By disinhibiting the subthalamic nucleus, the indirect pathway increases excitation of the globus pallidus internal segment. That, in turn, inhibits the thalamus, which is the opposite effect of the direct pathway that disinhibits the thalamus.

Watch this video to learn about the gray matter of the spinal cord that receives input from fibers of the dorsal (posterior) root and sends information out through the fibers of the ventral (anterior) root. As discussed in this video, these connections represent the interactions of the CNS with peripheral structures for both sensory and motor functions. The cervical and lumbar spinal cords have enlargements as a result of larger populations of neurons. What are these enlargements responsible for?

There are more motor neurons in the anterior horns that are responsible for movement in the limbs. The cervical enlargement is for the arms, and the lumbar enlargement is for the legs.

Compared with the nearest evolutionary relative, the chimpanzee, the human has a brain that is huge. At a point in the past, a common ancestor gave rise to the two species of humans and chimpanzees. That evolutionary history is long and is still an area of intense study. But something happened to increase the size of the human brain relative to the chimpanzee. Read this article in which the author explores the current understanding of why this happened.

According to one hypothesis about the expansion of brain size, what tissue might have been sacrificed so energy was available to grow our larger brain? Based on what you know about that tissue and nervous tissue, why would there be a trade-off between them in terms of energy use?

Original post:
14.3 The Brain and Spinal Cord Anatomy & Physiology

What are Brain and Spinal Cord Tumors?Overview of the brain and spinal cordWhat causes CNS tumors?Who is at risk?How are tumors graded?What are the possible symptoms?How are CNS tumors diagnosed?How are brain and spinal cord tumors treated?

NeurosurgeryRadiation TherapyRadiosurgeryChemotherapyTargeted TherapyAlternative and Complementary Therapy

What Research is Being Done?Appendix: Some CNS Tumors and Tumor-Related ConditionsWhere can I get more information?

A tumor is a mass of abnormal cells that either form into a new growth or the growth was there when you were born (congenital). Tumors occur when something goes wrong with genes that regulate cell growth, allowing cells to grow and divide out of control. Tumors can form anywhere in your body. Brain and spinal cord tumors form in the tissue inside your brain or spinal cord, which make up the central nervous system (CNS).

Depending on its type, a growing tumor may not cause any symptoms or can killor displace healthy cells or disrupt their function. A tumor can move or press on sensitive tissue and block the flow of blood and other fluid, causing pain and inflammation. A tumor can also block the normal flow of activity in the brain or signaling to and from the brain. Some tumors dont cause any changes.Tumors can be noncancerous (benign) or cancerous (malignant).

Tumors can be primary or secondary.

There are more than 120 types of brain and spinal cord tumors. Some are named by the type of normal cell they most closely resemble or by location. Brain and spinal cord tumors are not contagious or, at this time, preventable.

See theAppendix at the end of this guide for a listing of some CNS tumors and tumor-related conditions.

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The brain has three major parts:

The brains two halves, or hemispheres, use nerve cells (neurons) to speak with each other.Each hemisphere has four sections, called lobes, which handle different neurological functions.

For more information, see General Information About Adult Central Nervous System Tumors.

The spinal cordan extension of the brainlies protected inside the bony spinal column. It contains bundles of nerves that carry messages between the brain and other parts of the body, such as instructions to move an arm or information from the skin that signals pain.

A tumor that forms on or near the spinal cord can disrupt communication between the brain and the nerves or restrict the cord's supply of blood. Because the spinal column is narrow, a tumor hereunlike a brain tumorcan cause symptoms on both sides of the body.

Spinal cord tumors, regardless of location, often cause pain, numbness, weakness or lack of coordination in the arms and legs, usually on both sides of the body. They also often cause bladder or bowel problems.

Spinal cord tumors are described based on where on the cord the tumor is located and each vertebra (part of a series of bones that form the backbone) is numbered from top to bottom. The neck region is called cervical (C), the back region is called thoracic (T), and the lower back region is called lumbar (L) or sacral/cauda equina (S). Tumors are further described by whether the tumor begins in the cells inside the spinal cord (intramedullary) or outside the spinal cord (extramedullary). Extramedullary tumors grow in the membrane surrounding the spinal cord (intradural) or outside (extradural).

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Researchers really don't know why primary brain and spinal cord tumors develop. Possible causes include viruses, defective genes, exposure to certain chemicals and other hazardous materials, and immune system disorders. Sometimes CNS tumors may result from specific genetic diseases, such as neurofibromatosis and tuberous sclerosis, or exposure to radiation.

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Anyone can develop a primary brain or spinal cord tumor, but the overall risk is very small. Brain tumors occur more often in males than in females and are most common in middle-aged to older persons. Although uncommon in children, brain tumors tend to occur more often in children under age 9, and some tumors tend to run in families. Most brain tumors in children are primary tumors.

Other risk factors for developing a primary brain or spinal cord tumor include race (Caucasians are more likely to develop a CNS tumor) and occupation. Workers in jobs that require repeated contact with ionizing radiation or certain chemicals, including those materials used in building supplies or plastics and textiles, have a greater chance of developing a brain tumor.

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The grade of a tumor may be used to tell the difference between slow-growing and fast-growing types of the tumor. The World Health Organization (WHO) tumor grades are based on how abnormal the cancer cells look under the microscope and how quickly the tumor is likely to grow and spread. Some tumors change grade as they progress, usually to a higher grade. The tumor is graded by a pathologist following a biopsy or during surgery.

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Brain and spinal cord tumors cause many different symptoms, which can make detection tricky. Symptoms depend on tumor type, location, size, and rate of growth. Certain symptoms are quite specific because they result from damage to particular areas of the brain and spinal cord. Symptoms generally develop slowly and worsen as the tumor grows.

Brain tumor

In infants, the most obvious sign of a brain tumor is a rapidly widening head or bulging crown. Other more common symptoms of a pediatric brain tumor can include:

In older children and adults, a tumor can cause a variety of symptoms, including headaches, seizures, balance problems, and personality changes.

Other symptoms may include endocrine disorders or abnormal hormonal regulation, difficulty swallowing, facial paralysis and sagging eyelids, fatigue, weakened sense of smell, or disrupted sleep and changes in sleep patterns.

Spinal cord tumors

Common symptoms of a spinal cord tumor include:

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If you are suspected of having a brain or spinal cord tumor, your doctor (usually a neurologist, oncologist, or neuro-oncologist) will perform a neurologic exam and may order a variety of tests based on your symptoms, personal and family medical history, and results of the physical exam. Once a tumor is found on diagnostic imaging studies, surgery to obtain tissue for a biopsy or removal is often recommended. Diagnosing the type of brain or spinal cord tumor is often difficult. Some tumor types are rare and the molecular and genetic alterations of some tumors are not well understood. You may want to ask your primary care doctor or oncologist for a second opinion from a comprehensive cancer center or neuro-oncologist with experience treating your diagnosis or tumor type. Even a secondopinion that confirms the originaldiagnosis can be reassuring and help you better prepare for your care and treatment.

A neurological exam

A neurological exam can be done in your doctors office. It assesses your movement and sensory skills, hearing and speech, reflexes, vision, coordination and balance, mental status, and changes in mood or behavior.

Some advanced tests are performed and analyzed by a specialist.

Diagnostic imaging

Diagnostic imaging produces extremely detailed views of structures inside the body, including tissues, organs, bones, and nerves. Such imagingcan confirm the diagnosis and helpdoctors determine the tumor's type, treatment options, and later, whether the treatment is working.

See the NINDS publication, Neurological Diagnostic Tests and Procedures, for a more complete description of the following tests:

Usually a contrast agent (such as a dye) is injected into a vein before a CT or MRI. Many tumors become much easier to identify on the scan after the contrast is given.

Laboratory and other tests

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A specialized team of doctors advises and assists individuals throughout treatment and rehabilitation. These doctors may include:

For more information, see: https://www.cancer.gov/rare-brain-spine-tumor/tumors/about-cns-tumors#who-treats-central-nervous-system-cns-tumors.

Your health care team will recommend a treatment plan based on the tumor's location, type, size and aggressiveness, as well as medical history, age, and general health. Malignant tumors require some form of treatment, while some small benign tumors may need onlymonitoring. Treatment for a brain or spinal tumor can include surgery, radiation therapy, chemotherapy, targeted therapy, or a combination of treatments.Initial treatment for a CNS tumor may involve a variety of drugs to treat or ease symptoms, including:

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Surgery is usually the first treatment to both obtain tissue for diagnosis and remove as much tumor as can be done safely. Surgery may be the only treatment you need if your tumor is considered benign or low grade. Based on the type and grade (low versus high), doctors often recommend follow-up treatment, including radiation and chemotherapy, or an experimental treatment. You will be referred to the specialists above to provide guidance on this treatment.

Surgery is usually the first step in treating an accessible tumorone that can be removed without risk of neurological damage. Many low-grade tumors and secondary (metastatic) cancerous tumors can be removed entirely. Some tumors have a clearly defined shape and can be removed more easily. Your surgeon will try removing (called resecting or excising) all or as much tumor as possible. For malignant CNS tumors, this is best performed by a neurosurgeon.

An inaccessible or inoperable tumor is one that cannot be removed surgically because of the risk of severe nervous system damage during the operation. These tumors are frequently located deep within the brain or near vital structures such as the brain stem and may not have well-defined edges. In these cases, a biopsy may be performed.

A biopsy is sometimes performed to diagnose and help doctors determine how to treat a tumor. Biopsies can sometimes be performed by inserting a needle through a small hole in the body and taking a small piece of the tumor tissue. A pathologist will examine the tissue for certain changes that signal cancer and determine its stage or grade.

In some cases, a surgeon may need to insert a shunt into the skull to drain any dangerous buildup of CSF caused by the tumor. A shunt is a flexible plastic tube that is used to divert the flow of CSF from the central nervous system to another part of the body, where it can be absorbed as part of the normal circulatory process.

During surgery, some tools used in the operating room include a surgical microscope, the endoscope (a small viewing tube attached to a video camera), and miniature precision instruments that allow surgery to be performed through a small incision in the brain or spine. Other tools include:

For more information, see: Surgery to Treat Cancer.

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Radiation therapy usually involvesrepeated doses of high-energy beams such as x-rays or protons to kill cancer cells or keep them from multiplying. Radiation therapy can shrink the tumor mass. It can be used to treat surgically inaccessible tumors or tumor cells that may remain following surgery.

Radiation treatment can be delivered externally, using focused beams of energy or charged particles that are directed at the tumor, or from inside the body, using a surgically implanted device. The stronger the radiation, the deeper it can penetrate to the target site. Healthy cells may also be damaged by radiation therapy, but current radiation treatment is designed to minimize injury to normal tissue.

Treatment often begins soon after surgery and may continue for several weeks. Depending on the tumor type and location, a person may be able to receive a modified form of therapy to lessen damage to healthy cells and improve the overall treatment.

Externally delivered radiation therapy poses no risk of radioactivity to the person or family and friends. Types of external radiation therapy include:

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Radiosurgery is usually a one-time treatment using multiple, sharply focused radiation beams aimed at the brain or spinal cord tumor from multiple angles.It does not cut into the person but, like other forms of radiation therapy, harms a tumor cells ability to grow and divide. It is commonly used to treat surgically inaccessible tumors and maybe used at the end of conventional radiation treatment. Two common radiosurgery procedures are:

Side effects of radiation: Side effects of radiation therapy vary from person to person and are usually temporary. They typically begin about two weeks after treatment starts and may include fatigue, nausea, vomiting, reddened or sore skin in the treated area, headache, hearing loss, problems with sleep, and hair loss (although the hair usually grows back once the treatment has stopped). Radiation therapy in young children, particularly those age three years or younger, can cause problems with learning, processing information, thinking, and growing.

There are late side effects of radiation that may occur months to years after treatment that include shrinkage (atrophy) of the brain or spinal cord region that was treated.

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Chemotherapy uses powerful drugs to kill cancer cells or stop them from growing or spreading. These drugs are usually given orally, intravenously, or through a catheter or port and travel through the body to the cancerous cells. Your oncologist will recommend a treatment plan based on the type of cancer, drug(s) to be used, the frequency of administration, and the number of cycles needed. Chemotherapy is given in cycles to more effectively damage and kill cancer cells and give normal cells time to recover from any damage.

Individuals might receive chemotherapy to shrink the tumor before surgery called neo-adjuvant therapy (a first step treatment to shrink a tumor before the primary treatment). Radiation therapy can also be given as neo-adjuvant therapy. After surgery, or radiation treatment if radiation is the primary treatment, chemotherapy could be called adjuvant therapy (treatment in addition to the primary treatment). Metronomic therapy involves continuous low-dose chemotherapy to block mechanisms that stimulate the growth of new blood vessels needed to feed the tumor.

Not all tumors are vulnerable to the same anticancer drugs, so a persons treatment may include a combination of drugs. Common CNS chemotherapies include temozolomide, carmustine (also called BCNU), lomustine (also called CCNU), and bevacizumab. Individuals should be sure to discuss all options with their medical team.

Side effects of chemotherapy may include hair loss, nausea, digestive problems, reduced bone marrow production, and fatigue. The treatment can also harm normal cells that are growing or dividing at the same time, but these cells usually recover and side effects often improve or stop once the treatment has ended.

For more information about chemotherapy, see: Chemotherapy to Treat Cancer .

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Targeted therapy is a cancer treatment that uses drugs to target specific genes and proteins that are involved in tumor cell growth. This helps slow uncontrolled growth and reduce the production of tumor cells. Targeted therapies include oncogenes, growth factors, and molecules aimed at blocking gene activity.

Alternative and complementary approaches may help tumor patients better cope with their diagnosis and treatment. Some of these therapies, however, may be harmful if used during or after cancer treatment and should be discussed in advance with a doctor. Common approaches include nutritional and herbal supplements, vitamins, special diets, and mental or physical techniques to reduce stress.

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Scientists continue to investigate ways to better understand, diagnose, and treat CNS tumors. Several of todays treatments were experimental therapies only a decade ago.Clinical studies are research studies that test or observe how well medical approaches work in people.Some clinical studies test new treatments such as a new drug or medical therapy. Treatment studies help researchers learn if a new treatment is effective or less harmful than standard treatments. Studies can be considered at any point, from the time of diagnosis through recurrence. For more information about clinical studies, see: National Cancer Institute Clinical Trials.

Current clinical studies of genetic risk factors, environmental causes, and molecular mechanisms of cancers may translate into tomorrows treatment of, or perhaps cure for, these tumors.Much of this work is supported by the National Institutes of Health (NIH), through the collaborative efforts of its National Institute of Neurological Disorders and Stroke (NINDS) and National Cancer Institute (NCI), as well as other federal agencies, nonprofit groups, pharmaceutical companies, and private institutions. Some of this research is conducted through the collaborative neuroscience and cancer research community at the NIH or through research grants to academic centers throughout the United States.

The jointly sponsored NCI-NINDS Neuro-Oncology Branch coordinates research to develop and test the effectiveness and safety of novel therapies for people with CNS tumors. These experimental treatment options may include new drugs, combination therapy, gene therapy, advanced imaging and artificial intelligence, biologic immuno-agents, surgery, and radiation. Information about these trials, and trials for other disorders, can be accessed at the federal governments database of clinical trials, ClinicalTrials.gov.

Scientists at NIH and universities across the United States are exploring a variety of approaches to treat CNS tumors. These experimental approaches include boosting the immune system to better fight tumor cells, developing therapies that target the tumor cell while sparing normal cells,making improvementsin radiation therapy, disabling the tumor using genes attached to viruses, and defining biomarkers that may predict the response of a CNS tumor to a particular treatment.

Biological therapy (also called immunotherapy)involves enhancing the bodys overall immune response to recognize and fight cancer cells. The immune system is designed to attack foreign substances in the body, but because cancer cells arent foreign, they usually do not generate much of an immune response. Researchers are using different methods to provoke a strong immune response to tumor cells, including:

Targeted therapy uses molecularly targeted drugs that seek out the cellular changes that convert normal cells into cancer. Targeted therapies include:

Biomarkersare molecules or other substances in the blood or tissue that can be used to diagnose or monitor a disorder. Some CNS tumor biomarkers have been found, such as the epithelial growth factor receptor (EGRF) gene. Researchers continue to search for additional clinical biomarkers of CNS tumors, to better assess risk from environmental toxins and other possible causes and monitor and predict the outcome of CNS tumor treatment. Identifying biomarkers may also lead to the development of new disease models and novel therapies for tumor treatment.

Radiation therapyresearch includes testing several new anticancer drugs, either independently or in combination with other drugs. Researchers are also investigating combined therapies including drugs, radiation, and radiosurgery to effectively treat CNS tumors. Research areas under investigation include radiosensitizersdrugs that make rapidly dividing tumor tissue more vulnerable to radiation.

Chemotherapeutic drugresearch focuses on ways to better deliver drugsacross the blood-brain barrier and into the site of the tumor. Since chemotherapeutic drugs work in different ways to stop tumor cells from dividing, several trials are testing whether giving more than one drug, and perhaps giving them in different ways (such as staggered delivery and low-dose, long-term treatment), may kill more tumor cells without causing damaging side effects than present therapy. Researchers are examining different levels of chemotherapeutic drugs to determine whether they are less toxic to normal tissue when combined with other cancer treatments, and ways to make cancer cells more sensitive to chemotherapy. Research areas include:

Surgery studies are ongoing to better define the potential benefits of surgery, including better response to biologic therapy and chemotherapy, improved quality of life, and prolonged survival.

Clinical trials can help doctors and scientists discover whether new treatments are effective and safe for many people with spinal and brain tumors. Both healthy people and those with a disease participate in clinical trials, which increases our understanding about diseases including brain and spinal tumors. To learn more about clinical trials for CNS tumors and how to participate in them, visit http://www.clinicaltrials.gov, a database of thousands of studies, some of which include results and papers on findings.

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There are many types of brain and spinal cord tumors. These tumors are named by their location in the body, cell of origin, rate of growth, and malignancy. Some tumor types are more prevalent in children than in adults. Here is a listing of some common benign and malignant CNS tumors.

Glioma

Glioma tumorsgrow from several types of glial cells, which support the function of neurons. Gliomasusually occur in the brains cerebral hemispheres but may also strike other areas. Gliomas are classified based on the type of normal glial cells they resemble.

Mixed gliomas contain more than one type of glial cell and are usually found in the cerebrum. These tumors can spread to other sites in the brain.Other gliomas are named after the part of the body they affect. Among them are:

ChordomaChordomas are rare congenital tumors which develop from remnants of the flexible spine-like structure that forms and dissolves early in fetal development (and is later replaced by the bones of the spine). Chordomas often occur near the top or the bottom of the spine, outside the dura mater, and can invade the spinal canal and skull cavity.

Choroid plexus papillomaThis rare, usually benign childhood tumor develops slowly and can increase the production and block the flow of CSF, causing symptoms that include headaches and increased intracranial pressure. A rarer cancerous form can spread via the cerebrospinal fluid.

Germ cell tumorsThese very rare childhood tumors may start in cells that fail to leave the CNS during development. Germ cell tumors usually form in the center of the brain and can spread elsewhere in the brain and spinal cord. Different tumors are named after the type of germ cell.

MeningiomaMeningiomas are benign tumors that develop from the thin membranes, or meninges, that cover the brain and spinal cord. Meningiomas usually grow slowly, generally do not invade surrounding normal tissue, and rarely spread to other parts of the CNS or body.

Pineal TumorsThese tumors form in the pineal gland, a small structure located between the cerebellum and the cerebrum. The three most common types of pineal region tumors are gliomas, germ cell tumors, and pineal cell tumors

Pituitary Tumors (also called pituitary adenomas)These small tumors form in the pituitary gland. Most pituitary tumors are benign and their incidence increases with age. Pituitary tumors are classified as either non-secreting or secreting (secreting tumors release unusually high levels of pituitary hormones, which can trigger neurological conditions and symptoms including Cushings syndromea harmful overproduction of the hormone cortisol).

Primitive Neuroectodermal Tumors (PNET)These malignant tumors may spring from primitive or immature cells left over from early development of the nervous system. PNETS can spread throughout the brain and spinal cord in a scattered, patchy pattern and, in rare cases, cause cancer outside the CNS. The two most common PNETs are:

Vascular TumorsThese rare, noncancerous tumors arise from the blood vessels of the brain and spinal cord. The most common vascular tumor is the hemangioblastoma, a cyst-like mass of tangled blood vessels, which does not usually spread.

For information on some rare brain and spinal cord tumors, see: https://www.cancer.gov/rare-brain-spine-tumor/tumors.

Arachnoid cystsare benign, fluid-filled masses that form within a thin membrane lining (tumors are solid tissue masses). Cysts in the CNS can cause tumor-like symptoms including headache and seizures. Some cysts occur more often in the spinal cord than in the brain, and certain cysts are seen most frequently in children.

Hydrocephalusinvolves the build-up of cerebrospinal fluid in the brain. The excessive fluidcan cause harmful pressure, headaches, and nausea.

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Brain and Spinal Cord Tumors: Hope Through Research

Traumatic spinal cord injury (SCI) results in direct and indirect damage to neural tissues, which results in motor and sensory dysfunction, dystonia, and pathological reflex that ultimately lead to paraplegia or tetraplegia. A loss of cells, axon regeneration failure, and time-sensitive pathophysiology make tissue repair difficult. Despite various medical developments, there are currently no effective regenerative treatments. Stem cell therapy is a promising treatment for SCI due to its multiple targets and reactivity benefits. The present review focuses on SCI stem cell therapy, including bone marrow mesenchymal stem cells, umbilical mesenchymal stem cells, adipose-derived mesenchymal stem cells, neural stem cells, neural progenitor cells, embryonic stem cells, induced pluripotent stem cells, and extracellular vesicles. Each cell type targets certain features of SCI pathology and shows therapeutic effects via cell replacement, nutritional support, scaffolds, and immunomodulation mechanisms. However, many preclinical studies and a growing number of clinical trials found that single-cell treatments had only limited benefits for SCI. SCI damage is multifaceted, and there is a growing consensus that a combined treatment is needed.

Keywords: AD-MSCs; BM-MSCs; ESCs; EVs; NPCs; NSCs; U-MSCs; iPSCs; spinal cord injury; stem cells.

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Stem Cell Therapy for Spinal Cord Injury - PubMed

CAMBRIDGE, Mass., Dec. 22, 2022 (GLOBE NEWSWIRE) -- Mersana Therapeutics, Inc. (NASDAQ: MRSN), a clinical-stage biopharmaceutical company focused on discovering and developing a pipeline of antibody-drug conjugates (ADCs) targeting cancers in areas of high unmet medical need, today announced a research collaboration and commercial license agreement with a subsidiary of Merck KGaA, Darmstadt, Germany to discover novel Immunosynthen ADCs directed against up to two targets. Immunosynthen, Mersana’s proprietary STING-agonist ADC platform, is designed to generate systemically administered ADCs that locally activate STING signaling in both ?tumor-resident immune cells and in antigen-expressing tumor cells, unlocking the anti-tumor potential of innate immune stimulation.?

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Mersana Therapeutics Announces Research Collaboration and Commercial License Agreement with Merck KGaA, Darmstadt, Germany to Develop Novel...

Basel, 23 December 2022 - Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that the U.S. Food and Drug Administration (FDA) has approved Lunsumio® (mosunetuzumab-axgb) for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after two or more lines of systemic therapy. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Lunsumio, a CD20xCD3 T-cell engaging bispecific antibody, represents a new class of fixed-duration cancer immunotherapy, which is off-the-shelf and readily available, so that patients do not have to wait to start treatment. Lunsumio will be available in the United States in the coming weeks. “This approval is a significant milestone for people with relapsed or refractory follicular lymphoma, who have had limited treatment options until now,” said Elizabeth Budde, M.D., Ph.D., Haematologic Oncologist and Associate Professor, City of Hope Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, and Lunsumio clinical trial investigator. “As a first-in-class T-cell engaging bispecific antibody that can be initiated in an outpatient setting, Lunsumio’s high response rates and fixed-duration could change the way advanced follicular lymphoma is treated.”“Despite treatment advances, follicular lymphoma remains incurable and relapse is common, with outcomes worsening following each consecutive treatment,” said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. “Lunsumio represents our first approved T-cell engaging bispecific antibody and builds on our legacy of more than 20 years of innovation in blood cancer.”The FDA approval is based on positive results from the phase II GO29781 study of Lunsumio in people with heavily pre-treated FL, including those who were at high risk of disease progression or whose disease was refractory to prior therapies. Results from the study showed high and durable response rates. An objective response was seen in 80% (72/90 [95% confidence interval (CI): 70-88]) of patients treated with Lunsumio, with a majority maintaining responses for at least 18 months (57% [95% CI: 44-70]). The objective response rate is the combination of complete response (CR) rate (a disappearance of all signs and symptoms of cancer) and partial response rate (a decrease in the amount of cancer in the body). The median duration of response among those who responded was almost two years (22.8 months [95% CI: 10-not reached]). A CR was achieved in 60% of patients (54/90 [95% CI: 49-70]). Among 218 patients with haematologic malignancies who received Lunsumio at the recommended dose, the most common adverse event (AE) was cytokine release syndrome (CRS; 39%), which can be severe and life-threatening. The median duration of CRS events was three days (range: 1-29). Other common AEs (?20%) included fatigue, rash, pyrexia and headache.Lunsumio is administered as an intravenous infusion for a fixed-duration, which allows for time off therapy, and can be infused in an outpatient setting. Hospitalisation may be needed to manage select AEs, should be considered for subsequent infusions following a Grade 2 CRS event, and is recommended for subsequent infusions following a Grade 3 CRS event.Lunsumio was developed based on the Roche Group's broad expertise in creating bispecific antibodies. Lunsumio is designed to address the diverse needs of people with blood cancer, physicians, and practice settings, and is part of the company’s robust bispecific antibody clinical programme in lymphoma. Lunsumio is being further investigated as a subcutaneous formulation (i.e., administered under the skin) and in phase III studies that will expand the understanding of its impact in earlier lines of treatment in people with non-Hodgkin lymphoma.About the GO29781 studyThe GO29781 study [NCT02500407] is a phase II, multicentre, open-label, dose-escalation and expansion study evaluating the safety, efficacy and pharmacokinetics of Lunsumio® (mosunetuzumab-axgb) in people with relapsed or refractory B-cell non-Hodgkin lymphoma. Outcome measures include complete response rate (best response) by independent review facility (primary endpoint), objective response rate, duration of response, progression-free survival, safety, and tolerability (secondary endpoints).About follicular lymphomaFollicular lymphoma (FL) is the most common slow-growing (indolent) form of non-Hodgkin lymphoma, accounting for about one in five cases.1 It typically responds well to treatment but is often characterised by periods of remission and relapse. The disease typically becomes harder to treat each time a patient relapses, and early progression can be associated with poor long-term prognosis. It is estimated that, in the United States, approximately 13,000 new cases of FL will be diagnosed in 2022 and more than 100,000 people are diagnosed with FL each year worldwide.1,2About Lunsumio® (mosunetuzumab-axgb)Lunsumio is a first-in-class CD20xCD3 T-cell engaging bispecific antibody designed to target CD20 on the surface of B-cells and CD3 on the surface of T-cells. This dual targeting activates and redirects a patient’s existing T-cells to engage and eliminate target B-cells by releasing cytotoxic proteins into the B-cells. A robust clinical development programme for Lunsumio is ongoing, investigating the molecule as a monotherapy and in combination with other medicines, for the treatment of people with B-cell non-Hodgkin lymphomas, including follicular lymphoma and diffuse large B-cell lymphoma, and other blood cancers.About Roche in haematologyRoche has been developing medicines for people with malignant and non-malignant blood diseases for more than 20 years; our experience and knowledge in this therapeutic area runs deep. Today, we are investing more than ever in our effort to bring innovative treatment options to patients across a wide range of haematologic diseases. Our approved medicines include MabThera®/Rituxan® (rituximab), Gazyva®/Gazyvaro® (obinutuzumab), Polivy® (polatuzumab vedotin), Venclexta®/Venclyxto® (venetoclax) in collaboration with AbbVie, Hemlibra® (emicizumab) and Lunsumio® (mosunetuzumab-axgb). Our pipeline of investigational haematology medicines includes T-cell engaging bispecific antibodies, glofitamab, targeting both CD20 and CD3, and cevostamab, targeting both FcRH5 and CD3; Tecentriq® (atezolizumab), a monoclonal antibody designed to bind with PD-L1 and crovalimab, an anti-C5 antibody engineered to optimise complement inhibition. Our scientific expertise, combined with the breadth of our portfolio and pipeline, also provides a unique opportunity to develop combination regimens that aim to improve the lives of patients even further.About Roche Founded in 1896 in Basel, Switzerland, as one of the first industrial manufacturers of branded medicines, Roche has grown into the world’s largest biotechnology company and the global leader in in-vitro diagnostics. The company pursues scientific excellence to discover and develop medicines and diagnostics for improving and saving the lives of people around the world. We are a pioneer in personalised healthcare and want to further transform how healthcare is delivered to have an even greater impact. To provide the best care for each person we partner with many stakeholders and combine our strengths in Diagnostics and Pharma with data insights from the clinical practice.In recognising our endeavour to pursue a long-term perspective in all we do, Roche has been named one of the most sustainable companies in the pharmaceuticals industry by the Dow Jones Sustainability Indices for the thirteenth consecutive year. This distinction also reflects our efforts to improve access to healthcare together with local partners in every country we work. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan.

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FDA approves Roche’s Lunsumio, a first-in-class bispecific antibody, to treat people with relapsed or refractory follicular lymphoma

A bone marrow transplant is a medical treatment that replaces your bone marrow with healthy bone marrow stem cells. It is also called a stem cell transplant or, more specifically, a hematopoietic stem cell transplant. This type of transplantation can treat certain types of cancer and other diseases that affect the bone marrow. Like any cancer treatment, it can cause side effects. These side effects can be different for everyone and depend on the type of transplant you receive, your general health, and other factors.

It is a good idea to talk with your health care team about the possible side effects before starting your transplant process. This includes short-term side effects that are expected to go away over time, as well as side effects that may occur later, last longer, or be permanent. This will help you feel more prepared and supported if a side effect does occur.

And, talk with your health care team regularly about any symptoms or side effects you experience throughout your transplantation process and recovery. This includes when a side effect worsens or a new problem appears. Managing side effects is an important part of cancer care and treatment and it is especially important during transplantation. This type of care is called palliative or supportive care. It can help people with any stage of cancer feel better.

There are different kinds of bone marrow transplants and the side effects can be different. The side effects for an autologous transplant and an allogenic transplant are detailed below.

An autologous bone marrow transplant is also called an AUTO transplant or stem cell rescue. During an AUTO transplant, your own stem cells are removed from your body before an intensive chemotherapy treatment. This intensive treatment, which can also include radiation therapy, damages your stem cells. The healthy stem cells are then put back in your body to "replace" the ones damaged by the treatment.

Many side effects of an AUTO transplant are similar to common side effects of chemotherapy and radiation therapy. The most serious side effect is a higher risk of infection from your body's low levels of white blood cells.

Infection. Chemotherapy and some other treatments weaken your body's infection-fighting system, called the immune system. This is especially true of treatment given for a bone marrow/stem cell transplant, because the bone marrow is part of the immune system. When your immune system is weakened, your body cannot protect itself as well against germs. Most of these germs already live in your body. When your immune system is strong, these germs do not make you sick. But after a transplant, they can cause an infection. Fortunately, most of these infections can be easily treated with antibiotics.

About 2 weeks after your transplant day, your immune system will begin to recover. You have the highest risk of infections in the first few weeks after transplant, but you will still be at a higher risk of infections for a year or more after. Your health care team will talk to you about ways to reduce your risk of infections during your recovery. Learn more about infections as a side effect of cancer treatment.

Other immediate side effects of AUTO transplants. The following side effects can develop right after the high doses of chemotherapy used for AUTO transplants:

Long-term side effects of AUTO transplants. Some transplant side effects happen months or years later. These can include:

An allogenic transplant is also called an ALLO transplant. In an ALLO transplant, the replacement cells come from another person, called a donor. After a round of chemotherapy and sometimes radiation therapy, you will receive the donor's healthy cells.

The side effects of an ALLO transplant are similar to common side effects of chemotherapy and radiation therapy. This includes a high risk for infections. You are also at risk of side effects caused by having another person's stem cells, including a risk of graft-versus-host disease (GVHD; see below). Many people also have a "graft-versus-cancer-cell effect" along with GVHD. This is because the new stem cells recognize and destroy cancer cells that are still in the body. It is the main way ALLO transplants work to cure cancers like leukemia.

Infection. After an ALLO transplant, your doctor will give you chemotherapy, with or without radiation therapy or other drugs, to keep your body's immune system from destroying the new donated cells. These treatments affect your immune system and make infection risk higher. A weak immune system makes you more likely to get infections.

You are at the highest risk of infection in the first few weeks after receiving the donor's cells. The risks lessen over time, but infection risk reduction is an important part of your long-term recovery.

Graft-versus-host disease (GVHD). Sometimes donor cells can attack your body, causing inflammation. This is a specific side effect of ALLO transplantation called GVHD. Even if your donor was a 100% match, you can still get GVHD. Your health care team can give you medication to prevent GVHD. If you still experience GVHD, your doctor will give you more medications to manage the condition. GVHD can be life-threatening in some cases.

There are 2 types of GVHD: acute and chronic. Both can range from mild to severe.

This form of GVHD happens in the first 3 months after an ALLO transplant. It often affects the skin, intestines, and liver. It can cause rashes, diarrhea, and jaundice. Jaundice is a liver problem that makes skin and the whites of the eyes look yellow.

The treatment for acute GVHD is to block T cells. T cells are white blood cells that help the immune system fight infections. Blocking them keeps your transplanted immune system from attacking your body's own cells.

Chronic GVHD usually develops more than 3 months after an ALLO transplant. It can last a few months or the rest of your life.

Chronic GVHD may or may not cause symptoms or need treatment. You may need treatment for specific problems. Some common problems of chronic GVHD include:

There are 2 medications approved by the U.S. Food and Drug Administration (FDA) to treat chronic graft-versus-host disease.

Ruxolitinib (Jakafi) in adults and children 12 years and older after 1 or more treatments with systemic therapy

Ibrutinib (Imbruvica) in children 1 year and older after 1 or more treatments with systemic therapy

Chronic GVHD can be treated with medications called corticosteroids. If this does not work well, you might take other medications to make your immune system less active.

Other immediate side effects. Side effects that can develop right after the high doses of chemotherapy used for ALLO transplantation include the following.

Late or long-term side effects. Some transplantation side effects can happen months or years later. These can include:

People who have less powerful chemotherapy treatments before their transplant tend to have fewer long-term physical effects.

Talk with your health care team about possible physical side effects of your bone marrow transplant, as well as what signs to watch for. They can help answer your questions and make a plan to manage short-term and long-term side effects.

Bone marrow transplantation is an extended medical process, and many people experience a variety of emotional and social challenges during this treatment and recovery. This can include anxiety and depression. It can also include the uncertainty and stress that cancer brings, self-image changes, changes in relationships with loved ones, feelings of isolation, and grieving losses from cancer and its treatment.

Be sure to share your feelings, including with your health care team. They want to know how you are feeling during and after transplantation. There are many ways to help support your mental health during this stressful time, including counseling, joining a support group, journaling, art therapy, mindfulness, and meditation.

It is important to talk often with your health care team about different types of side effects, before, during, and after your transplant. This helps you gather information and make decisions on treatment and care. Here are some possible questions to ask.

What tests will be done before the transplant process starts to check my general health?

When could I start to experience side effects during this process?

What specific side effects are common with this type of transplant? How can each one be managed or relieved?

Who should I call if I experience any side effects from my transplant?

What signs of an infection should I look out for?

What precautions to prevent infection should I follow? For how long?

What side effects should I tell my health care team right away?

If I will have an ALLO transplant, will I take any medications to prevent GVHD?

If I will have an ALLO transplant, what are the signs of GVHD that I should watch for?

What tests will I need later? How often?

What are the possible late effects of a transplant? How can they be managed or relieved?

How will having a transplant affect my daily life? Can I work? Can I exercise and do regular activities? Or, when can I restart these activities during my recovery?

Will having a transplant affect my sex life? If so, how and for how long?

Will having this transplant affect my ability to have a child in the future? If so, can you refer me to a fertility specialist before treatment begins?

Why is good nutrition important during and after a transplant? Should I meet with an oncology registered dietitian?

Who can I talk with about the emotional effects of cancer and this treatment?

What can I do at home to keep myself as healthy as possible?

What is a Bone Marrow Transplant (Stem Cell Transplant)?

Resources on Bone Marrow/Stem Cell Transplant

Coping With the Fear of Treatment-Related Side Effects

Survivorship

Bone Marrow Transplant and Older Adults

Be the Match: Life After Transplant

Be the Match: GVHD Signs and Symptoms

BMT InfoNet: Transplant Basics

National Bone Marrow Transplant Link: Publications on Side Effects and Survivorship

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Side Effects of a Bone Marrow Transplant (Stem Cell Transplant)

RUDN Physician And Russian Scientists Investigate Long-term Effects Of Treating Diabetic Ulcers With Stem Cells  India Education Diary

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RUDN Physician And Russian Scientists Investigate Long-term Effects Of Treating Diabetic Ulcers With Stem Cells - India Education Diary

A heart surgeon, Professor Massimo Caputo from the Bristol Heart Institute has stated he "saved the life" of a baby by carrying out a "world-first" operation using stem cells from placentas.

Professor Massimo Caputo used pioneering stem cell injections to correct baby Finley's heart defect and says he now hopes to develop the technology so children born with congenital cardiac disease won't need much surgical operations.

Finley was born with the main arteries in his heart positioned the wrong way round and at just four days old had his first open-heart surgery at Bristol Royal Hospital for Children

Unfortunately the surgery did not solve the issue and his heart function deteriorated significantly, with the left side of the heart suffering from a severe lack of blood flow.

His mother, Melissa, from Corsham, in Wiltshire, said: "We were prepared from the start that the odds of him surviving were not good.

"After 12 hours, Finley finally came out of surgery but he needed a heart and lung bypass machine to keep alive, and his heart function had deteriorated significantly."

After weeks in intensive care it looked like there was no way to treat Finley's condition and he was reliant on drugs to keep his heart going.

But a new procedure was tried, involving stem cells from a placenta bank.

Prof Caputo injected the cells directly into Finley's heart in the hope they would help damaged blood vessels grow.

The so-called "allogeneic" cells were grown by scientists at the Royal Free Hospital in London, and millions of them were injected into Finley's heart muscle.

Allogeneic cells have the ability to grow into tissue that is not rejected and in Finley's case, have regenerated damaged heart muscle.

"We weaned him from all the drugs he was on, we weaned him from ventilation," said Prof Caputo.

"He was discharged from ITU and is now a happy growing little boy."

Finley is now aged two years.

Using a bio-printer, a stem cell scaffold is made to repair abnormalities to valves in blood vessels, and to mend holes between the two main pumping chambers of the heart.

In cardiac surgery, artificial tissue is normally used on babies for cardiac repairs, but it can fail and it does not grow with the heart, so as the children grow, they require more operations.

A child might therefore have to go through the same heart operation multiple times throughout its childhood but Prof Caputo and his team say the stem cell technology could save the UK government an estimated 30,000 for every operation no longer needed.

Dr Stephen Minger, an expert in stem cell biology and director of SLM Blue Skies Innovations Ltd said;

"Most studies that I am aware of in adults with heart dysfunction or failure show only minimal therapeutic benefit with stem cell infusion.

"I'm happy that the clinical team will go on to do a standard clinical trial which should tell us if this was a 'one-off' success and also give us some better understanding of mechanisms behind this."

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Baby's life saved by surgeon who carried out world's first surgery ...

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An organoid model of colorectal circulating tumor cells with stem cell ...