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Molecular & Cellular Medicine

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Research in the Molecular and Cellular Medicine department spans a wide range of biological processes, from structure and function of biomolecules to cell physiology. Emphasis is placed on understanding normal and abnormal biological function at the molecular and cellular levels. Using state-of-the-art biophysical technologies, research programs at the molecular level focus on understanding how proteins are synthesized, folded, assembled into functional macromolecules and trafficked throughout the cell. Reverse genetic approaches are used to elucidate the roles of newly discovered proteins and define functional protein domains. Research programs that bridge molecular and cellular levels focus on understanding mechanisms of basic cellular physiology (DNA replication, transcription, translation and protein sorting), molecules that control complex regulatory pathways (signal transduction, gene regulation, epigenetics, development and differentiation) and the molecular basis for cancer. Many faculty members have strong collaborative ties with Texas A&M University research groups in the Chemistry and Biochemistry/Biophysics departments or belong to multi-disciplinary research groups affiliated with Texas A&M University, including programs in Genetics, Neurosciences and Virology.

440 Reynolds Medical Building College Station, TX 77843-1114 Phone: (979) 436-0856 Fax: (979) 847-9481 Toll Free: (800) 298-2260 (U.S. only)

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Molecular & Cellular Medicine

Sickle Cell Anemia: MedlinePlus – National Library of Medicine

Sickle cell anemia is a disease in which your body produces abnormally shaped red blood cells. The cells are shaped like a crescent or sickle. They don't last as long as normal, round red blood cells. This leads to anemia. The sickle cells also get stuck in blood vessels, blocking blood flow. This can cause pain and organ damage.

A genetic problem causes sickle cell anemia. People with the disease are born with two sickle cell genes, one from each parent. If you only have one sickle cell gene, it's called sickle cell trait. About 1 in 12 African Americans has sickle cell trait.

The most common symptoms are pain and problems from anemia. Anemia can make you feel tired or weak. In addition, you might have shortness of breath, dizziness, headaches, or coldness in the hands and feet.

A blood test can show if you have the trait or anemia. Most states test newborn babies as part of their newborn screening programs.

Sickle cell anemia has no widely available cure. Treatments can help relieve symptoms and lessen complications. Researchers are investigating new treatments such as blood and marrow stem cell transplants, gene therapy, and new medicines.

NIH: National Heart, Lung, and Blood Institute

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Sickle Cell Anemia: MedlinePlus - National Library of Medicine

Cell Therapy and Regenerative Medicine

Adult (Somatic) stem cells are unspecialized cells that are found in different parts of the body and, depending on the source tissue, have different properties. Adult stem cells are capable of self-renewal and give rise to daughter cells that are specialized to form the cell types found in the original body part.

Adult stem cells are multipotent, meaning that they appear to be limited in the cell types that they can produce based on current evidence. However, recent scientific studies suggest that adult stem cells may have more plasticity than originally thought. Stem cell plasticity is the ability of a stem cell from one tissue to generate the specialized cell type(s) of another tissue. For example, bone marrow stromal cells are known to give rise to bone cells, cartilage cells, fat cells and other types of connective tissue (which is expected), but they may also differentiate into cardiac muscle cells and skeletal muscle cells (this was not initially thought possible).

Hematopoietic stem cells that give rise to all blood and immune cells are today the most understood of the adult stem cells. Hematopoietic stem cells from bone marrow have been providing lifesaving cures for leukemia and other blood disorders for over 40 years. Hematopoietic stem cells are primarily found in the bone marrow but have also been found in the peripheral blood in very low numbers. Compared to adult stem cells from other tissues, hematopoietic stem cells are relatively easy to obtain.

Mesenchymal stem cells are also found in the bone marrow. Mesenchymal stem cells are a mixed population of cells that can form fat cells, bone, cartilage and ligaments, muscle cells, skin cells and nerve cells.

Hematopoietic and stromal stem cell differentiation:4

Umbilical cord blood from newborns is a rich source of hematopoietic stem cells. Research has found that these stem cells are less mature than other adult stem cells, meaning that they are able to proliferate longer in culture and may contribute to a broader range of tissues. Research is ongoing to determine whether umbilical cord stem cells are pluripotent or multipotent and the extent of their plasticity.

Cord blood, which traditionally has been discarded, has emerged as an alternative source of hematopoietic stem cells for the treatment of leukemia, lymphoma and other lethal blood disorders. It has also been used as a life-saving treatment for children with infantile Krabbes disease, a lysosomal storage disease that produces progressive neurological deterioration and death in early childhood.

Regardless of the adult stem cells' source bone marrow, umbilical cord blood or other tissues these cells are present in minute quantities. This makes identification, isolation and purification challenging. Scientists are currently trying to determine how many kinds of adult stem cells exist and where they are located in the body.

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Cell Therapy and Regenerative Medicine

Oxidative Medicine and Cellular Longevity An Open Access …

Oxidative Medicine and Cellular Longevity is a unique peer-reviewed, open access journal that publishes original research and review articles dealing with the cellular and molecular mechanisms of oxidative stress in the nervous system and related organ systems in relation to aging, immune function, vascular biology, metabolism, cellular survival and cellular longevity. Oxidative stress impacts almost all acute and chronic progressive disorders and on a cellular basis is intimately linked to aging, cardiovascular disease, cancer, immune function, metabolism and neurodegeneration. The journal fills a significant void in todays scientific literature and serves as an international forum for the scientific community worldwide to translate pioneering bench to bedside research into clinical strategies.

Oxidative Medicine and Cellular Longevity was founded in 2008 by Professor Kenneth Maiese who served as the Editor-in-Chief of the journal between 2008 and 2011.

The most recent Impact Factor for Oxidative Medicine and Cellular Longevity is 3.516 according to 2014 Journal Citation Reports released by Thomson Reuters in 2015.

Oxidative Medicine and Cellular Longevity currently has an acceptance rate of 42%. The average time between submission and final decision is 52 days and the average time between acceptance and publication is 28 days.

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Department of Regenerative Medicine and Cell Biology

Message from the Chair

Welcome to the Department of Regenerative Medicine and Cell Biology. The goal of the department is to apply our knowledge of molecular and cellular biology to understand and reverse human disease. Regenerative medicine is an emerging field that aims to revolutionize the treatment of disease by providing cures rather than treating symptoms. It relies on multidisciplinary approaches that require expertise in diverse areas. Approaches include the use of stem cells to provide limitless supplies of cells for transplant therapy and disease modeling, bioengineering and tissue engineering to generate replacement tissues and organs, and the production of transgenic animals to study the fundamental molecular basis of organ formation and disease. The department has active research programs in tissue fabrication and bioengineering, developmental biology, cardiovascular and liver disease, cancer biology, cell signaling, and drug development. The Department is also heavily involved in biomedical education through the training of medical and graduate students. Regenerative medicine is at a particularly exciting stage, with investigators being poised to make discipline-changing advances of high impact. The field is on the cusp of revolutionizing biomedical science, and as regenerative medicine researchers we are limited only by our imaginations.

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Department of Regenerative Medicine and Cell Biology

Personalized RegenerativeMedicine : Dr David Steenblock

Personalized Regenerative Medicine

Making sure the bases are covered. That is how Dr David Steenblock and Personalized Regenerative Medicine delivers on its mission is to provide advanced care for chronic and degenerative disease. Our first step is to do a complete physical evaluation, including all appropriate lab work to help us determine what are the issues that each View Article

When a doctor sees a patient for the first time he will ask for copies of medical records as part of gathering information and data that, in combination with taking a medical history and doing relevant exams and tests, helps him arrive at a diagnosis (or confirm previously made ones) and formulate a medical care View Article

Providing advanced care for chronic and degenerative disease often times requires augmenting natures own repair & restoration mechanism with stem cells. This is one way that Dr David Steenblock and Personalized Regenerative Medicine provide comprehensive care it our patients. When diseasesets in and begins to progress the sufferers bodytries to repair the damage by activating View Article

In his decades of private practice, Dr David Steenblock and Personalized Regenerative Medicine has established himself as a pioneer in many fields of medicine. Dr David Steenblock and Personalized Regenerative Medicines mission is to deliver advanced care for chronic and degenerative diseases such as ALS, Stroke, Cerebral Palsy and Cardiac conditions. From stroke care andacute View Article

Putting it all together. This where Dr David Steenblock and Personalized Regenerative Medicine separate themselves from their peers in delivering advanced care for chronic and degenerative disease. Once a patients diagnosis is confirmed, modified or even overturned and the results of all tests ordered are in, Dr. Steenblock formulates a treatment plan. The therapeutic regimen View Article

Researchers in the USA have offered an explanation for the sparse inflammatory responses seen in some fungal infections.This may help physicians netter understand how to treat certain chronic and degenerative diseases, such as ALS. Stephen Klotz at the University of Arizona and co-workers examined autopsy specimens from 15 patients with histological evidence of aspergillosis, mucormycosis, View Article

Supercharged Chelation therapy is now available. If you already have read about or experienced the benefits of chelation but wondering if there was some way to enhance the therapy Dr Steenblock has come up with a better method for re-vitalization of your arteries and your entire body. The secret is STEM CELLS! The most simple View Article

While the promise of stem cell medicine has never been greater, the question of outcomes has long been an issue. Until now. Dr Steenblock has been focused on two critical issues in his career: identifying the causes of disease and treating patients. Over his many years of practice, Dr Steenblock has treated tens of thousands View Article

Dr Steenblock has long believed that Alzheimers Disease is connected to bacteria that enters the nervous system due to trauma. Recent articles have come to show that his ideas and research are correct. Traces of fungus have been discovered in the brains of Alzheimers sufferers, researchers said Thursday, relaunching the question: might the disease be View Article

Chelation therapy, an alternative technique long dismissed by conventional heart doctors, has taken a giant step toward becoming a first-line mainstream medical treatment, thanks to a boost from the National Institutes of Health. Dr Steenblock has been utilizing this powerful therapeutic approach for many years to treat various conditions. The federal health agencys National Center View Article

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Herbal medicine | Cancer Research UK

Herbal medicine uses plants, or mixtures of plant extracts, to treat illness and promote health. It aims to restore your body's ability to protect, regulate and heal itself. It is a whole body approach, so looks at your physical, mental and emotional well being. It is sometimes called phytomedicine, phytotherapy or botanical medicine.

The two most common types of herbal medicine used in the UK are Western herbal medicine and Chinese herbal medicine. Some herbalists practice less common types of herbal medicine such as Tibetan or Ayurvedic medicine (Indian).

Many modern drugs are made from plants. But herbalists dont extract plant substances in the way the drug industry does. Herbalists believe that the remedy works due to the delicate chemical balance of the whole plant, or mixtures of plants, not one particular active ingredient.

Western herbal medicine focuses on the whole person rather than their illness. So the herbalist looks at your personal health history, family history, diet and lifestyle. Herbalists use remedies made from whole plants, or plant parts, to help your body heal itself or reduce the side effects of medical treatments. Western herbal therapies are usually made from herbs that grow in Europe and North America but also use herbs from China and India.

Chinese herbal medicine is part of a whole system of medicine called Traditional Chinese Medicine (TCM) which includes

TCM aims to restore the balance of your Qi (pronounced chee). TCM practitioners believe that Qi is the flow of energy in your body, and is essential for good health. Chinese herbalists use plants according to their taste and how they affect a particular part of the body or an energy channel in the body. They may use a mixture of plants and other substances.

The Chinese remedy reference book used by TCM practitioners contains hundreds of medicinal substances. Most of the substances are plants but there are also some minerals and animal products. Practitioners may use different parts of plants such as the leaves, roots, stems, flowers or seeds. Usually, herbs are combined and you take them as teas, capsules, tinctures, or powders.

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Herbal medicine | Cancer Research UK

Beta cell regeneration – Center for Regenerative Medicine …

Researchers and physicians are studying how to regenerate beta cells in the lab and within the pancreas, which may lead to new treatments for type 1 and type 2 diabetes.

Beta cell dysfunction is a characteristic of both type 1 and type 2 diabetes. In type 1 diabetes, beta cells insulin-producing cells found in the pancreas are destroyed, while in type 2 diabetes, they may not produce enough insulin.

Since it's not possible today to generate new, patient-specific, functional beta cells, people with type 1 diabetes need insulin therapy. People with type 2 diabetes often need medications, with certain cases requiring insulin therapy.

Center for Regenerative Medicine researchers, led by Yasuhiro Ikeda, D.V.M., Ph.D., and Yogish C. Kudva, MBBS, both of Mayo Clinic in Rochester, Minn., are taking two related approaches to beta cell regeneration that may lead to new treatments for diabetes.

In the laboratory. In vitro beta cell regeneration uses induced pluripotent stem (iPS) cells, a type of bioengineered stem cell that acts like an embryonic stem cell. Using a person's own skin cells or blood cells as a starting point, Mayo researchers have successfully generated patient-specific iPS cells and subsequently converted them into glucose-responsive, insulin-producing cells in the laboratory.

Once fully optimized, such cells may enable a novel cell therapy for beta cell dysfunction in diabetes. And since the transplanted cells are derived from the patient's own cells, there would be no need to give the patient any immunosuppressive drugs, which are necessary for pancreas and islet cell transplants today.

In a patient's own pancreas. Mayo researchers are working to enhance a person's natural ability to regenerate beta cells using gene therapy, which involves delivering to the pancreas cellular factors known to enhance beta cell growth and regeneration.

Investigators have developed pancreatic beta cell- and exocrine tissue-specific gene delivery vectors, and they are now studying the therapeutic effects of pancreatic overexpression of beta cell regenerating factors.

Recent results have shown that pancreatic delivery of a synthesized artificial fusion protein can prevent diabetes development in drug-induced diabetic mice. Several other strategies are also being evaluated.

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The Stem Cell Theory of Cancer – Stanford Medicine Center

Research has shown that cancer cells are not all the same. Within a malignant tumor or among the circulating cancerous cells of a leukemia, there can be a variety of types of cells. The stem cell theory of cancer proposes that among all cancerous cells, a few act as stem cells that reproduce themselves and sustain the cancer, much like normal stem cells normally renew and sustain our organs and tissues. In this view, cancer cells that are not stem cells can cause problems, but they cannot sustain an attack on our bodies over the long term.

The idea that cancer is primarily driven by a smaller population of stem cells has important implications. For instance, many new anti-cancer therapies are evaluated based on their ability to shrink tumors, but if the therapies are not killing the cancer stem cells, the tumor will soon grow back (often with a vexing resistance to the previously used therapy). An analogy would be a weeding technique that is evaluated based on how low it can chop the weed stalksbut no matter how low the weeks are cut, if the roots arent taken out, the weeds will just grow back.

Another important implication is that it is the cancer stem cells that give rise to metastases (when cancer travels from one part of the body to another) and can also act as a reservoir of cancer cells that may cause a relapse after surgery, radiation or chemotherapy has eliminated all observable signs of a cancer.

One component of the cancer stem cell theory concerns how cancers arise. In order for a cell to become cancerous, it must undergo a significant number of essential changes in the DNA sequences that regulate the cell. Conventional cancer theory is that any cell in the body can undergo these changes and become a cancerous outlaw. But researchers at the Ludwig Center observe that our normal stem cells are the only cells that reproduce themselves and are therefore around long enough to accumulate all the necessary changes to produce cancer. The theory, therefore, is that cancer stem cells arise out of normal stem cells or the precursor cells that normal stem cells produce.

Thus, another important implication of the cancer stem cell theory is that cancer stem cells are closely related to normal stem cells and will share many of the behaviors and features of those normal stem cells. The other cancer cells produced by cancer stem cells should follow many of the rules observed by daughter cells in normal tissues. Some researchers say that cancerous cells are like a caricature of normal cells: they display many of the same features as normal tissues, but in a distorted way. If this is true, then we can use what we know about normal stem cells to identify and attack cancer stem cells and the malignant cells they produce. One recent success illustrating this approach is research on anti-CD47 therapy.

Next Section >> Case Study: Leukemia

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The Stem Cell Theory of Cancer - Stanford Medicine Center

Penn Medicine News: Genetically Modified "Serial Killer" T …

(PHILADELPHIA) -- In a cancer treatment breakthrough 20 years in the making, researchers from the University of Pennsylvania's Abramson Cancer Center and Perelman School of Medicine have shown sustained remissions of up to a year among a small group of advanced chronic lymphocytic leukemia (CLL) patients treated with genetically engineered versions of their own T cells. The protocol, which involves removing patients' cells and modifying them in Penn's vaccine production facility, then infusing the new cells back into the patient's body following chemotherapy, provides a tumor-attack roadmap for the treatment of other cancers including those of the lung and ovaries and myeloma and melanoma. The findings, published simultaneously today in the New England Journal of Medicine and Science Translational Medicine, are the first demonstration of the use of gene transfer therapy to create "serial killer" T cells aimed at cancerous tumors.

"Within three weeks, the tumors had been blown away, in a way that was much more violent than we ever expected," said senior author Carl June, MD, director of Translational Research and a professor of Pathology and Laboratory Medicine in the Abramson Cancer Center, who led the work. "It worked much better than we thought it would."

The results of the pilot trial of three patients are a stark contrast to existing therapies for CLL. The patients involved in the new study had few other treatment options. The only potential curative therapy would have involved a bone marrow transplant, a procedure which requires a lengthy hospitalization and carries at least a 20 percent mortality risk -- and even then offers only about a 50 percent chance of a cure, at best.

"Most of what I do is treat patients with no other options, with a very, very risky therapy with the intent to cure them," says co-principal investigator David Porter, MD, professor of Medicine and director of Blood and Marrow Transplantation. "This approach has the potential to do the same thing, but in a safer manner."

Secret Ingredients June thinks there were several "secret ingredients" that made the difference between the lackluster results that have been seen in previous trials with modified T cells and the remarkable responses seen in the current trial. The details of the new cancer immunotherapy are detailed in Science Translational Medicine.

After removing the patients' cells, the team reprogrammed them to attack tumor cells by genetically modifying them using a lentivirus vector. The vector encodes an antibody-like protein, called a chimeric antigen receptor (CAR), which is expressed on the surface of the T cells and designed to bind to a protein called CD19.

Once the T cells start expressing the CAR, they focus all of their killing activity on cells that express CD19, which includes CLL tumor cells and normal B cells. All of the other cells in the patient that do not express CD19 are ignored by the modified T cells, which limits side effects typically experienced during standard therapies.

The team engineered a signaling molecule into the part of the CAR that resides inside the cell. When it binds to CD19, initiating the cancer-cell death, it also tells the cell to produce cytokines that trigger other T cells to multiply -- building a bigger and bigger army until all the target cells in the tumor are destroyed.

Serial Killers "We saw at least a 1000-fold increase in the number of modified T cells in each of the patients. Drugs don't do that," June says. "In addition to an extensive capacity for self-replication, the infused T cells are serial killers. On average, each infused T cell led to the killing of thousands of tumor cells and overall, destroyed at least two pounds of tumor in each patient."

The importance of the T cell self-replication is illustrated in the New England Journal of Medicine paper, which describes the response of one patient, a 64-year old man. Prior to his T cell treatment, his blood and marrow were replete with tumor cells. For the first two weeks after treatment, nothing seemed to change. Then on day 14, the patient began experiencing chills, nausea, and increasing fever, among other symptoms. Tests during that time showed an enormous increase in the number of T cells in his blood that led to a tumor lysis syndrome, which occurs when a large number of cancer cells die all at once.

By day 28, the patient had recovered from the tumor lysis syndrome and his blood and marrow showed no evidence of leukemia.

"This massive killing of tumor is a direct proof of principle of the concept," Porter says.

The Penn team pioneered the use of the HIV-derived vector in a clinical trial in 2003 in which they treated HIV patients with an antisense version of the virus. That trial demonstrated the safety of the lentiviral vector used in the present work.

The cell culture methods used in this trial reawaken T cells that have been suppressed by the leukemia and stimulate the generation of so-called "memory" T cells, which the team hopes will provide ongoing protection against recurrence. Although long-term viability of the treatment is unknown, the doctors have found evidence that months after infusion, the new cells had multiplied and were capable of continuing their seek-and-destroy mission against cancerous cells throughout the patients bodies.

Moving forward, the team plans to test the same CD19 CAR construct in patients with other types of CD19-positive tumors, including non-Hodgkin's lymphoma and acute lymphocytic leukemia. They also plan to study the approach in pediatric leukemia patients who have failed standard therapy. Additionally, the team has engineered a CAR vector that binds to mesothelin, a protein expressed on the surface of mesothelioma cancer cells, as well as on ovarian and pancreatic cancer cells.

In addition to June and Porter, co-authors on the NEJM paper include Bruce Levine, Michael Kalos, and Adam Bagg, all from Penn Medicine. Michael Kalos and Bruce Levine are co-first authors on the Science Translational Medicine paper. Other co-authors include June, Porter, Sharyn Katz and Adam Bagg from Penn and Stephan Grupp the Children's Hospital of Philadelphia.

The work was supported by the Alliance for Cancer Gene Therapy, a foundation started by Penn graduates Barbara and Edward Netter, to promote gene therapy research to treat cancer, and the Leukemia & Lymphoma Society.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according toU.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals byU.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided$814million to benefit our community.

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