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Oncologist & Cancer Survivor David Johnson, MD, of UT Southwestern Honored As “Giant of Cancer Care” by OncLive at ASCO 2019

When David Johnson, MD, talks about his part in cancer drug development, he says, “I played a small role.” Others don’t use the word “small” to describe his contributions. They use the word “giant.” According to a June 3, 2019 release from the University of Texas (UT) Southwestern, Dr. Johnson was honored as one of 15 Giants of Cancer Care (https://www.giantsofcancercare.com/recipients/2019) recognized at the American Society of Clinical Oncology (ASCO) conference in Chicago on Friday, May 30. The award was given by OncLive, the website for the Oncology Specialty Group (https://www.onclive.com/publications/obtn/2010/april2010/oncology_specia...). Past inductees have included leading cancer experts from Harvard Medical School, Stanford, Yale, and the National Cancer Institute. Dr. John Minna, Professor and Director of the Hamon Center for Therapeutic Oncology Research at UT Southwestern Medical Center, was among the oncologists honored as a Giant of Cancer Care in 2015. The honor comes as Dr. Johnson prepares to step down after nine years of service as UT Southwestern’s Chair of Internal Medicine. He holds the Donald W. Seldin Distinguished Chair in Internal Medicine. He is an oncologist who has been on all sides of cancer: he’s an attending physician, a leading expert in clinical trials, an enthusiastic supporter of cancer research, and a former cancer patient himself. Dr. Johnson was in his early 40s, treating cancer patients in Tennessee, when he was diagnosed with lymphoma. “It came as somewhat of a shock to say the least,” he said. He soon had the chemotherapy he had prescribed for hundreds of patients in the past. He lost his hair and was hit with every side effect: neuropathy, neutropenia, fever, infections, and more.

“Only the Stressed Die Young”* Molecular Switch in Flies Is Decisive for Long Life and Stress Resilience; Transcription Factor Must Be Tightly Controlled As Too Little Leads to Longer Life, But Reduced Stress Resistance; Too Much Leads to Early Aging

The survival and fitness of multi-cellular organisms have been tightly associated with their capacity to renew their tissues. This is particularly important for tissues that are permanently exposed to and challenged by the external environment, such as the epithelium, which lines our digestive tract. Researchers led by Professor Dr. Mirka Uhlirova from CECAD (Cluster of Excellence for Aging Research at the University of Cologne) collaborated with the laboratory of Dr. Tony Southall from Imperial College London to identify the transcription factor Ets21c as a vital regulator of the regenerative program in the adult intestine of the fruit fly Drosophila. Moreover, their work highlighted the existence of trade-off mechanisms between stress resilience and longevity. The results were published online on June 4, 2019 in Cell Reports. The open-access article is titled “Ets21c Governs Tissue Renewal, Stress Tolerance, and Aging in the Drosophila Intestine.” While primarily involved in nutrient absorption and digestion, the intestinal epithelium also serves as a selective barrier that restricts the passage of pathogens and toxic substances. The renewal of the intestine is accomplished by stem cells which proliferate and differentiate to maintain tissue integrity and it functions throughout an organism's lifetime. In contrast, stem cell malfunctions have been linked to tissue degeneration or cancer development. The new research contributes to a better understanding of the molecular underpinnings of the regenerative processes under favorable as well as stress conditions.

Dogma-Shattering Work Shows That One Cell Type Can Change into Another Cell Type After Development; Key Incisive Observation Comes in Long-Studied Zebrafish (“Secret Hiding in Plain Sight”); Finding May Have Major Implications for Regenerative Medicine

A new study by researchers at the University of Virginia (UVA) and other institutions has revealed the existence of a type of pigment cell in zebrafish that can transform after development into another cell type. The work was reported online on May 28, 2019 in PNAS in an open-access article titled “Fate Plasticity and Reprogramming in Genetically Distinct Populations of Danio leucophores.” David Parichy, PhD, the Pratt-Ivy Foundation Distinguished Professor of Morphogenesis in UVA's Department of Biology, said that researchers in his lab noticed that some black pigment cells on zebrafish became gray and then eventually white. When they looked more closely, they found dramatic changes in gene expression and pigment chemistry. "We realized that the cells have a secret history hiding in plain sight," he said. "Zebrafish have been studied closely for more than 30 years - we know a lot about them - but this is the first time this transformation has been noticed. It's a very surprising discovery." The unique cell population sheds the pigment melanin, changing in color from black to white during the life cycle of an individual fish. These special cells are found at the edges of the fins, where they seem to act as a signal to other zebrafish. The ability of a developed cell to differentiate directly into another type of cell is exceptionally rare. Normally such a change requires experimental intervention, returning the cell to a stem-cell state in a dish, before it can differentiate, or transform, as something else. The new finding suggests that some developed cells might be more amenable to change than generally believed.

Gum Disease May Help Cause/Accelerate Loss of Memory & Alzheimer’s Disease; Small Molecule Inhibitors Designed to Block Neurotoxic Enzymes (Gingipains) Produced by Gum Disease Bacteria May Prove Helpful

Researchers have determined that gum disease (gingivitis) may play a decisive role in whether a person develops Alzheimer´s disease (AD) or not. "We discovered DNA-based proof that the bacteria causing gingivitis can move from the mouth to the brain," says researcher Piotr Mydel, PhD, at Broegelmanns Research Laboratory, Department of Clinical Science, University of Bergen (UiB) in Norway. The bacteria produce enzymes (gingipains) that destroy nerve cells in the brain, which in turn leads to loss of memory and, ultimately, Alzheimer´s. The research results of Dr. Mydel and his team were published in the January 23, 2019 issue of Science Advances. The open-access article is titled “Porphyromonas gingivalis in Alzheimer’s Disease Brains: Evidence for Disease Causation and Treatment with Small-Molecule Inhibitors.” Dr. Mydel points out that the bacteria is not causing Alzheimer´s alone, but the presence of these bacteria substantially raises the risk for developing the disease and the bacteria are also implicated in a more rapid progression of the disease. However, the good news is that this study shows that there are some things you can do yourself to slow down Alzheimer´s. First--"Brush your teeth and use floss.” Dr. Mydel adds that it is important, if you have established gingivitis and have Alzheimer´s in your family, to go to your dentist regularly and clean your teeth properly. Researchers have previously discovered that the bacteria causing gingivitis can move from the mouth to the brain where the harmful enzymes they excrete can destroy the nerve cells in the brain. Now, for the first time, Dr. Mydel has DNA-evidence for this process from human brains. Dr.

New Chemical Process Should Be “Important First Step Toward Establishing New Technology Platform to Greatly Facilitate Drug Discovery Across Diverse Landscape of Therapeutic Indications”—Glioblastoma & Estrogen Receptor β Are Early Targets

A research team at Dartmouth College has developed a new strategy for drug discovery and development that can be used to produce targeted therapies against diseases such as cancer and neurodegeneration, according to a study published online on June 4, 2019 in Nature Communications. The open-access article is titled “A Synthesis Strategy for Tetracyclic Terpenoids Leads to Agonists of ERβ.” It is hoped that the process will also be useful in the large-scale production of new pharmaceuticals. The team has already used the new approach to develop a molecule that is selectively effective against glioblastoma, without little effects on non-cancerous human neural stem cells and human astrocytes, and to the development of a potent inhibitor of the the nuclear hormone receptor estrogen receptor beta. The new technique uses a novel synthesis approach for a class of organic compounds known as tetracyclic terpenoids. Tetracyclic terpenoids are responsible for more than 100 FDA-approved drugs and are considered the most successful class of natural product-inspired pharmaceuticals. "Until now, there was nothing like this available for drug discovery and development," said Glenn Micalizio (photo), PhD, the New Hampshire Professor of Chemistry at Dartmouth. "While additional development is expected to enhance the power of this new technology, I believe that we are at the beginning of establishing a truly enabling and potentially transformative technology for the pharmaceutical industry." The process combines two new chemical reactions that establish bonds between carbon atoms with a unique metal-centered ring-forming reaction, also developed by Dr. Micalizio. The new technique allows for uniting molecular building blocks en route to developing a terpenoid skeleton in just a few chemical transformations.

Lithium Boosts Muscle Mass & Strength in Mouse Model of Rare Muscular Dystrophy (LGMD1D); Possible Therapeutic Target Identified

Standing up from a chair, climbing stairs, brushing one's hair – all can be a struggle for people with a rare form of muscular dystrophy that causes progressive weakness in the shoulders and hips. Over time, many such people lose the ability to walk or to lift their arms above their heads. This form of the disease, called limb girdle muscular dystrophy (LGMD), affects a few thousand people nationwide in the United States. As other rare illnesses, LGMD tends not to attract much attention from researchers and funding agencies, so progress toward developing therapies has been slow. But a team at Washington University School of Medicine in St. Louis that identified a subtype (LGMD1D) of the disease in 2012 has shown that lithium improves muscle size and strength in mice with this form of muscular dystrophy. The new findings, published in the April 2019 issue of Neurology Genetics, could lead to a drug for the disabling condition. The open-access article is titled “Lithium Chloride Corrects Weakness and Myopathology in a Preclinical Model of LGMD1D.” "There are no medications available for people with limb girdle muscular dystrophy, so we are very excited to have a good therapeutic target and a potential therapy," said senior author C. Chris Weihl, MD, PhD, a Professor of Neurology who treats people with muscular dystrophy at the university's Neuromuscular Disease Center. "This has been an amazing project. It all began when we diagnosed a patient with muscular dystrophy of unknown cause. Genetic sequencing then helped us identify a new subtype, and we've been able to take that all the way through to a possible therapy."

20 Gene Loci Are Newly Associated with Bipolar Disorder in Major International Study of Over 50,000 Subjects; New Gene Clues May Give More Refined Direction to Therapy Development

In the largest study of its kind, involving more than 50,000 subjects in 14 countries, researchers at the Icahn School of Medicine at Mount Sinai in New York City and more than 200 collaborating institutions have identified 20 new genetic associations with one of the most prevalent and elusive mental illnesses of our time--bipolar disorder. The study is reported in the May 2019 issue of Nature Genetics. A total of 30 associated loci (10 already known) were identified in the genome-wide association study. The elevated morbidity and mortality associated with bipolar disorder make it a major public health problem and a leading contributor to the global burden of disease. The identification of genes associated with bipolar disorder can help identify therapeutic targets for treatment and prevention. The title of the Nature Genetics article is “Genome-Wide Association Study Identifies 30 Loci Associated with Bipolar Disorder.” Bipolar disorder, a neuropsychiatric condition characterized by dramatic shifts in a person's mood, affects approximately 60 million people globally, 10 million of them in the United States. Unlike many other illnesses, bipolar disorder has been found to affect men, women, and people of all ethnic groups equally. While genetic and environmental factors have been demonstrated to play a role in the illness, the exact cause of bipolar disorder remains unknown. To identify genes associated with the disorder, researchers conducted a genome-wide association study (GWAS)--a study type used to look across the entire genome for differences in the genetic code that are associated with a particular trait, such as having a mental illness.

Body’s Response to Disease’s Basic Gene Defect Leads to Buildup of Mis-Produced Fat Cells That Causes Abrupt Decline in Muscle Function and Is Key to Sudden Onset of Symptoms in Limb-Girdle Muscular Dystrophy Type 2 (LGMD2B) in Young Adulthood

Research led by faculty at Children's National in Washington, DC, and published online on June 3, 2019 in Nature Communications, shows that the sudden appearance of symptoms in limb-girdle muscular dystrophy type 2B (LGMD2B) is a result of impaired communication between different cell types that facilitate repair in healthy muscle. The open-access article is titled “Fibroadipogenic Progenitors Are Responsible for Muscle Loss in Limb Girdle Muscular Dystrophy 2B.” Of particular interest are the fibro/adipogenic precursors (FAPs), cells that typically play a helpful role in regenerating muscle after injury by removing debris and enhancing the fusion of muscle cells into new myofibers. LGMD2B is caused by mutations in the DYSF gene that impair the function of dysferlin, a protein essential for repairing injured muscle fibers. Symptoms, like difficulty climbing or running, do not appear in patients until young adulthood. This late onset has long puzzled researchers, as the cellular consequences of dysferlin's absence are present from birth and continue through development, but do not impact patients until later in life. The study found that in the absence of dysferlin, muscle gradually increases the expression of the protein annexin A2 which, like dysferlin, facilitates repair of injured muscle fiber. However, increasing annexin A2 accumulates outside the muscle fiber and drives an increase in FAPs within the muscle and also influences these FAPs to differentiate into adipocytes, forming fatty deposits. Shutting down annexin A2 or blocking the adipocyte fate of FAPs using an off-the-shelf medicine arrests the fatty replacement of dysferlinopathic muscle.

Atlas of ~10,000 Genome Regions of Epigenetic Variation Between Individuals, But Consistent Across Different Tissues in Individuals, Established for DNA Methylation Marks Detectable in Blood; Work Should Aid Unraveling of Epigenetic Causes of Disease

More than 15 years after scientists first mapped the human genome, most diseases still cannot be predicted based on one's genes, leading researchers to explore epigenetic causes of disease. But the study of epigenetics cannot be approached in the same way as genetics, so progress has been slow. Now, researchers at the USDA/ARS Children's Nutrition Research Center at Baylor College of Medicine and Texas Children's Hospital have determined a unique fraction of the genome that scientists should focus on. Their report, which provides a "treasure map" to accelerate research in epigenetics and human disease, was published online on June 3, 2019 in Genome Biology. The open-access article is titled “A Genomic Atlas of Systemic Interindividual Epigenetic Variation in Humans.” Epigenetics is a system for molecular marking of DNA that tells the different cells in the body which genes to turn on or off in that cell type. But the cell-specific nature of epigenetics makes it challenging to study. Whereas a blood sample can be used to “genotype” an individual, most epigenetic marks in blood DNA provide no clues about epigenetic dysregulation in other parts of the body, such as the brain or heart. The authors note the following. “DNA methylation is thought to be an important determinant of human phenotypic variation, but its inherent cell type specificity has impeded progress on this question. At exceptional genomic regions, interindividual variation in DNA methylation occurs systemically. Like genetic variants, systemic interindividual epigenetic variants are stable, can influence phenotype, and can be assessed in any easily biopsiable DNA sample. We describe an unbiased screen for human genomic regions at which interindividual variation in DNA methylation is not tissue-specific.” Senior author Robert A.

Novartis Drug Ribociclib (Kisqali®) Shows Significant Promise in Targeted Treatment of Young Women with Advanced HR+/HER2-Negative Breast Cancer, Who Are Also Treated with Standard-of-Care Endocrine Therapy, According to Announcement at ASCO 2019

On June 1, 2019, it was announced that the international, randomized phase III MONALEESA-7 clinical trial has found that adding the Novartis drug ribociclib (Kisqali®) to standard-of-care endocrine therapy significantly improved overall survival for pre-menopausal women with advanced hormone receptor (HR)-positive/HER2-negative breast cancer compared with endocrine therapy alone. After 42 months of follow-up, the survival rate was 70% for women who took the combination therapy compared with 46% for women who received endocrine therapy only. Advanced breast cancer is the leading cause of cancer death in women 20 to 59 years of age. The MONALEESA-7 study results were presented on June 1, 2019 at the American Society of Clinical Oncology (ASCO) Annual Meeting (https://meetings.asco.org/am/learn-engage )in Chicago, Illinois, and were featured in a June 1 ASCO press briefing. The ASCO abstract (LBA 1008) is titled “Phase III MONALEESA-7 trial of Premenopausal Patients with HR+/HER2- Advanced Breast Cancer (ABC) Treated with Endocrine Therapy ± Ribociclib: Overall Survival (OS) Results.” “This is the first study to show improved survival for any targeted therapy when used with endocrine therapy as a first-line treatment for advanced breast cancer,” said the study’s lead author Sara A. Hurvitz (photo), MD, Director of the Breast Cancer Clinical Research Program at the UCLA Jonsson Comprehensive Cancer Center in Los Angeles, CA. “The use of ribociclib as a front-line therapy significantly prolonged overall survival, which is good news for women with this terrible disease. Overall survival benefit is considered the 'gold standard' in cancer trials, but is challenging to achieve in HR+/HER2- metastatic breast cancer. MONALEESA-7 reached this important endpoint earlier than anticipated.

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