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Penn Scientists Uncover Dose of Medication More Likely to Put Patients with Pemphigus (Chronic, Sometimes Fatal Skin Disease) into Remission; Findings May Inform Use of Recent FDA Approved Drug Rituximab to Better Treat Patients with Pemphigus

Pemphigus, an autoimmune disease mediated by B cells and which causes painful blisters and sores on the skin and mucous membranes, is a rare chronic autoimmune condition that can be fatal if not treated. Treatment for pemphigus, most commonly through an oral medication, was often slow and would not result in complete remission. Now, new research from a team in the Perelman School of Medicine at the University of Pennsylvania shows that a lymphoma-dose regimen of rituximab, a medication regularly used to treat lymphoma and rheumatoid arthritis, is more likely to put patients with pemphigus into complete remission as compared to a rheumatoid arthritis (RA) regimen of the same medication. The findings--which were published online on October 23, 2019 in JAMA Dermatology -- have direct implications for patient care. The article is titled " Factors Associated with Complete Remission After Rituximab Therapy for Pemphigus.” When rituximab, an antibody which was first used to treat B cell lymphoma, became a treatment for pemphigus vulgaris, clinicians could choose to prescribe either a "lymphoma dose" or an "RA dose." A lymphoma-dose regimen of rituximab is a more aggressive approach to treatment compared to the dosing method for patients with rheumatoid arthritis. What's more, the U.S. Food and Drug Administration (FDA) now has an approved dosing regimen for pemphigus vulgaris, but it closely resembles the often less-effective RA dose. While both lymphoma and RA dosing approaches deplete B cells that cause disease, the lymphoma regimen takes into account a person's height and weight to determine a dose and is given weekly for four weeks. A rheumatoid arthritis dose is a fixed dose of two 1000 mg infusions given two weeks apart.

Computer Analysis Reveals Over 1 Million Nucleic Acid Polymer Molecules That Are Possible Alternatives to DNA & RNA

Biology encodes information in DNA and RNA, which are complex molecules finely tuned to their functions. But are they the only way to store hereditary molecular information? Some scientists believe life as we know it could not have existed before there were nucleic acids, thus understanding how they came to exist on the primitive Earth is a fundamental goal of basic research. The central role of nucleic acids in biological information flow also makes them key targets for pharmaceutical research, and synthetic molecules mimicking nucleic acids form the basis of many treatments for viral diseases, including HIV. Other nucleic acid-like polymers are known, yet much remains unknown regarding possible alternatives for hereditary information storage. Using sophisticated computational methods, scientists from the Earth-Life Science Institute (ELSI) at the Tokyo Institute of Technology, the German Aerospace Center (DLR), and Emory University explored the "chemical neighborhood" of nucleic acid analogues. Surprisingly, they found well over a million variants, suggesting a vast unexplored universe of chemistry relevant to pharmacology, biochemistry and efforts to understand the origins of life. The molecules revealed by this study could be further modified to gives hundreds of millions of potential pharmaceutical drug leads. The study results were published on September 9, 2019, in the Journal of Chemical Information and Modeling.

Genetic Diversity Facilitates Effectiveness of Cancer Therapy; Cancer Patients with Broader Diversity of HLA Genes Respond Better to Treatment with Checkpoint Inhibitors

The constant battle against infectious pathogens has had a decisive influence on the human immune system over the course of our evolution. A key role in our adaptation to pathogens is played by HLA molecules. These proteins activate the immune system by presenting it with fragments of pathogens that have entered the body. People with a wide variety of different HLA proteins are thus better armed against a large number of pathogens. Researchers at the Max Planck Institute for Evolutionary Biology in Plön, Germany, together with colleagues in New York, have been investigating the diversity of HLA genes in cancer patients being treated with immune checkpoint inhibitors. This form of immunotherapy activates the body's own immune cells to enable them to identify and eliminate tumor cells. The researchers discovered that patients with a wide variety of HLA molecules derive more benefit from this type of therapy. This means that in future, doctors may be able to offer improved individual treatment based on a patient's HLA gene profile. In the evolution of an organism, the characteristics which often prevail are those which increase the chances of survival and reproduction of their carrier. In contrast, for a robust immune system it could be advantageous for it to be variable, keeping as many options open as possible - a hypothesis which has been tested and confirmed in an early study carried out specifically on HLA molecules by Fr. Federica Pierini and Dr. Tobias Lenz at the Max Planck Institute for Evolutionary Biology. It is therefore essential for the effectiveness of an immune system to have many different variants of HLA molecules, Because each variant can bind to several different pathogen or cancer cell protein fragments.

For First Time, Potential Treatment Path Becomes Clear for Subtype of Charcot-Marie-Tooth Disease

An unexpected finding from the Scripps Research laboratory of Xiang-Lei Yang (photo), PhD, has illuminated a potential strategy for treating the inherited neurological disease Charcot-Marie-Tooth (CMT), for which there is no approved medicine today. CMT is a progressive disease that typically develops early in life, affecting roughly 1 in 2,500 people. Over time, the disease inflicts damage on patients' peripheral nervous system--which extends from the spinal cord into the hands and feet--often resulting in difficulties with balance, walking, and fine motor skills such as writing or buttoning a shirt. In a study that was published online on November 6, 2019 in Nature Communications, Dr. Yang and her team show that a drug may be able to prevent the disease-causing mechanisms from occurring within cells, quelling many key symptoms, Including Motor Deficits. The open-access article is titled “Transcriptional Dysregulation by a Nucleus-Localized Aminoacyl-tRNA Synthetase Associated With Charcot-Marie-Tooth Neuropathy.” The approach centers on enzymes known as aminoacyl-tRNA synthetases (aaRSs), which are pervasive throughout the body. They are the largest protein family linked to CMT disease, and also the long-running research specialty of Dr. Yang's lab. These enzymes are essential to life because they kick off the first step of making new proteins, which are the building blocks of everything from blood and hormones to skin and bones. But in patients with CMT, some of the aaRS enzymes don't function as they should. As a result, peripheral neurons aren't made properly and become toxic to the peripheral nervous system. In her search for a potential treatment approach, Dr. Yang wanted to find out why the mutated enzymes only seem to affect peripheral neurons.

Researchers Seek to Attack Leukemia Stem Cells in Effort to Cure Chronic Myeloid Leukemia

Why do some cancers come back? Sometimes, a treatment can effectively eliminate cancer cells to undetectable levels, but, if the treatment stops, cancer may return. This is the case with chronic myeloid leukemia treated with drugs known as tyrosine kinase inhibitors. These drugs have dramatically improved clinical outcomes and generated unprecedented rates of complete responses and long-term survival. To achieve these results, patients have to take the drug for the rest of their lives. "Clinical trials testing the effect of discontinuing the drug have shown that at least half of the patients achieve treatment-free remission, but in the other half the cancer returns," said Daniel Lacorazza (photo), PhD, Associate Professor of Pathology & Immunology at Baylor College of Medicine and Principal Investigator in the Experimental Immunology & Hematology Laboratory at Texas Children's Hospital. "We think that relapse occurs because tyrosine kinase inhibitors affect most chronic myeloid leukemia cells, but not leukemia stem cells. It's like removing the tree, but leaving the roots that can sprout new shoots." Leukemia stem cells are an elusive, small cell population that initiates and sustains leukemia. Stem cells can regenerate via a poorly understood mechanism of self-renewal and enter a path of development that gives rise to new leukemia cells. Dr. Lacorazza and his colleagues think that clues to treatment-free remission might be found in this little known, self-renewal mechanism. "The results of the drug discontinuation trials suggest that a cure may not be possible with tyrosine kinase inhibitors alone.

Early Results from First-In-U.S. Trial of CRISPR-Edited Immune Cells for Cancer Patients Suggest Safety of Approach

On November 6, 2019, it was announced that genetically editing a cancer patient’s immune cells using CRISPR/Cas9 technology, then infusing those cells back into the patient appears safe and feasible, based on early data from the first-ever clinical trial to test the approach in humans in the United States. Researchers from the Abramson Cancer Center of the University of Pennsylvania (https://www.pennmedicine.org/cancer) have infused three participants in the trial thus far – two with multiple myeloma and one with sarcoma – and have observed that the edited T cells expand and bind to their tumor target with no serious side effects related to the investigational approach. Penn is conducting the ongoing study in cooperation with the Parker Institute for Cancer Immunotherapy (PICI) (https://www.parkerici.org/) and Tmunity Therapeutics (https://www.tmunity.com/). “This trial is primarily concerned with three questions: can we edit T cells in this specific way? Are the resulting T cells functional? And are these cells safe to infuse into a patient? This early data suggests that the answer to all three questions may be yes,” said the study’s principal investigator Edward A. Stadtmauer, MD, Section Chief of Hematologic Malignancies at Penn. Dr. Stadtmauer will present the findings on December 7, 2019 at the 61st American Society of Hematology Annual Meeting and Exposition in Orlando (Abstract #49)(https://www.hematology.org/Annual-Meeting/)(December 7-10).

Blood Test for CA125 Level Can Help General Practitioners Spot Ovarian Cancer in Women with Suspicious Symptoms

Testing for levels of CA125 in the blood is a useful tool for gauging the likelihood of ovarian cancer and could help detect other types of cancer among patients in primary care, according to research presented at the 2019 National Cancer Research Institute (NCRI) Cancer Conference in Glasgow, UK (November 3-5). Although the CA125 test is already in use in countries around the world, this is the first large study to look at how well it performs in general practice for testing women who have possible symptoms of ovarian cancer. Researchers say their results could guide women and their general practitioners (GPs) on whether more invasive tests are needed to check for ovarian and other cancers. They also say that clinical guidelines could now be improved to ensure urgent referrals are made for women most at risk. The research was led by Dr. Garth Funston (photo), a Clinical Research Fellow at the University of Cambridge, UK. He said: "Less than half of women with ovarian cancer survive for five years following diagnosis. The majority of women are not diagnosed until the disease is advanced, which makes it more difficult to cure. It's important that GPs have effective tools to detect ovarian cancer early and ensure patients are referred appropriately. While CA125 is widely used in general practice in the UK and internationally, prior to this study, it was unclear how effective a test it really was in general practice." The research included data on 50,780 women who visited GPs in England with possible signs of ovarian cancer, such as persistent bloating or abdominal pain, and were tested for levels of CA125 in their blood between May 2011 and December 2014.

Critical Protein (ZBP1) That Could Spur West Nile/Zika Virus Treatments Is Identified

A protein that is critical in controlling replication of West Nile and Zika viruses -- and could be important for developing therapies to prevent and treat those viruses -- has been identified by a Georgia State University (GSU) biologist and his research group. The researchers found Z-DNA binding protein 1 (ZBP1) is a sensor that plays a significant role in triggering a robust immune response when it detects a viral infection within cells. The Georgia State study, published online on September 11, 2019 in the journal Frontiers in Microbiology, found that ZBP1 is essential for restricting both West Nile and Zika virus replication, and that it prevents West Nile-associated encephalitis (inflammation of the brain) in mice. The article is titled “"Z-DNA-Binding Protein 1 Is Critical for Controlling Virus Replication and Survival in West Nile Virus Encephalitis.” The absence of ZBP1 in mice leads to 100 percent mortality when mice are infected with even a non-disease-producing strain of West Nile Virus, the study found. "It's significant because you take a virus that has never been shown to kill anything and, if you block this protein, the virus will just kill everything," said Mukesh Kumar, PhD, Assistant Professor of Biology at GSU, and senior author of the study. "We discovered that when cells are infected with viruses such as Zika and West Nile, they respond by triggering necroptosis, a form of programmed cell death, via ZBP1 signaling. This inhibits viral replication and spread, allowing the immune system to clear the virus." Dr. Kumar said the findings could present new treatment strategies for viruses that can infect the central nervous system by modulating ZBP1 expression. Subsequent research by Dr. Kumar's team will explore effectiveness against similar viruses such as Eastern equine encephalitis and Powassan virus.

From Cone Snail Venom to Pain Relief; One Conotoxin (Prialt) Has Been Approved by FDA As Treatment for Sever Chronic Pain and Is 1,000 Times More Potent Than Morphine & Triggers No Dedpendence

Conotoxins are bioactive peptides found in the venom that marine cone snails produce for prey capture and defense. These peptides are used as pharmacological tools to study pain signaling and have the potential to become a new class of analgesics. To date, more than 10,000 conotoxin sequences have been discovered. Associate Professor Markus Muttenthaler, PhD, from the Faculty of Chemistry at the University of Vienna and his colleagues from the University of Queensland in Australia are experts in the field of venom drug discovery and have now provided an overview on the status quo of conotoxin research in the top-of-its-class journal "Chemical Reviews” (https://pubs.acs.org/doi/abs/10.1021/acs.chemrev.9b00207). That article, published on Octobder 21, 2019 is titled “Conotoxins: Chemistry and Biology.” In another study accepted on October 16 for publication in the Australian Journal of Chemistry, the authors describe an “On-Resin Strategy to Label Α-Conotoxins: Cy5-Rgia(https://www.publish.csiro.au/CH/justaccepted/CH19456), the researchers have furthermore developed fluorescently labeled conotoxin versions to visualize pain receptors in cells. The marine predatory cone snail is well-known for its effective envenomation strategy, which helps the relatively slow-moving animal to catch their prey such as fish or molluscs and to defend itself. The cone snail paralyzes and kills its prey with the help of a very selective and potent cocktail of venom peptides, which is injected into prey through a harpoon-like needle. "Cone snails can control their venom composition depending if they hunt or defend themselves," says Dr. Muttenthaler.

Commonly Used Diabetes Drug (Pioglitazone) Relieves Symptoms of Nicotine Withdrawal; May Provide New Strategy in Efforts to Help Individuals Stop Smoking

A drug commonly used to treat Type II diabetes abolishes the characteristic signs of nicotine withdrawal in rats and mice, according to new research published on November 4, 2019 in the Journal of Neuroscience. The finding may offer an important new strategy in the battle to end smoking. The article is titled “Activation of PPARγ attenuates the expression of physical and affective nicotine withdrawal symptoms through mechanisms involving amygdala and hippocampusneurotransmission.” Smokers trying to quit face potent side effects from nicotine withdrawal, including cravings, increased appetite, restlessness, anxiety, irritability, and depression. Even though they may want to quit, many smokers continue to smoke simply because the withdrawal experience is so unpleasant. The diabetes drug, pioglitazone, targets a specific form of the peroxisome proliferator-activated receptors in the nucleus. This receptor, PPARγ, is found in areas of the brain involved in drug addiction. In their current work, Esi Domi(photo), PhD, post-doc at the Center for Social and Affective Neuroscience-Linköping University (Sweden), and colleagues have demonstrated that direct injections of pioglitazone into the hippocampi of male mice reduced the signs of physical nicotine withdrawal, including paw tremors, chattering, and head shakes. Injecting pioglitazone into the amygdala of male mice ameliorated signs of anxiety associated with nicotine withdrawal. Nicotine abusers face a 30% higher risk of developing Type II diabetes. The researchers suggest pioglitazone may help diabetic smokers quit by lessening the physical and emotional withdrawal symptoms while reducing insulin resistance.

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