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October 23rd, 2019

Breakthrough in Genetic Skin Disease; Epigenetic Modifers DNMT3A and BCOR Are Recurrently Mutated in CYLD Cutaneous Syndrome (CCS)

A breakthrough has been made in understanding a rare genetic skin disease that causes progressively enlarging skin tumors over the scalp, face, and body. For the first time, scientists at Newcastle University, UK, have identified changes in the DNA of the tumor cells in those with CYLD (CYLD lysine 63 deubiquitinase) (image) cutaneous syndrome (CCS) that may help them grow. A study published online on October 17, 2019 in Nature Communications suggest that the tumor cells gain a “survival advantage” when the changes occur - an important step in understanding ways to develop treatments. The open-access article is titled “Epigenetic Modifiers DNMT3A and BCOR Are Recurrently Mutated in CYLD Cutaneous Syndrome.” CCS is a hereditary condition that affects areas of the body where there are hair follicles and leads to skin tumors called "cylindromas" forming and continually growing. The alterations discovered by the experts were in two genes (DNMT3A and BCOR) that are found in the skin tumors. One of the changes highlights a mechanism that the skin tumor cells use to survive and it is hoped that these could be targeted with a new class of drug to inhibit their growth. The change to the second gene is novel for skin tumors and warrants further investigation to establish the significance it has on the growth of the tumors. Dr. Neil Rajan, Senior Lecturer and Honorary Consultant Dermatologist at Newcastle University's Faculty of Medical Sciences, led the research, which was done in collaboration with Dr Serena Nik-Zainal's team at the University of Cambridge.Dr. Rajan said: "This research is an important step in the ongoing work to develop treatments for patients with CCS, which is a central goal of my research group.

Scientists Reveal Novel Oncogenic Driver Gene (DEPDC5) on Chromosome 22q in Human Gastrointestinal Stromal Tumors (GISTs); Intriguing Connection with Focal Epilepsy; DEPCD5 Agonists May Serve As Anti-Cancer Drugs

Sarcomas - cancers that arise from transformed mesenchymal cells (a type of connective tissue) - are quite deadly. Gastrointestinal stromal tumors (GISTs) are the most common human sarcoma and are initiated by activating mutations in the KIT receptor tyrosine kinase. Micro-GISTs are a smaller variation of clinical GISTs and are found in one-third of the general population without clinical symptoms. Although the micro-GISTs and clinical GISTs share the same KIT mutations, micro-GISTs have limited growth potential and do not exceed a centimeter. This size limitation suggests that additional genetic alterations contribute to the progression of clinical GISTs. Chromosome 22q deletions are frequent chromosomal abnormalities in human GISTs, occurring in ~50% of GISTs, and are thought to contribute to the pathogenesis of this disease. However, the crucial gene in 22q was unknown for decades. In a study published online on October 21, 2019 in PNAS, a team led by Professor Yuexiang Wang of the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences, together with Professor Jonathan Fletcher from Brigham and Women's Hospital and Harvard Medical School, described a novel druggable driver gene in GISTs. The PNAS article is titled “Mutational Inactivation of mTORC1 Repressor Gene DEPDC5 in Human Gastrointestinal Stromal Tumors.” The researchers performed whole exome sequencing and reported recurrent genomic inactivated DEPDC5 gene mutations in GISTs. DEPDC5 was shown to be a chromosome 22q-targeting tumor suppressor, silenced by mutations in GIST specifically. The scientists further provided evidence that inactivation of DEPDC5 promotes GIST cell proliferation by activating the mTORC1 signaling pathway and subsequently inhibiting cell cycle arrest.

October 23rd

In Nine-Year Effort, Scientists Sequence Transcriptomes of Over 1,100 Plants, Illuminating 1 Billion Years of Evolution

Plants are evolutionary champions, dominating Earth's ecosystems for more than a billion years and making the planet habitable for countless other life forms, including us. Now, scientists have completed a nine-year genetic quest to shine a light on the long, complex history of land plants and green algae, revealing the plot twists and furious pace of the rise of this super group of organisms. The project, known as the “One Thousand Plant Transcriptomes Initiative” (1KP), brought together nearly 200 plant biologists to sequence and analyze genes from more than 1,100 plant species spanning the green tree of life. A summary of the team’s findings was published online on October 23, 2019 in Nature. The open-access article is tited “One Thousand Plant Transcriptomes and the Phylogenomics of Green Plants.” "In the tree of life, everything is interrelated," said Gane Ka-Shu Wong, PhD, lead investigator of 1KP and Professor in the University of Alberta's Department of Biological Sciences. "And if we want to understand how the tree of life works, we need to examine the relationships between species. That's where genetic sequencing comes in." Much of plant research has focused on crops and a few model species, obscuring the evolutionary backstory of a clade that is nearly half a million species strong. To get a bird's-eye view of plant evolution, the 1KP team sequenced transcriptomes - the set of genes that is actively expressed to produce proteins - to illuminate the genetic underpinnings of green algae, mosses, ferns, conifers, flowering plants, and all other lineages of green plants.

MIT Scientists Build Proteins That Avoid Crosstalk with Existing Molecules; Engineered Signaling Pathways Could Offer New Strategy for Building Synthetic Biology Circuits; Approach Could Improve CAR-T Cell Therapy for Cancer, Among Other Applications

Inside a living cell, many important messages are communicated via interactions between proteins. For these signals to be accurately relayed, each protein must interact only with its specific partner, avoiding unwanted crosstalk with any similar proteins. A new MIT study sheds light on how cells are able to prevent crosstalk between these proteins, and also shows that there remains a huge number of possible protein interactions that cells have not used for signaling. This means that synthetic biologists could generate new pairs of proteins that can act as artificial circuits for applications such as diagnosing disease, without interfering with cells’ existing signaling pathways. “Using our high-throughput approach, you can generate many orthogonal versions of a particular interaction, allowing you to see how many different insulated versions of that protein complex can be built,” says Conor McClune, an MIT graduate student and the lead author of the study. In the new paper, which was published online on October 23, 2019 in Nature (https://www.nature.com/articles/s41586-019-1639-8), the researchers produced novel pairs of signaling proteins and demonstrated how they can be used to link new signals to new outputs by engineering E. coli cells that produce yellow fluorescence after encountering a specific plant hormone. The Nature article is titled “Engineering Orthogonal Signalling Pathways Reveals the Sparse Occupancy Of Sequence Space.” Michael Laub (photo), PhD, an MIT Professor of Biology, is the senior author of the study. Other authors are recent MIT graduate Aurora Alvarez-Buylla and Christopher Voigt, PhD, the Daniel I.C. Wang Professor of Advanced Biotechnology.

October 22nd

Haptoglobin Binds Free Hemoglobin and Can Prevent Neuron Damage After Brain Hemorrhage; Haptoglobin Not Normally Present at Effective Concentration in Brain, But Direct Administration in Cerebrospinal Fluid Is Protective in Animal Model

Patients who survive a cerebral hemorrhage may suffer delayed severe brain damage caused by free hemoglobin, which comes from red blood cells and damages neurons. Researchers at the University of Zurich and the University Hospital Zurich have now discovered a protective protein in the body called haptoglobin, which prevents this effect. Bleeding in the narrow space between the inner and middle meninges is life-threatening. This type of cerebral hemorrhage is normally caused by small protrusions in the major arteries at the base of the brain (aneurysms) that can burst without warning. A third of patients suffering such a hemorrhage, who are often still young, die as a result of the massive increase of pressure inside the skull. "Even if we manage to stop the bleeding and to stabilize the patients, in the first two weeks after bleeding there can be delayed brain damage. This often leads to severe impairments or can even be fatal," explains Luca Regli, MD, Director of the Department of Neurosurgery at the University Hospital Zurich (USZ). Despite great research efforts, until now, it has not been possible to prevent these serious consequences of bleeding in the subarachnoid space. An interdisciplinary team of researchers from the University of Zurich (UZH), USZ, and the Veterinary Teaching Hospital Zurich have now discovered a promising strategy: haptoglobin, a protective protein found in the blood, binds the hemoglobin that has been released in the cerebrospinal fluid before it can cause damage. The results of their work were published online on August 27, 2019 in the Journal of Clinical Investigation. The open-access article is titled “Haptoglobin Administration into the Subarachnoid Space Prevents Hemoglobin-Induced Cerebral Vasospasm.”

Blood Factor (GDF11) Stimulates Secretion of Adiponectin and Induces Calorie-Restriction-Like Phenotype in Aged Mice; Injection of GDF11 Stimulates Neurogenesis and Blood Vessel Remodeling

Aging is a process that affects all functions of the human body, particularly brain function. However, aging can be delayed through lifestyle changes (physical exercise, restricting calorie intake, etc.). Researchers at the Institut Pasteur and CNRS (Centre National de la Recherche Scientifique) have elucidated the properties of a molecule in the blood - GDF11 (image) - whose mechanisms were previously unknown. In a mouse model, they showed that this molecule could mimic the benefits of certain calorie restrictions - dietary regimens that have proven their efficacy in reducing cardiovascular disease, preventing cancer, and increasing neurogenesis in the brain. The results of this research were published in the journal Aging Cell on October 22, 2019. The open-access article is titled “Systemic GDF11 Stimulates the Secretion of Adiponectin and Induces a Calorie Restriction-Like Phenotype in Aged Mice.” Today it is possible to maintain a healthy brain in the long term. For the past 30 years, it has been generally acknowledged that certain diet restrictions such as intermittent fasting can improve cognitive performance and extend life expectancy in several species. It has also been proven that calorie restriction (a reduction in calorie intake of 20% to 30% while preserving nutritional quality) reduces the risk of cardiovascular disease and cancer, while increasing production of new neurons in the brain. In a previous study using mouse models, scientists observed that injecting aged mice with blood from young mice rejuvenated blood vessels in the brain, and consequently improved cerebral blood flow, while increasing neurogenesis and cognition .

White Bellbirds in Amazon Shatter Record for Loudest Bird Call Ever Measured

Researchers reporting in the journal Current Biology, on October 21, 2019, have captured the loudest bird calls yet documented. The calls are the mating songs of male white bellbirds, which live atop mountains in the Amazon region of northern Brazil. The open-access Current Biology article is titled “"Extremely Loud Mating Songs At Close Range In White Bellbirds.” The calls have a sound pressure about three times that of screaming pihas, now the second loudest bird singer that's been documented. In fact, the calls are so loud that the researchers are left to wonder how white bellbird females listen to them at close range without doing permanent damage to their hearing. "While watching white bellbirds, we were lucky enough to see females join males on their display perches," said Jeff Podos, PhD, of the University of Massachusetts, Amherst. "In these cases, we saw that the males sing only their loudest songs. Not only that, they swivel dramatically during these songs, so as to blast the song's final note directly at the females." "We would love to know why females willingly stay so close to males as they sing so loudly," he says. "Maybe they are trying to assess males up close, though at the risk of some damage to their hearing systems." The researchers say it's hard to describe just how loud the call really is because it's tough to make comparisons between sounds heard at different distances. Dr. Podos says that the howls of howler monkeys and bellows of bison are well studied and are both pretty loud. But they are not nearly as loud as the songs of bellbirds. That's especially impressive because of the bellbird's tiny size in comparison to those mammals. Bellbirds weigh only about a quarter of a kilogram.

Promising Treatment for Incurable, Deadly Kidney Disease—Autosomal Dominant Polycystic Kidney Disease (AD-PKD); New Drug Blocks Cyst-Promoting MicroRNA

A potential drug treatment for autosomal dominant polycystic kidney disease (AD-PKD)– a genetic disorder that causes the kidneys to swell with multiple cysts and can eventually lead to organ failure – has shown promising results in animal testing. A study describing the drug’s development and testing was published on September 12, 2019 in Nature Communications (https://www.nature.com/articles/s41467-019-11918-y). (Note: Image shows polycystic kidney at left and normal kidney at right). The study shows an approximately 50 percent reduction in kidney size in afflicted mice following treatment. The drug is now in early clinical trials in human subjects, said Dr. Vishal Patel, Associate Professor of Internal Medicine at the University of Texas (UT) Southwestern Medical Center and senior author of the study. The open-access article is titled “Discovery and Preclinical Evaluation of Anti-miR-17 Oligonucleotide RGLS4326 for the Treatment of Polycystic Kidney Disease.” Autosomal dominant polycystic kidney disease (AD-PKD) affects approximately 12 million people worldwide, with half developing end-stage kidney disease by age 60, according to the study. “Once the kidneys have failed, the only options for survival are dialysis or a kidney transplant,” Dr. Patel said.

Takeda Acquires License for First-in-Class Celiac Disease Therapy from COUR Pharmaceuticals Following Positive Phase 2a Proof-of-Concept Study

On October 22, 2019, Takeda Pharmaceutical Company Limited (TSE:4502/NYSE:TAK) (“Takeda”) and COUR Pharmaceutical Development Company, Inc. (“COUR”) announced that Takeda has acquired an exclusive global license to develop and commercialize the investigational medicine CNP-101/TAK-101, an immune-modifying nanoparticle containing gliadin proteins. Based on COUR’s antigen-specific immune tolerance platform, TAK-101 is a potential first-in-class treatment targeting the aberrant immune response in celiac disease, a serious autoimmune disease where the ingestion of gluten leads to inflammation and damage in the small intestine. Results of a randomized, double-blind, placebo-controlled clinical trial to assess the markers of potential efficacy and safety of the investigational medicine in 34 adults with proven celiac disease was presented on October 22, 2019 as a late-breaking abstract at UEG Week 2019, Barcelona, Spain (https://live.ueg.eu/week/). At inclusion, patients had well-controlled, biopsy-proven celiac disease. After inclusion, they underwent an oral gluten challenge. Based on the study, Takeda exercised its option to acquire the exclusive global license to TAK-101. “While many people living with celiac disease can manage their symptoms by following a gluten-free diet, there are currently no treatment options for those who continue to have symptoms,” said Asit Parikh MD, PhD, Head, Gastroenterology Therapeutic Area Unit at Takeda. “Our collaboration with COUR has shown, for the first time, that it is possible to induce specific immune tolerance to a foreign antigen in autoimmune diseases such as celiac disease.

New Treatment May Reverse Celiac Disease; Novel Nanotechnology Approach May Be Applicable to Other Autoimmune Diseases and Allergies, Including Multiple Sclerosis, Type 1 Diabetes, & Asthma; Takeda Acquires License for First-in-Kind Celiac Disease Therapy

Results of a new phase 2 clinical trial using technology developed at Northwestern Medicine show it is possible to induce immune tolerance to gluten in individuals with celiac disease. The findings may pave the way for treated celiac patients to eventually tolerate gluten in their diet. After treatment with the technology, the patients were able to eat gluten with a substantial reduction in inflammation. The results also show a trend toward protecting patients' small intestine from gluten exposure. The findings were presented as a late-breaking presentation on October 22 at the European Gastroenterology Week 2019 conference in Barcelona, Spain (October 19-23) (https://live.ueg.eu/week/). The technology is a biodegradable nanoparticle containing gluten that “teaches” the immune system that the antigen (allergen) is safe. The nanoparticle acts like a Trojan horse, hiding the allergen in a friendly shell, to convince the immune system not to attack it. Beyond celiac disease, the finding sets the stage for the technology -- a nanoparticle containing the antigen triggering the allergy or autoimmune disease -- to treat a host of other diseases and allergies including multiple sclerosis, type 1 diabetes, peanut allergy, asthma, and more. The technology was developed in the lab of Stephen Miller, PhD, Professor of Microbiology and Immunology at Northwestern University Feinberg School of Medicine, who has spent decades refining the technology. "This is the first demonstration the technology works in patients," said Dr. Miller, the Judy Gugenheim Research Professor of Microbiology and Immunology.