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Immunotherapy-Resistant Tumors Export PD-L1-Packed Exosomes That Travel to Lymph Nodes to Remotely Inhibit Immune Cell Activation; Understanding Biology of Exosomal PD-L1 May Be First Step Toward Novel Therapies

Immunotherapy drugs known as checkpoint inhibitors have recently revolutionized cancer treatment: many patients with malignancies that, until recently, would have been considered untreatable are experiencing long-term remissions. But the majority of patients do not respond to these drugs, and they work far better in some cancers than others, for reasons that have befuddled scientists. Now, researchers at the University of California, San Francisco (UCSF), and a collaborator at UC Berkeley, have identified a surprising phenomenon that may explain why many cancers don’t respond to these drugs, and hints at new strategies to unleash the immune system against disease. “In the best-case scenarios, like melanoma, only 20 to 30 percent of patients respond to immune checkpoint inhibitors, while in other cases, like prostate cancer, there is only a single-digit response rate,” said Robert Blelloch (https://profiles.ucsf.edu/robert.blelloch), MD, PhD, Professor of Urology at UCSF and senior author of the new study, published online on April 4, 2019 in Cell. “That means a majority of patients are not responding. We wanted to know why.” In malignant tissue, a protein called PD-L1 functions as an “invisibility cloak”: by displaying PD-L1 on their surfaces, cancer cells protect themselves from attacks by the immune system. Some of the most successful immunotherapies work by interfering with PD-L1 or with its receptor, PD-1, which resides on immune cells. When the interaction between PD-L1 and PD-1 is blocked, tumors lose their ability to hide from the immune system and become vulnerable to anti-cancer immune attacks.

Mother Nature to the Rescue--Flavonoid Derivatives from Hyacinth Family Could Prevent Blindness Caused by Diabetes, Retinopathy of Prematurity, and Wet Age-Related Macular Degeneration

Mother Nature could have the answer to treating several causes of blindness, according to a ground-breaking study involving scientists from the University of Surrey (UK), the Eugene and Marilyn Glick Eye Institute at Indiana University School of Medicine in the USA, and Kingston University-London. The scientists have found and tested compounds from a group of plants that could possibly be used to treat the causes of degenerative eye diseases such as proliferative diabetic retinopathy. This abnormal growth of new blood vessel cells in the eye is linked to a number of types of blindness, including in premature babies (retinopathy of prematurity), in diabetics (proliferative diabetic retinopathy), and in older adults (wet age-related macular degeneration). In a paper published online on April 5, 2019 in the American Chemical Society’s Journal of Natural Products, scientists from the University of Surrey, together with experts from Indiana University in America and Kingston University-London, detailed their testing of naturally occurring homoisoflavonoids found in the Hyacinthaceae plant family and their synthetic derivatives. The team tested how well these compounds were able to stop the growth of new blood vessels and isolated several active compounds. One synthetic derivative, in particular, could be used to develop future treatments. Further work is continuing to synthesize more related compounds. The article is titled “The Antiangiogenic Activity of Naturally Occurring and Synthetic Homoisoflavonoids from the Hyacinthaceae (sensu APGII).” According to Great Ormond Street Hospital (London), retinopathy of prematurity affects approximately 20 per cent of premature babies and mainly occurs mainly in those babies who are born before week 32 of pregnancy or weigh less than 1500 grams.

Genetics of Beauty—Genes Associated with Facial Attractiveness Vary Depending on Sex, According to New Study from University of Wisconsin-Madison

Genes play a role in determining the beauty of a person's face, but that role varies with the person's sex, according to a new study by Qiongshi Lu, PhD, Assistant Professor, Department of Biostatistics & Medical Bionformatics, and colleagues at the University of Wisconsin-Madison, published on April 4, 2019 in PLOS Genetics. The open-access article is titled “Genome-Wide Association Study Reveals Sex-Specific Genetic Architecture of Facial Attractiveness.” Humans tend to be preoccupied with beauty - a person's attractiveness is associated with academic performance, career success and economic mobility. But despite its importance, scientists know little about the genetic basis for having a pretty face. In the current work, researchers performed a genome-wide association study (GWAS) using genetic information from 4,383 individuals to pinpoint parts of the genome linked to facial beauty. They had volunteers score yearbook photos based on attractiveness from participants with European ancestry and compared the scores to each person's genetic information. The researchers identified several genes related to facial attractiveness, but their roles and relatedness to other human traits varied by sex. In women, certain genetic variations linked to beauty also appeared to be related to genes impacting body mass, while in males, variants in facial attractiveness were linked to genes affecting blood cholesterol levels. The study provides new insights into the genetic factors underlying facial attractiveness and highlights the complex relationships between beauty and other human traits. "Similar to many other human traits, there is not a 'master gene' that determines a person's attractiveness," author Qiongshi Lu observed. "Instead, it is most likely associated with a large number of genetic components with weak effects.

Dr. Andrew Hill, World-Class Biochemist & President of International Society for Extracellular Vesicles (ISEV) Named Winner of Prestigious 2019 Beckman Coulter Discovery Science Award

On April 2, 2019, the Australian Society for Biochemistry and Molecular Biology (ASBMB) announced that the Beckman Coulter Discovery Science Award has been awarded to Andrew Hill, PhD, Director of Australia's La Trobe Institute for Molecular Science(LIMS); Head of the Department of Biochemistry and Genetics, LIMS; Director of the La Trobe’s University-Wide Research Focus Area “Understanding Disease;” and President of the International Society for Extracellular Vesicles (ISEV). This award is presented annually to an ASBMB member for distinguished contributions to the field of biochemistry and molecular biology. Recipients have demonstrated involvement in research innovation, technology transfer, and communication. The Award is intended as a Travelling Lectureship to enable the awardee to present his/her work at a number of centers within Australia and New Zealand. The awardee will also present a Symposium talk at the ASBMB 2019 annual conference October 1-3 in Perth, Western Australia (https://asbmb2019.com.au/). Nominees must have been members of the Society for at least two years before the year in which the Award nomination is to be considered. The contribution to travel expenses is provided through the generosity of Beckman Coulter. Award winner Dr. Hill briefly described his distinguished career thus far as follows. “I gained my BSc(Hons) in Biochemistry and Molecular Biology from Victoria University of Wellington in New Zealand, where my Honors project involved using DNA fingerprinting on sheep to identify potential disease biomarkers. “In 1992, I travelled to the UK in search of a PhD position and began working on prion diseases, firstly as a research assistant and subsequently studying for a PhD in Professor John Collinge’s group at Imperial College.

Scientists Discover First Organism with Chlorophyll Genes That Does Not Photosynthesize; Unusual Organism May Provide Clues on How to Protect Endangered Coral Reefs

For the first time, scientists have found an organism that can produce chlorophyll, but does not engage in photosynthesis. The peculiar organism is dubbed “corallicolid” because it is found in 70 per cent of corals around the world and may provide clues as to how to protect coral reefs in the future. "This is the second most abundant cohabitant of coral on the planet and it hasn't been seen until now," says Patrick Keeling, a University of British Columbia (UBC) botanist and senior researcher overseeing the study published online on April 3, 2019 in Nature. The article is titled “A Widespread Coral-Infecting Apicomplexan with Chlorophyll Biosynthesis Genes.” "This organism poses completely new biochemical questions. It looks like a parasite, and it's definitely not photosynthetic. But it still makes chlorophyll." Chlorophyll is the green pigment found in plants and algae that allows them to absorb energy from sunlight during photosynthesis. "Having chlorophyll without photosynthesis is actually very dangerous because chlorophyll is very good at capturing energy, but without photosynthesis to release the energy slowly it is like living with a bomb in your cells," Dr. Keeling says. Corallicolids live in the gastric cavity of a wide array of corals responsible for building reefs, as well as in black corals, fan corals, mushroom corals, and anemones. They are an apicomplexan, part of a vast group of parasites that have a cellular compartment called a plastid, which is the part of plant and algal cells where photosynthesis takes place. The most famous apicomplexan is the parasite (Plasmodium falciparum and other Plasmodium species), responsible for malaria.

Experimental Immune-Based Therapy Completely Clears HPV in One-Third of Cervical Cancer Precursor Neoplasias; Injection of Genes for Three Proteins Triggers Immune System Response to High-Risk HPV Types

A potential new immune-based therapy to treat pre-cancers in the cervix completely eliminated both the lesion and the underlying HPV infection in a third of women enrolled in a clinical trial. The shot, a therapeutic vaccine, injects genes for three specific proteins that trigger an immune system response to attack high-risk human papilloma virus (HPV) types that cause nearly all cervical cancer precursors, known as cervical intraepithelial neoplasia (CIN). "There are very few products trying to cure women who already have an HPV infection," says Diane Harper (photo), MD, MPH, MS, Professor of Family Medicine and Obstetrics and Gynecology at Michigan Medicine. "It's very exciting. This is the first time we've seen something with this success rate that is relatively easy to implement." Cervical precancerous lesions are divided into three grades of severity: CIN 1 lesions generally clear up on their own; CIN 2 lesions often clear up on their own, but can also progress to CIN 3 lesions; CIN 3 is the most severe--it's a very slow-growing disease, though, with less than half of CIN 3 lesions becoming cancer within 30 years. "But we have no way to determine which women with CIN 3 will progress to cancer and which women will not. So, we treat all women with CIN 2 or 3 as if they are likely to develop cancer," Dr. Harper says. The study enrolled 192 women diagnosed with CIN2 or CIN3, randomizing 129 to receive the vaccine and 63 to receive a placebo. Women were given three shots in their thigh, one per week for three weeks. Six months later, the women were treated with standard surgical procedures for CIN 2/3 and the removed tissue was examined.

Violet Light Therapy Activates Opsin 5 Signaling to Restore Proper Timing Cues; May Help Prevent/Treat Retinopathy of Prematurity & Myopia in Premature Babies; Opsin-5-Dopamine Pathway Mediates Light-Dependent Vascular Development in Eye

Scientists have discovered a light-dependent molecular pathway that regulates how blood vessels develop in the eye. The findings, published online on April 1, 2019 in Nature Cell Biolog, suggest it may be possible to use light therapy to help premature infants, whose eyes are still developing, avoid certain vision problems associated with premature birth, such as retinopathy of prematurity (ROP) (https://nei.nih.gov/health/rop/rop) and myopia (sever near-sightedness), according to researchers at Cincinnati Children's Hospital Medical Center. The article is titled “An Opsin 5–Dopamine Pathway Mediates Light-Dependent Vascular Development in the Eye.” The novel molecular process, called the opsin 5-dopamine pathway helps ensure that blood-vessel development in the eye is appropriately balanced to prepare it for visual function. The process can be thrown out of balance in medically fragile premature babies. Researchers are looking for ways to prevent or treat the eye diseases known as retinopathy of prematurity (ROP) and myopia that can often result. Myopia is becoming a more common condition in adults around the globe. "Our study indicates that the opsin 5-dopamine pathway is probably part of a light-dependent disease process for conditions like myopia, which is now a worldwide epidemic," said Richard A. Lang, PhD, Director of the Visual Systems Group at Cincinnati Children's and study senior author. "It raises the interesting possibility that we might be able to use light exposure to treat conditions like retinopathy of prematurity after a premature infant is born or in people with myopia." The new study is a collaboration of research institutions in the United States and the Czech Republic that was led by Dr. Lang's team in Cincinnati.

Scientists Validate FKBP51 Protein Inhibition As Novel Pharmacological Treatment Option for Depression, Obesity, and Chronic Pain

Major depression, obesity, and chronic pain are all linked to the effects of one protein, called "FK506-binding protein 51" (FKBP51). Until now, efforts to inhibit this target have been hampered by the difficulty of finding something specific enough to do the job and not affect similar proteins. Now, a research group has developed a highly selective compound that can effectively block FKBP51 in mice, relieving chronic pain and having positive effects on diet-induced obesity and mood. The new compound also could have applications in alcoholism and brain cancer. The researchers will present their results at the American Chemical Society (ACS) Spring 2019 National Meeting & Exposition in Orlando, Florida (March 31-April 4) (https://www.acs.org/content/acs/en/meetings/national-meeting.html). ACS, the world's largest scientific society, is holding its meeting in Orlando through Thursday, April 4. The meeting features nearly 13,000 presentations on a wide range of science topics. The presentation is titled “Selective FKBP51 Inhibitors Enabled by Transient Pocket Binding” (https://plan.core-apps.com/acsorlando2019/abstract/a32c347b-962f-4303-b8...). "The FKBP51 protein plays an important role in depression, obesity, diabetes, and chronic pain states," says Felix Hausch, PhD, the project's principal investigator. "We developed the first highly potent, highly selective FKBP51 inhibitor, called SAFit2, which is now being tested in mice. Inhibition of FKBP51 could thus be a new therapeutic option to treat all of these conditions." Dr. Hausch, who is at the Technical University of Darmstadt, in Germany, started the project when studies were published linking the protein to depression. "I was intrigued by the peculiar regulatory role it seemed to play in cells," he says.

Combination of PD-1 Checkpoint Inhibitor & Antibody to CD40, Together with Standard Chemotherapy, Shows Promise in Treatment of Pancreatic Cancer

A new combination of immunotherapy and chemotherapy for pancreatic cancer caused tumors to shrink in the majority of evaluable patients, namely 20 out of 24 as of an interim analysis of the phase 1b trial data. The early findings provide hope that this strategy involving an antibody to CD40, a checkpoint inhibitor, and standard-of-care chemotherapy could be effective for treating the nation's third deadliest type of cancer. Researchers from the Abramson Cancer Center at the University of Pennsylvania (Penn) presented the findings on March 31, 2019 in a clinical trials plenary session at the American Association for Cancer Research 2019 Annual Meeting in Atlanta, Georgia (Abstract #8060). The title of the presentation is “A Phase Ib Study of CD40 Agonistic Monoclonal Antibody APX005M Together with Gemcitabine (Gem) and Nab-Paclitaxel (NP) with or without Nivolumab (Nivo) in Untreated Metastatic Ductal Pancreatic Adenocarcinoma (PDAC) Patients.” The ongoing study is being conducted in collaboration with the Parker Institute for Cancer Immunotherapy (where/what) and its other member institutions and partners. These are the first clinical trial data ever presented as a result of this collaboration. "These findings give us clues that this new and innovative combination therapy can be effective against pancreatic cancer," said the study's co-lead author Mark H. O'Hara, MD, an Assistant Professor of Hematology-Oncology at Penn, who gave the presentation. "Although only time and further research will truly tell, our data are a reason for optimism." Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and it kills more Americans each year than any cancer type other than lung and colorectal.

Glioblastoma Vaccine Shows Promising Results in Phase Ib Clinical Trial-- More Than 20 Years in the Making, Autologous Tumor-Based Vaccine with Anti-Sense DNA Oligos Suspends Cancer Growth in Early-Stage Trial—Results Termed “Incredibly Important Advance”

Glioblastoma is the most aggressive type of primary brain cancer, one with a prognosis of 11-15 months with standard treatment. Results from a phase 1b clinical trial of a new experimental glioblastoma vaccine developed by Jefferson Health (https://www.jeffersonhealth.org) and Imvax (https://www.imvax.com/), both in Philadelphia, Pennsylvania, show the experimental treatment was tolerated well by patients, slowed tumor recurrence, and prolonged patient survival. The research was presented at an oral session (https://www.abstractsonline.com/pp8/#!/6812/presentation/9839)of the American Association for Cancer Research (AACR) 2019 annual meeting on March 31, 2019 in Atlanta, Georgia. The presentation was titled "Results of a Phase Ib Trial of an Autologous Cell Vaccine for Newly Diagnosed Glioblastoma." Researchers treated 33 patients with newly diagnosed glioblastoma multiforme (GBM) with the novel cancer vaccine (IGV-001) in a prospective phase 1b clinical study and compared outcomes to a historical comparator group of 35 patients treated with standard of care at the same institution. The results showed that patients treated with the vaccine had improved progression-free survival and overall survival compared to the control group treated with standard of care alone. "The response we see in some patients is very encouraging," says David Andrews (https://hospitals.jefferson.edu/find-a-doctor/a/andrews-david-w.html), MD, Professor of Neurosurgery at the Vickie & Jack Farber Institute for Neuroscience -- Jefferson Health (https://hospitals.jefferson.edu/departments-and-services/vickie-and-jack...) and Co-Founder, Chief Medical Officer, and interim Chief Executive Officer of Imvax.

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