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Gladstone Study Reveals How to Reprogram Cells in Our Immune System; Discovery Could Improve Treatments for Autoimmune Diseases and Cancer

When the immune system is imbalanced, either due to overly-active cells or cells that suppress its function, it causes a wide range of diseases, from psoriasis to cancer. By manipulating the function of certain immune cells, called T cells, researchers could help restore the system's balance and create new treatments to target these diseases. Scientists at the Gladstone Institutes in San Francisco revealed, for the first time, a method to reprogram specific T cells. More precisely, they discovered how to turn pro-inflammatory cells that boost the immune system into anti-inflammatory cells that suppress it, and vice versa. The researchers studied two types of cells called effector T cells, which activate the immune system to defend our body against different pathogens, and regulatory T cells, which help control the immune system and prevent it from attacking healthy parts of its environment. "Our findings could have a significant impact on the treatment of autoimmune diseases, as well as on stem cell and immuno-oncology therapies," said Gladstone Senior Investigator Sheng Ding, PhD, who is also a Professor of Pharmaceutical Chemistry at the University of California, San Francisco. By drawing on their expertise in drug discovery, Dr. Ding's team identified a small-molecule drug that can successfully reprogram effector T cells into regulatory T cells. Their study, published online on August 2, 2017 in Nature, describes, in detail, a metabolic mechanism that helps convert one cell type into another. The article is titled “Metabolic Control of TH17 and Induced Treg Cell Balance By An Epigenetic Mechanism.” This new approach to reprogram T cells could have several medical applications. For instance, in autoimmune disease, effector T cells are overly activated and cause damage to body.

Serum Exosomal miR-125b Is a Novel Prognostic Marker For Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide with high mortality. Circulating miRNA has been demonstrated as a novel noninvasive biomarker for many tumors. A new study by collaborators in China sought to investigate the potential of circulating miR-125b as a prognostic marker of HCC. In the work, exosomes were extracted from serum samples collected from two independent cohorts: cohort 1: HCC (n=30), chronic hepatitis B (CHB, n=30), liver cirrhosis (LC, n=30); cohort 2: HCC (n=128). The researchers found that miR-125b levels were remarkably increased in exosomes compared to those in serum from patients with CHB, LC, and HCC (P<0.01, respectively). However, miR-125b levels in exosomes and the serum from HCC patients were inferior to that of CHB (P<0.01 and P=0.06) and LC patients (P<0.01 for all). Additionally, miR-125b levels in exosomes were associated with tumor number (P=0.02), encapsulation (P<0.01), and TNM stage (P<0.01). In TMN, T describes the size of the original tumor and whether it has invaded nearby tissue; N describes nearby (regional) lymph nodes that are involved; and M describes distant metastasis. Kaplan–Meier analysis indicated that HCC patients with lower exosomal miR-125b levels showed reduced time to recurrence (TTR) (P<0.01) and overall survival (OS) (P<0.01). Furthermore, multivariate analysis revealed that miR-125b level in exosomes, but not in serum, was an independent predictive factor for TTR (P<0.001) and OS (P=0.011). Exosomal miR-125b levels predicted the recurrence and survival of HCC patients with an area under the ROC curve of 0.739 (83.0% sensitivity and 67.9% specificity) and 0.702 (82.5% sensitivity and 53.4% specificity). In conclusion, the researchers believe that exosomal miR-125b could serve as a promising prognostic marker for HCC.

Scientists Uncover Secrets of Potent DNA Toxin

One of the most potent of known toxins acts by joining the two strands of the DNA double helix together in a unique fashion which foils the standard repair mechanisms cells use to protect their DNA. A team of Vanderbilt University researchers has worked out the molecular details that explain how this bacterial toxin -- yatakemycin (YTM) -- prevents DNA replication. The team’s results, described in a paper published online on July 24, 2017 in Nature Chemical Biology, explain YTM's extraordinary toxicity and could be used to fine-tune the compound's impressive antimicrobial and antifungal properties. The article is titled “Toxicity and Repair of DNA Adducts Produced by the Natural Product Yatakemycin.” YTM is produced by some members of the Streptomyces family of soil bacteria to kill competing strains of bacteria. It belongs to a class of bacterial compounds that are currently being tested for cancer chemotherapy because their toxicity is extremely effective against tumor cells. "In the past, we have thought about DNA repair in terms of protecting DNA against different kinds of chemical insults," said Professor of Biological Sciences Brandt Eichman. "Now, toxins like YTM are forcing us to consider their role as part of the ongoing chemical warfare that exists among bacteria, which can have important side effects on human health." Cells have developed several basic types of DNA repair, including base excision repair (BER) and nucleotide excision repair (NER). BER generally fixes small lesions and NER removes large, bulky lesions. A number of DNA toxins create bulky lesions that destabilize the double helix. However, some of the most toxic lesions bond to both strands of DNA, thereby preventing the cell's elaborate replication machinery from separating the DNA strands so they can be copied.

House Spider & Venomous Scorpion Share Common Ancestor; Genome Duplication Revealed by Genome Sequencing

In collaboration with scientists from the UK, Europe, Japan, and the United States, researchers at the Human Genome Sequencing Center at Baylor College of Medicine in Houston, Texas have discovered a whole genome duplication during the evolution of spiders and scorpions. The study was published online on July 31, 2017 in BMC Biology. The open-access article is titled “The House Spider Genome Reveals an Ancient Whole-Genome Duplication During Arachnid Evolution.” Researchers have long been studying spiders and scorpions for both applied reasons, such as studying venom components for pharmaceuticals and silks for materials science, and for basic questions such as the reasons for the evolution and to understand the development and ecological success of this diverse group of carnivorous organisms. As part of a pilot project for the i5K, a project to study the genomes of 5,000 arthropod species, the Human Genome Sequencing Center analyzed the genome of the house spider Parasteatoda tepidariorum - a model species studied in laboratories - and the Arizona bark scorpion Centruroides sculpturatus, - the most venomous scorpion in North America. Analysis of these genomes revealed that spiders and scorpions evolved from a shared ancestor more than 400 million years ago, which made new copies of all of the genes in its genome, a process called whole genome duplication. Such an event is one of the largest evolutionary changes that can happen to a genome and is relatively rare during animal evolution. Dr. Stephen Richards, Associate Professor in the Human Genome Sequencing Center, who led the genome sequencing at Baylor, said, "It is tremendously exciting to see rapid progress in our molecular understanding of a species that we coexist with on planet earth.

History of Gum Disease Increases Cancer Risk in Older Women; New Study Is First to Report Association Between Periodontal Disease and Gallbladder Cancer Risk In Women or Men

Postmenopausal women who have a history of gum disease also have a higher risk of cancer, according to a new study of more than 65,000 women. The study, led by researchers at the University at Buffalo (UB) in New York, is the first national study of its kind involving U.S. women, and the first to focus specifically on older women. It's also the first study to find an association between periodontal disease and gallbladder cancer risk in women or men. The findings were published on August 1, 2017 in Cancer Epidemiology, Biomarkers & Prevention. "This study is the first national study focused on women, particularly older women," said Dr. Jean Wactawski-Wende, the study's senior author. "Our study was sufficiently large and detailed enough to examine not just overall risk of cancer among older women with periodontal disease, but also to provide useful information on a number of cancer-specific sites," added Dr. Wactawski-Wende, Dean of UB's School of Public Health and Health Professions and a Professor of Epidemiology and Environmental Health. The study included 65,869 postmenopausal women enrolled in the Women's Health Initiative, an ongoing national prospective study designed to investigate factors affecting disease and death risk in older American women. The average age of the participants was 68, and most were non-Hispanic white women. As part of a follow-up health questionnaire, participants were asked "Has a dentist or dental hygienist ever told you that you had periodontal or gum disease?" Women who reported a history of gum disease had a 14 percent increased risk of overall cancer. Of the 7,149 cancers that occurred in the study participants, the majority -- or 2,416 -- were breast cancer.

CLL Cancer Cells Put Brakes on Immune System Using Exosomes Containing Y RNA; Tumor-Derived Exosomes Modulate PD-L1 Expression in Monocytes

In order for cancer cells to successfully spread and multiply, they must find a way to avoid the body's immune system. Scientists at the German Cancer Research Center (DKFZ) have recently published an explanation for how this occurs with chronic lymphatic leukemia (CLL). The CLL cells cause an inflammatory reaction and influence other blood cells with it so much, that the immune system is suppressed. The cells send out messages via exosomes, little subcellular vesicles, that the cells transmit to their surroundings. The new discovery by the DKFZ scientists paves the way for new therapy approaches. Tumor cells influence their environment in order to avoid an immune response and to facilitate favorable conditions for growth. It has been known for a long time that solid tumors, those that grow as solid tissue inside an organ, manipulate macrophages, the “big eater” cells of the immune system, for their own purposes. "Recently, we have seen more and more evidence that something similar must be happening in leukemia,” says Dr. Martina Seiffert of the DKFZ in Heidelberg. So, leukemia cells, acquired by the patient through CLL, could only survive in a culture cell if it also contains macrophages or monocytes, the precursors of the “big eaters.” They serve as a form of nourishment for cancer cells. Dr. Seiffert's team has now discovered how the interplay between leukemia cells and monocytes becomes a catalyst for cancer development. "We know that the so-called PD-L1 receptor occurs more frequently on the surface of these nourishing cells, and suppresses the immune response,” says Dr. Seiffert. "What we have here is a so-called immune checkpoint, which prevents excessive immune responses." In this case, however, the immune response is suppressed so much that the cancer cells can multiply unopposed.

New Drug May Treat and Limit Progression of Parkinson's Disease--Multifunctional Compound D-512 Provides Longer Relief Than Current Medications in Rat Model of Parkinson’s

Researchers at Binghamton University in New York have developed a new drug that may limit the progression of Parkinson's disease while providing better symptom relief to potentially hundreds of thousands of people with the disease. Symptoms of Parkinson's disease are commonly managed using selective dopamine receptor agonists. While these drugs are useful in early-stage Parkinson's, they tend to lose efficacy in later disease stages. Equally important is the fact that currently marketed drugs do not appear to modify disease progression. A research team including Binghamton University psychology professor Chris Bishop, PhD, and former graduate student Dr. David Lindenbach recently employed a preclinical model of Parkinson's disease to compare the effects of the dopamine agonist ropinirole to their new drug, known as D-512. Results demonstrated that D-512 was more efficacious than ropinirole in treating the symptoms of Parkinson's disease while also prolonging the time window during which the animals showed benefits. These findings followed on the heels of prior work by this collaborative group which demonstrated that D-512 may also protect again the progression of Parkinson's disease. "A major issue for Parkinson's disease patients is the need to take multiple medications, multiple times per day. So, we were quite astounded to discover that our new compound, D-512, was superior to the widely-used drug, ropinirole, in terms of maximal symptom relief and duration of action," said Dr. Lidenbach. The researchers also noted that D-512 may have fewer side effects than current medications. When patients take anti-parkinsonian drugs, over time they develop hyperkinetic movements that are hard to control, called dyskinesia.

Katherine Ward Wins California Outstanding Biology Teacher Award 2017 from National Association of Biology Teachers

Katherine (Katie) E. Ward (photo) has been named the Outstanding Biology Teacher from California (2017) by the National Association of Biology Teachers (NABT). Ms. Ward will be recognized at the NABT Honors Luncheon at the NABT Professional Development Conference in St. Louis this November. Ms. Ward is a lead teacher at Aragon High School in San Mateo, CA, where she teaches AP Biology and Biotechnology. She also serves as a teacher in residence at the Exploratorium Museum in San Francisco, is an active AP Leadership Academy participant, and is a Next Generation Science Standards (NGSS) Professional Development Leader, She also facilitates professional development for educators using activities sponsored by the Howard Hughes Medical Institute (HHMI).

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“Clinical Exome Sequencing Goes Live”—UCSF Hosts Symposium on Delivering Precision Medicine

by Michael A. Goldman, PhD
Professor & Chair, Biology, San Francisco State University
© 2017 by Michael A. Goldman

Stem Cell Advance at UW-Madison Brings Bioengineered Arteries Closer to Reality

Stem cell biologists have tried unsuccessfully for years to produce cells that will give rise to functional arteries and give physicians new options to combat cardiovascular disease, the world’s leading cause of death. Now, new techniques developed at the Morgridge Institute for Research in Madison, Wisconsin, and at the University of Wisconsin-Madison have produced, for the first time, functional arterial cells at both the quality and scale to be relevant for disease modeling and clinical application. Reporting in the July 10, 2017 issue of PNAS, scientists in the lab of stem cell pioneer Dr. James Thomson describe methods for generating and characterizing arterial endothelial cells — the cells that initiate artery development — that exhibit many of the specific functions required by the body. The PNAS article is titled “Functional Characterization of Human Pluripotent Stem Cell-Derived Arterial Endothelial Cells.” Further, these cells contributed both to new artery formation and improved survival rate of mice used in a model for myocardial infarction. Mice treated with this cell line had an 83 percent survival rate, compared to 33 percent for controls. “The cardiovascular diseases that kill people mostly affect the arteries, and no one has been able to make those kinds of cells efficiently before,” says Dr. Jue Zhang, a Morgridge assistant scientist and lead author. “The key finding here is a way to make arterial endothelial cells more functional and clinically useful.” The challenge is that generic endothelial cells are relatively easy to create, but they lack true arterial properties and thus have little clinical value, Dr. Zhang says. The research team applied two pioneering technologies to the project.

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