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Archive - May 2015

May 31st

ASCO News: Removing More Tissue During Partial Mastectomy Could Spare Thousands of Breast Cancer Patients a Second Surgery, Yale Study Concludes; Possible “Huge Impact” for Patients, Lead Author States

Removing more tissue during a partial mastectomy could spare thousands of breast cancer patients a second surgery, according to a Yale Cancer Center study. The findings were published online on May 30, 2015 in an open-access article in the New England Journal of Medicine and presented at the 2015 Annual Meeting of the American Society of Clinical Oncology in Chicago, which runs from May 29 through June 2. The NEJM article is titled “A Randomized, Controlled Trial of Cavity Shave Margins in Breast Cancer.” Nearly 300,000 women in the United States are diagnosed with breast cancer each year; more than half undergo breast-conserving surgery with a partial mastectomy to remove the disease. However, between 20% and 40% of patients who undergo this procedure have "positive margins," or cancer cells found at the edge of what is removed. The presence of positive margins often leads to a second surgery to ensure that no cancer remains. The Yale study explored how removing more tissue all the way around the tumor site during the initial surgery -- known as cavity shave margins (CSM) -- could reduce the need for a second surgery. In this study of 235 patients with breast cancer ranging from stage 0 to stage III, surgeons performed a partial mastectomy as they normally would. Patients were then randomized in the operating room to either have additional CSM removed or not. "Despite their best efforts, surgeons could not predict where the cancer was close to the edge," said the study's lead author, Dr. Anees Chagpar, Associate Professor of Surgery (Oncology) at Yale School of Medicine and director of The Breast Center at Smilow Cancer Hospital at Yale-New Haven.

Breast Cancer Cells Release Key Enzyme (Lysyl Oxidase) to Pre-Condition Bone for Metastasis; Blocking Enzyme May Help Thwart Secondary Cancers; Biphosphonates Effective in Animal Model

Leading scientists from the University of Sheffield in the UK and the University of Copenhagen in Denmark have identified a possible key to preventing secondary cancers in breast cancer patients, after discovering an enzyme which enhances the spread of the disease. Secondary (metastatic) breast cancer is the main cause of the 12,000 deaths which occur from breast cancer in the UK every year. The most common site for the disease to spread is the bone – occurring in approximately 85 per cent of secondary breast cancer patients. The new research found that the enzyme lysyl oxidase (LOX) released from the primary tumor creates holes in bone and prepares the bone for the future arrival of cancer cells. The work was published online on May 27, 2015 in an open-access article in Nature. The article is titled “ The findings suggest that identifying LOX in estrogen-receptor-negative (ER-negative) breast cancer patients early on, could allow doctors to block the enzyme’s activity, preventing bone damage, and the subsequent spread of breast tumor cells to the bone (metastasis), halting the progression of the disease. The researchers also showed that treatment with bisphosphonate, an existing class of drug which prevents the loss of bone mass and is already used to treat diseases such as osteoporosis, was able to prevent the changes in the bone and the spread of the disease in mice. The pioneering research, co-led by Dr. Alison Gartland at the University of Sheffield’s Department of Human Metabolism, could lead to a better prognosis for cancer patients in the longer term. Dr. Gartland said: “This is important progress in the fight against breast cancer metastasis and these findings could lead to new treatments to stop secondary breast tumors growing in the bone, increasing the chances of survival for thousands of patients.”

May 30th

Fruit Flies Remember the Time of Day

Flies might be smarter than you think. According to research reported online on May 28, 2015 in the Cell Press journal Current Biology, fruit flies know what time of day it is. What's more, the insects can learn to connect different scents with the sweet reward of sugar, depending on the hour: menthol in the morning and mushrooms in the afternoon. Researchers say that the findings show the surprising mental abilities of animals, no matter how small. "If even the fly, with its miniature brain, has the sense of time, most animals may have it," says Dr. Martin Heisenberg of the Rudolf Virchow Center in Germany. In earlier studies, researchers had shown that mice and honeybees can associate a reward--food or a mate, for instance--with a particular time of day. To understand how this memory for time works in the new study, Dr. Heisenberg and his colleagues looked to the fruit fly. The researchers trained hungry flies to associate two different chemical odors with sugar in the morning or in the afternoon on two consecutive days. On the third day, they tested the flies' preference for one scent or the other. The results were clear: the flies learned to switch their scent preference over the course of the day. Flies tested in the morning preferred the odor paired during training with sucrose in the morning, while flies tested in the afternoon preferred the odor paired with sucrose in the afternoon. Their ability to tell time remained as long as the two separate events were separated by a period of at least four hours. The researchers found that the flies' time-keeping ability remained both in constant darkness and with a regular light-dark cycle. The flies couldn't keep time, however, when the lights were kept on around the clock.

New Chromosome Phasing Technique “Will Greatly Accelerate Our Understanding of Disease Genomics,” Author States; Approach Is Rapid, Scalable, and Cost-Effective

Researchers at Harvard Medical School and the Digital Biology Center at Bio-Rad Laboratories, Inc., have developed a rapid, scalable, and cost-effective method for chromosomal phasing that provides researchers with a new method to determine if genetic variants are linked on the same chromosome. Using Bio-Rad's Droplet Digital PCR (ddPCR(TM)) technology, the Drop-Phase method can rapidly determine the chromosomal phase of allelic markers hundreds of kilobases apart. This ability may provide new insights into the cause, penetrance, and severity of diseases. The collaborators published their findings online on March 4, 2015 in the open-access journal PLOS ONE in a research article titled "A Rapid Molecular Approach for Chromosomal Phasing." The "phase" (or linked arrangement) of variants along a single chromosome is known as the haplotype, which is an important piece of the genetic puzzle of a disease. Haplotype cannot be determined from standard DNA sequencing, due to short read lengths. Unlike conventional phasing methods that are tedious and expensive, Drop-Phase can be used to quickly and affordably determine the phase of multiple sequence variants in a region of interest after a sample has been sequenced. The resulting haplotype data can then be used to characterize how specific combinations of variants contribute to the severity of a disease. Drop-Phase can also be used to screen individuals for specific haplotypes when sequencing data are unavailable. This is particularly valuable for prospective clinical trials. "We expect researchers to use Drop-Phase to resolve the configuration of variants discovered from genome-wide association studies and determine whether certain haplotypes contribute to the severity of a disease," said Dr.

ASCO News: Targeted Drug (Pacritinib) Reduces Symptoms and Burden of Advanced Myelofibrosis, Mayo Researcher Says

Use of the targeted agent pacritinib (image) significantly reduced the symptoms and burden of advanced myelofibrosis in patients, says a Mayo Clinic researcher who co-led PERSIST-1, the worldwide phase III clinical trial that tested the therapy. Specifically, pacritinib substantially reduced severe enlargement of the spleen, a typical feature of advanced myelofibrosis, in more than 20 percent of patients and alleviated debilitating side effects in more than 46 percent of patients. Investigators further found that pacritinib could be used safely in patients with myelofibrosis who have thrombocytopenia, a life-threating loss of blood platelets that can lead to deadly bleeding. The only currently approved therapy for myelofibrosis -- ruxolitinib -- is not recommended in patients who have severe thrombocytopenia. Ruben A. Mesa, M.D., Chair of Hematology and Medical Oncology at the Mayo Clinic in Arizona, will present these results at a press conference held during the 2015 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, May 29 through June 2. “Use of pacritinib can alleviate the burden and diminish the suffering that this cancer causes,” says Dr. Mesa. “For many of the patients who used it, pacritinib is a very good drug. The agent was significantly superior to other medical treatments. It is too early to know if pacritinib has an impact on survival, but that is clearly our expectation,” he adds. Mayo researchers led by Dr. Mesa were also part of a phase II trial that found pacritinib offered significant benefit in treating the disorder. Myelofibrosis is a chronic bone-marrow disorder that can lead to lowering of blood counts, scarring in the bone marrow, severe symptoms, and enlargement of the spleen.

Balance Between WOX5 Transcription Factor and CDF4 Differentiation Protein Key to Maintaining Pluripotent Stem Cells in Plant Roots

The roots of a plant are constantly growing, so that they can provide the plant with water and minerals while also giving it a firm anchor in the ground. Responsible for these functions are pluripotent stem cells. In order to avoid differentiation and to remain pluripotent, these stem cells are dependent on signals from their neighboring cells. These signals are generated by only a small group of slowly dividing cells in the so-called quiescent center inside the root. An international consortium under the leadership of Prof. Dr. Thomas Laux, a biologist from the University of Freiburg in Germany, has identified the transcription factor Wuschel homeobox (WOX) 5 as the signaling molecule, showing that it moves through pores from the cells inside the quiescent center into the stem cells. The Laux team of researchers has published its findings online on May 28, 2015 in Develomental Cell. The article is titled “Organizer-Derived WOX5 Signal Maintains Root Columella Stem Cells through Chromatin-Mediated Repression of CDF4 Expression.” “Solving the mechanism by which signals within the root control stem cell activity has implications for the general workings of the stem cell regulation in plants and humans,” Dr. Laux said. He also explained that this will allow scientists to study how plant growth adjusts to different environmental conditions, adding that, “this is a fascinating field of research in the era of climate change.” Dr. Laux is the head of a laboratory at the Institute of Biology III and a member of the cluster of excellence BIOSS Centre for Biological Signaling Studies at the University of Freiburg.

Exosomes Release miR155 to Neuroblastoma Cells, Silencing TERF1 Inhibitor of Telomerase, Promoting Tumor Growth, and Increasing Resistance to Chemotherapy; Blocking Exosome Delivery of miR155 Decreases Chemotherapy Resistance of Neuroblastoma

Researchers at Children’s Hospital Los Angeles (CHLA) have made an important step toward finding a target in the fight against drug-resistant neuroblastoma (NBL), the most common solid malignancy found outside of the skull in children. Led by Muller Fabbri, M.D., Ph.D., of the Children’s Center for Cancer and Blood Diseases and The Saban Research Institute of CHLA and published online in the Journal of the National Cancer Institute on May 13, 2015, the study looked at how exosomic miRNAs released within the tumor environment affect resistance to chemotherapy. The article is titled” Exosome-Mediated Transfer of microRNAs Within the Tumor Microenvironment and Neuroblastoma Resistance to Chemotherapy.” Exosomes are vesicles or “envelopes” that are secreted by cells and that can deliver their cargo to other cells. This cargo can include microRNA (miRNA) – small molecules that are not translated into working proteins, but may regulate basic cellular processes. For example, miRNAs are important for regulating protein production by repressing or turning off genes. “The main reason for the recurrence of neuroblastoma – and essentially all types of cancer – is a growing resistance to treatments such as chemotherapy” said Dr. Fabbri, who is also with the Norris Cancer Center at Keck School of Medicine of the University of Southern California. “The goal of this study was to assess whether, and to what extent, exosomic miRNAs are involved in the development of drug resistance through the tumor microenvironment.” Within the tumor microenvironment, where cancers grow and acquire the ability to metastasize and develop resistance to treatment, there is a lot of cross-talk.

May 29th

386 Novel Proteins Identified in Human Aqueous Humor

Researchers conducting a comprehensive proteomics analysis of human aqueous humor samples identified 763 proteins, including 386 proteins detected for the first time, in this clear fluid that helps maintain pressure in the eye and nourishes the cornea and the lens. These proteins could have a role in disease processes affecting the eye and serve as valuable biomarkers for the development of diagnostics and drug candidates to improve visual health, as discussed in the article "Proteomics of Human Aqueous Humor," published in the May 1, 2015 issue of OMICS: A Journal of Integrative Biology, the peer-reviewed interdisciplinary journal published by Mary Ann Liebert, Inc., publishers. The complete article is available free on the OMICS website until June 26, 2015 (see link below). A team of researchers from the United States and India, led by Akhilesh Pandey, M.D., Ph.D., Johns Hopkins University School of Medicine, and Krishna Murthy, DO, MRCOphth (Lon) Institute of Bioinformatics (Bangalore, India), used high-resolution mass spectrometry to analyze and identify the proteins isolated from aqueous humor samples collected from 250 individuals. More than a third of the proteins were located outside of cells, in the extracellular matrix, and are involved in cell communication and signal transduction. Others have roles in cell growth, differentiation, and proliferation. Among the proteins unique to this study are growth factors, immunomodulators, and proteins that regulate blood vessel formation. Other enzymes have a role in metabolism and the energy needs of ocular components such as the lens and cornea. For example, sorbitol dehydrogenase, one of the 386 novel proteins identified in the aqueous humor, plays an important role in the metabolism of glucose in the lens.

New Tool Developed to Predict R-Loop (Triple-Stranded) Hybrid Structures of DNA and RNA; Should Accelerate Expanding Field of R-Loop Research; May Improve Prediction and Treatment of Some Diseases

Scientists from A*STAR's Bioinformatics Institute (BII) have developed an analytical model and computational tool to rapidly and accurately predict the occurrence and locations of R-loop Forming Sequences (RLFSs) in any genome or artificial nucleic acid sequences. R-loops, which are three-stranded RNA and DNA hybrid structures, can be crucial to many normal biological processes and have also been associated with triggering mutations, DNA breaks, and diseases. These hybrid structures provide intriguing possibilities for use as novel targets for diagnostics and treatment of diseases including cancer, autoimmune diseases, and neurodegenerative conditions. While R-loops were first described in 1976 and were for many years associated with only a few specific genes, it is only in recent years that understanding of their critical function and prevalence in the genomes has advanced, revolutionizing the field. Scientists from BII's Genome and Gene Expression Data Analysis Division developed the Quantitative Model of R-loop Forming Sequence finder (QmRLFS-finder), and are making it freely available to accelerate research in this area. Using the QmRLFS-finder, the scientists made a surprising discovery that 75% of well-annotated human genes and/or their vicinities contain RLFSs. The tool has also proven to have an accuracy of between 80% and 90% in predicting the location of RLFS in any genome sequence. The high accuracy would significantly accelerate R-loop detection and dramatically reduce the cost and time taken compared to currently available experimental methods, paving the way for further improvement and development in the relatively nascent field of R-loop biology.

Symbiotic Bacterial Producer of Anti-Cancer Drug ET-743 Identified; Scientists Hope to Grow in Lab without Its Host to Simplify and Speed Up Drug Production

For decades, scientists have known that ET-743, a compound extracted from a marine invertebrate called a mangrove tunicate, can kill cancer cells. The drug has been approved for use in patients in Europe and is currently in clinical trials in the U.S. Scientists suspected that the mangrove tunicate, which is a type of a sea squirt, doesn't actually make ET-743. But the precise origins of the drug, which is also known as trabectedin, were a mystery. By analyzing the genome of the tunicate, along with the microbes that live inside it, using advanced sequencing techniques, researchers at the University of Michigan (U-M) were able to isolate the genetic blueprint of the ET-743's producer--which turns out to be a type of bacteria called Candidatus Endoecteinascidia frumentensis. The findings greatly expand understanding of this microbe and of how ET-743 is produced, the researchers reported online on May 27. 2015 in the journal Environmental Microbiology. They're optimistic that the insights will help make it possible to culture the bacteria in the laboratory without its host. "These symbiotic microbes have long been thought to be the true sources of many of the natural products that have been isolated from invertebrates in the ocean and on the land. But very little is known about them because we're not able to get most of them to grow in a laboratory setting," said study senior author Dr. David Sherman, the Hans W. Vahlteich Professor of Medicinal Chemistry in the College of Pharmacy and a faculty member of the U-M Life Sciences Institute, where his lab is located.