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UCSF-Led Study Suggests Superiority of Non-Invasive, Cell-Free DNA Blood Test in Detecting Down Syndrome; Test Not As Widely Comprehensive for Other Ailments As Standard Tests, However

A blood test undertaken between 10 to 14 weeks of pregnancy may be more effective in diagnosing Down syndrome and two other less common chromosomal abnormalities than standard non-invasive screening techniques, according to a multicenter study led by a University of Californian, San Francisco (UCSF) researcher. In the study, which followed pregnancy outcomes in close to 16,000 women, the cell-free DNA blood test resulted in correctly identifying all 38 fetuses with Down syndrome, a condition associated with cognitive impairments and an increased risk of several medical disorders. The diagnosis was confirmed by newborn exam, prenatal, or postnatal genetic analysis. The test focuses on the small percentage of fetal DNA found floating in a pregnant woman's blood. DNA is amplified with a molecular "photocopying" technique known as polymerase chain reaction (PCR), and sequenced so that comparisons can be made between relative amounts of each chromosome's DNA. A greater quantity of DNA is indicative of some chromosomal conditions, including Down syndrome, which is characterized by an extra copy of chromosome 21, one of the 23 pairs of chromosomes. When the same women underwent standard screening, 30 of the 38 fetuses with Down syndrome were flagged, according to the study published online on April 1, 2015, in the New England Journal of Medicine. The article title is “Cell-Free DNA Analysis for Noninvasive Examination of Trisomy.” The screening comprises a blood draw in which hormones and proteins associated with chromosomal defects are identified, together with an ultrasound of the nuchal fold fluid in the back of the neck, an excess of which is suggestive of Down syndrome.

Scientists Achieve Small Molecule Inhibition of Aberrant Transcription Factor at Root of Recurring Acute Myeloid Leukemia (AML)

A novel molecule designed by scientists at the University of Massachusetts Medical School and the University of Virginia inhibits progression of a hard-to-treat form of recurring acute myeloid leukemia (AML) in patient tissue. The small molecule is one of the first designed to specifically target a cancer-causing transcription factor. Previously thought to be an undruggable target, this strategy may be used to design other novel molecules that can specifically inhibit cancer-causing transcription factors. Details of the work were published in the February 13, 2015 issue of Science. The article is titled “A Small-Molecule Inhibitor of the Aberrant Transcription Factor CBFβ-SMMHC Delays Leukemia in Mice.” Transcription factors are single- or multi-protein complexes that regulate transcription of DNA into messenger RNA and gene expression by binding to regions on the genome next to a gene. Mutations in transcription factors can result in altered gene expression programs that give way to new, cancer-causing functions. Although these aberrant transcription factors are promising targets for new therapeutics, the complexity of interrupting very specific protein-to-protein interactions has made it difficult to find small molecules or design drugs that treat these transcription factor-related cancers. "When we look at inhibitors, they usually target an enzyme or receptor. There aren't a lot of good examples of transcription factor inhibitors in clinical trials," said Lucio H. Castilla, Ph.D., Associate Professor of Molecular, Cell, and Cancer Biology at the U-Mass Medical School, and co-leader of the study. "Here, we've used our extensive knowledge of a mutant transcription factor found in a subset for acute myeloid leukemia patients to design a molecule that can specifically sequester only the oncogenic mutant.

Synchronization of Womb’s and Mother’s Biological Clocks Plays Key Role in Successful Pregnancies

If you are trying to have a baby, a good night's sleep is more important than ever. A new research report appearing in April 2015 issue of The FASEB Journal shows that the womb has its own "body clock" that needs to synchronize with the mother's body clock to ensure optimal conditions for fetal growth and development. The inability of a mother's body clock to synchronize with the womb's clock may be at least part of the reason why some women have difficulty carrying a pregnancy to full term. Specifically, the failed synchronization switches off body clock genes in cells lining the womb, which in turn, may jeopardize the pregnancy. This information may help researchers and fertility experts develop strategies to optimize the fetal environment to help more women have children. "Infertility affects one in six couples across the world. Miscarriage is the most common complication of pregnancy," said Jan Brosens, M.D., a researcher involved in the work from the Division of Translational and Systems Medicine and Reproductive Health at Warwick Medical School at the University of Warwick in Coventry, UK. "Approximately one in seven clinical pregnancies result in miscarriage, mostly prior to 12 weeks of pregnancy. It is estimated that five percent of women experience two clinical miscarriages and approximately one percent have three or more losses. From a medical perspective, recurrent miscarriages and implantation failure have remained frustratingly devoid of effective therapeutic strategies." To make the current discovery, Dr. Brosens and colleagues, obtained womb biopsies from 70 women who have experienced recurrent pregnancy loss. The cells from these biopsies were purified and then treated in such a way as to simulate a pregnancy.

Shorter and Still Effective Cas9 Enzyme from S. aureus Enables Easier Packaging into AAV Delivery Vehicle; Nobelist Sharp Is One of Study Leaders

A collaborative study among researchers from the Broad Institute of MIT and Harvard, Massachusetts Institute of Technology, and the National Center for Biotechnology Information of the National Institutes of Health (NIH-NCBI) has identified a highly efficient Cas9 nuclease that overcomes one of the primary challenges to in vivo genome editing. This finding, published online on April 1, 2015 in Nature, is expected to help make the CRISPR toolbox accessible for in vivo experimental and therapeutic applications. Originally discovered in bacteria, the CRISPR-Cas9 system enables the cutting of DNA as a defense mechanism against viral infection. Although numerous microbial species possess this system, the Cas9 enzyme from Streptococcus pyogenes (SpCas9) was the first to be engineered for altering the DNA of higher organisms, and has since emerged as the basis for a series of highly versatile genome modification technologies. In order to perturb genes in adult animals, key components of the CRISPR-Cas9 system must be introduced into cells using delivery vehicles known as vectors. Adeno-associated virus (AAV) is considered one of the most promising candidate vectors, as it is not known to cause human disease and has already gained clinical regulatory approval in Europe. However, the small cargo capacity of AAV makes it challenging to package both the SpCas9 enzyme and the other components required for gene editing into a single viral particle. The Cas9 nuclease from the bacteria Staphylococcus aureus (SaCas9), presented in this new work, is 25% smaller than SpCas9, offering a solution to the AAV packaging problem. The Broad/MIT team, led by Dr. Feng Zhang, core member of the Broad Institute and investigator at the McGovern Institute for Brain Research at MIT, along with collaborators at MIT, led by MIT Institute Professor Dr.

NO APRIL FOOL'S: Tiny Blackpoll Warbler Migrates 1,500 Miles in Non-Stop “Fly-or-Die” Journey Over Atlantic Ocean in 2-3 Days; “One of the Most Extraordinary Migratory Routes on the Planet” Expert Says

For more than 50 years, scientists had tantalizing clues suggesting that a tiny, boreal forest songbird known as the blackpoll warbler departs each fall from New England and eastern Canada to migrate nonstop in a direct line over the Atlantic Ocean toward South America, but proof was hard to come by. Now, for the first time, an international team of biologists report "irrefutable evidence" that the birds complete a nonstop flight ranging from about 1,410 to 1,721 miles (2,270 to 2,770 km) in just two to three days, making landfall somewhere in Puerto Rico, Cuba and the islands known as the Greater Antilles, from there going on to northern Venezuela and Columbia. Details of the new study, which used light-level, or solar, geolocators, were published online on April 1, 2015 in Biology Letters. First author Dr. Bill DeLuca, an Environmental Conservation Research Fellow at the University of Massachusetts Amherst, with colleagues at the University of Guelph, Ontario, the Vermont Center for Ecostudies, and other institutions, says, "For small songbirds, we are only just now beginning to understand the migratory routes that connect temperate breeding grounds to tropical wintering areas. We're really excited to report that this is one of the longest nonstop overwater flights ever recorded for a songbird, and finally confirms what has long been believed to be one of the most extraordinary migratory feats on the planet."While other birds, such as albatrosses, sandpipers, and gulls are known for trans-oceanic flights, the blackpoll warbler is a forest dweller that migrates boldly where few of its relatives dare to travel. Most migratory songbirds that winter in South America take a less risky, continental route south through Mexico and Central America, the authors note. A water landing would be fatal to a warbler.

New Dual-Affinity Antibody (FcDART) Against H5N1 Influenza Is 100% Protective in Long-Used Ferret Model of the Human Disease

Since 2003, the H5N1 influenza virus, more commonly known as the bird flu, has been responsible for the deaths of millions of chickens and ducks and has infected more than 650 people, leading to a 60 percent mortality rate for the latter. Luckily, this virus has yet to achieve human-to-human transmission, but a small number of mutations could change that, resulting in a pandemic. Now a team of investigators from St. Jude Children’s Research Hospital, Stanford University Medical Center, and MacroGenics has developed an antibody that has proven 100 percent protective against the virus in two species of animal models [ferrets (image) and mice]. The research was published online on February 11, 2015 in the Journal of Virology, a publication of the American Society for Microbiology (ASM). Antivirals have been potential sources of protection, but they are hampered by the propensity of viruses to rapidly mutate, which often results in resistance. “We have seen this in H5N1 viruses,” said corresponding author Richard Webby, Ph.D., a Member in the Infectious Diseases Department at St. Jude Children’s Research Hospital, Memphis, TN, and Director of the World Health Organization (WHO) Collaborating Center for Studies on the Ecology of Influenza Viruses in Lower Animals and Birds. Vaccines, Dr. Webby said, must be developed to match each flu virus, something which would likely take at least six months following the emergence of a pandemic. Additionally, vaccines are somewhat ineffective in the elderly and in immunocompromised individuals. The investigators turned to antibodies, which target antigens on viruses as specifically as keys to locks, thus disabling them. Regardless, mutations can also render antibodies ineffective.

Modified Polio Virus Used in Fight Against Glioblastomas, 60 Minutes Reports

Dr. Matthias Gromeier's original notion that polio virus (image) might be used to kill cancerous tumors was met for some time with much disdain. But now, two decades later, use of the virus known for crippling and killing millions is showing promise against one of the deadliest forms of cancer - glioblastoma brain tumors. In a 60 Minutes story airing on CBS the evening of March 29, 2015, reporter Scott Pelley meets two patients participating in the phase 1 clinical trial of the polio-virus-based anti-glioblastoma therapy, who have been declared cancer-free by doctors. "I got a range of responses, from crazy to you're lying... most people just thought it was too dangerous," said Dr. Gromeier, an Associate Professor of Surgery and Associate Professor in Molecular Genetics and Microbiology at Duke, where he has been for the last 15 years, when he started pushing his idea to attack tumors with the polio virus. One of those naysayers was Dr. Henry Friedman, a neuro-oncologist who is now the Deputy Director of the Brain Tumor Center at Duke University where the phase 1 clinical trial of the polio-virus therapy is now being carried out. "I thought he was nuts," Dr. Friedman told Pelley. "I really thought he was using a weapon that produced paralysis." That was 15 years ago. Today, after research, animal trials, and now this human clinical trial, Dr. Friedman is more than optimistic. "This, to me, is the most promising therapy I have seen in my career, period," said Dr. Friedman who has been researching a cure for glioblastoma for more than 30 years. Dr. Gromeier's research yielded a genetically modified polio virus that could be used safely in animals and now, it seems, in humans.

Triple-Negative Breast Cancer Appears to Be Two Different Diseases; Very Serious One Starts from Stem Cells, More Benign One Starts from More Specialized Cells; High Levels of ID4 Associated with Very Poor Prognosis

Australian researchers have found that so-called “triple-negative breast cancers” are two distinct diseases that likely originate from different cell types. This helps explain why survival prospects for women with the diagnosis tend to be either very good or very bad. The Sydney-based research team has found a gene that drives the aggressive disease, and hopes to find a way to “switch it off.” The aggressive form of triple-negative breast cancer appears to arise from stem cells, while the more benign form appears to arise from specialized cells. Stem cells have many of the same features as cancers. They are plastic and flexible, and have the ability to proliferate and spread into other tissues - deadly traits in cancers. Previous studies have shown that breast stem cells are needed for breast growth and development during puberty and pregnancy, although how they evolve from stem cells into specialist cells has been unclear. The new study has shown that a gene known as “inhibitor of differentiation 4” (ID4) determines whether a stem cell remains a stem cell, or whether it differentiates into a specialist cell. Notably, when the high levels of ID4 in a stem cell are “switched off,” other genes that drive cell specialization are “switched on.” Dr. Alex Swarbrick and Dr. Simon Junankar from Sydney's Garvan Institute of Medical Research spearheaded this large interdisciplinary study, which employed an ID4GFP knock-in reporter mouse and single-cell transcriptomics to show that ID4 marks a stem-cell-enriched subset of the mammary basal cell population. The study’s main finding, that ID4 not only “marks,” but appears to control, the highly aggressive form of triple negative breast cancer was published online on March 27, 2015 in Nature Communications.

deCODE Shows Power of Iceland Population Sequencing

deCODE Genetics, a global leader in analyzing and understanding the human genome, has published online, on March 25, 2015, in Nature Genetics, four landmark papers built on whole-genome sequence data from more than 100,000 people from across the country of Iceland. The studies, written by a team of deCODE scientists, when taken together, present the most detailed portrait of a population yet assembled using the latest technology for reading DNA. "This work is a demonstration of the unique power sequencing gives us for learning more about the history of our species and for contributing to new means of diagnosing, treating, and preventing disease," said Kari Stefansson, M.D., Founder and CEO of deCODE, and senior author on the four Nature Genetics papers. "It also shows how a small population such as ours, with the generous participation of the majority of its citizens, can advance science and medicine worldwide. In that sense, this is very much more than a molecular national ‘selfie.’ We're contributing to important tools for making more accurate diagnostics for rare diseases; finding new risk factors and potential drug targets for diseases like Alzheimer's; and even showing how the Y chromosome, a loner in the paired world of our genome, repairs itself as it passes from father to son. Other countries are now preparing to undertake their own large-scale sequencing projects, and I would tell them the rewards are great," Dr. Stefansson concluded. The four Nature Genetics papers and their highlights are described below.

Study Demonstrates Feedback Loop Between Brown Fat and the Brain

Brown fat tissue communicates with the brain through sensory nerves, possibly sharing information that is important for fighting obesity, such as how much fat we have and how much fat we've lost, according to researchers at Georgia State University. The findings, published in the February 4, 2015 issue of The Journal of Neuroscience, help to describe the conversation that takes place between the brain and brown fat tissue while brown fat is generating heat. The article is titled “Brown Adipose Tissue Has Sympathetic-Sensory Feedback Circuits.” The experiments in this work were carried out in Siberian hamsters. Brown fat is considered "good fat" or "healthy fat" because it burns calories to help generate heat for our bodies and expend energy, while the far-more-abundant white fat stores energy for later use and can increase the risk for health issues, such as diabetes and heart disease. Studies have suggested that brown fat plays a significant role in someone having the capability to burn more energy, becoming a tool to stay trim and fight obesity. Pharmaceutical companies are trying to target brown fat and learn how to further activate it, said John Garretson, second author on the study and a doctoral student in the Neuroscience Institute and Center for Obesity Reversal at Georgia State. The current study found that when brown fat tissue was activated with a drug that mimics the sympathetic nervous system messages that normally come from the brain, the brown fat talked back to the brain by activating sensory nerves. The sensory nerves from brown fat increased their activity in response to direct chemical activation and heat generation. "This is the first time that the function of sensory nerves from brown fat has been examined," Garretson said.

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