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December 30th, 2017

Cancer Cells Use Unfolded Protein Response (UPR) to Manipulate Circadian Clock in Ways That Allow Them to Survive Conditions That Are Toxic to Normal Cells

Tumor cells use the unfolded protein response to alter circadian rhythm, which contributes to more tumor growth, Hollings Cancer Center researchers at the Medical University of South Carolina (MUSC) have found. A key part of the circadian clock opposes this process, according to a paper published online on December 11, 2017 in Nature Cell Biology. The article is titled “A PERK–miR-211 Axis Suppresses Circadian Regulators and Protein Synthesis to Promote Cancer Cell Survival.” For tumors to grow and spread, cancer cells must make larger than normal amounts of nucleic acids and protein, so they can replicate themselves. Yet, in both normal and cancer cells that increase their synthesis of protein, a small percent of those proteins do not fold properly. When that happens, the cell activates its unfolded protein response (UPR), which slows down the making of new proteins while the misfolded proteins are refolded. Eventually, the buildup of misfolded proteins becomes toxic and leads to cell death. However, cancer cells have learned to use the UPR to slow protein synthesis when needed, in order to handle the backlog of misfolded proteins. This helps them survive in conditions that would kill normal cells. This pattern of adaptation is often seen in tumor cells, according to J. Alan Diehl, PhD, the SmartState Endowed Chair in Lipidomics, Pathobiology, and Therapy at the MUSC Hollings Cancer Center and senior researcher on the project. "What a tumor cell is doing is taking a pathway that's already in the cell and using it to its advantage," said Dr. Diehl. Yet it was not clear exactly how cancer cells were able to use UPR activity to influence circadian rhythm. Dr.

December 29th

Hopkins Study Shows Increased Risk of Uterine Fibroids in African-American Women with a Common Form of Hair Loss

In a study of medical records gathered on hundreds of thousands of African-American women, Johns Hopkins researchers say they have evidence that women with a common form of hair loss have an increased chance of developing uterine leiomyomas, or fibroids. In a report on the research, published in the December 27, 2017 issue of JAMA Dermatology, the researchers call on physicians who treat women with central centrifugal cicatricial alopecia (CCCA) to make patients aware that they may be at increased risk for fibroids and should be screened for the condition, particularly if they have symptoms such as heavy bleeding and pain. CCCA predominantly affects black women and is the most common form of permanent alopecia in this population. The excess scar tissue that forms as a result of this type of hair loss may also explain the higher risk for uterine fibroids, which are characterized by fibrous growths in the lining of the womb. Crystal Aguh, M.D., Assistant Professor of Dermatology at the Johns Hopkins University School of Medicine, says the scarring associated with CCCA is similar to the scarring associated with excess fibrous tissue elsewhere in the body, a situation that may explain why women with this type of hair loss are at a higher risk for fibroids. People of African descent, she notes, are more prone to develop other disorders of abnormal scarring, termed fibroproliferative disorders, such as keloids (a type of raised scar after trauma), scleroderma (an autoimmune disorder marked by thickening of the skin as well as internal organs), some types of lupus, and clogged arteries. During a four-year period from 2013-2017, the researchers analyzed patient data from the Johns Hopkins electronic medical record system (Epic) of 487,104 black women ages 18 and over. The prevalence of those with fibroids was compared in patients with and without CCCA.

Study of Phosphoethanolamine Methyl Transferases (PMTs) May Lead to Development of Hardier Crops and Therapies for Malaria, JBC Article Suggests

Recent findings by researchers at Washington University in St. Louis may aid in the development of therapies to treat parasitic infections, including malaria, and may help plant scientists one day produce hardier crops. The research team's work was published in the December 29, 2017 issue of the Journal of Biological Chemistry. The article is titled “Conformational Changes in the Di-Domain Structure of Arabidopsis Phosphoethanolamine Methyltransferase Leads to Active-Site Formation.” The article is a JBC editors’ pick and is the subject of a JBC Highlights article titled “Covering Their Bases: The Phosphobase Methylation Pathway in Plants.” Choline is an essential nutrient that humans get from certain foods, including eggs, meat, leafy greens, and nuts. The human body converts choline into phosphocholine (pCho), which it in turn converts into (among other essential building blocks) phosphatidylcholine (PtdCho), a component of cell membranes. Plants, however, can't acquire the nutrient from the environment and so must synthesize pCho from scratch. The biochemical pathway plants use to synthesize pCho is also found in nematodes and the malaria parasite Plasmodium. In plants, the enzymatic reaction that produces pCho is essential for both normal function and for responding to stresses. Plant pCho is converted into PtdCho, which builds membranes that can adjust their rigidity in response to temperature changes. Plant pCho also gets converted into molecules that help the plant survive high salt. The enzymes that produce plant pCho are called called phosphoethanolamine methyltransferases (PMTs). Dr. Soon Goo Lee, a postdoctoral research fellow at Washington University in the laboratory of Dr.

Blueberry Extract May Increase Effectiveness of Radiation Therapy in Cervical Cancer

According to the Centers for Disease Control and Prevention (CDC), approximately 12,000 women in the United States are diagnosed with cervical cancer each year. One of the most common treatments for cervical cancer is radiation. While radiation therapy destroys cancer cells, it also destroys nearby healthy cells. University of Missouri (MU)School of Medicine researchers studied in vitro human cancer cells to show that combining blueberry extract with radiation can increase the treatment's effectiveness. "Radiation therapy uses high-energy X-rays and other particles such as gamma rays to destroy cancer cells," said Yujiang Fang, MD, PhD, a visiting professor at the MU School of Medicine and lead author of the study. "For some cancers, such as late-stage cervical cancer, radiation is a good treatment option. However, collateral damage to healthy cells always occurs. Based on previous research, we studied blueberry extract to verify it could be used as a radiosensitizer." The study, "Blueberry as a Potential Radiosensitizer for Treating Cervical Cancer," recently was published online on September 30, 2017 in Pathology & Oncology Research. Radiosensitizers are non-toxic chemicals that make cancer cells more responsive to radiation therapy. In a previous study, Dr. Fang and his research team showed that resveratrol, a compound in red grapes, could be used as a radiosensitizer for treating prostate cancer. Blueberries also contain resveratrol. "In addition to resveratrol, blueberries also contain flavonoids," said Dr. Fang, who also has appointments as an academic pathologist and Assistant Professor of Microbiology and Immunology at Des Moines University in Iowa. "Flavonoids are chemicals that may have antioxidant, anti-inflammatory, and antibacterial properties."

Ancient Jumping Genes May Give Corals New Lease on Life

Jumping genes could make an alga, and its coral host, more tolerant to warming sea temperatures. A particular gene is shown by researchers at the King Abdullah University of Science and Technology (KAUST) in Saudi Arabia to help the heat tolerance of an alga that lives symbiotically with coral, which could potentially help Red Sea corals adapt to some warming. Symbiodinium is a unicellular alga that provides its coral host with photosynthetic products in return for nutrients and shelter. However, high sea temperatures can cause the breakdown of this symbiotic relationship and lead to the widespread expulsion of Symbiodinium from host tissues, an event known as coral bleaching. If bleached corals do not recover, they starve to death, leaving only their white, calcium-carbonate exoskeleton. Now, researchers from KAUST have identified special genes, called retrotransposons, which could help the algae adapt more rapidly to heat stress. The team, led by postdoc Jit Ern Chen and PhD student Guoxin Cui, conducted analyses to find out which genes were turned on or off when Symbiodinium was exposed to heat stress. Surprisingly, most genes commonly associated with heat stress were turned off, while a small number of retrotransposons were turned on. Retrotransposons are small genetic sequences that have the ability to replicate and position themselves in new locations in their host's genome. "The ability of retrotransposons to copy themselves and integrate these new copies into the host genome makes them genetic parasites," says geneticist and principal investigator, Dr. Manuel Aranda. "Every integration event is basically a new mutation in the host genome. Very often these new copies disable or disrupt host genes. However, sometimes they can also change how certain genes behave.

Microbes in Space Station Identified by PCR and DNA Sequencing Carried Out in Orbit

Being able to identify microbes in real time aboard the International Space Station, without having to send them back to Earth for identification first, would be revolutionary for the world of microbiology and space exploration. The Genes in Space-3 team turned that possibility into a reality this year, when it completed the first-ever sample-to-sequence process entirely aboard the space station. The ability to identify microbes in space could aid in the ability to diagnose and treat astronaut ailments in real time, as well as assisting in the identification of DNA-based life on other planets. It could also benefit other experiments aboard the orbiting laboratory. Identifying microbes involves isolating the DNA of samples, and then amplifying that DNA that can then be sequenced, or identified. The investigation was broken into two parts: the collection of the microbial samples and amplification by polymerase chain reaction (PCR), then sequencing and identification of the microbes. NASA astronaut Peggy Whitson (photo), PhD, conducted the experiment aboard the orbiting laboratory, with NASA microbiologist and the project's Principal Investigator Dr. Sarah Wallace and her team watching and guiding her from Houston. As part of regular microbial monitoring, petri plates were touched to various surfaces of the space station. Working within the Microgravity Science Glovebox (MSG) about a week later, Whitson transferred cells from growing bacterial colonies on those plates into miniature test tubes, something that had never been done before in space. Once the cells were successfully collected, it was time to isolate the DNA and prepare it for sequencing, enabling the identification of the unknown organisms - another first for space microbiology.

December 28th

Double Strike Against Tuberculosis: Beta-Lactone Inhibits Mycomembrane Biosynthesis & Enhances Effects of Antibiotics

In search of new strategies against life-threatening tuberculosis infections, a team from the Technical University of Munich (TUM), as well as Harvard University and Texas A&M University in the USA have found a new ally. They discovered a substance that interferes with the mycomembrane formation of the bacterium. It is effective even in low concentrations and when combined with known antibiotics their effectiveness is improved by up to 100-fold. Among the greatest challenges when treating life-threatening tuberculosis infections is the increasing resistance to antibiotics. But the pathogen itself also makes the life of doctors difficult: its dense mycomembrane hampers the effect of many medications. A team of scientists headed by Stephan A. Sieber, Professor of Organic Chemistry at TU Munich, has discovered a substance that perturbs the formation of this membrane significantly. The mycomembrane of the tuberculosis pathogen Mycobacterium tuberculosis consists of a lipid double layer that encapsulates the cell wall, forming an exterior barrier. Structural hallmarks are mycolic acids, branched beta-hydroxy fatty acids with two long hydrocarbon chains. The team hypothesized that similarly structured beta lactones could "mask" themselves as mycolic acid to enter the mycolic acid metabolic pathways and then block the decisive enzymes. In the context of an extensive search, the interdisciplinary team of scientists hit the bullseye with the beta lactone EZ120. It does indeed inhibit the biosynthesis of the mycomembrane and kills mycobacteria effectively. Using enzyme assays and mass spectroscopy investigations, Dr.

Biotech Journalist Will Climb Mount Everest to Support Cancer Research at Fred Hutchinson Cancer Center

Hi, I’m Luke Timmerman, a biotech journalist, and I am carrying my 80-pound training backpack up and down the hills of Seattle for a reason. I’m training to climb Mount Everest, the highest mountain in the world, in 2018. Why do this? Of course, I love mountains. But mostly, I’m doing it to support the top-notch research at the Fred Hutchinson Cancer Research Center. I’m doing it to support my hometown of Seattle, and I’m doing it to support science itself. As a biotech journalist for 15 years, I’ve had the privilege to meet scientists around the world doing amazing work. I see a cancer revolution happening. Immunotherapies are emerging that harness the power of the immune system to attack cancer cells much like the viruses and bacteria we fight off every day. Fast DNA sequencers and other sensitive instruments are making it possible to detect cancer earlier than ever before, when it’s most easily treated. Fred Hutch is at the leading edge of cancer cures. Their pioneering research is helping people with many types of cancer live longer, and lead better lives. We’re seeing just the beginning of what is possible. We can’t let up—especially during this time of so much thrilling progress. So I ask you to please give generously to this important cause at a crucial moment in time. Let’s take this all the way. DONATE TO “THE CLIMB TO FIGHT CANCER AT FRED HUTCH,” ( and you’ll help scientist push to the top of the mountain—the cure. Donations are 100 percent tax-deductible, and Fred Hutch sends donors a receipt automatically. (This text was drawn from Luke’s publication, the Timmerman Report, with permission. Luke is the author of the award-winning biography of legendary scientist Leroy Hood, titled simply “Hood.”)

University of Wisconsin Study of Aortic Valves in Pigs Provides Key Insight into Calcific Aortic Valve Disease (CAVD) in Humans

The diminutive size of our aortic valve -- just shy of a -- belies its essential role in pushing oxygen-rich blood from the heart into the aorta, our body's largest vessel, and from there to all other organs. Yet for decades, researchers have focused less on damaged valves than on atherosclerosis, the gradual hardening of the blood vessels themselves. Thanks, in part, to pigs at the University of Wisconsin (UW)-Madison's Arlington Agricultural Research Station, scientists are now catching up on understanding the roots of calcific aortic valve disease (CAVD). "For a long time, people thought CAVD was just the valvular equivalent of atherosclerosis," says Kristyn Masters (see photo at end), PhD, a Professor of Biomedical Engineering at UW-Madison and Vice Chair of the department. "Today, we know that valve cells are quite unique and distinct from the smooth muscle cells in our blood vessels, which explains why some treatments for atherosclerosis, such as statins, don't work for CAVD, and why the search for drugs has to start from scratch." A team led by Dr. Masters has cleared a longstanding hurdle in that search with a study published online on December 27, 2017 in PNAS. The researchers teased apart, for the first time, the early cascade of events that may eventually cause stenosis, a severe narrowing of the aortic valve that reduces blood flow to body tissues and weakens the heart. The only current treatment for stenosis is valve replacement, which typically requires risky and expensive open-heart surgery. "Our study sheds new light on the differences between atherosclerosis and CAVD, especially in terms of bottleneck events that we can target with drugs," says Dr. Masters, whose work is supported by the National Institutes of Health and the American Heart Association.

Scientists Identify Signaling Hub That May Be Key to Cancer Metastasis

A University of Hawai'i Cancer Center researcher has identified how some cancer cells are made to move during metastasis. The research provides a better understanding of how cancer spreads and may create new opportunities for cancer drug development. Metastasis causes the deaths of 90 percent of cancer patients. The spread of cancer by metastasis is driven by a set of mutant proteins called oncogenes, which cause cancer cells to multiply uncontrollably and promote their ability to move. How oncogene activity specifically directs the increased movement and metastasis is highly complex and remains largely unknown. Joe W. Ramos, PhD, Deputy Director of the UH Cancer Center and collaborators focused on investigating how these oncogenes and related signals lead to dysregulation of normal processes within the cell and activate highly mobile and invasive cancer cell behavior. The findings, published online on December 26, 2017 in PNAS, define a mechanism in which the oncogenes turn on a protein called RSK2 that is required for cancer cells to move. The open-access article is titled “RSK2 Drives Cell Motility by Serine Phosphorylation of LARG and Activation of Rho GTPases.” Dr. Ramos and colleagues found that the RSK2 protein forms a signaling hub that includes proteins called LARG and RhoA. They show that turning on this signaling hub activates the movement of the cancer cells. These results significantly advance understanding of how cancer cells are made to move during metastasis and may provide more precise targets for drugs to stop cancer metastasis in patients where there are oncogenic mutations. "These new data are very exciting. Blocking cancer invasion and metastasis remains a central challenge in treating patients.