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Archive - Sep 7, 2017

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Discovery of Chromosome Motor in Condensin Comlex Supports DNA Loop Extrusion Model for DNA Packaging in Cell Division

It is one of the great mysteries in biology: how does a cell neatly distribute its replicated DNA between two daughter cells? For more than a century, it has been known that DNA in the cell is comparable to a plate of spaghetti: a big jumble of intermingled strands. If a human cell wants to divide, it has to pack two meters of DNA into tidy little packages: chromosomes. This packing occurs using proteins called condensin, but how? When it comes to this question, scientists are split into two camps: the first argues that the protein works like a hook, randomly grasping somewhere in the jumble of DNA and tying it all together. The other camp thinks that the ring-shaped protein pulls the DNA inwards to create a loop. With an article published online on September 7, 2017 in Science, researchers from TU Delft, Heidelberg, and Columbia University give the “loop-extrustion camp” a significant boost: they demonstrate that condensin does indeed have the putative 'motor power' on board. The article is titled “The Condensin Complex Is a Mechanochemical Motor That Translocates Along DNA.” As early as 1882, the renowned biologist Walter Flemming recorded the process of “condensation” of DNA. Looking through a microscope, he saw how a cell neatly organized the bundles of DNA and subsequently divided them into two new cells. However, the exact details of this process have remained a mystery for more than 100 years. “There are different schools on this question within the field of cell biology,” explains nanobiologist and Head of Research Professor Cees Dekker from TU Delft's Kavli Institute. “In recent years, the hypothesis that condensin extrudes loops has been winning ground, supported by computer simulations. The idea is that that the ring-shaped condensin grabs the DNA and pulls it through its ring in a loop-like fashion.

Researchers Discover Why Redheads Are More Prone to Melanoma; Pharmacological Activation of Palmitoylation in MC1R Prevents Melanoma in Model System

Red-haired people are known for pale skin, freckles, poor tanning ability and, unfortunately, an increased risk for developing skin cancer. Research has shown that they have variants in melanocortin 1 receptor (MC1R), a protein crucial for pigmentation in humans, but how this translates to increased risk for cancer and whether that risk can be reversed has remained an active area of investigation--until now. For the first time, researchers from Boston University School of Medicine (BUSM) have shown that there is a way to reduce cancer risk in redheads. These findings were published online on September 6, 2017 in Nature. The article is titled “Palmitoylation-Dependent Activation of MC1R Prevents Melanomagenesis.” Specifically the scientist proved that MC1R, the protein involved in pigmentation, is affected by a special modification process called palmitoylation that is critical for its function. By enhancing palmitoylation in the variant MC1R proteins of redheads cancer risk can be reduced. Making up one to two percent of the world's population, redheads carry variants of MC1R that are responsible for their characteristic features, but that also increase risk of skin cancers, the most dangerous of which is melanoma, a major public health concern with more than 3 million active cases in 2015. Much public health work has emphasized prevention by reducing sun exposure, particularly to DNA-damaging UV rays, but redheads bear a higher burden of disease making alternative risk reductions strategies an area of active interest.

Immunotherapy Combination Is Safe and 62 Percent Effective In Metastatic Melanoma Patients

Immunotherapy is a promising approach in the treatment of metastatic melanoma, an aggressive and deadly form of skin cancer; but for most patients, immunotherapy drugs so far have so far failed to live up to their promise and provided little or no benefit. In a phase 1b clinical trial with 21 patients, researchers tested the safety and efficacy of combining the immunotherapy drug pembrolizumab with an oncolytic virus called T-VEC. The results suggest that this combination treatment, which had a 62% response rate, may work better than using either therapy on its own. The study was published in the September 7, 2017 issue of Cell. The article is titled “Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy.” "We had a hypothesis about how these treatments would work together, and when we did biopsies of patients' tumors we found that they were cooperating in just the way we thought they would," says lead author Dr. Antoni Ribas, Director of the Immunology Program at the UCLA Jonsson Comprehensive Cancer Center. Pembrolizumab is in a class of drugs called checkpoint inhibitors. These drugs are designed to get around one of the ways that cancer protects itself from the immune system: tumors can activate the body's natural protective response from autoimmunity, called a checkpoint, and thereby thwart cytotoxic T cells. The drugs work by taking the brakes off the checkpoint and allowing T cells to attack the tumor. "Some people put tumors into the categories of either 'hot' and 'cold,'" Dr. Ribas explains. "Hot tumors, also called inflamed tumors, have a lot of immune cells in and around them, but cold tumors do not." Drugs like pembrolizumab boost the response in tumors where immune cells are present but don't work in tumors where there is no immune response to boost.

Technology Unlocks Mold Genomes to Identify New Drug Candidates

Fungi are rich sources of natural molecules for drug discovery, but numerous challenges have pushed pharmaceutical companies away from tapping into this bounty. Now, scientists have developed technology that uses genomics and data analytics to efficiently screen for molecules produced by molds to find new drug leads — maybe even the next penicillin. The research, from scientists at Northwestern University, the University of Wisconsin-Madison, and the biotech company Intact Genomics, was published online on June 12, 2017 in Nature Chemical Biology. The article is titled “A Scalable Platform to Identify Fungal Secondary Metabolites and Their Gene Clusters.” “Drug discovery needs to get back to nature, and molds are a gold mine for new drugs,” said Neil Kelleher (photo), PhD, Director of the Proteomics Center of Excellence and a professor in the Weinberg College of Arts and Sciences and of Medicine in the Division of Hematology and Oncology. “We have established a new platform that can be scaled for industry to provide a veritable fountain of new medicines. Instead of rediscovering penicillin, our method systematically pulls out valuable new chemicals and the genes that make them. They can then be studied in depth.” Scientists believe there are thousands or even millions of fungal molecules waiting to be discovered, with enormous potential health, social, and economic benefits. The new technology systematically identifies powerful bioactive molecules from the microbial world — honed through millennia of evolution — for new drug leads. These small molecules could lead to new antibiotics, immunosuppressant drugs, and treatments for high cholesterol, for example. For four years, Dr. Kelleher has collaborated with Nancy Keller, PhD, the Robert L. Metzenberg and Kenneth B.

Lasker-DeBakey Clinical Medical Research Award 2017 Goes to NCI’s Douglas R. Lowy & John T. Schiller for Technological Advances That Enabled Development of HPV Vaccines for Prevention of Cervical Cancer and Other Tumors Caused by HPV

The 2017 Lasker-DeBakey Clinical Medical Research Award honors two scientists whose technological advances enabled the development of human papillomavirus (HPV) vaccines, which prevent cervical cancer and other tumors. Dr. Douglas R. Lowy and Dr. John T. Schiller (both from the National Cancer Institute) took a bold, but calculated, approach toward a major public-health problem whose solution required them to vault formidable hurdles. They devised a blueprint for several safe and effective vaccines that promise to slash the incidence of cervical cancer and mortality, the fourth most common cancer among women worldwide, as well as other malignancies and disorders that arise from human papillomaviruses. More than 500,000 new cases of cervical cancer are diagnosed annually, and each year, more than 250,000 women die from the malignancy. In the 1980s, Dr. Harald zur Hausen (2008 Nobel Prize in Physiology or Medicine) linked the disease to infection with certain types of HPV. Two of the viruses—HPV16 and 18—give rise to about 70 percent of cases, and approximately ten additional types account for the vast majority of the remaining 30 percent. HPV16 and 18 plus these other “high-risk” HPVs also underlie many cancers of the vulva, vagina, penis, anus, and throat. Different HPV family members cause genital warts. Sexual activity transmits these viruses, and infections usually clear spontaneously. Some persist, however, and high-risk HPVs harbor oncogenes, whose activity can lead to unrestrained proliferation of host cells. The process of transforming normal cells into cancerous ones typically takes at least 15 years, usually longer. By the early 1990s, scientists realized that a vaccine that blocks persistent infection with dangerous HPV types would bestow substantial public-health rewards.