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Archive - Sep 15, 2015

Scientists Find Genetic Clue to Treating Cancer Cachexia and Other Muscle-Wasting Syndromes of Disease & Aging

It is estimated that half of all cancer patients suffer from a muscle-wasting syndrome called cachexia. Cancer cachexia impairs quality of life and response to therapy, which increases morbidity and mortality of cancer patients. Currently, there is no approved treatment for muscle wasting, but a new study from the Research Institute of the McGill University Health Centre (RI-MUHC) and University of Alberta, both in Canada, could be a game-changer for patients, improving both quality of life and longevity. The research team discovered that a newly identified gene involved in muscle wasting could be a good target for drug development. The findings, which were published in September's print edition of the FASEB (Federation of American Societies for Experimental Biology) Journal could have huge clinical implications, as muscle wasting is also associated with other serious illnesses such as HIV/AIDS, heart failure, rheumatoid arthritis, and chronic obstructive pulmonary disease, and is also a prominent feature of aging. "We discovered that the gene USP19 (coding for ubiquitini-specific protease 19 debiquitinating enzyme) appears to be involved in human muscle wasting and that in mice, once inhibited, it could protect against muscle wasting,” says lead author Dr. Simon Wing, MUHC endocrinologist and Professor of Medicine at McGill University. "Muscle wasting is a huge unmet clinical need. Recent studies show that muscle wasting is much more common in cancer than we think." In the current study, researchers worked with mice models that were lacking USP19 (i.e., USP19 KO) and decided to look at two common causes of muscle wasting.

Nearly Forgotten 80-Year-Old Tissue Allograft Method for Transplanting Fly Tissue Resurrected, Enables Resurgent Study of Tissue Regeneration and Tumor Growth in Drosophila

A study conducted by ICREA (Catalan Institution for Research and Advanced Studies) researcher Dr. Cayetano González, at the Institute for Research in Biomedicine (IRB Barcelona), and published online on September 10, 2015 in Nature Protocols describes a virtually forgotten technique used in the fly Drosophila melanogaster dating back 80 years. This method allows the transplantation of tissue from larvae to adult flies, thus allowing research into tumor growth and other biological processes of biomedical interest, such as tissue regeneration. The article is titled “Studying Tumor Growth in Drosophila Using the Tissue Allograft Method.” In 2002, Dr. González, head of the Cell Division lab at IRB Barcelona, faced a major technical problem with respect to research into tumor growth in Drosophila, namely the limitless growth of malignant tumours, which kill the fly. The solution seemed straightforward—tumor transplants, a common technique used in cancer research in mammals, including humans, which involves the transplantation of the tumor mass to mice. With over a century of research into the fly, it was hoped that the many tools available for this model would include one for tissue transplants. “And this was indeed the case, but the articles devoted to methodologies were few and incomplete and therefore reproducing the technique in the lab was very complicated,” explains Professor González. Developed in 1935, the technique was used extensively in the following decades and then fell into disuse and practically disappeared towards the end of the last century. “In 2002, only a small number of researchers worldwide were aware of the existence of the technique,” he says. Professor János Szabad, from the University of Szeged, in Hungary, was one of the few who continued to use the method and he invited Dr.

Japanese Chemists Achieve Enantioselective Phenoxylation of β-Keto Esters; Novel Method Allows Synthesis of α-Aryloxy-β-Keto Esters with High Enantioselectivity; Compounds Already Synthesized for Potential Treatment of Type 2 Diabetes

Aryl alkyl ethers are important structural motifs found in many biologically active compounds. Therefore, stereoselective etherification is a highly important synthetic operation in the preparation of drug candidates. However, very few enantioselective methods have been described for the synthesis of chiral tertiary aryl ethers. Researchers at Toyohashi Tech in Japan have now found that the SN2 reaction of α-chloro-β-keto esters with phenols proceeded smoothly, despite the fact that the reaction occurred at a tertiary carbon [1]. The scientists previously reported the highly enantioselective chlorination of β-keto esters with a chiral Lewis acid catalyst [2]. Thus, in the two investigations, the researchers have successfully demonstrated the enantioselective phenoxylation of β-keto esters. The novel presented method allows the synthesis of α-aryloxy-β-keto esters with high enantioselectivity. "Etherification by the SN2 reaction is an older synthetic method called Williamson ether synthesis, but very few researchers have succeeded in conducting this reaction with tertiary halides," said Associate Professor Kazutaka Shibatomi. “This is the first example of the enantioselective synthesis of α-aryloxy-β-keto esters, which would be useful synthetic intermediates for new drug candidates." Using this method, the researchers have already demonstrated the synthesis of some biologically active compounds, including a GPR119 agonist and a PPARγ (image) modulator, for the potential treatment of type 2 diabetes. The researchers expect that the present method will also be helpful in preparing other types of synthetic drugs.

BRD4 Inhibitors, AML, Enhancers; Cancer Vulnerability to BRD4 Inhibition Enhanced by Weak WNT Signaling; Loss of PRC2 Complex Increases Cancer Resistance to BRD4 Inhibition

BRD4 inhibitors are among the most promising new agents in cancer therapy and they are currently being evaluated in clinical trials. BRD4 is a member of the BET (bromo- and extra-terminal (BET) family of proteins: BRD2 (bromodomain-containing protein 2), BRD3 (bromodomain-containing protein 3), and BRD4 (bromodomain-containing protein 4). In a study published online on September 14, 2015 in Nature, a team of researchers at the Research Institute of Molecular Pathology (IMP) and Boehringer Ingelheim. both in Vienna, Austria reveals how leukemia cells can evade the deadly effects of BRD4 inhibition. The article is titled “Transcriptional Plasticity Promotes Primary and Acquired Resistance to BET Inhibition.” Understanding this adaptation process could aid the development of sequential therapies to outsmart resistant leukemias. Over the past years, scientists have drawn an almost complete map of mutations in cancer. However, translating complex genetic knowledge into effective cancer therapies turns out to be a major challenge for modern medicine. Searching for new ways to attack cancer cells, the laboratory of Dr. Johannes Zuber at the IMP in Vienna uses so-called functional genetic screens to probe vulnerabilities of cancer cells in a systematic and unbiased way. The major goal is to find genes that cancer cells particularly depend on, and then exploit these “Achilles’ heels” for the development of targeted therapies. In a first study applying this technology, Dr. Zuber and his former colleagues at Cold Spring Harbor Laboratory (CSHL) (New York) in 2011 found that the gene BRD4 is such an “Achilles’ heel” in acute myeloid leukemia (AML), an aggressive form of blood cancer.

First-Draft Genome Sequence of Tiger Mosquito Determined, Insect Transmits Dengue Fever and Chikungunya Fever, and Other Deadly Diseases, Infecting Millions Annually

On September 14, 2015, Pathogens and Global Health journal published online, in an open-access article, details of the first-draft genome sequence of Aedes albopictus, commonly known as the tiger mosquito and responsible for transmitting several deadly diseases to humans, such as dengue fever and chikungunya fever, both carried by viruses, potentially offering hope to millions around the world. "This sequencing…offers great hope to our understanding of the mosquito and our ability to control it, potentially saving millions of lives in many areas of the world," said Professor Andrea Crisanti, Editor-in-Chief of Pathogens and Global Health. The Pathogens and Global Health article provides a first look into the genetics of a most dangerous and invasive insect and the possibility of developing ways to prevent the spread of the dengue and chikungunya fevers that infect millions of people annually. The advance is all the more urgent now, given increasingly high levels of mosquito migration and the fact that Aedes albopictus has been moving in recent years from its natural habitats in tropical South East Asia to many parts of the world, including Europe, the United States, and Africa. It is estimated that as many as 400 million people are infected by the dengue and chikungunya viruses carried by the tiger mosquito and transmitted to people as it feeds on their blood. The article is titled “A Draft Genome Sequence of an Invasive Mosquito: an Italian Aedes albopictus.” Major global upheavals have undoubtedly contributed to the large-scale spread of Aedes albopictus, and these are believed to include climate change, urbanization of rural areas, and, indeed, changes in the use of land itself. This has all led to fears among many populations of a risk of infection from Aedes albopictus.