Coffee Consumption Reduces Mortality Risk from Liver Cirrhosis

New research reveals that consuming two or more cups of coffee each day reduces the risk of death from liver cirrhosis by 66%, specifically cirrhosis caused by non-viral hepatitis. Findings in Hepatology, a journal published by Wiley on behalf of the American Association for the Study of Liver Diseases, show that tea, fruit juice, and soft drink consumption are not linked to cirrhosis mortality risk. As with previous studies heavy alcohol use was found to increase risk of death from cirrhosis.A 2004 report from The World Health Organization (WHO) estimates that each year 1.3% of total death worldwide is caused by liver cirrhosis. Previous research shows that 29 million Europeans have chronic liver disease, with 17,000 deaths annually attributed to cirrhosis. Further WHO reports state that liver cirrhosis is the 11th leading cause of death in the U.S.”Prior evidence suggests that coffee may reduce liver damage in patients with chronic liver disease,” said lead researcher, Dr. Woon-Puay Koh with Duke-NUS Graduate Medical School Singapore and the National University of Singapore. “Our study examined the effects of consuming coffee, alcohol, black tea, green tea, and soft drinks on risk of mortality from cirrhosis.”This prospective population-based study, known as The Singapore Chinese Health Study, recruited 63,275 Chinese subjects between the ages of 45 and 74 living in Singapore. Participants provided information on diet, lifestyle choices, and medical history during in-person interviews conducted between 1993 and 1998. Patients were followed for an average of nearly 15 years, during which time there were 14,928 deaths (24%); 114 of them died from liver cirrhosis. The mean age of death was 67 years.Findings indicate that those who drank at least 20 g of ethanol daily had a greater risk of cirrhosis mortality compared to non-drinker. …

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A holistic approach catches eye disease early

Oct. 11, 2013 — An automated assessment of multiple datasets using artificial intelligence accurately diagnoses a common cause of blindness.Pathological myopia is a condition characterized by severe, progressive nearsightedness caused by the protrusion of pigmented tissue from the back of the eye. The disease is one of the leading causes of blindness worldwide and the leading cause in Asian countries. Early diagnosis is essential for preventing permanent loss of vision but heavily relies on manual screening and involves a complete eye exam, which can take up to an hour.Zhuo Zhang of the A*STAR Institute for Infocomm Research in Singapore and her colleagues have now developed an automated, computer-assisted informatics method that uses artificial intelligence to diagnose the condition accurately.In earlier work, Zhang and her colleagues developed an algorithm that could extract information about tissue texture from biomedical images of the back of the eye, or fundus, and use it to detect pathological myopia with an accuracy of 87.5%. They then showed that combining the images with demographic data such as age, sex and ethnicity, improved the accuracy further.The latest automated method — Pathological Myopia diagnosis through Biomedical and Image Informatics (PM-BMII) — takes the process one step further; it uses an artificial intelligence approach known as multiple kernel learning to fuse the demographic data and clinical fundus images with genomic information and then analyze the combined datasets.Zhang and her colleagues tested the method on data collected from 2,258 patients, 58 of whom had already been diagnosed with pathological myopia. They found that the method could detect the condition with a high degree of accuracy and that the combination of all three datasets was more accurate than any one alone or any two combined.Combining the three datasets probably produced the best results because each set contains different information that complements the other sets, therefore providing a holistic assessment of the disease.The researchers suggest that the method could also be applied to the detection of other eye diseases, “including age-related macular degeneration and glaucoma. These diseases have common characteristics,” says Zhang. “They result from both environmental and genetic risk factors, and can be observed from fundus images.”Zhang adds that it is still unclear whether adding additional types of data to the analyses would improve the accuracy of the diagnoses. “More types of data may introduce complexity into the computational model, so we cannot draw the conclusion that accuracy would be improved without further investigation.”

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Novel way discovered to ‘switch on’ tumor suppressors that have been silenced

Oct. 9, 2013 — A team of scientists from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) and their collaborators from the Harvard Stem Cell Institute have found that a novel noncoding ribonucleic acid (RNA) offers the potential for “switching on” of tumour suppressors that have been shut off.The research group, led by Professor Daniel Tenen, Director of CSI Singapore, demonstrated for first time that RNA interacts with an enzyme essential for DNA methylation, known as DNA methyl transferase 1 (DNMT1), offering strategies for the treatment of diseases such as cancer.In this study, the researchers focused on a new class of RNAs, which is critical in regulating DNA methylation. This is a process in which certain building blocks of DNA, the genetic code, are chemically modified without resulting in a change in the code itself. DNA methylation is associated with silencing of gene expression and found in many diseases. For example, in cancer, genes called tumour suppressors, which inhibit tumour formation, are often silenced or shut off in the cancer cells, and this is associated with DNA methylation.This novel study was first published online in the research journal Nature on 9 October 2013.How the novel noncoding RNA inhibits DNA methylationThe study focused on this novel noncoding RNA in a specific tumour suppressor, known as CEBPA. The silencing of CEPBA is associated with Acute Myeloid Leukemia, lung cancer and other types of cancer. The scientists demonstrated that the noncoding RNA binds to the enzyme DNMT1 and prevents DNA methylation of the CEBPA gene. This principle, which is likely to extend to thousands of other genes, can potentially be used to “switch on” tumour suppressors that have been shut off.Prof Tenen said, “We started out by studying the noncoding RNA to satisfy our scientific curiosity. In the process, we discovered the novel finding that RNA inhibits methylation and experimentally, we can introduce RNAs to ‘switch on’ tumour suppressors which have been shut off. Our results suggest strategies for gene-selective demethylation of therapeutic targets in human diseases such as cancer.”Further ResearchIn the next phase of their research, the scientists will look into developing tools for targeted activation of other tumour suppressors, besides CEBPA, and investigate the role of RNA in regulating other epigenetic marks.

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Coffee and tea may contribute to a healthy liver

Aug. 16, 2013 — Surprise! Your morning cup of tea or coffee may be doing more than just perking you up before work.An international team of researchers led by Duke-NUS Graduate Medical School (Duke-NUS) and the Duke University School of Medicine suggest that increased caffeine intake may reduce fatty liver in people with non-alcoholic fatty liver disease (NAFLD).Worldwide, 70 percent of people diagnosed with diabetes and obesity have NAFLD, the major cause of fatty liver not due to excessive alcohol consumption. It is estimated that 30 percent of adults in the United States have this condition, and its prevalence is rising in Singapore. There are no effective treatments for NAFLD except diet and exercise.Using cell culture and mouse models, the study authors — led by Paul Yen, M.D., associate professor and research fellow, and Rohit Sinha, Ph.D of the Duke-NUS Graduate Medical School’s Cardiovascular and Metabolic Disorders Program in Singapore — observed that caffeine stimulates the metabolization of lipids stored in liver cells and decreased the fatty liver of mice that were fed a high-fat diet. These findings suggest that consuming the equivalent caffeine intake of four cups of coffee or tea a day may be beneficial in preventing and protecting against the progression of NAFLD in humans.The findings will be published in the September issue of the journal Hepatology.”This is the first detailed study of the mechanism for caffeine action on lipids in liver and the results are very interesting,” Yen said. “Coffee and tea are so commonly consumed and the notion that they may be therapeutic, especially since they have a reputation for being “bad” for health, is especially enlightening.”The team said this research could lead to the development of caffeine-like drugs that do not have the usual side effects related to caffeine, but retain its therapeutic effects on the liver. It could serve as a starting point for studies on the full benefits of caffeine and related therapeutics in humans.In addition to Yen and Sinha, collaborators included Christopher Newgard, PhD, director of the Sarah W. Stedman Nutrition and Metabolism Center at Duke University School of Medicine, where the metabolomics analysis of the data was conducted.The study was supported by funding from Singapore’s Agency for Science, Technology, and Research; the Ministry of Health; and the Ministry of Education.

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New drug targets for aggressive breast cancer

July 26, 2013 — Scientists at A*STAR’s Genome Institute of Singapore (GIS) led in a study that has identified genes that are potential targets for therapeutic drugs against aggressive breast cancer. These findings were reported in the July 2013 issue of PNAS.Out of the 1.5 million women diagnosed with breast cancer in the world annually, nearly one in seven of these is classified as triple negative. Patients with triple-negative breast cancer (TNBC) have tumours that are missing three important proteins that are found in other types of breast cancer. The absence of these three proteins make TNBC patients succumb to a higher rate of relapse following treatment and have lower overall survival rates. There is currently no effective therapy for TNBC.Using integrated genomic approaches, GIS scientists led by Dr. Qiang Yu, in collaboration with local and international institutions, set out to search for targets that can be affected by drugs. The scientists discovered that a protein tyrosine phosphatase[1], called UBASH3B, is overexpressed in one third of TNBC patients. UBASH3B controls the activity of an important breast cancer gene. The researchers found that deleting this gene expression markedly inhibits TNBC cell invasive growth and lung metastasis in a mouse model. They also showed that patients with TNBC tumours that have high levels of UBASH3B tend to be more likely to have early recurrence and metastasis.Lead author Dr Qiang Yu said, “The identification of target genes is always the most crucial first step towards treating a disease. …

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Discovery of a new class of white blood cells uncovers target for better vaccine design

July 17, 2013 — Scientists at A*STAR’s Singapore Immunology Network (SIgN) have discovered a new class of white blood cells in human lung and gut tissues that play a critical role as the first line of defence against harmful fungal and bacterial infections. This research will have significant impact on the design of vaccines and targeted immunotherapies for diseases caused by infectious microbes such as the hospital-acquired pneumonia.The scientists also showed for the first time that key immune functions of this new class of white blood cells are similar to those found in mice. This means that findings in the mouse studies can be applied to develop advanced clinical therapies for the human immune system. The study done in collaboration with Newcastle University was published in the journal Immunity.New Class of White Blood CellsAll immune responses against infectious agents are activated and regulated by dendritic cells (DCs), a specialised group of white blood cells which present tiny fragments from micro-organisms, vaccines or tumours to the T cells. T cells are immune cells that circulate around our bodies to scan for cellular abnormalities and infections. Of the different T cells, T helper 17 (Th17) cells specialise in activating a protective response crucial for our body to eliminate harmful bacteria or fungi.In this study, the scientists identified a new subset of DCs (named CD11b+ DCs), which are capable of activating such protective Th17 response. They also showed that mice lacking the CD11b+ DCs were unable to induce the protective Th17 response against the Aspergillus fumigatus, one of the most common fungal species in hospital-acquired infections.The team leader, Dr Florent Ginhoux from SIgN said, “As dendritic cells have the unique ability to ‘sense’ the type of pathogen present in order to activate the appropriate immune response, they are attractive targets to explore for vaccine development. This discovery revealed fresh inroads to better exploit dendritic cells for improved vaccine design against life-threatening fungal infections.”Acting Executive Director of SIgN, Associate Professor Laurent Rénia said, “Life-threatening fungal infections have increased over the years yet treatment options remain limited. This study demonstrates how fundamental research that deepens our understanding of the body’s immune system can translate into potential clinical applications that could save lives and impact healthcare.”

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‘Undruggable’ cancer may be druggable after all: New target identified

June 17, 2013 — Harvard Stem Cell Institute (HSCI) researchers have identified in the most aggressive forms of cancer a gene known to regulate embryonic stem cell self-renewal, beginning a creative search for a drug that can block its activity.The gene, SALL4, gives stem cells their ability to continue dividing as stem cells rather than becoming mature cells. Typically, cells only express SALL4 during embryonic development, but the gene is re-expressed in nearly all cases of acute myeloid leukemia and 10 to 30 percent of liver, lung, gastric, ovarian, endometrial, and breast cancers, strongly suggesting it plays a role in tumor formation.In work published in the New England Journal of Medicine, two HSCI-affiliated labs — one in Singapore and the other in Boston — show that knocking out the SALL4 gene in mouse liver tumors, or interfering with the activity of its protein product with a small inhibitor, treats the cancer.”Our paper is about liver cancer, but it is likely true about lung cancer, breast cancer, ovarian cancer, many, many cancers,” said HSCI Blood Diseases Program leader Daniel Tenen, who also heads a laboratory at the Cancer Science Institute of Singapore (CSI Singapore). “SALL4 is a marker, so if we had a small molecule drug blocking SALL4 function, we could also predict which patients would be responsive.”Studying the therapeutic potential of a transcription factor is unusual in the field of cancer research. Transcription factors are typically avoided because of the difficulty of developing drugs that safely interfere with genetic targets. Most cancer researchers focus their attention on kinases.The HSCI researchers’ inquiry into the basic biology of the SALL4 gene, however, revealed another way to interfere with its activity in cancer cells. The gene’s protein product is responsible for turning off a tumor-suppressor gene, causing the cell to divide uncontrollably. Using this knowledge, the researchers demonstrated that targeting the SALL4 protein with druglike molecules could halt tumor growth. “The pharmaceutical companies decided that if it is not a kinase and it is not a cell surface molecule, then it is ‘undruggable,’ ” Tenen said. “To me, if you say anything is ‘undoable,’ you are limiting yourself as a biomedical scientist.”Earlier this year, Tenen’s co-author, HSCI-affiliated faculty member Li Chai, a Harvard Medical School assistant professor of pathology at Brigham and Women’s Hospital, published a paper in the journal Blood, reporting that a SALL4 inhibitor has similar treatment potential in leukemia cells.Chai took blood samples from patients with acute myeloid leukemia, treated the leukemic cells with the inhibitor that interferes with SALL4 protein activity, and then transplanted the blood into mice. The result was a gradual regression of the same cancer in mice.”I am excited about being on the front line of this new drug development,” Chai said. …

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Scientists identify potential drug target for treatment-resistant anemias

June 9, 2013 — Researchers at Whitehead Institute have identified a protein that is the target of glucocorticoids, the drugs that are used to increase red blood cell production in patients with certain types of anemia, including those resulting from trauma, sepsis, malaria, kidney dialysis, and chemotherapy. The discovery could spur development of drugs capable of increasing this protein’s production without causing the severe side effects associated with glucocorticoids.”This research is medically important, and we are using it to find a better way to increase the production of red blood cells for these patients,” says Harvey Lodish, who is a Whitehead Institute Founding Member and a professor of biology at MIT. “It is also a new insight into how self-renewal in stem cells can be controlled, and a new way to think about how we can use an RNA binding protein to maintain stem and progenitor cells.”Anemia occurs due to a breakdown in erythropoiesis, the multi-step process that creates red blood cells. Some common anemias can be treated with a recombinant form of the hormone erythropoietin (EPO), which normally stimulates red blood-cell production at a fairly late stage of erythropoiesis.However, certain anemias fail to respond to EPO, creating a large unmet medical need. In the case of Diamond Blackfan anemia (DBA), patients lack a sufficient number of EPO-responsive cells. Instead, glucocorticoids such as prednisone or prednisolone are used to treat DBA and other anemias resistant to EPO by increasing the numbers of the later progenitor cells that respond to EPO. These drugs cause a host of negative side effects, including decreased bone density, immunosuppression, stunted growth, and cataracts, all of which are particularly burdensome for young patients.Earlier work in the Lodish lab determined that glucocorticoids increase red blood cell production by acting on early progenitors of red blood cells, called burst forming unit-erythroids (BFU-Es). During erythropoiesis, BFU-Es produce later progenitors called colony forming unit-erythroids (CFU-Es), which are then stimulated by EPO to generate the pro-erythroblasts that eventually become red blood cells. By dividing numerous times before maturing, BFU-Es have a limited ability to self-renew. After exposure to glucocorticoids, BFU-Es divide more times than usual, which ultimately increases the total number of red blood cells they produce.To determine how glucocorticoids prolong BFU-Es’ self-renewing phase, Lingbo Zhang, a graduate student in the Lodish lab, studied the drugs’ effects in mouse BFU-Es. …

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Scientists reveals escalating cost of forest conservation

Apr. 23, 2013 — Researchers illustrate how changes to farming could dramatically increase future costs of conservation.

In the face of unprecedented deforestation and biodiversity loss, policy makers are increasingly using financial incentives to encourage conservation.

However, a research team led by the National University of Singapore (NUS) revealed that in the long run, conservation incentives may struggle to compete with future agricultural yields.

Their findings were first published online in the Proceedings of the National Academy of Sciences on 15 April 2013.

Financial incentives for conservation

Incentives are being leveraged in dozens of tropical developing countries to conserve forests, to protect biodiversity and reduce carbon emissions from deforestation. This incentive-based approach is comparatively inexpensive, as low agricultural yields and widespread poverty often mean that relatively small incentives can motivate many landholders to protect their land for conservation.

As a result, this approach has become a leading climate change mitigation strategy adopted by the United Nations as policies for Reducing Emissions from Deforestation and Degradation.

Costs of conservation in the long run

In a bid to assess the future viability of these types of conservation programmes, the team, comprising researchers from NUS, ETH Zurich and University of Cambridge, developed a framework and model that looked at the strategy’s effectiveness in the context of intensified farming practices.

The researchers modeled conservation payments necessary to protect forests in the Democratic Republic of Congo (DRC), which has some of the largest remaining forests in the world. They found that a new agricultural intensification and conservation programme could double or triple cassava and maize yields by introducing disease-resistant plant varieties, increasing fertilizer use and improving farming practices.

Increased farm yields will bring dramatic benefits to DRC farmers, and could increase land area spared for conservation. Similar agricultural intensification policies are being promoted across the tropics.

However, the researchers highlight how those higher yields and incomes will also increase financial incentives for farmers to clear more forest for agriculture. As a result, financial incentives to encourage farmers to protect forests and not expand agriculture would need to escalate as well. They expect farmers who were once willing to protect forests for a comparative pittance could, in a matter of years, demand more for their conservation actions. Small-scale farmers might also be displaced by larger commercial ventures as farming becomes more lucrative, and as profits increase with growing global demand for agricultural products.

After taking these factors into account, the researchers found that while the current costs of forest conservation in many countries are very low, future changes in agricultural practices could radically increase the cost of conservation.

Escalating cost is top concern

The NUS-led study illustrated that these contemporary policies tend to focus on short-term conservation and on improving the livelihoods of poor communities around forested areas. However, they risk overlooking impacts of on long-term conservation.

The researchers warn that conservation expenditure will have to dramatically increase to compete with future agriculture.

Said Jacob Phelps, a PhD candidate in the Department of Biological Sciences at the NUS Faculty of Science and first author of the study, “Our research suggests that as agriculture becomes more intensive, the small payments successful at incentivising forest conservation today could increase to well beyond what is considered economically efficient, or even feasible. We anticipate that similar patterns are likely across the tropics, including in places like Indonesia.”

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