A research team led by National University Health System (NUHS) and Duke-NUS Medical School has used genomic technologies to better understand intestinal metaplasia (IM), a known risk factor for gastric (stomach) cancer. Patients with IM are six times more likely to develop stomach cancer than those without. This study is an important part of an ambitious investigation to understand why some people develop stomach cancer, while others do not. The research could also help detect patients who are infected with the Helicobacter pylori bacteria, which is also linked to the disease.
Stomach cancer is the third deadliest cancer in the world according to World Health Organization (WHO) statistics, and claims more than 300 lives yearly in Singapore. The disease is believed to be caused by infection with Helicobacter pylori but is potentially treatable if detected early. Unfortunately, more than two-thirds of stomach cancer patients are only diagnosed at an advanced stage.
"Previous genetic studies on IM have mainly focused on patients who were already diagnosed with stomach cancer but these are limited in their ability to predict who are likely to develop the disease and how the disease will progress," said Professor Patrick Tan, co-lead investigator and Professor, Duke-NUS Medical School. Professor Tan is also Deputy Executive Director, Biomedical Research Council, Agency for Science, Technology, and Research, and a Senior Principal Investigator at the Cancer Science Institute of Singapore. "This new study is the first to comprehensively map out the genetic changes in IM in a cohort of stomach cancer-free subjects, which helps us better predict the possible occurrence and progression of the disease."
Dr Yeoh Khay Guan, co-lead investigator and Deputy Chief Executive, NUHS as well as Dean, NUS Yong Loo Lin School of Medicine added, "Our study is the largest series of IM to be studied in detail by genetic analysis. These new findings help us understand why some people have a higher risk of progression to stomach cancer, and identify those who may benefit from closer follow-up to prevent cancer or to detect it early so that it can be cured."
The researchers leveraged the near 3,000 participants-strong Gastric Cancer Epidemiology Programme (GCEP) cohort, recruited with the support of patients and doctors from four local public hospitals (National University Hospital, Tan Tock Seng Hospital, Singapore General Hospital, Changi General Hospital), to show that a comprehensive analysis of the genetic patterns of IM can predict its subsequent progression towards stomach cancer. The genetic analysis of IM helps to identify those with a higher risk of progression to stomach cancer, adding further information to what is available by microscopic examination alone.
The research team is using this new information to identify biomarkers that can be applied in future in the clinic to identify people who have a high risk of progression to stomach cancer.
EurekAlertwww.eurekalert.org/pub_releases/2018-01/nuos-lgs010518.php

Hong Kong Baptist University (HKBU) Chemistry scholars have invented a new class of multifunctional cyanine compounds that can be used for detection, imaging and thus treatment of Alzheimer’s disease. The discovery has been granted four US patents and a patent by the Chinese government.
The research team was jointly led by Professor Ricky Wong Man-shing and Associate Professor Dr Li Hung-wing with members from the Department of Chemistry of HKBU. By making use of the proprietary compounds, the HKBU team, on one hand, has proved that the cyanine compounds applied onto a “nano”-detection platform can quantify trace amounts of Alzheimer’s disease related protein biomarkers present in human fluids such as cerebrospinal fluid, serum, saliva, and urine. It is a rapid, low-cost and ultrasensitive detection assay. On the other hand, the compounds also serve as an imaging agent for in vivo detection and monitoring of disease progression and understanding the disease pathogenesis as well as a drug candidate for treatment of the disease.
Alzheimer’s disease is the most common neurodegenerative disorder, it is incurable and the underlying cause is still not well understood. Alzheimer’s disease is characterized by the formation of amyloid plaque in human brains. Clinical evaluation, cognitive tests and neuroimaging (monitoring the brain’s structural changes) are commonly used to diagnose Alzheimer’s disease, but are only effective after symptoms appear. Moreover, neuroimaging, such as magnetic resonance imaging (MRI), requires injecting contrast agents into a person that may bring health risks.
The proteins of interest, namely beta amyloid peptide, tau, and p-tau, in human’s cerebrospinal fluid are linked to Alzheimer’s disease. The versatile detection assay using the compounds developed by the team requires only a minute amount of the sample fluids (a few microliters) to reliably quantify the target proteins. The detection assay developed by the team is fast, cheaper and more sensitive than traditional commercially available biological methods.
Detection is based on the specific immuno-interactions between the target antigen and detection antibody that is immobilised on the surface of magnetic nanoparticles. The sandwiched immuno-assembly is then labelled with a newly developed turn-on cyanine compound that enhances the fluorescence signal, which is quantified by an imaging system.
Dr Li said, “This newly developed assay will be particularly useful as a low-cost yet accurate diagnostic and prognostic tool for Alzheimer’s disease. It can also serve as a novel alternative non-invasive tool for population-wide screening for the disease. This scientific detection assay has a high potential to serve as a practical diagnosis tool.”
Dr Li said that the new approach is universal and general enough to be readily modified and elaborated further, such as replacing the antibodies with other disease-associated antibodies, nucleic acids, for a broad range of biomedical research and disease diagnostics.   
Hong Kong Baptist Universityhkbuenews.hkbu.edu.hk/?t=press_release_details/2196

An urgent question for cancer scientists is why immunotherapy achieves dramatic results in some cases but doesn’t help most patients. Now, two research groups from Dana-Farber Cancer Institute have independently discovered a genetic mechanism in cancer cells that influences whether they resist or respond to immunotherapy drugs known as checkpoint inhibitors.
The scientists say the findings reveal potential new drug targets and might aid efforts to extend the benefits of immunotherapy treatment to more patients and additional types of cancer.
One report, focusing on clinical trial patients with advanced kidney cancer treated with checkpoint inhibitors, is from scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, led by Eliezer Van Allen, MD, of Dana-Farber and the Broad, and Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber.
The second report, which identifies the immunotherapy resistance mechanism in melanoma cells, is from a group led by Kai Wucherpfennig, MD, PhD, director of Dana-Farber’s Center for Cancer Immunotherapy Research, and Shirley Liu, PhD, of Dana-Farber.
The two groups converged on a discovery that resistance to immune checkpoint blockade is critically controlled by changes in a group of proteins that regulate how DNA is packaged in cells. The collection of proteins, called a chromatin remodelling complex, is known as SWI/SNF; its components are encoded by different genes, among them ARID2, PBRM1, and BRD7. SWI/SNF’s job is to open up stretches of tightly wound DNA so that its blueprints can be read by the cell to activate certain genes to make proteins.
Researchers led by Van Allen and Choueiri sought an explanation for why some patients with a form of metastatic kidney cancer called clear cell renal cell cancer (ccRCC) gain clinical benefit — sometimes durable — from treatment with immune checkpoint inhibitors that block the PD-1 checkpoint, while other patients don’t.
The scientists’ curiosity was piqued by the fact that ccRCC differs from other types of cancer that respond well to immunotherapy, such as melanoma, non-small cell lung cancer, and a specific type of colorectal cancer. Cells of the latter cancer types contain many DNA mutations, which are thought to make distinctive "neoantigens" that help the patient’s immune system recognize and attack tumours, and make the cancer cells’ “microenvironment” hospitable to tumour-fighting T cells. By contrast, ccRCC kidney cancer cells contain few mutations, yet some patients even with advanced, metastatic disease respond well to immunotherapy.
To search for other characteristics of ccRCC tumours that influence immunotherapy response or resistance, the researchers used whole-exome DNA sequencing to analyse tumour samples from 35 patients treated in a clinical trial with the checkpoint blocker nivolumab (Opdivo). They also analysed samples from another group of 63 patients with metastatic ccRCC treated with similar drugs.
When the data was sorted and refined, the scientists discovered that patients who benefited from the immunotherapy treatment with longer survival and progression-free survival were those whose tumours lacked a functioning PRBM1 gene. (About 41 percent of patients with ccRCC kidney cancer have a non-functioning PRBM1 gene.) That gene encodes a protein called BAF 180, which is a subunit of the PBAF subtype of the SWI/SNF chromatin remodelling complex.
Loss of the PRBM1 gene function caused the cancer cells to have increased expression of other genes, including a gene pathway known as IL6/JAK-STAT3, which are involved in immune system stimulation.
While the finding does not directly lead to a test for immunotherapy response yet, Choueiri said, "We intend to look at these specific genomic alterations in larger, randomized controlled trials, and we hope that one day these findings will be the impetus for prospective clinical trials based on these alterations."
In the second report, the scientists led by Wucherpfennig came at the issue from a different angle. They used the gene-editing CRISPR/Cas9 technique to sift the genomes of melanoma cells for changes that made tumours resistant to being killed by immune T cells, which are the main actors in the immune system response against infections and cancer cells.
The search turned up about 100 genes which appeared to govern melanoma cells’ resistance to being killed by T cells. Inactivating those genes rendered the cancer cells sensitive to T-cell killing. Narrowing down their search, the Wucherpfennig team identified the PBAF subtype of the SWI/SNF chromatin remodelling complex — the same group of proteins implicated by the Van Allen and Choueiri team in kidney cancer cells — as being involved in resistance to immune T cells.
When the PRBM1 gene was knocked out in experiments, the melanoma cells became more sensitive to interferon-gamma produced by T cells, and in response produced signaling molecules that recruited more tumor-fighting T cells into the tumor. The two other genes in the PBAF complex — ARID2 and BRD7 — are also found mutated in some cancers, according to the researchers, and those cancers, like the melanoma lacking ARID2 function, may also respond better to checkpoint blockade. The protein products of these genes, the authors note, "represent targets for immunotherapy, because inactivating mutations sensitize tumor cells to T-cell mediated attack." Finding ways to alter those target molecules, they add, "will be important to extend the benefit of immunotherapy to larger patient populations, including cancers that thus far are refractory to immunotherapy."
Dana-Farber Cancer Institutewww.dana-farber.org/newsroom/news-releases/2018/mechanism-for-resistance-to-immunotherapy-treatment-discovered/

The research carried out at Queen Mary University of London, University of Exeter and Vanderbilt University could lead to the development of novel treatments for both rare and common forms of diabetes.
In addition to the more common forms of diabetes (type 1 or type 2), in about 1-2 per cent of cases diabetes is due to a genetic disorder, known as maturity onset diabetes of the young (MODY). A defective gene typically affects the function of insulin-producing cells in the pancreas, known as beta cells.
The research team studied the unique case of a family where several individuals suffer from diabetes, while other family members had developed insulin-producing tumours in their pancreas. These tumours, known as insulinomas, typically cause low blood sugar levels, in contrast to diabetes which leads to high blood sugar levels.
Lead author Professor Márta Korbonits from Queen Mary’s William Harvey Research Institute said: “We were initially surprised about the association of two apparently contrasting conditions within the same families – diabetes which is associated with high blood sugar and insulinomas associated with low blood sugar. Our research shows that, surprisingly, the same gene defect can impact the insulin-producing beta cells of the pancreas to lead to these two opposing medical conditions.”
The team also observed that males were more prone to developing diabetes, while insulinomas were more commonly found in females, but the reasons behind this difference are as yet unknown.
Professor Korbonits added: “One exciting avenue to explore will be seeing if we can use this finding to uncover new ways to help regenerate beta cells and treat the more common forms of diabetes.”
The researchers identified a genetic disorder in a gene called MAFA, which controls the production of insulin in beta cells. Unexpectedly, this gene defect was present in both the family members with diabetes and those with insulinomas, and was also identified in a second, unrelated family with the same unusual dual picture.
This is the first time a defect in this gene has been linked with a disease. The resultant mutant protein was found to be abnormally stable, having a longer life in the cell, and therefore significantly more abundant in the beta cells than its normal version.
First author Dr Donato Iacovazzo from Queen Mary’s William Harvey Research Institute added: “We believe this gene defect is critical in the development of the disease and we are now performing further studies to determine how this defect can, on the one hand, impair the production of insulin to cause diabetes, and on the other, cause insulinomas.”
Queen Mary University of Londonwww.qmul.ac.uk/media/news/2018/smd/diabetes-gene-found-that-causes-low-and-high-blood-sugar-levels-in-the-same-family.html