Women with high levels of a common liver enzyme measured prior to pregnancy were twice as likely to subsequently develop gestational diabetes than those with the lowest levels, according to a Kaiser Permanente study.

The liver plays an important role in regulating glucose levels in the body. The liver enzyme, called gamma-glutamyl transferase (known as GGT), is a common marker of liver function and has also been associated with insulin resistance, which can be a precursor to gestational diabetes and type 2 diabetes.

‘Several biomarkers appear to be associated with the risk of gestational diabetes,’ said Monique M. Hedderson, PhD, senior author of the study and research scientist with the Kaiser Permanente Division of Research in Oakland, Calif. ‘This study and others we’ve done provide evidence that women who develop gestational diabetes have metabolic abnormalities even before pregnancy. In the future, we could potentially try to prevent gestational diabetes by intervening before women get pregnant.’

Gestational diabetes, or glucose intolerance during pregnancy, has increased dramatically in recent decades and is now one of the most common complications of pregnancy. It can lead to the birth of larger-than-normal babies and subsequent delivery complications. According to recent studies, women with gestational diabetes are seven times more likely to develop type 2 diabetes later in life, and their children are at greater risk of becoming obese and developing diabetes themselves.

Researchers examined the medical records of 256 women who developed gestational diabetes during pregnancy and compared them with 497 women who did not. Those studied had voluntarily given blood samples between 1985 and 1996 during routine care and subsequently delivered an infant in Kaiser Permanente’s Northern California region.

After adjusting for numerous possible confounding factors, including body mass index and alcohol use, the researchers found that women in the highest quartile of GGT had nearly twice the risk of subsequent gestational diabetes than those in the lowest quartile. No associations were found with two other commonly monitored liver enzymes, alanine aminotransferase and aspartate aminotransferase.

‘A few studies have looked at liver enzyme levels during pregnancy and the risk of gestational diabetes, but to our knowledge this is the first to look at liver enzyme levels measured before pregnancy,’ said lead author Sneha Sridhar, MPH, project coordinator with the Kaiser Permanente Division of Research.

This study is the third in a series using the same cohort of mothers to examine the role of biomarkers prior to pregnancy in predicting the risk of gestational diabetes. The researchers ultimately hope to develop a risk model to help identify women who would benefit from interventions during the pre-conception period. Kaiser Permanente

Researchers and doctors at the Institute of Bioengineering and Nanotechnology (IBN), Singapore General Hospital (SGH) and National Cancer Centre Singapore (NCCS) have co-developed the first molecular test kit that can predict treatment and survival outcomes in kidney cancer patients.

According to IBN Executive Director Professor Jackie Y. Ying, “By combining our expertise in molecular diagnostics and cancer research, we have developed the first genetic test to help doctors prescribe the appropriate treatment for kidney cancer patients based on their tumor profile.”

Dr. Min-Han Tan, who is IBN Team Leader and Principal Research Scientist and a visiting consultant at the Division of Medical Oncology NCCS, shared his motivation, “As a practicing oncologist, I have cared for many patients with kidney cancer. I see the high costs of cancer care, the unpredictable outcomes and occasional futility of even the best available drugs. This experience inspired our development of this assay to improve all these for patients.”

The study was conducted retrospectively with tissue samples collected from close to 280 clear cell renal cell carcinoma (ccRCC) patients who underwent surgery at SGH between 1999 and 2012.

“High quality tissue samples are crucial in achieving significant findings in biomedical research. As an Academic Medical Center, we wish to promote the translation of research into advances in healthcare and personalised medicine. The development of this test kit for patient care, utilizing the robust tissue archive that we have at SGH, is a good example of this,” said Professor Tan Puay Hoon, Head and Senior Consultant, Department of Pathology, SGH.

Kidney cancer is among the ten most frequent cancers affecting men in Singapore, according to The Singapore Cancer Registry (2009-2013). The most common type of kidney cancer is clear cell renal cell carcinoma. Treatment options include surgery, ablation or removal of the tumour, or targeted therapy to shrink or slow the growth of the cancer. The latter works by blocking the growth of new blood vessels (angiogenesis) or important proteins in cancer cells (tyrosine kinase) that nourish the tumours and help them survive.

According to Dr. Min-Han Tan, there are currently about 250 new patients diagnosed with kidney cancer per year in Singapore. “Outcomes can be very different. Some patients can be observed for years on end, some benefit from immediate treatment including surgery or targeted therapy, and for some patients, treatment can be futile. Experience is required in making the right judgment for patients. We hope our assay will play a role in helping that judgment.”

Targeted drugs are prescribed routinely for cancer patients. Revenues from anti-angiogenic drugs, such as Sutent and Nexavar, are estimated at several billion dollars annually.

Such drugs, however, are not only expensive but may cause side effects in patients, including fatigue, loss of appetite, nausea, diarrhea, pain, high blood pressure, bleeding and heart problems. Due to genetic variations, individual patients respond differently to these drugs and have different survival outcomes.

Pharmaceutical companies and academic institutions have invested heavily in seeking out tools and biomarkers to predict personalized outcomes with these therapies, and the development of a reliable anti-angiogenic predictor would be of significant interest to them.

Extensive molecular characterization of ccRCC by the team and other researchers worldwide in recent studies has suggested the existence of specific subtypes with different survival outcomes. The researchers therefore set out to discover reliable biomarkers that could improve the prognostic prediction, and identify patients who would be likely to benefit from one type of treatment.

For this purpose, the team designed a practical assay for studying/diagnosing real-world tumour samples from ccRCC patients. The assay was able to distinguish patients into groups of different survival and treatment outcomes. This is one of the first assays capable of predicting outcomes of anti-angiogenic therapy, a key goal for cancer care and industry.

Dr. Tan added, “Our diagnostic assay successfully classified ccRCC into groups correlating to different survival and treatment outcomes. This allows patients and doctors to make more educated choices in their treatment options. Additionally, the development of such assays in Singapore demonstrates the highest levels of research, care and expertise that are available to our patients here.” A-Star

A newborn screening test for severe combined immunodeficiency (SCID) reliably identifies infants with this life-threatening inherited condition, leading to prompt treatment and high survival rates, according to a study supported by the National Institutes of Health. Researchers led by Jennifer Puck, M.D., of the University of California, San Francisco, also found that SCID affects approximately 1 in 58,000 newborns, indicating that the disorder is less rare than previously thought. The study was funded in part by NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

SCID is a group of disorders caused by defects in genes involved in the development and function of T cells and other infection-fighting immune cells. Infants with SCID are highly susceptible to life-threatening infections. SCID is fatal, usually within the first year or two of life, unless affected infants are given immune-restoring treatments such as transplants of blood-forming stem cells or gene therapy. More than 80 percent of affected infants do not have a family history of the condition.

“The results of this study highlight the important role of newborn screening for SCID,” said NIAID Director Anthony S. Fauci, M.D. “The findings demonstrate that detecting SCID before symptoms such as severe infections appear helps ensure that infants with this serious condition receive lifesaving treatments.”

The SCID newborn screening test, originally developed at NIH, measures T cell receptor excision circles (TRECs), a by-product of T-cell development. Infants with SCID have few or no T cells, regardless of the underlying genetic defect, and the absence of TRECs may indicate SCID. The TREC test also may help doctors identify infants with non-SCID T-cell deficiencies. SCID was added in 2010 to the U.S. Department of Health and Human Services’ Recommended Uniform Screening Panel for newborns in the United States. However, the TREC test has not yet been adopted universally. Nearly half of states conduct newborn screening for SCID, and the test is performed for almost two thirds of infants born across the country.

“We have made great strides in our knowledge of SCID and other related immunodeficiencies in a relatively short period of time, thanks to newborn screening,” said Tiina Urv, Ph.D., a program director in the Intellectual and Developmental Disabilities Branch at NICHD. “Such collaborative research efforts could serve as a model for other disorders.” Eunice Kennedy Shriver National Institute of Child Health and Human Development

Researchers have discovered how a gene commonly linked to obesity—FTO—contributes to weight gain. The study shows that variations in FTO indirectly affect the function of the primary cilium, a little-understood hair-like appendage on brain and other cells. Specific abnormalities of cilium molecules, in turn, increase body weight, in some instances, by affecting the function of receptors for leptin, a hormone that suppresses appetite. The findings, made in mice, suggest that it might be possible to modify obesity through interventions that alter the function of the cilium, according to scientists at Columbia University Medical Center (CUMC).

‘If our findings are confirmed, they could explain how common genetic variants in the gene FTO affect human body weight and lead to obesity,’ said study leader Rudolph L. Leibel, MD, the Christopher J. Murphy Memorial Professor of Diabetes Research, professor of pediatrics and medicine, and co-director of the Naomi Berrie Diabetes Center at CUMC. ‘The better we can understand the molecular machinery of obesity, the better we will be able to manipulate these mechanisms and help people lose weight.’
Since 2007, researchers have known that common variants in the fat mass and obesity-associated protein gene, also known as FTO, are strongly associated with increased body weight in adults. But it was not understood how alterations in FTO might contribute to obesity. ‘Studies have shown that knocking out FTO in mice doesn’t necessarily lead to obesity, and not all humans with FTO variants are obese,’ said Dr. Leibel. ‘Something else is going on at this location that we were missing.’

In experiments with mice, the CUMC team observed that as FTO expression increased or decreased, so did the expression of a nearby gene, RPGRIP1L. RPGRIP1L is known to play a role in regulating the primary cilium. ‘Aberrations in the cilium have been implicated in rare forms of obesity,’ said Dr. Leibel. ‘But it wasn’t clear how this structure might be involved in garden-variety obesity.’

Dr. Leibel and his colleague, George Stratigopoulos, PhD, associate research scientist, hypothesised that common FTO variations in noncoding regions of the gene do not change its primary function, which is to produce an enzyme that modifies DNA and RNA. Instead, they suspected that FTO variations indirectly affect the expression of RPGRIP1L. ‘When Dr. Stratigopoulos analysed the sequence of FTO’s intron—its noncoding, or nonprotein-producing, portion—we found that it serves as a binding site for a protein called CUX1,’ said Dr. Leibel. ‘CUX1 is a transcription factor that modifies the expression of RPGRIP1L.’

Next, Dr. Stratigopoulos set out to determine whether RPGRIP1L plays a role in obesity. He created mice lacking one of their two RPGRIP1L genes, in effect, reducing but not eliminating the gene’s function. (Mice that lack both copies of the gene have several serious defects that would obscure the effects on food intake.) Mice with one copy of RPGRIP1L had a higher food intake, gained significantly more weight, and had a higher percentage of body fat than controls.

In a subsequent experiment, the CUMC team found that RPGRIP1L-deficient mice had impaired leptin signalling. ‘The receptors didn’t convene properly on the cell surface around the base of cilium,’ said Dr. Leibel. ‘RPGRIP1L appears to play a role in getting leptin receptors to form clusters, where they are more efficient in signalling.’

‘Overall,’ said Dr. Leibel, ‘our findings open a window onto the possible role of the primary cilium in common forms of obesity.’ Columbia University Medical Center

Researchers led by geneticists at the Miller School have discovered a new gene mutation that causes hearing loss. Their study, which focused on a large Turkish family in which six individuals have been affected by hereditary deafness, identified a mutated form of the gene FAM65B as a cause of sensorineural hearing loss.

The research also demonstrates that FAM65B is a previously unrecognized component of the inner ear that is required for hearing.

“Hearing loss is the most common human sensory problem,” said Tekin. “We hope that identifying a new genetic cause of this disorder will lead to a better understanding of the molecular components of normal hearing.”

Hearing loss, which affects approximately 1 in 500 newborns, most often results from mutations of single genes that perform specific functions in the inner ear, where sound waves are converted to electrical signals. This process originates in the stereocilia — “hairs” projecting from cochlear hair cells that interconnect to form the hair bundle. Most of the approximately 50 previously identified hair bundle proteins are the products of genes that, when mutated, lead to hearing loss.

Researchers in this study, who conducted a genetic analysis of the subject family, identified a mutated form of FAM65B — a protein previously unassociated with hearing — as the cause. Further characterization of the protein product of FAM65B in rodents and zebrafish has confirmed the findings of the family study. Miller School of Medicine