A look at the latest research

A new preoperative molecular malignancy classifier for identifying BRAF V600E mutation status among thyroid nodule biopsies has been shown to be clinically valid, according to a study recently published in Proceedings of the Pacific Symposium on Biocomputing. The data from the study show that the classifier detects the BRAF V600E mutation — often predictive of papillary thyroid cancer (PTC) — with high diagnostic accuracy. This new test is marketed as Afirma BRAF by Veracyte, Inc., and is part of a broader offering that centers on a genomic test to identify benign thyroid nodules among those deemed indeterminate by cytopathology to enable these patients to avoid unnecessary surgery.

When surgery is warranted, preoperative identification of BRAF V600E in thyroid nodule fine needle aspiration biopsies (FNABs) may enable physicians to better assess individual patients’ risk of cancer and determine the most appropriate surgical strategy, such as whether to perform a total or partial thyroidectomy. PCR- or sequencing-based DNA analysis is often limited by the need for a DNA quantity that is dificult to procure from an FNA biopsy.

Researchers led by Giulia C. Kennedy, PhD, chief scientific oficer and senior vice president of research, product, and clinical development at Veracyte, evaluated 535 FNA samples using both its Afirma RNA-based classifier and a sensitive, standard PCR DNA-based test. The Afirma BRAF RNA-based classifier accurately determined the presence or absence of the BRAF V600E DNA mutation with equal performance but with a lower non-diagnostic rate than the DNA-based test (7.6% vs. 24.5%). According to the authors, since Afirma BRAF uses a genomic expression signature associated with altered BRAF signaling, it has the potential to detect BRAF mutations other than V600E, giving it a broader clinical utility

The authors concluded, “Afirma BRAF accurately determined the presence or absence of the BRAF V600E DNA mutation in FNABs, a collection method directly relevant to solid tumor assessment, with performance equal to that of an established, highly sensitive DNA-based assay and with a lower nondiagnostic rate. This is the first such test in thyroid cancer to undergo sufficient analytical and clinical validation for real-world use in a personalized medicine context to frame individual patient risk and inform surgical choice.”

Novel Drug Candidate Regenerates Pancreatic Cells Lost to Diabetes

After a screen of more than 100,000 chemicals, harmine emerged as a drug class that drives the sustained division and multiplication of adult human beta cells in culture and tripled the number of beta cells and led to better control of blood sugar in three groups of mice engineered to mimic human diabetes, according to a study recently published in Nature Medicine.

Researchers led by Andrew Stewart, MD, director of the Diabetes, Obesity and Metabolism Institute at the Icahn School of Medicine at Mount Sinai, New York, N.Y., wrote that “whereas beta cell expansion seems an obvious therapeutic approach to beta cell deficiency, adult human beta cells have proven recalcitrant to such e orts. Hence, there remains an urgent need for antidiabetic therapeutic agents that can induce regeneration and expansion of adult human beta cells in vivo or ex vivo.”

So over several years, Stewart and his colleagues unraveled genes and signaling pathways that drive proliferation of beta cells, and then confirmed proposed mechanisms with gene therapy. Based on the study results, the team believes a particular enzyme, “dual specificity tyrosine-regulated kinase-1a (DYRK1A),” is the likely target of harmine. With this discovery, DYRK1A, known from past studies to drive cell division in other cell types, becomes a drug development target.

“We found that harmine, likely by interacting with DYRK1A, increases levels of other known drivers of cell division,” says Peng Wang, PhD, assistant professor of Medicine, Endocrinology, Diabetes, and Bone Disease at the Icahn School of Medicine and first author of the paper. “These drivers include the protein c-MYC, the gene for which was the basis of the screen we used to identify harmine as a potential treatment.”

Wang says the team designed a sensor to glow (thanks to a firefly gene) when any compound activated the promoter DNA snippet responsible for turning on the c-MYC gene. Of more than 100,000 compounds analyzed in a high-speed robotic screen, harmine was among 86 that caused the brightest glow and was the only one of these that caused beta cell proliferation. The c-MYC pathway appeared to some researchers to be an unlikely therapeutic target for beta cell regeneration because past studies had found it to cause beta cell death when activated in high doses. However, the current study found that harmine causes only modest increases in c-MYC levels and no beta cell death. The research team will now focus on making changes to the harmine and its relatives (harmalogs) to find drug candidates that target only beta cells.

“Our results provide a large body of evidence demonstrating that the harmine drug class can make human beta cells proliferate at levels that may be relevant for diabetes treatment,” says Stewart, who is a former Annual Meeting steering committee chair, past council member, past secretary-treasurer, and “longtime fan” of the Endocrine Society. “While we still have a lot of work to do in improving the specificity and potency of the harmine and related compounds, we believe these results represent a key step toward more effective future treatment of diabetes.”

Interventions Lower Diabetes Risk in Women Who had Gestational Diabetes

Women with a history of gestational diabetes face a heightened risk of developing type 2 diabetes for years after giving birth, but intensive lifestyle intervention or a medication regimen can have a protective effect in this population, according to a study recently published in the Journal of Clinical Endocrinology & Metabolism.

The Diabetes Prevention Program Outcomes Study (DPPOS) analyzed long-term metabolic health in 288 women who had a previous diagnosis of gestational diabetes and 1,226 mothers who did not have a history of the condition. The women all participated in the initial DPPOS, a randomized clinical trial where they were assigned to intensive lifestyle intervention, the diabetes medication metformin, or a placebo. The intensive lifestyle intervention was aimed at reducing body weight by 7 percent and participating in moderate cardio exercise for 150 minutes a week.

During the DPPOS, the women continued to have their blood glucose levels measured twice a year for six years. The study looked at long-term health outcomes in participants for about a decade after the women first enrolled in the study. Women with a history of gestational diabetes who were assigned to take the medication metformin or undergo the intensive lifestyle intervention were less likely to develop type 2 diabetes than women who received the placebo. When they were assigned the placebo, women who had a history of gestational diabetes had a 48.0% higher risk of developing diabetes compared to women who were never diagnosed with the condition. Women who had been diagnosed with gestational diabetes and underwent intensive lifestyle intervention had a 35.2% reduction in their risk of developing type 2 diabetes. The risk was reduced by 40.4% among women with a history of the condition who were assigned to take metformin.

“Our long-term follow-up study found the elevated risk of developing type 2 diabetes persisted for years in women who had been diagnosed with gestational diabetes, and this long-term risk can be reduced with either intensive lifestyle intervention or the medication metformin,” says one of the study’s authors, Vanita Aroda, MD, of the MedStar Health Research Institute in Hyattsville, Md.

Vitamin D Deciency Linked More Closely to Diabetes than Obesity

People who have low levels of vitamin D are more likely to have diabetes, regardless of how much they weigh, according to a new study published in the Journal of Clinical Endocrinology & Metabolism. “The major strength of this study is that it compares vitamin D levels in people at a wide range of weights (from lean to morbidly obese subjects) while taking whether they had diabetes into account,” says one of the study’s authors, Mercedes Clemente-Postigo, MSc, of Instituto de Investigación Biomédica de Málaga (IBIMA) at Complejo Hospitalario de Málaga (Virgen de la Victoria) and Universidad de Málaga in Malaga, Spain.

The cross-sectional study compared vitamin D biomarkers in 118 participants at the university hospital Virgen de la Victoria in Malaga as well as 30 participants from the Hospital Universitari Dr. Josep Trueta in Girona, Spain. All participants were classified by their body mass index (BMI) as well as whether they had diabetes, prediabetes, or no glycemic disorders. Researchers measured levels of vitamin D in the participants’ blood streams and vitamin D receptor gene expression in adipose tissue.

The analysis found that obese subjects who did not have glucose metabolism disorders had higher levels of vitamin D than diabetic subjects. Likewise, lean subjects with diabetes or another glucose metabolism disorder were more likely to have low levels of vitamin D. Vitamin D levels were directly correlated with glucose levels but not with BMI.

“Our findings indicate that vitamin D is associated more closely with glucose metabolism than obesity,” says one of the study’s authors, Manuel Macías-González, PhD, of Complejo Hospitalario de Málaga (Virgen de la Victoria) and the University of Málaga. “The study suggests that vitamin D deficiency and obesity interact synergistically to heighten the risk of diabetes and other metabolic disorders. The average person may be able to reduce their risk by maintaining a healthy diet and getting enough outdoor activity.”

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