A look at the latest research

LOSS OF NTRK2/KISS1R
SIGNALING in oocytes Causes
Premature ovarian Failure

A recent mouse study may provide clues to early adult infertility, specifically premature ovarian failure (POF), a disorder that affects 1% of women of reproductive age.

Researchers led by Sergio R. Ojeda, DVM, of the Oregon National Primate Research Center/Oregon Health and Science University, and Manuel Tena-Sempere, MD, of the University of Cordoba, Spain, wrote in Endocrinology that identifying “the factors required for oocyte survival during the reproductive lifespan is an important endeavor because knowledge of the underlying pathways may provide significant new insights into the pathology of ” the disorder.

Ojeda and his team looked at neurotrophins (NTs), which had been previously shown to provide developmental cues to non-neural cells, and contribute to the formation and development of follicles in the ovary. According to the scientists, oocyte-specific deletion of the Ntrk2 gene that encodes the NTRK2 receptor (NTRK2) for neurotrophin-4/5 and brain-derived neurotrophic factor (BDNF) results in post-pubertal oocyte death, loss of follicular organization, and early adulthood infertility.

They studied NTRK2 receptors in mice before and at puberty and found that full-length receptors (NTRK2.FL) became expressed in oocytes at puberty because they are rapidly induced by the preovulatory gonadotropin surge. Th e authors observed that if there are no NTRK2.FL receptors, the gonadotropins are unable to activate the wellestablished oocyte PI3K/AKT-mediated survival pathway. They wrote, “A cell line expressing both [a truncated NTRK2 form] NTRK2.T1 and the kisspeptin receptor (KISS1R) responds to BDNF stimulation with activation of Ntrk2 expression only if kisspeptin is present. Th is suggests that BDNF and kisspeptin that are produced by granulosa cells (GCs) of periovulatory follicles act in concert to mediate the effect of gonadotropins on Ntrk2 expression in oocytes. In keeping with this finding, the oocytes of NTRK2-intact mice fail to respond to gonadotropins with increased Ntrk2 expression in the absence of KISS1R.”

They concluded that the preovulatory gonadotropin surge promotes the survival of the oocyte by inducing the expression of NTRK2.FL receptors, setting in motion an AKT-mediated survival pathway. The authors wrote that their findings “also suggest that gonadotropins activate NTRK2.FL expression via a dual communication pathway involving BDNF and kisspeptin produced in GCs and their respective receptors NTRK2.T1 and KISS1R expressed in oocytes.”

APOBEC3B Linked to Er+ Breast Cancers

Elevated levels of the gene APOBEC3B is associated with poorer clinical outcomes in patients with estrogen receptor-positive (ER+) breast cancer, according to research recently published inHormones and Cancer.

According to the study, APOBEC3B is a member of a larger family of polynucleotide cytosine deaminases with diverse physiological functions in innate and adaptive immunity, lipid metabolism, and heart development. Researchers led by John W. Martens, PhD, of the Erasmus MC Cancer Institute in Rotterdam, Netherlands, wrote that there have been recent observations connecting DNA cytosine deaminase APOBEC3B to the genetic evolution of breast cancer, saying that the gene is a “major enzymatic source of somatic driver and passenger mutations in breast cancer.”

Martens and his team pointed out that APOBEC3B mRNA levels were related in 1,491 primary breast cancers to disease-free (DFS), metastasisfree (MFS), and overall survival (OS). They wanted to validate these results independently, so they used univariate Cox regression analysis to study patient outcome data in five additional cohorts comprising more than 3,500 breast cancer cases.

Th e scientists found that “increasing APOBEC3B expression as a continuous variable was associated with worse DFS, MFS, and OS (Hazard Ratio [HR]=1.20; 1.21, and 1.24, respectively; all P<.001). Also in untreated ER+, but not in ER-, lymph node-negative patients, high APOBEC3B levels were associated with a poor DFS (continuous variable: HR=1.29, P=.001; dichotomised at the median level, HR=1.66, P=.0002).” These findings were confirmed in all five cohorts, suggesting that APOBEC3B is a “marker of pure prognosis, and poor outcomes for ER+ breast cancer.” The authors concluded that genetic aberrations induced by APOBEC3B contribute to breast cancer progression, writing that more aggressive treatments of ER+ tumors could target and eradicate APOBEC3B-high ER+ cells.

African Americans respond Better to FIRST-LINE DIABETES DRUG

African Americans taking the diabetes drug metformin saw greater improvements in their blood sugar control than white individuals who were prescribed the same medication, according to a new study published in the Journal of Clinical Endocrinology & Metabolism.

“Metformin is normally the first treatment physicians prescribe for type 2 diabetes, but the standard of care is based on clinical trials where the vast majority of participants were white,” says one of the study’s authors, L. Keoki Williams, MD, MPH, of Henry Ford Health System in Detroit, Mich. “We wanted to examine how the drug performed in an African American population. Our findings suggest that African Americans who have diabetes actually respond better to metformin than whites.”

The observational study used medical and pharmacy records from Henry Ford Health System to examine blood sugar control in 19,672 people with diabetes who were prescribed metformin between January 1, 1997, and June 2, 2013. Among the participants, 7,429 were African American and 8,783 were white. Using pharmacy records, the researchers estimated each individual’s exposure to metformin and other diabetes medications. Each study participant had at least two hemoglobin A1c (HbA1C) blood sugar measurements taken at least four months apart while they were on metformin.

Because the HbA1C test measures a person’s average blood sugar level from the past three months, researchers ran an analysis to measure the change in participants’ blood sugar levels in relation to the amount of metformin taken. Th e study found the maximum dose of metformin was associated with an absolute decrease in HbA1C values of 0.9% among African Americans. In contrast, the same analysis found a 0.42% reduction in HbA1C numbers among whites.

“When one considers that the goal HbA1c level for individuals being treated for diabetes is less than 7% and that the average starting HbA1c level in our patients was around 7.5%, these differences in treatment response are clinically important,” Williams says. “Moreover, since African Americans are more likely to suffer from diabetic complications when compared with white individuals, it is heartening to observe that metformin is likely more effective at controlling blood glucose in the former group.”

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