Circulating progesterone and breast cancer risk

Endogenous progesterone could play a role in breast cancer risk, but their role has been largely unexplored due to limitations in assay sensitivity and low progesterone levels in postmenopausal women. Researchers used a sensitive liquid chromatography-tandem mass spectrometry assay, to quantify prediagnostic serum levels of progesterone and progesterone metabolites in a case-cohort study within the Breast and Bone Follow-up to the Fracture Intervention Trial. Participants included 405 women with incident breast cancer and a subcohort of 495 postmenopausal women, with a mean age of 67.2 years when their blood was sampled in 1992-93. The team found that women with higher circulating progesterone levels were at greater risk for breast cancer per mean increase in progesterone concentrations (HR, 1.16; 95% CI, 1.00-1.35; P = .048). The association was linear in a 5-knot spline and more robust with invasive breast cancers (n = 267) (HR, 1.24; 95% CI, 1.07-1.43; P = .004). Women with the lowest value of circulating estradiol (<6.30 pg/mL) elevated progesterone levels were at lower risk of breast cancer per standard deviation in progesterone levels, while higher estradiol values increased the risk. “Given that the women in our study were limited to those reporting no use of hormones within 4 months of the blood draw, our data provide support for a differential role of progesterone at physiologic levels that is possibly predicated on the level of circulating estradiol,” the team wrote. “We believe our data support that, at very low circulating estradiol levels, higher progesterone levels were associated with reduced breast cancer risk, suggesting that relatively higher progesterone levels may have a weak antimitotic effect on proliferation in the breast in this context.” Their work appeared online April 24, 2020, in JAMA Network Open.

Llamas aid in fight against COVID-19

Researchers at the University of Texas – Austin, the National Institutes of Health and Ghent University in Belgium have combined two copies of an antibody produced by llamas to create a new antibody that binds securely to the spike protein on SARS-CoV-2, the coronavirus that causes COVID-19. Early tests in culture suggest the new antibody prevents the spike protein from entering and infecting host cells. The initial antibodies were derived from the blood of a four-year-old llama named Winter in 2016. One showed the potential to neutralize the SARS-CoV-1 virus, while the other showed promise against MERS-CoV receptor-binding domains (RBDs). The heavy-chain-only antibodies, which contain a single variant domain (VHH), were elicited in response to Winter’s immunization with prefusion-stabilized SARS-CoV-1 and MERS-CoV RBDs. “Because of the current lack of treatments for MERS, SARS, and COVID-19 and the devastating effects associated with pandemic coronavirus outbreaks, both prophylactic and therapeutic interventions are sorely needed,” the authors wrote. They noted that the “possibility of administering these molecules via a nebulized spray is particularly attractive in the case of respiratory pathogens because the VHHs could theoretically be inhaled directly to the site of infection in an effort to maximize bioavailability and function.” The team is preparing to test the antibody in animals, with hopes of progressing to human trials. The aim is to develop a means of treating people in the early stages of infection. Their work was published online May 5, 2020, in the journal Cell.

Transcriptomic insights into Parkinson’s disease

Researchers at the Karolinska Institute have used single cell transcriptomics to identify the cell types that are changed by risk variants for Parkinson’s disease (PD). Genomewide association studies have identified multiple genetic risk factors for both neurodevelopmental and neurodegenerative disorders in recent years. But which cell types are functionally affected by those risk variants remains unclear in many instances. The authors used single-cell transcriptomics in both mouse and postmortem human brains and showed that unlike neurodevelopmental disorders, where projection neurons are the main affected cell types, in PD there were changes in dopaminergic and other midbrain neurons, as well as in the enteric nervous system and oligodendrocytes. “Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression,” the authors wrote. “Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease.” They published their findings in the April 27, 2020, online issue of Nature Genetics.

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