Mainstreaming in parallel with ovarian cancer tumor testing to improve genetic testing uptake.

OBJECTIVES: Although genetic testing (GT) is universally recommended for patients with epithelial ovarian cancer (EOC), rates are low (34%). In 1/2019, we implemented mainstreaming-GT in parallel with tumor testing via MSK-IMPACT within oncology clinics. We sought to determine GT rates pre/post-mainstreaming and patient characteristics associated with GT. METHODS: Patients with newly diagnosed EOC seen at our institution from 7/1/2015-3/31/2022 were included. Clinical data were abstracted including social determinants of health (SDOH) variables, race/ethnicity, marital status, insurance, language, comorbidities, employment, and Yost index, a measure of socioeconomic status. GT rates were calculated overall and pre-/post-mainstreaming (1/2019). Logistic regression models were fit to identify variables associated with GT. RESULTS: Of 1742 patients with EOC, 1591 (91%) underwent GT. Rates of GT increased from 87% to 95% after mainstreaming (p < 0.001). Among 151 patients not undergoing GT, major reasons were lack of provider recommendation (n = 76, 50%) and logistical issues (n = 38, 25%) with few declining (n = 14, 9%) or having medical complications preventing GT (n = 7, 4.6%). High-grade serous histology, advanced stage (III/IV), and having a spouse/partner were associated with increased GT uptake (p < 0.01). Among SDOH variables, there were no differences by insurance, Yost score, language, comorbidities, employment, or race/ethnicity. In multivariable models, likelihood of GT increased with mainstreaming, even after adjustment for histology, stage, and marital status (OR 3.77; 95% CI: 2.56-5.66). CONCLUSIONS: Mainstreaming increased the likelihood of GT in patients with EOC. We found lower testing rates in patients without partners/spouses, non-high-grade serous histology, and early-stage disease, representing potential areas for future interventions.

Obesity shapes selection for driver mutations in cancer.

Obesity is a leading risk factor for cancer, but whether obesity is linked to specific genomic subtypes of cancer is unknown. Here, we examined the relationship between obesity and tumor genotype in two large clinicogenomic corpora. Obesity was associated with specific driver mutations in lung adenocarcinoma, endometrial carcinoma, and cancers of unknown primary, independent of clinical covariates and genetic ancestry. Obesity is therefore a putative driver of etiologic heterogeneity across cancers.

Tumor sequencing of African ancestry reveals differences in clinically relevant alterations across common cancers.

Cancer genomes from patients with African (AFR) ancestry have been poorly studied in clinical research. We leverage two large genomic cohorts to investigate the relationship between genomic alterations and AFR ancestry in six common cancers. Cross-cancer type associations, such as an enrichment of MYC amplification with AFR ancestry in lung, breast, and prostate cancers, and depletion of BRAF alterations are observed in colorectal and pancreatic cancers. There are differences in actionable alterations, such as depletion of KRAS G12C and EGFR L858R, and enrichment of ROS1 fusion with AFR ancestry in lung cancers. Interestingly, in lung cancer, KRAS mutations are less common in both smokers and non-smokers with AFR ancestry, whereas the association of TP53 mutations with AFR ancestry is only seen in smokers, suggesting an ancestry-environment interaction that modifies driver rates. Our study highlights the need to increase representation of patients with AFR ancestry in drug development and biomarker discovery.

Keratin biomaterials augment anti-inflammatory macrophage phenotype in vitro.

Tissue regeneration following injury is mediated by macrophage recruitment and differentiation in response to environmental signals. In general, macrophages adopt either a classically M1 (M[IFN-γ, LPS]) or alternatively activated M2 (M[IL-4, IL-13] or M[IL-10]) phenotype. Recent studies have highlighted the importance of alternatively activated macrophages in tissue remodeling and repair as well as the contribution of an imbalance of classically and alternatively activated macrophages to tissue degeneration and disease progression. Keratin biomaterials have recently demonstrated their ability to promote alternatively activated macrophage polarization in an in vitro model using a monocytic cell line. In the present study, the ability of extracted human hair keratins to influence alternative activation of human primary monocytes in vitro is assessed by evaluating changes in surface receptor expression, inflammatory cytokine secretion, and phagocytic activity. The impact of keratin molecular weight fractionation on these outcomes was also investigated. High and low molecular weight fractions of the oxidized form of extractable human hair keratins - referred to as keratose (KOSH and KOSP, respectively) - were characterized by size exclusion chromatography, mass spectrometry, and Western blot. Primary macrophages underwent traditional differentiation to the M[IFN-γ, LPS], M[IL-4, IL-13], or M[IL-10]) phenotypes or were plated on different molecular weight keratin coatings (KOSH and KOSP). Macrophages plated on keratin and analyzed via flow cytometry yielded the largest CD163+ cell populations and CD163 mean fluorescence intensities. Cells in the KOSP group were significantly more phagocytic than all other cell types at the 1.5 and 3 h time points and exhibited behavior and a cytokine production profile most similar to the M[IL-10] treated group. These findings may have important implications for understanding and evaluating the ability of keratin biomaterials to influence inflammation and tissue regeneration in disease and injury models. STATEMENT OF SIGNIFICANCE: Biomaterials made from human hair keratins have previously been shown to elicit anti-inflammatory responses from naïve macrophages and polarize them toward an M2 phenotype. In this work we show for the first time that primary human cells respond similarly, that it is the M2c phenotype that predominates, that a sub-fraction of hydrolyzed keratin peptides are most likely responsible for the response, and that immobilization of the keratin peptides to a surface is required. Keratin biomaterials have been used to regenerate several tissues such as skin, muscle, bone, nerve, and cornea, in vitro and in animal studies. Our current findings will help guide the development of keratin-based biomaterials that seek to direct responses toward regenerative outcomes by attenuating inflammation.

Age and the experience of strong self-conscious emotion.

OBJECTIVES: It remains unclear whether there are age-related changes in the experience of strong self-conscious emotion, such as shame, guilt, pride and embarrassment. Because shame and guilt figure prominently in the aetiology of depressive symptoms and other mental health problems, a better understanding of how age affects the strong experience of these two negative self-conscious emotions is of particular importance. METHODS: Thirty younger, 30 middle-aged and 30 older adults were compared on standardised cognitive assessments, in addition to an interview-based measure that assessed whether there are age differences in the likelihood of strongly experiencing four different types of self-conscious emotion within the past five years (shame, guilt, embarrassment and pride). RESULTS: The three groups did not differ in their likelihood of reporting an event that strongly elicited the positive self-conscious emotion of pride. However, older adults were more likely to report sources of pride that were other (as opposed to self) focused. Older adults were also less likely to report experiencing events that elicited all three negative self-conscious emotions, in particular, shame. CONCLUSIONS: Strong negative self-conscious emotion, and in particular shame, appears to be experienced less by older than younger adults.

Fluid shear stress induces the clustering of heparan sulfate via mobility of glypican-1 in lipid rafts.

The endothelial glycocalyx plays important roles in mechanotransduction. We recently investigated the distribution and interaction of glycocalyx components on statically cultured endothelial cells. In the present study, we further explored the unknown organization of the glycocalyx during early exposure (first 30 min) to shear stress and tested the hypothesis that proteoglycans with glycosaminoglycans, which are localized in different lipid microdomains, respond distinctly to shear stress. During the initial 30 min of exposure to shear stress, the very early responses of the glycocalyx and membrane rafts were detected using confocal microscopy. We observed that heparan sulfate (HS) and glypican-1 clustered in the cell junctions. In contrast, chondroitin sulfate (CS), bound albumin, and syndecan-1 did not move. The caveolae marker caveolin-1 did not move, indicating that caveolae are anchored sufficiently to resist shear stress during the 30 min of exposure. Shear stress induced significant changes in the distribution of ganglioside GM1 (a marker for membrane rafts labeled with cholera toxin B subunit). These data suggest that fluid shear stress induced the cell junctional clustering of lipid rafts with their anchored glypican-1 and associated HS. In contrast, the mobility of CS, transmembrane bound syndecan-1, and caveolae were constrained during exposure to shear stress. This study illuminates the role of changes in glycocalyx organization that underlie mechanisms of mechanotransduction.