Coronary Artery Disease Manifestations in HIV: What,How, and Why

Understanding why persons with human immunodeficiency virus (HIV) have accelerated atherosclerosis and its sequelae, including coronary artery disease (CAD) and myocardial infarction, is necessary to provide appropriate care to a large and aging population with HIV. In this review, we delineate the diverse pathophysiologies underlying HIV-associated CAD and discuss how these are implicated in the clinical manifestations of CAD among persons with HIV. Several factors contribute to HIV-associated CAD, with chronic inflammation and immune activation likely representing the primary drivers. Increased monocyte activation, inflammation, and hyperlipidemia present in chronic HIV infection also mirror the pathophysiology of plaque rupture. Furthermore, mechanisms central to plaque erosion, such as activation of toll-like receptor 2 and formation of neutrophil extracellular traps, are also abundant in HIV. In addition to inflammation and immune activation in general, persons with HIV have a higher prevalence than uninfected persons of traditional cardiovascular risk factors, including dyslipidemia, hypertension, insulin resistance, and tobacco use. Antiretroviral therapies, although clearly necessary for HIV treatment and survival, have had varied effects on CAD, but newer generation regimens have reduced cardiovascular toxicities. From a clinical standpoint, this mix of risk factors is implicated in earlier CAD among persons with HIV than uninfected persons; whether the distribution and underlying plaque content of CAD for persons with HIV differs considerably from uninfected persons has not been definitively studied. Furthermore, the role of cardiovascular risk estimators in HIV remains unclear, as does the role of traditional and emerging therapies; no trials of CAD therapies powered to detect clinical events have been completed among persons with HIV.     

Leading progress: the role of the chief diversity officer in anesthesiology departments

Canadian Journal of Anesthesia/Journal canadien d'anesthésie -     

Putative protective neural mechanisms in prereaders with a family history of dyslexia who subsequently develop typical reading skills

Developmental dyslexia affects 40–60% of children with a familial risk (FHD+) compared to a general prevalence of 5–10%. Despite the increased risk, about half of FHD+ children develop typical reading abilities (FHD+Typical). Yet the underlying neural characteristics of favorable reading outcomes in at‐risk children remain unknown. Utilizing a retrospective, longitudinal approach, this study examined whether putative protective neural mechanisms can be observed in FHD+Typical at the prereading stage. Functional and structural brain characteristics were examined in 47 FHD+ prereaders who subsequently developed typical (n = 35) or impaired (n = 12) reading abilities and 34 controls (FHD?Typical). Searchlight‐based multivariate pattern analyses identified distinct activation patterns during phonological processing between FHD+Typical and FHD?Typical in right inferior frontal gyrus (RIFG) and left temporo‐parietal cortex (LTPC) regions. Follow‐up analyses on group‐specific classification patterns demonstrated LTPC hypoactivation in FHD+Typical compared to FHD?Typical, suggesting this neural characteristic as an FHD+ phenotype. In contrast, RIFG showed hyperactivation in FHD+Typical than FHD?Typical, and its activation pattern was positively correlated with subsequent reading abilities in FHD+ but not controls (FHD?Typical). RIFG hyperactivation in FHD+Typical was further associated with increased interhemispheric functional and structural connectivity. These results suggest that some protective neural mechanisms are already established in FHD+Typical prereaders supporting their typical reading development.     

GPER-induced signaling is essential for the survival of breast cancer stem cells

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER⁻/PR⁺ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs.     

SMYD3 promotes implant metastasis of ovarian cancer via H3K4 trimethylation of integrin promoters

Detachment of cancer cells from the primary tumor and formation of spheroids in ascites is required for implantation metastasis in epithelial ovarian cancer (EOC), but the underlying mechanism of this process has not been thoroughly elucidated. To mimic this process, ovarian cancer cells were grown in 3D and 2D culture. Hey and OVCA433 spheroids exhibited decreased cell proliferation and enhanced adhesion and invasion. SMYD3 expression was elevated in ovarian carcinoma spheroids in association with increased H3K4 methylation. Depletion of SMYD3 by transient siRNA, stable shRNA knockdown and the SMYD3 inhibitor BCI-121 all decreased spheroid invasion and adhesion. Gene expression arrays revealed downregulation of integrin family members. Inhibition assays confirmed that invasion and adhesion of spheroids are mediated by ITGB6 and ITGAM. SMYD3-deficient cells regained the ability to invade and adhere after forced overexpression of SMYD3, ITGB6 and ITGAM. However, this biological ability was not restored by forced overexpression of SMYD3 in ITGB6- and/or ITGAM-deficient cancer cells. SMYD3 and H3K4me3 binding at the ITGB6 and ITGAM promoters was increased in spheroids compared to that in monolayer cells, and the binding was decreased when SMYD3 expression was inhibited, consistent with the expression changes in integrins. SMYD3 expression and integrin-mediated adhesion were also activated in an intraperitoneal xenograft model and in EOC patient spheroids. In vivo, SMYD3 knockdown inhibited tumor metastasis and reduced ascites volume in both the intraperitoneal xenograft model and a PDX model. Overall, our results suggest that the SMYD3-H3K4me3-integrin pathway plays a crucial role in ovarian cancer metastasis to the peritoneal surface.