👤 Paolo Raggi

Polycystic ovary syndrome (PCOS) is associated with increased cardiometabolic risk in young women of reproductive age. There are limited studies on atherogenic dyslipidemia, inclusive of triglycerides (TG), Apolipoprotein (apo) B-lipoproteins and remnant-cholesterol (C), atherosclerotic cardiovascular disease (ACVD), cardiac function and remodeling in young women with and without PCOS. The aim of this pilot study was to investigate the relationship of atherogenic dyslipidemia and other cardiometabolic risk factors with ACVD, cardiac function-remodeling in high-risk young overweight-obese PCOS women compared to non-PCOS and healthy-weight controls. Women with and without PCOS (non-PCOS control) aged 18 - 45 years who were overweight and obese (>25kg/m PCOS (n=48) and non-PCOS control overweight-obese age-BMI matched groups (n=19) were shown to have significantly higher fasting and non-fasting lipids including TG, remnant-C, total ApoB and ApoB48, compared to healthy-weight non-PCOS controls (n=10). PCOS and non-PCOS control overweight-obese groups had significantly higher SBP, DBP, cIMT and evidence of cardiac dysfunction and remodeling, with reduced Mitral E/A ratio, intraventricular (IV) relaxation time and increased Left ventricle (LV) end diastolic and systolic diameter, LV posterior wall thickness and IV septal thickness, compared to healthy-weight non-PCOS controls. Individuals with PCOS had significantly higher fasting plasma TG and remnant-C compared to the non-PCOS overweight-obese control group. The PCOS group tended to have 25% higher carotid plaque height, although this was not significant, compared to the non-PCOS overweight-obese control group. DBP, HOMA-IR and ApoB predicted 40% of the variability in cIMT and ApoB was shown to predict 14% of the variability in carotid plaque height, independent of age and BMI. A 1mg/ml increase in ApoB was associated with a 0.041mm increase in cIMT and a 0.75mm increase in carotid plaque height in all young women. Our pilot results supports the potential of apoB-dyslipidemia, cIMT, carotid plaque height and left ventricular diastolic dysfunction and remodeling to be used in screening for CVD risk in high-risk populations such as overweight-obese women with and without PCOS. ApoB may be useful to predict atherosclerotic vascular burden and progression of cIMT and carotid plaque, and could be used to develop a female specific algorithm for ACVD risk in high-risk young women with and without PCOS. Show less

White adipose tissue dysfunction has emerged as a critical factor in cardiometabolic disease development, yet the cellular microstructure and genetic architecture of adipocyte morphology remain poorly explored. We introduce Adipocyte U-Net 2.0, an advanced deep learning method for the semantic segmentation of adipose tissue histology, enabling analysis of over 27 million adipocytes from 2,667 individuals. Our approach revealed that adipocyte hypertrophy associates with metabolic dysfunction, including increased fasting glucose, glycated hemoglobin, leptin, and triglycerides, with decreased adiponectin and HDL cholesterol levels. Through the largest genome-wide association study of adipocyte size to date (N Our findings demonstrate the utility of deep learning for adipocyte phenotyping at scale and provide novel insights into the genetic basis of adipocyte morphology and its relationship to metabolic disease. Show less

In the tumor microenvironment, Cancer Associated Fibroblasts (CAFs) become activated by cancer cells and increase their secretory activity to produce soluble factors that contribute to tumor cells proliferation, invasion and dissemination to distant organs. The pro-tumorigenic transcription factor STAT3 and its canonical inducer, the pro-inflammatory cytokine IL-6, act conjunctly in a positive feedback loop that maintains high levels of IL-6 secretion and STAT3 activation in both tumor and stromal cells. Here, we demonstrate that STAT3 is essential for the pro-tumorigenic functions of murine breast cancer CAFs both in vitro and in vivo, and identify a STAT3 signature significantly enriched for genes encoding for secreted proteins. Among these, ANGPTL4, MMP13 and STC-1 were functionally validated as STAT3-dependent mediators of CAF pro-tumorigenic functions by different approaches. Both in vitro and in vivo CAFs activities were moreover impaired by MMP13 inhibition, supporting the feasibility of a therapeutic approach based on inhibiting STAT3-induced CAF-secreted proteins. The clinical potential of such an approach is supported by the observation that an equivalent CAF-STAT3 signature in humans is expressed at high levels in breast cancer stromal cells and characterizes patients with a shorter disease specific survival, including those with basal-like disease. Show less

The early detection of cutaneous melanoma, a potentially lethal cancer with rising incidence, is fundamental to increasing survival and therapeutic adjustment. In stages II-IV especially, additional indications for adjuvant therapy purposes after resection and for treatment of metastatic patients are urgently needed. We investigated whether the fatty acid (FA) and protein compositions of small extracellular vesicles (sEV) derived from the plasma of stage 0-I, II and III-IV melanoma patients ( Show less