RESUMEN
There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear. While biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Here, we show that skin fibroblasts undergo age-mediated, sex-dependent changes in their proliferation, senescence, ROS levels, and stress response. We find that aged male fibroblasts selectively drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Intrinsic aging in male fibroblasts mediated by EZH2 decline increases BMP2 secretion, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotypes and sensitizes melanoma cells to BRAF/MEK inhibition.
RESUMEN
OBJECTIVES: No article on serum lipids in ankylosing spondylitis (AS) and control subjects has been reported from USA. The primary aim of this study was to determine if any difference occurred in serum lipid levels in AS and control rheumatic disorders in two time periods, 1978-98 and 2000-10. The secondary aim was to investigate variables associated with lipid levels and if a difference was found between AS and control disorders. METHODS: The AS patients were compared to non-inflammatory rheumatic disorders (NIRDs) in 1978-98 and 2000-10 surveys and to rheumatoid arthritis (RA) in the 2000-10 survey. Patients were matched within 5 years of age, sex, and clinic or hospital source. RESULTS: In the 1978-98 survey, entry mean (SEM) serum cholesterol level [mg/dL] was highly (p<0.001) significantly lower in 69 AS [179.0 (4.8)] than 69 matched NIRD controls [208.0 (5.6)]. In 29 pairs of AS and NIRD subjects having manual labour occupations, mean (SEM) cholesterol level was additionally lower in AS [156.7 (5.9)] and higher in 29 NIRD controls [213.3 (8.6)] (p<0.001). In manual labour workers, mean (SEM) serum triglyceride was significantly lower (p=0.004) in 15 AS [110.3 (14.1)] than 14 NIRD controls [185.2 (19.3)]. In the 2000-10 survey, no lipid difference was found between AS vs. NIRD control patients. CONCLUSIONS: In the 1978-98 survey, AS had significantly lower mean serum cholesterol and triglyceride levels than NIRD control patients. Associated manual labour occupations may have significantly contributed to results, possibly related to increased energy expenditures from physical activity in the pre-2000 era.
RESUMEN
OBJECTIVES: Ankylosing spondylitis (AS) is suspected to have increased risk of atherosclerosis and cardiovascular disease (CVD) mortality. This systematic review and meta-analysis aims to critically study serum lipids and lipoprotein ratios in AS compared to healthy control (HC) subjects and determine any significant difference. METHODS: English-language articles were systematically searched in PubMed, Ovid Medline, Embase (Medline records removed), and Scopus databases from 1970 to 2021. Random-effects model was used to pool results expressed as standardised mean difference (SMD) in the lipid outcomes. Lipid ratios of total ÷ HDL-C and the log10 (TG/HDL-C), i.e. atherogenic index of plasma (AIP), were analysed by histograms of differences in weighted means and weighted SDs between AS and HC exposure cohorts. RESULTS: The meta-analysis included a total of 68 articles, 47 from database search and 21 from reference reviews. Pooled Hedges' g effect size revealed no difference in mean total cholesterol, mean triglycerides, and mean LDL-C between AS and HC subjects. However, mean HDL-C was significantly (p<0.001) lower in AS than HC subjects, with pooled Hedges' g (SE) for HDL-C of -0.484 (0.092), with 95% mean CIs [-0.664, -0.305]. In comparing differencesin AS minus HC weighted means of total HDL-C ratios, 8 values in HC were below the lowest ratio in AS. CONCLUSIONS: Highly significantly lower HDL-C levels occurred in AS versus HC subjects. The lower HDL-C levels in AS than HC populations deserve further study and may be attributable to uninvestigated demographic, exercise capacity, or clinical manifestations.