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.

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BACKGROUND: Females live longer than males, which results in a sex gap in life expectancy. This study examines the contribution of female cancers to this differential by world region and country 1990-2019 with special focus to the 15-69 age group.
METHODS: Cause-specific mortality data for 30 cancers, including four female-specific cancers from 238 countries and territories was retrieved from the Global Burden of Disease Study 2019. Using life table techniques and demographic decomposition analysis, we estimated the contribution of cancer deaths to the sex gap in life expectancy by age and calendar period.
RESULTS: At ages 15-69, females had a higher life expectancy than males in 2019. Countries with the largest sex gaps or the largest female advantage in life expectancy were in Eastern Europe and Northern Asia, Latin America and Southern Africa. In contrast, countries with the smallest sex gaps were mainly located in Northern Africa, Northern America, and Northern Europe. The contribution of female-specific cancers to sex gaps in life expectancy were largely negative, ranging from -0.15 years in the Western Pacific to -0.26 years in the Eastern Mediterranean Region, implying that the disproportionately higher premature cancer mortality among females contributed to a reduction in the female life expectancy advantage.
CONCLUSIONS: Female-specific cancers are important determinants of sex gaps in life expectancy. Their negative impact on life expectancy at working and reproductive age groups has far-reaching consequences for society. Increasing the availability and access to prevention, screening, timely diagnosis, and effective treatment can reduce this gap.

UNASSIGNED: Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC.
UNASSIGNED: Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed.
UNASSIGNED: In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT.
UNASSIGNED: Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Several risk factors contribute to the development of Alzheimer\'s disease (AD), including genetics, metabolic health, cardiovascular history, and diet. It has been observed that women appear to face a higher risk of developing AD. Among the various hypotheses surrounding the gender disparity in AD, one pertains to the potential neuroprotective properties of estrogen. Compared to men, women are believed to be more susceptible to neuropathology due to the significant decline in circulating estrogen levels following menopause. Studies have shown, however, that estrogen replacement therapies in post-menopausal women do not consistently reduce the risk of AD. While menopause and estrogen levels are potential factors in the elevated incidence rates of AD among women, this review highlights the possible roles estrogen has in other pathways that may also contribute to the sex disparity observed in AD such as olfaction, sleep, and glymphatic functionality.

In Eurotransplant, relatively more females than males die while waiting for liver transplantation, and relatively fewer females undergo transplantation. With adult liver transplantation candidates listed between 2007 and 2019 (n = 21 170), we study whether sex disparity is inherent to the model for end-stage liver disease (MELD) scoring system, or the indirect result of a small candidate body size limiting access to transplantation. Cox proportional hazard models are used to quantify the direct effect of sex on waitlist mortality, independent of the effect of sex through MELD scores, and the direct effect of sex on the transplantation rate, independent of the effect of sex through MELD and candidate body size. Adjusted waitlist mortality hazard ratios (HRs) for female sex are insignificant (HR: 1.03, 95% CI: 0.88-1.20). We thus lack evidence that MELD systematically underestimates waitlist mortality rates for females. Transplantation rates are 25% lower for females than males in unadjusted analyses (HR: 0.74, 95% CI: 0.71-0.77), but HRs become insignificant with adjustment for mediators (HR: 0.98, 95% CI: 0.93-1.04), most importantly candidate body size. Sex disparity in Eurotransplant thus appears to be largely a consequence of lower transplantation rates for females, which are explained by sex differences in body size.

Hepatocellular carcinoma (HCC) is characterized by a notable sex disparity in incidence and tumor aggressiveness. Revealing differences in genetic landscapes between male and female HCCs may expand the understanding of sexual disparities mechanisms and assist the development of precision medicine. Although reports on the sex disparity of HCC are accumulated, studies focusing on sex-related biomarkers among Asian populations remain limited. Here, we conducted a comprehensive genomic profiling analysis to explore differences between male and female patients within a cohort of 195 Taiwanese HCC patients. We did not detect any sex-biased genomic alterations. However, when our investigation extended to the TCGA dataset, we found higher frequencies of gene copy gains in CCNE2 and mutations in CTNNB1 and TP53 among male patients. Besides, we further evaluated the associations between genomic alterations and patients\' prognosis by sex. The results showed that female patients harboring tumors with STAT3 gain and alterations in the JAK-STAT pathway displayed a poor prognosis. These two factors remained independently associated with unfavorable prognosis even after adjusting for the patient\'s age and stage characteristics (Hazard ratio = 10.434, 95% CI 3.331-32.677, P < 0.001; Hazard ratio = 2.547, 95% CI 1.195-5.432, P = 0.016, respectively). In summary, this study provides valuable insights into understanding sex disparity in HCC in the East Asian population. Validation through larger cohorts and extensive sequencing efforts is warranted.

Elevated fasting glucagon concentrations and/or attenuated postprandial glucagon suppression are characteristics of type 2 diabetes (T2D) and contribute to hyperglycaemia. This study shows that hyperglucagonaemia is more prominent in males than females after a nutrient load in T2D, adding insights into sex differences in relation to the pathophysiology of T2D.

BACKGROUND: The relationship between inflammation and covert cerebral small vessel disease (SVD) with regards to sex difference has received limited attention in research. We aim to unravel the intricate associations between inflammation and covert SVD, while also scrutinizing potential sex-based differences in these connections.
METHODS: Non-stroke/dementia-free study population was from the I-Lan longitudinal Aging Study. Severity and etiology of SVD were assessed by 3T-MRI in each participant. Systemic and vascular inflammatory-status was determined by the circulatory levels of high-sensitivity C-reactive protein (hsCRP) and homocysteine, respectively. Sex-specific multivariate logistic regression to calculate odds ratios (ORs) and interaction models to scrutinize women-to-men ratios of ORs (RORs) were used to evaluate the potential impact of sex on the associations between inflammatory factors and SVD.
RESULTS: Overall, 708 participants (62.19 ± 8.51 years; 392 women) were included. Only women had significant associations between homocysteine levels and covert SVD, particularly in arteriosclerosis/lipohyalinosis SVD (ORs[95%CI]: 1.14[1.03-1.27] and 1.15[1.05-1.27] for more severe and arteriosclerosis/lipohyalinosis SVD, respectively). Furthermore, higher circulatory levels of homocysteine were associated with a greater risk of covert SVD in women compared to men, as evidenced by the RORs [95%CI]: 1.14[1.01-1.29] and 1.14[1.02-1.28] for more severe and arteriosclerosis/lipohyalinosis SVD, respectively. No significant associations were found between circulatory hsCRP levels and SVD in either sex.
CONCLUSIONS: Circulatory homocysteine is associated with covert SVD of arteriosclerosis/lipohyalinosis solely in women. The intricacies underlying the sex-specific effects of homocysteine on SVD at the preclinical stage warrant further investigations, potentially leading to personalized/tailored managements.
BACKGROUND: Not applicable.

Background/Objectives: Metabolic syndrome (MS) is a constellation of several cardiometabolic risk factors. We investigated sex disparity in the associations between MS and cognitive impairment using cross-sectional data from Taiwan Biobank. Methods: We determined the associations of MS and its five components with cognitive impairment (mini-mental state examination, MMSE < 24) and the five domains of MMSE using logistic regression analyses. Results: A total of 7399 men and 11,546 women were included, and MS was significantly associated with cognitive impairment only in women (adjusted OR 1.48, 95% CI 1.29-1.71, p = 0.001) (p for interaction 0.005). In women, the association with MS was significant in orientation (adjusted OR 1.21, 95% CI 1.07-1.37, p = 0.003), memory (adjusted OR 1.12, 95% CI 1.01-1.25, p = 0.034) and design copying (adjusted OR 1.41, 95% CI 1.23-1.62, p = 0.001) (p value for interaction 0.039, 0.023, and 0.093, respectively). Among the components of MS, a large waist circumference (adjusted OR 1.25, 95% CI 1.08-1.46, p = 0.003), high fasting glucose (adjusted OR 1.16, 95% CI 1.00-1.34, p = 0.046), and low HDL cholesterol (adjusted OR 1.16, 95% CI 1.00-1.34, p = 0.049) were significantly associated with cognitive impairment in women. Conclusions: Our findings suggest that sex has a significant influence on the association between MS and cognitive dysfunction, especially in orientation and memory.