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Abstract The relationship between psoriasis and site-specific cancers remains unclear. Here, we aim to investigate whether psoriasis is causally associated with site-specific cancers. We use observational and genetic data from the UK Biobank, obtaining GWAS summary data, eQTL analysis data, TCGA data, and GTEx data from public datasets. We perform PheWAS, polygenic risk score analysis, and one-sample and two-sample Mendelian randomization analyses to investigate the potential causal associations between psoriasis and cancers. In the unselected PheWAS analysis, psoriasis is associated with higher risks of 16 types of cancer. Using one-sample Mendelian randomization analyses, it is found that genetically predicted psoriasis is associated with higher risks of anal canal cancer, breast cancer, follicular non-Hodgkin’s lymphoma and nonmelanoma skin cancer in women; and lung cancer and kidney cancer in men. Our two-sample Mendelian randomization analysis indicates that psoriasis is causally associated with breast cancer and lung cancer. Gene annotation shows that psoriasis-related genes, such as ERAP1, are significantly different in lung and breast cancer tissues. Taken together, clinical attention to lung cancer and breast cancer may be warranted among patients with psoriasis.

Abstract Background Dyslipidemia frequently coexists with hypertension in the population. Apolipoprotein B (ApoB) is increasingly considered a more potent predictor of cardiovascular disease (CVD). Abnormal levels of serum ApoB can potentially impact the mortality risk. Methods The prospective cohort study employed data from the National Health and Nutrition Examination Survey (NHANES), which was performed between 2005 and 2016, with follow-ups extended until December 2019. Serum ApoB concentrations were quantified using nephelometry. In line with the NHANES descriptions and recommendations, the reference ranges for ApoB concentrations are 55–140 and 55–125 mg/dL for men and women, respectively. Participants were categorized into low, normal, and high ApoB levels. The low and high groups were combined into the abnormal group. In this study, all-cause mortality (ACM) and CVD mortality (CVM) were the endpoints. Survey-weighted cox hazards models were used for evaluating the correlation between serum ApoB levels and ACM and CVM. A generalized additive model (GAM) was employed to examine the dose-dependent relationship between ApoB levels and mortality risk. Results After a median of 95 (interquartile range: 62–135) months of follow-up, 986 all-cause and 286 CVD deaths were recorded. The abnormal ApoB group exhibited a trend toward an elevated risk of ACM in relative to the normal group (HR 1.22, 95% CI: 0.96–1.53). The risk of CVM was elevated by 76% in the ApoB abnormal group (HR 1.76, 95% CI: 1.28–2.42). According to the GAM, there existed a nonlinear association between serum ApoB levels and ACM (P = 0.005) and CVM (P = 0.009). Conclusions In the US hypertensive population, serum Apo B levels were U-shaped and correlated with ACM and CVM risk, with the lowest risk at 100 mg/dL. Importantly, abnormal Apo B levels were related to an elevated risk of ACM and CVM. These risks were especially high at lower Apo B levels. The obtained findings emphasize the importance of maintaining appropriate Apo B levels to prevent adverse outcomes in hypertensive individuals.

Abstract Cholesterol 25‐hydroxylase (CH25H), an enzyme involved in cholesterol metabolism, regulates inflammatory responses and lipid metabolism. However, its role in kidney disease is not known. The author found that CH25H transcript is expressed mostly in glomerular and peritubular endothelial cells and that its expression increased in human and mouse diabetic kidneys. Global deletion of Ch25h in Leprdb/db mice aggravated diabetic kidney disease (DKD), which is associated with increased endothelial cell apoptosis. Treatment of 25‐hydroxycholesterol (25‐HC), the product of CH25H, alleviated kidney injury in Leprdb/db mice. Mechanistically, 25‐HC binds to GTP‐binding protein ADP‐ribosylation factor 4 (ARF4), an essential protein required for maintaining protein transport in the Golgi apparatus. Interestingly, ARF4's GTPase‐activating protein ASAP1 is also predominantly expressed in endothelial cells and its expression increased in DKD. Suppression of ARF4 activity by deleting ARF4 or overexpressing ASAP1 results in endothelial cell death. These results indicate that 25‐HC binds ARF4 to inhibit its interaction with ASAP1, and thereby resulting in enhanced ARF4 activity to confer renoprotection. Therefore, treatment of 25‐HC improves kidney injury in DKD in part by restoring ARF4 activity to maintain endothelial cell survival. This study provides a novel mechanism and a potential new therapy for DKD.

Abstract Background Estimated pulse wave velocity (ePWV) has been proposed as a potential approach to estimate carotid-femoral pulse wave velocity. However, the potential of ePWV in predicting all-cause mortality (ACM) and cardiovascular disease mortality (CVM) in the general population is unclear. Methods We conducted a prospective cohort study using the data of 33,930 adults (age ≥ 20 years) from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014 until the end of December 2019. The study outcomes included ACM and CVM. Survey-weighted Cox proportional hazards models were used to assess hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the association between ePWV and ACM and CVM. To further investigate whether ePWV was superior to traditional risk factors in predicting ACM and CVM, comparisons between ePWV and the Framingham Risk Score (FRS) and Pooled Cohort Equations (PCE) models were performed. Integrated Discriminant Improvement (IDI) and Net Reclassification Improvement (NRI) were employed to analyze differences in predictive ability between models. Results The weighted mean age of the 33,930 adults included was 45.2 years, and 50.28% of all participants were men. In the fully adjusted Cox regression model, each 1 m/s increase in ePWV was associated with 50% and 49% increases in the risk of ACM (HR 1.50; 95% CI, 1.45–1.54) and CVM (HR 1.49; 95% CI, 1.41–1.57), respectively. After adjusting for FRS, each 1 m/s increase in ePWV was still associated with 29% (HR 1.29; 95% CI, 1.24–1.34) and 34% (HR 1.34; 95% CI, 1.23–1.45) increases in the risk of ACM and CVM, respectively. The area under the curve (AUC) predicted by ePWV for 10-year ACM and CVM were 0.822 and 0.835, respectively. Compared with the FRS model, the ePWV model improved the predictive value of ACM and CVM by 5.1% and 3.8%, respectively, with no further improvement in event classification. In comparison with the PCE model, the ePWV model’s ability to predict 10-year ACM and CVM was improved by 5.1% and 3.5%, and event classification improvement was improved by 34.5% and 37.4%. Conclusions In the U.S. adults, ePWV is an independent risk factor for ACM and CVM and is independent of traditional risk factors. In the general population aged 20 to 85 years, ePWV has a robust predictive value for the risk of ACM and CVM, superior to the FRS and PCE models. The predictive power of ePWV likely originates from the traditional risk factors incorporated into its calculation, rather than from an indirect association with measured pulse wave velocity.

Glypicans are closely associated with organ development and tumorigenesis in animals. Dally-like (Dlp), a membrane-bound glypican, plays pivotal roles in various biological processes in Drosophila. In this study, we observed that an excess of Dlp led to the malformation of legs, particularly affecting the distal part. Accordingly, the leg disc was shrunken and frequently exhibited aberrant morphology. In addition, elevated Dlp levels induced ectopic cell death with no apparent cell proliferation changes. Furthermore, Dlp overexpression in the posterior compartment significantly altered Wingless (Wg) distribution. We observed a marked expansion of Wg distribution within the posterior compartment, accompanied by a corresponding decrease in the anterior compartment. It appears that excess Dlp guides Wg to diffuse to cells with higher Dlp levels. In addition, the distal-less (dll) gene, which is crucial for leg patterning, was up-regulated significantly. Notably, dachshund (dac) and homothorax (hth) expression, also essential for leg patterning and development, only appeared to be negligibly affected. Based on these findings, we speculate that excess Dlp may contribute to malformations of the distal leg region of Drosophila, possibly through its influence on Wg distribution, dll expression and induced cell death. Our research advances the understanding of Dlp function in Drosophila leg development.