Search

Cisplatin resistance is a major challenge for systemic therapy against advanced bladder cancer (BC). Little information is available on the regulation of cisplatin resistance and the underlying mechanisms require elucidation. Here, we detected that downregulation of the tumor suppressor, PPP2R2B (a serine/threonine protein phosphatase 2 A regulatory subunit), in BC promoted cell proliferation and migration. What's more, low PPP2R2B expression was correlated with cisplatin resistance. In vitro and in vivo experiments verified that PPP2R2B could promote BC sensitivity to cisplatin. In terms of mechanism, we identified a novel function of PPP2R2B as a nucleocytoplasmic transport molecule. PPP2R2B promoted ISG15 entry into the nucleus by mediating binding of IPO5 with ISG15. Nuclear translocation of ISG15 inhibited DNA repair, further increasing ISG15 expression through activation of the STING pathway. Besides, PPP2R2B was down-regulated by SUV39H1-mediated histone 3 lysine 9 trimethylation, which could be restored by the SUV39H1-specific inhibitor, chaetocin. Our data suggest that PPP2R2B expression level is a potential biomarker for chemotherapy response and that chemotherapy in combination with chaetocin may be a feasible treatment strategy for patients with BC. [ABSTRACT FROM AUTHOR]

Prior studies have revealed an increased susceptibility to epilepsy in hyperthyroid individuals, but the genetic basis of the hyperthyroidism–epilepsy relationship is not fully comprehended, prompting this study to explore this potential association. We conducted a two-sample Mendelian randomization (TSMR) study to explore the relationship between hyperthyroidism and epilepsy by utilizing aggregated statistics from Genome-Wide Association Studies (GWAS). Data for hyperthyroidism were derived from a GWAS encompassing 462,933 participants, while epilepsy data were sourced from the International League Against Epilepsy (ILAE) consortium. Five distinct methods were employed for TSMR analysis, which included the inverse variance weighting method, MR Egger method, weighted median method, simple model, and weighted model. In our sensitivity analysis, we employed the MR Egger and MR PRESSO methods to assess pleiotropy, and inverse variance weighting and MR Egger in Cochran's Q statistics to assess heterogeneity. In the IEU database, utilizing the MR-Egger method, we obtained an odds ratio (OR) of 2.631 (95% CI 0.608, 9.796) with a p-value of 0.122. Meanwhile, employing the Weighted Median method yielded an OR of 1.813 (95% CI 0.786, 4.181) with a p-value of 0.163. The IVW method exhibited an OR of 1.986 (95% CI 1.127, 3.502) with a p-value of 0.018. In the assessment of heterogeneity, the MR-Egger method produced a Q statistic of 65.205, accompanied by a p-value of 0.087, while the IVW method recorded a Q statistic of 66.668 with a p-value of 0.083. The multifactorial analysis results showed an intercept term with a standard error (SE) value of 0.009 and a p-value of 0.291. In the FinnGen database, employing the MR-Egger method for all epilepsy data, we observed an OR of 0.952 (95% CI 0.831, 1.093) with a p-value of 0.539. Simultaneously, the Weighted Median method produced an OR of 0.986 (95% CI 0.953, 1.021) with a p-value of 0.423. The IVW method indicated an OR of 0.992 (95% CI 0.965, 1.019) with a p-value of 0.541. The MR-Egger method's assessment of heterogeneity resulted in a Q statistic of 2.671, associated with a p-value of 0.445, while the IVW method generated a Q statistic of 3.011 with a p-value of 0.556. The multifactorial analysis results displayed an intercept term with a SE-value of 0.019 and a p-value of 0.601. Sensitivity analysis found no evidence of horizontal pleiotropy or heterogeneity. Hyperthyroidism was found to be causally related to all epilepsy but had no effect on other types of epilepsy. [ABSTRACT FROM AUTHOR]

The underlying mechanisms of human umbilical cord mesenchymal stem cells (hucMSCs) and their exosomes (hucMSC-Exs), which play significant roles in skin wound healing, remain poorly understood. By using a rat model of deep second-degree burn injury, the roles of hucMSC-Exs in angiogenesis and cutaneous wound healing in vivo were investigated. We found that hucMSC-Exs accelerated skin wound healing and angiogenesis, inducing a higher wound-closure rate and increased expression of CD31 in vivo. We also discovered that hucMSC-Exs contained angiopoietin-2 (Ang-2), and treatment with hucMSC-Exs enhanced the expression of the Ang-2 protein in the wound area and human umbilical vein endothelial cells (HUVECs) through exosomal-mediated Ang-2 transfer. Moreover, hucMSC-Exs promoted the proliferative, migratory, and tube-forming ability of HUVECs. Furthermore, overexpression of Ang-2 in hucMSC-Exs further enhanced HUVEC migration and tube formation and exerted therapeutic and proangiogenic effects in cutaneous wounds in rats, whereas knockdown of Ang-2 in hucMSC-Exs abrogated these therapeutic and proangiogenic effects. Taken together, our results indicated that hucMSC-Ex-derived Ang-2 plays a significant role in tube formation of HUVECs and promotion of angiogenesis, and further suggested that hucMSC-Ex-based therapy may serve as a promising therapeutic approach for promoting cutaneous wound healing. [ABSTRACT FROM AUTHOR]

Carbon nanotubes (CNTs) are among the strongest materials known, making their use in composites, a field with very high commercial potential for structural applications. Many of the methods reported to date to form metal composites have an excessive number of steps. Here, a facile chemical vapor deposition method to infiltrate multiwalled carbon nanotubes directly into pure stainless steel pellets and pellets from stainless steel mixed with iron particles is reported. The iron powder was dry-coated before vapor filtration with nanosized iron oxide catalyst precursor, a critical step to increase catalytic activity. This CVD method results in a substantial increase in the elastic modulus, yield strength, and hardness by 47, 104, and over 93 %, respectively, for composites made from mixed, dry-coated particles compared with corresponding control samples without nanotubes. This is the highest enhancement reported, to the best of our knowledge, of the mechanical properties for a metal-nanotube composite prepared using a metal other than copper. The addition of CNTs results in a relatively small increase in corrosion rate which can be mitigated to negligible levels by coating with a thin epoxy-carbon nanotube composite. [ABSTRACT FROM AUTHOR]