Citations

AbstractBackgroundAccumulating evidence demonstrates that 40‐50% of Alzheimer’s disease (AD) brains present with concomitant Lewy pathologies at autopsy, suggesting that α‐synuclein (α‐SYN) aggregation is likely involved in the pathogenesis of AD. Interestingly, the genome‐wide association study (GWAS) revealed that the ε4 allele of APOE (APOE4) gene, the strongest genetic risk factor for AD, is also the most replicated genetic risk factor for Lewy body dementia (LBD), signifying the important role of APOE4 in both amyloid β (Aβ) and α‐SYN pathogenesis. However, how APOE4 modulates the α‐SYN aggregation in AD is still unclear.MethodWe performed biochemical analyses measuring α‐SYN levels on a pathologically confirmed human AD cohort (N = 469) obtained from the Mayo Clinic Brain Bank, wherein 54.4% of our cohort presented with co‐morbid α‐SYN pathology upon diagnosis of AD with Lewy Body pathology (hereinafter referred to as AD+LB), which was subdivided into APOE4 non‐carriers (APOE4−) and carriers (APOE4+). To determine the seeding activity of α‐SYN, we performed Real‐time quaking‐induced conversion (RT‐QuIC) assays with the soluble TBS protein fractions of the brain lysates. The cytotoxicities of the amplified α‐SYN seeds were tested with MTT assay for cell viability and neuronal outgrowth measurement by immunofluorescence staining with human induced pluripotent stem cells (iPSC)‐derived neurons.ResultWe found that AD+LB cases showed the significantly higher seeding activity of α‐SYN compared to AD cases without LB pathologies. Furthermore, APOE4+ AD+LB brains had the highest α‐SYN seeding activity compared to AD+LB APOE4− cases. The α‐SYN seeding activity was associated with the level of α‐SYN, tau, or APOE aggregates, but not Aβ. Finally, we showed that the amplified α‐SYN aggregates derived from AD+LB APOE4+ had highest protease resistance and cytotoxicities in iPSC‐derived neurons.ConclusionThese findings suggest that APOE4 modulates the conformation of α‐SYN seeds which leads to high seeding activity and toxicity of α‐SYN in AD.

Background: It is unclear whether peripheral arterial cannulation is superior to central arterial cannulation for postcardiotomy veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Methods: A systematic review was conducted using PubMed, Scopus, and Google Scholar to identify studies on postcardiotomy VA-ECMO for the present individual patient data (IPD) meta-analysis. Analysis was performed according to the intention-to-treat principle. Results: The investigators of 10 studies agreed to participate in the present IPD meta-analysis. Overall, 1269 patients were included in the analysis. Crude rates of in-hospital mortality after central versus peripheral arterial cannulation for VA-ECMO were 70.7% vs. 63.7%, respectively (adjusted OR 1.38, 95% CI 1.08–1.75). Propensity score matching yielded 538 pairs of patients with balanced baseline characteristics and operative variables. Among these matched cohorts, central arterial cannulation VA-ECMO was associated with significantly higher in-hospital mortality compared to peripheral arterial cannulation VA-ECMO (64.5% vs. 70.8%, p = 0.027). These findings were confirmed by aggregate data meta-analysis, which showed that central arterial cannulation was associated with an increased risk of in-hospital mortality compared to peripheral arterial cannulation (OR 1.35, 95% CI 1.04–1.76, I2 21%). Conclusions: Among patients requiring postcardiotomy VA-ECMO, central arterial cannulation was associated with an increased risk of in-hospital mortality compared to peripheral arterial cannulation. This increased risk is of limited magnitude, and further studies are needed to confirm the present findings and to identify the mechanisms underlying the potential beneficial effects of peripheral VA-ECMO.

Abstract Speckle-type POZ protein (SPOP) is a substrate-binding adaptor of the CULLIN3/RING-box1 E3 ubiquitin ligase complex. SPOP is frequently mutated in prostate and endometrial cancers, whereas it is overexpressed in renal cell carcinoma (RCC). SPOP can mediate both degradable and nondegradable polyubiquitination of a number of substrates with diverse biological functions such as androgen receptor (AR), SRC-3, TRIM24, BRD4, PD-L1, 53BP1, GLP/G9a, c-Myc, SENP7, among others. Cancer-associated SPOP mutants often impair SPOP binding and polyubiquitination of its substrates to influence various cancer-relevant pathways, which include androgen/AR signaling, DNA repair and methylation, cellular stress surveillance, cancer metabolism, and immunity. Although SPOP is recognized as a tumor suppressor in prostate and endometrial cancers, it acts like an oncoprotein in RCC. This review provides an overview of the recent progress in understanding of the upstream regulators of SPOP and its downstream targets, highlights the significant impact of SPOP mutations and overexpression on cancer pathogenesis, and discusses the potential of targeting SPOP for cancer treatment.

Dysregulation of kinase signaling pathways favors tumor cell survival and therapy resistance in cancer. Here, we reveal a posttranslational regulation of kinase signaling and nuclear receptor activity via deubiquitination in T cell acute lymphoblastic leukemia (T-ALL). We observed that the ubiquitin-specific protease 11 (USP11) is highly expressed and associates with poor prognosis in T-ALL. USP11 ablation inhibits leukemia progression in vivo, sparing normal hematopoiesis. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell–specific protein-tyrosine kinase (LCK) and enhance its activity. Impairment of LCK activity leads to increased glucocorticoid receptor (GR) expression and glucocorticoids sensitivity. Genetic knockout of USP7 improved the antileukemic efficacy of glucocorticoids in vivo. The transcriptional activation of GR target genes is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Our data unveil how dysregulated deubiquitination controls leukemia survival and drug resistance, suggesting previously unidentified therapeutic combinations toward targeting leukemia.

(1) Background: To determine the optimal cut-off values of two risk stratification systems to discriminate malignant thyroid nodules and to compare the diagnostic performance; (2) Methods: True and false positive and negative data were collected, and methodological quality was assessed for forty-six studies involving 39,085 patients; (3) Results: The highest area under the receiver operating characteristic (ROC) curve (AUC) of ACR and Kwak TI-RADS were 0.875 and 0.884. Based on the optimal sensitivity and specificity, the highest accuracy values of ROC curves or diagnostic odds ratios (DOR) were taken as the cut-off values for TR4 (moderate suspicious) and 4B. The sensitivity, specificity, DOR, and AUC by ACR (TR4) and Kwak TI-RADS (4B) for malignancy risk stratification of thyroid nodules were 94.3% and 96.4%; 52.2% and 53.7%; 17.5185 and 31.8051; 0.786 and 0.884, respectively. There were no significant differences in diagnostic accuracy in any of the direction comparisons of the two systems; (4) Conclusions: ACR and Kwak TI-RADS had good diagnostic performances (AUCs > 85%). Although we determined the best cut-off values in individual risk stratification systems based on statistical assessment, clinicians can adjust the optimal cut-off value according to the clinical purpose of the ultrasonography because raising or lowering cut-points leads to reciprocal changes in sensitivity and specificity.