Berberine ameliorates chronic intermittent hypoxia-induced cardiac remodelling by preserving mitochondrial function, role of SIRT6 signalling.

Chronic intermittent hypoxia (CIH) is associated with an increased risk of cardiovascular diseases. Previously, we have shown that berberine (BBR) is a potential cardioprotective agent. However, its effect and mechanism on CIH-induced cardiomyopathy remain uncovered. This study was designed to determine the effects of BBR against CIH-induced cardiac damage and to explore the molecular mechanisms. Mice were exposed to 5 weeks of CIH with or without the treatment of BBR and adeno-associated virus 9 (AAV9) carrying SIRT6 or SIRT6-specific short hairpin RNA. The effect of BBR was evaluated by echocardiography, histological analysis and western blot analysis. CIH caused the inactivation of myocardial SIRT6 and AMPK-FOXO3a signalling. BBR dose-dependently ameliorated cardiac injury in CIH-induced mice, as evidenced by increased cardiac function and decreased fibrosis. Notably, SIRT6 overexpression mimicked these beneficial effects, whereas infection with recombinant AAV9 carrying SIRT6-specific short hairpin RNA abrogated them. Mechanistically, BBR reduced oxidative stress damage and preserved mitochondrial function via activating SIRT6-AMPK-FOXO3a signalling, enhancing mitochondrial biogenesis as well as PINK1-Parkin-mediated mitophagy. Taken together, these data demonstrate that SIRT6 activation protects against the pathogenesis of CIH-induced cardiac dysfunction. BBR attenuates CIH-induced myocardial injury by improving mitochondrial biogenesis and PINK1-Parkin-dependent mitophagy via the SIRT6-AMPK-FOXO3a signalling pathway.

Endoscopic Submucosal Dissection Criteria for Differentiated-type Early Gastric Cancer Are Applicable to Mixed-type Differentiated Predominant.

BACKGROUND: There is a lack of sufficient evidence on whether mixed-type differentiated predominant early gastric cancer (MD-EGC) can be treated endoscopically by referring to the criteria for differentiated-type early gastric cancer (EGC). This study aims to evaluate the efficacy of endoscopic submucosal dissection (ESD) in MD-EGC. METHODS: Patients with differentiated-type EGC treated with ESD first from January 2015 to June 2021 were reviewed, including MD-EGC and pure differentiated-type EGC (PD-EGC). Clinical data, including the clinicopathological characteristics, resection outcomes of ESD, and recurrence and survival time, were collected, and the difference between MD-EGC and PD-EGC was tested. RESULTS: A total of 48 patients (48 lesions) with MD-EGC and 850 patients (890 lesions) with PD-EGC were included. Compared with PD-EGC, MD-EGC had a higher submucosal invasion rate (37.5% vs. 13.7%, P<0.001) and lymphatic invasion rate (10.4% vs. 0.4%, P<0.001). The rates of complete resection (70.8% vs. 92.5%, P<0.001) and curative resection (54.2% vs. 87.4%, P<0.001) in MD-EGC were lower than those of PD-EGC. Multivariate analysis revealed that MD-EGC (OR 4.26, 95% CI, 2.22-8.17, P<0.001) was an independent risk factor for noncurative resection. However, when curative resection was achieved, there was no significant difference in the rates of recurrence (P=0.424) between the 2 groups, whether local or metachronous recurrence. Similarly, the rates of survival(P=0.168) were no significant difference. CONCLUSIONS: Despite the greater malignancy and lower endoscopic curative resection rate of MD-EGC, patients who met curative resection had a favorable long-term prognosis.

Identification of hub genes associated with Helicobacter pylori infection and type 2 diabetes mellitus: A pilot bioinformatics study.

BACKGROUND: Helicobacter pylori (H. pylori) infection is related to various extragastric diseases including type 2 diabetes mellitus (T2DM). However, the possible mechanisms connecting H. pylori infection and T2DM remain unknown. AIM: To explore potential molecular connections between H. pylori infection and T2DM. METHODS: We extracted gene expression arrays from three online datasets (GSE60427, GSE27411 and GSE115601). Differentially expressed genes (DEGs) commonly present in patients with H. pylori infection and T2DM were identified. Hub genes were validated using human gastric biopsy samples. Correlations between hub genes and immune cell infiltration, miRNAs, and transcription factors (TFs) were further analyzed. RESULTS: A total of 67 DEGs were commonly presented in patients with H. pylori infection and T2DM. Five significantly upregulated hub genes, including TLR4, ITGAM, C5AR1, FCER1G, and FCGR2A, were finally identified, all of which are closely related to immune cell infiltration. The gene-miRNA analysis detected 13 miRNAs with at least two gene cross-links. TF-gene interaction networks showed that TLR4 was coregulated by 26 TFs, the largest number of TFs among the 5 hub genes. CONCLUSION: We identified five hub genes that may have molecular connections between H. pylori infection and T2DM. This study provides new insights into the pathogenesis of H. pylori-induced onset of T2DM.

Long-term efficacy of peroral endoscopic myotomy for achalasia under different criteria.

BACKGROUND: Peroral endoscopic myotomy (POEM) has emerged as a widely accepted treatment for achalasia, with limited studies for over 2 years. Additionally, traditional measurements of achalasia after POEM have deficiencies. The study aimed to analyze the long-term outcomes of POEM under different criteria. METHODS: Patients with achalasia who received POEM between November 2012 and March 2021 were recruited. Patients and characteristics were shown, and risk factors related to two novel definitions of recurrence, symptomatic reflux, and reflux esophagitis were analyzed. RESULTS: Three hundred and twenty-one patients were included. At a median follow-up of 52 months, twenty-three failures happened (7.17%) under the modified criterion, and forty-seven failures occurred (14.64%) under the normal standard. Hospitalization (P = 0.027) and esophageal myotomy length (P = 0.039) were significantly associated with long-term efficacy under the modified and normal criteria, respectively. Fifty-two patients (16.20%) reported reflux symptoms and endoscopy performed in 88 patients revealed reflux esophagitis in 22 cases (25.00%). There were no predictors in the analysis of symptomatic reflux and gender (P = 0.010), LESP (P = 0.013), IRP (P = 0.015), and the esophageal myotomy length (P = 0.032) were statistically related to reflux esophagitis. CONCLUSION: POEM is an extremely safe and effective treatment for achalasia with long-term follow-up. Shorter hospitalization and shorter esophageal myotomy length may decrease the incidence of recurrence under the modified and normal criteria, respectively. Long-term outcomes of POEM are unpredictable. No risk factors were related to symptomatic reflux, and male patients with low preoperative LESP and IRP needed relatively shorter esophageal myotomy to prevent reflux esophagitis.

Endoscopic resection vs. endoscopic resection plus chemoradiation for T1 stage colorectal cancer: a real-world retrospective cohort study.

Background: Early-stage colorectal cancer (CRC) patients treated with either endoscopic resection (ER) alone or combined ER with chemoradiotherapy (CRT) have unknown survival rates. A national descriptive epidemiological study was conducted to compare the long-term survival of patients with T1 stage CRC with or without the two different treatment options. Methods: Our study identified the records of patients with T1-stage CRC between 2010 and 2018 by searching the Surveillance, Epidemiology, and End Results (SEER) database. Long-term survival was compared using Kaplan-Meier methods and Cox proportional hazard models based on patient demographic and cancer parameters. Results: After propensity score matching (PSM), 825 T1-stage CRC patients were finally enrolled in this study, with 718 patients treated with ER and 107 patients treated with ER + CRT. The overall survival (OS) and cancer specific survival (CSS) rates were similar between the two treatment options (OS: P=0.47; CSS: P=0.28). According to subgroup analysis, older patients and patients with rectal tumor locations exhibited significantly higher OS and CSS rates in the ER + CRT group than in the ER group (OS: P<0.0001; CSS: P<0.0001). Conclusions: The findings from the SEER database showed that OS and CSS rates were similar between the ER and ER + CRT treated groups. Older patients and patients with rectal cancer benefited the most from ER + CRT treatment.

Causal effects of lipid-lowering therapies on aging-related outcomes and risk of cancers: a drug-target Mendelian randomization study.

BACKGROUND: Despite the widespread use of statins, newer lipid-lowering drugs have been emerging. It remains unclear how the long-term use of novel lipid-lowering drugs affects the occurrence of cancers and age-related diseases. METHODS: A drug-target Mendelian randomization study was performed. Genetic variants of nine lipid-lowering drug-target genes (HMGCR, PCKS9, NPC1L1, LDLR, APOB, CETP, LPL, APOC3, and ANGPTL3) were extracted as exposures from the summary data of Global Lipids Genetics Consortium Genome-Wide Association Studies (GWAS). GWAS summary data of cancers and noncancerous diseases were used as outcomes. The inverse-variance weighted method was applied as the main statistical approach. Sensitivity tests were conducted to evaluate the robustness, pleiotropy, and heterogeneity of the results. RESULTS: In addition to marked effects on decreased risks of atherosclerotic cardiovascular diseases, genetically proxied lipid-lowering variants of PCKS9, CETP, LPL, LDLR, and APOC3 were associated with longer human lifespans (q<0.05). Lipid-lowering variants of ANGPTL3 and LDLR were associated with reduced risks of colorectal cancer, and ANGPTL3 was also associated with lower risks of gastric cancer (q<0.05). Lipid-lowering LPL variants were associated with decreased risks of hypertension, type 2 diabetes, nonalcoholic fatty liver disease, and bladder cancer (q<0.05). Lipid-lowering variants of PCKS9 and HMGCR were associated with decreased risks of osteoporosis (q<0.05). Lipid-lowering APOB variants were associated with a decreased risk of thyroid cancer (q<0.05). CONCLUSIONS: Our study provides genetic evidence that newer nonstatin lipid-lowering agents have causal effects on decreased risks of several common cancers and cardiometabolic diseases. These data provide genetic insights into the potential benefits of newer nonstatin therapies.

A novel risk score model of esophageal stricture for patients undergoing endoscopic submucosal dissection.

BACKGROUND AND PURPOSE: Endoscopic submucosal dissection (ESD) is a promising technique for superficial esophageal lesions. However, stricture is a frequent adverse complication. This study was performed to develop a precise and convenient score prediction model for esophageal strictures after ESD, and compare its efficacy with a previously published predictive model. METHODS: This study enrolled clinical data of patients who underwent esophageal ESD for superficial esophageal lesions. Possible risk factors for esophageal stricture were identified by univariate and multivariate logistic regression analysis. Then we developed a prediction model according to the Framingham system for the first time and presented a convenient table containing the risk probability for each patient. In addition, we validated our score model and the previously published model in our center. RESULTS: A total of 838 patients were enrolled in this study and 6 variables, including age, surgery time, location of the lesion, circumference of the lesion, longitudinal resection length, and depth of infiltration were comprised in the score model. The total score ranged from 0 to 16 points and the risk probability was presented in one concise table for each patient. Areas under receiver-operator characteristic curves for the prediction model were 0.715 in derivation group and 0.804 in validation group. CONCLUSION: We designed and validated a prediction score model for esophageal stricture after ESD, which can be applied conveniently to stratify the stricture risk after esophageal ESD and may facilitate appropriate clinical decision-making for these patients.

Prognostic model of hepatocellular carcinoma based on cancer grade.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. With highly invasive biological characteristics and a lack of obvious clinical manifestations, HCC usually has a poor prognosis and ranks fourth in cancer mortality. The aetiology and exact molecular mechanism of primary HCC are still unclear. AIM: To select the characteristic genes that are significantly associated with the prognosis of HCC patients and construct a prognosis model of this malignancy. METHODS: By comparing the gene expression levels of patients with different cancer grades of HCC, we screened out differentially expressed genes associated with tumour grade. By protein-protein interaction (PPI) network analysis, we obtained the top 2 PPI networks and hub genes from these differentially expressed genes. By using least absolute shrinkage and selection operator Cox regression, 13 prognostic genes were selected for feature extraction, and a prognostic risk model of HCC was established. RESULTS: The model had significant prognostic ability in HCC. We also analysed the biological functions of these prognostic genes. CONCLUSION: By comparing the gene profiles of patients with different stages of HCC, We have constructed a prognosis model consisting of 13 genes that have important prognostic value. This model has good application value and can be explained clinically.

Cellular and molecular characteristics of the premetastatic niches.

The premetastatic niches (PMN) formed by primary tumor-derived molecules regulate distant organs and tissues to further favor tumor colonization. Targeted PMN therapy may prevent tumor metastasis in the early stages, which is becoming increasingly important. At present, there is a lack of in-depth understanding of the cellular and molecular characteristics of the PMN. Here, we summarize current research advances on the cellular and molecular characteristics of the PMN. We emphasize that PMN intervention is a potential therapeutic strategy for early prevention of tumor metastasis, which provides a promising basis for future research and clinical application.

Optimization of an Artificial Solid Electrolyte Interphase Formed on an Aluminum Anode and Its Application in Rechargeable Aqueous Aluminum Batteries.

Electrochemical cells that incorporate aluminum (Al) as the active material have become increasingly popular due to the advantages of high energy density, cost-effectiveness, and superior safety features. Despite the progress made by research groups in developing rechargeable Al//MxOy (M = Mn, V, etc.) cells using an aqueous Al trifluoromethanesulfonate-based electrolyte, the reactions occurring at the Al anode are still not fully understood. In this study, we explore the artificial solid electrolyte interphase (ASEI) on the Al anode by soaking it in AlCl3/urea ionic liquid. Surprisingly, our findings reveal that the ASEI actually promotes the corrosion of Al by providing chloride anions rather than facilitating the transport of Al3+ ions during charge/discharge cycles. Importantly, the ASEI significantly enhances the cycling stability and activity of Al cells. The primary reactions occurring at the Al anode during the charge/discharge cycle were determined to be irreversible oxidation and gas evolution. Furthermore, we demonstrate the successful realization of urea-treated Al (UTAl)//AlxMnO2 cells (discharge operating voltage of ∼1.45 V and specific capacity of 280 mAh/g), providing a platform to investigate the underlying mechanisms of these cells further. Overall, our work highlights the importance of ASEI in controlling the corrosion of Al in aqueous electrolytes, emphasizing the need for the further development of electrolytic materials that facilitate the transport of Al3+ ions in rechargeable Al batteries.

Constructing S-deficient nickel sulfide/N-doped carbon interface for improved water splitting activity.

Transition-metal sulfides are an intriguing family of electrocatalysts, yet their water-splitting applications are severely hampered by uncontrollable phase reconstruction and unsatisfactory in-service durability. Herein, we developed an efficient method to construct nickel sulfide (NiS) nanoarrays on foam nickel (NF) while being protected by highly N-doped formamide-derived carbon (termed NiS-NC@NF). The NiS nanocrystals were transformed in situ from highly dispersed Ni-N-C deposited on NF, ensuring a strong coupling effect that tunes the surface properties of NiS nanocrystals via the in situ constructed NiS/N-doped carbon interface. Electrochemical measurements reveal that very low overpotentials of 88.0 and 170.0 mV (vs. RHE) are required to achieve a current density of 10.0 mA cm-2 for hydrogen and oxygen evolution, respectively. The highly N-doped carbon matrix additionally regulates the potential-driven reconstruction of NiS in a controlled extent. Remarkably, the water electrolyzer built with NiS-NC@NF as both anode and cathode delivers an extremely low cell voltage of 1.51 V to initiate water splitting in the alkaline medium.

Clinicopathological characteristics of synchronous multiple primary early esophageal cancer and risk factors for multiple lesions.

Background: With the development of endoscopic technology, the detection rate of synchronous multiple primary early esophageal cancer (SMPEEC) is increasing; however, the risk factors remain unclear. We aimed to assess the clinicopathological characteristics of patients with SMPEEC and investigate the risk factors contributing to the development of multiple lesions. Methods: A retrospective cohort study was conducted on 911 consecutive patients who underwent Endoscopic submucosal dissection (ESD) for primary esophageal neoplasms from January 2013 to June 2021. The patients were divided into the SMPEEC group and the solitary early esophageal cancer (SEEC) group. We compared the differences in clinicopathological characteristics between the two groups and investigated the risk factors linked to multiple lesions. Additionally, we investigated the relationship between the main and accessory lesions. Results: A total of 87 SMPEEC patients were included in this study, and the frequency of synchronous multiple lesions was 9.55% in patients with early esophageal cancer. The lesions in the SMPEEC group were mainly located in the lower segment of the esophagus (46[52.9%]), whereas those in the SEEC group were in the middle segment (412[50.0%]). The pathology type, tumor location, and circumferential rate of lesions were independent risk factors(P<0.05) for SMPEEC by logistic regression analysis. Significant positive correlations were observed between the main and accessory lesions in terms of morphologic type (r=0.632, P=0.000), tumor location(r=0.325, P=0.037), pathologic type (r=0.299, P=0.003), and depth of invasion (r=0.562, P=0.000). Conclusion: Pathology type, tumor location, and circumferential rate of lesions were identified as independent risk factors for SMEPPC. Understanding these risk factors and the correlation between the main and accessory lesions could significantly improve the detection rate of SMPEEC.

Prediction of lymph node metastasis in early gastric signet-ring cell carcinoma: A real-world retrospective cohort study.

BACKGROUND: Signet-ring cell carcinoma (SRCC) was previously thought to have a worse prognosis than other differentiated gastric cancer (GC), however, recent studies have shown that the prognosis of SRCC is related to pathological type. We hypothesize that patients with SRCC and with different SRCC pathological components have different probability of lymph node metastasis (LNM). AIM: To establish models to predict LNM in early GC (EGC), including early gastric SRCC. METHODS: Clinical data from EGC patients who had undergone gastrectomy at the First Affiliated Hospital of Nanjing Medical University from January 2012 to March 2022 were reviewed. The patients were divided into three groups based on type: Pure SRCC, mixed SRCC, and non-signet ring cell carcinoma (NSRC). The risk factors were identified through statistical tests using SPSS 23.0, R, and Em-powerStats software. RESULTS: A total of 1922 subjects with EGC were enrolled in this study, and included 249 SRCC patients and 1673 NSRC patients, while 278 of the patients (14.46%) presented with LNM. Multivariable analysis showed that gender, tumor size, depth of invasion, lymphovascular invasion, ulceration, and histological subtype were independent risk factors for LNM in EGC. Establishment and analysis using prediction models of EGC showed that the artificial neural network model was better than the logistic regression model in terms of sensitivity and accuracy (98.0% vs 58.1%, P = 0.034; 88.4% vs 86.8%, P < 0.001, respectively). Among the 249 SRCC patients, LNM was more common in mixed (35.06%) rather than in pure SRCC (8.42%, P < 0.001). The area under the ROC curve of the logistic regression model for LNM in SRCC was 0.760 (95%CI: 0.682-0.843), while the area under the operating characteristic curve of the internal validation set was 0.734 (95%CI: 0.643-0.826). The subgroups analysis of pure types showed that LNM was more common in patients with a tumor size > 2 cm (OR = 5.422, P = 0.038). CONCLUSION: A validated prediction model was developed to recognize the risk of LNM in EGC and early gastric SRCC, which can aid in pre-surgical decision making of the best method of treatment for patients.

HKDC1 reprograms lipid metabolism to enhance gastric cancer metastasis and cisplatin resistance via forming a ribonucleoprotein complex.

As essential modulators of transcription and translation, RNA-binding proteins (RBPs) are frequently dysregulated in cancer. Bioinformatics study reveals that the RNA-binding protein hexokinase domain component 1 (HKDC1) is overexpressed in gastric cancer (GC). As HKDC1 plays a role in lipid homeostasis in the liver and glucose metabolism in certain cancers, the exact mechanism of action of HKDC1 in GC remains largely unknown. Upregulation of HKDC1 correlates with chemoresistance and poor prognosis in GC patients. HKDC1 enhances invasion, migration and resistance to cisplatin (CDDP) in GC cells in vitro and in vivo. Comprehensive transcriptomic sequencing and metabolomic analysis reveal that HKDC1 mediates abnormal lipid metabolism in GC cells. Herein, we identify a number of HKDC1-binding endogenous RNAs in GC cells, including protein kinase, DNA-activated, catalytic subunit (PRKDC) mRNA. We further validate that PRKDC is a crucial downstream effector of HKDC1 induced-GC tumorigenesis depends on lipid metabolism. Interestingly, G3BP1, a well-known oncoprotein, can be bound by HKDC1. HKDC1 cooperates with G3BP1 to enhance the stability of PRKDC transcript. Our results reveal a novel HKDC1/G3BP1-PRKDC regulatory axis that induces GC metastasis and chemoresistance via reprogramming lipid metabolism, which may provide an effective therapeutic strategy for a subset of GC with HKDC1 overexpression.

Effects of folic acid supplementation on chronic atrophic gastritis based on MTHFR C677T polymorphism.

BACKGROUND: It has been shown the methylenetetrahydrofolate reductase (MTHFR) 677TT (rs 1801133) genotype predicts histopathological alterations in the incisura of patients with chronic atrophic gastritis (CAG). MTHFR is a crucial enzyme in fatty acid (FA) metabolism. This study aimed to evaluate the influence of FA supplementation in CAG patients without Helicobacter pylori infection and the MTHFR C677T (rs 1801133) genotype as a potential CAG predictor. METHODS: A total of 96 CAG patients, aged 21 to 72 years old, were enrolled in this study. After 6 months of treatment, histopathological outcomes were compared among patients treated with weifuchun (WFC) (1.44 g 3 times per os per day), those treated with WFC and FA (5 mg once daily), and those treated with WFC, FA, and vitamin B12 (VB12) (0.5 mg 3 times per day) based on the Operative Link on Gastritis/Intestinal Metaplasia assessment staging systems. RESULTS: Atrophic lesions in patients treated with WFC and FA improved more than in patients treated only with WFC therapy (78.1% vs 53.3%, P = .04). Atrophic or intestinal metaplasia (IM) lesions in the incisura of patients with the TT genotype were better than those in patients with the CC/CT genotype (P = .02). CONCLUSION: The treatment of CAG patients with 5 mg of FA supplements daily for 6 months improved their gastric atrophy status, especially for the Operative Link on Gastritis/Intestinal Metaplasia assessment stages I/II. Moreover, our study is the first to reveal that patients with the MTHFR 677TT genotype require more timely and effective FA treatment than those with the CC/CT genotype.

Individualized Endoscopic Surveillance for Metachronous Gastric Cancer After Endoscopic Submucosal Dissection: A Retrospective Observational Study.

BACKGROUND/AIMS: Endoscopic submucosal dissection has been widely applied for curative resection of early gastric cancer or high-grade dysplasia, and metachronous gastric cancer is a major issue after endoscopic therapy. Here, we studied the recurrence patterns of metachronous gastric cancer and its correlation with the primary lesions. MATERIALS AND METHODS: A total of 286 consecutive patients undergoing endoscopic submucosal dissection for early gastric cancer or high-grade dysplasia between March 2011 and March 2018 were retrospectively reviewed. Metachronous gastric cancer was defined as a new gastric cancer detected more than 1 year after endoscopic submucosal dissection. RESULTS: During a median follow-up of 36 months, 24 patients developed metachronous gastric cancer. The 5-year cumulative incidence was 13.4% and the annual incidence was 24.3 cases per 1000 person-years. Subgroup analysis revealed that the third year after early gastric cancer resection and the fifth year after high-grade dysplasia resection were the predilection periods of metachronous gastric cancer. Correlation analysis suggested that the metachronous and primary lesions showed a significant correlation in cross-sectional position (C = 0.627, P = .027) but not in pathological characteristics (P > .05). When the primary lesions were located in the posterior walls, the metachronous lesions were prone to occur in the lesser curvatures (C = 0.494, P = .008) and the reverse was also true (C = 0.422, P = .029). CONCLUSIONS: The predilection periods and common sites of metachronous gastric cancer are associated with the primary lesions. Meticulous individualized endoscopic surveillance after endoscopic submucosal dissection requires to be conducted, taking into account the characteristics of primary lesions.

Islet amyloid polypeptide triggers α-synuclein pathology in Parkinson's disease.

Pathologic aggregation and prion-like propagation of α-synuclein (α-syn) are the hallmarks of Parkinson's disease (PD). Emerging evidence shows that type 2 diabetes mellitus (T2DM) is a risk factor for PD. Interestingly, T2DM is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. Although T2DM and PD share pathological similarities, the underlying molecular mechanisms bridging these two diseases remain unknown. Here, we report that IAPP co-deposits with α-syn in the brains of PD patients. IAPP interacts with α-syn and accelerates its aggregation. In addition, the IAPP-seeded α-syn fibrils show enhanced seeding activity and neurotoxicity compared with pure α-syn fibrils in vitro and in vivo. Strikingly, intravenous injection of IAPP fibrils into α-syn A53T transgenic mice or human SNCA transgenic mice accelerated the aggregation of α-syn and PD-like motor deficits. Taken together, these findings support that IAPP acts as a trigger of α-syn pathology in PD, and provide a mechanistic explanation for the increased risk and faster progression of PD in patients with T2DM.

Sorting nexin 10 sustains PDGF receptor signaling in glioblastoma stem cells via endosomal protein sorting.

Glioblastoma is the most malignant primary brain tumor, the prognosis of which remains dismal even with aggressive surgical, medical, and radiation therapies. Glioblastoma stem cells (GSCs) promote therapeutic resistance and cellular heterogeneity due to their self-renewal properties and capacity for plasticity. To understand the molecular processes essential for maintaining GSCs, we performed an integrative analysis comparing active enhancer landscapes, transcriptional profiles, and functional genomics profiles of GSCs and non-neoplastic neural stem cells (NSCs). We identified sorting nexin 10 (SNX10), an endosomal protein sorting factor, as selectively expressed in GSCs compared with NSCs and essential for GSC survival. Targeting SNX10 impaired GSC viability and proliferation, induced apoptosis, and reduced self-renewal capacity. Mechanistically, GSCs utilized endosomal protein sorting to promote platelet-derived growth factor receptor ß (PDGFRß) proliferative and stem cell signaling pathways through posttranscriptional regulation of the PDGFR tyrosine kinase. Targeting SNX10 expression extended survival of orthotopic xenograft-bearing mice, and high SNX10 expression correlated with poor glioblastoma patient prognosis, suggesting its potential clinical importance. Thus, our study reveals an essential connection between endosomal protein sorting and oncogenic receptor tyrosine kinase signaling and suggests that targeting endosomal sorting may represent a promising therapeutic approach for glioblastoma treatment.