A nomogram to predict the risk of acute ischemic stroke in patients with maintenance hemodialysis: a retrospective cohort study.

OBJECTIVE: Acute ischemic stroke (AIS) stands as a leading cause of death and disability globally. This study aimed to investigate the risk factors linked with AIS in patients undergoing maintenance hemodialysis (MHD) and to create and validate nomogram models. METHODS: We examined the medical records of 314 patients with stage 5 chronic kidney disease (CKD5) undergoing MHD, who sought neurology outpatient department consultation for suspected AIS symptoms between January 2018 and December 2023. These 314 patients were randomly divided into the training cohort (n=222) and validation cohort (n=92). The Least Absolute Shrinkage Selection Operator (LASSO) regression model was employed for optimal feature selection in the AIS risk model. Subsequently, multivariable logistic regression analysis was used to construct a predictive model incorporating the features selected through LASSO. This predictive model's performance was assessed using the C-index and the area under the receiver operating characteristic curve (AUC). Additionally, calibration and clinical utility were evaluated through calibration plots and decision curve analysis (DCA). The model's internal validation was conducted using the validation cohort. Resaults: Predictors integrated into the prediction nomogram encompassed cardiovascular disease (CVD) (Odds Ratio [OR] 7.95, 95% confidence interval [CI] 2.400-29.979), smoking (OR 5.7, 95% CI 1.661-21.955), dialysis time (OR 5.91, 95% CI 5.866-29.979), low-density lipoprotein (LDL) (OR 2.99, 95% CI 0.751-13.007), and fibrin degradation products (FDP) (OR 5.47, 95% CI 1.563-23.162). The model exhibited robust discrimination, with a C-index of 0.877 and 0.915 in the internal training and validation cohorts, respectively. The AUC for the training set was 0.857, and a similar AUC of 0.905 was achieved in the validation cohort. Decision curve analysis (DCA) demonstrated a positive net benefit within a threshold risk range of 2 to 96%. CONCLUSION: The proposed nomogram effectively identifies MHD patients at high risk of AIS at an early stage. This model holds the potential to aid clinicians in making preventive recommendations.

Identification of four biotypes in temporal lobe epilepsy via machine learning on brain images.

Artificial intelligence provides an opportunity to try to redefine disease subtypes based on similar pathobiology. Using a machine-learning algorithm (Subtype and Stage Inference) with cross-sectional MRI from 296 individuals with focal epilepsy originating from the temporal lobe (TLE) and 91 healthy controls, we show phenotypic heterogeneity in the pathophysiological progression of TLE. This study was registered in the Chinese Clinical Trials Registry (number: ChiCTR2200062562). We identify two hippocampus-predominant phenotypes, characterized by atrophy beginning in the left or right hippocampus; a third cortex-predominant phenotype, characterized by hippocampus atrophy after the neocortex; and a fourth phenotype without atrophy but amygdala enlargement. These four subtypes are replicated in the independent validation cohort (109 individuals). These subtypes show differences in neuroanatomical signature, disease progression and epilepsy characteristics. Five-year follow-up observations of these individuals reveal differential seizure outcomes among subtypes, indicating that specific subtypes may benefit from temporal surgery or pharmacological treatment. These findings suggest a diverse pathobiological basis underlying focal epilepsy that potentially yields to stratification and prognostication - a necessary step for precise medicine.

Experimental study on the effect and mechanism of adipose stem cell-derived exosomes combined with botulinum toxin A on skin trauma in rats.

BACKGROUND: Adipose stem cell-derived exosomes (ADSC-EXO) and botulinum toxin type A (BTX-A) individually showed a therapeutic effect on skin wound repair. AIMS: This study investigated their synergistic effect on promoting skin wound healing in vitro and in vivo and the underlying molecular events. METHODS: ADSCs were isolated from Sprague-Dawley (SD) rats to obtain ADSC-EXO by ultrafiltration and ultracentrifugation and were confirmed using nanoparticle tracking analysis and transmission electron microscopy. Human skin fibroblasts (HSF) were cultured and treated with or without ADSC-EXO, BTX-A, or their combination. Changes in cell phenotypes and protein expression were analyzed using different in vitro assays, and a rat skin wound model was used to assess their in vivo effects. RESULTS: The isolated ADSC-EXO from primarily cultured ADSCs had a circular vesicle shape with a 30-180 nm diameter. Treatment of HSF with ADSC-EXO and/or BTX-A significantly accelerated HSF migration in vitro and skin wound healing in a rat model. Moreover, ADSC-EXO plus BTX-A treatment dramatically induced VEGFA expression but reduced COL III and COL I levels in vivo. ADSC-EXO and/or BTX-A treatment significantly upregulated TGF-ß3 expression on Day 16 after surgery but downregulated TGF-ß1 expression, suggesting that ADSC-EXO plus BTX-A promoted skin wound healing and reduced inflammatory cell infiltration. CONCLUSIONS: The ADSC-EXO plus BTX-A treatment demonstrated a synergistic effect on skin wound healing through upregulation of VEGF expression and the TGF-ß3/TGF-ß1 and COL III/COL I ratio.

Identifying KCNJ5 Mutation in Aldosterone-Producing Adenoma Patients With Baseline Characteristics Using Machine Learning Technology.

Background: Primary aldosteronism is characterized by inappropriate aldosterone production, and unilateral aldosterone-producing adenoma (uPA) is a common type of PA. KCNJ5 mutation is a protective factor in uPA; however, there is no preoperative approach to detect KCNJ5 mutation in patients with uPA. Objectives: This study aimed to provide a personalized surgical recommendation that enables more confidence in advising patients to pursue surgical treatment. Methods: We enrolled 328 patients with uPA harboring KCNJ5 mutations (n = 158) or not (n = 170) who had undergone adrenalectomy. Eighty-seven features were collected, including demographics, various blood and urine test results, and clinical comorbidities. We designed 2 versions of the prediction model: one for institutes with complete blood tests (full version), and the other for institutes that may not be equipped with comprehensive testing facilities (condensed version). Results: The results show that in the full version, the Light Gradient Boosting Machine outperformed other classifiers, achieving area under the curve and accuracy values of 0.905 and 0.864, respectively. The Light Gradient Boosting Machine also showed excellent performance in the condensed version, achieving area under the curve and accuracy values of 0.867 and 0.803, respectively. Conclusions: We simplified the preoperative diagnosis of KCNJ5 mutations successfully using machine learning. The proposed lightweight tool that requires only baseline characteristics and blood/urine test results can be widely applied and can aid personalized prediction during preoperative counseling for patients with uPA.

Deep immunophenotyping reveals clinically distinct cellular states and ecosystems in large-scale colorectal cancer.

Determining the diverse cell types in the tumor microenvironment (TME) and their organization into cellular communities, is critical for understanding the biological heterogeneity and therapy of cancer. Here, we deeply immunophenotype the colorectal cancer (CRC) by integrative analysis of large-scale bulk and single cell transcriptome of 2350 patients and 53,137 cells. A rich landscape of 42 cellular states and 7 ecosystems in TMEs is uncovered and extend the previous immune classifications of CRC. Functional pathways and potential transcriptional regulators analysis of cellular states and ecosystems reveal cancer hallmark-related pathways and several critical transcription factors in CRC. High-resolution characterization of the TMEs, we discover the potential utility of cellular states (i.e., Monocytes/Macrophages and CD8 T cell) and ecosystems for prognosis and clinical therapy selection of CRC. Together, our results expand our understanding of cellular organization in TMEs of CRC, with potential implications for the development of biomarkers and precision therapies.

A Potential Anti-Glioblastoma Compound LH20 Induces Apoptosis and Arrest of Human Glioblastoma Cells via CDK4/6 Inhibition.

Glioblastoma (GBM) is a deadly brain tumor characterized by signaling dysregulation and aberrant cell cycle control. The CDK4/6-Rb axis is dysregulated in approximately 80% of all GBM cases. In this study, the anti-GBM effect of a novel pyrimidin-2-amine, LH20 was evaluated in vitro using the primary GBM cell lines U87MG and U251. GBM cells were administered LH20 at concentrations of 0.1, 1, 4, 8, 10, 20, 100, and 200 µM for 24 and 48 h, and the proliferation rate was evaluated using a CCK8 assay. Migration, apoptosis, and cell cycle were also assessed using a wound healing assay, Annexin V-FITC/PI apoptosis assay, and cell cycle staining, respectively. The targets of LH20 were predicted using SwissTargetPrediction and molecular docking. Western blotting analysis was performed to confirm the anti-GBM mechanism of LH20. We found that at concentrations of 4, 8, and 10 µM, LH20 significantly inhibited the proliferation and migration of U87MG and U251 cells, induced late phase apoptosis, promoted tumor cell necrosis, and arrested the G2/M phase of the cell cycle. LH20 also inhibited CDK4 and CDK6 activities by decreasing the phosphorylation of Rb. Our results suggest LH20 as a potential treatment strategy against GBM.

The Effect of Catgut Embedding at Acupoints Versus Nonacupoints in Abdominal Obesity: Protocol for a Multicenter, Double-Blind, 16-Week Randomized Controlled Trial.

BACKGROUND: Obesity is an increasing problem worldwide. The effective treatments for obesity mainly include diet, physical activity, behavioral intervention, pharmacotherapy, and bariatric surgery, which all have certain limitations. As a specific type of acupuncture therapy, acupoint catgut embedding (ACE) has gained substantial attention in the management of obesity in recent years. Previous studies suggested that ACE may be an effective obesity treatment. However, the evidence for the efficacy of ACE in abdominal obesity (AO) remains inadequate due to the paucity of high-quality studies. OBJECTIVE: This study aims to investigate the difference in the effectiveness of catgut embedding at acupoints and catgut embedding at nonacupoints in patients with AO and to further validate the efficacy and safety of ACE for AO. METHODS: This is a multicenter, double-blind, 16-week randomized controlled trial. A total of 92 eligible participants with AO will be randomly divided into 2 groups (1:1 allocation ratio). The ACE group will receive catgut embedding at acupoints and the control group will receive catgut embedding at nonacupoints. The intervention will be performed every 2 weeks for a total of 6 sessions. Follow-up will be performed every 2 weeks for a total of 2 visits. The primary outcome is waist circumference. Secondary outcomes include body weight, BMI, hip circumference, and the visual analog scale of appetite. Upon the completion of the trial, we will evaluate the effect of catgut embedding at acupoints or nonacupoints on obesity indicators in patients with AO. For treatment outcomes, an intention-to-treat analysis will be performed. RESULTS: The start of recruitment began in August 2019 and is expected to end in September 2023. CONCLUSIONS: Although studies have been conducted to demonstrate the effectiveness of ACE in the treatment of obesity, the evidence for the efficacy of ACE in AO remains insufficient due to the quality of the studies. This rigorous normative randomized controlled trial will verify the effect of catgut embedding at acupoints or nonacupoints in patients with AO. The findings will provide credible evidence as to whether ACE is an effective and safe treatment for AO. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800016947; https://tinyurl.com/2p82257p. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46863.

Drug Repurposing-Based Brain-Targeting Self-Assembly Nanoplatform Using Enhanced Ferroptosis against Glioblastoma.

Glioblastoma (GBM), the most aggressive and lethal form of malignant brain tumor, is a therapeutic challenge due to the drug filtration capabilities of the blood-brain barrier (BBB). Interestingly, glioblastoma tends to resist apoptosis during chemotherapy, but is susceptible to ferroptosis. Developing therapies that can effectively target glioblastoma by crossing the BBB and evoke ferroptosis are, therefore, crucial for improving treatment outcomes. Herein, a versatile biomimetic nanoplatform, L-D-I/NPs, is designed that self-assembled by loading the antimalarial drug dihydroartemisinin (DHA) and the photosensitizer indocyanine green (ICG) onto lactoferrin (LF). This nanoplatform can selectively target glioblastoma by binding to low-density lipoprotein receptor-related protein-1 (LRP1) and crossing the BBB, thus inducing glioblastoma cell ferroptosis by boosting intracellular reactive oxygen species (ROS) accumulation and iron overload. In addition, L-D-I/NPs have demonstrated the ability to effectively suppress the progression of orthotopic glioblastoma and significantly prolong survival in a mouse glioblastoma model. This nanoplatform has facilitated the application of non-chemotherapeutic drugs in tumor treatment with minimal adverse effects, paving the way for highly efficient ferroptosis-based therapies for glioblastoma.

The clinical characteristics of acute cerebral infarction patients with thalassemia in a tropic area in China.

This study aimed to explore the clinical characteristics of acute cerebral infarction (ACI) patients with thalassemia through the analysis of clinical data. Adult patients with ACI who were admitted to the First Affiliated Hospital of Hainan Medical College, the Second Affiliated Hospital of Hainan Medical College, Hainan Provincial People's Hospital, and the Department of Neurology of Haikou People's Hospital from January 2008 to December 2018 were enrolled. According to the eligibility criteria, 183 ACI patients were examined, of whom there were 33 cases with thalassemia, 50 cases with iron-deficiency anemia (IDA), and 100 non-anemic cases. Laboratory data, including platelet count, homocysteine count, and hemoglobin level, were collected. Besides, the results of auxiliary examinations, such as brain magnetic resonance imaging or computed tomography, carotid ultrasound, electrocardiogram, and cardiac color ultrasound, were collected. Baseline clinical data (e.g., history of smoking and drinking) were acquired. The clinical characteristics were compared and analyzed among the three groups. There were more female ACI patients with thalassemia than male ones. Furthermore, lesions in the thalassemia and IDA groups were mainly located in the region from the corona radiata and the centrum semiovale, in which multiple small infarcts were dominant. In the non-anemia group, patients' lesions were mainly found in the basal ganglia area, and single small infarcts had the highest proportion.

Secondhand smoke, genetic susceptibility, and incident chronic kidney disease in never smokers: A prospective study of a selected population from the UK Biobank.

INTRODUCTION: A large number of people around the world are exposed to the risks of passive smoking. This prospective study aimed to examine the association between secondhand smoke exposure, exposure time, and the incidence of chronic kidney disease (CKD) and determine whether this association was influenced by genetic susceptibility. METHODS: The study included 214244 participants of the UK Biobank who were initially free of CKD. Cox proportional hazards model was used to estimate the associations between secondhand smoke exposure time and the risks of CKD in people who have never smoked. The genetic risk score for CKD was calculated by a weighted method. The likelihood ratio test comparing models was used to examine the cross-product term between secondhand smoke exposure and genetic susceptibility to CKD outcomes. RESULTS: During a median of 11.9 years of follow-up, 6583 incidents of CKD were documented. Secondhand smoke exposure increased the risk of CKD (HR=1.09; 95% CI: 1.03-1.16, p<0.01), and a dose-response relationship between CKD prevalence and secondhand smoke exposure time was found (p for trend<0.01). Secondhand smoke exposure increases the risk of CKD even in people who never smoke and have a low genetic risk (HR=1.13; 95% CI: 1.02-1.26, p=0.02). There was no statistically significant interaction between secondhand smoke exposure and genetic susceptibility to CKD (p for interaction=0.80). CONCLUSIONS: Secondhand smoke exposure is associated with higher risk of CKD, even in people with low genetic risk, and the relationship is dose dependent. These findings change the belief that people with low genetic susceptibility and without direct participation in smoking activities are not prone to CKD, emphasizing the need to avoid the harm of secondhand smoke in public places.

MicroRNA-27a, downregulated in human obesity, exerts an antiapoptotic function in adipocytes.

Adipocyte apoptosis is a key initial event that contributes to macrophage infiltration into adipose tissue (AT) and thus triggers AT inflammation in obesity. MicroRNA-27a (miR-27a) was shown to mediate the pathological processes of many metabolic disorders; however, whether miR-27a is involved in adipocyte apoptosis of obese AT remains unknown. The present study aimed to investigate the alteration of miR-27a in obese individuals and its antiapoptotic function in adipocytes. In vivo, serum samples and omental adipose tissue from humans as well as epididymal fat pads from mice were collected to detect miR-27a expression. In vitro, 3T3-L1 preadipocytes and mature adipocytes were treated with TNF-α to induce apoptosis and transfected with a mimic for overexpressing miR-27a-3p. The results showed that miR-27a was markedly decreased in the serum and AT of obese human patients and in the AT of high-fat diet-fed mice. Regression analyses revealed that the serum level of miR-27a was correlated with metabolic parameters in human obesity. Notably, TNF-α induced cell apoptosis in both preadipocytes and mature adipocytes, as evidenced by the upregulation of cleaved caspase 3 and cleaved caspase 8 and the ratio of Bax to Bcl-2, while these effects were partly diminished by miR-27a overexpression. In addition, TUNEL and Hoechst 33258 staining verified that miR-27a overexpression markedly inhibited the apoptosis of adipocytes under TNF-α stimulation. Thus, miR-27a was downregulated in the AT of obese subjects with proapoptotic status, and overexpression of miR-27a exerted an antiapoptotic effect on preadipocytes, providing a novel potential target for preventing AT dysfunction.

Phosphoproteomics Reveals the Wolframin-Calcium Axis as an Important Pathogenic Signaling Node in Primary Aldosteronism.

BACKGROUND: Aldosterone-producing adenoma (APA) is a benign adrenal tumor with autonomous aldosterone production which causes hypertension and excess cardiovascular risk. Protein phosphorylation regulates aldosterone secretion from adrenal cortical cells, but how signaling networks are remodeled in APA remains unknown. METHODS: We performed an integrated proteomic and phosphoproteomic profiling of 15 APA and 10 matched nonfunctioning adrenocortical tumors (NFAT) based on the 4-dimensional label-free technique. We further validated our main findings in enlarged APA samples, mice, and adrenocortical cell line. RESULTS: The proteomic and phosphoproteomic profiling of APA and NFAT quantified 5989 proteins and 9011 phosphopeptides. We highlighted differentially expressed and phosphorylated proteins which modulated aldosterone synthesis and secretion from APA. As intracellular calcium is the central signal for aldosterone synthesis, our integrated calcium signaling network implicated wolframin in the control of calcium influx and CYP11B2 (aldosterone synthase) activation in APA (ratio of wolframin expression in APA to NFAT: 6.411, P<0.001). Among 97 APA cases for validation, a higher expression level of wolframin was associated with a higher plasma aldosterone concentration postcaptopril challenge test and a higher systolic blood pressure. In vitro, the secretion of aldosterone was enhanced by wolframin overexpression, while aldosterone secretion in response to potassium or angiotensin II was inhibited by the knockdown of wolframin. Further in vivo and in vitro data demonstrated the wolframin-calcium axis as an important regulator of CYP11B2 expression and aldosterone production. CONCLUSIONS: Wolframin is a regulatory protein in aldosterone hypersecretion. Remodeled calcium transportation and mitochondrial function are involved in wolframin-related aldosterone secretion.

TRAP-induced PAR1 expression with its mechanism during AMI in a rat model.

BACKGROUND AND OBJECTIVE: Protease-activated receptor 1 (PAR1) is crucial in individuals with acute myocardial infarction (AMI). The continuous and prompt PAR1 activation mainly dependent on PAR1 trafficking is essential for the role of PAR1 during AMI in which cardiomyocytes are in hypoxia. However, the PAR1 trafficking in cardiomyocytes specially during the hypoxia is still unclear. METHODS AND RESULT: A rat AMI model was created. PAR1 activation with thrombin-receptor activated peptide (TRAP) had a transient effect on cardiac function in normal rats but persistent improvement in rats with AMI. Cardiomyocytes from neonatal rats were cultured in a normal CO2 incubator and a hypoxic modular incubator chamber. The cells were then subjected to western blot for the total protein expression and staining with fluorescent reagent and antibody for PAR1 localization. No change in total PAR1 expression following TRAP stimulation was observed; however, it led to increased PAR1 expression in the early endosomes in normoxic cells and decreased expression in the early endosomes in hypoxic cells. Under hypoxic conditions, TRAP restored the PAR1 expression on both cell and endosomal surfaces within an hour by decreasing Rab11A (8.5-fold; 179.93 ± 9.82% of the normoxic control group, n = 5) and increasing Rab11B (15.5-fold) expression after 4 h of hypoxia. Similarly, Rab11A knockdown upregulated PAR1 expression under normoxia, and Rab11B knockdown downregulated PAR1 expression under both normoxic and hypoxic conditions. Cardiomyocytes knocked out of both Rab11A, and Rad11B lost the TRAP-induced PAR1 expression but still exhibited the early endosomal TRAP-induced PAR1 expression under hypoxia. CONCLUSIONS: TRAP-mediated activation of PAR1 in cardiomyocytes did not alter the total PAR1 expression under normoxic conditions. Instead, it triggers a redistribution of PAR1 levels under normoxic and hypoxic conditions. TRAP reverses the hypoxia-inhibited PAR1 expression in cardiomyocytes by downregulating Rab11A expression and upregulating Rab11B expression.

Association between fat mass and mortality: analysis of Mendelian randomization and lifestyle modification.

BACKGROUND: The association between fat mass and mortality has been equivocally shown to be linear, J-shaped, and U-shaped. We aimed to clarify this relationship based on Mendelian randomization (MR) analysis and lifestyle modification. METHODS: This prospective analysis included 449,831 participants from UK Biobank. Linear MR analysis was used to estimate the linear relationship between fat mass and mortality. We assessed whole body fat mass by bioimpedance analysis at baseline and categorized subjects into five equal groups based on fat mass index (FMI). The association between FMI and mortality were investigated among whole population and in subgroups stratified by individual lifestyle factors, including diet, physical activity, smoking, alcohol, sleep and psychological health. FINDINGS: Linear MR analyses indicated a positive association between genetically predicted fat mass and all-cause mortality (HR 1.10, 95 % CI 1.08-1.12, P < 0.001). The association between FMI and all-cause mortality was manifested as J-shaped (HRs across FMI categories: 1.04, 1.00, 1.07, 1.21, 1.54), which was significantly modified by the number of low-risk lifestyle factors (P for interaction<0.001). When evaluating individual lifestyle factors, we observed a nonlinear relationship between FMI and all-cause mortality among participants who had high-risk lifestyle factors, while a linear relationship was observed among participants who had low-risk lifestyle factors, especially for those with adequate physical activity (HRs across FMI categories: 0.95, 1.00, 1.05, 1.17, 1.44) and who never smoked (0.96, 1.00, 1.03, 1.14, 1.51). INTERPRETATION: Genetically determined fat mass is causally and linearly associated with mortality. The J-shape association between anthropometric FMI and mortality is caused by high-risk lifestyle factors.

Prevalence and Characteristics of Adrenal Tumors in an Unselected Screening Population : A Cross-Sectional Study.

BACKGROUND: With the widespread use of advanced imaging technology, adrenal tumors are increasingly being identified. OBJECTIVE: To investigate the prevalence and characteristics of adrenal tumors in an unselected screening population in China. DESIGN: Cross-sectional study. (ClinicalTrials.gov: NCT04682938). SETTING: A health examination center in China. PATIENTS: Adults having an annual checkup were invited to be screened for adrenal tumors by adrenal computed tomography. MEASUREMENTS: The participants with adrenal tumors had further evaluation for malignancy risk and adrenal function. RESULTS: A total of 25 356 participants were screened, 351 of whom were found to have adrenal tumors, for a prevalence of 1.4%. The prevalence increased with age, from 0.2% in participants aged 18 to 25 years to 3.2% in those older than 65 years. Among 351 participants with adrenal tumors, 337 were diagnosed with an adrenocortical adenoma, 14 with another benign nodule, and none with a malignant mass. In 212 participants with an adenoma who completed endocrine testing, 69.3% were diagnosed with a nonfunctioning adenoma, 18.9% with cortisol autonomy, 11.8% with primary aldosteronism, and none with pheochromocytoma. Proportions of nonfunctioning adenomas were similarly high in various age groups (72.2%, 67.8%, and 72.2% in those aged <46, 46 to 65, and ≥66 years, respectively). LIMITATION: Only 212 of 337 participants with an adrenocortical adenoma had endocrine testing. CONCLUSION: The prevalence of adrenal tumors in the general adult screening population is 1.4%, and most of these tumors are nonfunctioning regardless of patient age. Cortisol and aldosterone secretion are the main causes of functional adenomas. PRIMARY FUNDING SOURCE: National Key Research and Development Program of China and National Natural Science Foundation of China.

Drug repurposing in cancer neuroscience: From the viewpoint of the autophagy-mediated innervated niche.

Based on the bidirectional interactions between neurology and cancer science, the burgeoning field "cancer neuroscience" has been proposed. An important node in the communications between nerves and cancer is the innervated niche, which has physical contact with the cancer parenchyma or nerve located in the proximity of the tumor. In the innervated niche, autophagy has recently been reported to be a double-edged sword that plays a significant role in maintaining homeostasis. Therefore, regulating the innervated niche by targeting the autophagy pathway may represent a novel therapeutic strategy for cancer treatment. Drug repurposing has received considerable attention for its advantages in cost-effectiveness and safety. The utilization of existing drugs that potentially regulate the innervated niche via the autophagy pathway is therefore a promising pharmacological approach for clinical practice and treatment selection in cancer neuroscience. Herein, we present the cancer neuroscience landscape with an emphasis on the crosstalk between the innervated niche and autophagy, while also summarizing the underlying mechanisms of candidate drugs in modulating the autophagy pathway. This review provides a strong rationale for drug repurposing in cancer treatment from the viewpoint of the autophagy-mediated innervated niche.

Lifestyle and chronic kidney disease: A machine learning modeling study.

Background: Individual lifestyle varies in the real world, and the comparative efficacy of lifestyles to preserve renal function remains indeterminate. We aimed to systematically compare the effects of lifestyles on chronic kidney disease (CKD) incidence, and establish a lifestyle scoring system for CKD risk identification. Methods: Using the data of the UK Biobank cohort, we included 470,778 participants who were free of CKD at the baseline. We harnessed the light gradient boosting machine algorithm to rank the importance of 37 lifestyle factors (such as dietary patterns, physical activity (PA), sleep, psychological health, smoking, and alcohol) on the risk of CKD. The lifestyle score was calculated by a combination of machine learning and the Cox proportional-hazards model. A CKD event was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m2, mortality and hospitalization due to chronic renal failure, and self-reported chronic renal failure, initiated renal replacement therapy. Results: During a median of the 11-year follow-up, 13,555 participants developed the CKD event. Bread, walking time, moderate activity, and vigorous activity ranked as the top four risk factors of CKD. A healthy lifestyle mainly consisted of whole grain bread, walking, moderate physical activity, oat cereal, and muesli, which have scored 12, 12, 10, 7, and 7, respectively. An unhealthy lifestyle mainly included white bread, tea >4 cups/day, biscuit cereal, low drink temperature, and processed meat, which have scored -12, -9, -7, -4, and -3, respectively. In restricted cubic spline regression analysis, a higher lifestyle score was associated with a lower risk of CKD event (p for linear relation < 0.001). Compared to participants with the lifestyle score < 0, participants scoring 0-20, 20-40, 40-60, and >60 exhibited 25, 42, 55, and 70% lower risk of CKD event, respectively. The C-statistic of the age-adjusted lifestyle score for predicting CKD events was 0.710 (0.703-0.718). Conclusion: A lifestyle scoring system for CKD prevention was established. Based on the system, individuals could flexibly choose healthy lifestyles and avoid unhealthy lifestyles to prevent CKD.

Development and validation of model for sparing adrenal venous sampling in diagnosing unilateral primary aldosteronism.

CONTEXT: Current guidelines recommend adrenal venous sampling (AVS) to identify unilateral primary aldosteronism (UPA) before offering adrenalectomy. However, AVS is costly and technically challenging, limiting its use to expert centres. OBJECTIVE: To establish a model to predict UPA, and therefore, bypass the need for AVS prior to surgery. DESIGN AND SETTING: The model was developed in a Chinese cohort and validated in an Australian cohort. Previously published prediction models of UPA were also tested. PARTICIPANTS: primary aldosteronism patients with a definite subtyping diagnosis based on AVS and/or surgery. MAIN OUTCOME MEASURE: Diagnostic value of the model. RESULTS: In the development cohort (268 UPA and 88 bilateral primary aldosteronism), combinations of different levels of low serum potassium (≤3.0 or 3.5 mmol/l), high PAC (≥15-30 ng/dl), low PRC (≤2.5-10 µIU/ml) and presence of unilateral nodule on adrenal CT (>8-15 mm in diameter) showed specificity of 1.00 and sensitivity of 0.16-0.52. The model of serum potassium 3.5 mmol/l or less, PAC at least 20 ng/dl, PRC 5 µIU/ml or less plus a unilateral nodule at least 10 mm had the highest sensitivity of 0.52 (0.45-0.58) and specificity of 1.00 (0.96-1.00). In the validation cohort (84 UPA and 117 bilateral primary aldosteronism), the sensitivity and specificity of the model were 0.13 (0.07-0.22) and 1.00 (0.97-1.00), respectively. Ten previous models were tested, and only one had a specificity of 1.00 in our cohorts but with a very low sensitivity [0.07 (0.04-0.10) and 0.01 (0.00-0.06) in our development and validation cohorts, respectively]. CONCLUSION: A combination of high PAC, low PRC, low serum potassium and unilateral adrenal nodule could accurately determine primary aldosteronism subtype in 13-52% of patients with UPA and obviate the need for AVS before surgery.

Early-phase insulin hypersecretion associated with weight loss outcome after LSG: a prospective cohort study in Asian patients with BMI ≥28 kg/m2.

BACKGROUND: Obesity has become a global problem that poses a serious threat to human health. Laparoscopic sleeve gastrectomy (LSG) is an effective long-term treatment. However, the weight loss of some patients after LSG is still insufficient. It is necessary to investigate the factors associated with inadequate weight loss after LSG. OBJECTIVE: The objective of this study was to explore whether preoperative insulin secretion could be associated with weight loss after LSG in patients with obesity. SETTING: This is a single-center prospective cohort study conducted in a university hospital. METHODS: Patients from a prospective database who underwent LSG were analyzed. All 178 participants underwent a 75-g oral glucose tolerance test (OGTT) to assess preoperative insulin and c-peptide secretion before LSG. The areas under the curve (AUCs) for glucose, insulin, and c-peptide were determined in the OGTT. The percentage of excess weight loss (%EWL) and the percentage of total weight loss (%TWL) were used to estimate the effect of weight loss after LSG. Regression models were used to assess the correlation between preoperative insulin and c-peptide secretion with %EWL ≥75% and TWL ≥35% at 12 months after LSG. RESULTS: The AUCs of insulin and c-peptide were significantly lower in the %EWL ≥75% and %TWL ≥35% groups at 0-30 minutes, 0-60 minutes, and 0-120 minutes during the OGTT. At 30, 60, and 120 minutes during the OGTT, c-peptide levels were significantly lower in the %EWL ≥75% group and %TWL ≥35% group. The preoperative c-peptide level at 30 minutes during the OGTT (C30) was significantly negatively correlated with %EWL (ß = -.37, P < .001) and %TWL (ß = -.28, P = .011). Univariate logistic regression analysis showed that preoperative C30 was associated with %EWL ≥75% and %TWL ≥35% after LSG. According to multiple logistic regression analysis, patients with a low preoperative C30 had an 8-fold higher %TWL ≥35% after LSG than those with a high C30 (odds ratio: 8.41 [95% confidence interval: 1.46-48.58], P = .017). Similarly, patients with a low preoperative C30 had a 7-fold higher EWL% ≥75% after LSG than patients with a high C30 (odds ratio: 7.25 [95% confidence interval: 1.11-47.50], P = .039). CONCLUSIONS: The rate of weight loss after LSG is low among patients with preoperative hyperinsulinemia. The preoperative c-peptide level at 30 minutes during the OGTT is associated with weight loss after LSG.

Hippocampal overexpression of TREM2 ameliorates high fat diet induced cognitive impairment and modulates phenotypic polarization of the microglia.

Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) share several common pathophysiological features. Rare variants of triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of developing AD, suggesting the involvement of TREM2 and innate immunity in AD development. It is still unknown whether TREM2 is related to cognitive impairment in T2DM. Here, we investigated the effects of the hippocampal overexpression of TREM2 on cognitive in long-term high-fat diet (HFD)-fed mice. Male C57BL/6J mice were maintained on HFD for 50 weeks. TREM2 was overexpressed in the hippocampus 36 weeks after HFD feeding using adeno-associated virus vector (AAV)-mediated gene delivery. The results showed that the HFD feeding induced rapid and persistent weight gain, glucose intolerance and significant impairments in learning and memory. Compared with AAV-con, AAV-TREM2 significantly ameliorated cognitive impairment without altering body weight and glucose homeostasis in HFD mice. The overexpression of TREM2 upregulated the synaptic proteins spinophilin, PSD95 and synaptophysin, suggesting the improvement in synaptic transmission. Dendritic complexity and spine density in the CA1 region were rescued after TREM2 overexpression. Furthermore, TREM2 markedly increased the number of iba-1/Arg-1-positive microglia in the hippocampus, suppressed neuroinflammation and microglial activation. In sum, hippocampal TREM2 plays an important role in improving HFD-induced cognitive dysfunction and promoting microglial polarization towards the M2 anti-inflammatory phenotype. Our study also suggests that TREM2 might be a novel target for the intervention of obesity/diabetes-associated cognitive decline.