Construction of an Early Risk Prediction Model for Type 2 Diabetic Peripheral Neuropathy Based on Random Forest.

Diabetic peripheral neuropathy is a major cause of disability and death in the later stages of diabetes. A retrospective chart review was performed using a hospital-based electronic medical record database to identify 1020 patients who met the criteria. The objective of this study was to explore and analyze the early risk factors for peripheral neuropathy in patients with type 2 diabetes, even in the absence of specific clinical symptoms or signs. Finally, the random forest algorithm was used to rank the influencing factors and construct a predictive model, and then the model performance was evaluated. Logistic regression analysis revealed that vitamin D plays a crucial protective role in preventing diabetic peripheral neuropathy. The top three risk factors with significant contributions to the model in the random forest algorithm eigenvalue ranking were glycosylated hemoglobin, disease duration, and vitamin D. The areas under the receiver operating characteristic curve of the model ware 0.90. The accuracy, precision, specificity, and sensitivity were 0.85, 0.83, 0.92, and 0.71, respectively. The predictive model, which is based on the random forest algorithm, is intended to support clinical decision-making by healthcare professionals and help them target timely interventions to key factors in early diabetic peripheral neuropathy.

Prediction of vascular complications in free flap reconstruction with machine learning.

OBJECTIVE: This study aims to explore the risk factors of vascular complications following free flap reconstruction and to develop a clinical auxiliary assessment tool for predicting vascular complications in patients undergoing free flap reconstruction leveraging machine learning methods. METHODS: We reviewed the medical data of patients who underwent free flap reconstruction at the Affiliated Hospital of Zunyi Medical University retrospectively from January 1, 2019, to December 31, 2021. Statistical analysis was used to screen risk factors. A training data set was generated and augmented using the synthetic minority oversampling technique. Logistic regression, random forest and neural network, models were trained, using this dataset. The performance of these three predictive models was then evaluated and compared using a test set, with four metrics, area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. RESULTS: A total of 570 patients who underwent free flap reconstruction were included in this study, 46 of whom developed postoperative vascular complications. Among the models tested, the neural network model exhibited superior performance on the test set, achieving an AUC of 0.828. Multivariate logistic regression analysis identified that preoperative hemoglobin levels, preoperative fibrinogen levels, operation duration, smoking history, the number of anastomoses, and peripheral vascular injury as statistically significant independent risk factors for vascular complications post-free flap reconstruction. The top five predictive factors in the neural network were fibrinogen content, operation duration, donor site, body mass index (BMI), and platelet count. CONCLUSION: Hemoglobin levels, fibrinogen levels, operation duration, smoking history, and anastomotic veins are independent risk factors for vascular complications following free flap reconstruction. These risk factors enhance the ability of machine learning models to predict the occurrence of vascular complications and identify high-risk patients. The neural network model outperformed the logistic regression and random forest models, suggesting its potential to aid clinicians in early identification of high-risk patients thereby mitigating patient suffering and improving prognosis.

Chidamide plus envafolimab as subsequent treatment in advanced non-small cell lung cancer patients resistant to anti-PD-1 therapy: A multicohort, open-label, phase II trial with biomarker analysis.

BACKGROUND: Combination of chidamide and anti-PD-L1 inhibitor produce synergistic anti-tumor effect in advanced NSCLC patients resistant to anti-PD-1 treatment. However, the effect of chidamide plus envafolimab has not been reported. AIMS: This study aimed to evaluate the efficacy of chidamide plus envafolimab in advanced NSCLC patients resistant toanti-PD-1 treatment. MATERIALS AND METHODS: Eligible advanced NSCLC patients after resistant to anti-PD-1 therapy received chidamide and envafolimab. The primary endpoint was objective response rate (ORR). The secondary end points included disease control rate (DCR), progression-free survival (PFS), and safety. The expression of histone deacetylase 2 (HDAC2), PD-L1, and blood TMB (bTMB) was also analyzed. RESULTS: After a median follow-up of 8.1 (range: 7.6-9.2) months, only two patients achieved partial response. The ORR was 6.7% (2/30), DCR was 50% (15/30), and median PFS (mPFS) was 3.5 (95% confidence interval: 1.9-5.5) months. Biomarker analysis revealed that patients with high-level HDAC2 expression had numerically superior ORR (4.3% vs. 0), DCR (52.2% vs. 0) and mPFS (3.7 vs. 1.4m). Patients with negative PD-L1 had numerically superior DCR (52.2% vs. 33.3%) and mPFS (3.7m vs. 1.8m), so were those with low-level bTMB (DCR: 59.1% vs. 16.7%, mPFS: 3.8 vs.1.9m). Overall safety was controllable. DISCUSSION: High HDAC2patients showed better ORR, DCR, and PFS. In addition, patient with negative PD-L1 and low-level bTMB had better DCR and PFS. This may be related to the epigenetic function of chidamide. However, the sample size was not big enough, so it is necessary to increase sample size to confirm the conclusion. CONCLUSION: Combination of chidamide and envafolimab showed efficacy signals in certain NSCLC patients. But further identification of beneficial population is necessary for precision treatment.

Continuous intravenous infusion of recombinant human endostatin using infusion pump plus chemotherapy in non-small cell lung cancer.

BACKGROUND: Lung cancer is one of the deadliest cancers in the world with the highest incidence and mortality rate among all cancers. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of primary lung cancer. However, efficacy and safety of the current regimens for NSCLC is unsatisfactory. Therefore, there has been an increasing urgency for development of potential therapeutic therapies for NSCLC. AIM: To investigate the therapeutic outcomes and safety of continuous intravenous infusion of recombinant human endostatin (Rh-endostain) using an infusion pump in retreated advanced NSCLC. METHODS: Patients with retreated advanced NSCLC who were admitted to Zhejiang Provincial People's Hospital from October 2017 to April 2019 were recruited. These patients received continuous intravenous infusion of Rh-endostain using an infusion pump. Objective response rate (ORR), clinical benefit rate (CBR), median progression-free survival (mPFS), and incidences of adverse events (AEs) were analyzed after treatment. RESULTS: A total of 45 patients with retreated advanced NSCLC were included, and all of them were evaluated. In these patients, ORR was 22.2%, CBR was 84.4%, and mPFS was 5.3 mo. The following AEs were observed, decreased hemoglobin (34 cases, 75.6%), nausea/vomiting (32 cases, 71.1%), elevated transaminase (24 cases, 53.3%), leukopenia (16 cases, 35.6%), thrombocytopenia (14 cases, 31.1%), and constipation (1 case, 3.4%). None of the patients had leukopenia, nausea /vomiting, and constipation of grade III and above. CONCLUSION: The patients showed improved adherence to 5-d continuous intravenous infusion of Rh-endostain using an infusion pump. Favorable efficacy and safety of this treatment regimen were achieved in retreated advanced NSCLC.

Glucotoxicity Activation of IL6 and IL11 and Subsequent Induction of Fibrosis May Be Involved in the Pathogenesis of Islet Dysfunction.

Background: Islet dysfunction is the main pathological process of type 2 diabetes mellitus (T2DM). Fibrosis causes islet dysfunction, but the current mechanism is still unclear. Here, bioinformatics analysis identified gene clusters closely related to T2DM and differentially expressed genes related to fibrosis, and animal models verified the roles of these genes. Methods: Human islet transcriptomic datasets were obtained from the Gene Expression Omnibus (GEO), and weighted gene coexpression network analysis (WGCNA) was applied to screen the key gene modules related to T2DM and analyze the correlations between the modules and clinical characteristics. Enrichment analysis was performed to identify the functions and pathways of the key module genes. WGCNA, protein-protein interaction (PPI) analysis and receiver operating characteristic (ROC) curve analysis were used to screen the hub genes. The hub genes were verified in another GEO dataset, the islets of high-fat diet (HFD)-fed Sprague-Dawley rats were observed by H&E and Masson's trichrome staining, the fibrotic proteins were verified by immunofluorescence, and the hub genes were tested by immunohistochemistry. Results: The top 5,000 genes were selected according to the median absolute deviation, and 18 modules were analyzed. The yellow module was highly associated with T2DM, and its positive correlation with glycated hemoglobin (HbA1c) was significantly stronger than that with body mass index (BMI). Enrichment analysis revealed that extracellular matrix organization, the collagen-containing extracellular matrix and cytokine-cytokine receptor interaction might influence T2DM progression. The top three hub genes, interleukin 6 (IL6), IL11 and prostaglandin-endoperoxide synthase 2 (PTGS2), showed upregulated expression in T2DM. In the validation dataset, IL6, IL11, and PTGS2 levels were upregulated in T2DM, and IL6 and PTGS2 expression was positively correlated with HbA1c and BMI; however, IL11 was positively correlated only with HbA1c. In HFD-fed Sprague-Dawley rats, the positive of IL6 and IL11 in islets was stronger, but PTGS2 expression was not significantly altered. The extent of fibrosis, irregular cellular arrangement and positive actin alpha 2 (ACTA2) staining in islets was significantly greater in HFD-fed rats than in normal diet-fed rats. Conclusion: Glucotoxicity is a major factor leading to increased IL6 and IL11 expression, and IL6-and IL11-induced fibrosis might be involved in islet dysfunction.

Development and assessment of the efficacy and safety of human lung-targeting liposomal methylprednisolone crosslinked with nanobody.

Glucocorticoid (GC) hormone has been commonly used to treat systemic inflammation and immune disorders. However, the side effects associated with long-term use of high-dose GC hormone limit its clinical application seriously. GC hormone that can specifically target the lung might decrease the effective dosage and thus reduce GC-associated side effects. In this study, we successfully prepared human lung-targeting liposomal methylprednisolone crosslinked with nanobody (MPS-NSSLs-SPANb). Our findings indicate that MPS-NSSLs-SPANb may reduce the effective therapeutic dosage of MPS, achieve better efficacy, and reduce GC-associated side effects. In addition, MPS-NSSLs-SPANb showed higher efficacy and lower toxicity than conventional MPS.

Ion therapy of pulmonary fibrosis by inhalation of ionic solution derived from silicate bioceramics.

Pulmonary fibrosis (PF) is a chronic and progressively fatal disease, but clinically available therapeutic drugs are limited due to efficacy and side effects. The possible mechanism of pulmonary fibrosis includes the damage of alveolar epithelial cells II (AEC2), and activation of immune cells such as macrophages. The ions released from bioceramics have shown the activity in stimulating soft tissue derived cells such as fibroblasts, endothelia cells and epithelia cells, and regulating macrophage polarization. Therefore, this study proposes an "ion therapy" approach based on the active ions of bioceramic materials, and investigates the therapeutic effect of bioactive ions derived from calcium silicate (CS) bioceramics on mouse models of pulmonary fibrosis. We demonstrate that silicate ions significantly reduce pulmonary fibrosis by simultaneously regulating the functions of AEC2 and macrophages. This result suggests potential clinical applications of ion therapy for lung fibrosis.

Transcriptome profiling analysis reveals that ATP6V0E2 is involved in the lysosomal activation by anlotinib.

Anlotinib is a receptor tyrosine kinase inhibitor with potential anti-neoplastic and anti-angiogenic activities. It has been approved for the treatment of non-small-cell lung cancer. Lysosomes are acidic organelles and have been implicated in various mechanisms of cancer therapeutics. However, the effect of anlotinib on lysosomal function has not been investigated. In the present study, anlotinib induces apoptosis in human colon cancer cells. Through transcriptome sequencing, we found for the first time that anlotinib treatment upregulates ATP6V0E2 (ATPase H+ Transporting V0 Subunit E2) and other lysosome-related genes expression in human colon cancer. In human colon cancer, we validated that anlotinib activates lysosomal function and enhances the fusion of autophagosomes and lysosomes. Moreover, anlotinib treatment is shown to inhibit mTOR (mammalian target of rapamycin) signaling and the activation of lysosomal function by anlotinib is mTOR dependent. Furthermore, anlotinib treatment activates TFEB, a key nuclear transcription factor that controls lysosome biogenesis and function. We found that anlotinib treatment promotes TFEB nuclear translocation and enhances its transcriptional activity. When TFEB or ATP6V0E2 are knocked down, the enhanced lysosomal function and autophagy by anlotinib are attenuated. Finally, inhibition of lysosomal function enhances anlotinib-induced cell death and tumor suppression, which may be attributed to high levels of ROS (reactive oxygen species). These findings suggest that the activation of lysosomal function protects against anlotinib-mediated cell apoptosis via regulating the cellular redox status. Taken together, our results provide novel insights into the regulatory mechanisms of anlotinib on lysosomes, and this information could facilitate the development of potential novel cancer therapeutic agents that inhibit lysosomal function.

Long-term safety of icotinib in patients with non-small cell lung cancer: a retrospective, real-world study.

BACKGROUND: Lung cancer is a global health problem with a high mortality, and the development of target therapy has led to a revolution in the treatment of lung cancer in recent years. Favorable efficacy and safety of icotinib have been demonstrated in patients with non-small cell lung cancer (NSCLC). Currently, minimal data are available to describe the long-term safety of icotinib in NSCLC patients. METHODS: We reviewed the safety data from 1,321 advanced NSCLC patients who were treated with icotinib. The primary endpoint was the long-term safety, defined as any adverse drug reactions (ADRs) occurred after 6 months of icotinib administration. RESULTS: Fewer ADRs were noticed over 6 month administration of icotinib than within 6 months in overall population (24.3% vs. 65.4%), and elderly patients (23.6% vs. 66.9%). The majority of ADRs were grade 1-2 in severity over 6 month exposure of icotinib in overall population as well as elderly patients. In overall population, the most common ADRs of icotinib during long-term use were rash (16.4%) and diarrhea (5.3%), while the incidences were 31.8% and 13.2% in the induction period, respectively. In elderly population, the most common ADRs of icotinib during long-term use were rash (15.7%) and diarrhea (4.7%), while the incidences were 27.8% and 14.9% in the induction period, respectively, and more inching was observed in the induction period as compared with long term use (6.3% vs. 0.3%). CONCLUSIONS: There was an evidence of decreased frequency of icotinib-induced ADRs over time, and icotinib was well-tolerated in elderly NSCLC patients.

Xanthohumol from Humulus lupulus L. potentiates the killing of Mycobacterium tuberculosis and mitigates liver toxicity by the combination of isoniazid in mouse tuberculosis models.

Anti-tuberculosis drug induced hepatotoxicity is the main problem in tuberculosis patients. Xanthohumol, a major prenyl chalcone present in hops, has diverse biological activities including antibacterial and hepatoprotective activities. The present research aimed to investigate the combined effect of xanthohumol with isoniazid against Mycobacterium tuberculosis-infected mice. The liver damage was induced by treatment with isoniazid daily for 8 weeks. During the experiment, the uninfected group and the normal control group received an equal volume of saline, the xanthohumol group received an equal volume of xanthohumol only, and the isoniazid group received an equal volume of isoniazid only. The combination therapy group received not only isoniazid but also the corresponding xanthohumol. Experimental results showed that isoniazid combined with xanthohumol resulted in the lowest lung and spleen colony-forming unit counts compared to other groups. Furthermore, other positive outcomes implied that isoniazid combined with xanthohumol obviously alleviated anti-tuberculosis drug induced liver damage as indicated by the declined levels of ALT, AST, ALP, bilirubin and MDA and the increased levels of SOD, GSH-Px and ATPases. The study of the mechanisms underlying the hepatoprotective activity showed that xanthohumol was able to activate the antioxidative defense system and protect the hepatocellular membrane. The combination of isoniazid and xanthohumol had more effective bacteriostatic and hepatoprotective activities on Mycobacterium tuberculosis-infected mice than isoniazid alone. In conclusion, xanthohumol has the potential to be an effective adjuvant in tuberculosis treatment.

IL-17A Can Promote Propionibacterium acnes-Induced Sarcoidosis-Like Granulomatosis in Mice.

The etiology of sarcoidosis is unknown. In this study, Propionibacterium acnes (PA) was used to induce sarcoidosis-like granulomatous inflammation in a mouse model. Wild-Type (WT) C57BL/6 mice were divided into three groups: (1) WT-PA group; (2) WT-PA + Incomplete Freund's Adjuvant (IFA) group; and (3) WT-PBS group. Loose granuloma formation was observed in the lungs on day 56 in the WT-PA and WT-PA + IFA groups. The proportions of peripheral Th17 cells in the WT-PA (p = 0.0004) and WT-PA + IFA groups (p = 0.0005) were significantly higher than that in the WT-PBS group. The proportions of peripheral Treg cells in the WT-PA (p < 0.0001) and WT-PA + IFA groups (p < 0.0001) were lower than that in the WT-PBS group. Then, to explore the mechanism of IL-17, Wild-Type (WT) C57BL/6 mice were divided into three groups: (1) WT-PBS group (2) WT-PA group; (3) WT-PA + mouse IL-17A neutralizing antibody (IL-17Ab) group. IL-17A gene knockout mice (KO) were divided into two groups: (1) KO -PA group; (2) KO-PBS group. The KO-PA and WT-PA + IL-17Ab groups showed reduced inflammation and no loose granuloma formation on day 56. As compared to the WT-PA group, the ratio of peripheral Th17 in the KO-PA (p < 0.0001) and WT-PA + IL-17Ab groups (p < 0.0001) decreased, while the ratio of peripheral Treg in the KO-PA (p < 0.0001) and WT-PA + IL-17Ab (p = 0.0069) groups increased on day 56. Hence, PA can be used to establish a mouse model of sarcoidosis-like granuloma. IL-17A plays an important role in experimental sarcoidosis-like granuloma formation.

Efficacy and safety of sustained-release oxycodone compared with immediate-release morphine for pain titration in cancer patients: A multicenter, open-label, randomized controlled trial (SOCIAL).

BACKGROUND: The study aims to investigate the effect and safety of sustained-release oxycodone hydrochloride as background dose on pain titration in patients with moderate-to-severe cancer pain. MATERIAL AND METHODS: Adult patients scheduled with a regular strong opioid for cancer-related pain were recruited and randomly assigned to sustained-release oxycodone group (tablets, 12 hourly) and immediate-release morphine group (5 mg initially, hourly). All patients were hourly reassessed for efficacy and dose titration. RESULTS: The primary end point was the number of titration cycles required to achieve adequate pain relief (numerical rating scale, NRS ≤ 3). Secondary end points included the proportion of patients achieving adequate pain relief during each cycle, potential predictive factors for titration performance, and side effects. Ninety (94.7%) patients in oxycodone group and 78 (86.7%) patients in morphine group achieved adequate pain control during 1 to 4 cycles of titration. Patients in oxycodone group reached adequate pain control within the first 2 cycles of titration, which was significantly shorter than morphine group wherein the number of titration cycles ranged from 1 to 4 (P = .034). Oxycodone prescription significantly increased the response rate of patients to morphine titration during the first cycle of titration (P = .010). The initial NRS score and oxycodone administration were significantly associated with titration performance. The mild or moderate adverse effects were similar in 2 groups, while severe adverse effects were only identified in morphine group (P = .001). CONCLUSION: Use of background sustained-release oxycodone is more efficient and better tolerated on dose titration than immediate-release morphine.

IL-17A contributes to HSV1 infection-induced acute lung injury in a mouse model of pulmonary fibrosis.

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) often experience acute exacerbation (AE) after an episode of common cold. AIMS: To establish a mouse model of virus infection-induced AE-IPF and investigate the mechanism underlying the AE-IPF. METHODS: Herpes simplex virus 1 (HSV1) was inoculated intranasally to wild-type (WT) and IL-17A gene knockout (IL-17A-/- ) mice 21 days after intratracheal administration of bleomycin (BLM). RESULTS: HSV1 infection caused acute exacerbation in mice with BLM-induced fibrosis. Compared with the BLM+Saline mice, the mice with BLM+HSV1 showed significantly higher acute lung injury (ALI) score (P < 0.0001), lower survival rate (100% vs 21.4%, P < 0.0001), poorer lung function and higher inflammatory response representing by increased total inflammatory cells in bronchoalveolar lavage fluid (BALF) (P = 0.0323), increased proportion of Th17 cells in peripheral blood (P = 0.0004) and higher inflammatory factors in BALF. In addition, HSV1 infection increased the expression of endoplasmic reticulum stress (ERS)-related proteins in mice with BLM-induced fibrosis. The inhibition of ERS by tauroursodeoxycholic acid (TUDCA, an ERS inhibitor) significantly reduced the IL-17A levels in BALF (P = 0.0140) and TH17 cells in the peripheral blood (P = 0.0084) of mice with BLM+HSV1, suggesting that suppression of ERS may reduce TH17 response in mice with AE-IPF. Compared with WT mice with BLM+HSV1, IL-17A-/- mice with BLM+HSV1 had lower ALI score (P = 0.0119), higher survival rate (78.6% vs 21.4%, P = 0.004), improved lung function, and milder inflammatory response. CONCLUSIONS: HSV1 infection in addition to BLM-induced IPF can successfully establish AE-IPF in mice. IL-17A and ERS promote lung inflammation in AE-IPF development.

Azithromycin treats diffuse panbronchiolitis by targeting T cells via inhibition of mTOR pathway.

Azithromycin (AZM), that is a macrolide antibiotic, has been found to treat diffuse panbronchiolitis (DPB) effectively. However, the mechanism of action underlying the therapeutic effects remains unclear. We selected 64 patients with DPB from 305 patients who were diagnosed with DPB at the outpatient clinic in Shanghai Pulmonary Hospital from Jan 2010 to Oct 2014. The primary PBLs, CD4 + T cells, and Jurkat T cells were treated with AZM or erythromycin (EM), and the effects of AZM and EM on IL-17A and CXCL-2 production, proliferation, apoptosis and autophagy were evaluated. AZM and EM significantly inhibited IL-17A and CXCL-2 production in patients' PBLs (all P < 0.05). AZM significantly inhibited proliferation and promoted apoptosis of T cells from DPB patients. AZM can enhance autophagosome formation of T cells by suppressing S6RP phosphorylation, which is a downstream target of mTOR pathway (all P < 0.05). AZM and EM significantly decreased secreted IL-17A levels (P < 0.05) in the primary CD4 + T cells of patients with DPB. AZM may treat DPB patients by targeting cytokine production, proliferation, apoptosis and autophagy of T cell. The mechanism of therapeutic effects of AZM on DPB may be associated with a specific inhibition of mTOR pathway in the T lymphocytes.

Artesunate-induced mitophagy alters cellular redox status.

Artesunate (ART) is a prominent anti-malarial with significant anti-cancer properties. Our previous studies showed that ART enhances lysosomal function and ferritin degradation, which was necessary for its anti-cancer properties. ART targeting to mitochondria also significantly improved its efficacy, but the effect of ART on mitophagy, an important cellular pathway that facilitates the removal of damaged mitochondria, remains unknown. Here, we first observed that ART mainly localizes in the mitochondria and its probe labeling revealed that it binds to a large number of mitochondrial proteins and causes mitochondrial fission. Second, we found that ART treatment leads to autophagy induction and the decrease of mitochondrial proteins. When autophagy is inhibited, the decrease of mitochondrial proteins could be reversed, indicating that the degradation of mitochondrial proteins is through mitophagy. Third, our results showed that ART treatment stabilizes the full-length form of PTEN induced putative kinase 1 (PINK1) on the mitochondria and activates the PINK1-dependent pathway. This in turn leads to the recruitment of Parkin, sequestosome 1 (SQSTM1), ubiquitin and microtubule-associated proteins 1A/1B light chain 3 (LC3) to the mitochondria and culminates in mitophagy. When PINK1 is knocked down, ART-induced mitophagy is markedly suppressed. Finally, we investigated the effect of mitophagy by ART on mitochondrial functions and found that knockdown of PINK1 alters the cellular redox status in ART-treated cells, which is accompanied with a significant decrease in glutathione (GSH) and increase in mitochondrial reactive oxidative species (mROS) and cellular lactate levels. Additionally, knockdown of PINK1 leads to a significant increase of mitochondrial depolarization and more cell apoptosis by ART, suggesting that mitophagy protects from ART-induced cell death. Taken together, our findings reveal the molecular mechanism that ART induces cytoprotective mitophagy through the PINK1-dependent pathway, suggesting that mitophagy inhibition could enhance the anti-cancer activity of ART.

Association between parental occupational exposure to extremely low frequency magnetic fields and childhood nervous system tumors risk: A meta-analysis.

BACKGROUND AND OBJECTIVE: Previous epidemiological studies suggested association between parental occupational exposure to extremely low frequency magnetic fields (ELF-MF) and risk of childhood nervous system tumors, but the results were inconsistent. We conducted a meta-analysis of case-control and cohort studies to re-evaluate this association. METHODS: Relevant studies were identified by searching PubMed and Web of Science databases as well as by manual searching. Summary odds ratio (OR) with 95% confidence interval (CI) were pooled with a fixed-effects or random-effects model. RESULTS: A total of 22 eligible articles (21 case-control studies and 1 cohort study) were included for the quantitative analysis. The results showed that parental occupational ELF-MF exposure was significantly associated with an increased risk of childhood nervous system tumors (OR = 1.11, 95% CI = 1.02-1.21), and this association remained in studies on central nervous system (CNS) tumors (OR = 1.13, 95% CI = 1.02-1.27) but not neuroblastoma (OR = 1.02, 95% CI = 0.92-1.14). Furthermore, maternal (OR = 1.14, 95% CI = 1.05-1.23) but not paternal (OR = 1.05, 95% CI = 0.98-1.13) occupational ELF-MF exposure significantly increased risk of childhood nervous system tumors. Increased risk of childhood CNS tumors was significant associated with maternal (OR = 1.16, 95% CI = 1.06-1.26) but not paternal (OR = 1.15, 95% CI = 0.98-1.34) occupational ELF-MF exposure. CONCLUSION: In conclusion, our results provide limited evidence for the association between maternal occupational exposure to ELF-MF and increased risk of childhood CNS tumors, which should be explained with cautions. Future studies are needed to further evaluate the association of paternal occupational ELF-MF exposure with risk of childhood CNS tumors.

Importance of TFEB acetylation in control of its transcriptional activity and lysosomal function in response to histone deacetylase inhibitors.

TFEB (transcription factor EB) is a master regulator of lysosomal biogenesis, function and autophagy. The transcriptional activity of TFEB is mainly controlled by its phosphorylation status mediated by the MTOR (mechanistic target of rapamycin [serine/threonine kinase]) complex 1 (MTORC1). At present, little is known whether other forms of posttranslational modifications (PTMs) such as acetylation also affects is transcriptional activity. In this study, we first observed that a well-established histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) activated lysosomal function in human cancer cells, a process independent of the MTORC1 pathway. Second, SAHA treatment activated TFEB transcriptional activity, as evidenced by increased TFEB luciferase activity and expression of its target genes. Third and more importantly, we observed the enhanced TFEB acetylation in SAHA-treated cells, with identification of 4 acetylation sites. Mutation of these 4 sites markedly diminished TFEB transcriptional activity and lysosomal function induced by SAHA. Finally, we found that TFEB acetylation was functionally implicated in SAHA-mediated autophagy and cell death in cancer cells. Taken together, our results demonstrate that TFEB acetylation is a novel form of PTMs in TFEB that plays an important role in determining its transcriptional activity, lysosomal function and autophagy in cancer cells. ABBREVIATIONS: ACAT1: acetyl-coenzyme A acetyltransferase 1; AHA: L-azidohomoalanine; AO: acidic orange; ATG: autophagy related; CLEAR: Coordinated Lysosomal Expression and Regulation; CQ: chloroquine; CTSB: cathepsin B; HATs: histone acetyltransferases; HDACIs: HDACs inhibitors; HDACs: histone deacetylases; IP: immunoprecipitation; MEFs: mouse embryonic fibroblasts; MS: mass spectrometry; MTOR: mechanistic target of rapamycin (serine/threonine kinase); MTORC1: mechanistic target of rapamycin (serine/threonine kinase) complex 1; PTMs: posttranslational modifications; SAHA: suberoylanilidehydroxamic acid; TFEB: transcription factor EB.

Docetaxel enhances lysosomal function through TFEB activation.

Docetaxel is an effective and commonly used chemotherapeutic drug for cancer. Autophagy has been reported to be involved in the anticancer mechanism of docetaxel. However, the effect of docetaxel on lysosomal function remains elusive. In the present study, we first found that docetaxel treatment enhances autophagic flux in different cancer cells. Moreover, docetaxel treatment activates lysosomal function and promotes its fusion with autophagosome. Second, doctaxel treatment activates TFEB (transcription factor EB), a key nuclear transcription factor in control of lysosome biogenesis and function. We found that docetaxel promotes TFEB nuclear translocation and increases its transcriptional activity while knockdown of TFEB impairs lysosomal activation by docetaxel. Thirdly, TFEB activation by docetaxel is mediated by ROS (reactive oxygen species) generation and scavenging of ROS suppresses TFEB activity and lysosomal function in docetaxel-treated cells. Finally, inhibition of lysosomal function leads to increased docetaxel-induced cell death, suggesting that lysosomal activation protects against docetaxel-mediated apoptosis. Taken together, our results provide novel insights into the regulatory mechanisms of docetaxel on lysosomes, which could facilitate the development of novel potential cancer therapeutic agents via lysosomal inhibition.

The Polyphenolic Compound Curcumin Conjugation with an Alkyne Moiety in the Process of Autophagy.

Curcumin is a hydrophobic polyphenol derived from turmeric: the rhizome of the herb Curcumalonga. Autophagy is an evolutionarily conserved process, in which cellular proteins and organelles are engulfed in autophagosome and then fuses with lysosome for degradation. Our previous study showed that Curcumin activates lysosome and induce autophagy through inhibition of AKT (protein kinase K, PKB)-mammalian target of rapamycin (mTOR) pathway. But whether Curucmin affects the fusion of autophagosome-lysosome is still not clear. Here, we used Curcumin-probe conjugation with an alkyne moiety to label mouse embryonic fibroblasts (MEFs) and found that Curcumin targets autophagy-related proteins, enhances autophagic flux and activates lysosome in cells. Moreover, Curcumin treatment promotes the fusion of autophasosome-lysosome in MEFs. Second, the enhanced fusion of autophagosome-lysosome is attributed to mTOR suppression. Third, blockage of the autophagosome-lysosome fusion leads to cell growth inhibition by Curcumin. Taken together, data from our study indicates the importance of the fusion of autophagosome-lysosome in Curcumin-induced autophagy, which may facilitate the development of Curcumin as a potential therapeutic agent for oxidative stress-related diseases.