Occupational factors and low back pain: a Mendelian randomization study.

Background: Low back pain (LBP) is a common condition and a leading cause of health function loss worldwide. This study assessed the impact of occupational factors on LBP using Mendelian Randomization (MR) method, controlling for confounding variables. Methods: Based on publicly available genome-wide association studies (GWAS), two-sample univariate and multivariate MR analyses were performed to assess the causal effect of occupational factors on LBP. We used the inverse variance weighted (IVW) method and sensitivity analyses to generate the total results for the univariate MR analysis. Furthermore, we performed multivariate MR analysis to assess the direct causal association between occupational factors and LBP after accounting for potential confounding variables. Results: The total causal effect of genetically predicted job involves heavy manual or physical work on LBP was found to be significant (IVW OR, 2.117; 95% CI, 1,288-3.479; p = 0.003). Upon adjusting for potential confounding variables, the direct effect of job involves heavy manual or physical work on LBP remained statistically significant. Similarly, the total causal effect of genetically predicted job involves mainly walking or standing on LBP was also found to be significant (IVW OR, 1.429; 95% CI, 1,035-1.975; p = 0.030). However, upon adjusting for potential confounding variables, the direct effect of job involves mainly walking or standing on LBP became insignificant. In contrast, the findings from the MR analysis indicated a lack of association between work/job satisfaction and LBP. Sensitivity analysis consistently supported these trends. Conclusion: Our results supported a causal link between job involves heavy manual or physical work and increased risk of LBP, while finding no significant associations between prolonged walking/standing at work, job satisfaction, and LBP, providing valuable insights for the development of targeted prevention and intervention strategies for LBP.

The role of maintenance therapy in the treatment of advanced urothelial cancer: a comprehensive systematic review and network meta-analysis.

Concerns increase with maintenance therapy for advanced urothelial cancer (aUC). We perform a comprehensive network meta-analysis (NMA) to investigate the efficacy and toxicities of maintenance therapy in aUC patients. Trials assessing maintenance treatment with either a continuous or a switch strategy for aUC were identified. The primary outcome was overall survival (OS), and secondary outcome was progression-free survival (PFS) and toxicities. Nine articles reporting eight trials were included. The pooled hazard ratio demonstrated that maintenance therapy significantly improved OS giving HR 0.83 (95%CI: 0.74-0.93, P = 0.0013) and PFS with HR of 0.78 (95%CI: 0.62-0.99, P = 0.05), but increased the risk of developing severe adverse events and treated-related discontinues (P < 0.05). Sub-group analysis indicated that 'switch' ICI (immune checkpoint inhibitor) maintenance therapy significantly improved OS and PFS when compared to best support care (BSC) (P < 0.05). NMA showed that chemotherapy followed by 'switch' maintenance with ICI significantly improved OS (HR 0.70, 95%CI: 0.57-0.87) when compared to BSC. 'Continuous' maintenance with ICI alone had a tendency to improve OS (HR 0.85, 95%CI: 0.71-1.01), and TA (HR0.93, 95%CI: 0.58-1.50) and vinflunine (HR 0.74, 95%CI: 0.44-1.24) was no significantly associated with a lower likelihood of disease death. Based on the analysis of the treatment ranking, 'switch' maintenance with ICI appeared as the best treatment approach. Our pooled results confirm that maintenance therapy yields a significant survival advantage for aUC patients. NMA indicates that switch maintenance with ICI is the optimum maintenance treatment for aUC and reduces mortality by about a third.

A Seven-Autophagy-Related Long Non-Coding RNA Signature Can Accurately Predict the Prognosis of Patients with Renal Cell Carcinoma.

Introduction: Introduction. Renal cell carcinoma (RCC) is a common malignant tumor worldwide, and to explore, accurate prediction models are essential to the diagnosis and treatment. Methods: In the present study, the profile expression of RCC patients for long non-coding RNAs (lncRNAs) were obtained from the database of The Cancer Genome Atlas (TCGA). The Gene Set Enrichment Analysis (GSEA) showed that the gene sets related to autophagy are significantly differentially expressed among the paired normal tissues and RCC. Multivariate and univariate Cox analyses were used to construct the gene signature related to prognosis. Receiver Operating Characteristic (ROC) dependent on the time factor and the Kaplan-Meier curves are used for evaluating identified signatures. For gene signature combination, a nomogram with associated clinical constraints was designed. Results: Multivariate and Univariate Cox analyses presented seven autophagy-related lncRNAs were significantly correlated with Overall Survival (OS) for people with RCC. Risk scores of lncRNA prognostic signature, related to autophagy helped in distinguishing the patients accurately among the low-risk and high-risk RCC based on age, sex, grade of tumor, T, M, N, and AJCC stages. The RCC condition patients, as per their signature were put into the category of low and high-risk groups, having varying prognostic outcomes. Gene signature is an independent prognosticator for OS, accurately predicting 3-5 year survival time for RCC patients from either of the two groups. GSEA revealed that high-risk scores of the prognostic seven-long non-coding signature correlate with immune-regulatory and cancer, signaling pathways, whereas a low-risk score correlates with metabolism. The quantitative reverse chain reaction of transcription-polymerase verified differential expression of seven lncRNAs autophagy-related samples. Conclusion: The results depict that seven autophagy-related lncRNA prognostic signature helps in predicting the prognosis accurately among people with RCC.

[Effects of silencing HMGB1 combined with docetaxel chemotherapy on the proliferation and apoptosis of prostate cancer cells and its action mechanism].

Objective: To investigate the effect of silencing the high-mobility group box-1 protein (HMGB1) combined with docetaxel (DTX) on the proliferation and apoptosis of PCa cells and its possible action mechanism. METHODS: The expression of HMGB1 mRNA in different PCa cell lines and normal prostatic epithelial cells was detected by RT-qPCR. The PC-3 cells were transfected with different HMGB1 small interfering RNAs (si-HMGB1, si-HMGB1-2 and si-HMGB1-3), and the silencing effect was detected. The effects of different concentrations of DTX on the proliferation of the PC-3 cells was determined by MTT. Then the PC-3 cells were randomly divided into five groups: control (conventional culture), si-HMGB1-NC (si-HMGB1-NC transfection), si-HMGB1 (si-HMGB1-3 transfection), DTX (20 nmol/L DTX), and si-HMGB1+DTX (si-HMGB1-3+20 nmol/L DTX transfection), followed by measurement of the survival rate of the cells by MTT, their apoptosis rate by flow cytometry, and the expressions of HMGB1, B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X (Bax) proteins in different groups by Western blot. RESULTS: The expression of HMGB1 mRNA in the PC-3 cells was the highest and the lowest after transfection with si-HMGB1-3. DTX inhibited the proliferation of the PC-3 cells at various concentrations. Compared with the control group, the si-HMGB1 and DTX groups showed significantly decreased A values, cell survival rates and HMGB1 and Bcl-2 expressions, but increased cell apoptosis rates and Bax expressions (P < 0.05). In comparison with the si-HMGB1 and DTX groups, the si-HMGB1+DTX group exhibited a remarkably decreased A value, cell survival rate and Bcl-2 expression, but increased cell apoptosis and Bax expression. The expression of the HMGB1 protein was markedly lower in the si-HMGB1+DTX than in the DTX group (P < 0.05). CONCLUSIONS: Silencing HMGB1 combined with DTX chemotherapy can inhibit the proliferation and promote the apoptosis of PCa cells, which may be attributed to its regulatory effect on the expressions of the Bcl-2 family-related proteins.、.

The analgesic efficacy of paravertebral block for percutaneous nephrolithotomy: A meta-analysis of randomized controlled studies.

INTRODUCTION: The analgesic efficacy of paravertebral block for percutaneous nephrolithotomy remains controversial. We conduct a systematic review and meta-analysis to explore the analgesic efficacy of paravertebral block for patients with percutaneous nephrolithotomy. METHODS: We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases, and randomized controlled trials (RCTs) assessing analgesic efficacy of paravertebral block for percutaneous nephrolithotomy are included in this meta-analysis. RESULTS: Five RCTs are included in the meta-analysis. Overall, compared with control group after percutaneous nephrolithotomy, paravertebral block is associated with the decrease in analgesic consumption (standard mean difference (Std. MD) = -1.55; 95% confidence interval (CI) = -2.18 to -0.92; P < .00001) and additional analgesics (risk ratio (RR) = 0.17; 95% CI = 0.07 to 0.44; P = .0003), prolonged time to first analgesic requirement (Std. MD = 1.51; 95% CI = 0.26 to 2.76; P = .02). There is no statistical difference of adverse events including nausea or vomiting (RR = 0.51; 95% CI = 0.11 to 2.35; P = .38), or itching (RR = 0.69; 95% CI = 0.26 to 1.81; P = .45) between 2 groups. CONCLUSIONS: Paravertebral block is effective for pain control after percutaneous nephrolithotomy.

Nesfatin-1 functions as a switch for phenotype transformation and proliferation of VSMCs in hypertensive vascular remodeling.

The phenotypic transformation from differentiated to dedifferentiated vascular smooth muscle cells (VSMCs) plays a crucial role in VSMC proliferation and vascular remodeling in many cardiovascular diseases including hypertension. Nesfatin-1, a multifunctional adipocytokine, is critically involved in the regulation of blood pressure. However, it is still largely unexplored whether nesfatin-1 is a potential candidate in VSMC phenotypic switch and proliferation in hypertension. Experiments were carried out in Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), human VSMCs and primary rat aortic VSMCs. We showed that the expression of nesfatin-1 was upregulated in media layer of the aorta in SHR and SHR-derived VSMCs. Nesfatin-1 promoted VSMC phenotypic transformation, accelerated cell cycle progression and proliferation. Knockdown of nesfatin-1 inhibited the VSMC phenotype switch from a contractile to a synthetic state, attenuated cell cycle progression and retarded VSMC proliferation in SHR-derived VSMCs. Moreover, nesfatin-1-activated PI3K/Akt/mTOR signaling was abolished by JAK/STAT inhibitor WP1066, and the increased phosphorylation levels of JAK2/STAT3 in response to nesfatin-1 were suppressed by inhibition of PI3K/Akt/mTOR in VSMCs. Pharmacological blockade of the forming feedback loop between PI3K/Akt/mTOR and JAK2/STAT3 prevented the proliferation of nesfatin-1-incubated VSMCs and primary VSMCs from SHR. Chronic intraperitoneal injection of nesfatin-1 caused severe hypertension and cardiovascular remodeling in normal rats. In contrast, silencing of nesfatin-1 gene ameliorated hypertension, phenotype switching, and vascular remodeling in the aorta of SHR. Therefore, our data identified nesfatin-1 as a key modulator in hypertension and vascular remodeling by facilitating VSMC phenotypic switching and proliferation.

Nesfatin-1 promotes VSMC migration and neointimal hyperplasia by upregulating matrix metalloproteinases and downregulating PPARγ.

The dedifferentiation, proliferation and migration of vascular smooth muscle cells (VSMCs) are essential in the progression of hypertension, atherosclerosis and intimal hyperplasia. Nesfatin-1 is a potential modulator in cardiovascular functions. However, the role of nesfatin-1 in VSMC biology has not been explored. The present study was designed to determine the regulatory role of nesfatin-1 in VSMC proliferation, migration and intimal hyperplasia after vascular injury. Herein, we demonstrated that nesfatin-1 promoted VSMC phenotype switch from a contractile to a synthetic state, stimulated VSMC proliferation and migration in vitro. At the molecular level, nesfatin-1 upregulated the protein and mRNA levels, as well as the promoter activities of matrix metalloproteinase 2 (MMP-2) and MMP-9, but downregulated peroxisome proliferator-activated receptor γ (PPARγ) levels and promoter activity in VSMCs. Blockade of MMP-2/9 or activation of PPARγ prevented the nesfatin-1-induced VSMC proliferation and migration. In vivo, knockdown of nesfatin-1 ameliorated neointima formation following rat carotid injury. Taken together, our results indicated that nesfatin-1 stimulated VSMC proliferation, migration and neointimal hyperplasia by elevating MMP2/MMP-9 levels and inhibiting PPARγ gene expression.