The potential causal relationship between BMI, T1D, urolithiasis, and hydronephrosis in European ancestry: A Mendelian randomization analysis.

Body mass index (BMI), type 1 diabetes (T1D), urolithiasis, and hydronephrosis are interrelated. Our aim was to analyze their causal relationships at the genetic level. Mendelian randomization is an instrumental variable analysis method that follows Mendel genetic law of random allocation of parental alleles to offspring. In observational studies, genetic variants are used as instrumental variables to infer causal relationships between exposure factors and study outcomes. All the genome-wide association study data in our study were publicly available and from published genome-wide association studies, UK Biobank, and FinnGen. Random-effects inverse variance weighted was the primary analysis method, with R Egger, weighted median, and weighted mode as supplementary methods. We examined heterogeneity, horizontal pleiotropy, and the influence of individual single nucleotide polymorphisms on the analysis. We further explored the causal relationships between BMI, T1D, urolithiasis, and hydronephrosis, as well as the robustness of the analysis results. Inverse variance weighted results showed genetic causal relationships between BMI (P = .034, odds ratio [OR] 95% confidence interval [CI] = 1.273 [1.019-1.589]), T1D (P = .028, OR 95% CI = 0.921 [0.855-0.991]), urolithiasis (P < .001, OR 95% CI = 1.361 [1.175-1.576]), and hydronephrosis. Sensitivity analyses confirmed the accuracy and robustness of these findings. Our results support significant causal roles of BMI, T1D, and urolithiasis in hydronephrosis, potentially offering new intervention strategies for preventing its development.

NUAK1-Mediated Phosphorylation of NADK Mitigates ROS Accumulation to Promote Osimertinib Resistance in Non-Small Cell Lung Carcinoma.

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is approved as a first-line therapy in advanced non-small cell lung carcinoma (NSCLC) patients with EGFR-activating mutations or the T790M resistance mutation. However, the efficacy of osimertinib is limited due to acquired resistance, highlighting the need to elucidate resistance mechanisms to facilitate the development of improved treatment strategies. Here, we screened for significantly upregulated genes encoding protein kinases in osimertinib-resistant NSCLC cells and identified NUAK1 as a pivotal regulator of osimertinib resistance. NUAK1 was highly expressed in osimertinib-resistant NSCLC and promoted the emergence of osimertinib resistance. Genetic or pharmacological blockade of NUAK1 restored the sensitivity of resistant NSCLC cells to osimertinib in vitro and in vivo. Mechanistically, NUAK1 directly interacted with and phosphorylated NADK at serine 64 (S64), which mitigated osimertinib-induced accumulation of reactive oxygen species (ROS) and contributed to the acquisition of osimertinib resistance in NSCLC. Furthermore, virtual drug screening identified T21195 as an inhibitor of NADK-S64 phosphorylation, and T21195 synergized with osimertinib to reverse acquired resistance by inducing ROS accumulation. Collectively, these findings highlight the role of the NUAK1-NADK axis in governing osimertinib resistance in NSCLC and indicate the potential of targeting this axis as a strategy for circumventing resistance.

Promoting reactive oxygen species accumulation to overcome tyrosine kinase inhibitor resistance in cancer.

BACKGROUND: In tumor treatment, protein tyrosine kinase inhibitors (TKIs) have been extensively utilized. However, the efficacy of TKI is significantly compromised by drug resistance. Consequently, finding an effective solution to overcome TKI resistance becomes crucial. Reactive oxygen species (ROS) are a group of highly active molecules that play important roles in targeted cancer therapy including TKI targeted therapy. In this review, we concentrate on the ROS-associated mechanisms of TKI lethality in tumors and strategies for regulating ROS to reverse TKI resistance in cancer. MAIN BODY: Elevated ROS levels often manifest during TKI therapy in cancers, potentially causing organelle damage and cell death, which are critical to the success of TKIs in eradicating cancer cells. However, it is noteworthy that cancer cells might initiate resistance pathways to shield themselves from ROS-induced damage, leading to TKI resistance. Addressing this challenge involves blocking these resistance pathways, for instance, the NRF2-KEAP1 axis and protective autophagy, to promote ROS accumulation in cells, thereby resensitizing drug-resistant cancer cells to TKIs. Additional effective approaches inducing ROS generation within drug-resistant cells and providing exogenous ROS stimulation. CONCLUSION: ROS play pivotal roles in the eradication of tumor cells by TKI. Harnessing the accumulation of ROS to overcome TKI resistance is an effective and widely applicable approach.

Prognostic roles of dysregulated METTL3 protein expression in cancers and potential anticancer value by inhibiting METTL3 function.

BACKGROUND: Many studies have demonstrated the relationship between METTL3 protein expression and clinical outcomes in various cancers and elucidated the mechanism by which METTL3 disrupts the behavior of cancer cells. Here, we attempted to define the prognostic value of METTL3 protein in patients with cancer via systematic analysis and explored the potential effect of inhibiting METTL3 using its specific inhibitor. METHODS: We searched PubMed, Embase, and the Web of Science databases for studies that elucidated the prognostic value of METTL3 protein expression in all cancer types and then calculated the pooled hazard ratios with 95% confidence intervals for the overall survival (OS) of all cancer types and subgroups. Data from The Cancer Genome Atlas dataset were used to study METTL3 mRNA expression in cancers. Further, the effects of a METTL3-specific inhibitor were studied in cancer cells via the colony formation assay, the cell proliferation assay, and apoptosis detection. RESULTS: Meta-analysis of the 33 cohorts in 32 studies (3666 patients in total) revealed that higher METTL3 protein expression indicated poor OS in the majority of cancers. Bioinformatics analysis of METTL3 mRNA expression and cancer prognosis did not show the extremely prominent prognostic value of METTL3 mRNA. Nevertheless, the METTL3-specific inhibitor attenuated cell proliferation and cell cloning formation and promoted apoptosis. CONCLUSIONS: METTL3 protein expression is associated with poor prognosis in most cancer types and could be a biomarker for OS. Further, METTL3 inhibition might be a potential treatment strategy for cancers.

G protein-coupled estrogen receptor activates PI3K/AKT/mTOR signaling to suppress ferroptosis via SREBP1/SCD1-mediated lipogenesis.

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. The sex differences in the occurrence and fatality rates of non-small cell lung cancer (NSCLC), along with its association with estrogen dependence, suggest that estrogen receptors (ERs) contribute to the development of NSCLC. However, the influence of G protein-coupled estrogen receptor (GPER1) on NSCLC remains to be determined. Escape from ferroptosis is one of the hallmarks of tumor discovered in recent years. In this context, the present study evaluated whether GPER1 promotes NSCLC progression by preventing ferroptosis, and the underlying mechanism through which GPER1 protects against ferroptosis was also explored. METHODS: The effects of GPER1 on the cytotoxicity of H2O2, the ferroptosis inducer RSL3, and Erastin were assessed using the CCK8 assay and plate cloning. Lipid peroxidation levels were measured based on the levels of MDA and BODIPY™581/591C11. GPER1 overexpression and knockdown were performed and G1 was used, and the expression of SCD1 and PI3K/AKT/mTOR signaling factors was measured. Immunofluorescence analysis and immunohistochemistry were performed on paired specimens to measure the correlation between the expression of GPER1 and SCD1 in NSCLC tissues. The effect of GPER1 on the cytotoxicity of cisplatin was measured in vitro using the CCK8 assay and in vivo using xenograft tumor models. RESULTS: GPER1 and G1 alleviated the cytotoxicity of H2O2, reduced sensitivity to RSL3, and impaired lipid peroxidation in NSCLC tissues. In addition, GPER1 and G1 promoted the protein and mRNA expression of SCD1 and the activation of PI3K/AKT/mTOR signaling. GPER1 and SCD1 expression were elevated and positively correlated in NSCLC tissues, and high GPER1 expression predicted a poor prognosis. GPER1 knockdown enhanced the antitumor activity of cisplatin in vitro and in vivo. CONCLUSION: GPER1 prevents ferroptosis in NSCLC by promoting the activation of PI3K/AKT/mTOR signaling, thereby inducing SCD1 expression. Therefore, treatments targeting GPER1 combined with cisplatin would exhibit better antitumor effects.

Immune characteristics analysis and construction of a four-gene prognostic signature for lung adenocarcinoma based on estrogen reactivity.

Lung adenocarcinoma (LUAD) is a common type of malignant tumor with poor prognosis and high mortality. In our previous studies, we found that estrogen is an important risk factor for LUAD, and different estrogen statuses can predict different prognoses. Therefore, in this study, we constructed a prognostic signature related to estrogen reactivity to determine the relationship between different estrogen reactivities and prognosis. We downloaded the LUAD dataset from The Cancer Genome Atlas (TCGA) database, calculated the estrogen reactivity of each sample, and divided them into a high-estrogen reactivity group and a low-estrogen reactivity group. The difference in overall survival between the groups was significant. We also analyzed the status of immune cell infiltration and immune checkpoint expression between the groups. We analyzed the differential gene expression between the groups and screened four key prognostic factors by the least absolute shrinkage and selection operator (LASSO) regression and univariable and multivariable Cox regression. Based on the four genes, a risk signature was established. To a certain extent, the receiver operating characteristic (ROC) curve showed the predictive ability of the risk signature, which was further verified using the GSE31210 dataset. We also determined the role of estrogen in LUAD using an orthotopic mouse model. Additionally, we developed a predictive nomogram combining the risk signature with other clinical characteristics. In conclusion, our four-gene prognostic signature based on estrogen reactivity had prognostic value and can provide new insights into the development of treatment strategies for LUAD.

Risk factor analysis for infection and bleeding after lateral decubitus percutaneous nephrolithotomy.

This study aimed to explore the risk factors for infection and bleeding after lateral decubitus percutaneous nephrolithotomy procedures to prevent their occurrence and improve surgical outcomes. A retrospective analysis was conducted on 356 patients who underwent lateral decubitus percutaneous nephrolithotomy for the treatment of kidney stones and upper ureteral stones from January 2015 to August 2022. Among them, 290 patients had complete clinical data. General clinical data, perioperative data, and stone characteristics were collected for each patient. Univariate and multivariate logistic regression analyses were performed to identify risk factors for infection and bleeding after lateral decubitus percutaneous nephrolithotomy. The postoperative infection rate after lateral decubitus percutaneous nephrolithotomy was 19.31%, and the postoperative bleeding rate was 12.07%. Independent risk factors for postoperative infection were multiple stones (P < .001), stone size (P < .001), and stone co-infection (P = .012). Independent risk factors for postoperative bleeding were multiple stones (P = .008) and stone size (P = .014). Multiple stones, stone size, and stone co-infection are independent risk factors for postoperative infection after lateral decubitus percutaneous nephrolithotomy. Multiple stones and stone size are independent risk factors for postoperative bleeding after lateral decubitus percutaneous nephrolithotomy.

ERß promoted invadopodia formation-mediated non-small cell lung cancer metastasis via the ICAM1/p-Src/p-Cortactin signaling pathway.

In a previous study, our research group observed that estrogen promotes the metastasis of non-small cell lung cancer (NSCLC) through the estrogen receptor ß (ERß). Invadopodia are key structures involved in tumor metastasis. However, it is unclear whether ERß is involved in the promotion of NSCLC metastasis through invadopodia. In our study, we used scanning electron microscopy to observe the formation of invadopodia following the overexpression of ERß and treatment with E2. In vitro experiments using multiple NSCLC cell lines demonstrated that ERß can increase the formation of invadopodia and cell invasion. Mechanistic studies revealed that ERß can upregulate the expression of ICAM1 by directly binding to estrogen-responsive elements (EREs) located on the ICAM1 promoter, which in turn can enhance the phosphorylation of Src/cortactin. We also confirmed these findings in vivo using an orthotopic lung transplantation mouse model, which validated the results obtained from the in vitro experiments. Finally, we examined the expressions of ERß and ICAM1 using immunohistochemistry in both NSCLC tissue and paired metastatic lymph nodes. The results confirmed that ERß promotes the formation of invadopodia in NSCLC cells through the ICAM1/p-Src/p-Cortactin signaling pathway.

Analysis of the Efficacy and Risk Factors for Failure of Balloon Dilation for Benign Ureteral Stricture.

This study aimed to investigate the efficacy of balloon dilation in ureteral stricture and to analyze the risk factors for the failure of balloon dilation, which will hopefully provide some reference for clinicians to develop treatment plans. We retrospectively analyzed 196 patients who underwent balloon dilation between January 2012 and August 2022, 127 of whom had complete baseline and follow-up data. General clinical data, perioperative data, balloon parameters at the time of surgery, and follow-up results were collected from the patients. Univariate and multivariate logistic regression analyses were performed for the risk factors for surgical failure in patients undergoing balloon dilatation. The success rates of balloon dilatation (n = 30) and balloon dilatation combined with endoureterotomy (n = 37) for lower ureteral stricture at 3 months, 6 months, and 1 year were 81.08%, 78.38%, and 78.38% and 90%, 90%, and 86.67%, respectively. The success rates of balloon dilation at 3 months, 6 months, and 1 year in patients with recurrent upper ureteral stricture after pyeloplasty (n = 15) and primary treatment (n = 30) were 73.33%, 60%, and 53.33% and 80%, 80%, and 73.33%, respectively. The success rates of surgery at 3 months, 6 months, and 1 year for patients with recurrence of lower ureteral stricture after ureteral reimplantation or endoureterotomy (n = 4) and primary treatment with balloon dilatation (n = 34) were 75%, 75%, and 75% and 85.29%, 79.41%, and 79.41%, respectively. Multivariate analysis of the failure of balloon dilation showed that balloon circumference and multiple ureteral strictures were risk factors for balloon dilation failure (OR = 0.143, 95% CI: 0.023-0.895, p = 0.038; OR = 1.221, 95% CI: 1.002-1.491, p = 0.05). Balloon dilation combined with endoureterotomy in lower ureteral stricture had a higher success rate than balloon dilation alone. The success rate of balloon dilation in the primary treatment of the upper and lower ureter was higher than that of balloon dilation in the secondary treatment after failed repair surgery. Balloon circumference and multiple ureteral strictures are risk factors for balloon dilation failure.

MicroRNA-21 as a diagnostic and prognostic biomarker of lung cancer: a systematic review and meta-analysis.

BACKGROUND: The relationship between microRNA-21 (miRNA-21) and pathogenesis of lung cancer is a considerable focus of research interest. However, to our knowledge, no in-depth meta-analyses based on existing evidence to ascertain the value of miRNA-21 in diagnosis and clinical prognosis of lung cancer have been documented. METHODS: We comprehensively searched all the literature pertaining to 'miRNA-21' and 'lung cancer' from four databases from the period of inception of each database until May 2020. Using specific inclusion and exclusion criteria, the literature for inclusion was identified and the necessary data extracted. RESULTS: In total, 46 articles were included in the meta-analysis, among which 31 focused on diagnostic value and 15 on prognostic value. Combined sensitivity (SEN) of miRNA-21 in diagnosis of lung cancer was 0.77 (95% confidence interval (CI): 0.72-0.81), specificity (SPE) was 0.86 (95% CI: 0.80-0.90), diagnostic odds ratio (DOR) was (95% CI: 12-33), and area under the SROC curve (AUC) was 0.87 (95% CI: 0.84-0.90). No significant correlations were observed between abnormal expression of miRNA-21 and gender, smoking habits, pathological type and clinical stage of lung cancer (P>0.05). In terms of overall survival (OS), univariate analysis (hazards ratio (HR) = 1.49, 95% CI: 1.22-1.82) revealed high expression of miRNA-21 as an influencing factor for lung cancer. MiRNA-21 was confirmed as an independent risk factor for poor prognosis in multivariate analysis (HR = 1.65, 95% CI: 1.24-2.19). CONCLUSION: MiRNA-21 has potential clinical value in the diagnosis and prognosis of lung cancer and may serve as an effective diagnostic marker and therapeutic target in the future.