White matter fiber integrity and structural brain network topology: implications for balance function in postischemic stroke patients.

Previous studies have suggested that ischemic stroke can result in white matter fiber injury and modifications in the structural brain network. However, the relationship with balance function scores remains insufficiently explored. Therefore, this study aims to explore the alterations in the microstructural properties of brain white matter and the topological characteristics of the structural brain network in postischemic stroke patients and their potential correlations with balance function. We enrolled 21 postischemic stroke patients and 21 age, sex, and education-matched healthy controls (HC). All participants underwent balance function assessment and brain diffusion tensor imaging. Tract-based spatial statistics (TBSS) were used to compare the fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity of white matter fibers between the two groups. The white matter structural brain network was constructed based on the automated anatomical labeling atlas, and we conducted a graph theory-based analysis of its topological properties, including global network properties and local node properties. Additionally, the correlation between the significant structural differences and balance function score was analyzed. The TBSS results showed that in comparison to the HC, postischemic stroke patients exhibited extensive damage to their whole-brain white matter fiber tracts (P < 0.05). Graph theory analysis showed that in comparison to the HC, postischemic stroke patients exhibited statistically significant reductions in the values of global efficiency, local efficiency, and clustering coefficient, as well as an increase in characteristic path length (P < 0.05). In addition, the degree centrality and nodal efficiency of some nodes in postischemic stroke patients were significantly reduced (P < 0.05). The white matter fibers of the entire brain in postischemic stroke patients are extensively damaged, and the topological properties of the structural brain network are altered, which are closely related to balance function. This study is helpful in further understanding the neural mechanism of balance function after ischemic stroke from the white matter fiber and structural brain network topological properties.

Proteomic analysis of mitochondria associated membranes in renal ischemic reperfusion injury.

BACKGROUND: The mitochondria and endoplasmic reticulum (ER) communicate via contact sites known as mitochondria associated membranes (MAMs). Many important cellular functions such as bioenergetics, mitophagy, apoptosis, and calcium signaling are regulated by MAMs, which are thought to be closely related to ischemic reperfusion injury (IRI). However, there exists a gap in systematic proteomic research addressing the relationship between these cellular processes. METHODS: A 4D label free mass spectrometry-based proteomic analysis of mitochondria associated membranes (MAMs) from the human renal proximal tubular epithelial cell line (HK-2 cells) was conducted under both normal (N) and hypoxia/reperfusion (HR) conditions. Subsequent differential proteins analysis aimed to characterize disease-relevant signaling molecules. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was applied to total proteins and differentially expressed proteins, encompassing Biological Process (BP), Cell Component (CC), Molecular Function (MF), and KEGG pathways. Further, Protein-Protein Interaction Network (PPI) exploration was carried out, leading to the identification of hub genes from differentially expressed proteins. Notably, Mitofusion 2 (MFN2) and BCL2/Adenovirus E1B 19-kDa interacting protein 3(BNIP3) were identified and subsequently validated both in vitro and in vivo. Finally, the impact of MFN2 on MAMs during hypoxia/reoxygenation was explored through regulation of gene expression. Subsequently, a comparative proteomics analysis was conducted between OE-MFN2 and normal HK-2 cells, providing further insights into the underlying mechanisms. RESULTS: A total of 4489 proteins were identified, with 3531 successfully quantified. GO/KEGG analysis revealed that MAM proteins were primarily associated with mitochondrial function and energy metabolism. Differential analysis between the two groups showed that 688 proteins in HR HK-2 cells exhibited significant changes in expression level with P-value < 0.05 and HR/N > 1.5 or HR/N < 0.66 set as the threshold criteria. Enrichment analysis of differentially expressed proteins unveiled biological processes such as mRNA splicing, apoptosis regulation, and cell division, while molecular functions were predominantly associated with energy metabolic activity. These proteins play key roles in the cellular responses during HR, offering insights into the IRI mechanisms and potential therapeutic targets. The validation of hub genes MFN2 and BNIP3 both in vitro and vivo was consistent with the proteomic findings. MFN2 demonstrated a protective role in maintaining the integrity of mitochondria associated membranes (MAMs) and mitigating mitochondrial damage following hypoxia/reoxygenation injury, this protective effect may be associated with the activation of the PI3K/AKT pathway. CONCLUSIONS: The proteins located in mitochondria associated membranes (MAMs) are implicated in crucial roles during renal ischemic reperfusion injury (IRI), with MFN2 playing a pivotal regulatory role in this context.

Comparative efficacy of different noninvasive brain stimulation protocols on upper-extremity motor function and activities of daily living after stroke: a systematic review and network meta-analysis.

The objectives of the study were to systematically evaluate the rehabilitation effect of noninvasive brain stimulation (NIBS) on upper extremity motor function and activities of daily living in stroke patients and to prioritize various stimulation protocols for reliable evidence-based medical recommendations in patients with upper extremity motor dysfunction after stroke. Web of Science, PubMed, Embase, Cochrane Library, CNKI, Wanfang, VIP, and CBM were searched to collect all randomized controlled trials (RCTs) of NIBS to improve upper extremity motor function in stroke patients. The retrieval time was from the establishment of all databases to May 2023. According to the Cochrane system evaluation manual, the quality of the included studies was evaluated, and the data were extracted. Statistical analysis was carried out by using RevMan 5.3, R 4.3.0, and Stata 17.0 software. Finally, 94 RCTs were included, with a total of 5546 patients. Meta-analysis showed that NIBS improved the Fugl-Meyer assessment (FMA) score (mean difference (MD) = 6.51, 95% CI 6.20 ~ 6.82, P < 0.05), MBI score (MD = 7.69, 95% CI 6.57 ~ 8.81, P < 0.05), ARAT score (MD = 5.06, 95% CI 3.85 ~ 6.27, P < 0.05), and motor evoked potential (MEP) amplitude. The modified Ashworth scale score (MD = - 0.37, 95% CI - 0.60 to - 0.14, P < 0.05), National Institutes of Health Stroke Scale score (MD = - 2.17, 95% CI - 3.32 to - 1.11, P < 0.05), incubation period of MEP (MD = - 0.72, 95% CI - 1.06 to - 0.38, P < 0.05), and central motor conduction time (MD = - 0.90, 95% CI - 1.29 to - 0.50, P < 0.05) were decreased in stroke patients. Network meta-analysis showed that the order of interventions in improving FMA scores from high to low was anodal-transcranial direct current stimulation (tDCS) (surface under the cumulative ranking curve (SUCRA) = 83.7%) > cathodal-tDCS (SUCRA = 80.2%) > high-frequency (HF)-repetitive transcranial magnetic stimulation (rTMS) (SUCRA = 68.5%) > low-frequency (LF)-rTMS (SUCRA = 66.5%) > continuous theta burst stimulation (cTBS) (SUCRA = 54.2%) > bilateral-tDCS (SUCRA = 45.2%) > intermittent theta burst stimulation (iTBS) (SUCRA = 34.1%) > sham-NIBS (SUCRA = 16.0%) > CR (SUCRA = 1.6%). In terms of improving MBI scores, the order from high to low was anodal-tDCS (SUCRA = 88.7%) > cathodal-tDCS (SUCRA = 85.4%) > HF-rTMS (SUCRA = 63.4%) > bilateral-tDCS (SUCRA = 56.0%) > LF-rTMS (SUCRA = 54.2%) > iTBS (SUCRA = 32.4%) > sham-NIBS (SUCRA = 13.8%) > CR (SUCRA = 6.1%). NIBS can effectively improve upper extremity motor function and activities of daily living after stroke. Among the various NIBS protocols, anodal-tDCS demonstrated the most significant intervention effect, followed by cathodal-tDCS and HF-rTMS.

Contrast-enhanced ultrasound versus conventional ultrasound-guided percutaneous nephrolithotomy in patients with a non-dilated collecting system: results of a pooled analysis of randomized controlled trials.

BACKGROUND: Contrast-enhanced ultrasound in percutaneous nephrolithotomy (CEUS-PCNL) is an economical and practical technique for the treatment of patients with renal stones without significant collecting system dilatation. The aim of this systematic review is to compare the safety and efficacy of CEUS-PCNL and conventional ultrasound (US)-guided (US-PCNL) treatment of patients with renal calculi without significant hydronephrosis. METHODS: This review was conducted with strict adherence to the PRISMA guidelines. Comparative studies on CEUS-PCNL and US-PCNL published in PubMed, SinoMed, Google Scholar, Embase, and Web of science until March 1, 2023, were systematically searched. RevMan 5.1 software was used for meta-analysis. Pooled odds ratios (ORs), weight mean differences (WMDs) and standard mean differences (SMDs) with 95% confidence intervals (CIs) were calculated using the fixed-effects or random-effects model. Publication bias was evaluated using funnel plots. RESULTS: Four randomized controlled trials involving 334 patients (168 with CEUS-guided PCNL and 166 with US-guided PCNL) were identified. There was no statistically significant difference between CEUS-guided PCNL and US-guided PCNL in terms of the operation time (SMD: - 0.14; 95% CI - 0.35 to 0.08; p = 0.21), minor complications (p = 0.48), major complications (p = 0.28) and overall complications (p = 0.25). However, CEUS-guided PCNL had a higher stone-free rate (OR: 2.22; 95% CI 1.2 to 4.12; p = 0.01), higher success rate of single-needle punctures (OR:3.29; 95% CI 1.82 to 5.95; p < 0.0001), shorter puncture time (SMD: - 1.35; 95% CI - 1.9 to - 0.79; p < 0.00001), shorter hospital stay (SMD: - 0.34; 95% CI - 0.55 to - 0.12; p = 0.002) and lesser hemoglobin loss (SMD: - 0.83; 95% CI - 1.06 to - 0.61; p < 0.00001) as compared with conventional US-guided PCNL. CONCLUSIONS: According to almost all pooled data, CEUS-guided PCNL is superior to US-guided PCNL in terms of the perioperative outcomes. However, many rigorous clinical randomized controlled studies are required to obtain more accurate results. Registration The study protocol was registered with PROSPERO (CRD42022367060).

Inflammatory bowel disease and bladder cancer risk: based on a Mendelian randomization study.

BACKGROUND: Prior epidemiological observational studies have duly documented a correlative link between inflammatory bowel disease (IBD) and bladder cancer (BC); however, the establishment of a definitive causal relationship has remained elusive. The principal objective of this meticulous investigation was to rigorously evaluate the causal nexus between IBD and BC, employing the robust methodology of Mendelian randomization (MR) analysis. METHODS: We meticulously performed both univariate and multivariate Mendelian randomization (MVMR) analyses employing publicly accessible genome-wide association study (GWAS) data. The central approach employed for our investigations was inverse variance weighting (IVW) method, while diligently scrutinizing potential sources of heterogeneity and horizontal pleiotropy via the rigorous utilization of Cochran's Q test, the MR-PRESSO method, and MR-Egger. RESULTS: In the univariate MR analysis, no causal link was observed between genetic prediction of IBD and BC. Furthermore, both Crohn's disease (CD) and ulcerative colitis (UC) showed no causal association with BC. The consistent association between CD and UC in the MVMR analysis supports this finding. CONCLUSION: This study found no genetic basis for the causative association of IBD and BC. It is crucial to emphasize that further comprehensive investigations are warranted to delve into the intricate underlying mechanisms that may contribute to these associations.

Oncologic and perioperative outcomes of laparoscopic versus open radical nephrectomy for the treatment of renal tumor (> 7 cm): a systematic review and pooled analysis of comparative outcomes.

OBJECTIVE: Systematic evaluation of the effectiveness and safety of laparoscopic radical nephrectomy (LRN) for renal tumor (>7 cm). METHODS: The databases PubMed, Scopus, SinoMed, ScienceDirect, and Google Scholar were systematically searched for trials up to November 2022. The pooled results were evaluated by weighted mean difference (WMD), odds ratio (OR), and hazard ratio (HR). RESULTS: This meta-analysis (18 trials) demonstrated that compared to open radical nephrectomy (ORN), LRN had a longer operative time (OT) (WMD=15.99, 95% CI: 6.74 to 25.24, p = 0.0007), lower estimated blood loss (EBL) (WMD = -237.07, 95% CI: -300.02 to -174.12, p < 0.00001), lower transfusion rates (OR = 0.37, 95% CI: 0.24 to 0.55, p < 0.00001), and shorter length of stay (LOS) (WMD = -2.95, 95% CI: -3.86 to -2.03, p < 0.00001). No statistically relevant differences were found in overall survival (OS) (HR = 1.04, 95% CI: 0.81 to 1.35, p = 0.76), cancer-specific survival (CSS) (HR = 1.28, 95% CI: 0.97 to 1.68, p = 0.08), progression-free survival (PFS) (HR = 1.20, 95% CI 0.97 to 1.48, p = 0.1), recurrence-free survival (RFS) (OR = 1.27, 95% CI: 0.89 to 1.81, p = 0.56), local recurrence rate (OR = 0.85, 95% CI: 0.42 to 1.71, p = 0.65), and intraoperative and postoperative complications. CONCLUSION: For patients with renal tumors (> 7 cm), LRN has specific perioperative advantages over ORN (LOS, EBL, and transfusion rates). However, the OT was prolonged in the LRN group. In addition, no differences in complication or oncological outcomes (OS, CSS, PFS, RFS, and local recurrence rate) were reported. TRIAL REGISTRATION: PROSPERO CRD42022367114.

Perioperative and oncologic outcomes of transperitoneal versus retroperitoneal laparoscopic nephroureterectomy for upper urinary tract urothelial carcinoma: a systematic review and pooled analysis of comparative outcomes.

BACKGROUND: The debate on whether to choose a transperitoneal (TP) or retroperitoneal (RP) approach for treating upper urinary tract urothelial carcinoma (UTUC) with laparoscopic surgery has been drawing attention. This study aimed to systematically review and meta-analyze the existing evidence regarding oncologic and perioperative outcomes of transperitoneal laparoscopic radical nephroureterectomy (TLNU) and retroperitoneal laparoscopic radical nephroureterectomy (RLNU) in managing UTUC. METHODS: A comprehensive literature search was conducted using PubMed, Scopus, Embase, and Google Scholar for identifying randomized controlled trials (RCTs) and observational studies that evaluated the outcomes of TLNU and RLNU for UTUC. Continuous variables were represented by weighted mean difference (WMD) and standard mean difference (SMD), while binary variables were represented by odds ratio (OR), with 95% confidence intervals (CIs). The quality was assessed using the Newcastle-Ottawa scale. A sensitivity analysis was performed to evaluate the robustness of the estimates. RESULT: Six observational studies were incorporated into this meta-analysis. The overall TLNU was associated with significantly shorter operating time (WMD - 19.85; 95% CI - 38.03 to - 1.68; P = 0.03); longer recovery time of intestinal function (SMD 0.46; 95% CI 0.08 to 0.84; P = 0.02). However, the terms of estimated blood loss (WMD - 5.72; 95% CI - 19.6 to - 8.15; P = 0.42); length of stay (WMD - 0.35; 95% CI - 1.61 to 0.91; P = 0.59), visual analog pain scale (WMD - 0.38; 95% CI - 0.99 to 0.84; P = 0.22); drainage duration (WMD - 0.22; 95% CI - 0.61 to 0.17; P = 0.26); overall complication rates (OR 1.24; 95% CI 0.58 to 2.63; P = 0.58); local recurrence rate (OR 0.6; 95% CI 0.3 to 1.21; P = 0.16); distant metastasis (OR 0.94; 95% CI 0.04 to 20.77; P = 0.97); 1-year overall survival (OS) (OR 0.45; 95% CI 0.1 to 2.01; P = 0.3) showed no difference between TLNU and RLUN. CONCLUSION: TLNU provides similar surgical outcomes and oncologic results compared to RLUN; however, TLNU has a shorter procedure time and prolonged intestinal function recovery time. Due to the heterogeneity among the studies, randomized clinical trials with follow-ups in the long term are required to obtain more definite results. TRIAL REGISTRATION: www.crd.york.ac.uk/prospero/ , identifier CRD42023388554.

Perioperative and oncologic outcomes of transperitoneal versus retroperitoneal laparoscopic radical nephrectomy for large-volume renal carcinoma (> 7 cm): a systematic review and pooled analysis of comparative outcomes.

BACKGROUND: Recently, there has been a significant amount of debate concerning the question of whether laparoscopic surgery should be performed transperitoneally or retroperitoneally for treating large renal tumors. AIM: The purpose of this research is to conduct a comprehensive review and meta-analysis of the previous research on the safety and efficacy of transperitoneal laparoscopic radical nephrectomy (TLRN) and retroperitoneal laparoscopic radical nephrectomy (RLRN) in the treatment of large-volume renal malignancies. METHODS: An extensive search of the scientific literature was carried out utilizing PubMed, Scopus, Embase, SinoMed, and Google Scholar in order to locate randomized controlled trials (RCTs) and prospective and retrospective studies that compared the effectiveness of RLRN versus TLRN in the treatment of for large renal malignancies. For the purpose of comparing the oncologic and perioperative outcomes of the two techniques, data were taken from the research studies that were included and pooled together. RESULTS: A total of 14 studies (five RCTs and nine retrospective studies) were incorporated into this meta-analysis. The overall RLRN had an association with significantly shorter operating time (OT) (MD [mean difference]: - 26.57; 95% CI [confidence interval]: - 33.39 to - 19.75; p < 0.00001); less estimated blood loss (EBL) (MD: - 20.55; CI: - 32.86 to - 8.23; p = 0.001); faster postoperative intestinal exhaust (MD: - 0.65; CI: - 0.95 to - 0.36; p < 0.00001). The terms of length of stay (LOS) (p = 0.26), blood transfusion (p = 0.26), conversion rate (p = 0.26), intraoperative complications (p = 0.5), postoperative complications (p = 0.18), local recurrence rate (p = 0.56), positive surgical margin (PSM) (p = 0.45), and distant recurrence rate (p = 0.7) did not show any differences. CONCLUSIONS: RLRN provides surgical and oncologic results similar to TLRN, with potential advantages regarding shorter OT, EBL, and postoperative intestinal exhaust. Due to the high heterogeneity among the studies, long-term randomized clinical trials are required to obtain more definitive results.

Narrative Review of Noninvasive Brain Stimulation in Stroke Rehabilitation.

Stroke is a disease with a high incidence and disability rate, resulting in changes in neural network and corticoid-subcortical excitability and various functional disabilities. The aim of the present study was to discuss the current status of research and limitations and potential direction in the application of noninvasive brain stimulation (NIBS) on post-stroke patients. This literature review focused on clinical studies and reviews. Literature retrieval was conducted in PubMed, Cochrane, Scopus, and CNKI, using the following keywords: Repeated transcranial magnetic stimulation, Transcranial direct current stimulation, Transcranial alternating current stimulation, Transcranial alternating current stimulation, Transcranial focused ultrasound, Noninvasive vagus nerve stimulation, Stroke, and Rehabilitation. We selected 200 relevant publications from 1985 to 2022. An overview of recent research on the use of NIBS on post-stroke patients, including its mechanism, therapeutic parameters, effects, and safety, is presented. It was found that NIBS has positive therapeutic effects on dysfunctions of motor, sensory, cognitive, speech, swallowing, and depression after stroke, but standardized stimulus programs are still lacking. The literature suggests that rTMS and tDCS are more beneficial to post-stroke patients, while tFUS and tVNS are currently less studied for post-stroke rehabilitation, but are also potential interventions.

Cytogenetic relationships among Citrullus species in comparison with some genera of the tribe Benincaseae (Cucurbitaceae) as inferred from rDNA distribution patterns.

BACKGROUND: Comparative mapping of 5S and 45S rDNA by fluorescent in situ hybridization (FISH) technique is an excellent tool to determine cytogenetic relationships among closely related species. RESULTS: In this study, the number and position of 5S and 45S rDNA loci in all Citrullus species and subspecies were determined. The cultivated watermelon (C. lanatus subsp. vulgaris), C. lanatus subsp. mucosospermus, C. colocynthis and C. naudinianus (or Acanthosicyos naudinianus) had two 45S rDNA loci and one 5S rDNA locus which was located syntenic to one of the 45S rDNA loci. C. ecirrhosus and C. lanatus subsp. lanatus had one 45S rDNA locus and two 5S rDNA loci, each located on a different chromosome. C. rehmii had one 5S and one 45S rDNA locus positioned on different chromosomes. The distribution of 5S and 45S rDNA in several species belonging to other genera in Benincaseae tribe was also investigated. The distribution pattern of rDNAs showed a great difference among these species. CONCLUSIONS: The present study confirmed evolutionary closeness among cultivated watermelon (C. lanatus subsp. vulgaris), C. lanatus subsp. mucosospermus and C. colocynthis. Our result also supported that C. lanatus subsp. lanatus was not a wild form of the cultivated watermelon instead was a separate crop species. In addition, present cytogenetic analysis suggested that A. naudinianus was more closely related to Cucumis than to Citrullus or Acanthosicyos, but with a unique position and may be a link bridge between the Citrullus and the Cucumis.

Sirolimus induces apoptosis and reverses multidrug resistance in human osteosarcoma cells in vitro via increasing microRNA-34b expression.

AIM: Multi-drug resistance poses a critical bottleneck in chemotherapy. Given the up-regulation of mTOR pathway in many chemoresistant cancers, we examined whether sirolimus (rapamycin), a first generation mTOR inhibitor, might induce human osteosarcoma (OS) cell apoptosis and increase the sensitivity of OS cells to anticancer drugs in vitro. METHODS: Human OS cell line MG63/ADM was treated with sirolimus alone or in combination with doxorubicin (ADM), gemcitabine (GEM) or methotrexate (MTX). Cell proliferation and apoptosis were detected using CCK-8 assay and flow cytometry, respectively. MiRNAs in the cells were analyzed with miRNA microarray. The targets of miR-34b were determined based on TargetScan analysis and luciferase reporter assays. The expression of relevant mRNA and proteins was measured using qRT-PCR and Western blotting. MiR-34, PAK1 and ABCB1 levels in 40 tissue samples of OS patients were analyzed using qRT-PCR and in situ hybridization assays. RESULTS: Sirolimus (1-100 nmol/L) dose-dependently suppressed the cell proliferation (IC50=23.97 nmol/L) and induced apoptosis. Sirolimus (10 nmol/L) significantly sensitized the cells to anticancer drugs, leading to decreased IC50 values of ADM, GEM and MTX (from 25.48, 621.41 and 21.72 µmol/L to 4.93, 73.92 and 6.77 µmol/L, respectively). Treatment of with sirolimus increased miR-34b levels by a factor of 7.5 in the cells. Upregulation of miR-34b also induced apoptosis and increased the sensitivity of the cells to the anticancer drugs, whereas transfection with miR-34b-AMO, an inhibitor of miR-34b, reversed the anti-proliferation effect of sirolimus. Two key regulators of cell cycle, apoptosis and multiple drug resistance, PAK1 and ABCB1, were demonstrated to be the direct targets of miR-34b. In 40 tissue samples of OS patients, significantly higher miR-34 ISH score and lower PAK5 and ABCB1 scores were detected in the chemo-sensitive group. CONCLUSION: Sirolimus increases the sensitivity of human OS cells to anticancer drugs in vitro by up-regulating miR-34b interacting with PAK1 and ABCB1. A low miR-34 level is an indicator of poor prognosis in OS patients.

Perioperative and oncological outcomes of robot-assisted laparoscopic partial nephrectomy for cystic and solid renal masses: Evidence from controlled trials.

To evaluate the outcomes of robot-assisted partial nephrectomy (RAPN) for solid and cystic renal tumors. We systematically searched the Cochrane Library, PubMed, EMBASE, and Scopus databases up to March 2023. Review Manager 5.4 performed a pooled analysis of the data for random effects. Besides, sensitivity and subgroup analyses to explore heterogeneity, Newcastle-Ottawa scale, and GRADE to evaluate study quality and level of evidence. Five observational studies comprising 1353 patients (Cystic tumor: 183; Solid tumor: 1083) were included in this study. Compared to solid masses, cystic masses were associated with fewer major complications (odds ratio [OR] = 2.2; 95% confidence intervals [CI] = 1.17 to 4.13; p = 0.01). Additionally, no significant differences were observed between the two groups in terms of operative time, warm ischemia time, blood loss, hospital stay, intraoperative complications, postoperative complications, transfusion rate, postoperative estimated glomerular filtration rate (eGFR), eGFR preservation, positive surgical margin (PSM), recurrence, overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS) and trifecta achievement. RAPN can be performed in cystic renal tumors with perioperative, functional, and oncologic outcomes like those achievable in solid tumors. However, our findings need further validation in a large-sample prospective randomized study.

Immunologic Crosstalk of Endoplasmic Reticulum Stress Signaling in Bladder Cancer.

Bladder cancer (BC) is a common malignant tumor of the urinary system. While current approaches involving adjuvant chemotherapy, radiotherapy, and immunotherapy have shown significant progress in BC treatment, challenges, such as recurrence and drug resistance, persist, especially in the case of muscle-invasive bladder cancer (MIBC). This is mainly due to the lack of pre-existing immune response cells in the tumor immune microenvironment. Micro-environmental changes (such as hypoxia and under-nutrition) can cause the aggregation of unfolded and misfolded proteins in the lumen, which induces endoplasmic reticulum (ER) stress. ER stress and its downstream signaling pathways are closely related to immunogenicity and tumor drug resistance. ER stress plays a pivotal role in a spectrum of processes within immune cells and the progression of BC cells, encompassing cell proliferation, autophagy, apoptosis, and resistance to therapies. Recent studies have increasingly recognized the potential of natural compounds to exhibit anti-BC properties through ER stress induction. Still, the efficacy of these natural compounds remains less than that of immune checkpoint inhibitors (ICIs). Currently, the ER stress-mediated immunogenic cell death (ICD) pathway is more encouraging, which can enhance ICI responses by mediating immune stemness. This article provides an overview of the recent developments in understanding how ER stress influences tumor immunity and its implications for BC. Targeting this pathway may soon emerge as a compelling therapeutic strategy for BC.

Causal relationship between gut microbiota and prostate cancer contributes to the gut-prostate axis: insights from a Mendelian randomization study.

BACKGROUND: Changes in gut microbiota abundance have been linked to prostate cancer development. However, the causality of the gut-prostate axis remains unclear. METHODS: The genome-wide association study (GWAS) data for gut microbiota sourced from MiBioGen (n = 14,306), alongside prostate cancer summary data from PRACTICAL (n = 140,254) and FinnGen Consortium (n = 133,164). Inverse-variance-weighted (IVW) was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl), after diligently scrutinizing potential sources of heterogeneity and horizontal pleiotropy via the rigorous utilization of Cochran's Q test, the MR-PRESSO method, and MR-Egger. We used meta-analysis methods in random effects to combine the Mendelian randomization (MR) estimates from the two sources. RESULTS: The pooled analyses of MR results show that genus Eubacterium fissicatena (OR = 1.07, 95% CI 1.01 to 1.13, P = 0.011) and genus Odoribacter (OR = 1.14, 95% CI 1.01 to 1.27, P = 0.025) were positively associated with prostate cancer. However, genus Adlercreutzia (OR = 0.89, 95% CI 0.83 to 0.96, P = 0.002), Roseburia (OR = 0.90, 95% CI 0.83 to 0.99, P = 0.03), Holdemania (OR = 0.92, 95% CI 0.86 to 0.97, P = 0.005), Flavonifractor (OR = 0.85, 95% CI 0.74 to 0.98, P = 0.024) and Allisonella (OR = 0.93, 95% CI 0.89 to 0.98, P = 0.011) seems to be a protective factor for prostate cancer. Sensitivity analysis found no significant heterogeneity, horizontal pleiotropy, or reverse causal links in all causal associations. CONCLUSION: This MR study lends support to a causal relationship between genetically predicted gut microbiota and prostate cancer. Research on the gut-prostate axis, along with further multi-omics analyses, holds significant implications for the prevention and treatment of prostate cancer.

Oral chemotherapy versus observation alone in nasopharyngeal carcinoma patients with persistently detected circulating cell-free Epstein-Barr virus DNA during follow-up.

AIM: Despite the high risk of tumor recurrence, patients with nasopharyngeal carcinoma (NPC) with persistently (at least twice) detected circulating cell-free Epstein-Barr virus (EBV) DNA levels during follow-up are routinely recommended to keep observation. For these patients, whether administering more aggressive treatment could improve survival outcomes remains unknown. MATERIALS AND METHODS: We retrospectively included 431 patients with nonmetastatic NPC with persistently detected EBV DNA during follow-up, who do not have clinical or imaging evidence of recurrence. Among these patients, 79 were administered oral chemotherapy, and the remaining 352 underwent observation alone. Baseline characteristics were balanced with propensity score matching (PSM) analysis. The primary endpoint was modified disease-free survival (mDFS), defined as time from detectable EBV DNA result to tumor recurrence or death. The secondary endpoints were disease-free survival (DFS) and overall survival (OS). RESULTS: One-to-three PSM resulted in 251 eligible patients (oral chemotherapy group, 73; observation group, 178). In the matched cohort, the oral chemotherapy group had higher median mDFS (12.9 months [95 % confidence interval [CI] 9.6-16.3] vs. 6.8 months [95 % CI 5.8-7.8], p = 0.009) and DFS (24.1 months [95 % CI 18.5-29.7] vs. 16.7 months [95 % CI 14.4-19.1], p = 0.035) than the observation group. The median OS was numerically higher in the oral chemotherapy group than in the observation group (57.9 months [95 % CI 42.5-73.3] vs. 50.8 months [95 % CI 39.7-61.9], p = 0.71). A consistent benefit favoring oral chemotherapy was observed for mDFS in all subgroups analyses for male, <45 years, stage III-IVa disease, pretreatment EBV DNA load ≥ 4,000 copies/mL, no induction chemotherapy, or a detectable EBV DNA load ≥ 1,200 copies/mL. After adjusting for other confounders in the multivariate analysis, oral chemotherapy remained a significantly favorable factor for both mDFS (hazard ratio [HR] 0.67, 95 % CI 0.50-0.89; p = 0.006) and DFS (HR 0.68, 95 % CI 0.51-0.91; p = 0.01), but not a significant factor for OS (HR 0.89, 95 % CI 0.62-1.27; p = 0.52). CONCLUSIONS: In patients with NPC having persistently detected EBV DNA levels but without clinical or imaging evidence of recurrence during follow-up, oral chemotherapy significantly prolongs mDFS and DFS. Employing oral chemotherapy as a more aggressive treatment option, as opposed to mere observation, could potentially benefit these patients, although further prospective validation is necessitated.

Reduced-Volume Irradiation of Uninvolved Neck in Patients With Nasopharyngeal Cancer: Updated Results From an Open-Label, Noninferiority, Multicenter, Randomized Phase III Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported comparable 3-year regional relapse-free survival (RRFS) using elective upper-neck irradiation (UNI) in N0-1 nasopharyngeal carcinoma (NPC) compared with standard whole-neck irradiation (WNI). Here, we present the prespecified 5-year overall survival (OS), RRFS, late toxicity, and additional analyses. In this randomized trial, patients received UNI (n = 224) or WNI (n = 222) for an uninvolved neck. After a median follow-up of 74 months, the UNI and WNI groups had similar 5-year OS (95.9% v 93.1%, hazard ratio [HR], 0.63 [95% CI, 0.30 to 1.35]; P = .24) and RRFS (95.0% v 94.9%, HR, 0.96 [95% CI, 0.43 to 2.13]; P = .91) rates. The 5-year disease-free survivors in the UNI group had a lower frequency of hypothyroidism (34% v 48%; P = .004), neck tissue damage (29% v 46%; P < .001), dysphagia (14% v 27%; P = .002), and lower-neck common carotid artery stenosis (15% v 26%; P = .043). The UNI group had higher postradiotherapy circulating lymphocyte counts than the WNI group (median: 400 cells/µL v 335 cells/µL, P = .007). In conclusion, these updated data confirmed that UNI of the uninvolved neck is a standard of care in N0-1 NPC, providing outstanding efficacy and reduced long-term toxicity, and might retain more immune function.

Set9, NF-κB, and microRNA-21 mediate berberine-induced apoptosis of human multiple myeloma cells.

AIM: To investigate the mechanisms by which berberine suppressed the proliferation of human multiple myeloma cells. METHODS: Human U266 multiple myeloma cell line was tested. Cell proliferation, apoptosis, ultramicrostructure and secretion function were examined using Cell Counting Kit-8 (CCK8), flow cytometry (FCM), electron and fluorescence microscopy, as well as ELISA assay. The microRNAs (miRs) and transcription factors in U266 cells were detected using arrays and verified by qRT-PCR. EMSA and luciferase assays were used to verify the p65-dependent transactivation of miR-21 gene. RESULTS: Treatment of U266 cells with berberine (40-160 µmol/L) suppressed cell proliferation and IL-6 secretion in dose- and time-dependent manners. Meanwhile, berberine dose-dependently induced ROS generation, G(2)/M phase arrest and apoptosis in U266 cells, and decreased the levels of miR-21 and Bcl-2. Overexpression of miR-21 counteracted berberine-induced suppression of cell proliferation and IL-6 secretion. In U266 cells treated with berberine (80 µmol/L), the activity of NF-κB was decreased by approximately 50%, followed by significant reduction of miR-21 level. berberine (80-160 µmol/L) increased the level of Set9 (lysine methyltransferase) by more than 2-fold, caused methylation of the RelA subunit, which inhibited NF-κB nuclear translocation and miR-21 transcription. In U266 cells treated with berberine (80 µmol/L), knockdown of Set9 with siRNAs significantly increased NF-κB protein level accompanying with a partial recovery of proliferation. CONCLUSION: In U266 cells, berberine suppresses NF-κB nuclear translocation via Set9-mediated lysine methylation, leads to decrease in the levels miR21 and Bcl-2, which induces ROS generation and apoptosis.

Laparoscopic simple prostatectomy versus robot-assisted simple prostatectomy for large benign prostatic hyperplasia: a systematic review and meta-analysis of comparative trials.

Laparoscopic simple prostatectomy (LSP) and robot-assisted simple prostatectomy (RASP) are important approaches for large benign prostatic hyperplasia (BPH), though it is still unclear which is superior. This study aimed to perform a pooled analysis to compare the safety and efficacy profiles of LSP and RASP. We systematically searched the databases of Science, PubMed, Embase, Web of Science, and Cochrane Library database for randomized controlled trials (RCTs) and non-RCTs, comparing LSP to RASP. The principal outcomes included perioperative, functional and complications variables. The results are presented as odds ratio (OR) or weighted mean difference (WMD) with 95% confidence intervals (CI) of dichotomous and continuous variables. Five comparative trials involving 1928 patients were included. RASP demonstrated a shorter length of hospital stay compared to LSP (WMD 1.20 days, 95% CI 0.09, 2.32; p = 0.03). However, there was no difference between the two groups regarding operative time, estimated blood loss, catheterization time and complications. Moreover, RASP had a higher maximum flow rate (Qmax) (WMD - 2.15 mL/s, 95% CI - 3.75, - 0.55; p = 0.0009) and comparable international prostate symptom score (IPSS) and sexual health inventory (SHIM) in men with LSP. The results of this study demonstrated that RASP offered comparable efficacy and safety to LSP, while maintaining a superior perioperative and functional profile. However, treatment selection should also be based on the availability and experience of the operator.

Perioperative and oncologic outcomes of single-port versus conventional robotic-assisted partial nephrectomy: an evidence-based analysis of comparative outcomes.

This study aims to evaluate the effectiveness and safety between single-port robotic-assisted partial nephrectomy (da Vinci SP system) with conventional robotic-assisted partial nephrectomy (da Vinci Si or Xi system). We systematically searched PubMed, Science Embase, Web of Science and Cochrane Library database for articles comparing single-port robotic-assisted partial nephrectomies (SP-RAPN) and conventional robotic-assisted partial nephrectomy (Con-RAPN) till September 2022. The principal outcomes included perioperative outcomes, complications, and oncologic outcomes were evaluated. A total of 586 patients were included in six studies. There were no significant differences in operative time (p = 0.19), transfusion rates (p = 0.11), off-clamp (p = 0.32), total perioperative milligram morphine equivalents (MME) (p = 0.44), intraoperative complications (p = 0.60), major complications (p = 0.84), overall complications (p = 0.90), positive surgical margins (PSM) (p = 0.75) and local recurrence (p = 0.50) between SP-RAPN and Con-RAPN. In addition, the marginal results were recorded in length of hospital stay subgroup (WMD - 0.35 days, 95% CI - 0.70, 0.01; p = 0.06) and blood loss (WMD - 27.16 ml, 95% CI - 56.90, 2.58; p = 0.07). However, SP-RAPN had longer warm ischemia time compared to Con-RAPN (WMD 3.42 min, 95% CI 1.71, 5.13; p < 0.0001). The results of this study demonstrated that SP-RAPN provided similar effectiveness and safety to Con-RAPN, while SP-RAPN might be associated with a marginally shorter length of hospital stay and less blood loss.

Comparison between minimally invasive partial nephrectomy and open partial nephrectomy for complex renal tumors: a systematic review and meta-analysis.

BACKGROUND: The present study aimed to conduct a pooled analysis to compare the efficacy and safety of minimally invasive partial nephrectomy (MIPN) with open partial nephrectomy (OPN) in patients with complex renal tumors (defined as PADUA or RENAL score ≥7). METHODS: The present study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, Supplemental Digital Content 1, http://links.lww.com/JS9/A394 . We conducted a systematic search of the PubMed, Embase, Web of Science, and Cochrane Library databases until October 2022. MIPN and OPN-controlled trials for complex renal tumors were included. The primary outcomes were perioperative results, complications, renal function, and oncologic outcomes. RESULTS: A total of 2405 patients were included in 13 studies. MIPN outperformed OPN in terms of hospital stay [weighted mean difference (WMD) -1.84 days, 95% CI -2.35 to -1.33; P <0.00001], blood loss (WMD -52.42 ml, 95% CI -71.43 to -33.41; P <0.00001), transfusion rates [odds ratio (OR) 0.34, 95% CI 0.17-0.67; P =0.002], major complications (OR 0.59, 95% CI 0.40-0.86; P =0.007) and overall complications (OR 0.43, 95% CI 0.31-0.59; P <0.0001), while operative time, warm ischemia time, conversion to radical nephrectomy rates, estimated glomerular decline, positive surgical margins, local recurrence, overall survival, recurrence-free survival, and cancer-specific survival were not significantly different. CONCLUSIONS: The present study demonstrated that MIPN was associated with a shorter length of hospital stay, less blood loss, and fewer complications in treating complex renal tumors. MIPN may be considered a better treatment for patients with complex tumors when technically feasible.