PD-1 signaling limits expression of phospholipid phosphatase 1 and promotes intratumoral CD8+ T cell ferroptosis.

The tumor microenvironment (TME) promotes metabolic reprogramming and dysfunction in immune cells. Here, we examined the impact of the TME on phospholipid metabolism in CD8+ T cells. In lung cancer, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were lower in intratumoral CD8+ T cells than in circulating CD8+ T cells. Intratumoral CD8+ T cells exhibited decreased expression of phospholipid phosphatase 1 (PLPP1), which catalyzes PE and PC synthesis. T cell-specific deletion of Plpp1 impaired antitumor immunity and promoted T cell death by ferroptosis. Unsaturated fatty acids in the TME stimulated ferroptosis of Plpp1-/- CD8+ T cells. Mechanistically, programmed death-1 (PD-1) signaling in CD8+ T cells induced GATA1 binding to the promoter region Plpp1 and thereby suppressed Plpp1 expression. PD-1 blockade increased Plpp1 expression and restored CD8+ T cell antitumor function but did not rescue dysfunction of Plpp1-/- CD8+ T cells. Thus, PD-1 signaling regulates phospholipid metabolism in CD8+ T cells, with therapeutic implications for immunotherapy.

Signal mining and gender differences analysis of adverse events in NMIBC treatment with gemcitabine and BCG bladder instillation based on the FAERS database.

OBJECTIVE: To explore safety differences and perform a gender-based analysis of adverse events related to gemcitabine and Bacillus Calmette-Guérin (BCG) vaccine using the U.S. FDA Adverse Event Reporting System (FAERS) database. METHODS: Using the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) methods, adverse events associated with gemcitabine and BCG were mined from FAERS database reports spanning from Q1 2004 to Q3 2023. RESULTS: The study extracted 37,855 reports with gemcitabine and 5,455 reports with BCG as the primary suspected drugs. Adverse events were more prevalent in males (male-to-female ratio: gemcitabine 1.10, BCG 4.25). Differences in high-frequency adverse events among the top 20 signals were detected for both drugs. Both drugs affected similar organ systems, including potential pulmonary, ocular, and renal toxicity, with gemcitabine showing a broader range of adverse events. Gender analysis revealed fewer adverse reactions to gemcitabine in females, while males had fewer adverse reactions to BCG. CONCLUSION: Differences in high-frequency adverse events between gemcitabine and BCG, including some not listed on drug labels, were observed. Both drugs affect similar organ systems, with gemcitabine showing a broader range of adverse events. Gender differences in adverse events were notable.

A Mendelian randomization study between metabolic syndrome and its components with prostate cancer.

Previous research has produced inconsistent findings concerning the connection between metabolic syndrome and prostate cancer. It is challenging for observational studies to establish a conclusive causal relationship between the two. However, Mendelian randomization can provide stronger evidence of causality in this context. To examine the causal link between a metabolic composite and its components with prostate cancer, we performed a two-sample Mendelian randomization (MR) study utilizing aggregated data from genome-wide association studies, followed by meta-analyses. In our study, we employed inverse variance weighting as the primary method for MR analysis. Additionally, we assessed potential sources of heterogeneity and horizontal pleiotropy through the Cochran's Q test and MR-Egger regression. Moreover, we used multivariate MR to determine whether smoking versus alcohol consumption had an effect on the outcomes. We found no causal relationship between metabolic syndrome and its components and prostate cancer(MetS, odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.738-1.223, p = 0.691; TG, [OR] = 1.02, 95%[CI] = 0.96-1.08, p = 0.59); HDL, [OR] = 1.02, 95% [CI] = 0.97-1.07, p = 0.47; DBP, [OR] = 1.00, 95%[CI] = 0.99-1.01, p = 0.87; SBP, [OR] = 1.00, 95%[CI] = 0.99-1.00, p = 0.26; FBG [OR] = 0.92, 95%[CI] = 0.81-1.05, p = 0.23; WC, [OR] = 0.93, 95%[CI] = 0.84-1.03, p = 0.16). Finally, the MVMR confirms that the metabolic syndrome and its components are independent of smoking and alcohol consumption in prostate cancer. We didn't find significant evidence to determine a causal relationship between the metabolic syndrome and its components and prostate cancer through MR analysis. Further research is necessary to explore the potential pathogenesis between the two diseases.

Peripheral CX3CR1+ T cells combined with PD-1 blockade therapy potentiates the anti-tumor efficacy for lung cancer.

Identifying tumor-relevant T cell subsets in the peripheral blood (PB) has become a potential strategy for cancer treatment. However, the subset of PB that could be used to treat cancer remains poorly defined. Here, we found that the CX3CR1+ T cell subset in the blood of patients with lung cancer exhibited effector properties and had a higher TCR matching ratio with tumor-infiltrating lymphocytes (TILs) compared to CX3CR1- T cells, as determined by paired single-cell RNA and TCR sequencing. Meanwhile, the anti-tumor activities, effector cytokine production, and mitochondrial function were enhanced in CX3CR1+ T cells both in vitro and in vivo. However, in the co-culture system of H322 cells with T cells, the percentages of apoptotic cells and Fas were substantially higher in CX3CR1+ T cells than those in CX3CR1- T cells. Fas-mediated apoptosis was rescued by treatment with an anti-PD-1 antibody. Accordingly, the combination of adoptive transfer of CX3CR1+ T cells and anti-PD-1 treatment considerably decreased Fas expression and improved the survival of lung xenograft mice. Moreover, an increased frequency of CX3CR1+ T cells in the PB correlated with a better response and prolonged survival of patients with lung cancer who received anti-PD-1 therapy. These findings indicate the promising potential of adoptive transfer of peripheral CX3CR1+ T cells as an individual cancer immunotherapy.

Body mass index influence on short-term perioperative results in robotic-assisted laparoscopic partial nephrectomy: a comprehensive systematic review and meta-analysis.

The objective of this meta-analysis was to evaluate the perioperative outcomes of robotic-assisted partial nephrectomy (RAPN) in obese and non-obese patients. Through March 2024, we executed an exhaustive search in internationally acclaimed databases such as PubMed, Cochrane Library, and Web of Science, limiting our scope to publications in English. We discarded review articles, protocols lacking empirical data, conference abstracts, and materials not pertinent to our research. Our analytical framework utilized the Cochran-Mantel-Haenszel method alongside a random-effects model for evaluating dichotomous variables' mean differences, expressed through odds ratios (OR) with 95% confidence intervals (CI). We established statistical significance at a P value below 0.05. The comprehensive meta-analysis incorporated data from eight cohort studies, collectively assessing 3657 patients. Findings indicated that, relative to individuals of normal weight, those in the obese category had prolonged operative durations (WMD - 25.68 95% CI - 42.07 to - 9.29; P = 0.002), increased estimated blood loss (WMD - 48.55ml, 95% CI - 78.27 to - 18.83; P = 0.001), and longer warm ischemia times (WMD - 1.11, 95% CI - 2.03 to - 0.19; P = 0.02). However, no significant disparities were observed in hospital stay duration, intraoperative and total postoperative complications, severe postoperative complications, or alterations in postoperative estimated glomerular filtration rate (eGFR). Our findings conclude that robotic-assisted partial nephrectomy (RAPN) represents a viable and safe surgical approach for obese patients. This assertion is backed by the observation that crucial metrics, including postoperative renal function alterations, surgical complication rates, and hospitalization duration, exhibit no substantial variances when juxtaposed with counterparts of normal weight.

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.

[Corrigendum] Induction of microRNA­let­7a inhibits lung adeno-carcinoma cell growth by regulating cyclin D1.

After the publication of the article, an interested reader drew to the authors' attention that, in the western blots shown in Fig. 5C and D, a pair of data panels were inadvertently duplicated comparing between panels (C) and (D); in addition, the cell migration data shown in Fig. 7F on p. 1852 were selected incorrectly. The authors have examined their original data, and realize that these errors arose inadvertently as a consequence of their mishandling of their data. The revised versions of Figs. 5 and 7, featuring the corrected data for the caspase-8 experiment in Fig. 5C and alternative data for the cell migration assay experiments in Fig. 7F, are shown on the next two pages. The revised data shown for these Figures do not affect the overall conclusions reported in the paper. All the authors agree to the publication of this corrigendum, and are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this. Furthermore, the authors apologize to the readership for any inconvenience caused. [Oncology Reports 40: 1843-1854, 2018; DOI: 10.3892/or.2018.6593].

A positive association between BMI and kidney stones among the diabetic population: a cross-sectional study from NHANES.

BACKGROUND: In the past, research has shown that a higher body mass index (BMI) is one of the variables that increase the likelihood of kidney stones; however, no studies have found a connection between the two in the type II diabetic population. The purpose of this research is to reveal the association between BMI and kidney stones in the type II diabetic population. METHODS: We selected demographic data, laboratory data, lifestyle, and medical history from the NHANES. Specifically includes age, gender, systemic immune-inflammation index (SII), poverty income rate (PIR), body mass index (BMI), kidney stones, education, coronary artery disease, smoking, and drinking. RESULTS: BMI and kidney stones were shown to have a positive association in type II diabetics (blood sugar level > 7.0 mmol/L or diagnosed by a doctor) (OR = 1.021, 95% CI 1.008-1.033, P = 0.001), even after controlling for factors, such as age, gender, race, education level, coronary heart disease, smoking, and drinking. The subgroup analysis revealed a more significant positive association among the 67-80 years, female and Non-Hispanic White population. CONCLUSIONS: There is a positive correlation between BMI and kidney stones among the type II diabetic population.

IL-12-Overexpressed Nanoparticles Suppress the Proliferation of Melanoma Through Inducing ICD and Activating DC, CD8+ T, and CD4+ T Cells.

Purpose: The drug resistance and low response rates of immunotherapy limit its application. This study aimed to construct a new nanoparticle (CaCO3-polydopamine-polyethylenimine, CPP) to effectively deliver interleukin-12 (IL-12) and suppress cancer progress through immunotherapy. Methods: The size distribution of CPP and its zeta potential were measured using a Malvern Zetasizer Nano-ZS90. The morphology and electrophoresis tentative delay of CPP were analyzed using a JEM-1400 transmission electron microscope and an ultraviolet spectrophotometer, respectively. Cell proliferation was analyzed by MTT assay. Proteins were analyzed by Western blot. IL-12 and HMGB1 levels were estimated by ELISA kits. Live/dead staining assay was performed using a Calcein-AM/PI kit. ATP production was detected using an ATP assay kit. The xenografts in vivo were estimated in C57BL/6 mice. The levels of CD80+/CD86+, CD3+/CD4+ and CD3+/CD8+ were analyzed by flow cytometry. Results: CPP could effectively express EGFP or IL-12 and increase ROS levels. Laser treatment promoted CPP-IL-12 induced the number of dead or apoptotic cell. CPP-IL-12 and laser could further enhance CALR levels and extracellular HMGB1 levels and decrease intracellular HMGB1 and ATP levels, indicating that it may induce immunogenic cell death (ICD). The tumors and weights of xenografts in CPP-IL-12 or laser-treated mice were significantly reduced than in controls. The IL-12 expression, the CD80+/CD86+ expression of DC from lymph glands, and the number of CD3+/CD8+T or CD3+/CD4+T cells from the spleen increased in CPP-IL-12-treated or laser-treated xenografts compared with controls. The levels of granzyme B, IFN-γ, and TNF-α in the serum of CPP-IL-12-treated mice increased. Interestingly, CPP-IL-12 treatment in local xenografts in the back of mice could effectively inhibit the growth of the distant untreated tumor. Conclusion: The novel CPP-IL-12 could overexpress IL-12 in melanoma cells and achieve immunotherapy to melanoma through inducing ICD, activating CD4+ T cell, and enhancing the function of tumor-reactive CD8+ T cells.

DNA of Neutrophil Extracellular Traps Binds TMCO6 to Impair CD8+ T-cell Immunity in Hepatocellular Carcinoma.

Neutrophil extracellular traps (NET), formed by the extracellular release of decondensed chromatin and granules, have been shown to promote tumor progression and metastasis. Tumor-associated neutrophils in hepatocellular carcinoma (HCC) are prone to NET formation, highlighting the need for a more comprehensive understanding of the mechanisms of action of NETs in liver cancer. Here, we showed that DNA of NETs (NET-DNA) binds transmembrane and coiled-coil domains 6 (TMCO6) on CD8+ T cells to impair antitumor immunity and thereby promote HCC progression. TGFß1 induced NET formation, which recruited CD8+ T cells. Binding to NET-DNA inhibited CD8+ T cells function while increasing apoptosis and TGFß1 secretion, forming a positive feedback loop to further stimulate NET formation and immunosuppression. Mechanistically, the N-terminus of TMCO6 interacted with NET-DNA and suppressed T-cell receptor signaling and NFκB p65 nuclear translocation. Blocking NET formation by inhibiting PAD4 induced potent antitumor effects in wild-type mice but not TMCO6-/- mice. In clinical samples, CD8+ T cells expressing TMCO6 had an exhausted phenotype. TGFß1 signaling inhibition or TMCO6 deficiency combined with anti-PD-1 abolished NET-driven HCC progression in vivo. Collectively, this study unveils the role of NET-DNA in impairing CD8+ T-cell immunity by binding TMCO6 and identifies targeting this axis as an immunotherapeutic strategy for blocking HCC progression. SIGNIFICANCE: TMCO6 is a receptor for DNA of NETs that mediates CD8+ T-cell dysfunction in HCC, indicating that the NET-TMCO6 axis is a promising target for overcoming immunosuppression in liver cancer.

Metabolomic biomarkers in liquid biopsy: accurate cancer diagnosis and prognosis monitoring.

Liquid biopsy, a novel detection method, has recently become an active research area in clinical cancer owing to its unique advantages. Studies on circulating free DNA, circulating tumor cells, and exosomes obtained by liquid biopsy have shown great advances and they have entered clinical practice as new cancer biomarkers. The metabolism of the body is dynamic as cancer originates and progresses. Metabolic abnormalities caused by cancer can be detected in the blood, sputum, urine, and other biological fluids via systemic or local circulation. A considerable number of recent studies have focused on the roles of metabolic molecules in cancer. The purpose of this review is to provide an overview of metabolic markers from various biological fluids in the latest clinical studies, which may contribute to cancer screening and diagnosis, differentiation of cancer typing, grading and staging, and prediction of therapeutic response and prognosis.

m6A-methylated KCTD21-AS1 regulates macrophage phagocytosis through CD47 and cell autophagy through TIPR.

Blocking immune checkpoint CD47/SIRPα is a useful strategy to engineer macrophages for cancer immunotherapy. However, the roles of CD47-related noncoding RNA in regulating macrophage phagocytosis for lung cancer therapy remain unclear. This study aims to investigate the effects of long noncoding RNA (lncRNA) on the phagocytosis of macrophage via CD47 and the proliferation of non-small cell lung cancer (NSCLC) via TIPRL. Our results demonstrate that lncRNA KCTD21-AS1 increases in NSCLC tissues and is associated with poor survival of patients. KCTD21-AS1 and its m6A modification by Mettl14 promote NSCLC cell proliferation. miR-519d-5p gain suppresses the proliferation and metastasis of NSCLC cells by regulating CD47 and TIPRL. Through ceRNA with miR-519d-5p, KCTD21-AS1 regulates the expression of CD47 and TIPRL, which further regulates macrophage phagocytosis and cancer cell autophagy. Low miR-519d-5p in patients with NSCLC corresponds with poor survival. High TIPRL or CD47 levels in patients with NSCLC corresponds with poor survival. In conclusion, we demonstrate that KCTD21-AS1 and its m6A modification promote NSCLC cell proliferation, whereas miR-519d-5p inhibits this process by regulating CD47 and TIPRL expression, which further affects macrophage phagocytosis and cell autophagy. This study provides a strategy through miR-519-5p gain or KCTD21-AS1 depletion for NSCLC therapy by regulating CD47 and TIPRL.

Perioperative, functional, and oncological outcomes after cryoablation or partial nephrectomy for small renal masses in solitary kidneys: a systematic review and meta-analysis.

AIM: This study aims to compare the perioperative, functional, and oncological outcomes of cryoablation (CA) and partial nephrectomy (PN) for managing small renal masses in patients with solitary kidneys. The study seeks to assess the efficacy and safety of both interventions, evaluating their impact on kidney function and their ability to mitigate cancer recurrence. METHODS: Searches were systematically conducted on PubMed, Scopus, EMBASE, SinoMed, and Google Scholar, identifying seven observational studies. Statistical analysis was performed using Stata v.12.0 and Review Manager version 5.2. Results for dichotomous variables are expressed using odds ratios, and weighted mean differences are used for continuous variables. RESULTS: Our findings revealed that patients undergoing CA experienced significantly shorter operative time (p < 0.0001), reduced estimated blood loss (p < 0.00001), a shorter length of stay (p = 0.0001), and fewer postoperative complications (p = 0.02) compared to those undergoing PN. Although the CA group exhibited a lower transfusion rate (p = 0.69) compared with the PN group, the difference was not statistically significant. The combined data analysis demonstrated a significantly lower increase in serum creatinine levels after surgery in the CA group compared with the PN group (p = 0.003). Similarly, there was a noteworthy decrease in the estimated glomerular filtration rate after surgery in the PN group compared with the CA group (p < 0.0001). While not statistically significant, the CA group showed a lower postoperative dialysis rate (p = 0.11). Regarding oncological outcomes, the analysis revealed no significant differences between CA and PN concerning local recurrence (p = 0.2) and distant metastasis (p = 0.12), respectively. CONCLUSIONS: Our analysis indicates comparable efficacy between PN and CA in controlling tumour recurrence and metastasis. However, CA is associated with superior preservation of renal function, significantly enhanced perioperative outcomes, and fewer postoperative complications. Based on our data, it can be inferred that the scope for applying CA might be expanded to encompass more patients seeking a less invasive treatment option.

Allogeneic CAR-T cells with of HLA-A/B and TRAC disruption exhibit promising antitumor capacity against B cell malignancies.

BACKGROUND: Although chimeric antigen receptor T (CAR-T) cells have been proven to be an effective way of treating B cell malignancies, a lot of patients could not benefit from it because of failure in CAR-T cell manufacturing, disease progression, and unaffordable price. The study aimed to explore universal CAR-T cell products to extend the clinical accessibility. METHODS: The antitumor activity of CRISPR/Cas9-edited allogeneic anti-CD19 CAR-T (CAR-T19) cells was assessed in vitro, in animal models, and in patients with relapsed/refractory (R/R) acute B cell lymphoblastic leukemia (B-ALL) or diffuse large B cell lymphoma. RESULTS: B2M-/TRAC- universal CAR-T19 (U-CAR-T19) cells exhibited powerful anti-leukemia abilities both in vitro and in animal models, as did primary CD19+ leukemia cells from leukemia patients. However, expansion, antitumor efficacy, or graft-versus-host-disease (GvHD) was not observed in six patients with R/R B cell malignancies after U-CAR-T19 cell infusion. Accordingly, significant activation of natural killer (NK) cells by U-CAR-T19 cells was proven both clinically and in vitro. HLA-A-/B-/TRAC- novel CAR-T19 (nU-CAR-T19) cells were constructed with similar tumoricidal capacity but resistance to NK cells in vitro. Surprisingly, robust expansion of nU-CAR-T19 cells, along with rapid eradication of CD19+ abnormal B cells, was observed in the peripheral blood and bone marrow of another three patients with R/R B-ALL. The patients achieved complete remission with no detectable minimal residual disease 14 days after the infusion of nU-CAR-T19 cells. Two of the three patients had grade 2 cytokine release syndrome, which were managed using an IL-6 receptor blocker. Most importantly, GvHD was not observed in any patient, suggesting the safety of TRAC-disrupted CAR-T cells generated using the CRISPR/Cas9 method for clinical application. CONCLUSIONS: The nU-CAR-T19 cells showed a strong response in R/R B-ALL. nU-CAR-T19 cells have the potential to be a promising new approach for treating R/R B cell malignancies.

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.

LFA-1 regulated by IL-2/STAT5 pathway boosts antitumor function of intratumoral CD8+ T cells for improving anti-PD-1 antibody therapy.

Anti-PD-1 antibody therapy has achieved success in tumor treatment; however, the duration of its clinical benefits are typically short. The functional state of intratumoral CD8+ T cells substantially affects the efficacy of anti-PD-1 antibody therapy. Understanding how intratumoral CD8+ T cells change will contribute to the improvement in anti-PD-1 antibody therapy. In this study, we found that tumor growth was not arrested after the late administration of anti-PD-1 antibody and that the antitumor function of CD8+ T cells decreased with tumor progression. The results of the RNA sequencing of CD8+ T cells infiltrating the tumor site on days 7 and 14 showed that the cell adhesion molecule Lymphocyte Function-associated Antigen-1 (LFA-1) participates in regulating the antitumor function of CD8+ T cells and that decreased LFA-1 expression in intratumoral CD8+ T cells is associated with tumor progression. By analyzing the Gene Expression Omnibus (GEO) database and our results, we found that the antitumor function of intratumoral CD8+ T cells with high LFA-1 expression was stronger. The formation of immune synapses is impaired in Itgal-si CD8+ T cells, resulting in decreased anti-tumor function. LFA-1 expression in intratumoral CD8+ T cells is regulated by the IL-2/STAT5 pathway. The combination of IL-2 and anti-PD-1 antibody effectively enhanced LFA-1 expression and the antitumor function of intratumoral CD8+ T cells. The adoptive transfer of OT-1 T cells overexpressing LFA-1, STAT5A, or STAT5B resulted in higher antitumor function, deferred tumor growth, and prolonged survival. These findings indicate that LFA-1-mediated immune synapse acts as a regulator of the antitumor function of intratumoral CD8+ T cells, which can be applied to improve anti-PD-1 antibody therapy.

The causal association between smoking, alcohol consumption and risk of upper urinary calculi: insights from a Mendelian randomization study.

Background: The causal link between smoking, alcohol consumption, and upper urinary calculi remains uncertain in observational studies due to confounding factors. To uncover potential causal associations, we utilized two-sample univariable and multivariable Mendelian randomization (MR) methods. Methods: Five risk factors related to lifestyles (cigarettes per day, lifetime smoking index, smoking initiation, drinks per week and alcohol intake frequency) were chosen from the Genome-Wide Association Study (GWAS). Upper urinary calculi were obtained from the FinnGen and United Kingdom Biobank consortium. Inverse-variance-weighted (IVW) was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl). 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: The summary OR for upper urinary calculi was 0.6 (IVW 95% CI: 0.49-0.74; p = 1.31 × 10-06) per standard deviation decrease in drinks per week. Interestingly, the genetically predicted alcohol intake frequency was associated with a significantly increased risk upper urinary calculi (OR = 1.27; 95% CI: 1.11-1.45; p = 0.0005). Our study found no association between smoking initiation, the number of cigarettes per day, and the lifetime smoking index and the risk of upper urinary calculi. By adjusting for body mass index and education, estimates of drinks per week remained consistent in multivariate MR analyses, while alcohol intake frequency became non-significant. Conclusion: MR analysis showed that drinks per week was negatively associated with upper urinary calculi, whereas the effect of tobacco on upper urinary calculi was not significant and the detrimental effect of alcohol intake frequency on upper urinary calculi became non-significant after adjusting for BMI and education.

Efficacy and Safety of Programmed Death-1/Programmed Death-Ligand 1 Inhibitor for Metastatic Urothelial Carcinoma: A Systematic Review and Meta-Analysis.

Objective: The purpose of this study was to evaluate the efficacy and safety of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for the treatment of metastatic urothelial carcinoma (mUC). Methods: A literature search was conducted of PubMed, EMBASE, and the Cochrane Library and was limited to the English literature. Randomized controlled trials (RCTs) published up to July 2022 were considered for inclusion. The outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade ≥ 3 treatment-related AEs (TRAE). Subgroup analysis was performed based on the PD-L1 expression status, and the differences between first- and second-line PD-1/PD-L1 inhibitors were estimated. Results: We included five RCTs comprising 3584 patients in the analysis. Compared with chemotherapy alone, the use of PD-1/PD-L1 inhibitors as monotherapy did not significantly prolong OS [hazard ratios (HR), 0.90; 95% CI, 0.81-1.00] or PFS (HR, 1.12; 95% CI, 0.95-1.32). However, the PD-1/PD-L1 inhibitor combined with chemotherapy significantly improved both OS (HR, 0.85; 95% CI, 0.74-0.96) and PFS (HR, 0.80; 95% CI, 0.71-0.90). Additionally, subgroup analysis showed that in mUC with PD-L1 expression ≥ 5%, treatment with the PD-1/PD-L1 inhibitor alone did not reduce the risk of death. Safety analysis showed that the PD-1/PD-L1 inhibitor alone did not significantly increase the incidence rates of grade ≥ 3 TRAEs. Conclusions: The results show that use of the PD-1/PD-L1 inhibitor alone as first-line treatment is similar to chemotherapy in terms of both survival and response rates. However, the PD-1/PD-L1 inhibitor plus chemotherapy has a significant benefit in terms of PFS or OS. Nonetheless, more RCTs are warranted to evaluate efficiency and safety in the combination regimen of chemotherapy and PD-1/PD-L1 inhibitors.

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.

Perioperative, functional, and oncological outcomes of robotic vs. laparoscopic partial nephrectomy for complex renal tumors (RENAL score ≥7): an evidence-based analysis.

Objective: To evaluate the current literature comparing outcomes of robotic partial nephrectomy (RPN) versus laparoscopic partial nephrectomy (LPN) treating complex renal tumors (RENAL nephrometry score ≥7). Methods: We systematically searched the Cochrane Library, PubMed, Google Scholar, 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. Results: Eight observational studies comprising 1346 patients (RPN: 695; LPN: 651) were included in this study. Compared to LPN, RPN had a shorter operative time (OT) (weight mean difference [WMD]: -14.73 min; p = 0.0003), shorter warm ischemia time (WIT) (WMD: -3.47 min; p = 0.002), lower transfusion rate (odds ratio [OR]: 0.66; p = 0.04), shorter length of stay (LOS) (WMD: -0.65 days; p < 0.00001), lower postoperative estimated glomerular filtration rate (eGFR) change (WMD = -2.33 mL/min/1.73 m2; p = 0.002) and lower intraoperative complications (OR: 0.52; p = 0.04). No significant differences were observed between the two groups in terms of estimated blood loss (EBL) (p = 0.84), conversion to radical nephrectomy (p = 0.12), postoperative complications (p = 0.11), major complications (defined Clavien-Dindo grade 3 (p = 0.43), overall complications (p = 0.15), postoperative eGFR (p = 0.28), local recurrence (p = 0.35), positive surgical margin (PSM) (p = 0.63), overall survival (OS) (p = 0.47), cancer-specific survival (CSS) (p = 0.22) and 3-year recurrence-free survival (RFS) (p = 0.53). Conclusion: Patients with complex renal tumors (RENAL score ≥7), RPN is superior to LPN in decreasing the OT, WIT, LOS, transfusion rate, change in eGFR and the incidence of intraoperative complications while maintaining oncological control and avoiding a decline in renal function. However, our findings need further validation in a large-sample prospective randomized study.