Structural basis for the tethered peptide activation of adhesion GPCRs.

Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes1-6. Many aGPCRs are activated by a conserved internal (tethered) agonist sequence known as the Stachel sequence7-12. Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with Gs: GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an α-helical-bulge-ß-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved 'toggle switch' W6.53 and the constitution of a hydrogen-bond network formed by Q7.49/Y7.49 and the P6.47/V6.47φφG6.50 motif (φ indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and Gs coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common Gs-binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with Gs. Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their Gs coupling.

Structures of the glucocorticoid-bound adhesion receptor GPR97-Go complex.

Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available1-3. Here we report that glucocorticoid stress hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97)4-6, a prototypical adhesion GPCR. The cryo-electron microscopy structures of GPR97-Go complexes bound to the anti-inflammatory drug beclomethasone or the steroid hormone cortisol revealed that glucocorticoids bind to a pocket within the transmembrane domain. The steroidal core of glucocorticoids is packed against the 'toggle switch' residue W6.53, which senses the binding of a ligand and induces activation of the receptor. Active GPR97 uses a quaternary core and HLY motif to fasten the seven-transmembrane bundle and to mediate G protein coupling. The cytoplasmic side of GPR97 has an open cavity, where all three intracellular loops interact with the Go protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the Go protein was found to be essential for efficient engagement with GPR97 but is not observed in other solved GPCR complex structures. Our work provides a structural basis for ligand binding to the seven-transmembrane domain of an adhesion GPCR and subsequent G protein coupling.

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.

Structures of the ADGRG2-Gs complex in apo and ligand-bound forms.

Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a Gs trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2. The cryo-EM structures of DHEA-ADGRG2-Gs provided interaction details for DHEA within the seven transmembrane domains of ADGRG2. Collectively, our data provide a structural basis for the activation and signaling of ADGRG2, as well as characterization of steroid hormones as ADGRG2 ligands, which might be used as useful tools for further functional studies of the orphan ADGRG2.

Renewable Electroconductive Hydrogels for Accelerated Diabetic Wound Healing and Motion Monitoring.

Diabetic foot ulcers (DFUs), a prevalent complication of diabetes mellitus, may result in an amputation. Natural and renewable hydrogels are desirable materials for DFU dressings due to their outstanding biosafety and degradability. However, most hydrogels are usually only used for wound repair and cannot be employed to monitor motion because of their inherent poor mechanical properties and electrical conductivity. Given that proper wound stretching is beneficial for wound healing, the development of natural hydrogel patches integrated with wound repair properties and motion monitoring was expected to achieve efficient and accurate wound healing. Here, we designed a dual-network (chitosan and sodium alginate) hydrogel embedded with lignin-Ag and quercetin-melanin nanoparticles to achieve efficient wound healing and motion monitoring. The double network formed by the covalent bond and electrostatic interaction confers the hydrogel with superior mechanical properties. Instead of the usual chemical reagents, genipin extracted from Gardenia was used as a cross-linking agent for the hydrogel and consequently improved its biosafety. Furthermore, the incorporation of lignin-Ag nanoparticles greatly enhanced the mechanical strength, antibacterial efficacy, and conductivity of the hydrogel. The electrical conductivity of hydrogels gives them the capability of motion monitoring. The motion sensing mechanism is that stretching of the hydrogel induced by motion changes the conductivity of the hydrogel, thus converting the motion into an electrical signal. Meanwhile, quercetin-melanin nanoparticles confer exceptional adhesion, antioxidant, and anti-inflammatory properties to the hydrogels. The system ultimately achieved excellent wound repair and motion monitoring performance and was expected to be used for stretch-assisted safe and accurate wound repair in the future.

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.

Rhodium(I)/Chiral Diene Complexes Catalyzed Asymmetric Desymmetrization of Alkynyl-Tethered 2,5-Cyclohexadienones Through an Arylative Cyclization Cascade.

Cis-hydrobenzofurans, cis-hydroindoles, and cis-hydrindanes, privileged structural motifs found in numerous biologically active natural and synthetic compounds, are efficiently prepared by a Rh(I)-catalyzed cascade syn-arylation/1,4-addition protocol. This approach starts with the regioselective syn-arylation of the alkyne tethered to 2,5-hexadienone moieties, using a chiral Rh(I) catalyst generated in situ from a chiral bicyclo[2.2.1]hepatadiene ligand L4f. By forging two new carbon-carbon bonds and introducing two chiral centers, the resulting alkenylrhodium species undergoes desymmetrization via an intramolecular 1,4-addition reaction, delivering annulated products with high yields and enantioselectivities.

Clinical Correlation of Function and TCR vß Diversity of MAGE-C2-Specific CD8+ T Cell Response in Esophageal Cancer.

Melanoma-associated Ag (MAGE)-C2, an immunogenic cancer germline (testis) Ag, is highly expressed by various tumor cells, thymic medullary epithelial cells, and germ cells. In this study, we aimed to explore the immunologic properties of MAGE-C2-specific CD8+ T cells and the relationship of its TCR ß-chain V region (TCR vß) subfamily distribution to prognosis of patients with esophageal cancer. PBMCs and tumor-infiltrating lymphocytes expanded by CD3/CD28 Dynabeads and MAGE-C2 peptides in vitro resulted in the induction of lysosome-associated membrane protein-1 (LAMP-1 or CD107a) on the cell surface and the production of IFN-γ by MAGE-C2-specific CD8+ T cells. We found differential TCR vß subfamily distribution among flow-sorted CD107a+IFN-γ+ and CD107a-IFN-γ- CD8+ T cells. The proportion of CD107a+ and/or IFN-γ+ tetramer+ CD8+ T cells was lower in patients with lymph node metastasis, late tumor stage, and poorly differentiated state (p < 0.05). T-box transcription factor was positively correlated with CD107a and IFN-γ. Kaplan-Meier analysis showed that patients whose MAGE-C2-specific CD8+ T cells expressed high CD107a and/or IFN-γ had a longer survival time when compared with patients whose MAGE-C2-specific CD8+ T cells expressed low levels of CD107a and/or IFN-γ. Moreover, analysis of TCR vß subfamily distribution revealed that a higher frequency of TCR vß16 in MAGE-C2-specific CD8+ T cells was positively correlated with a better prognosis. These results suggest that the presence of functional MAGE-C2-specific CD8+ T cells had an independent prognostic impact on the survival of patients with esophageal cancer.

Long Noncoding RNA lncNDEPD1 Regulates PD-1 Expression via miR-3619-5p in CD8+ T Cells.

Therapies targeting programmed cell death protein 1 (PD-1) have gained great success in patients with multiple types of cancer. The regulatory mechanisms underlying PD-1 expression have been extensively explored. However, the impact of long noncoding RNAs on PD-1 expression remains elusive. In this study, we identified the Notch1/lncNDEPD1 axis, which plays a critical role in PD-1 expression in human CD8+ T cells. RNA sequencing and quantitative reverse transcription PCR data showed that lncNDEPD1 was upregulated in activated T cells, especially in PD-1high subsets. Fluorescence in situ hybridization demonstrated that lncNDEPD1 was localized in the cytoplasm. A mechanistic study showed that lncNDEPD1 could bind with miR-3619-5p and PDCD1 mRNA to prevent PDCD1 mRNA degradation and then upregulate PD-1 expression. A chromatin immunoprecipitation assay showed that Notch1 directly binds to the promoter of lncNDEPD1 instead of PDCD1 Furthermore, chimeric Ag receptor T cells expressing lncNDEPD1-specific short hairpin RNAs were generated. Chimeric Ag receptor T cells with decreased lncNDEPD1 expression showed enhanced tumoricidal effects when PD-L1 was present. Our work uncovered a new regulatory mechanism of PD-1 expression and thus provided a potential target to decrease PD-1 without affecting T cell function.

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.

The effect of telemedicine on stoma-related complications in adults with enterostomy: A systematic review and meta-analysis.

To assess the effect of telemedicine on stoma-related complications in adults with enterostomy, we conducted a meta-analysis to evaluate the effects of the telemedicine group compared to the usual group. Literature searches were performed in PubMed, Embase, Web of Science, The Cochrane Library, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), WanFang and VIP databases from their inception up to October 2023. Two authors independently screened and extracted data from the included and excluded literature according to predetermined criteria. Data collected were subjected to meta-analysis using Review Manager 5.3 software. The final analysis included a total of 22 articles, encompassing 2237 patients (telemedicine group: 1125 patients, usual group: 1112 patients). The meta-analysis results demonstrated that, compared to the usual group, the telemedicine group significantly reduced the overall occurrence of stoma-related complications, with an odds ratio (OR) of 0.22 (95% CI = 0.15-0.32, p < 0.00001). Furthermore, it resulted in a decrease in stoma complications (OR = 0.27, 95% CI = 0.15-0.47, p < 0.00001) and peristomal complications (OR = 0.25, 95% CI = 0.19-0.34, p < 0.00001). Therefore, the existing evidence suggests that the application of telemedicine can reduce the incidence of stoma and peristomal complications, making it a valuable clinical recommendation.

Taurine enhances the antitumor efficacy of PD-1 antibody by boosting CD8+ T cell function.

The functional state of CD8+ T cells determines the therapeutic efficacy of PD-1 blockade antibodies in tumors. Amino acids are key nutrients for maintaining T cell antitumor immunity. In this study, we used samples from lung cancer patients treated with PD-1 blockade antibodies to assay the amino acids in their serum by mass spectrometry. We found that lung cancer patients with high serum taurine levels generally responded to PD-1 blockade antibody therapy, in parallel with the secretion of high levels of cytotoxic cytokines (IFN-γ and TNF-α). CD8+ T cells cultured with exogenous taurine exhibited decreased apoptosis, enhanced proliferation, and increased secretion of cytotoxic cytokines. High SLC6A6 expression in CD8+ T cells was positively associated with an effector T cell signature. SLC6A6 knockdown limited the function and proliferation of CD8+ T cells. RNA sequencing revealed that SLC6A6 knockdown altered the calcium signaling pathway, oxidative phosphorylation, and T cell receptor signaling in CD8+ T cells. Furthermore, taurine enhanced T cell proliferation and function in vitro by stimulation of PLCγ1-mediated calcium and MAPK signaling. Taurine plus immune checkpoint blockade antibody significantly attenuated tumor growth and markedly improved the function and proliferation of CD8+ T cells in a mouse tumor model. Thus, our findings indicate that taurine is an important driver for improving CD8+ T cell immune responses and could serve as a potential therapeutic agent for cancer patients.

Coenzyme Q0 defeats NLRP3-mediated inflammation, EMT/metastasis, and Warburg effects by inhibiting HIF-1α expression in human triple-negative breast cancer cells.

Coenzyme Q0 (CoQ0) is a derivative quinone from Antrodia camphorata (AC) that exerts anticancer activities. This study examined the anticancer attributes of CoQ0 (0-4 µM) on inhibited anti-EMT/metastasis and NLRP3 inflammasome, and altered Warburg effects via HIF-1α inhibition in triple-negative breast cancer (MDA-MB-231 and 468) cells. MTT assay, cell migration/invasion assays, Western blotting, immunofluorescence, metabolic reprogramming, and LC-ESI-MS were carried out to assess the therapy potential of CoQ0. CoQ0 inhibited HIF-1α expression and suppressed the NLRP3 inflammasome and ASC/caspase-1 expression, followed by downregulation of IL-1ß and IL-18 expression in MDA-MB-231 and 468 cells. CoQ0 ameliorated cancer stem-like markers by decreasing CD44 and increasing CD24 expression. Notably, CoQ0 modulated EMT by upregulating the epithelial marker E-cadherin and downregulating the mesenchymal marker N-cadherin. CoQ0 inhibited glucose uptake and lactate accumulation. CoQ0 also inhibited HIF-1α downstream genes involved in glycolysis, such as HK-2, LDH-A, PDK-1, and PKM-2 enzymes. CoQ0 decreased extracellular acidification rate (ECAR), glycolysis, glycolytic capacity, and glycolytic reserve in MDA-MB-231 and 468 cells under normoxic and hypoxic (CoCl2) conditions. CoQ0 inhibited the glycolytic intermediates lactate, FBP, and 2/3-PG, and PEP levels. CoQ0 increased oxygen consumption rate (OCR), basal respiration, ATP production, maximal respiration, and spare capacity under normoxic and hypoxic (CoCl2) conditions. CoQ0 increased TCA cycle metabolites, such as citrate, isocitrate, and succinate. CoQ0 inhibited aerobic glycolysis and enhanced mitochondrial oxidative phosphorylation in TNBC cells. Under hypoxic conditions, CoQ0 also mitigated HIF-1α, GLUT1, glycolytic-related (HK-2, LDH-A, and PFK-1), and metastasis-related (E-cadherin, N-cadherin, and MMP-9) protein or mRNA expression in MDA-MB-231 and/or 468 cells. Under LPS/ATP stimulation, CoQ0 inhibited NLRP3 inflammasome/procaspase-1/IL-18 activation and NFκB/iNOS expression. CoQ0 also hindered LPS/ATP-stimulated tumor migration and downregulated LPS/ATP-stimulated N-cadherin and MMP-2/-9 expression. The present study revealed that suppression of HIF-1α expression caused by CoQ0 may contribute to inhibition of NLRP3-mediated inflammation, EMT/metastasis, and Warburg effects of triple-negative breast cancers.

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.

Modeling Heme Peroxidase: Heme Saddling Facilitates Reactions with Hyperperoxides To Form High-Valent FeIV -Oxo Species.

Saddle-shaped hemes have been discovered in the structures of most peroxidases. How such a macrocycle deformation affects the reaction of FeIII hemes with hydrogen peroxide (H2 O2 ) to form high-valent Fe-oxo species remains uncertain. Through examination of the ESI-MS spectra, absorption changes and 1 H NMR chemical shifts, we investigated the reactions of two FeIII porphyrins with different degrees of saddling deformation, namely FeIII (OETPP)ClO4 (1OE ) and FeIII (OMTPP)ClO4 (1OM ), with tert-butyl hydroperoxide (tBuOOH) in CH2 Cl2 at -40 °C, which quickly resulted in O-O bond homolysis from a highly unstable FeIII -alkylperoxo intermediate, FeIII -O(H)OR (2) into FeIV -oxo porphyrins (3). Insight into the reaction mechanism was obtained from [tBuOOH]-dependent kinetics. At -40 °C, the reaction of 1OE with tBuOOH exhibited an equilibrium constant (Ka =362.3 M-1 ) and rate constant (k=1.87×10-2  sM->1 ) for the homolytic cleavage of the 2 O-O bond that were 2.1 and 1.4 times higher, respectively, than those exhibited by 1OM (Ka =171.8 M-1 and k=1.36×10-2 s-1 ). DFT calculations indicated that an FeIII porphyrin with greater saddling deformation can achieve a higher HOMO ([Fe(d z 2 ,d x 2 - y 2 )-porphyrin(a2u )]) to strengthen the orbital interaction with the LUMO (O-O bond σ*) to facilitate O-O cleavage.

BPIFB2 is highly expressed in "cold" lung adenocarcinoma and decreases T cell chemotaxis via activation of the STAT3 pathway.

BACKGROUND: Studies have shown that patients with lung adenocarcinoma exhibit a poor prognosis, and the overall effective rate of immunotherapy is relatively low. Previous studies reported on the BPIFB2 gene have shown that it participates in immune regulation in gastric cancer; however, the role and mechanisms of BPIFB2 in lung cancer remain unclear. The present study evaluated the mechanism of BPIFB2 in lung adenocarcinoma. METHODS: First, the immune infiltration status of lung adenocarcinoma was analyzed by performing bioinformatics analysis and the BPIFB2 gene was screened. Expression of BPIFB2 in lung adenocarcinoma was studied in vitro, and it was confirmed that BPIFB2 exerted effects on the chemotaxis of tumor cells to T cells. The mechanism was further analyzed and verified via in vivo experiments. Finally, the molecular mechanism of the effect of BPIFB2 on tumor cell chemotaxis T cells was confirmed in clinical specimens. RESULTS: Patients with lung adenocarcinoma presented with different degrees of immune cell infiltration, wherein the tumor tissue exhibiting a low infiltration of CD8+T cells was defined as a cold tumor, demonstrating a high expression of BPIFB2. In vitro experiments revealed that although the knockdown of BPIFB2 exerted no significant effect on the proliferation and apoptosis of tumor cells, it could significantly increase the number of T cells presenting with chemotaxis in lung adenocarcinoma cells, and this might be attributable to a decrease in STAT3 activation and an increase in CCL5 expression after BPIFB2 knockdown. In vivo experiments showed that after BPIFB2 knockdown, the expression of CCL5 increased in tumor cells and the recruitment of T cells increased by tumor cells. It was also confirmed that the expression of BPIFB2 was negatively correlated with CCL5 expression in clinical specimens. CONCLUSION: Our study indicated that BPIFB2 was highly expressed in patients presenting with a cold tumor of lung adenocarcinoma. BPIFB2 knockdown increased the expression of CCL5 and the number of chemotactic CD8+T cells in lung adenocarcinoma. BPIFB2 may thus be considered an important target for immunotherapy.