Comparing the diagnostic efficacy of [18F]FDG PET/CT and MRI in the initial diagnosis of ovarian cancer: a meta-analysis.

PURPOSE: This meta-analysis was conducted to assess the relative diagnostic effectiveness of [18F]FDG PET/CT and MRI in the initial detection of ovarian cancer. METHODS: A thorough literature search was conducted using PubMed, Embase, and Web of Science databases to locate relevant studies published up to April 2024. The selected studies were those that evaluated diagnostic performance of [18F]FDG PET/CT and MRI for the initial detection of ovarian cancer. Sensitivity and specificity metrics were analyzed employing the DerSimonian and Laird random-effects model, with further transformation utilizing the Freeman-Tukey double arcsine method. The quality of included studies was appraised using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. RESULTS: The meta-analysis included 23 articles encompassing a total of 1973 patients. The sensitivity of [18F]FDG PET/CT was found to be higher than that of MRI (0.94 vs. 0.87, P = 0.02). In terms of specificity, [18F]FDG PET/CT and MRI demonstrated similar values (0.87 vs. 0.86, P = 0.90). An assessment of publication bias using the funnel plot asymmetry test revealed no significant bias for any outcomes (Egger's test: all P > 0.05). CONCLUSIONS: Our meta-analysis reveals that [18F]FDG PET/CT exhibits higher sensitivity while maintaining similar specificity compared to MRI for the initial detection of ovarian cancer. However, the substantial heterogeneity observed across studies may influence these findings. Consequently, larger-scale prospective studies are necessary to validate these results.

Photodynamic Therapy Using RGD-Functionalized Quantum Dots Elicit a Potent Immune Response in a Syngeneic Mouse Model of Pancreatic Cancer.

Purpose: Photodynamic therapy (PDT) induces anti-tumor immune responses by triggering immunogenic cell death in tumor cells. Previously, we demonstrated that novel QDs-RGD nanoparticles exhibited high efficiency as photosensitizers in the treatment of pancreatic cancer. However, the underlying mechanism of the anti-tumor immune effects induced by the photosensitizer remains unknown. This study assessed the anticancer immune effect of QDs-RGD, as well as the conventional photosensitizer chlorine derivative, YLG-1, for comparison, against pancreatic cancer in support of superior therapeutic efficacy. Methods: The pancreatic cancer cell line, Panc02, was used for in vitro studies. C57BL/6 mice bearing pancreatic cancer cell-derived xenografts were generated for in vivo studies to assess the anti-tumor effects of QDs-RGD-PDT and YLG-1-PDT. The immunostimulatory ability of both photosensitizers was examined by measuring the expression of damage-associated molecular patterns (DAMP), such as calreticulin (CRT), assessing dendritic cell (DC) maturation, and analyzing cytokine expression. The specific immunity of QDs-RGD and YLG-1-PDT on distant tumor were determined by combining PDT with anti-CTLA-4 antibody. Results: QDs-RGD-PDT and YLG-1-PDT significantly inhibited pancreatic cancer cell growth in a dose- and time-dependent manner. While both photosensitizers significantly promoted CRT release, DC maturation, and interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) expression, QDs-RGD exerted a stronger immunostimulatory effect than YLG-1. Combination treatment with QDs-RGD and CTLA-4 blockade was able to significantly inhibit the growth of distant tumors. Conclusion: QDs-RGD is a novel and effective PDT strategy for treating pancreatic tumors by inducing anti-tumor immune responses.

Sintilimab combined with bevacizumab in relapsed or persistent ovarian clear cell carcinoma (INOVA): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Ovarian clear cell carcinoma rarely responds to second-line chemotherapy, the recommended treatment for relapsed epithelial ovarian cancer. Here, we report the activity and safety of sintilimab in combination with bevacizumab in patients with relapsed or persistent ovarian clear cell carcinoma. METHODS: In the prospective, multicentre, single-arm, phase 2 INOVA trial, patients aged 18-75 years with histologically confirmed relapsed or persistent ovarian clear cell carcinoma were enrolled from eight tertiary hospitals in China. Eligible patients had an Eastern Cooperative Oncology Group performance status score of 0-2 and previous exposure to at least one cycle of platinum-containing chemotherapy. Enrolled patients received sintilimab (200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks until disease progression. The primary endpoint was objective response rate assessed by independent central review based on Response Evaluation Criteria in Solid Tumours version 1.1. Eligible enrolled patients who received at least one cycle of treatment and had at least one tumour response assessment following the baseline assessment per protocol were included in the activity analysis. Patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04735861) and is ongoing. FINDINGS: Between April 8, 2021, and July 3, 2023, 51 patients were screened and 41 patients received at least one dose of sintilimab in combination with bevacizumab. Response evaluation was completed in 37 patients. Objective responses were observed in 15 patients (objective response rate 40·5%; 95% CI 24·8-57·9), of which five (14%) were complete responses and ten (27%) were partial responses. At data cutoff (Jan 29, 2024), the median follow-up was 16·9 months (IQR 7·5-23·4). Three (7%) patients developed grade 3 treatment-related adverse events including one patient with proteinuria, one patient with myocarditis, and one patient with rash. No treatment-related adverse events of worse than grade 3 severity were recorded. Treatment-related serious adverse events occurred in two (5%) patients including one patient with immune-related myocarditis and another with hypertension and renal dysfunction. No treatment-related deaths occurred. INTERPRETATION: Sintilimab in combination with bevacizumab showed promising anti-tumour activity and manageable safety in patients with relapsed or persistent ovarian clear cell carcinoma. Larger, randomised trials are warranted to compare this low-toxicity, chemotherapy-free combinatorial regimen with standard chemotherapy. FUNDING: National Key Technology Research and Development Program of China, National Natural Science Foundation of China, Beijing Xisike Clinical Oncology Research Foundation, and Innovent Biologics. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A randomized, multicenter phase III Study of once-per-cycle administration of efbemalenograstim alfa (F-627), a novel long-acting rhG-CSF, for prophylaxis of chemotherapy-induced neutropenia in patients with breast cancer.

BACKGROUND: F-627 (efbemalenograstim alfa) is a novel long acting granulocyte colony-stimulating factor (G-CSF) that contains two human G-CSF fused to a human immunoglobulin G2 (hIgG2) -Fc fragment with a peptide linker. This studyevaluated the efficacy and safety of F-627, also known as efbemalenograstim alfa (Ryzneuta®) in reducing neutropenia compared with filgrastim (GRAN®). METHODS: This was a multicenter, randomized, open-label, active-controlled non-inferiority study. Two hundred thirty nine (239) patients were enrolled in thirteen centers and received the chemotherapy with epirubicin (100 mg/m2) and cyclophosphamide (600 mg/m2) on day 1 of each cycle for a maximum of four cycles. Patients were randomized to receive either a single 20 mg subcutaneous (s.c.) injection of F-627 on day 3 of each cycle or daily s.c. injection of filgrastim 5 µg/kg/d starting from day 3 of each cycle. The primary endpoint was the duration of grade 3 or 4 neutropenia in cycle 1. The safety profile was also evaluated. RESULTS: The mean (SD) duration of grade 3 or 4 neutropenia in cycle 1 was 0.68 (1.10) and 0.71 (0.95) days for the F-627 and the filgrastim groups, respectively. The Hodges-Lehmann estimate of the between-group median difference (F-627 vs filgrastim) in the duration of grade 3 or 4 neutropenia in cycle 1 was 0 day and the upper limit of the one-sided 97.5% CI was 0 day, which was within the prespecified non-inferiority margin of 1-day. Results for all efficacy endpoints in cycles 2 - 4 were consistent with the results in cycle 1, however a trend towards a lower incidence and a shorter duration of grade 3 or 4 neutropenia and grade 4 neutropenia was observed in the F-627 group compared with the filgrastim group. The ANC nadir in the F-627 group was significantly higher than that in the filgrastim group in each cycle. A single fixed dose of F-627 was well tolerated and as safe as standard daily filgrastim. CONCLUSIONS: A single fixed dose of 20 mg of F-627 in each cycle was as safe and effective as a daily dose of filgrastim 5 µg/kg/d in reducing neutropenia and its complications in patients who received four cycles of EC. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04174599, on 22/11/2019.

Prediction on the chin advancement of the twin block functional appliance in growing Chinese patients using the cephalometric markers: a retrospective study.

In spite of the widespread use of functional appliances, broad variations were applied the treatment response. The aim of this study is to investigate the pre-treatment cephalometric predictors on the chin advancement of twin-block in growing Chinese patients with class II malocclusion. After screening, 90 patients treated by twin-block were included in the study. The treatment outcome was assessed by the alterations in the distance of skeletal pogonion (Pog) to the vertical reference plane perpendicular to the Frankfurt plane (ΔPog-VRP). Moreover, ΔPog-VRP was divided by the cranial growth indicated by the Nasion to Basion changes (ΔN-Ba) to minimize the growth discrepancy among individuals (adjΔPog-VRP). Patients with ΔPog-VRP/adjΔPog-VRP above the median value were categorized into good response group (GRG/adjGRG, N = 45), while the rest were poor response group (PRG/adjPRG, N = 45). Independent t-test was used to compare the pre-treatment cephalometric measurements between GRG/adjGRG and PRG/adjPRG. Stepwise multivariate regression models were used to determine the pre-treatment cephalometric predictors for the chin advancement. Generally, there were not any significant differences between GRG/adjGRG and PRG/adjPRG regarding age, gender and cervical stage before twin-block treatment. Patients from GRG had significantly reduced cephalometric measurements in the vertical dimensions, including ∠N-Go-Me, ∠Mandibular plane-Occlusal plane (∠MP-OP) and the sum of angles (p < 0.05) in comparison to PRG. When the individual growth was taken account, similar findings were observed. The patients from adjGRG had a significantly lower ∠Sella Nasion line-MP (∠SN-MP), ∠Ar-Go-Me and ∠N-Go-Me, as well as an increased Posterior facial height (PFH)/Anterior facial height (AFH) (p < 0.05) compared with their counterparts. ∠N-Go-Me variable was the independent predictor on Pog advancement with (ß = -0.26, 95% CI: -0.06 to -0.01, p = 0.01) and without (ß = -0.29, 95% CI: -0.06 to -0.01, p < 0.01) adjustments on individual growth. The results of this study showed that patients with a reduced N-Go-Me angle are more likely to experience a greater chin advancement following twin-block treatment.

Multilevel Systematic Optimization To Achieve Efficient Integrated Expression of Escherichia coli.

Genomic integration of heterologous genes is the preferred approach in industrial fermentation-related strains due to the drawbacks associated with plasmid-mediated microbial fermentation, including additional growth burden, genetic instability, and antibiotic contamination. Synthetic biology and genome editing advancements have made gene integration convenient. Integrated expression is extensively used in the field of biomanufacturing and is anticipated to become the prevailing method for expressing recombinant proteins. Therefore, it is pivotal to strengthen the expression of exogenous genes at the genome level. Here, we systematically optimized the integrated expression system of Escherichia coli from 3 aspects. First, the integration site slmA with the highest expression activity was screened out of 18 sites in the ORI region of the E. coli BL21 (DE3) genome. Second, we characterized 16 endogenous promoters in E. coli and combined them with the T7 promoter. A constitutive promoter, Plpp-T7, exhibited significantly higher expression strength than the T7 promoter, achieving a 3.3-fold increase in expression levels. Finally, to further enhance the T7 expression system, we proceeded with overexpression of T7 RNA polymerase at the chassis cell level. The resulting constitutive efficient integrated expression system (CEIES_Ecoli) showed a 2-fold increase in GFP expression compared to the pET3b recombinant plasmid. Therefore, CEIES_Ecoli was applied to the integrated expression of nitrilase and hyaluronidase, achieving stable and efficient enzyme expression, with enzyme activities of 22.87 and 12,195 U·mL-1, respectively, comparable to plasmid levels. Overall, CEIES_Ecoli provides a stable and efficient method of gene expression without the need for antibiotics or inducers, making it a robust tool for synthetic biology, enzyme engineering, and related applications.

On the Topotactic Phase Transition Achieving Superconducting Infinite-Layer Nickelates.

Topotactic reduction is critical to a wealth of phase transitions of current interest, including synthesis of the superconducting nickelate Nd0.8Sr0.2NiO2, reduced from the initial Nd0.8Sr0.2NiO3/SrTiO3 heterostructure. Due to the highly sensitive and often damaging nature of the topotactic reduction, however, only a handful of research groups have been able to reproduce the superconductivity results. A series of in situ synchrotron-based investigations reveal that this is due to the necessary formation of an initial, ultrathin layer at the Nd0.8Sr0.2NiO3 surface that helps to mediate the introduction of hydrogen into the film such that apical oxygens are first removed from the Nd0.8Sr0.2NiO3 / SrTiO3 (001) interface and delivered into the reducing environment. This allows the square-planar / perovskite interface to stabilize and propagate from the bottom to the top of the film without the formation of interphase defects. Importantly, neither geometric rotations in the square planar structure nor significant incorporation of hydrogen within the films is detected, obviating its need for superconductivity. These findings unveil the structural basis underlying the transformation pathway and provide important guidance on achieving the superconducting phase in reduced nickelate systems.

Ion migration in p-type perovskite MAPbI3 films under an electric field and thin-film transistor device failure.

This study demonstrated a dynamic analysis to investigate the ion migration in p-type perovskite MAPbI3 films under an electric field, revealing its detrimental effects on the electrical performance of MAPbI3-based devices. An additive strategy was proposed to suppress ion migration, thereby facilitating the fabrication of high-performance MAPbI3-based devices.

A self-bonding conductive electrode triggered by water-induced structure reconfiguration.

This study presents a self-bonding conductive electrode triggered by water-induced structure reconfiguration. Water wetting causes the swelling and mobility of cotton-derived cellulose nanofibers in the conductive electrode, and the formation of hydrogen bonds, which enables the conductive electrode to heal damage, bond separated pieces, and directly bond on diverse substrates.

Development and validation of a nomogram for predicting occurrence of severe case in children hospitalized with influenza A (H1N1) infection during the post-COVID-19 era.

Background: The significant rebound of influenza A (H1N1) virus activity, particularly among children, with rapidly growing number of hospitalized cases is of major concern in the post-COVID-19 era. The present study was performed to establish a prediction model of severe case in pediatric patients hospitalized with H1N1 infection during the post-COVID-19 era. Methods: This is a multicenter retrospective study across nine public tertiary hospitals in Yunnan, China, recruiting pediatric H1N1 inpatients hospitalized at five of these centers between February 1 and July 1, 2023, into the development dataset. Screening of 40 variables including demographic information, clinical features, and laboratory parameters were performed utilizing Least Absolute Shrinkage and Selection Operator (LASSO) regression and logistic regression to determine independent risk factors of severe H1N1 infection, thus constructing a prediction nomogram. Receiver operating characteristic (ROC) curve, calibration curve, as well as decision curve analysis (DCA) were employed to evaluate the model's performance. Data from four independent cohorts comprised of pediatric H1N1 inpatients from another four hospitals between July 25 and October 31, 2023, were utilized to externally validate this nomogram. Results: The development dataset included 527 subjects, 122 (23.1 %) of whom developed severe H1N1 infection. The external validation dataset included 352 subjects, 72 (20.5 %) of whom were eventually confirmed as severe H1N1 infection. The LASSO regression identified 19 candidate predictors, with logistic regression further narrowing down to 11 independent risk factors, including underlying conditions, prematurity, fever duration, wheezing, poor appetite, leukocyte count, neutrophil-lymphocyte ratio (NLR), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α). By integrating these 11 factors, a predictive nomogram was established. In terms of prediction of severe H1N1 infection, excellent discriminative capacity, favorable accuracy, and satisfactory clinical usefulness of this model were internally and externally validated via ROC curve, calibration curve, and DCA, respectively. Conclusion: Our study successfully established and validated a novel nomogram model integrating underlying conditions, prematurity, fever duration, wheezing, poor appetite, leukocyte count, NLR, ESR, LDH, IL-10, and TNF-α. This nomogram can effectively predict the occurrence of serious case in pediatric H1N1 inpatients during the post-COVID-19 era, facilitating the early recognition and more efficient clinical management of such patients.

Clinical Outcomes of Tirzepatide or GLP-1 Receptor Agonists in Individuals With Type 2 Diabetes.

Importance: Despite its demonstrated benefits in improving cardiovascular risk profiles, the association of tirzepatide with mortality and cardiovascular and kidney outcomes compared with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) remains unknown. Objective: To investigate the association of tirzepatide with mortality and adverse cardiovascular and kidney outcomes compared with GLP-1 RAs in patients with type 2 diabetes. Design, Setting, and Participants: This retrospective cohort study used US Collaborative Network of TriNetX data collected on individuals with type 2 diabetes aged 18 years or older initiating tirzepatide or GLP-1 RA between June 1, 2022, and June 30, 2023; without stage 5 chronic kidney disease or kidney failure at baseline; and without myocardial infarction or ischemic or hemorrhagic stroke within 60 days of drug initiation. Exposures: Treatment with tirzepatide compared with GLP-1 RA. Main Outcomes and Measures: The primary outcome was all-cause mortality, and secondary outcomes included major adverse cardiovascular events (MACEs), the composite of MACEs and all-cause mortality, kidney events, acute kidney injury, and major adverse kidney events. All outcomes were analyzed using Cox proportional hazards regression models. Results: There were 14 834 patients treated with tirzepatide (mean [SD] age, 55.4 [11.8] years; 8444 [56.9%] female) and 125 474 treated with GLP-1 RA (mean [SD] age, 58.1 [13.3] years; 67 474 [53.8%] female). After a median (IQR) follow-up of 10.5 (5.2-15.7) months, 95 patients (0.6%) in the tirzepatide group and 166 (1.1%) in the GLP-1 RA group died. Tirzepatide treatment was associated with lower hazards of all-cause mortality (adjusted hazard ratio [AHR], 0.58; 95% CI, 0.45-0.75), MACEs (AHR, 0.80; 95% CI, 0.71-0.91), the composite of MACEs and all-cause mortality (AHR, 0.76; 95% CI, 0.68-0.84), kidney events (AHR, 0.52; 95% CI, 0.37-0.73), acute kidney injury (AHR, 0.78; 95% CI, 0.70-0.88), and major adverse kidney events (AHR, 0.54; 95% CI, 0.44-0.67). Treatment with tirzepatide was associated with greater decreases in glycated hemoglobin (treatment difference, -0.34 percentage points; 95% CI, -0.44 to -0.24 percentage points) and body weight (treatment difference, -2.9 kg, 95% CI, -4.8 to -1.1 kg) compared with GLP-1 RA. An interaction test for subgroup analysis revealed consistent results stratified by estimated glomerular filtration rate, glycated hemoglobin level, body mass index, comedications, and comorbidities. Conclusions and Relevance: In this study, treatment with tirzepatide was associated with lower hazards of all-cause mortality, adverse cardiovascular events, acute kidney injury, and adverse kidney events compared with GLP-1 RA in patients with type 2 diabetes. These findings support the integration of tirzepatide into therapeutic strategies for this population.

The P2X7 receptor mediates NADPH transport across the plasma membrane.

Nicotinamide Adenine Dinucleotide Phosphate (NADPH) plays a vital role in regulating redox homeostasis and reductive biosynthesis. However, if exogenous NADPH can be transported across the plasma membrane has remained elusive. In this study, we present evidence supporting that NADPH can traverse the plasma membranes of cells through a mechanism mediated by the P2X7 receptor (P2X7R). Notably, we observed an augmentation of intracellular NADPH levels in cultured microglia upon exogenous NADPH supplementation in the presence of ATP. The P2X7R-mediated transmembrane transportation of NADPH was validated with P2X7R antagonists, including OX-ATP, BBG, and A-438079, or through P2X7 knockdown, which impeded NADPH transportation into cells. Conversely, overexpression of P2X7 resulted in an enhanced capacity for NADPH transport. Furthermore, transfection of hP2X7 demonstrated the ability to complement NADPH uptake in native HEK293 cells. Our findings provide evidence for the first time that NADPH is transported across the plasma membrane via a P2X7R-mediated pathway. Additionally, we propose an innovative avenue for modulating intracellular NADPH levels. This discovery holds promise for advancing our understanding of the role of NADPH in redox homeostasis and neuroinflammation.

CCKBR+ cancer cells contribute to the intratumor heterogeneity of gastric cancer and confer sensitivity to FOXO inhibition.

The existence of heterogeneity has plunged cancer treatment into a challenging dilemma. We profiled malignant epithelial cells from 5 gastric adenocarcinoma patients through single-cell sequencing (scRNA-seq) analysis, demonstrating the heterogeneity of gastric adenocarcinoma (GA), and identified the CCKBR+ stem cell-like cancer cells associated poorly differentiated and worse prognosis. We further conducted targeted analysis using single-cell transcriptome libraries, including 40 samples, to confirm these screening results. In addition, we revealed that FOXOs are involved in the progression and development of CCKBR+ gastric adenocarcinoma. Inhibited the expression of FOXOs and disrupting cancer cell stemness reduce the CCKBR+ GA organoid formation and impede tumor progression. Mechanically, CUT&Tag sequencing and Lectin pulldown revealed that FOXOs can activate ST3GAL3/4/5 as well as ST6GALNAC6, promoting elevated sialyation levels in CCKBR+ tumor cells. This FOXO-sialyltransferase axis contributes to the maintenance of homeostasis and the growth of CCKBR+ tumor cells. This insight provides novel perspectives for developing targeted therapeutic strategies aimed at the treating CCKBR associated gastric cancer.

Women's Revenge in Sexual Behavior? An Interpretation About "The Fourth Love" in Chinese Youth Culture From the Perspective of Gender Performativity.

In the current era of exploring changing sexual behavior, promoting and supporting the diversity of pleasure, the sexual health and rights of sexual minorities are getting more public attention, among which the "Fourth Love" emerges as a distinctive group within the framework of Chinese culture. Fourth Love refers to a loving relationship between couples of the opposite sex where the woman assumes the traditional male gender role and the man assumes the traditional female gender role, and always accompanied by a special pattern of sexual behavior that women penetrate the men's anus using their fingers or a device. This theoretical article begins by introducing and discussing the historical background, core concept "Fourth Love" and its related categories. Subsequently, we start from Judith Butler's gender performativity theory and interpret the Fourth Love from the perspective of "de-naturalization" and argue that the gender performativity theory provides a reasonable explanation for the gender characteristics (female top and male bottom) of the Fourth Love. Finally, we posit a discussion and outlook on the survival and development of the Fourth Love in the fields of sexual health, sexual pleasure, sexual right, and family and marriage, and calls for more understanding and psychological support from the society for them.

Endoscopic polidocanol foam sclerobanding for the treatment of grade II-III internal hemorrhoids: A prospective, multi-center, randomized study.

BACKGROUND: Endoscopic rubber band ligation (ERBL) is a nonsurgical technique for the treatment of symptomatic internal hemorrhoids but is limited by recurrence and post-procedural pain. AIM: To evaluate satisfaction, long-term recurrence, and post-procedural pain in managing internal hemorrhoids using a combination of polidocanol foam sclerotherapy and ERBL. METHODS: This was a prospective, multicenter, randomized study. A total of 195 consecutive patients diagnosed with grade II-III internal hemorrhoids were enrolled from four tertiary hospitals and randomly divided into a cap-assisted endoscopic polidocanol foam sclerobanding (EFSB) or an ERBL group. All patients were followed-up for 12 months. Symptom-based severity and post-procedural pain were assessed using a hemorrhoid severity score (HSS) and a visual analog scale (VAS). Continuous variables were reported as medians and interquartile range. RESULTS: One hundred and ninety-five patients were enrolled, with 98 in the EFSB group. HSS was lower in the EFSB group than in the ERBL group at 8 weeks [4.0 (3.0-5.0) vs 5.0 (4.0-6.0), P = 0.003] and 12-month [2.0 (1.0-3.0) vs 3.0 (2.0-3.0), P < 0.001] of follow-up. The prolapse recurrence rate was lower in the EFSB group at 12 months (11.2% vs 21.6%, P = 0.038). Multiple linear regression analysis demonstrated that EFSB treatment [B = -0.915, 95% confidence interval (CI): -1.301 to -0.530, P = 0.001] and rubber band number (B = 0.843, 95%CI: 0.595-1.092, P < 0.001) were negatively and independently associated with the VAS score 24 hours post-procedure. The median VAS was lower in the EFSB group than in the ERBL [2.0 (1.0-3.0) vs 3.0 (2.0-4.0), P < 0.001]. CONCLUSION: Cap-assisted EFSB provided long-term satisfaction and effective relief from the recurrence of prolapse and pain 24 hours post-procedure.

BCAA mediated microbiota-liver-heart crosstalk regulates diabetic cardiomyopathy via FGF21.

BACKGROUND: Diabetic cardiomyopathy (DCM) is one of leading causes of diabetes-associated mortality. The gut microbiota-derived branched-chain amino acids (BCAA) have been reported to play a central role in the onset and progression of DCM, but the potential mechanisms remain elusive. RESULTS: We found the type 1 diabetes (T1D) mice had higher circulating BCAA levels due to a reduced BCAA degradation ability of the gut microbiota. Excess BCAA decreased hepatic FGF21 production by inhibiting PPARα signaling pathway and thereby resulted in a higher expression level of cardiac LAT1 via transcription factor Zbtb7c. High cardiac LAT1 increased the levels of BCAA in the heart and then caused mitochondrial damage and myocardial apoptosis through mTOR signaling pathway, leading to cardiac fibrosis and dysfunction in T1D mice. Additionally, transplant of faecal microbiota from healthy mice alleviated cardiac dysfunction in T1D mice, but this effect was abolished by FGF21 knockdown. CONCLUSIONS: Our study sheds light on BCAA-mediated crosstalk among the gut microbiota, liver and heart to promote DCM and FGF21 serves as a key mediator. Video Abstract.

Capecitabine mitigates cardiac allograft rejection via inhibition of TYMS-Mediated Th1 differentiation in mice.

OBJECTIVES: Previous studies elucidated that capecitabine (CAP) works as an anti-tumor agent with putative immunosuppressive effects. However, the intricate mechanisms underpinning these effects remain to be elucidated. In this study, we aimed to unravel the molecular pathways by which CAP exerts its immunosuppressive effects to reduce allograft rejection. METHODS: Hearts were transplanted from male BALB/c donors to male C57BL/6 recipients and treated with CAP for seven days. The rejection of these heart transplants was assessed using a range of techniques, including H&E staining, immunohistochemistry, RNA sequencing, LS-MS/MS, and flow cytometry. In vitro, naïve CD4+ T cells were isolated and cultured under Th1 condition medium with varying treatments, flow cytometry, LS-MS/MS were employed to delineate the role of thymidine synthase (TYMS) during Th1 differentiation. RESULTS: CAP treatment significantly mitigated acute allograft rejection and enhanced graft survival by reducing graft damage, T cell infiltration, and levels of circulating pro-inflammatory cytokines. Additionally, it curtailed CD4+ T cell proliferation and the presence of Th1 cells in the spleen. RNA-seq showed that TYMS, the target of CAP, was robustly increased post-transplantation in splenocytes. In vitro, TYMS and its metabolic product dTMP were differentially expressed in Th0 and Th1, and were required after activation of CD4+ T cell and Th1 differentiation. TYMS-specific inhibitor, raltitrexed, and the metabolite of capecitabine, 5-fluorouracil, could inhibit the proliferation and differentiation of Th1. Finally, the combined use of CAP and the commonly used immunosuppressant rapamycin can induce long-term survival of allograft. CONCLUSION: CAP undergoes metabolism conversion to interfere pyrimidine metabolism, which targets TYMS-mediated differentiation of Th1, thereby playing a significant role in mitigating acute cardiac allograft rejection in murine models.

Highly sensitive chemiluminescent sensor for detecting o-toluenesulfonamide and sulfamethoxazole using Cu-doped carbon dots.

In this study, Cu doped carbon dots (Cu-CDs) of uniform particle size and good water solubility was synthesized using Angelica Sinensis Radix as precursor materials through a one-step hydrothermal. The Lucigenin-(Cu-CDs) chemiluminescence sensor allows the simultaneous determination of o-toluenesulfonamide (TFA) and sulfamethoxazole (STZ) concentrations. Under optimal conditions, the sensor demonstrates the capability to detect TFA and STZ within the ranges of 50 µM-800 µM and 15 µM-120 µM, respectively. The limits of detection (LOD) for TFA and STZ are determined as 0.09 µM and 0.05 µM, respectively. While the limits of quantification (LOQ) are established at 0.3 µM and 0.17 µM, respectively. The feasibility of the method for determining TFA and STZ content in chicken samples was substantiated, demonstrating spiked recovery rates ranging from 97.5% to 102.3 % and 97.5%-99.8 %, respectively. The possible reaction mechanism was clarified based on chemiluminescence, UV-vis measurement and free radical analysis results. The newly established system is characterized by stability, convenience, and robust anti-interference capabilities, thus expanding the application of carbon dots and offering a promising strategy for the detection of TFA and STZ.

Tumor immune microenvironment of NSCLC with EGFR exon 20 insertions may predict efficacy of first-line ICI-combined regimen.

OBJECTIVES: Non-small cell lung cancer (NSCLC) patients with exon 20 insertion mutations (ex20ins) of the epidermal growth factor receptor (EGFR) were resistant to monotherapy of immune checkpoint inhibitor (ICI). However, recent reports have shown that the combination of ICI and chemotherapy (ICI-combined regimen) exhibited certain efficacy for NSCLC with EGFR ex20ins. The mechanisms behind this phenomenon have not been thoroughly clarified. Hence, we conducted this study tofind correlations between the tumor immune microenvironment of EGFR ex20ins and the efficacy of ICI-combined regimen. METHODS: We performed single-cell transcriptome sequencing and multiplex immunofluorescence staining (mIF) to investigate the immune microenvironment of NSCLC patients with EGFR ex20ins, L858R, and EGFR wild-type. We analyzed 15 treatment-naïve NSCLC samples utilizing single-cell RNA sequencing (scRNA-seq). Another 30 cases of EGFR L858R and 4 cases of wild-type were recruited to compare the immune microenvironment with that of EGFR ex20ins (28 cases) by mIF. RESULTS: We observed that cell components, function and interactions varied between EGFR ex20ins, L858R, and wild-type NSCLC.We discovered similar T cell and CD8+ T cell distributions among groups but found noninferior or even better T cell activation in ex20ins patients. Infiltrating CD8+ FOXP3- T cells were significantly lower in the tumor region of EGFR ex20ins compared to wild-type. T cells from the ex20ins group had a greater tendency to promote cancer cell inflammation and epithelial-mesenchymal transition (EMT) compared to wild-type group. For macrophages, there were more M2-like macrophages in ex20ins patients. M1-like macrophages in ex20ins group produced fewer antitumor cytokines than in other groups. CONCLUSIONS: The immune microenvironment of EGFR ex20ins is more suppressive than that of L858R and wild-type, suggesting that ICI monotherapy may not be sufficient for these patients. ICI-combined regimen might be a treatment option for EGFR ex20ins due to tumor-promoting inflammation and noninferior T cell functions in the immune microenvironment.