Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.

BACKGROUND: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis. METHODS: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235. FINDINGS: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]). INTERPRETATION: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer. FUNDING: AstraZeneca.

Lactiplantibacillusplantarum JS19-adjunctly fermented goat milk alleviates D-galactose-induced aging by modulating oxidative stress and intestinal microbiota in mice.

Oxidative stress is a crucial factor in the age-related decline in physiological, genomic, metabolic, and immunological functions. We screened Lactiplantibacillus plantarum JS19 (L. plantarum JS19), which has been shown to possess therapeutic properties in mice with ulcerative colitis. In this study, L. plantarum JS19-adjunctly fermented goat milk (LAF) was employed to alleviate D-galactose-induced aging and regulate intestinal flora in an aging mouse model. The oral administration of LAF effectively improved the health of spleen and kidney in mice, while mitigating the hepatocyte and oxidative damage induced by D-galactose. Additionally, LAF alleviated D-galactose-induced dysbiosis of the intestinal flora by reducing the abundance of harmful bacteria Desulfovibrio and Helicobacter, while greatly promoting the growth of beneficial Rikenellaceae_RC9_gut_group and Eubacterium. Biomarker 5-hydroxyindole-3-acetic acid was found to be positively linked with those harmful bacteria, while bio-active metabolites were strongly correlated with the beneficial genus. These observations suggest that LAF possesses the capability to mitigate the effects of D-galactose-induced aging in a mouse model through the regulation of oxidative stress, the gut microbiota composition, and levels of fecal metabolites. Consequently, these findings shed light on the potential of LAF as a functional food with anti-aging properties.

Hydrogen Sulfide Promotes Postnatal Cardiomyocyte Proliferation by Upregulating SIRT1 Signaling Pathway.

Hydrogen sulfide (H2S) has been identified as a novel gasotransmitter and a substantial antioxidant that can activate various cellular targets to regulate physiological and pathological processes in mammals. However, under physiological conditions, it remains unclear whether it is involved in regulating cardiomyocyte (CM) proliferation during postnatal development in mice. This study mainly aimed to evaluate the role of H2S in postnatal CM proliferation and its regulating molecular mechanisms. We found that sodium hydrosulfide (NaHS, the most widely used H2S donor, 50-200 µM) increased neonatal mouse primary CM proliferation in a dose-dependent manner in vitro. Consistently, exogenous administration of H2S also promoted CM proliferation and increased the total number of CMs at postnatal 7 and 14 days in vivo. Moreover, we observed that the protein expression of SIRT1 was significantly upregulated after NaHS treatment. Inhibition of SIRT1 with EX-527 or si-SIRT1 decreased CM proliferation, while enhancement of the activation of SIRT1 with SRT1720 promoted CM proliferation. Meanwhile, pharmacological and genetic blocking of SIRT1 repressed the effect of NaHS on CM proliferation. Taken together, these results reveal that H2S plays a promotional role in proliferation of CMs in vivo and in vitro and SIRT1 is required for H2S-mediated CM proliferation, which indicates that H2S may be a potential modulator for heart development in postnatal time window.

Effectiveness of integrated care for older adults-based interventions on depressive symptoms: A systematic review and meta-analysis.

AIM: To pool existing studies to assess the overall effectiveness of integrated care for older adults (ICOPE)-based interventions in improving depressive symptoms in older adults. DESIGN: A systematic review and meta-analysis. DATA SOURCES: Ten databases were systematically searched from inception to 15 July 2023 and the search was last updated on 2 September 2023. METHODS: Standardized mean difference (SMD) was calculated using random effects models. RoB 2 and GRADEpro GDT were used to assess the methodological quality and confidence in the cumulative evidence. Funnel plots, egger's test and begg's test were used to analyse publication bias. Sensitivity, subgroup and meta-regression analyses were performed to explore potential sources of heterogeneity. RESULTS: The results of 18 studies showed ICOPE-based interventions had a significant effect on improving depressive symptoms (SMD = -.84; 95% CI, -1.20 to -.3647; p < .001; 18 RCTs, 5010 participants; very low-quality evidence). Subgroup analysis showed the intervention group was characterized by mean age (70-80 years old), intervention duration between 6 to 12 months, gender (female <50%), non-frail older adults, depressed older adults and mixed integration appeared to be more effective. Sensitivity analysis found the results to be robust. CONCLUSION: ICOPE-based interventions may be a potentially effective alternative approach to reduce depressive symptoms in the older adults. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Healthcare professionals are expected to use ICOPE as one of the interventions for depressive symptoms in older adults, and this ICOPE could provide more comprehensive care services for older adults to reduce depressive symptoms. IMPACT: ICOPE-based interventions may be a potentially effective alternative approach to reduce depressive symptoms in the older adults. ICOPE-based interventions had a significant effect on reducing depressive symptoms in the older adults. The intervention group characterized by mean age of older adults, intervention duration, gender ratio, health condition and integration types may influence the effect size. REPORTING METHOD: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

Dual-sensitized heterojunction Ag2S/ZnS/NiS composites with entire visible-light region absorption for ultrasensitive photoelectrochemical detection of tobramycin.

In this study, an ultrasensitive photoelectrochemical (PEC) aptasensor based on dual-sensitized heterojunction Ag2S/ZnS/NiS composites as a signal probe was proposed for the detection of tobramycin (TOB) by combining a cascaded quadratic signal amplification strategy. Specifically, compared to the limited visible light-harvesting capability of single sensitized composites, Ag2S/ZnS/NiS composites with p-n and n-n heterojunction could greatly improve the light energy utilization to tremendously strengthen the optical absorption in the entire visible-light region. Moreover, dual-sensitized heterojunction could effectively hinder the rapid recombination of photoelectrons and holes (carriers) to obtain a good photocurrent for improving the sensitivity of the aptasensor. Furthermore, a cascaded quadratic signal amplification strategy was applied to convert trace target TOB into plentiful gold nanoclusters (Au NCs) labelled double-stranded DNA for the construction of PEC aptasensor, with a broad linear detection range from 0.01 to 100 ng mL-1 and a low detection limit of 3.38 pg mL-1. Importantly, this study provided a versatile and sensitive PEC biosensing platform for TOB analysis, and demonstrated its successful application for TOB detection in milk samples. This protocol provides a novel dual-sensitized heterojunction composites to develop a highly efficient and harmfulless PEC aptasensor, which is expected to be used in food safety, environmental monitoring and other areas.

Clinical features and lymphocyte immunophenotyping analysis in primary immunodeficiency patients with non-transplant lymphoproliferative disorders.

Lymphoproliferative disorders (LPD) comprise a heterogeneous group and are originally classified into the "Disease of immune dysregulation" category. Of 96 Taiwanese patients during 2003-2022, 31 (median 66, range 0.03-675 months) developed LPD, mainly including palpable lymphadenopathy (in 10 patients), intestinal lymphadenopathy associated with refractory inflammatory bowel disease (IBD in 8) and hepatosplenomegaly (in 7) during long-term follow-up (median 144, range 3-252 months). They distributed in the categories of antibody deficiency (2 CVID, 2 TTC37, PIK3CD, PIK3R1 and AICDA each), phagocyte (4 CYBB, 1 STAT1 and 1 IFNRG1), immune dysregulation (2 FOXP3, 2 XIAP and 2 HLH), combined immunodeficiencies (2 IL2RG; CD40L, ZAP70 and unknown each), syndromic features (2 STAT3-LOF, 1 WAS and 1 ATM) and three with anti-IFN-γ autoantibodies. An increased senescent (CD8 + CD57+) and CD21-low, disturbed transitional B (CD38 + IgM++), plasmablast B (CD38++IgM-), memory B (CD19 + CD27+) and TEMRA (CD27-IgD-) components were often observed in cross-sectional immunophenotyping and trended to develop LPD.

Investigating adherence to tyrosine kinase inhibitors in renal cancer.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have been used as the first-line treatment for many patients with renal cell carcinoma (RCC), the seventh most common cancer in the United Kingdom. However, suboptimal adherence to TKIs can result in poor clinical prognosis. This study quantified RCC patients' adherence to TKIs and explored factors associated with suboptimal adherence. METHOD: This retrospective cohort study was conducted at a specialist oncology tertiary hospital in Northwest England, using pharmacy dispensing records between November 2021 and March 2022. TKI prescriptions dispensed to patients with RCC were extracted to calculate the persistency gaps (≥7 or ≥14 days) and medication possession ratio (MPR). Multilevel regression analysis was conducted to associate MPR and persistency gaps with specific patient-related and TKI-related factors. This study did not require ethics approval. RESULTS: Of the 2225 prescriptions dispensed to 109 patients, 469 (23.4%) and 274 (13.7%) persistency gaps of ≥7 and ≥14 days were identified. About 75% and 92% of patients had a persistency gap of ≥7 days within the first 90 days and 180 days. The length of time since the first TKI prescription (p < 0.001) and the use of sunitinib(p = 0.003) were significantly associated with the number of prescription gaps of ≥7 days. Moreover, the median MPR was 95.6% (interquartile range: 90.7%, 100.1%). Similarly, the length of time since the first TKI prescription was dispensed (p < 0.001) and the use of sunitinib (p = 0.034) were significantly associated with MPR. DISCUSSION AND CONCLUSION: This single-centre study found that patients with RCC generally adhere to TKIs (MPR > 90%), but many patients experienced a persistency gap. The crucial window to mitigate TKI utilisation is within 180 days after the initial dispensing of TKIs. Further large-scale studies are required to comprehensively investigate other factors associated with adherence to TKIs and develop interventions to improve adherence and medication use problems.

Theoretical Validation of Non-Noble Cu Sites Integrated on SnO2 Nanoflowers for Enhanced Gas Sensing of Ethanethiol at Room Temperature.

Ethanethiol (EtSH), being highly toxic, flammable, and explosive, poses significant risks to human health and safety and is capable of causing fires and explosions. Room-temperature detection using chemiresistive gas sensors is essential for managing these risks. However, the gas-sensing performance of conventional metal-oxide sensing materials may be limited by their weak interaction with EtSH at room temperature. Herein, SnO2 nanoflowers assembled with non-noble Cu-site-enriched porous nanosheets were designed and prepared by an in situ self-template pyrolysis synthesis strategy to enable highly sensitive and selective room-temperature detection of EtSH. By regulating the number of non-noble Cu sites, these nanoflowers achieved efficient EtSH sensing with a Ra/Rg value of 11.0 at 50 ppb, ensuring high selectivity, reproducibility, and stability at room temperature. Moreover, a comparative analysis of the room-temperature gas-sensing performance of SnO2 nanoflowers with non-noble Fe- or Ni-site-enriched nanosheets highlights the benefits of non-noble Cu sites for EtSH detection. Density functional theory (DFT) analysis reveals that non-noble Cu sites have a unique affinity for EtSH, offering preferential binding over other gases and explaining the outstanding sensing performance of non-noble Cu-site-enriched nanosheet-assembled SnO2 nanoflowers. The structural and interface engineering of the sensing materials presented in this work provides a promising approach for offering efficient and durable gas sensors operable at room temperature.

Inhibiting mitochondrial citrate shuttling induces hepatic triglyceride deposition in Nile tilapia (Oreochromis niloticus) through lipid anabolic remodeling.

The solute carrier family 25 member 1 (Slc25a1)-dependent mitochondrial citrate shuttle is responsible for exporting citrate from the mitochondria to the cytoplasm for supporting lipid biosynthesis and protein acetylation. Previous studies on Slc25a1 concentrated on pathological models. However, the importance of Slc25a1 in maintaining metabolic homeostasis under normal nutritional conditions remains poorly understood. Here, we investigated the mechanism of mitochondrial citrate shuttle in maintaining lipid metabolism homeostasis in male Nile tilapia (Oreochromis niloticus). To achieve the objective, we blocked the mitochondrial citrate shuttle by inhibiting Slc25a1 under normal nutritional conditions. Slc25a1 inhibition was established by feeding Nile tilapia with 250 mg/kg 1,2,3-benzenetricarboxylic acid hydrate for six weeks or intraperitoneal injecting them with dsRNA to knockdown slc25a1b for seven days. The Nile tilapia with Slc25a1 inhibition exhibited an obesity-like phenotype accompanied by fat deposition, liver damage and hyperglycemia. Moreover, Slc25a1 inhibition decreased hepatic citrate-derived acetyl-CoA, but increased hepatic triglyceride levels. Furthermore, Slc25a1 inhibition replenished cytoplasmic acetyl-CoA through enhanced acetate pathway, which led to hepatic triglycerides accumulation. However, acetate-derived acetyl-CoA caused by hepatic Slc25a1 inhibition did not activate de novo lipogenesis, but rather modified protein acetylation. In addition, hepatic Slc25a1 inhibition enhanced fatty acids esterification through acetate-derived acetyl-CoA, which increased Lipin1 acetylation and its protein stability. Collectively, our results illustrate that inhibiting mitochondrial citrate shuttle triggers lipid anabolic remodeling and results in lipid accumulation, indicating the importance of mitochondrial citrate shuttle in maintaining lipid metabolism homeostasis.

Clinical impact and role of major vessels involvement in laparoscopic resection for hepatic hemangioma.

BACKGROUND: Severe bleeding remains a significant concern in laparoscopic resection for hepatic hemangioma. It is rarely reported that how the degree of major vessels involvement impacts on severe bleeding. The present study primarily aimed to analyze the impacts of the number of involved major vessels (NIMV) during laparoscopic surgery for hepatic hemangioma and evaluate the risk factors associated with increased bleeding. METHODS: A database search was carried out for consecutive patients who underwent laparoscopic resection for liver hemangiomas at our department from January 2018 to December 2023. The collected data included demographics, characteristics of the hemangiomas, laboratory data, operation method, surgical and postoperative variables. RESULTS: A total of 72 patients were enrolled in the study. 42 patients were categorized into the group with NIMV < 2, while 30 patients were divided into the group with NIMV ≥ 2. The group with NIMV ≥ 2 demonstrated a significant correlation with special segments, involved multiple segments and diameter of the hemangiomas (P < 0.01). And the perioperative variables including the extent of resection, operative time, blood loss, Pringle maneuver times, postoperative stay, drainage tube duration, and postoperative liver function (ALT, AST) also showed significant differences between the two groups (P < 0.05). Notably, NIMV ≥ 2 was identified as the most important independent risk factor for intraoperative blood loss ≥ 500 ml in laparoscopic surgery for hepatic hemangioma (P = 0.011). For NIMV ≥ 2, the independent risk factor was special segments in multivariate analysis (P = 0.000). CONCLUSION: The involvement of multiple major vessels (NIMV ≥ 2) was significantly associated with special segments, resulting in increased intraoperative blood loss, operation difficulty, and delayed postoperative recovery. Moreover, it was identified as the single independent risk factor with a considerable risk for increased blood loss during laparoscopic resection for hepatic hemangioma.

Ultrasound-mediated delivery of doxorubicin to the brain results in immune modulation and improved responses to PD-1 blockade in gliomas.

Given the marginal penetration of most drugs across the blood-brain barrier, the efficacy of various agents remains limited for glioblastoma (GBM). Here we employ low-intensity pulsed ultrasound (LIPU) and intravenously administered microbubbles (MB) to open the blood-brain barrier and increase the concentration of liposomal doxorubicin and PD-1 blocking antibodies (aPD-1). We report results on a cohort of 4 GBM patients and preclinical models treated with this approach. LIPU/MB increases the concentration of doxorubicin by 2-fold and 3.9-fold in the human and murine brains two days after sonication, respectively. Similarly, LIPU/MB-mediated blood-brain barrier disruption leads to a 6-fold and a 2-fold increase in aPD-1 concentrations in murine brains and peritumoral brain regions from GBM patients treated with pembrolizumab, respectively. Doxorubicin and aPD-1 delivered with LIPU/MB upregulate major histocompatibility complex (MHC) class I and II in tumor cells. Increased brain concentrations of doxorubicin achieved by LIPU/MB elicit IFN-γ and MHC class I expression in microglia and macrophages. Doxorubicin and aPD-1 delivered with LIPU/MB results in the long-term survival of most glioma-bearing mice, which rely on myeloid cells and lymphocytes for their efficacy. Overall, this translational study supports the utility of LIPU/MB to potentiate the antitumoral activities of doxorubicin and aPD-1 for GBM.

Unveiling biochar potential to promote safe crop production in toxic metal(loid) contaminated soil: A meta-analysis.

Biochar application emerges as a promising and sustainable solution for the remediation of soils contaminated with potentially toxic metal (loid)s (PTMs), yet its potential to reduce PTM accumulation in crops remains to be fully elucidated. In our study, a hierarchical meta-analysis based on 276 research articles was conducted to quantify the effects of biochar application on crop growth and PTM accumulation. Meanwhile, a machine learning approach was developed to identify the major contributing features. Our findings revealed that biochar application significantly enhanced crop growth, and reduced PTM concentrations in crop tissues, showing a decrease trend of grains (36.1%, 33.6-38.6%) > shoots (31.1%, 29.3-32.8%) > roots (27.5%, 25.7-29.2%). Furthermore, biochar modifications were found to amplify its remediation potential in PTM-contaminated soils. Biochar application was observed to provide favorable conditions for reducing PTM uptake by crops, primarily through decreasing available PTM concentrations and improving overall soil quality. Employing machine learning techniques, we identified biochar properties, such as surface area and C content as a key factor in decreasing PTM bioavailability in soil-crop systems. Furthermore, our study indicated that biochar application could reduce probabilistic health risks associated with of the presence of PTMs in crop grains, thereby contributing to human health protection. These findings highlighted the essential role of biochar in remediating PTM-contaminated lands and offered guidelines for enhancing safe crop production.

Potential of artificial soil preparation for vegetation restoration using red mud and phosphogypsum.

Red mud and phosphogypsum have long been a focus and challenge in global industrial waste management, and their low-cost and large-scale utilization technology has always been an urgent need. This study is based on the strong acid-base neutralization reaction between red mud and phosphogypsum, which contain an elemental composition similar to that of natural soil, red mud itself has characteristic of clay minerals, and other auxiliary materials (i.e. rice husk powder, bentonite, fly ash, polyacrylamide flocculant and microbial suspension) were added, so as to explore the potential of synergistically prepared artificial soil for vegetation restoration. The results showed that the artificial soils exhibited physicochemical characteristics (e.g., pH, moisture content, cation exchange capacity) similar to those of natural soil, along with abundant organic matter, nitrogen, phosphorus, and potassium contents, meeting the growth requirements of plants. The artificial soils were able to support favorable growth of suitable plants (e.g., sunflower, wheat, rye grass), accumulating high levels of diverse enzymatic activities, comparable to those in natural soils (e.g., catalase, urease, phosphatase), or even surpassing natural soils (e.g., sucrase), and rich microorganism communities, such as Cyanobacteria, Proteobacteria, Actinobacteria in the bacteria domain, and Ascomycota in the fungi domain, were initially developed. It's suggested that preparing 1 ton of artificial soil entails synergistic consumption of 613.7 kg of red mud and 244.6 kg of phosphogypsum, accounting for mass proportions of 61.4 % and 24.5 %, respectively. In future, more evaluations on the leaching loss of nutrients and alkalinity and the environmental risks of heavy metals should be conducted to more references for the artificial soil application. In summary, the preparation of artificial soil is a very simple, efficient, scalable and low-cost collaborative resource utilization scheme of red mud and phosphogypsum, which has great potential for vegetation restoration in some places such as tailings field and soil-deficient depression.

Effectiveness of Kinesio tape in the treatment of patients with patellofemoral pain syndrome: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the clinical effectiveness of the Kinesio tape in the treatment of patellofemoral pain syndrome (PFPS) by meta-analysis. METHODS: Two investigators independently conducted an electronic literature search to assess the outcomes of intramuscular patches for PFPS. Electronic databases included PubMed, Embase, Web of Science, Cochrane Library, Wanfang Database, Chinese Journal Full Text Database (CNKI), and Wipo Database from November 2023. Extracted inclusion indicators included pain score VAS or NRS, knee function assessment knee pain syndrome (Kujala) score, and knee symptom score Lysholm knee score scale. Data were extracted and then meta-analyzed using Review Manager 5.3 software and Stata 17.0 software. RESULT: Fourteen studies were included, all of which were randomized controlled studies. The results showed that short-term pain relief was superior in the Kinesio tape (KT) group compared with the control group, with a statistically significant difference in the results (MD = -1.54, 95% CI [-2.32, -0.76], P = .0001); medium-term pain relief was superior in the KT group compared with the control group, with a statistically significant difference in the results (MD = -0.84, 95% CI [-1.50, -0.18], P = .01); long-term pain relief in the KT group was better than the control group, with statistically different results (MD = -0.56, 95% CI [-0.98, -0.13], P < .00001). In contrast, there was no significant difference between the KT group and the control group in the assessment of knee function (MD = -0.98, 95% CI [-4.03, 2.06], P = .03), and there was no significant difference between the KT group and the control group in the Lysholm knee score scale score of knee symptoms (MD = 4.18, 95% CI [-6.70, 15.05], P = .45). CONCLUSION: Kinesio taping can effectively relieve the pain of PFPS, but has no significant effect on the improvement of knee joint function and symptoms.

Rutin prevents EqHV-8 induced infection and oxidative stress via Nrf2/HO-1 signaling pathway.

Introduction: The Nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway has been extensively studied for its role in regulating antioxidant and antiviral responses. The Equid herpesvirus type 8 (EqHV-8) poses a significant threat to the equine industry, primarily manifesting as respiratory disease, abortions, and neurological disorders in horses and donkeys. Oxidative stress is considered a key factor associated with pathogenesis of EqHV-8 infection. Unfortunately, there is currently a dearth of therapeutic interventions available for the effective control of EqHV-8. Rutin has been well documented for its antioxidant and antiviral potential. In current study we focused on the evaluation of Rutin as a potential therapeutic agent against EqHV-8 infection. Methods: For this purpose, we encompassed both in-vitro and in-vivo investigations to assess the effectiveness of Rutin in combatting EqHV-8 infection. Results and Discussion: The results obtained from in vitro experiments demonstrated that Rutin exerted a pronounced inhibitory effect on EqHV-8 at multiple stages of the viral life cycle. Through meticulous experimentation, we elucidated that Rutin's antiviral action against EqHV-8 is intricately linked to the Nrf2/HO-1 signaling pathway-mediated antioxidant response. Activation of this pathway by Rutin was found to significantly impede EqHV-8 replication, thereby diminishing the viral load. This mechanistic insight not only enhances our understanding of the antiviral potential of Rutin but also highlights the significance of antioxidant stress responses in combating EqHV-8 infection. To complement our in vitro findings, we conducted in vivo studies employing a mouse model. These experiments revealed that Rutin administration resulted in a substantial reduction in EqHV-8 infection within the lungs of the mice, underscoring the compound's therapeutic promise in vivo. Conclusion: In summation, our finding showed that Rutin holds promise as a novel and effective therapeutic agent for the prevention and control of EqHV-8 infections.

Safety of subcutaneous immunotherapy with Novo-Helisen-Depot in the children: a retrospective analysis from a single center in Northern China.

Background: Little is known about the safety of mite extract product Novo-Helisen Depot (NHD) as subcutaneous immunotherapy (SCIT) in the children with mite allergy especially immediate/late local reaction (LRs). Methods: We conducted a retrospective study analyzing the adverse events of the children undergoing subcutaneous immunotherapy with NHD. Adverse events included local and systemic adverse reactions (SRs) at the very early and late stage. The correlation of the basic characteristics, laboratory analysis results, LRs and SRs were analyzed. Results: Two hundred and eighty-seven patients received at least 15 months of subcutaneous immunotherapy with NHD were included in the analysis. Skin-prick testing (SPT) results of D. pteronyssinus was associated with an increased risk of immediate LRs in build-up phase (OR = 1.53, 95% CI: 1.02, 2.37) and delayed LRs in maintenance phase (OR = 1.58, 95% CI: 1.05, 2.46), while SPT results of D. farinae was associated with an increased risk of SRs (OR = 3.22, 95% CI: 1.17, 10.00) and severe SRs (OR = 7.68, 95% CI: 1.13, 109.50). Serum IgE level of D. pteronyssinus was associated with an increased risk of SRs (OR = 1.01, 95% CI: 1.00, 1.03). Patients with both asthma and allergic rhinitis was associated with an increased risk of SR, and severe SRs (P < 0.05). Conclusion: NHD as SCIT is safe. The children with higher SPT level with D. farinae or D. pteronyssinus, higher serum IgE level of D. pteronyssinus, children with both asthma and allergic rhinitis, and the children with treatment interruption had higher risk of adverse events.

Improved accuracy of spectral-domain optical coherence tomography and optical coherence tomography angiography for monitoring myopic macular neovascularisation activity.

BACKGROUND/AIMS: To evaluate the diagnostic accuracy of spectral-domain optical coherence tomography (SD OCT) combined with OCT angiography (OCTA) for myopic myopic macular neovascularisation (MNV) activity. METHODS: Both eyes of patients with myopic MNV diagnosed with fluorescein angiography (FA), SD OCT and OCTA were assessed by unmasked investigators. The images were deidentified and randomised before graded by masked investigators, who determined the presence of active myopic MNV by using SD OCT together with OCTA without FA and by FA alone, respectively. The findings of masked investigators were compared with unmasked investigators. RESULTS: 213 eyes of 110 patients comprising 499 imaging episodes were eligible for grading. For diagnosing new-onset myopic MNV without FA, combined use of SD OCT and OCTA had a sensitivity of 0.94, specificity of 0.84 and area under the curve (AUC) of 0.92. FA had a sensitivity of 0.52 (p<0.01), specificity of 0.80 (p=0.38) and AUC of 0.66 (p<0.01). For recurrent myopic MNV, the combination of SD OCT and OCTA had a sensitivity of 0.98, specificity of 0.78 and AUC of 0.88. FA had a sensitivity of 0.50 (p=0.04), specificity of 0.76 (p=0.85) and AUC of 0.63 (p=0.01). Myopic traction maculopathy was more frequently associated with recurrent myopic MNV (p<0.01). CONCLUSION: SD OCT with dense volumetric scan was highly sensitive for diagnosing myopic MNV. The addition of OCTA improved the diagnostic specificity without FA. Monitoring of the longitudinal changes on SD OCT and judicious use of FA is a reliable surveillance strategy for myopic MNV.

PUM2 promoted osteoarthritis progression through PTEN-mediated chondrocyte ferroptosis by facilitating NEDD4 mRNA degradation.

Osteoarthritis (OA) is a prevalent degenerative joint disease with a lack of effective therapeutic. Chondrocyte ferroptosis contributes to the progression of OA. PUM2 is shown to exacerbate ischemia-reperfusion-induced neuroinflammation by promoting ferroptosis, but its role in OA remains unexplored. Here, primary mouse chondrocytes were stimulated with IL-1ß to mimic OA chondrocyte injury in vitro. And PUM2 was upregulated in OA cartilage tissues and IL-1ß-induced chondrocytes. Silencing PUM2 alleviated IL-1ß-induced chondrocyte inflammation and ECM degradation. Mechanistically, PUM2 facilitated the degradation of NEDD4 mRNA by binding to the 3'UTR of NEDD4 mRNA, which in turn inhibited NEDD4 induced PTEN ubiquitination and degradation. Consistently, NEDD4 silencing reversed the ameliorative effect of PUM2 knockdown on chondrocyte injury, and overexpression of PTEN abolished the improved role of NEDD4 in chondrocyte injury. Moreover, PTEN aggravated IL-1ß-induced ferroptosis in chondrocytes through the Nrf2/HO-1 pathway by increasing the levels of Fe2+, ROS, MDA, and ACSL4 protein, decreasing the activity of SOD and the levels of GSH and GPX4 protein, and aggravating mitochondrial damage. Additionally, destabilized medial meniscus (DMM) were conducted to establish the OA mouse model, and adenovirus-mediated PUM2 shRNA was administered intra-articularly. Silencing PUM2 attenuated OA-induced cartilage damage in vivo. In conclusion, PUM2 promoted OA progression through PTEN-mediated chondrocyte ferroptosis by facilitating NEDD4 mRNA degradation.

Comprehensive analysis of T-cell regulatory factors and tumor immune microenvironment in stomach adenocarcinoma.

BACKGROUND: Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide and is associated with high morbidity and mortality rates. However, the specific biomarkers used to predict the postoperative prognosis of patients with gastric cancer remain unknown. Recent research has shown that the tumor microenvironment (TME) has an increasingly positive effect on anti-tumor activity. This study aims to build signatures to study the effect of certain genes on gastric cancer. METHODS: Expression profiles of 37 T cell-related genes and their TME characteristics were comprehensively analyzed. A risk signature was constructed and validated based on the screened T cell-related genes, and the roles of hub genes in GC were experimentally validated. RESULTS: A novel T cell-related gene signature was constructed based on CD5, ABCA8, SERPINE2, ESM1, SERPINA5, and NMU. The high-risk group indicated lower overall survival (OS), poorer immune efficacy, and higher drug resistance, with SERPINE2 promoting GC cell proliferation, according to experiments. SERPINE2 and CXCL12 were significantly correlated, indicating poor OS via the Youjiang cohort. CONCLUSIONS: This study identified T cell-related genes in patients with stomach adenocarcinoma (STAD) for prognosis estimation and proposed potential immunotherapeutic targets for STAD.

CD200R promotes high glucose-induced oxidative stress and damage in human retinal pigment epithelial cells by activating the mTOR signaling pathway.

Diabetic retinopathy (DR) is established as the primary cause of visual impairment and preventable blindness, posing significant social and economic burdens on healthcare systems worldwide. Oxidative stress has been identified as a major contributor to DR, yet the precise role of the transmembrane glycoprotein CD200R in this context remains elusive. We studied human retinal pigment epithelia ARPE-19 cells to investigate the role of CD200R in high-glucose (HG) induced oxidative stress. Under HG conditions, we found a significant increase in CD200R expression in a time-dependent pattern. Conversely, knockdown of CD200R effectively alleviated oxidative stress and restored cell viability in HG-treated ARPE-19 cells, a phenomenon corroborated by the addition of a reactive oxygen species (ROS) scavenger. Exploration of the AKT/mTOR signaling pathway confirmed its mediating role regarding CD200R knockdown suppression of the expression of key proteins induced by HG conditions. Additionally, we found that the inhibition of mTOR signaling with Rapamycin effectively countered HG-induced oxidative stress in ARPE-19 cells, suggesting a promising therapeutic target against oxidative stress in the context of DR. This study establishes the crucial role of CD200R in HG-induced oxidative stress and identifies potential therapeutic avenues for the treatment of DR.