Oncologic outcomes and associated factors of colon cancer patients aged 70 years and older.

Purpose: The aim of this study was to examine the prognosis and associated risk factors, including adjuvant chemotherapy (CTx), in elderly patients with colon cancer. Methods: This retrospective study included patients who underwent radical resection for colon cancer between January 2010 and December 2014 at Asan Medical Center. The effects of stage, risk factors, and chemotherapy on overall survival (OS) and recurrence-free survival (RFS) were compared in patients aged ≥70 and <70 years. Results: Of 3,313 patients, 933 (28.1%) was aged ≥70 years. Of the 1,921 patients indicated for adjuvant CTx, 1,294 of 1,395 patients (92.8%) aged <70 years and 369 of 526 patients (70.2%) aged ≥70 years received adjuvant CTx. Old age (≥70 years) was independently associated with RFS in overall cohort. Among patients aged ≥70 years indicated for adjuvant CTx, the 5-year OS (81.6% vs. 50.4%, P<0.001) and RFS (82.9% vs. 67.4%, P=0.025) rates were significantly higher in those who did than did not receive adjuvant CTx. Additionally, adjuvant CTx was confirmed as independent risk factor of both OS and RFS in patients aged ≥70 years indicated for adjuvant CTx. Conclusion: Old age was associated with poor RFS and adjuvant CTx had benefits in OS as well as RFS in elderly patients eligible for adjuvant CTx.

Blocking CTLA-4 promotes pressure overload-induced heart failure via activating Th17 cells.

Targeting cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) with specific antibody offers long-term benefits for cancer immunotherapy but can cause severe adverse effects in the heart. This study aimed to investigate the role of anti-CTLA-4 antibody in pressure overload-induced cardiac remodeling and dysfunction. Transverse aortic constriction (TAC) was used to induce cardiac hypertrophy and heart failure in mice. Two weeks after the TAC treatment, mice received anti-CTLA-4 antibody injection twice a week at a dose of 10 mg/kg body weight. The administration of anti-CTLA-4 antibody exacerbated TAC-induced decline in cardiac function, intensifying myocardial hypertrophy and fibrosis. Further investigation revealed that anti-CTLA-4 antibody significantly elevated systemic inflammatory factors levels and facilitated the differentiation of T helper 17 (Th17) cells in the peripheral blood of TAC-treated mice. Importantly, anti-CTLA-4 mediated differentiation of Th17 cells and hypertrophic phenotype in TAC mice were dramatically alleviated by the inhibition of interleukin-17A (IL-17A) by an anti-IL-17A antibody. Furthermore, the C-X-C motif chemokine receptor 4 (CXCR4) antagonist AMD3100, also reversed anti-CTLA-4-mediated cardiotoxicity in TAC mice. Overall, these results suggest that the administration of anti-CTLA-4 antibody exacerbates pressure overload-induced heart failure by activating and promoting the differentiation of Th17 cells. Targeting the CXCR4/Th17/IL-17A axis could be a potential therapeutic strategy for mitigating immune checkpoint inhibitors-induced cardiotoxicity.

BEROLECMI: a novel prediction method to infer circRNA-miRNA interaction from the role definition of molecular attributes and biological networks.

Circular RNA (CircRNA)-microRNA (miRNA) interaction (CMI) is an important model for the regulation of biological processes by non-coding RNA (ncRNA), which provides a new perspective for the study of human complex diseases. However, the existing CMI prediction models mainly rely on the nearest neighbor structure in the biological network, ignoring the molecular network topology, so it is difficult to improve the prediction performance. In this paper, we proposed a new CMI prediction method, BEROLECMI, which uses molecular sequence attributes, molecular self-similarity, and biological network topology to define the specific role feature representation for molecules to infer the new CMI. BEROLECMI effectively makes up for the lack of network topology in the CMI prediction model and achieves the highest prediction performance in three commonly used data sets. In the case study, 14 of the 15 pairs of unknown CMIs were correctly predicted.

Cystathionine γ-lyase inhibits mitochondrial oxidative stress by releasing H2S nearby through the AKT/NRF2 signaling pathway.

Cystathionine γ-lyase (CSE) is a major enzyme that produces hydrogen sulfide (H2S). Herein, we report how CSE plays a previously unknown role in regulating the antioxidant effects of the mitochondria in human umbilical vein endothelial cells by releasing H2S nearby under stress conditions. We found that H2S partially promoted angiogenesis in the endothelial cells through the AKT/nuclear factor erythroid 2-related factor 2 (AKT/NRF2) signaling pathway. H2S improved mitochondrial function by altering the expressions of the mitofusin2 and dynamin-1-like mitochondrial fission proteins to inhibit oxidative stress and enhance NRF2 nuclear translocation. CSE is located only in the cytoplasm and not in the mitochondria, but it is transported to the vicinity of the mitochondria to produce H2S, which plays an antioxidant role in human umbilical vein endothelial cells under stress. The CSE mutant (with mutated CSE activity center: CSED187A) partially decreased the effects on promoting angiogenesis, resisting oxidative stress, and entering the mitochondria. These results show that CSE translocation is a unique mechanism that promotes H2S production inside the mitochondria under stress stimulation. Therefore, the CSE mutant site (CSED187A) may be a potential target for drug therapy.

Utilizing radiomics and dosiomics with AI for precision prediction of radiation dermatitis in breast cancer patients.

PURPOSE: This study explores integrating clinical features with radiomic and dosiomic characteristics into AI models to enhance the prediction accuracy of radiation dermatitis (RD) in breast cancer patients undergoing volumetric modulated arc therapy (VMAT). MATERIALS AND METHODS: This study involved a retrospective analysis of 120 breast cancer patients treated with VMAT at Kaohsiung Veterans General Hospital from 2018 to 2023. Patient data included CT images, radiation doses, Dose-Volume Histogram (DVH) data, and clinical information. Using a Treatment Planning System (TPS), we segmented CT images into Regions of Interest (ROIs) to extract radiomic and dosiomic features, focusing on intensity, shape, texture, and dose distribution characteristics. Features significantly associated with the development of RD were identified using ANOVA and LASSO regression (p-value < 0.05). These features were then employed to train and evaluate Logistic Regression (LR) and Random Forest (RF) models, using tenfold cross-validation to ensure robust assessment of model efficacy. RESULTS: In this study, 102 out of 120 VMAT-treated breast cancer patients were included in the detailed analysis. Thirty-two percent of these patients developed Grade 2+ RD. Age and BMI were identified as significant clinical predictors. Through feature selection, we narrowed down the vast pool of radiomic and dosiomic data to 689 features, distributed across 10 feature subsets for model construction. In the LR model, the J subset, comprising DVH, Radiomics, and Dosiomics features, demonstrated the highest predictive performance with an AUC of 0.82. The RF model showed that subset I, which includes clinical, radiomic, and dosiomic features, achieved the best predictive accuracy with an AUC of 0.83. These results emphasize that integrating radiomic and dosiomic features significantly enhances the prediction of Grade 2+ RD. CONCLUSION: Integrating clinical, radiomic, and dosiomic characteristics into AI models significantly improves the prediction of Grade 2+ RD risk in breast cancer patients post-VMAT. The RF model analysis demonstrates that a comprehensive feature set maximizes predictive efficacy, marking a promising step towards utilizing AI in radiation therapy risk assessment and enhancing patient care outcomes.

Unveiling the dynamics of respiratory infections revealed by multiplex PCR testing during the COVID-19 pandemic in Taiwan, 2020-2023.

BACKGROUND: The emergence of SARS-CoV-2 in late 2019 sparked the global COVID-19 pandemic, leading to varied vaccine policies worldwide. The evolving patterns of respiratory pathogens, aside from SARS-CoV-2, during the pandemic have had a significant impact on the development of vaccine strategies. METHODS: This study explores the landscape of respiratory pathogens, encompassing SARS-CoV-2, respiratory syncytial virus (RSV), and influenza viruses, through a retrospective analysis of data obtained from the BioFire Respiratory Panel 2.1 (RP 2.1) at China Medical University Hospital (Taichung, Taiwan) spanning from January 2020 to November 2023. RESULTS: Among the 7950 respiratory samples studied, pediatric cases exhibited higher positivity (64.9%, 2488/3835) and mixed detection rates (43.8%, 1090/2488) than adults. Annual mixed detection rates increased (27.9-48%). Prevalence analysis revealed diverse patterns across age groups, with higher rates in pediatrics. Notably, human rhinovirus/enterovirus predominated (48.1%). Mixed detection illustrated viral co-detections, notably with parainfluenza viruses and adenovirus. Government policies and pandemic dynamics influenced infection patterns, with RSV resurgence after May 2022. Age-specific RSV detection demonstrated a shift, influencing vaccine considerations. Amid global vaccine initiatives, RSV's increasing trend in adults warrants attention. CONCLUSIONS: This comprehensive analysis emphasizes the importance of multiplex PCR testing in shaping targeted vaccination strategies during evolving respiratory pathogen landscapes.

The delivery of PD-L1 siRNA by neutrophil-targeted lipid nanoparticles effectively ameliorates sepsis.

BACKGROUND: Sepsis, a complex and life-threatening disease, poses a significant global burden affecting over 48 million individuals. Recently, it has been reported that programmed death-ligand 1 (PD-L1) expressed on neutrophils is involved in both inflammatory organ dysfunction and immunoparalysis in sepsis. However, there is a dearth of strategies to specifically target PD-L1 in neutrophils in vivo. METHODS: We successfully developed two lipid nanoparticles (LNPs) specifically targeting neutrophils by delivering PD-L1 siRNA via neutrophil-specific antibodies and polypeptides. In vivo and in vitro experiments were performed to detect lipid nanoparticles into neutrophils. A mouse cecal ligation and puncture (CLP) model was used to detect neutrophil migration, neutrophil extracellular traps (NETs) level, and organ damage. RESULT: The PD-L1 siRNA-loaded LNPs that target neutrophils suppressed inflammation, reduced the release of NETs, and inhibited T-lymphocyte apoptosis. This approach could help maintain homeostasis of both the immune and inflammatory responses during sepsis. Furthermore, the PD-L1 siRNA-loaded LNPs targeting neutrophils have the potential to ameliorate the multi-organ damage and lethality resulting from CLP. CONCLUSIONS: Taken together, our data identify a previously unknown drug delivery strategy targeting neutrophils, which represents a novel, safe, and effective approach to sepsis therapy.

Effectiveness of a delirium risk assessment and multidisciplinary care approach in reducing delirium incidence among surgical intensive care unit patients: A retrospective pre-post intervention study.

BACKGROUND: Delirium is a common complication in intensive care unit (ICU) patients. It can lead to various adverse events. In this study, we investigated the effectiveness of combining the use of the PREdiction of DELIRium (PRE-DELIRIC) model for delirium risk assessment and the use of a multicomponent care bundle for delirium assessment, prevention, and care in terms of reductions in the incidence of delirium among surgical ICU patients. METHODS: This retrospective study included surgical ICU patients who had received PRE-DELIRIC-guided SMART/SmART care (SMART care: SmART bundle plus multidisciplinary team; SmART care: Sleep/sweet sense of home (creating a comforting and restful environment for patients), Assessment (regular and thorough evaluation of patient needs and conditions), Release (revised endotracheal tube care/removal, restraint device care, and immobility reduction for patient comfort), and Time (reorientation of time to optimize patient care schedules) in our hospital between May 2022 and March 2023 (intervention group) and individuals who had received usual care between January 2021 and April 2022 (historical control group). The SmART intervention involves providing care in the following domains: sleep/sweet sense of home, assessment, release, and time. Patients with a PRE-DELIRIC score of >30% received SMART care, which includes multidisciplinary (physicians, pharmacists, respiratory therapists, and physiotherapists) care in addition to SmART care. For the control group, usual care was provided following the guidelines for the prevention and management of pain, agitation, delirium, immobility, and sleep disruption. The primary outcome was delirium incidence during ICU stay, which was assessed using the Intensive Care Delirium Screening Checklist. The secondary outcomes were the duration of ICU stay, rate of unplanned self-extubation, and status of ICU discharge. RESULTS: The intervention and control groups comprised 184 and 197 patients, respectively; their mean ages were 63.7 ± 18.4 years and 62.4 ± 19.5 years, respectively. The incidence of delirium was significantly lower (p = 0.001) in the intervention group (22.3%) than in the control group (47.7%). CONCLUSION: Our findings suggest that the PRE-DELIRIC-guided SMART/SmART care intervention is effective in preventing and managing delirium among surgical ICU patients.

Global, regional, and national burden of female cancers in women of child-bearing age, 1990-2021: analysis of data from the global burden of disease study 2021.

Background: The global status of women's health is underestimated, particularly the burden on women of child-bearing age (WCBA). We aim to investigate the pattern and trend of female cancers among WCBA from 1990 to 2021. Methods: We retrieved data from the Global Burden of Disease Study (GBD) 2021 on the incidence and disability-adjusted life-years (DALYs) of four major female cancers (breast, cervical, uterine, and ovarian cancer) among WCBA (15-49 years) in 204 countries and territories from 1990 to 2021. Estimated annual percentage changes (EAPC) in the age-standardised incidence and DALY rates of female cancers, by age and socio-demographic index (SDI), were calculated to quantify the temporal trends. Spearman correlation analysis was used to examine the correlation between age-standardised rates and SDI. Findings: In 2021, an estimated 1,013,475 new cases of overall female cancers were reported globally, with a significant increase in age-standardised incidence rate (EAPC 0.16%), and a decrease in age-standardised DALY rate (-0.73%) from 1990 to 2021. Annual increase trends of age-standardised incidence rate were observed in all cancers, except for that in cervical cancer. Contrary, the age-standardised DALY rate decreased in all cancers. Breast and cervical cancers were prevalent among WCBA worldwide, followed by ovarian and uterine cancers, with regional disparities in the burden of four female cancers. In addition, the age-standardised incidence rates of breast, ovarian, and uterine cancers basically showed a consistent upward trend with increasing SDI, while both the age-standardised incidence and DALY rates in cervical cancer exhibited downward trends with SDI. Age-specific rates of female cancers increased with age in 2021, with the most significant changes observed in younger age groups, except for uterine cancer. Interpretation: The rising global incidence of female cancers, coupled with regional variations in DALYs, underscores the urgent need for innovative prevention and healthcare strategies to mitigate the burden among WCBA worldwide. Funding: This study was supported by the Science Foundation for Young Scholars of Sichuan Provincial People's Hospital (NO. 2022QN44 and NO. 2022QN18); the Key R&D Projects of Sichuan Provincial Department of Science and Technology (NO. 2023YFS0196); the National Natural Science Foundation of China (No. 82303701).

Effects of oilseed rape green manure on phosphorus availability of red soil and rice yield in rice-green manure rotation system.

Improving the nutrient content of red soils in southern China is a priority for efficient rice production there. To assess the effectiveness of oilseed rape as green manure for the improvement of soil phosphorus nutrient supply and rice yield in red soil areas, a long-term field plot experiment was conducted comparing two species of rape, Brassica napus (BN) and Brassica juncea (BJ). The effects of returning oilseed rape on soil phosphorus availability, phosphorus absorption, and yield of subsequent rice under rice-green manure rotation mode were analyzed, using data from the seasons of 2020 to 2021. The study found that compared with winter fallow treatment (WT) and no-tillage treatment (NT), the soil available phosphorus content of BN was increased, and that of BJ was significantly increased. The content of water-soluble inorganic phosphorus of BJ increased, and that of BN increased substantially. Compared with the WT, the soil organic matter content and soil total phosphorus content of BN significantly increased, as did the soil available potassium content of BJ, and the soil total phosphorus content of BJ was significantly increased compared with NT. The soil particulate phosphorus content of BJ and BN was significantly increased by 14.00% and 16.00%, respectively. Compared with the WT, the phosphorus activation coefficient of BJ was significantly increased by 11.41%. The rice plant tiller number under the green manure returning treatment was significantly increased by 43.16% compared with the winter fallow treatment. The green manure returning measures increased rice grain yield by promoting rice tiller numbers; BN increased rice grain yield by 9.91% and BJ by 11.68%. Based on these results, returning oilseed rape green manure could augment the phosphorus nutrients of red soil and promote phosphorus availability. Rice-oilseed rape green manure rotation could increase rice grain yield.

Atypical Guillain-Barré syndrome with positive anti-sulfatide, anti-GT1b, and anti-GT1a antibodies: A case report.

BACKGROUND: The role of diverse antibodies in mediating peripheral nerve injury in Guillain-Barré syndrome (GBS) is becoming clearer, but positivity for multiple antibodies in one case is uncommon. To our knowledge, this is the first case involving GBS with positive anti-sulfatide, anti-GT1a, and anti-GT1b antibodies. CASE SUMMARY: A 20-year-old female patient was admitted to the hospital due to weakness of limbs for 5 d, and deterioration of the weakness and muscle aches for 1 d. The patient's limbs were weak, but the tendon reflexes in the part of the limbs were normal. There was no comorbid peripheral nociception or deep sensory dysfunction. She was diagnosed with GBS and was discharged after receiving intravenous human immunoglobulin pulse therapy. CONCLUSION: In this article, the clinical manifestations, neurophysiological examination, and auxiliary examination findings of a GBS patient positive for multiple antibodies were analyzed to improve the identification of the disease by clinical physicians at an early stage.

DNA cytosine methyltransferases differentially regulate genome-wide hypermutation and interhomolog recombination in Trichoderma reesei meiosis.

Trichoderma reesei is an economically important enzyme producer with several unique meiotic features. spo11, the initiator of meiotic double-strand breaks (DSBs) in most sexual eukaryotes, is dispensable for T. reesei meiosis. T. reesei lacks the meiosis-specific recombinase Dmc1. Rad51 and Sae2, the activator of the Mre11 endonuclease complex, promote DSB repair and chromosome synapsis in wild-type and spo11Δ meiosis. DNA methyltransferases (DNMTs) perform multiple tasks in meiosis. Three DNMT genes (rid1, dim2 and dimX) differentially regulate genome-wide cytosine methylation and C:G-to-T:A hypermutations in different chromosomal regions. We have identified two types of DSBs: type I DSBs require spo11 or rid1 for initiation, whereas type II DSBs do not rely on spo11 and rid1 for initiation. rid1 (but not dim2) is essential for Rad51-mediated DSB repair and normal meiosis. rid1 and rad51 exhibit a locus heterogeneity (LH) relationship, in which LH-associated proteins often regulate interconnectivity in protein interaction networks. This LH relationship can be suppressed by deleting dim2 in a haploid rid1Δ (but not rad51Δ) parental strain, indicating that dim2 and rid1 share a redundant function that acts earlier than rad51 during early meiosis. In conclusion, our studies provide the first evidence of the involvement of DNMTs during meiotic initiation and recombination.

Palladium-catalyzed asymmetric hydrogenation of lactones under base-free conditions.

Asymmetric hydrogenation of esters through homogeneous catalysis is a significantly important transformation in organic synthesis. The systems developed so far mainly focused on chiral iridium and ruthenium catalysts, which required a base to facilitate the activity. Herein, we present a palladium-catalyzed asymmetric hydrogenation of lactones under base-free conditions through dynamic kinetic resolution and kinetic resolution. The reaction exhibits high enantioselectivity and excellent functional group tolerance. Remarkably, the hydrogenation proceeds smoothly at the gram scale, and the products can be transformed into several chiral potential building blocks without loss of optical purity. This work provides a new strategy for asymmetric hydrogenation of esters under base-free conditions.

Viscolin-mediated antiapoptotic and neuroprotective effects in cortical neurons exposed to oxygen-glucose deprivation and rats subjected to transient focal cerebral ischemia.

OBJECTIVE: Previously, we have successfully purified and synthesized viscolin, an agent derived from Viscum coloratum extract, which has shown significant potential in the treatment of stroke. Our study aimed to evaluate the neuroprotective effects of viscolin. METHODS: We first assessed the cytotoxicity of viscolin on primary neuronal cultures and determined its antioxidant and radical scavenging properties. Subsequently, we identified the optimal dose-response of viscolin in protecting against glutamate-induced neurotoxicity. RESULTS: Our results demonstrated that viscolin at a concentration of 10 µM effectively reduced neuronal cell death up to 6 hours after glutamate-induced neurotoxicity. Additionally, we investigated the therapeutic window of opportunity and the potential of viscolin in preventing necrotic and apoptotic damage in cultured neurons exposed to oxygen glucose deprivation-induced neurotoxicity. Our findings showed that viscolin treatment significantly reduced DNA breakage, prevented the release of cytochrome c from mitochondria to cytosol, increased the expression of anti-apoptotic protein Bcl-2, decreased the expression of pro-apoptotic protein Bax, and reduced the number of TUNEL-positive cells. Additionally, our in vivo investigation demonstrated a reduction in brain infarction following middle cerebral artery occlusion. CONCLUSION: Viscolin has potential utility as a therapeutic agent in the treatment of stroke.

Effects of Adjuvant Chemotherapy on Oncologic Outcomes in Patients With Stage â ¡A Rectal Cancer Above the Peritoneal Reflection Who Did Not Undergo Preoperative Chemoradiotherapy.

PURPOSE: This study aimed to evaluate the effects of adjuvant chemotherapy (AC) on oncologic outcomes for patients with stage IIA upper rectal cancer and to investigate whether AC is associated with improved survival outcomes. METHODS: This retrospective study comprised 432 patients with rectal cancer above the peritoneal reflection who had undergone curative resection without preoperative chemoradiotherapy between 2008 and 2016. This study cohort was divided according to whether AC was received (AC group) or not (no-AC group). Risk factors included obstruction, perforation, poorly-differentiated tumor, lympho-vascular invasion, perineural invasion, resection margin involvement, and < 12 lymph nodes harvested. RESULTS: Among the 432 patients, 279 (64.6%) had received AC. The AC group had significantly higher 5-year overall survival (OS) rates than those of the no-AC group (93.2% vs. 84.6%, P = .001). Among patients with ≥ 1 risk factors, the AC group (n = 123) had significantly higher rates of 5-year recurrence-free survival (RFS) (81.6% vs. 64.1%, P = .01) and 5-year OS (88.8% vs. 69.0%, P = .001) than those of the no-AC group (n = 59). No significant difference in survival outcomes was observed between the 2 groups in patients aged > 65 years. CONCLUSION: AC was significantly associated with better 5-year RFS and 5-year OS rates in patients with stage IIA rectal cancer above peritoneal reflection who did not receive preoperative chemoradiotherapy, especially in those with ≥ 1 risk factors.

Molecular epidemiology of hepatitis B, hepatitis C, and HIV-1 co-infections in Ethiopia: Implications for disease burden and intervention strategies.

BACKGROUND: Hepatitis B virus (HBV) exhibits high prevalence rates within Ethiopia. The genetic diversity of HBV, marked by mixed genotype infections, may hold significant implications for the trajectory of disease and responses to treatment. Ethiopia grapples with a substantial public health challenge posed by co-infections involving HBV, hepatitis C virus (HCV), and human immunodeficiency virus 1 (HIV-1), particularly among vulnerable populations. METHODS: A comprehensive investigation into HBV, HCV, and HIV-1 co-infection was conducted. A total of 7,789 blood samples were meticulously analyzed, among which 815 exhibited HBV positivity. Among the HBV-positive samples, 630 were subjected to genotyping procedures, resulting in the identification of a prevalent trend of mixed infections characterized by HBV genotypes A/E/F (67.30%). Serological assessments were performed on 492 specimens to ascertain the presence of HCV and HIV-1 co-infections, revealing respective co-infection rates of 13.02% for HBV/HIV, 3.31% for HBV/HCV, and 2.07% for triple infection. RESULTS: The investigation revealed the intricate prevalence of co-infections in Ethiopia, notably underlining the continued transmission of viruses. The prominent occurrence of mixed HBV genotypes A/E/F suggests dynamic viral interactions and ongoing transmission pathways. These findings accentuate the necessity for targeted interventions and enhanced patient care, as co-infections carry significant clinical complexities. CONCLUSIONS: This study furnishes crucial insights into the molecular epidemiology of HBV, HCV, and HIV-1 co-infections in Ethiopia. The acquired knowledge can contribute to the advancement of strategies for clinical management and the formulation of public health interventions aimed at ameliorating the burden of viral infections within the nation.

Anti-CTLA-4 m2a Antibody Exacerbates Cardiac Injury in Experimental Autoimmune Myocarditis Mice By Promoting Ccl5-Neutrophil Infiltration.

The risk for suffering immune checkpoint inhibitors (ICIs)-associated myocarditis increases in patients with pre-existing conditions and the mechanisms remain to be clarified. Spatial transcriptomics, single-cell RNA sequencing, and flow cytometry are used to decipher how anti-cytotoxic T lymphocyte antigen-4 m2a antibody (anti-CTLA-4 m2a antibody) aggravated cardiac injury in experimental autoimmune myocarditis (EAM) mice. It is found that anti-CTLA-4 m2a antibody increases cardiac fibroblast-derived C-X-C motif chemokine ligand 1 (Cxcl1), which promots neutrophil infiltration to the myocarditic zones (MZs) of EAM mice via enhanced Cxcl1-Cxcr2 chemotaxis. It is identified that the C-C motif chemokine ligand 5 (Ccl5)-neutrophil subpopulation is responsible for high activity of cytokine production, adaptive immune response, NF-κB signaling, and cellular response to interferon-gamma and that the Ccl5-neutrophil subpopulation and its-associated proinflammatory cytokines/chemokines promoted macrophage (Mφ) polarization to M1 Mφ. These altered infiltrating landscape and phenotypic switch of immune cells, and proinflammatory factors synergistically aggravated anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. Neutralizing neutrophils, Cxcl1, and applying Cxcr2 antagonist dramatically alleviates anti-CTLA-4 m2a antibody-induced leukocyte infiltration, cardiac fibrosis, and dysfunction. It is suggested that Ccl5-neutrophil subpopulation plays a critical role in aggravating anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. This data may provide a strategic rational for preventing/curing ICIs-associated myocarditis.

A putative endonuclease reduces the efficiency of oral RNA interference in Nilaparvata lugens.

BACKGROUND: The RNA interference (RNAi) efficiency of double-stranded RNA (dsRNA) delivery to insects by various methods is different and the reduced efficacy of feeding dsRNA is partly due to the presence of DNA/RNA non-specific endonuclease in the insect gut. However, the mechanism leading to the low RNAi efficiency of Nilaparvata lugens by feeding remains elusive. RESULTS: In this study, we identified a putatively DNA/RNA non-specific endonuclease gene in the N. lugens genome database that was highly expressed in the first nymphal instar and the midgut. Different expression levels of NldsRNase after feeding and injection suggested that NldsRNase might interfere with oral RNAi in N. lugens. A co-delivery RNAi strategy further revealed that the presence of NldsRNase reduces RNAi efficiency. In vitro dsRNA degradation experiments also showed that the stability of dsRNA was higher in a gut mixture from nymphs injected with dsNldsRNase. These results support the idea that the low oral RNAi response observed in N. lugens is likely due to the presence of NldsRNase. CONCLUSIONS: Our study provides insight into the differences in RNAi response between the injection and feeding of dsRNA in N. lugens and sheds light on the mechanisms underlying the reduced efficacy of RNAi via feeding. These findings may help to inform the development of more-effective RNAi-based strategies controlling N. lugens and other insect pests. © 2024 Society of Chemical Industry.

The alleviatory effects of koumine on MSU-induced gouty arthritis via the TLR4/NF-κB/NLRP3 pathway.

The aim of this study was to validate the preventive effects of koumine (KM), a monoterpene indole alkaloid, on gouty arthritis (GA) and to explore its possible mechanisms. C57BL/6 mice were intraperitoneally administered KM (0.8, 2.4 or 7.2 mg/kg), colchicine (3.0 mg/kg) or sterile saline. One hour later, a monosodium urate (MSU) suspension was injected into the right hind paws of the mice to establish an acute gout model. Inflammation symptoms were evaluated at 0, 3, 6, 12 and 24 h, and the mechanical withdrawal threshold was evaluated at 0, 6 and 24 h. After 24 h, the mice were euthanized, and the joint tissue, kidney and blood were collected for subsequent experiments. Histological examination and antioxidant enzyme, kidney index and serum uric acid (UA) measurements were taken. The expression levels of the signalling pathway components were determined. KM effectively alleviated the symptoms of redness, swelling and pain; counteracted inflammatory cell infiltration; and increased antioxidant enzyme levels, reduced kidney index and serum UA levels through regulating UA excretion in MSU-induced mice. The expression of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB)/nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) signalling pathway proteins and mRNA were reduced in the KM group. These results suggest that KM may be effective in alleviating GA through the TLR4/NF-κB/NLRP3 pathway.

Gabapentinoids for chemotherapy-induced peripheral neuropathy: systematic review and meta-analysis.

INTRODUCTION: Chemotherapy-induced peripheral neuropathy (CIPN) affects patients' quality of life and treatment effectiveness. Gabapentinoids, like gabapentin and pregabalin, are often used for CIPN treatment, but their efficacy and safety remain uncertain. This study reviews and analyses randomised controlled trial data on this topic. MATERIALS/METHODS: We searched PubMed, Embase and Cochrane CENTRAL until 29 August 2022 for studies on gabapentinoid use in CIPN. Meta-analysis was performed using RevMan V.5.4 and the Metafor package in R. Outcomes included pain scores, quality of life and adverse drug events. RESULTS: For the prevention setting, our meta-analysis shows that pregabalin did not significantly improve average pain (standardised mean difference (SMD) -0.14, 95% CI -0.51 to 0.23; I2=26% (95% CI 0% to >98%)) or quality of life (mean difference (MD) 2.5, 95% CI -4.67 to 9.67; p=0.49) in preventing CIPN compared with placebo. However, it showed a potential trend towards reducing the worst pain (SMD -0.28, 95% CI -0.57 to 0.01; I2=0% (95% CI 0% to 98%; p=0.06)). For the treatment setting, some studies have shown a potential therapeutic effect of gabapentinoids. However, the results are not consistent between studies. Given the studies' heterogeneity, a meta-analysis in treatment setting was not performed. CONCLUSION: There is limited evidence to support the use of gabapentinoids in CIPN. In prevention setting, gabapentinoids do not significantly prevent CIPN. In treatment setting, studies have been inconsistent in their conclusions, lacking definitive benefits over placebo. More comprehensive and higher quality research is needed in the future. PROSPERO REGISTRATION NUMBER: CRD42022361193.