Transition-Metal-Free Hydrodefluoroamination of Trifluoromethyl Enones for the Synthesis of α-Fluoroenamides.

A three-component strategy was developed to enable hydrodefluoroamination of ß-trifluoromethyl enones by selectively activating two C(sp3)-F bonds in the trifluoromethyl group. The method involved a sequence of carbonyl reduction, hydrodefluorination, and defluoroamination under transition-metal-free conditions. Synthetically useful (E)-stereospecific α-fluoroenamides were obtained in good yields with diverse functional group tolerance, which could be easily transformed into valuable organofluorides and heterocycles. The carbonyl auxiliary exerts both electronic and steric impacts on the CF3-alkenes, allowing for controllable and selective defluorination.

Lymphocyte-to-Monocyte Ratio Predicts Survival for Intraductal Papillary Mucinous Neoplasm with Associated Invasive Carcinoma of the Pancreas: Results from a High-volume Center.

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) is an important precursor lesion of pancreatic cancer. Systemic inflammatory parameters are widely used in the prognosis prediction of cancer; however, their prognostic implications in IPMN with associated invasive carcinoma (IPMN-INV) are unclear. This study aims to explore the prognostic value of systemic inflammatory parameters in patients with IPMN-INV. METHODS: From 2015 to 2021, patients with pathologically confirmed IPMN who underwent surgical resection at Peking Union Medical College Hospital were enrolled. The clinical, radiological and pathological data of the enrolled patients were collected and analyzed. Preoperative systemic inflammatory parameters were calculated as previously reported. RESULTS: Eighty-six patients with IPMN-INV met the inclusion criteria. The lymphocyte-to-monocyte ratio (LMR) was the only systemic inflammatory parameter independently associated with the cancer-specific survival (CSS). An LMR higher than 3.5 was significantly associated with a favorable CSS in univariate (hazard ratio (HR) 0.305, P = 0.003) and multivariate analyses (HR 0.221, P = 0.001). Other independently prognostic factors included the presence of clinical symptoms, cyst size, N stage and tumor differentiation. Additionally, a model including LMR was established for the prognosis prediction of IPMN-INV and had a C-index of 0.809. CONCLUSIONS: Preoperative LMR could serve as a feasible prognostic biomarker for IPMN-INV. A decreased LMR (cutoff value of 3.5) was an independent predictor of poor survival for IPMN-INV.

Modulating porous silicon-carbon anode stability: Carbon/silicon carbide semipermeable layer mitigates silicon-fluorine reaction and enhances lithium-ion transport.

Silicon-based material is regarded as one of the most promising anodes for next-generation high-performance lithium-ion batteries (LIBs) due to its high theoretical capacity and low cost. Harnessing silicon carbide's robustness, we designed a novel porous silicon with a sandwich structure of carbon/silicon carbide/Ag-modified porous silicon (Ag-PSi@SiC@C). Different from the conventional SiC interface characterized by a frail connection, a robust dual covalent bond configuration, dependent on SiC and SiOC, has been successfully established. Moreover, the innovative sandwich structure effectively reduces detrimental side reactions on the surface, eases volume expansion, and bolsters the structural integrity of the silicon anode. The incorporation of silver nanoparticles contributes to an improvement in overall electron transport capacity and enhances the kinetics of the overall reaction. Consequently, the Ag-PSi@SiC@C electrode, benefiting from the aforementioned advantages, demonstrates a notably elevated lithium-ion mobility (2.4 * 10-9 cm2·s-1), surpassing that of silicon (5.1 * 10-12 cm2·s-1). The half-cell featuring Ag-PSi@SiC@C as the anode demonstrated robust rate cycling stability at 2.0 A/g, maintaining a capacity of 1321.7 mAh/g, and after 200 cycles, it retained 962.6 mAh/g. Additionally, the full-cell, featuring an Ag-PSi@SiC@C anode and a LiFePO4 (LFP) cathode, exhibits outstanding longevity. Hence, the proposed approach has the potential to unearth novel avenues for the extended exploration of high-performance silicon-carbon anodes for LIBs.

Sleep Deprivation Induces Gut Damage via Ferroptosis.

Sleep deprivation (SD) has been associated with a plethora of severe pathophysiological syndromes, including gut damage, which recently has been elucidated as an outcome of the accumulation of reactive oxygen species (ROS). However, the spatiotemporal analysis conducted in this study has intriguingly shown that specific events cause harmful damage to the gut, particularly to goblet cells, before the accumulation of lethal ROS. Transcriptomic and metabolomic analyses have identified significant enrichment of metabolites related to ferroptosis in mice suffering from SD. Further analysis revealed that melatonin could rescue the ferroptotic damage in mice by suppressing lipid peroxidation associated with ALOX15 signaling. ALOX15 knockout protected the mice from the serious damage caused by SD-associated ferroptosis. These findings suggest that melatonin and ferroptosis could be targets to prevent devastating gut damage in animals exposed to SD. To sum up, this study is the first report that proposes a noncanonical modulation in SD-induced gut damage via ferroptosis with a clearly elucidated mechanism and highlights the active role of melatonin as a potential target to maximally sustain the state during SD.

miR-9-5p and miR-221-3p Promote Human Mesenchymal Stem Cells to Alleviate Carbon Tetrachloride-Induced Liver Injury by Enhancing Human Mesenchymal Stem Cell Engraftment and Inhibiting Hepatic Stellate Cell Activation.

Mesenchymal stem cells (MSCs) have shown great potential for the treatment of liver injuries, and the therapeutic efficacy greatly depends on their homing to the site of injury. In the present study, we detected significant upregulation of hepatocyte growth factor (HGF) in the serum and liver in mice with acute or chronic liver injury. In vitro study revealed that upregulation of miR-9-5p or miR-221-3p promoted the migration of human MSCs (hMSCs) toward HGF. Moreover, overexpression of miR-9-5p or miR-221-3p promoted hMSC homing to the injured liver and resulted in significantly higher engraftment upon peripheral infusion. hMSCs reduced hepatic necrosis and inflammatory infiltration but showed little effect on extracellular matrix (ECM) deposition. By contrast, hMSCs overexpressing miR-9-5p or miR-221-3p resulted in not only less centrilobular necrosis and venous congestion but also a significant reduction of ECM deposition, leading to obvious improvement of hepatocyte morphology and alleviation of fibrosis around central vein and portal triads. Further studies showed that hMSCs inhibited the activation of hepatic stellate cells (HSCs) but could not decrease the expression of TIMP-1 upon acute injury and the expression of MCP-1 and TIMP-1 upon chronic injury, while hMSCs overexpressing miR-9-5p or miR-221-3p led to further inactivation of HSCs and downregulation of all three fibrogenic and proinflammatory factors TGF-ß, MCP-1, and TIMP-1 upon both acute and chronic injuries. Overexpression of miR-9-5p or miR-221-3p significantly downregulated the expression of α-SMA and Col-1α1 in activated human hepatic stellate cell line LX-2, suggesting that miR-9-5p and miR-221-3p may partially contribute to the alleviation of liver injury by preventing HSC activation and collagen expression, shedding light on improving the therapeutic efficacy of hMSCs via microRNA modification.

Phagocytic Plasma Cells in Teleost Fish Provide Insights into the Origin and Evolution of B Cells in Vertebrates.

Teleost IgM+ B cells can phagocytose, like mammalian B1 cells, and secrete Ag-specific IgM, like mammalian B2 cells. Therefore, teleost IgM+ B cells may have the functions of both mammalian B1 and B2 cells. To support this view, we initially found that grass carp (Ctenopharyngodon idella) IgM+ plasma cells (PCs) exhibit robust phagocytic ability, akin to IgM+ naive B cells. Subsequently, we sorted grass carp IgM+ PCs into two subpopulations: nonphagocytic (Pha-IgM+ PCs) and phagocytic IgM+ PCs (Pha+IgM+ PCs), both of which demonstrated the capacity to secrete natural IgM with LPS and peptidoglycan binding capacity. Remarkably, following immunization of grass carp with an Ag, we observed that both Pha-IgM+ PCs and Pha+IgM+ PCs could secrete Ag-specific IgM. Furthermore, in vitro concatenated phagocytosis experiments in which Pha-IgM+ PCs from an initial phagocytosis experiment were sorted and exposed again to beads confirmed that these cells also have phagocytic capabilities, thereby suggesting that all teleost IgM+ B cells have phagocytic potential. Additionally, we found that grass carp IgM+ PCs display classical phenotypic features of macrophages, providing support for the hypothesis that vertebrate B cells evolved from ancient phagocytes. These findings together reveal that teleost B cells are a primitive B cell type with functions reminiscent of both mammalian B1 and B2 cells, providing insights into the origin and evolution of B cells in vertebrates.

The impact of combined administration of ropivacaine and dexamethasone on postoperative analgesia in perianal surgery with pudendal nerve block under ultrasound guidance: a prospective randomized controlled study.

Background: In recent years, severe pain after perianal surgery has seriously affected the prognosis of hospitalized patients. How to maximize the improvement of postoperative pain and perioperative comfort becomes particularly important. Methods: This study was a double-blind randomized controlled trial (Registration No.: ChiCTR2100048760, Registration Date: 16 July 2021, Link: www.chictr.org.cn/showproj.html?proj=130226), and patients were randomly divided into two groups: one group underwent postoperative 20 mL bilateral pudendal nerve block with 0.5% ropivacaine (P group), and the other group underwent postoperative 20 mL bilateral pudendal nerve block with 0.5% ropivacaine + 8 mg dexamethasone (PD group). The primary outcome was the incidence of moderate to severe pain at the first postoperative dressing change. Secondary outcomes included Quality of recovery-15 (QoR-15) score at 3 days after surgery, sleep quality, pain score at 3 days after surgery, and incidence of adverse events. Results: In the main outcome indicators, the incidence was 41.7% in the P group and 24.2% in the PD group (p = 0.01). The QoR-15 score and sleep quality in PD group were better than those in P group 2 days before surgery. The incidence of postoperative urinary retention was significantly decreased in PD group (p = 0.01). Conclusion: Local anesthesia with dexamethasone combined with pudendal nerve block after perianal surgery can reduce the incidence of moderate to severe pain during the first dressing change. This may be one of the approaches to multimodal analgesia after perianal surgery. Clinical Trial Registration: https://www.chictr.org.cn/, identifier ChiCTR2100048760.

Development and validation of a nomogram predictive model for cognitive impairment in cerebral small vessel disease: a comprehensive retrospective analysis.

Background: Cerebral small vessel disease (CSVD) is a common neurodegenerative condition in the elderly, closely associated with cognitive impairment. Early identification of individuals with CSVD who are at a higher risk of developing cognitive impairment is crucial for timely intervention and improving patient outcomes. Objective: The aim of this study is to construct a predictive model utilizing LASSO regression and binary logistic regression, with the objective of precisely forecasting the risk of cognitive impairment in patients with CSVD. Methods: The study utilized LASSO regression for feature selection and logistic regression for model construction in a cohort of CSVD patients. The model's validity was assessed through calibration curves and decision curve analysis (DCA). Results: A nomogram was developed to predict cognitive impairment, incorporating hypertension, CSVD burden, apolipoprotein A1 (ApoA1) levels, and age. The model exhibited high accuracy with AUC values of 0.866 and 0.852 for the training and validation sets, respectively. Calibration curves confirmed the model's reliability, and DCA highlighted its clinical utility. The model's sensitivity and specificity were 75.3 and 79.7% for the training set, and 76.9 and 74.0% for the validation set. Conclusion: This study successfully demonstrates the application of machine learning in developing a reliable predictive model for cognitive impairment in CSVD. The model's high accuracy and robust predictive capability provide a crucial tool for the early detection and intervention of cognitive impairment in patients with CSVD, potentially improving outcomes for this specific condition.

Population pharmacokinetics of valproic acid in children with epilepsy: Implications for dose tailoring when switching from oral syrup to sustained-release tablets.

Significant pharmacokinetic (PK) differences exist between different forms of valproic acid (VPA), such as syrup and sustained-release (SR) tablets. This study aimed to develop a population pharmacokinetic (PopPK) model for VPA in children with epilepsy and offer dose adjustment recommendation for switching dosage forms as needed. The study collected 1411 VPA steady-state trough concentrations (Ctrough) from 617 children with epilepsy. Using NONMEM software, a PopPK model was developed, employing a stepwise approach to identify possible variables such as demographic information and concomitant medications. The final model underwent internal and external evaluation via graphical and statistical methods. Moreover, Monte Carlo simulations were used to generate a dose tailoring strategy for typical patients weighting 20-50 kg. As a result, the PK characteristics of VPA were described using a one-compartment model with first-order absorption. The absorption rate constant (ka) was set at 2.64 and 0.46 h-1 for syrup and SR tablets. Body weight and sex were identified as significant factors affecting VPA's pharmacokinetics. The final PopPK model demonstrated acceptable prediction performance and stability during internal and external evaluation. For children taking syrup, a daily dose of 25 mg/kg resulted in the highest probability of achieving the desired target Ctrough, while a dose of 20 mg/kg/day was appropriate for those taking SR tablets. In conclusion, we established a PopPK model for VPA in children with epilepsy to tailor VPA dosage when switching between syrup and SR tablets, aiming to improve plasma VPA concentrations fluctuations.

Isogarcinol inhibits nasopharyngeal carcinoma growth through mitochondria-mediated autophagic cell death.

BACKGROUND AND AIMS: Isogarcinol, a natural compound extracted from the fruits of Garcinia oblongifolia, has potential chemopreventive activity. This study aimed to elucidate the anti-tumor effects and mechanism of action of isogarcinol on nasopharyngeal carcinoma (NPC). METHODS: Isogarcinol was isolated from Garcinia oblongifolia by using chromatographic separation. The anti-tumor effects of isogarcinol in NPC cells were tested by MTT assay, flow cytometry, wound healing assay, western blotting, transwell assay, colony formation assay, immunofluorescence, and transmission electron microscopy (TEM). The anti-tumor efficacy in vivo was evaluated in NPC cells xenograft models. RESULTS: Functional studies revealed that isogarcinol inhibited the proliferation, colony formation, migration and invasion abilities of NPC cells in vitro. Isogarcinol caused mitochondrial damage to overproduce reactive oxygen species through reducing the mitochondrial membrane potential and ΔΨm. Isogarcinol also substantially inhibited NPC cells growth in a xenograft tumor model without any obvious toxicity when compared with paclitaxel (PTX). Mechanistic studies have illustrated that isogarcinol increased the Bax/Bcl-2 ratio, cleaved caspase-3, and cytoplasmic cytochrome C levels to induce mitochondrial apoptosis. The ROS overproduction by isogarcinol could suppress EMT pathway via decreasing the levels of p-Akt and Snail. Furthermore, isogarcinol promoted the conversion of LC3-Ⅰ to LC3-Ⅱ, but increased p62 level to block autophagic flux, resulting in the accumulation of damaged mitochondria to promote autophagic cell death in NPC cells. CONCLUSION: This study provides a new theoretical foundation for the anti-tumor application of Garcinia oblongifolia and confirms that isogarcinol could be developed as a candidate drug for NPC treatment with low toxicity.

Immunoglobulin A vasculitis: The clinical features and pathophysiology.

Palpable purpura, gastrointestinal symptoms, joint involvement, and renal disease characterize immunoglobulin A vasculitis (IgAV). Renal involvement ranging from mild proteinuria to severe nephritic or nephrotic syndrome highlights the importance of monitoring kidney function in patients with IgAV. Recognizing these key features is crucial for early diagnosis and appropriate management to prevent long-term complications related to kidney disease. However, the pathogenesis of IgAV remains unclear. Disease mechanisms involve various factors, including the interplay of aberrantly glycosylated IgA, anti-endothelial cell antibodies, and neutrophils following infection triggers, which are the main pathogenic mechanisms of IgAV. Insights from cases of IgAV related to Coronavirus disease 2019 have offered additional understanding of the connection between infection and IgAV pathogenesis. This review provides a valuable resource for healthcare professionals and rheumatology researchers seeking a better understanding of the clinical features and pathophysiology of IgAV.

Peripheral blood cells RNA-seq identifies differentially expressed gene network linked to lymphocyte subsets alterations and active lupus nephritis associated with declines in renal function.

Background: The aim of this study was to investigate whether quantitative changes in lymphocyte subsets and gene expression in peripheral blood (PB) cells are related to the clinical manifestations and pathogenesis of lupus nephritis (LN). Methods: We enrolled 95 pediatric-onset SLE patients with renal involvement who presented with 450 clinical episodes suspicious for LN flare. Percentages of lymphocyte subsets at each episode were determined. We stratified 55 of 95 patients as high or low subset group according to the median percentage of each lymphocyte subset and the association with changes in the eGFR (ΔeGFR) were analyzed. Peripheral blood bulk RNA-seq to identify differentially expressed genes (DEGs) in 9 active LN vs. 9 inactive LN patients and the DEG-derived network was constructed by Ingenuity Pathway Analysis (IPA). Results: The mean ΔeGFR of low NK-low memory CD4+ T-high naive CD4+ T group (31.01 mL/min/1.73 m2) was significantly greater than that of high NK-high memory CD4+ T-low naive CD4+ T group (11.83 mL/min/1.73 m2; P = 0.0175). Kaplan-Meier analysis showed that the median time for ΔeGFR decline to mean ΔeGFR is approximately 10 years for high NK-high memory CD4+ T-low naive CD4+ T group and approximately 5 years for low NK-low memory CD4+ T-high naive CD4+ T group (log-rank test P = 0.0294). Conclusions: Our study highlighted important connections between DEG-derived network, lymphocyte subset composition, and disease status of LN and GN. A novel scoring system based on lymphocyte subset proportions effectively stratified patients into groups with differential risks for declining renal function.

Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood. METHODS: To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue. RESULTS: Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs. CONCLUSIONS: This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.

Efficacy and safety of Yangxinshi tablet for chronic heart failure: A systematic review and meta-analysis.

BACKGROUND: The specific benefits of Yangxinshi tablet (YXST) in the treating chronic heart failure (CHF) remain uncertain. AIM: To systematically evaluate the efficacy and safety of YXST in the treatment of CHF. METHODS: Randomized controlled trials (RCTs) investigating YXST for CHF treatment were retrieved from eight public databases up to November 2023. Meta-analyses of the included clinical studies were conducted using Review Manager 5.3. RESULTS: Twenty RCTs and 1845 patients were included. The meta-analysis results showed that the YXST combination group, compared to the conventional drug group, significantly increased the clinical efficacy rate by 23% [relative risk (RR) = 1.23, 95%CI: 1.17-1.29], P < 0.00001), left ventricular ejection fraction by 6.69% [mean difference (MD) = 6.69, 95%CI: 4.42-8.95, P < 0.00001] and 6-min walk test by 49.82 m (MD = 49.82, 95%C: 38.84-60.80, P < 0.00001), and reduced N-terminal pro-B-type natriuretic peptide by 1.03 ng/L [standardized MD (SMD) = -1.03, 95%CI: -1.32 to -0.74, P < 0.00001], brain natriuretic peptide by 80.95 ng/L (MD = -80.95, 95%CI: -143.31 to -18.59, P = 0.01), left ventricular end-diastolic diameter by 3.92 mm (MD = -3.92, 95%CI: -5.06 to -2.78, P < 0.00001), and left ventricular end-systolic diameter by 4.34 mm (MD = -4.34, 95%CI: -6.22 to -2.47, P < 0.00001). Regarding safety, neither group reported any serious adverse events during treatment (RR = 0.54, 95%CI: 0.15-1.90, P = 0.33). In addition, Egger's test results indicated no significant publication bias (P = 0.557). CONCLUSION: YXST effectively improves clinical symptoms and cardiac function in patients with CHF while maintaining a favorable safety profile, suggesting its potential as a therapeutic strategy for CHF.

The impact of mindfulness therapy combined with mentalization-based family therapy on suicidal ideation in adolescents with depressive disorder: randomized intervention study.

BACKGROUND: Adolescents with depression who engage in non-suicidal self harming behaviors are more likely to adopt negative coping strategies when faced with negative events. Therefore, these patients should be introduced to positive coping strategies. Evidences have showed that mindfulness-based interventions can positively impact the psychology of patients with mental disorders. This study was to explore the impact of a combination of mindfulness therapy and mentalization-based family therapy (MBFT) on suicidal ideation in adolescents with depressive disorder. METHODS: Eighty adolescent patients with depression and suicidal ideation admitted to our hospital from September 2021 to February 2022 were selected as subjects. They were divided into a control group and a study group using the random number table method, with each group comprising 40 subjects. The control group received MBFT, whereas the study group received both mindfulness therapy and MBFT. The psychological status and suicidal ideations of the two groups were compared before and after the intervention. RESULTS: The psychological health scores of both groups of patients were lower after the intervention, with the scores of the study group being lower than those of the control group (P < 0.05). The scores on the suicidal ideation scales for both groups were lower after intervention, and the study group scored lower than the control group (P < 0.05). The absolute values of the differences in psychological health scale scores and suicidal ideation scale scores before and after the intervention were higher in the study group than in the control group (P < 0.05). CONCLUSION: The combination of mindfulness therapy and MBFT can improve the psychological condition of adolescents with depression, reduce their suicidal ideations, and help them develop a healthy and positive outlook toward life, making this method worthy of clinical recommendation.

Effect of Chinese Medicine in Patients with COVID-19: A Multi-center Retrospective Cohort Study.

OBJECTIVE: To evaluate the effectiveness and safety of Chinese medicine (CM) in the treatment of coronavirus disease 2019 (COVID-19) in China. METHODS: A multi-center retrospective cohort study was carried out, with cumulative CM treatment period of ⩾3 days during hospitalization as exposure. Data came from consecutive inpatients from December 19, 2019 to May 16, 2020 in 4 medical centers in Wuhan, China. After data extraction, verification and cleaning, confounding factors were adjusted by inverse probability of treatment weighting (IPTW), and the Cox proportional hazards regression model was used for statistical analysis. RESULTS: A total of 2,272 COVID-19 patients were included. There were 1,684 patients in the CM group and 588 patients in the control group. Compared with the control group, the hazard ratio (HR) for the deterioration rate in the CM group was 0.52 [95% confidence interval (CI): 0.41 to 0.64, P<0.001]. The results were consistent across patients of varying severity at admission, and the robustness of the results were confirmed by 3 sensitivity analyses. In addition, the HR for all-cause mortality in the CM group was 0.29 (95% CI: 0.19 to 0.44, P<0.001). Regarding of safety, the proportion of patients with abnormal liver function or renal function in the CM group was smaller. CONCLUSION: This real-world study indicates that the combination of a full-course CM therapy on the basic conventional treatment, may safely reduce the deterioration rate and all-cause mortality of COVID-19 patients. This result can provide the new evidence to support the current treatment of COVID-19. Additional prospective clinical trial is needed to evaluate the efficacy and safety of specific CM interventions. (Registration No. ChiCTR2200062917).

Androgen receptor activity inversely correlates with immune cell infiltration and immunotherapy response across multiple cancer lineages.

There is now increasing recognition of the important role of androgen receptor (AR) in modulating immune function. To gain a comprehensive understanding of the effects of AR activity on cancer immunity, we employed a computational approach to profile AR activity in 33 human tumor types using RNA-Seq datasets from The Cancer Genome Atlas. Our pan-cancer analysis revealed that the genes most negatively correlated with AR activity across cancers are involved in active immune system processes. Importantly, we observed a significant negative correlation between AR activity and IFNγ pathway activity at the pan-cancer level. Indeed, using a matched biopsy dataset from subjects with prostate cancer before and after AR-targeted treatment, we verified that inhibiting AR enriches immune cell abundances and is associated with higher IFNγ pathway activity. Furthermore, by analyzing immunotherapy datasets in multiple cancers, our results demonstrate that low AR activity was significantly associated with a favorable response to immunotherapy. Together, our data provide a comprehensive assessment of the relationship between AR signaling and tumor immunity.

The impact of 5-aminosalicylates on the efficacy of mesenchymal stem cell therapy in a murine model of ulcerative colitis.

Inflammatory bowel disease (IBD) is distinguished by persistent immune-mediated inflammation of the gastrointestinal tract. Previous experimental investigations have shown encouraging outcomes for the use of mesenchymal stem cell (MSC)-based therapy in the treatment of IBD. However, as a primary medication for IBD patients, there is limited information regarding the potential interaction between 5-aminosalicylates (5-ASA) and MSCs. In this present study, we employed the dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mouse model to examine the influence of a combination of MSCs and 5-ASA on the development of UC. The mice were subjected to weight measurement, DAI scoring, assessment of calprotectin expression, and collection of colons for histological examination. The findings revealed that both 5-ASA and MSCs have demonstrated efficacy in the treatment of UC. However, it is noteworthy that 5-ASA exhibits a quicker onset of action, while MSCs demonstrate more advantageous and enduring therapeutic effects. Additionally, the combination of 5-ASA and MSC treatment shows a less favorable efficacy compared to the MSCs alone group. Moreover, our study conducted in vitro revealed that 5-ASA could promote MSC migration, but it could also inhibit MSC proliferation, induce apoptosis, overexpress inflammatory factors (IL-2, IL-12P70, and TNF-α), and reduce the expression of PD-L1 and PD-L2. Furthermore, a significant decrease in the viability of MSCs within the colon was observed as a result of 5-ASA induction. These findings collectively indicate that the use of 5-ASA has the potential to interfere with the therapeutic efficacy of MSC transplantation for the treatment of IBD.

LC-MS/MS and EMIT measure the whole blood concentration of cyclosporine A: The two methods yield concordant results within the dynamic range of the latter, but the former shows broader application scenarios.

Cyclosporine A (CsA) is a widely used immunosuppressive drug with a narrow therapeutic index and large individual differences. Its therapeutic and toxic effects are closely related to blood drug concentrations, requiring routine therapeutic drug monitoring (TDM). The current main methods for TDM of CsA are enzyme multiplied immunoassay technique (EMIT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, few study on the method comparison of the EMIT and LC-MS/MS for the measurement of whole blood CsA concentration in children has been reported. In this study, we developed a simple and sensitive LC-MS/MS assay for the determination of CsA, and 657 cases of CsA concentrations were determined from 197 pediatric patients by a routine EMIT assay and by the validated in-house LC-MS/MS method on the same batch of samples, aimed to address the aforementioned concern. Consistency between the two assays was evaluated using linear regression and Bland-Altman analysis. The linear range of LC-MS/MS was 0.500-2000 ng/mL and that of the EMIT was 40-500 ng/mL, respectively. Overall, the correlation between the two methods was significant (r-value ranging from 0.8842 to 0.9441). Unsatisfactory consistency was observed in the concentrations < 40 ng/mL (r = 0.7325) and 200-500 ng/mL (r = 0.6851). Bland-Altman plot showed a mean bias of -18.0 % (±1.96 SD, -73.8 to 37.8 %) between EMIT and LC-MS/MS. For Passing-Bablok regression between EMIT and LC-MS/MS did not differ significantly (p > 0.05). In conclusion, the two methods were closely correlated, but the CsA concentration by LC-MS/MS assay was slightly higher than that by EMIT method. Switching from the EMIT assay to the LC-MS/MS method was acceptable, and the LC-MS/MS method will receive broader application in clinical settings due to its better analytical capabilities, but the results need to be further verified in different laboratories.