ObjectiveTo investigate the role of DEAD-box helicase 3 X-linked （DDX3X） in immune-mediated liver injury （ILI）， and to clarify its mechanism by regulating endoplasmic reticulum stress （ERS）-dependent apoptotic pathway and its association with the clinical progression of hepatitis B. MethodsMice were given injection of concanavalin A （ConA） via the caudal vein to establish a model of ILI， PBS （control group） and different concentrations of ConA were injected into the tail vein of hepatocyte-specific DDX3X-knockout mice （DDX3X^ΔHep and DDX3X-flox mice （DDX3X^fl/fl）， respectively.. The log-rank survival analysis， measurement of the serum levels of aspartate aminotransferase （AST） and alanine aminotransferase （ALT）， and HE staining of liver tissue were performed to assess liver injury， and qRT-PCR and Western Blot were used to measure the mRNA and protein expression levels of glucose-regulated protein 78 （GRP78）， CCAAT/enhancer-binding protein homologous protein （CHOP）， and DDX3X in liver tissue. Intraperitoneal injection of 4-phenylbutyric acid （4-PBA， 100 mg/kg） was performed to inhibit ERS. Serum samples （n=30） and liver tissue samples （n=6） were collected from healthy controls， chronic hepatitis B （CHB） patients， and hepatitis B virus-associated liver failure （HBV-LF） patients； ELISA was used to measure the serum level of DDX3X， and qRT-PCR/Western Blot was used to analyze the expression of targets in liver tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the control group of mice， the expression of DDX3X in the liver of mice induced by ConA was significantly increased after liver injury （P<0.05）， and hepatocyte-specific DDX3X knockout increased the 72-hour survival rate of mice by 55% （compared with 20% in the DDX3X^fl/fl group）， with significant reductions in the serum levels of ALT and AST （P<0.000 1） and the expression levels of the ERS markers GRP78 and CHOP （P<0.05）. After ERS was inhibited by 4-PBA， there was alleviation of liver injury （with reductions in ALT and AST， P <0.001） and a reduction in DDX3X expression （P<0.01）. The analysis of clinical samples showed that the mRNA and protein expression levels of liver DDX3X in CHB patients and HBV-LF patients were significantly higher than those in healthy controls （all P<0.01）， and there was a significant increase in the serum level of DDX3X in HBV-LF patients （P<0.000 1）. ConclusionDDX3X exacerbates ILI by regulating the ERS-dependent apoptotic pathway （GRP78/CHOP）， and its expression is associated with the progression of hepatitis B. Therefore， it can be used as a potential therapeutic target.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a complex disease that is often accompanied by mental health disorders. However, the potential mechanisms underlying the heterogeneous clinical presentation of CP/CPPS remain uncertain. This study analyzed widely targeted metabolomic data of expressed prostatic secretions (EPS) and plasma to reveal the underlying pathological mechanisms of CP/CPPS. A total of 24 CP/CPPS patients from The Second Nanning People's Hospital (Nanning, China), and 35 asymptomatic control individuals from First Affiliated Hospital of Guangxi Medical University (Nanning, China) were enrolled. The indicators related to CP/CPPS and psychiatric symptoms were recorded. Differential analysis, coexpression network analysis, and correlation analysis were performed to identify metabolites that were specifically altered in patients and associated with various phenotypes of CP/CPPS. The crucial links between EPS and plasma were further investigated. The metabolomic data of EPS from CP/CPPS patients were significantly different from those from control individuals. Pathway analysis revealed dysregulation of amino acid metabolism, lipid metabolism, and the citrate cycle in EPS. The tryptophan metabolic pathway was found to be the most significantly altered pathway associated with distinct CP/CPPS phenotypes. Moreover, the dysregulation of tryptophan and tyrosine metabolism and elevation of oxidative stress-related metabolites in plasma were found to effectively elucidate the development of depression in CP/CPPS. Overall, metabolomic alterations in the EPS and plasma of patients were primarily associated with oxidative damage, energy metabolism abnormalities, neurological impairment, and immune dysregulation. These alterations may be associated with chronic pain, voiding symptoms, reduced fertility, and depression in CP/CPPS. This study provides a local-global perspective for understanding the pathological mechanisms of CP/CPPS and offers potential diagnostic and therapeutic targets.
Humans ; Male ; Prostatitis/blood* ; Adult ; Pelvic Pain/blood* ; Metabolomics ; Prostate/metabolism* ; Middle Aged ; Chronic Pain/blood* ; Metabolome ; Case-Control Studies ; Tryptophan/blood* ; Depression/blood* ; Oxidative Stress/physiology* ; Chronic Disease ; Lipid Metabolism/physiology*

Dry eye disease (DED) is a prevalent and intractable ocular disease induced by a variety of causes. Elevated sphingomyelin (SM) levels and pro-inflammatory cytokines were detected on the ocular surface of DED patients, particularly in the meibomian glands. Sphingomyelin synthase 2 (SMS2), one of the proteins involved in SM synthesis, would light a novel way of developing a DED therapy strategy. Herein, we report the design and optimization of a series of novel thiophene carboxamide derivatives to afford 14l with an improved highly potent inhibitory activity on SM synthesis (IC_{50, SMS2} = 28 nmol/L). Moreover, 14l exhibited a notable protective effect of anti-inflammation and anti-apoptosis on human corneal epithelial cells (HCEC) under TNF-α-hyperosmotic stress conditions in vitro, with an acceptable ocular specific distribution (corneas and meibomian glands) and pharmacokinetics (PK) profiles (t _{1/2, cornea} = 1.11 h; t _{1/2, meibomian glands} = 4.32 h) in rats. Furthermore, 14l alleviated the dry eye symptoms including corneal fluorescein staining scores and tear secretion in a dose-dependent manner in mice. Mechanically, 14l reduced the mRNA expression of Tnf-α, Il-1β and Mmp-9 in corneas, as well as the proportion of very long chain SM in meibomian glands. Our findings provide a new strategy for DED therapy based on selective SMS2 inhibitors.

The cooccurrence of NPM1, FLT3-ITD, and DNMT3A mutations (i.e., triple mutation) is related to dismal prognosis in patients with acute myeloid leukemia (AML) receiving chemotherapy alone. In this multicenter retrospective cohort study, we aimed to identify whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) could overcome the poor prognosis of DNMT3A^mutNPM1^mutFLT3-ITD^mut AML across four transplant centers in China. Fifty-three patients with triple-mutated AML receiving allo-HSCT in complete remission were enrolled. The 1.5-year probabilities of relapse, leukemia-free survival, and overall survival after allo-HSCT were 11.9%, 80.3%, and 81.8%, respectively. Multivariate analysis revealed that more than one course of induction chemotherapy and allo-HSCT beyond CR1 were associated with poor survival. To our knowledge, this work is the largest study to explore the up-to-date undefined role of allo-HSCT in patients with triple-mutated AML. Our real-world data suggest that allo-HSCT could overcome the poor prognosis of DNMT3A^mutNPM1^mutFLT3-ITD^mut in AML.
Humans ; Nucleophosmin ; Leukemia, Myeloid, Acute/mortality* ; Hematopoietic Stem Cell Transplantation/methods* ; Male ; Female ; DNA Methyltransferase 3A ; Adult ; China ; Retrospective Studies ; DNA (Cytosine-5-)-Methyltransferases/genetics* ; Middle Aged ; Prognosis ; fms-Like Tyrosine Kinase 3/genetics* ; Mutation ; Young Adult ; Transplantation, Homologous ; Nuclear Proteins/genetics* ; Adolescent ; Aged

Objective To investigate the spatiotemporal distribution characteristics and potential influencing factors of newly diagnosed echinococcosis cases in Qinghai Province from 2016 to 2022, so as to provide insights into the formulation of the echinococcosis control strategy in Qinghai Province. Methods The number of individuals screened for echinococcosis, number of newly diagnosed echinococcosis cases, number of registered dogs and number of stray dogs were captured from the annual reports of echinococcosis control program in Qinghai Province from 2016 to 2022, and the detection of newly diagnosed echinococcosis cases was calculated. The number of populations, precipitation, temperature, wind speed, sunshine hours, average altitude, number of year-end cattle stock, number of year-end sheep stock, gross domestic product (GDP) per capita, and number of village health centers in each county (district) of Qinghai Province were captured from the Qinghai Provincial Statistical Yearbook, and county-level electronic maps in Qinghai Province were downloaded from the National Platform for Common Geospatial Information Services. The software ArcGIS 10.8 was used to map the distribution of newly diagnosed echinococcosis cases in Qinghai Province, and the spatial autocorrelation analysis of newly diagnosed echinococcosis cases was performed. In addition, the spacetime scan analyses of number of individuals screened for echinococcosis, number of newly diagnosed echinococcosis cases and geographical coordinates in Qinghai Province were performed with the software SaTScan 10.1.2, and the spatial stratified heterogeneity of the detection of newly diagnosed echinococcosis cases was investigated with the software GeoDetector. Results A total of 6 569 426 residents were screened for echinococcosis in Qinghai Province from 2016 to 2022, and 5 924 newly diagnosed echinococcosis cases were found. The detection of newly diagnosed echinococcosis cases appeared a tendency towards a decline over years from 2016 to 2022 (χ² = 11.107, P < 0.01), with the highest detection in Guoluo Tibetan Autonomous Prefecture in 2017 (82.12/10⁵). There were spatial clusters in the detection of newly diagnosed echinococcosis cases in Qinghai Province from 2016 to 2018 (Moran’s I = 0.34 to 0.65, all Z values > 1.96, all P values < 0.05), and the distribution of newly diagnosed echinococcosis cases appeared random distribution from 2019 to 2022 (Moran’s I = −0.09 to 0.04, all Z values < 1.96, all P values > 0.05). Local spatial autocorrelation analysis showed high-high clusters and low-low clusters in the detection of new diagnosed echinococcosis cases in Qinghai Province from 2016 to 2022, and space-time scan analysis showed that the first most likely cluster areas of newly diagnosed echinococcosis cases in Qinghai Province from 2016 to 2022 were mainly distributed in Yushu Tibetan Autonomous Prefecture and Guoluo Tibetan Autonomous Prefecture. GeoDetector-based analysis of the driving factors for the spatial stratified heterogeneity of detection of newly diagnosed echinococcosis cases in Qinghai Province showed that average altitude, number of village health centers, number of cattle and sheep stock, GDP per capita, annual average sunshine hours, and annual average temperature had a strong explanatory power for the spatial distribution of newly diagnosed echinococcosis cases, with q values of 0.630, 0.610, 0.600, 0.590, 0.588, 0.537 and 0.526, respectively. Conclusions The detection of newly diagnosed echinococcosis cases appeared a tendency towards a decline in Qinghai Province over years from 2016 to 2022, showing spatial clustering. Targeted control measures are required in cluster areas of newly diagnosed echinococcosis cases for further control of the disease.

Objective:To describe the current status and trends in the outcomes and care practices of extremely preterm infants at 22-25 weeks′ gestation age from the Chinese Neonatal Network (CHNN) from 2019 to 2021.Methods:This cross-sectional study used data from the CHNN cohort of very preterm infants. All 963 extremely preterm infants with gestational age between 22-25 weeks who were admitted to neonatal intensive care units (NICU) of the CHNN from 2019 to 2021 were included. Infants admitted after 24 hours of life or transferred to non-CHNN hospitals were excluded. Perinatal care practices, survival rates, incidences of major morbidities, and NICU treatments were described according to different gestational age groups and admission years. Comparison among gestational age groups was conducted using χ2 and Kruskal-Wallis tests. Trends by year were evaluated by Cochran-Armitage and Jonckheere-Terpstra tests for trend. Results:Of the 963 extremely preterm infants enrolled, 588 extremely preterm infants (61.1%) were male. The gestational age was 25.0 (24.4, 25.6) weeks, with 29 extremely preterm infants (3.0%), 88 extremely preterm infants (9.1%), 264 extremely preterm infants (27.4%), and 582 extremely preterm infants (60.4%) at 22, 23, 24, and 25 weeks of gestation age, respectively. The birth weight was 770 (680, 840) g. From 2019 to 2021, the number of extremely preterm infants increased each year (285, 312, and 366 extremely preterm infants, respectively). Antenatal steroids and magnesium sulfate were administered to 67.7% (615/908) and 51.1% (453/886) mothers of extremely preterm infants. In the delivery room, 20.8% (200/963) and 69.5% (669/963) extremely preterm infants received noninvasive positive end-expiratory pressure support and endotracheal intubation. Delayed cord clamping and cord milking were performed in 19.0% (149/784) and 30.4% (241/794) extremely preterm infants. From 2019 to 2021, there were significant increases in the usage of antenatal steroids, antenatal magnesium sulfate, and delivery room noninvasive positive-end expiratory pressure support (all P<0.05). Overall, 349 extremely preterm infants (36.2%) did not receive complete care, 392 extremely preterm infants (40.7%) received complete care and survived to discharge, and 222 extremely preterm infants (23.1%) received complete care but died in hospital. The survival rates for extremely preterm infants at 22, 23, 24 and 25 weeks of gestation age were 10.3% (3/29), 23.9% (21/88), 33.0% (87/264) and 48.3% (281/582), respectively. From 2019 to 2021, there were no statistically significant trends in complete care, survival, and mortality rates (all P>0.05). Only 11.5% (45/392) extremely preterm infants survived without major morbidities. Moderate to severe bronchopulmonary dysplasia (67.3% (264/392)) and severe retinopathy of prematurity (61.5% (241/392)) were the most common morbidities among survivors. The incidences of severe intraventricular hemorrhage or periventricular leukomalacia, necrotizing enterocolitis, and sepsis were 15.3% (60/392), 5.9% (23/392) and 19.1% (75/392), respectively. Overall, 83.7% (328/392) survivors received invasive ventilation during hospitalization, with a duration of 22 (10, 42) days. The hospital stay for survivors was 97 (86, 116) days. Conclusions:With the increasing number of extremely preterm infants at 22-25 weeks′ gestation admitted to CHNN NICU, the survival rate remained low, especially the rate of survival without major morbidities. Further quality improvement initiatives are needed to facilitate the implementation of evidence-based care practices.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non Hodgkin's lymphoma. The current treatment plan can significantly improve the prognosis of patients, but about 30%-40% of DLBCL patients still experience drug resistance and relapse after treatment. For patients with refractory/relapse DLBCL, clinical treatment remains difficult and their prognosis is poor. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains one of the most important curative methods for refractory/relapse DLBCL patients. This article will review the role and progress of allo-HSCT in the treatment of refractory/relapse DLBCL.

Objective:To summarize the clinical features associated with respiratory syncytial virus (RSV) infection in patients following the hematopoietic stem cell transplant (HSCT) and exploring the risk factors for death.Methods:Patients who had RSV infection after undergoing HSCT from October 2023 to January 2024 in the hematology department of Peking University People’s Hospital were enrolled in the study. The clinical characteristics of the participating patients were summarized. The clinical characteristics of the surviving and the dying patients were compared, and the risk factors of death were analyzed by binary logistic regression.Results:Among the 43 RSV-positive HSCT patients, 20 (46.5%) were hypoxemic, six (14.0%) were admitted to the ICU for further treatment, four (9.3%) required tracheal intubation assisted ventilation, and seven patients (16.3%) died. A comparison of the clinical features of the surviving patients and the deceased patients demonstrated that the deceased patients had a lower PLT when infected with RSV [74.5 (8.0-348.0) ×10 9/L vs 15.0 (10.0-62.0) ×10 9/L, P=0.003], a higher incidence of simultaneous bacterial infections (85.7% vs 41.7%, P=0.046), and a higher rate of hematological recurrence (71.4% vs 13.9%, P=0.004). Hematological recurrence ( OR=15.500, 95% CI 2.336-102.848, P=0.005), influenza A viral infection ( OR=14.000, 95% CI 1.064-184.182, P=0.045), and low PLT at the time of RSV infection ( OR=0.945, 95% CI 0.894-0.999, P=0.048) were the factors associated with death following HSCT. Conclusion:Patients infected with RSV after undergoing HSCT have a poor prognosis, and active prevention and treatment of RSV in the autumn and winter requires urgent attention.

Objective To construct and validate an effective prognostic nomogram for the patients with incidental gallbladder cancer(IGBC).Methods The clinical data of 161 patients with IGBC requiring radical surgery admitted to the First Affiliated Hospital of Xi'an Jiaotong University from May 2011 to October 2022 was analyzed retrospectively.COX proportional risk regression model was used to screen for influencing factors on overall survival(OS)of IGBC.Nomogram was constructed based on independent influencing factors that affected the prognosis of IGBC patients.The concordance index(C-index)and calibration curve were used to validate the performance of the model.Receiver operating characteristic(ROC)curve analysis and decision curve analysis(DCA)were used to validate the predictive accuracy and net benefit of the plotted column chart.Results Univariate COX regression analysis suggested that age,T stage,N stage,M stage,preoperative carcinoembryonic antigen(CEA),preoperative carbohydrate antigenl9-9(CA19-9),preoperative red blood cell volume distribution on width coefficient of variation(RDW-CV),treatment method,and recurrence and metastasis were risk factors which affected the long-term survival of IGBC patients after radical surgery.Multivariate COX regression analysis suggested that T stage,N stage,preoperative CA19-9,preoperative RDW-CV,preoperative AST,treatment methods,and recurrence and metastasis were independent risk factors which affected the prognosis of IGBC patients.The C-index of the constructed prognostic model was 0.872.The calibration plot demonstrated good performance of the Nomogram.ROC curve analysis showed an area under the curve of 0.869,confirming a high sensitivity and specificity.A high net benefit was proven by DCA.Conclusions The constructed Nomogram.can accurately and intuitively predict the survival probability of IGBC patients after radical surgery.

Objective:To screen the interacting protein of ubiquitin-conjugating enzyme E2S(UBE2S)and construct the hepatocellular carcinoma(HCC)based on UBE2S interacting protein prognosis model(UIPM),and to discuss the value of UIPM in assessing the prognosis of the HCC patients.Methods:Co-immunoprecipitation(Co-IP)was used to screen the protein complexes binding to Flag-UBE2S.After validation by sodium dodecyl sulphate-polyacrylamide gel electrophoresis(SDS-PAGE)and Western blotting methods;liquid chromatography-mass spectrometer(LC-MS)was used to identify the UBE2S interacting proteins;Gene Ontology(GO)functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)signaling pathway enrichment analysis were conducted on these proteins;the prognosis-related proteins from The Cancer Genome Atlas(TCGA)were cross-referenced with UBE2S interacting proteins by survival package of R software;the key proteins were extracted through LASSO regression analysis to build the UIPM;the prognostic model risk scoring formula was established.The HCC patients in TCGA were divided into high risk group and low risk group based on median value of the risk scores.The predictive accuracy of UIPM was evaluated by receiver operating characteristic curve(ROC),and the predictive accuracy was further validated by International Cancer Genome Consortium(ICGC)Database;univariate regression analysis and multivariate Cox regression analysis were used to detect whether the UIPM risk score was an independent prognostic factor for HCC.Furthermore,the nomogram model was built.Results:A total of 97 UBE2S interacting proteins were identified through Co-IP combined with LC-MS analysis.The GO functional enrichment analysis and KEGG signaling pathway enrichment analysis results showed that the interacting proteins were closely associated with cysteine-type endopeptidase activity,oxidative stress,and cell death.The TCGA revealed 5 163 HCC prognosis-related proteins;after intersecting with UBE2S interacting proteins,40 prognosis-related interacting proteins were found.Seven key proteins were determined through LASSO regression analysis,including UBE2S,heat shock protein family A member 8(HSPA8),heterogeneous nuclear ribonucleoprotein H1(HNRNPH1),chaperonin containing TCP1 subunit 3(CCT3),eukaryotic translation initiation factor 2 subunit 1(EIF2S1),receptor for activated C kinase 1(RACK1),and actin related protein 2/3 complex subunit 4(ARPC4),and the UIPM was constructed.There was significant difference in survival rate of the patients between high risk group and low risk group(P<0.05).The ROC curve analysis results showed the area under ROC curve(AUC)values of UIPM for predicting 1-year,2-year,and 3-year survival risk scores of the HCC patients were all greater than 0.7,indicating the model had high predictive accuracy.This was also confirmed by ICGC Database data.The univariate and multivariate Cox regression analysis results showed that the UIPM risk score was an independent prognostic risk factor for the HCC patients(P<0.05).The nomogram results showed good consistency between predicted survival rate and actual survival rate of the patient.Conclusion:A total of 97 interacting proteins that interact with UBE2S may promote the occurence and devolopment of HCC through oxidative stress and dysregulation of ferroptosis pathways.The UIPM risk score is an independent risk factor for the prognosis of HCC and can be used to predict the outcomes of the patients.UBE2S,HSPA8,HNRNPH1,CCT3,EIF2S1,RACK1,and ARPC4 could be regarded as the new biomarkers and therapeutic targets for HCC.