INTRODUCTION: Hydroxychloroquine (HCQ), originally an antimalarial drug, is currently used to treat multiple disorders, especially rheumatic diseases. Given its good efficacy and safety, HCQ is widely administered in pregnant patients. However, the safety profile of HCQ during pregnancy remains controversial due to limited research. In addition, HCQ has been reported to reduce preeclampsia in patients with systemic lupus erythematosus (SLE) and could potentially alleviate the symptom of preeclampsia. However, the clinical profile and molecular mechanism of HCQ in preeclampsia is yet to be fully understood. METHOD: We reviewed the literature on HCQ treatment in pregnancy with rheumatic diseases and preeclamp-sia in PubMed and Web of Science. We also discussed the safety of long-term therapy with HCQ during pregnancy. RESULTS: HCQ mainly modulates autoimmune response through inhibition of lysosomal function, toll-like receptor (TLR) signalling, nicotinamide adenine dinucleotide phosphate-mediated oxidative stress and autophagy. Benefits of HCQ in treating rheumatic diseases, including antiphospholipid syndrome, rheumatoid arthritis and Sjogren's syndrome during pregnancy, has been demonstrated in clinics. In particular, multiple clinical guidelines recommend HCQ as an indispensable therapeutic drug for pregnant patients with SLE. Additionally, it may potentially function in preeclampsia to improve clinical symptoms. CONCLUSION HCQ is effectively used for rheumatic diseases during pregnancy. The benefits of HCQ treatment in rheumatic diseases outweigh the risk of adverse reactions it induces in pregnant women.
Humans ; Hydroxychloroquine/pharmacology* ; Pregnancy ; Female ; Antirheumatic Agents/pharmacology* ; Rheumatic Diseases/drug therapy* ; Pregnancy Complications/drug therapy* ; Pre-Eclampsia/prevention & control* ; Lupus Erythematosus, Systemic/drug therapy* ; Arthritis, Rheumatoid/drug therapy* ; Antiphospholipid Syndrome/drug therapy* ; Sjogren's Syndrome/drug therapy*

BACKGROUND: Arsenic trioxide (ATO) is indicated as a broad-spectrum medicine for a variety of diseases, including cancer and cardiac disease. While the role of ATO in hepatic ischemia/reperfusion injury (HIRI) has not been reported. Thus, the purpose of this study was to identify the effects of ATO on HIRI. METHODS: In the present study, we established a 70% hepatic warm I/R injury and partial hepatectomy (30% resection) animal models in vivo and hepatocytes anoxia/reoxygenation (A/R) models in vitro with ATO pretreatment and further assessed liver function by histopathologic changes, enzyme-linked immunosorbent assay, cell counting kit-8, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Small interfering RNA (siRNA) for extracellular signal-regulated kinase (ERK) 1/2 was transfected to evaluate the role of ERK1/2 pathway during HIRI, followed by ATO pretreatment. The dynamic process of autophagic flux and numbers of autophagosomes were detected by green fluorescent protein-monomeric red fluorescent protein-LC3 (GFP-mRFP-LC3) staining and transmission electron microscopy. RESULTS: A low dose of ATO (0.75 μmol/L in vitro and 1 mg/kg in vivo ) significantly reduced tissue necrosis, inflammatory infiltration, and hepatocyte apoptosis during the process of hepatic I/R. Meanwhile, ATO obviously promoted the ability of cell proliferation and liver regeneration. Mechanistically, in vitro  studies have shown that nontoxic concentrations of ATO can activate both ERK and phosphoinositide 3-kinase-serine/threonine kinase (PI3K-AKT) pathways and further induce autophagy. The hepatoprotective mechanism of ATO, at least in part, relies on the effects of ATO on the activation of autophagy, which is ERK-dependent. CONCLUSION Low, non-toxic doses of ATO can activate ERK/PI3K-AKT pathways and induce ERK-dependent autophagy in hepatocytes, protecting liver against I/R injury and accelerating hepatocyte regeneration after partial hepatectomy.
Animals ; Arsenic Trioxide ; Autophagy/physiology* ; Reperfusion Injury/prevention & control* ; Mice ; Male ; Proto-Oncogene Proteins c-akt/physiology* ; Arsenicals/therapeutic use* ; Oxides/therapeutic use* ; Liver/metabolism* ; Extracellular Signal-Regulated MAP Kinases/metabolism* ; Mice, Inbred C57BL

Over the past few decades, tumor immunotherapy has revolutionized the landscape of cancer clinical treatment. There is a flourishing development of combination strategies to improve the anti-tumor efficacy of mono-immunotherapy. However, instead of a straightforward combination of multiple therapeutics, it is more preferable to pursue a synergistic effect by designing rational combinations as well as administration strategies, which are based on a comprehensive understanding of the physiological and pathological features. In this case, the timing and spatial distribution of the combination drugs become essential factors in achieving improved therapeutic outcomes. Therefore, the concept of Sequential Drug Delivery System (SDDS) is proposed to define the spatiotemporally programmed drug delivery/release through triggers of internal conditions and/or external interventions, thus complying with the dynamic disease evolution and the human immunity. This review summarizes the recent advancements in biomaterial-based SDDSs used for spatiotemporally-tuned combination tumor immunotherapy. Furthermore, the rationales behind various engineering strategies are discussed. Finally, an overview of potential synergistic mechanisms as well as their prospects for combination immunotherapy is presented.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Objective:To investigate the association between abdominal fat-related indicators derived from quantitative computed tomography (QCT) and coronary artery calcification (CAC) in middle-aged and elderly individuals, as well as the diagnostic value of these indicators.Methods:This cross-sectional study enrolled middle-aged and elderly participants who underwent health check-ups at Kaifeng Central Hospital between January and December 2024. Participants were divided into a CAC group and a non-CAC group based on the presence or absence of CAC. The CAC group was then stratified into mild, moderate, and severe subgroups according to CAC severity. General clinical data were collected for all participants. All subjects underwent one-stop QCT scanning of the chest and abdomen. An automated abdominal fat analysis system was used to identify fat distribution regions. If accurate identification was not possible, a semi-automated segmentation algorithm combined with manual correction was applied instead. Two physicians performed the measurements independently, and inter-observer consistency was assessed. The average values were calculated to obtain visceral fat area (VFA) and subcutaneous fat area (SFA). The ratio of visceral fat area to subcutaneous fat area (VFA/SFA) was also computed. Multivariate logistic regression analysis was performed to identify the factors associated with CAC in middle-aged and elderly individuals. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic efficacy of these indicators for CAC. DeLong′s test was used to compare the differences in the area under the curve ( AUC). Results:A total of 252 middle-aged and elderly individuals were included, with a median age of 61 (interquartile rang: 59, 69) years. Of these individuals, 188(74.6%) were males. Among them, 172 were classified into the CAC group and 80 into the non-CAC group. Multivariate logistic regression analysis revealed that VFA, VFA/SFA ratio, age, low-density lipoprotein cholesterol(LDL-C), and hypertension were independently associated with CAC in middle-aged and elderly individuals (all P<0.05). The mild, moderate, and severe CAC subgroups comprised 78, 51, and 43 participants, respectively. Analysis of variance (ANOVA) demonstrated that VFA and VFA/SFA increased with CAC severity, and there were statistically significant differences between the subgroups (all P<0.05). ROC curve analysis showed that the AUCs of VFA and VFA/SFA for diagnosing CAC were 0.841 and 0.810, respectively, with no significant difference between them ( P>0.05). The optimal cutoff values were 177.45 cm2 for VFA (sensitivity: 83.1%, specificity: 72.5%) and 1.592 for VFA/SFA (sensitivity: 65.7%, specificity: 83.7%). For the diagnosis of moderate-to-severe CAC, the AUCs of VFA and VFA/SFA were 0.765 and 0.761, respectively ( P>0.05 for comparison), with cutoff values of 231.75 cm2 (sensitivity: 61.7%, specificity: 83.3%) and 1.962 (sensitivity: 64.9%, specificity: 80.8%). Conclusion:Abdominal VFA and VFA/SFA derived from QCT are independently associated with the presence of CAC in middle-aged and elderly individuals, demonstrating good diagnostic performance for both overall CAC and moderate-to-severe CAC.

Objective:To analyze the epidemiological and clinical characteristics of influenza A/B virus (IAV/IBV) infection in children aged 0-4 years in Jining city from 2022 to 2024.Methods:A retrospective analysis was conducted on the data of 3 106 influenza affected children who visited two monitoring outpost hospitals in Jining city from January 2022 to January 2024. They were separated into two groups based on the type of virus infection: IAV group (n=1 829) and IBV group (n=1 277). Two groups were compared for general information, epidemiological characteristics, and laboratory test indicators.Result:The majority of influenza patients were boys (59.01%) and 1-4 years old (63.01%), with peak body temperature mainly ranging from 37.8 to 38.9 ℃ (59.30%). Coughing (69.00%) and runny nose (66.03%) were the main manifestations. The onset season was concentrated in winter (42.43%) and spring (40.44%), and the exposure target were family members (51.90%), and the proportion of influenza vaccine injections (20.90%) was relatively low. The proportions of visit time≤3 d, peak body temperature≥39.0 ℃, myocardial damage, liver function damage, white blood cell count (WBC) of 4-10×10 9/L, and neutrophil percentage (N)>70% in the IAV group were higher than those in the IBV group ( P<0.05). The proportions of preschool children and WBC>10×10 9/L in the IBV group were higher than those in the IAV group ( P<0.05). Conclusions:Children aged 0-4 years who are infected with IAV in Jining City are more common in terms of high fever, early medical attention, impaired heart and liver function, normal WBC, and abnormal N elevation compared to those infected with IBV. However, children aged 0-4 who are infected with IBV have abnormally high WBC and are more common in daycare.

Objective:To analyze the association between remnant cholesterol (RC) and the risk of atherosclerotic cardiovascular disease (ASCVD) in community population in Shanghai.Methods:Using baseline and follow-up data from the Shanghai Suburban Adult Cohort and Biobank, individuals with ASCVD (including coronary heart disease, stroke, myocardial infarction, and peripheral artery disease) at baseline were excluded. A Cox proportional hazards regression model was employed to analyze the relationship between RC and ASCVD risk and the association under different LDL-C levels.Results:A total of 57 281 participants were included, with a median follow-up of 5.61 person-years. During the follow-up, 1 436 ASCVD events (2.51%) were recorded. After adjusting for potential confounders, individuals with moderate ( HR=1.18, 95% CI: 1.03-1.36) or high RC levels ( HR=1.32, 95% CI: 1.15-1.51) had an increased risk of ASCVD. The association was stronger in participants younger than 60 years-old (interaction P=0.048). Participants with RC ≥0.97 mmol/L and LDL-C <3.40 mmol/L demonstrated a 19% ( HR=1.19, 95% CI: 1.06-1.35) increased risk of ASCVD. When RC ≥0.97 mmol/L and LDL-C ≥3.40 mmol/L, ASCVD risk increased by 42% ( HR=1.42, 95% CI: 1.21-1.67). Conclusions:Elevated RC increases ASCVD risk, regardless of LDL-C levels. RC can serve as a valuable predictor and intervention target for ASCVD.

Objective:Effects of Qingsui Xiaoyan Decoction on osteoclast differentiation of RAW264.7 cells.Methods:Receptor activator of nuclear factor kappa B ligand (RANKL) was used to induce differentiation of RAW264.7 cells into osteoclasts. CCK-8 method was used to screen experimental drug concentrations and analyze the cytotoxicity of drug intervention on RAW264.7 cells. TRAP staining method was used to quantitatively detect the effects of Qingsui Xiaoyan Decoction on osteoclast differentiation ability. RT-PCR technology was used to detect the mRNA expressions of osteoclast differentiation genes TRAP, MMP-9, CK, CTR. Western blot was used to detect osteoclast-related protein expressions of NF-κBP65, IκB-αTRAP, and TRAP.Results:After 72 hours of intervention, 0.800, 4.000, 20.000, and 100.000 mg/ml of Qingsui Xiaoyan Decoction could inhibit cell proliferation ( P<0.05). Compared with the model group, the number of TRAP-positive cells decreased ( P<0.05) in the 5, 20, 80, and 160 μg/ml Qingsui Xiaoyan Decoction groups. Additionally, the mRNA levels of TRAP, MMP-9, CK, and CTR decreased ( P<0.05), the expression of NF-κB p65 and TRAP proteins decreased ( P<0.05), and the expression of IκB-α protein increased ( P<0.05). Conclusions:Qingsui Xiaoyan Decoction can inhibit the expressions of TRAP, MMP-9, CK, CTR genes and TRAP protein, reduce the degradation of I κ B - α protein by inhibiting the NF - κ B signaling pathway, inhibit the expression of NF - κ B p65 protein, and thus inhibit the differentiation of RAW264.7 into osteoclasts.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.