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.

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

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.

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.

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.

Objective:To investigate the values of two-dimensional and three-dimensional echocardiographic parameters in predicting pulmonary vascular resistance (PVR) in chronic pulmonary thromboembolic pulmonary hypertension (CTEPH).Methods:A total of 141 patients diagnosed with CTEPH in China-Japan Friendship Hospital from November 2015 to December 2022 were included. Two-dimensional echocardiographic indicators reflecting PVR were constructed according to the calculation formula of PVR: echocardiographic estimated systolic pulmonary artery pressure (sPAP Echo)/left ventricular end-diastolic diameter (LVIDd), echocardiographic estimated mean pulmonary artery pressure (mPAP Echo)/LVIDd. sPAP Echo/left ventricular end-diastolic volume (LVEDV), sPAP Echo/left ventricular cardiac output (LVCO) were measured by three-dimensional echocardiography. The correlations between two-dimensional and three-dimensional echocardiographic ratios and invasive PVR were then analyzed using the Spearman correlation method. Using receiver operating characteristic curve analysis, cut-off values for the ratios were generated to identify patients with PVR>1 000 dyn·s -1·cm -5. Pre- and postoperative hemodynamics and echocardiographic data were analyzed, as well as the correlation between the reduction rate of the echocardiographic index and PVR in 54 patients who underwent pulmonary endarterectomy (PEA). Results:sPAP Echo/LVIDd, sPAP Echo/LVEDV and sPAP Echo/LVCO were moderately correlated with PVR( rs=0.62, 0.52, 0.63, both P<0.001). The ratio of sPAP Echo to LVEDV, when greater than or equal to 1.41, had a sensitivity of 0.800 and a specificity of 0.930 for determining PVR >1 000 dyn·s -1·cm -5 (AUC=0.860, P<0.001). Similarly, the ratio of sPAP Echo to LVIDd, when greater than or equal to 2.14, had a sensitivity of 0.647 and a specificity of 0.861 for determining PVR >1000 dyn·s -1·cm -5 (AUC=0.830, P<0.001). The sPAP Echo/LVIDd and mPAP Echo/LVIDd significantly decreased after PEA (both P<0.001). The sPAP Echo/LVIDd and mPAP Echo/LVIDd reduction rate (ΔsPAP Echo/LVIDd and ΔmPAP Echo/LVIDd) were significantly correlated with PVR reduction rate (ΔPVR), respectively ( rs=0.61, 0.63, both P<0.05). Conclusions:Two-dimensional ratio sPAP Echo/LVIDd and three-dimensional ratio sPAP Echo/LVEDV can be used to noninvasively estimate PVR in CTEPH patients. The conventional ratio sPAP Echo/LVIDd is convenient and reproducibly suitable for monitoring the improvement of PVR before and after treatment, and its ratio of 2.14 can predict the significant increase of PVR in CTEPH patients (>1 000 dyn·s -1·cm -5).

Objective:To evaluate the association between preoperative serum β 2-microglobulin (β 2MG) concentrations and postoperative delirium (POD) in elderly patients. Methods:The study selected patients who underwent knee or hip arthroplasty under spinal-epidural anesthesia on an elective basis at Qingdao Municipal Hospital from May 2021 to November 2022. The patients were divided into a POD group and a non-POD group based on the occurrence of POD. The study was conducted as part of the Perioperative Neurocognitive Impairment and Biomarkers Lifestyle Cohort, which was a nested case-control study. The study collected baseline data from two groups of patients and analyzed the differences between them. Logistic regression was used to identify the risk factors for POD. The stability of the regression model was tested using sensitivity analysis. The mediation model was used to examine whether cerebrospinal fluid (CSF) biomarkers mediated the relationship between β 2MG and POD. The receiver operating characteristic curve was drawn and the area under the curve was calculated to evaluate the accuracy of preoperative β 2MG concentrations and CSF biomarker concentration in predicting POD. Results:There were 57 cases in POD group and 449 cases in non-POD group. The results of logistic regression analysis showed that the increased β 2MG and CSF total tau protein (t-tau) concentrations were risk factors for POD, and the increased CSF β-amyloid 42 concentration was a protective factor for POD after adjustment for multiple confounders such as age, gender, education, Mini-Mental State Examination, history of hypertension and infusion volume ( P<0.05). The results of mediation analysis showed that the serum β 2MG′s effect on POD was partly mediated by t-tau (18.1%). The results of the receiver operating characteristic curve showed that the area under the curve of the β 2MG concentration combined with the CSF biomarker concentration was 0.742. Conclusions:Elevated preoperative serum β 2MG concentration is a risk factor for POD in elderly patients, and the relationship may be partly mediated by CSF t-tau.

Purpose To observe the right ventricle and left ventricle blood pool T2 map in chronic thromboembolic pulmonary hypertension(CTEPH)and healthy controls,and to analyze the value of T2 mapping technique in evaluating CTEPH.Materials and Methods A total of 42 patients with CTEPH and 42 healthy volunteers had been prospectively recruited from January 2020 to January 2022 in China-Japan Friendship Hospital.All CTEPH patients underwent cardiac magnetic resonance with T2 mapping and right heart catheterization.Cardiac magnetic resonance was performed on healthy controls.Diastolic T2 mapping was performed in cardiac magnetic resonance,and then the ratio of right ventricular to left ventricular T2 values(RVT2/LVT2)between the CTEPH group and the healthy group was calculated and compared.Meanwhile,the correlation between RVT2/LVT2 and hemodynamic parameters in the CTEPH group was analyzed.Results RVT2/LVT2 in the CTEPH group was significantly lower than that in the healthy group(0.74±0.16 vs.0.86±0.12;t=3.673,P<0.001).RVT2/LVT2 in CTEPH group was negatively correlated with pulmonary vascular resistance(r=-0.534,P<0.001);while it was positively correlated with cardiac index,right atrium oxygen saturation,right ventricle oxygen saturation and pulmonary arteries oxygen saturation(r=0.600,0.603,0.648,0.582,P<0.001).Conclusion RVT2/LVT2 in the CTEPH group is positively correlated with right cardiac oxygen saturation and negatively correlated with pulmonary vascular resistance.T2 mapping may be a noninvasive evaluation of hemodynamics in CTEPH.