SERD-NHC-Au(I) complexes for dual targeting ER and TrxR to induce ICD in breast cancer.

The development of selective estrogen receptor degraders (SERDs) has brought new ideas for the clinical treatment of ER-positive advanced breast cancer. The successful application of combinational therapy inspired the exploration of other targets to prevent breast cancer progression. Thioredoxin reductase (TrxR) is an important enzyme that can regulate redox balance in cells and it was considered as a potential target for anticancer treatment. In this study, we firstly combine a clinical SERD candidate--G1T48 (NCT03455270), with a TrxR inhibitor--N-heterocyclic carbene gold(I) [NHC-Au(I)] to form dual targeting complexes that can regulate both signaling pathways. The most efficacious complex 23 exhibited significant antiproliferative profile through degrading ER and inhibiting TrxR activity. Interestingly, it can induce immunogenic cell death (ICD) caused by ROS. This is the first evidence to elucidate the role of ER/TrxR-ROS-ICD axis in ER positive breast cancer and this research may inspire new drug development with novel mechanisms. The in vivo xenograft study demonstrated that complex 23 had excellent antiproliferative activity toward MCF-7 cells in mice model.

The Effect of Artificial Liver Support System on Prognosis of HBV-Derived Hepatorenal Syndrome: A Retrospective Cohort Study.

Hepatorenal syndrome (HRS) could occur when patients get decompensated liver cirrhosis. Meanwhile, hepatitis B virus (HBV) infection raises the risk of mortality of the end-stage liver diseases. As the artificial liver support system (ALSS) has been applied in liver failure, whether ALSS could benefit HBV-derived HRS remains uncertain. We retrospectively enlisted eligible HRS patients and compared the baseline characteristics and prognosis between HBV-derived HRS and non-HBV-derived HRS. Furthermore, propensity score matching (PSM) and Cox regression analyses were used to assess the beneficial effect of ALSS on HBV-derived HRS. In addition, a stratified analysis was carried out according to the degree of acute kidney injury (AKI) and the number of organ failures to observe in which populations ALSS can obtain the most excellent therapeutic effect. 669 patients were diagnosed as HRS, including 298 HBV negative and 371 HBV positive. Baseline characteristics were different between patients with HBV positive and HBV negative. HBV-derived HRS has higher 28-day mortality, though without a statistical difference. After PSM, 50 patients treated with ALSS and 150 patients treated with standard medical treatment (SMT) constituted a new cohort for the following analysis. We found that ALSS could significantly benefit HRS patients (P = 0.025). Moreover, the median survival time of patients treated with ALSS was longer than those treated with SMT. INR, neutrophil percentage, and treatment with ALSS were independent predictive factors for short-term mortality in HBV-derived HRS. The stratified analysis showed that ALSS could reduce the 28-day mortality of patients with HBV-derived HRS, especially those in AKI stage 3 and with organ failure ≥ 2. Additionally, serum bilirubin was significantly lower after ALSS, and the alteration of INR and creatinine were independent predictive elements for the mortality of HBV-derived HRS. HBV-derived HRS is more severe than non-HBV-derived HRS and has a worse prognosis. ALSS could reduce the short-term mortality of patients with HBV-derived HRS, especially those in AKI stage 3 and with organ failure ≥ 2. INR and the change of creatinine and INR could predict the prognosis of HBV-derived HRS. ChiCTR2200060123.

Higher Mean Corpuscular Hemoglobin Concentration is Associated with Worse Prognosis of Hepatorenal Syndrome: A Multicenter Retrospective Study.

BACKGROUND: Hepatorenal syndrome (HRS) is a severe complication of decompensated cirrhosis with high mortality. However, few prognostic factors have been identified and studies are urgently needed to facilitate precise treatment. METHODS: Patients with decompensated cirrhosis and acute kidney injury were enrolled from four general hospitals between January 2010 and March 2020. Demographic and laboratory data were compared between surviving and non-surviving patients and also among different levels of HRS severity. COX regression analysis was performed to determine the effect of mean corpuscular hemoglobin concentration (MCHC) on survival of patients with HRS. RESULTS: Out of a total of 1287 patients enrolled, 325 patients were analyzed. MCHC was significantly higher in non-survivors than in survivors, and in patients with more serious disease, defined as failure of organ systems. The hazard ratio (HR) of mortality was 1.17, 1.18 and 1.11, when adjusted by the crude model, model 1 and model 2, respectively. When MCHC was converted to a categorical variable based on the quartile of MCHC, the HR for the highest quartile of MCHC was 2.11 (95% CI: 1.45-3.06, P <0.05) compared to the lowest quartile of MCHC in the crude model, and when adjusted for age and sex (model 1), the HR was 2.20 (95% CI: 1.52-3.20, P <0.05). In model 2, which was adjusted for complex characteristics, the HR was 1.77 (95% CI: 1.17-2.68, P <0.05). The results of Kaplan-Meier curves were consistent with those from Cox regression analysis. CONCLUSIONS: Higher MCHC was associated with worse prognosis in HRS.

Prognostic Nomogram for Patients with Hepatitis E Virus-related Acute Liver Failure: A Multicenter Study in China.

BACKGROUND AND AIMS: Timely and effective assessment scoring systems for predicting the mortality of patients with hepatitis E virus-related acute liver failure (HEV-ALF) are urgently needed. The present study aimed to establish an effective nomogram for predicting the mortality of HEV-ALF patients. METHODS: The nomogram was based on a cross-sectional set of 404 HEV-ALF patients who were identified and enrolled from a cohort of 650 patients with liver failure. To compare the performance with that of the model for end-stage liver disease (MELD) scoring and CLIF-Consortium-acute-on-chronic liver failure score (CLIF-C-ACLFs) models, we assessed the predictive accuracy of the nomogram using the concordance index (C-index), and its discriminative ability using time-dependent receiver operating characteristics (td-ROC) analysis, respectively. RESULTS: Multivariate logistic regression analysis of the development set carried out to predict mortality revealed that γ-glutamyl transpeptidase, albumin, total bilirubin, urea nitrogen, creatinine, international normalized ratio, and neutrophil-to-lymphocyte ratio were independent factors, all of which were incorporated into the new nomogram to predict the mortality of HEV-ALF patients. The area under the curve of this nomogram for mortality prediction was 0.671 (95% confidence interval: 0.602-0.740), which was higher than that of the MELD and CLIF-C-ACLFs models. Moreover, the td-ROC and decision curves analysis showed that both discriminative ability and threshold probabilities of the nomogram were superior to those of the MELD and CLIF-C-ACLFs models. A similar trend was observed in the validation set. CONCLUSIONS: The novel nomogram is an accurate and efficient mortality prediction method for HEV-ALF patients.

Association of ACEi/ARB Use and Clinical Outcomes of COVID-19 Patients With Hypertension.

Objectives: Evidence has shown that angiotensin-converting enzyme 2 (ACE2), which can be upregulated after angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, may play a dual role in the pathogenesis and progression of coronavirus disease 2019 (COVID-19). We aimed to assess the association between the use of ACEi/ARB and the outcome of COVID-19 patients with preexisting hypertension in non-endemic areas. Methods: From January 17, 2020, to February 19, 2020, 286 patients with hypertension were enrolled in this retrospective study out of 1,437 COVID-19 patients from 47 centers in Zhejiang and Jiangsu Province. The composite endpoints consisted of mechanical ventilation, intensive care unit (ICU) admission, or death. Cox proportional hazards analysis was performed to assess the association between ACEi/ARB and clinical outcomes of COVID-19 patients with hypertension. Results: In the main analysis, 103 patients receiving ACEi/ARB were compared with 173 patients receiving other regimens. Overall, 44 patients (15.94%) had an endpoint event. The risk probability of crude endpoints in the ACEi/ARB group (12.62%) was lower than that in the non-ACEi/ARB group (17.92%). After adjusting for confounding factors by inverse probability weighting, the results showed that the use of ACEi/ARB reduced the occurrence of end events by 47% [hazard ratio (HR) = 0.53; 95% CI, 0.34-0.83]. Similar results were obtained in multiple sensitivity analyses. Conclusions: In this retrospective study, among COVID-19 patients with hypertension, the use of ACEi/ARB is not associated with an increased risk of disease severity compared with patients without ACEi/ARB. The trends of beneficial effects of ACEi/ARB need to be further evaluated in randomized clinical trials.

Development and validation of a prognostic model for patients with hepatorenal syndrome: A retrospective cohort study.

BACKGROUND: Hepatorenal syndrome (HRS) is a severe complication of cirrhosis with high mortality, which necessitates accurate clinical decision. However, studies on prognostic factors and scoring systems to predict overall survival of HRS are not enough. Meanwhile, a multicenter cohort study with a long span of time could be more convincing. AIM: To develop a novel and effective prognostic model for patients with HRS and clarify new prognostic factors. METHODS: We retrospectively enrolled 1667 patients from four hospitals, and 371 eligible patients were finally analyzed to develop and validate a novel prognostic model for patients with HRS. Characteristics were compared between survivors and non-survivors, and potential prognostic factors were selected according to the impact on 28-d mortality. Accuracy in predicting 28-d mortality was compared between the novel and other scoring systems, including Model for End-Stage Liver Disease (MELD), Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA), and Chinese Group on the Study of Severe Hepatitis B-Acute-on-Chronic Liver Failure (COSSH-ACLF). RESULTS: Five prognostic factors, comprised of gender, international normalized ratio, mean corpuscular hemoglobin concentration, neutrophil percentage, and stage, were integrated into a new score, GIMNS; stage is a binary variable defined by the number of failed organs. GIMNS was positively correlated with MELD, CLIF-SOFA, and COSSH-ACLF. Additionally, it had better accuracy [area under the receiver operating characteristic curve (AUROC): 0.830] than MELD (AUROC: 0.759), CLIF-SOFA (AUROC: 0.767), and COSSH-ACLF (AUROC: 0.759) in the derivation cohort (P < 0.05). It performed better than MELD and CLIF-SOFA in the validation cohort (P < 0.050) and had a higher AUROC than COSSH-ACLF (P = 0.122). CONCLUSION: We have developed a new scoring system, GIMNS, to predict 28-d mortality of HRS patients. Mean corpuscular hemoglobin concentration and stage were first proposed and found to be related to the mortality of HRS. Additionally, the GIMNS score showed better accuracy than MELD and CLIF-SOFA, and the AUROC was higher than that of COSSH-ACLF.

Synthesis and in vitro anticancer activities of selenium N-heterocyclic carbene compounds.

Fourteen novel selenium N-heterocyclic carbene (Se-NHC) compounds derived from 4,5-diarylimidazole were designed, synthesized, and evaluated as antiproliferative agents. Most of them were more effective toward A2780 ovarian cancer cells than HepG2 hepatocellular carcinoma cells. Among them, the most active compound 2b was about fourfold more active than the positive control ebselen against A2780 cells. In addition, this compound displayed twofold higher cytotoxicity to A2780 cells than to IOSE80 normal ovarian epithelial cells. Further studies revealed that 2b could induce reactive oxygen species production, damage mitochondrial membrane potential, block the cells in the G0/G1 phase, and finally promote A2780 cell apoptosis.

A Nomogram Predicting the Prognosis of Renal Cell Carcinoma Patients with Lung Metastases.

BACKGROUND: The optimal tool for predicting the survival of renal cell carcinoma (RCC) patients with lung metastases remains controversial. METHODS: We selected patients diagnosed with RCC and lung metastases, from 2010 to 2015, from the Surveillance, Epidemiology, and End Results (SEER) database. After the selection of inclusion criteria and exclusion criterion, the rest of the patients were incorporated into model analysis. Least absolute shrinkage and selection operator (LASSO) regression was used to select the most important features for construction of a nomogram predicting cancer-specific survival. A calibration plot and the concordance index (C-index) were used to estimate nomogram efficacy in a validation cohort. The association between important factors selected by LASSO regression, and prognosis was assessed by the Kaplan-Meier (KM) survival curve. The receiver operating characteristic (ROC) curves were drawn to compare sensitivity and specificity between the nomogram we built and the TNM stage-based model. RESULTS: A total of 1,369 patients met the inclusion criteria, but not the exclusion criteria. The LASSO regression model reduced 15 features to seven potential predictors of survival, including tumor grade, the extent of surgery, N and T status, histological profile, and brain and bone metastasis status. Such features had good discrimination in the KM survival curves. The nomogram showed excellent discriminatory power (C-index, 0.71; 95% confidence interval: 0.70 to 0.72) and good calibration in terms of both 1- and 2-year cancer-specific survival. The nomogram showed great discriminatory power (C-index 0.68) and adequate calibration when applied to the validation cohort. The areas under the curve (AUCs) of nomogram were 0.767 and 0.780, respectively, and the AUCs of TNM stage were 0.617 and 0.618 at 1 and 2 years, respectively. CONCLUSIONS: Our nomogram might play a major role in predicting the cancer-specific survival of RCC patients with lung metastases.

Mesenchymal stromal cell-dependent immunoregulation in chemically-induced acute liver failure.

Drug-induced liver injury (DILI), which refers to liver damage caused by a drug or its metabolites, has emerged as an important cause of acute liver failure (ALF) in recent years. Chemically-induced ALF in animal models mimics the pathology of DILI in humans; thus, these models are used to study the mechanism of potentially effective treatment strategies. Mesenchymal stromal cells (MSCs) possess immunomodulatory properties, and they alleviate acute liver injury and decrease the mortality of animals with chemically-induced ALF. Here, we summarize some of the existing research on the interaction between MSCs and immune cells, and discuss the possible mechanisms underlying the immuno-modulatory activity of MSCs in chemically-induced ALF. We conclude that MSCs can impact the phenotype and function of macrophages, as well as the differentiation and maturation of dendritic cells, and inhibit the proliferation and activation of T lymphocytes or B lymphocytes. MSCs also have immuno-modulatory effects on the production of cytokines, such as prostaglandin E2 and tumor necrosis factor-alpha-stimulated gene 6, in animal models. Thus, MSCs have significant benefits in the treatment of chemically-induced ALF by interacting with immune cells and they may be applied to DILI in humans in the near future.

Human placenta mesenchymal stem cell-derived exosomes delay H2O2-induced aging in mouse cholangioids.

BACKGROUND: Cholangiocyte senescence is an important pathological process in diseases such as primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC). Stem cell/induced pluripotent stem cell-derived exosomes have shown anti-senescence effects in various diseases. We applied novel organoid culture technology to establish and characterize cholangiocyte organoids (cholangioids) with oxidative stress-induced senescence and then investigated whether human placenta mesenchymal stem cell (hPMSC)-derived exosomes exerted a protective effect in senescent cholangioids. METHODS: We identified the growth characteristics of cholangioids by light microscopy and confocal microscopy. Exosomes were introduced concurrently with H2O2 into the cholangioids. Using immunohistochemistry and immunofluorescence staining analyses, we assessed the expression patterns of the senescence markers p16INK4a, p21WAF1/Cip1, and senescence-associated ß-galactosidase (SA-ß-gal) and then characterized the mRNA and protein expression levels of chemokines and senescence-associated secretory phenotype (SASP) components. RESULTS: Well-established cholangioids expressed cholangiocyte-specific markers. Oxidative stress-induced senescence enhanced the expression of the senescence-associated proteins p16INK4a, p21WAF1/Cip1, and SA-ß-gal in senescent cholangioids compared with the control group. Treatment with hPMSC-derived exosomes delayed the cholangioid aging progress and reduced the levels of SASP components (i.e., interleukin-6 and chemokine CC ligand 2). CONCLUSIONS: Senescent organoids are a potential novel model for better understanding senescence progression in cholangiocytes. hPMSC-derived exosomes exert protective effects against senescent cholangioids under oxidative stress-induced injury by delaying aging and reducing SASP components, which might have therapeutic potential for PSC or PBC.

Mesenchymal stem cell-mediated immunomodulation of recruited mononuclear phagocytes during acute lung injury: a high-dimensional analysis study.

Rationale: Acute lung injury (ALI)-recruited mononuclear phagocytes play a pivotal role in lung injury and repair. This study investigated the types of recruited mononuclear phagocytes and the immunotherapeutic effects of allograft mesenchymal stem cells (MSCs) in a mouse model of lipopolysaccharide (LPS)-induced ALI. Methods: C57BL/6 mice were orotracheally instilled with LPS (20 mg/kg). Compact bone-derived MSCs were administered orotracheally 4 h after LPS inhalation. Mononuclear phagocytes recruited in the lung tissues were characterized at different timepoints by high-dimensional analysis including flow cytometry, mass cytometry, and single-cell RNA sequencing. Results: Eight mononuclear phagocyte subsets recruited to LPS-challenged lungs were precisely identified. On day 3 after LPS administration, both Ly6ChiCD38+ and Ly6ClowCD38+ monocytes were recruited into acutely injured lungs, which was associated with increased secretion of neutrophil chemokines. Ly6ChiCD38+ monocytes differentiated into M1 macrophages on day 3, and subsequently differentiated into CD38+ monocyte-derived dendritic cells (mo-DCs) on day 7, while Ly6ClowCD38+ monocytes differentiated into CD11b+CD38+ DCs on day 7. When ALI mice were treated with MSCs, the mortality significantly reduced. Notably, MSCs reduced the amount of M1 macrophages and reduced the secretion of neutrophil chemokines on day 3. Furthermore, MSCs reduced the number of CD38+ mo-DCs and CD11b+CD38+ DCs on day 7, suppressing the antigen presentation process. Recruited mononuclear phagocyte subsets with a high level of CD38 exhibited an activated phenotype and could secrete higher levels of cytokines and chemokines. Conclusions: This study characterized the dynamic functions and phenotypes of recruited mononuclear phagocytes in ALI mice and MSC-treated ALI mice.

Mesenchymal stem cells alleviate LPS-induced acute lung injury by inhibiting the proinflammatory function of Ly6C+ CD8+ T cells.

Systemic inflammatory processes, including alveolar injury, cytokine induction, and neutrophil accumulation, play key roles in the pathophysiology of acute lung injury (ALI). The immunomodulatory effects of mesenchymal stem cells (MSCs) can contribute to the treatment of inflammatory disorders. In previous studies, the focus was on innate immune cells and the effects of MSCs on ALI through CD8+ T cells remain unclear. In the present study, lipopolysaccharide (LPS) was used to induce ALI in mice. ALI mice were treated with MSCs via intratracheal instillation. Survival rate, histopathological changes, protein levels, total cell count, cytokine levels, and chemokine levels in alveolar lavage fluid were used to determine the efficacy of MSCs. Mass cytometry and single-cell RNA sequencing (scRNA-seq) were used to characterize the CD8+ T cells in the lungs. Ly6C- CD8+ T cells are prevalent in normal mice, whereas a specialized effector phenotype expressing a high level of Ly6C is predominant in advanced disease. MSCs significantly mitigated ALI and improved survival. MSCs decreased the infiltration of CD8+ T cells, especially Ly6C+ CD8+ T cells into the lungs. Mass cytometry revealed that CD8+ T cells expressing high Ly6C and CXCR3 levels caused tissue damage in the lungs of ALI mice, which was alleviated by MSCs. The scRNA-seq showed that Ly6C+ CD8+ T cells exhibited a more activated phenotype and decreased expression of proinflammatory factors that were enriched the most in immune chemotaxis after treatment with MSCs. We showed that CD8+ T cells play an important role in MSC-mediated ALI remission, and both infiltration quantity and proinflammatory function were inhibited by MSCs, indicating a potential mechanism for therapeutic intervention.

Immunosuppressive effects of mesenchymal stem cells on lung B cell gene expression in LPS-induced acute lung injury.

BACKGROUND: Immune system disorders play important roles in acute lung injury (ALI), and mesenchymal stem cell (MSC) treatment can reduce inflammation during ALI. In this study, we compared the changes in lung B cells during MSC treatment. METHODS: We investigated the effects of MSCs on lung B cells in a mouse model of lipopolysaccharide (LPS)-induced ALI. MSCs were administered intratracheally 4 h after LPS. As vehicle-treated controls, mice were treated with phosphate-buffered saline (PBS) containing 2% C57BL/6 (PBS group). Histopathological changes, survival rate, inflammatory factor levels, and the number of neutrophils in bronchoalveolar lavage fluid (BALF) were determined. Single-cell RNA sequencing (scRNA-Seq) analysis was performed to evaluate the transcriptional changes in lung B cells between the PBS, LPS, and LPS/MSC groups on days 3 and 7. RESULTS: MSC treatment ameliorated LPS-induced ALI, as indicated by the reductions in mortality, the levels of chemokines and cytokines in BALF, and the severity of lung tissue histopathology in ALI mice. Lung B cells in the PBS group remained undifferentiated and had an inhibitory phenotype. Based on our scRNA-Seq results, the differentially expressed genes (DEGs) in lung B cells in both the PBS group and LPS group were involved in chemotaxis processes and some proinflammatory pathways. MSC treatment inhibited the expression of chemokine genes that were upregulated by LPS and were related to the recruitment of neutrophils into lung tissues. Immunoglobulin-related gene expression was decreased in lung B cells of mice treated with LPS/MSC for 7 days. The DEGs regulated by MSCs were enriched in biological processes, including humoral immune response and apoptotic signaling. CONCLUSIONS: Lung B cells played an important role in the effects of treatment of ALI with MSCs. These observations provide new insights into the mechanisms underlying the effects of MSC treatment for ALI.

Characteristics and outcomes of acute-on-chronic liver failure patients with or without cirrhosis using two criteria.

The aim of the study was to identify the characteristics and outcomes in acute-on-chronic liver failure (ACLF) patients with or without cirrhosis using two criteria. Patients with acute deterioration of chronic hepatic disease or acute decompensation of cirrhosis were included retrospectively from April 10, 2016 to April 10, 2019. European Association for the Study of the Liver-chronic liver failure (EASL-CLIF) criterion except for consideration of cirrhosis and Chinese Group on the Study of Severe Hepatitis B (COSSH) criterion were used. Clinical features, laboratory data and survival curves were compared between the ACLF patients with and without cirrhosis. A total of 799 patients were included. Among them, 328 had COSSH and EASL ACLF, 197 had COSSH alone, and 104 had EASL alone. There were 11.6% more ACLF with COSSH criterion. Furthermore, EASL ACLF patients with non-cirrhosis vs. cirrhosis had different laboratory characteristics: ALT (423 vs. 154, p < 0.001), AST (303 vs. 157, p < 0.001), γ-GT (86 vs. 75, p < 0.01), and INR (2.7 vs. 2.6, p < 0.001) were significantly higher but creatinine (71 vs. 77, p < 0.01) were significantly lower; but importantly there was no statistical changes between non-cirrhosis and cirrhosis in EASL ACLF patients on 28-day (p = 0.398) and 90-day (p = 0.376) survival curves. However, 90-day (p = 0.030) survival curve was different between non-cirrhosis and cirrhosis in COSSH ACLF patients. COSSH ACLF score (auROC = 0.778 or 0.792, 95%CI 0.706-0.839 or 0.721-0.851) displayed the better prognostic ability for EASL ACLF patients with non-cirrhosis, but CLIF-C ACLF score (auROC = 0.757 or 0.796, 95%CI 0.701-0.807 or 0.743-0.843) still was the best prognostic scoring system in EASL ACLF patients with cirrhosis. In conclusions, EASL definition exhibited better performance on homogeneous identification of ACLF regardless of cirrhosis or non-cirrhosis. And COSSH ACLF score displayed the better prognostic ability for EASL ACLF patients without cirrhosis.

Immunomodulatory effect of mesenchymal stem cells in chemical-induced liver injury: a high-dimensional analysis.

BACKGROUND: The efficacy of mesenchymal stem cell (MSC)-based therapy for acute liver injury (ALI) involves coordination with the hepatic immune system, a complex and coordinated network of immune-cell interactions. However, studies of the immunomodulatory effects of MSCs have focused on a limited number of cell subsets rather than a systematic assessment. METHODS: Carbon tetrachloride (CCl4) was used to induce ALI in mice. To determine the efficacy of MSCs, ALI mice were injected with MSCs via the tail vein, and histopathological changes, survival rate, and the serum levels of liver enzymes were determined. To assess the immune response induced by MSCs, a mass cytometry panel of 43 metal isotope-tagged antibodies was used to characterize the hepatic immune compartment at days 1, 2, 3, and 7 after administration of MSCs or PBS. RESULTS: MSC treatment significantly alleviated CCl4-induced ALI and improved the survival rate. MSC treatment also modulated the hepatic immune system in terms of the distribution of immune-cell subsets and the phenotype of single cells. During the injured phase, MSCs inhibited a systemic response by reducing the numbers of Ly6ClowCD8+ TRM cells, conventional NK cells, and IgM+IgD+ B cells; suppressing the activation of Ly6ChiCD8+ TRM cells; downregulating MHC II and IgM expression in IgM+IgD+ B cells; and increasing the number of immunosuppressive monocyte-derived macrophages. During the recovery phase, MSCs promoted the retention of Ly6ClowCD8+ TRM cells and maintained the immunosuppressive activity of monocyte-derived macrophages. The response to MSC treatment differed between the injured and recovery phases, emphasizing the benefit of dynamic assessment of the immunomodulatory effects of MSCs. CONCLUSIONS: We determined the immunomodulatory effects of MSC treatment on the subtype distribution and phenotypes of hepatic immune cells.

The role of hepatitis B core-related antigen in predicting hepatitis B virus recurrence after liver transplantation.

BACKGROUND: Hepatitis B core-related antigen (HBcrAg) is a viral marker for the development of cirrhosis and hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). However, the relationship between HBcrAg and HBV recurrence after liver transplantation (LT) is unclear. AIM: To investigate the correlation of serum HBcrAg level with HBV recurrence post-LT to evaluate the prognostic role of the pre-LT HBcrAg level. METHODS: This retrospective cohort study enrolled 357 CHB patients who received LT for a median of 36.6 months. Univariate and multivariate analyses and time-dependent receiver operating characteristic (ROC) curves for markers associated with HBV recurrence were analysed. RESULTS: 48 patients (13.4%) had HBV recurrence after LT. HBcrAg, detectable HBV DNA, HCC and HCC recurrence were associated with HBV recurrence. In a multivariate analysis, HBcrAg level was independently associated with HBV recurrence, and the relationship between HBcrAg level and incident HBV recurrence was significant and graded (HR: 3.17 per unit; 95% CI: 1.97-5.11; P for trend < .001). Additionally, HBcrAg level was superior to HBV DNA level in predicting HBV recurrence by time-dependent ROC analysis. Patients with an HBcrAg ≥ 5.0 log U/mL had a significantly higher 5-year cumulative recurrence rate than those with an HBcrAg < 5.0 log U/mL (37.6% vs 6%, P < .001); the adjusted hazard ratio was 5.27 (95% CI 2.47-11.25, P < .001). CONCLUSION: An elevated serum HBcrAg level was independently associated with the risk of HBV recurrence in patients with CHB after LT.

The Sensitivity of Orthopaedic Surgeons to the Secondary Prevention of Fragility Fractures.

BACKGROUND: Orthopaedic surgeons must play an important role in the secondary prevention of fragility fractures; however, some surgeons are more aware than others of their responsibility regarding fracture prevention. The purpose of the present study was to identify which factors can lead to a higher sensitivity for fracture prevention. METHODS: A cross-sectional survey was distributed to orthopaedic surgeons via online invitation or at academic conferences in China from July through October 2015. A total of 452 surgeons responded. As the primary outcome measure, we created a sensitivity scoring system for fracture prevention based on the respondents' answers to 5 questions regarding behavior in the following areas: risk-factor evaluation, pharmacologic therapy, nonpharmacologic therapy, patient education, and follow-up. Multivariable linear regression and multivariable logistic regression analyses were used to identify factors related to surgeon sensitivity to fracture prevention. RESULTS: Very few surgeons reported having received adequate training regarding fracture prevention or reading guidelines or other fracture prevention literature (22% and 30%, respectively). Most respondents initiated pharmacologic or nonpharmacologic therapy (82% and 75%, respectively) for the treatment of confirmed osteoporosis among patients with fragility fractures, but only half performed a risk-factor evaluation, patient education, or timely patient follow-up (51%, 52%, and 48%, respectively). In the multivariable linear regression model, the orthopaedic surgeon's age (ß = 0.09, p = 0.003), self-rated knowledge level regarding osteoporosis or related issues (ß = 0.16, p < 0.001), self-perceived effectiveness in using preventive measures for patients with a fragility fracture (ß = 0.62, p < 0.001), and use of clinical pathways for fragility fractures in his or her workplace (ß = 1.24, p < 0.001) were independently associated with sensitivity scores for fracture prevention. Similar results were obtained from a multivariable logistic regression model. CONCLUSIONS: In China, the sensitivity of orthopaedic surgeons to the secondary prevention of fragility fractures is relatively low. Implementation of a comprehensive prevention approach and targeted continuing medical education are required to encourage surgeons to take greater responsibility for screening, treating, educating, and following their patients with fragility fractures.