Mid1 promotes synovitis in rheumatoid arthritis via ubiquitin-dependent post-translational modification.

INTRODUCTION: Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed. OBJECTIVES: To explore the role of Midline-1 (Mid1) in synovial activation. METHODS: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were used to establish a subcutaneous xenograft model. Wild-type C57BL/6, Mid1-/-, Dpp4-/-, and Mid1-/-Dpp4-/- mice were used to establish a collagen-induced arthritis model. Cell viability, cell cycle, qPCR and western blotting analysis were used to detect MH7A proliferation, dipeptidyl peptidase-4 (DPP4) and Mid1 levels. Co-immunoprecipitation and proteomic analysis identified the candidate protein of Mid1 substrates. Ubiquitination assays were used to determine DPP4 ubiquitination status. RESULTS: An increase in Mid1, an E3 ubiquitin ligase, was observed in human RA synovial tissue by GEO dataset analysis, and this elevation was confirmed in a collagen-induced mouse arthritis model. Notably, deletion of Mid1 in a collagen-induced arthritis model completely protected mice from developing arthritis. Subsequent overexpression and knockdown experiments on MH7A, a human synoviocyte cell line, unveiled a previously unrecognized role of Mid1 in synoviocyte proliferation and migration, the key aspects of synovial activation. Co-immunoprecipitation and proteomic analysis identified DPP4 as the most significant candidate of Mid1 substrates. Mechanistically, Mid1 promoted synoviocyte proliferation and migration by inducing ubiquitin-mediated proteasomal degradation of DPP4. DPP4 deficiency led to increased proliferation, migration, and inflammatory cytokine production in MH7A, while reconstitution of DPP4 significantly abolished Mid1-induced augmentation of cell proliferation and activation. Additionally, double knockout model showed that DPP4 deficiency abolished the protective effect of Mid1 defect on arthritis. CONCLUSION: Overall, our findings suggest that the ubiquitination of DPP4 by Mid1 promotes synovial cell proliferation and invasion, exacerbating synovitis in RA. These results reveal a novel mechanism that controls synovial activation, positioning Mid1 as a promising target for therapeutic intervention in RA.

A Desperate Need for Psoriasis Health Care in Remote Regions as Revealed by a Live Interactive Teledermatology Program Serving Penghu Islands in Taiwan Strait.

Introduction: Several studies indicated that teledermatology is good for people living on offshore islands. However, what disease benefits the most from interactive dermatology geographically in offshore islands remain uncertain. Objectives: This study aimed to investigate the seasonal and geographical distribution with different diseases in remote regions of Penghu islands in Taiwan Strait, thus to study the medical needs for specific disease in remote islands. The cost differences among three models by professional dermatologists were analyzed. Methods: This interactive teledermatology program serving Penghu Hospital, Ministry of Health and Welfare (MOHW-PH, March 2020 to February 2021) from a medical center in Taiwan recruited 145 patients with 280 patient-visits. The seasons, the timing from residential houses to MOHW-PH, the number of disease diagnosis, and the numbers of teledermatology visits are compared. The association of the distance from residential houses to MOHW-PH with different disease diagnosis was analyzed. Results: Eczema (33%), dermatophytosis (13%), and psoriasis (11%) were most common. Seasonal analysis showed dermatophytosis and eczema are more common in summer and winter, respectively. Geographical analysis showed that psoriasis has relatively higher case numbers, higher visits per case, with cases living in longer distances. The patient satisfaction was good (>95%). Among the three care modes of dermatologist, the cost estimation of interactive teledermatology and in-person clinic were similar yearly (2.4-2.9 million New Taiwan Dollars, roughly 80,000-90,000 USD). Conclusions: The study indicates that health care for psoriasis, being underprivileged but in desperate need in distant regions, could be delivered with quality and satisfaction by interactive teledermatology.

The influence of personality traits and socio-demographic characteristics on paediatric nurses' compassion satisfaction and fatigue.

AIMS: To explore the level of and the association between, compassion satisfaction and fatigue of paediatric nurses; to determine the association between personality traits and compassion satisfaction and fatigue; to identify the determinants of compassion satisfaction and fatigue. BACKGROUND: Paediatric nurses are prone to experiencing compassion fatigue associated with caring for children with illness and their families, yet its connection with nurses' personality traits remains unknown. DESIGN: A cross-sectional descriptive study design was used. METHODS: The data collection used three instruments measuring socio-demography, responses to the compassion satisfaction and fatigue test and the revised NEO personality inventory. The study used descriptive, correlation and multiple regression analysis for the data collected between April - July 2014. RESULTS: From 173 female paediatric nurses, two-thirds worked in critical care units and indicated a satisfactory level of compassion satisfaction and a low level of compassion fatigue, despite a lack of association between the two concepts. Four determinants-agreeableness, extraversion, conscientiousness and engaging with outdoor activities-were predictive and explained 43.6% of total variance of compassion satisfaction. Two risk factors of compassion fatigue identified were less emotional stability and singlehood (marital status) and these explained 26.1% of total variance of compassion fatigue. CONCLUSION: Support for improving agreeableness and emotional stability in paediatric nurses' workplaces including involvement in the outdoor activities and an increase in social connection may enhance compassion satisfaction and prevent exhaustive compassion fatigue.

Active immunization for prevention of De novo hepatitis B virus infection after adult living donor liver transplantation with a hepatitis B core antigen-positive graft.

De novo hepatitis B virus (DNHB) infections may occur in recipients who do not receive prophylaxis after liver transplantation (LT) with antibody to hepatitis B core antigen (anti-HBc)-positive donor grafts. Active immunization has been shown to prevent DNHB in pediatric recipients. Our aim is to investigate the efficacy of HBV vaccination for preventing DNHB in adult living donor liver transplantation (LDLT). In total, 71 adult antibody to hepatitis B surface antigen (anti-HBs)-negative LDLT patients who received anti-HBc+ grafts from 2000 to 2010 were enrolled into this study. Patients were given hepatitis B virus vaccinations with the aim of achieving anti-HBs > 1000 IU/L before transplant and >100 IU/L after transplant. The cohort was stratified into 3 groups: patients with pretransplant anti-HBs titer of > 1000 IU/L without the need for posttransplant prophylaxis (group 1, n = 24), patients with pretransplant low titer of <1000 IU/L who were given posttransplant lamivudine prophylaxis and responded appropriately to posttransplant vaccination by maintaining anti-HBs titers of > 100 IU/L (group 2, n = 30), and low titer nonresponders (anti-HBs titer of < 100 IU/L despite vaccination), for whom lamivudine was continued indefinitely (group 3, n = 17). All DNHB occurred in group 3 patients with posttransplant anti-HBs levels of < 100 IU/L, with an incidence rate of 17.6% compared with 0% in patients with posttransplant anti-HBs levels of > 100 IU/L (P = 0.001). A pretransplant anti-HBs level of >1000 IU/L was significantly associated with early attainment and a sustained level of posttransplant anti-HBs of >100 IU/L (P < 0.001). Active immunization is effective in preventing DNHB in adult LDLT if the posttransplant anti-HBs level is maintained above 100 IU/L with vaccination. Antiviral prophylaxis can be safely discontinued in patients who obtain this immunity. Liver Transplantation 23 1266-1272 2017 AASLD.

Long-term renal outcomes comparison between patients with chronic kidney disease and hepatorenal syndrome after living donor liver transplantation.

Background and aims: Hepatorenal syndrome (HRS) is a disastrous renal complication of advanced liver disease with a poor prognosis. Restoring normal liver function through liver transplantation (LT) is a standardized treatment with favorable short-term survival. However, the long-term renal outcomes in patients with HRS receiving living donor LT (LDLT) are controversial. This study aimed to investigate the prognostic impact of LDLT in patients with HRS. Methods: We reviewed adult patients who underwent LDLT between July 2008 and September 2017. Recipients were classified into 1) HRS type 1 (HRS1, N = 11), 2) HRS type 2 (HRS2, N = 19), 3) non-HRS recipients with pre-existing chronic kidney disease (CKD, N = 43), and 4) matched normal renal function (N = 67). Results: Postoperative complications and 30-day surgical mortality were comparable among the HRS1, HRS2, CKD, and normal renal function groups. The 5-year survival rate was >90% and estimated glomerular filtration rate (eGFR) transiently improved and peaked at 4 weeks post-transplantation in patients with HRS. However, renal function deteriorated and resulted in CKD stage ≥ III in 72.7% of HRS1 and 78.9% of HRS2 patients (eGFR <60 ml/min/1.73 m2). The incidence of developing CKD and end-stage renal disease (ESRD) was similar between the HRS1, HRS2, and CKD groups, but significantly higher than that in the normal renal function group (both P < 0.001). In multivariate logistic regression, pre-LDLT eGFR <46.4 ml/min/1.73 m2 predicted the development of post-LDLT CKD stage ≥ III in patients with HRS (AUC = 0.807, 95% CI = 0.617-0.997, P = 0.011). Conclusions: LDLT provides a significant survival benefit for patients with HRS. However, the risk of CKD stage ≥ III and ESRD among patients with HRS was similar to that in pre-transplant CKD recipients. An early preventative renal-sparing strategy in patients with HRS is recommended.

Study on the Immune Escape Mechanism of Acute Myeloid Leukemia With DNMT3A Mutation.

DNA (cytosine-5)-methyltransferase 3A (DNMT3A)-mutated acute myeloid leukemia (AML) has a poor prognosis, but the exact mechanism is still unclear. Here, we aimed to explore the mechanism of immune escape in AML with DNMT3A mutation. We constructed a DNMT3A knockout clone and DNMT3A-R882H-mutated clones. RNA-seq results showed that transcription factors and macrophage inflammatory proteins were significantly downregulated in the DNMT3A mutant clones. KEGG enrichment and gene set enrichment analysis (GSEA) showed that a large number of genes were enriched in inflammatory immune-related pathways, such as the toll-like receptor signaling pathway. Therefore, we co-cultured AML cells with macrophages. The DNMT3A-mutated AML cells attenuated M1 macrophage polarization and resisted its killing effect in vitro and in vivo. In xenografts, the tumor volumes in the experimental group were significantly larger than those in the control group, and the proportion of M2 macrophages was significantly higher. After the co-culture, the increase in pro-inflammatory cytokine expression in the mutant cells was significantly lower than that in the control group, while that in immunosuppressive factors was not significantly different. In co-cultivated supernatants, the concentration of inflammatory factors in the experimental group was significantly lower than that in the control group, while that of immunosuppressive factors was significantly higher. Resistin significantly promoted the expression of inflammatory proteins in AML cells. It relieved the inhibitory effect of DNMT3A mutation, promoted the phenotypic recovery of the co-cultured macrophages, eliminated resistance, and regulated the immune microenvironment. Thus, resistin may serve as an ancillary drug for patients with DNMT3A-mutated AML.

Chidamide Inhibits Acute Myeloid Leukemia Cell Proliferation by lncRNA VPS9D1-AS1 Downregulation via MEK/ERK Signaling Pathway.

Irregular histone modification and aberrant lncRNAs expression are closely related to the occurrence of tumors including acute myeloid leukemia (AML). However, the effects and specific underlying molecular mechanism of histone deacetylase inhibitors on lncRNA expression in AML cells are unclear. Here, we reported the effects of a novel histone deacetylase inhibitor Chidamide on proliferation and lncRNA expression in AML cells. Chidamide inhibited cell proliferation, blocked G1/S phase transition, and induced cell apoptosis through the caspase-dependent apoptotic pathway in AML cells. Chidamide also inhibited the formation of subcutaneous tumors. Transcriptome sequencing results showed that 1,195 lncRNAs were co-upregulated and 780 lncRNAs were co-downregulated after Chidamide treatment of SKM-1 cells and THP-1 cells. Combined with transcriptome sequencing data and the gene expression profiling interactive analysis dataset, we found that VPS9D1-AS1 expression was negatively correlated with the survival of AML patients. VPS9D1-AS1 knockdown inhibited cell proliferation, arrested cell cycle, as well as inhibited the formation of subcutaneous tumors in vivo. VPS9D1-AS1 overexpression had the reverse effect. Furthermore, VPS9D1-AS1 knockdown inhibited the MEK/ERK signaling pathway, and thus enhanced the inhibitory effect of Chidamide on AML cell proliferation. These findings suggested that targeted regulation of VPS9D1-AS1 might overcome the limitations of Chidamide in the treatment of AML.

Clinical Features and MicroRNA Expression Patterns Between AML Patients With DNMT3A R882 and Frameshift Mutations.

Background: DNA methyltransferase 3A (DNMT3A) plays a unique role in hematopoiesis and acute myeloid leukemia (AML) pathogenesis. While the influences of DNMT3A mutation subtypes are still under debate. Purpose: Exploration of the clinical and molecular differences between AML patients carrying DNMT3A R882 mutations and DNMT3A frameshift mutations. Methods: Next generation of sequencing (NGS) and clinical data of 118 AML patients in our center were analyzed and compared. NGS, mRNA and miRNA profiling and clinical data from 12 patients in TCGA database were integrative analyzed. Results: Among all patients enrolled, 113 patients were positive for the variants of interest. Overall, a total of 295 variants were discovered, among which 24 DNMT3A mutations were detected, including 1 non-sense, 20 missense, 3 frameshift mutations. And 7 DNMT3A R882 mutations (3 R882H, 2 R882C, and 2 R882P) were found. Clinical analysis from our cohort and TCGA database indicated that patients carrying DNMT3A R882 mutation exhibited significantly higher levels of peripheral blood hemoglobin and non-significantly inferior prognosis compared with patients with DNMT3A frameshift mutations. Integrative analysis indicated that miR-10b, miR-143, and miR-30a were significantly decreased in the DNMT3A R882 group. High miR-143 expression is significantly associated with better prognosis in AML patients with DNMT3A mutations. Conclusion: Different molecular and clinical characteristics existed between patients with DNMT3A variant subtypes. The distinct microRNA expression pattern for DNMT3A R882 AML patients might not only act as markers to predict disease prognosis, but also could be further investigated to develop novel therapeutic targets for patients with DNMT3A mutations.

FDG-PET predicted unfavorable tumor histology in living donor liver transplant recipients; a retrospective cohort study.

BACKGROUND: Tumor histology affects outcome after liver transplantation (LT) for hepatocellular carcinoma (HCC). This study explores the association between F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and tumor histology in living donor liver transplantation (LDLT) recipients and their outcome. MATERIALS AND METHODS: Two hundred fifty-eight patients with primary liver tumors who underwent FDG-PET before LDLT were enrolled in this retrospective study. Unfavorable tumor histology was defined as primary liver tumor other than a well- or moderately differentiated HCC. Thirteen patients had unfavorable tumor histology, including 2 poorly differentiated HCC, 2 sarcomatoid HCC, 5 combined hepatocellular cholangiocarcinoma, 3 intrahepatic cholangiocarcinoma, and 1 hilar cholangiocarcinoma. RESULTS: FDG-PET positivity was significantly associated with unfavorable tumor histology (P < 0.001). Both FDG-PET positivity and unfavorable tumor histology were significant independent predictors of tumor recurrence and overall survival. In a subgroup analysis of patients with FDG-PET-positive tumors, unfavorable tumor histology was a significant independent predictor of tumor recurrence and overall survival. High FDG uptake (tumor to non-tumor uptake ratio ≥ 2) was a significant predictor of unfavorable tumor histology. Patients with high FDG uptake and/or unfavorable tumors had significantly higher 3-year cumulative recurrence rate (70.8% versus 26.2%, P = 0.004) and worse 3-year overall survival (34.1% versus 70.8%, P = 0.012) compared to those with low FDG uptake favorable tumors. CONCLUSIONS: The expression of FDG-PET is highly associated with histology of explanted HCC and predicts the recurrence. FDG-PET-positive tumors with high FDG uptake may be considered contraindication for LDLT due to high recurrence rate except when pathology proves favorable histology.

Clinical Outcomes of Tuberculosis in Recipients After Living Donor Liver Transplantation.

BACKGROUND This study aimed to determine clinical outcomes using various drugs during tuberculosis (TB) treatment among living donor liver transplant (LDLT) recipients with TB and to assess the impact of performing LDLT in patients with active TB at the time of LDLT. MATERIAL AND METHODS Out of 1313 LDLT performed from June 1994 to May 2016, 26 (2%) adult patients diagnosed with active TB were included in this study. Active TB was diagnosed using either TB culture, PCR, and/or tissue biopsy. RESULTS The median age was 56 years and the male/female ratio was 1.6: 1. Most patients had pulmonary TB (69.2%), followed by extrapulmonary and disseminated TB (15.4% each). Fourteen (53.8%) patients underwent LDLT even with the presence of active TB. All patients concurrently received anti-TB [Rifampicin-based: 13 (50%); Rifabutin-based: 12 (46.2%); INH-based: 1 (3.8%)] and immunosuppressive drugs [Tacrolimus-based: 6 (23%); Sirolimus/Everolimus-based: 20 (77%)]. During treatment, adverse drug reactions (ADR) occurred in 34.6% of patients: acute rejection in 6 (23.1%), hepatotoxicity in 2 (7.7%), and blurred vision in 1 (3.8%). Twenty-three (88%) patients completed their TB treatment. Neither TB recurrence nor TB-specific mortality were observed. Three (11.5%) patients died of non-TB-related causes. The overall 5-year survival rate was 86.2%. Patients with ADRs had a higher incidence of incomplete TB treatment (log-rank: p=0.012). Furthermore, patients with incomplete treatment were significantly associated with decreased overall survival (log-rank: p<0.001). Immunosuppressive and anti-TB drugs used during TB treatment and performing LDLT in patients with active TB at the time of LDLT were not associated with ADRs and overall survival. CONCLUSIONS Outcomes are generally favorable with intensive peri-operative evaluation and surveillance. ADRs and incomplete TB treatment may result in poor prognosis and increased mortality rates.

Prediction of the Development of Persistent Massive Ascites After Living Donor Liver Transplantation Using a Perioperative Risk Score.

BACKGROUND: Persistent massive ascites (PMAS) longer than 14 days after living donor liver transplantation is not uncommon and associated with worse outcome. A predictive risk scoring system was constructed after analysis of recipient, graft, and surgery-related factors. METHODS: We retrospectively reviewed adult living donor liver transplantation recipients from 2005 to 2011 after excluding cases that experienced any intervention for perioperative vascular-related events. Two groups were identified, PMAS and non-PMAS. The score was constructed from significant factors using weighted odds ratios (OR). RESULTS: The study population included 439 recipients. Persistent massive ascites was evident in 74 cases (17%). Five significant risk predictors were identified in multivariate analysis: pretransplant serum creatinine greater than 1.5 mg/dL (OR, 5.693; weighted OR, 2), recipient spleen to graft volume ratio greater than 1.3 (OR, 4.466; weighted OR, 2), left lobe graft (OR, 3.196; weighted OR, 1), more than 1000 mL ascites at laparotomy (OR, 2.541; weighted OR, 1), and graft recipient weight ratio less than 0.8 (OR, 2.419; weighted OR, 1). The clinical scoring system was constructed and ranged from 0 to 7. Receiver operating characteristic analysis showed an area under the curve (0.778, P < 0.001). Internal validation of the score showed an area under the curve of 0.783. The 5- and 10-year survival rates for the non-PMAS versus the PMAS groups were 89% and 84% versus 81% and 48%, respectively (P = 0.001). CONCLUSIONS: The PMAS score is a predictive pretransplant clinical tool. A Clinical cutoff score of 4 might be decision-changing. Pretransplant correction of renal functions, deciding to harvest a large graft and/or consideration of splenic artery embolization could reduce the risk of PMAS.