Safety and efficacy of baricitinib in steroid-resistant or relapsed immune thrombocytopenia: An open-label pilot study.

Patients with steroid-resistant or relapsed immune thrombocytopenia (ITP) suffer increased bleeding risk and impaired quality of life. Baricitinib, an oral Janus-associated kinases (JAK) inhibitor, could alleviate both innate and adaptive immune disorders without inducing thrombocytopenia in several autoimmune diseases. Accordingly, an open-label, single-arm, phase 2 trial (NCT05446831) was initiated to explore the safety and efficacy of baricitinib in ITP. Eligible patients were adults with primary ITP who were refractory to corticosteroids and at least one subsequent treatment, and had platelet counts below 30 × 109/L at enrolment. Participants received baricitinib 4 mg daily for 6 months. The primary endpoint was durable response at the 6-month follow-up. A total of 35 patients were enrolled. Durable response was achieved in 20 patients (57.1%, 95% confidence interval, 39.9 to 74.4), and initial response in 23 (65.7%) patients. For patients responding to baricitinib, the median time to response was 12 (IQR 6-20) days, and the median peak platelet count was 94 (IQR 72-128) × 109/L. Among the 27 patients undergoing extend observation, 12 (44.4%) remained responsive for a median duration of approximately 20 weeks after baricitinib discontinuation. Adverse events were reported in 11 (31.4%) patients, including infections in 6 (17.1%) patients during the treatment period. Treatment discontinuation due to an adverse event was reported in 2 (5.7%) patients. Evidence from this pilot study suggested that baricitinib might be a novel candidate for the armamentarium of ITP-modifying agents. Future studies are warranted to validate the safety, efficacy, and optimal dosing of baricitinib in patients with ITP.

Predicting short-term and long-term mortalities from sepsis in patients who receive allogeneic haematopoietic stem cell transplantation.

Patients who receive allogeneic haematopoietic stem cell transplantation (allo-HSCT) may develop sepsis, which result in a highly intensive care unit admission rate and mortality. Therefore, short-term and long-term prognostic models for sepsis after allo-HSCT are urgently needed. We enrolled patients receiving allo-HSCT who developed sepsis after allo-HSCT at Peking University People's Hospital between 2012 and 2021, including 287 patients who received allo-HSCT in 2018-2021 in the derivation cohort, and 337 patients in 2012-2017 in the validation cohort. Multivariate logistic regression analysis was used to identify prognostic factors, and these identified factors were incorporated into two scoring models. Seven independent factors (acute graft-versus-host disease (GVHD), chronic GVHD (cGVHD), total bilirubin, lactate dehydrogenase (LDH) and organ dysfunction [renal, lung and heart]) were included in the 6-month prognostic model, and six factors (cGVHD, C-reactive protein, LDH, organ dysfunction [lung, neurologic and coagulation]) were included in the 14-day prognostic model. The area under the receiver operating characteristic curves, calibration plots and decision curve analysis demonstrated the robust predictive performance of the models, better than the Sequential Organ Failure Assessment score. Early identification of patients with high risk of 6-month and 14-day death may allow clinicians to provide timely treatments and improve the therapeutic effects.

Prediction of postpartum hemorrhage in pregnant women with immune thrombocytopenia: Development and validation of the MONITOR model in a nationwide multicenter study.

Globally, postpartum hemorrhage (PPH) is the leading cause of maternal death. Women with immune thrombocytopenia (ITP) are at increased risk of developing PPH. Early identification of PPH helps to prevent adverse outcomes, but is underused because clinicians do not have a tool to predict PPH for women with ITP. We therefore conducted a nationwide multicenter retrospective study to develop and validate a prediction model of PPH in patients with ITP. We included 432 pregnant women (677 pregnancies) with primary ITP from 18 academic tertiary centers in China from January 2008 to August 2018. A total of 157 (23.2%) pregnancies experienced PPH. The derivation cohort included 450 pregnancies. For the validation cohort, we included 117 pregnancies in the temporal validation cohort and 110 pregnancies in the geographical validation cohort. We assessed 25 clinical parameters as candidate predictors and used multivariable logistic regression to develop our prediction model. The final model included seven variables and was named MONITOR (maternal complication, WHO bleeding score, antepartum platelet transfusion, placental abnormalities, platelet count, previous uterine surgery, and primiparity). We established an easy-to-use risk heatmap and risk score of PPH based on the seven risk factors. We externally validated this model using both a temporal validation cohort and a geographical validation cohort. The MONITOR model had an AUC of 0.868 (95% CI 0.828-0.909) in internal validation, 0.869 (95% CI 0.802-0.937) in the temporal validation, and 0.811 (95% CI 0.713-0.908) in the geographical validation. Calibration plots demonstrated good agreement between MONITOR-predicted probability and actual observation in both internal validation and external validation. Therefore, we developed and validated a very accurate prediction model for PPH. We hope that the model will contribute to more precise clinical care, decreased adverse outcomes, and better health care resource allocation.

Risk stratification and outcomes of intracranial hemorrhage in patients with immune thrombocytopenia under 60 years of age.

Intracranial hemorrhage (ICH) is a devastating complication of immune thrombocytopenia (ITP). However, information on ICH in ITP patients under the age of 60 years is limited, and no predictive tools are available in clinical practice. A total of 93 adult patients with ITP who developed ICH before 60 years of age were retrospectively identified from 2005 to 2019 by 27 centers in China. For each case, 2 controls matched by the time of ITP diagnosis and the duration of ITP were provided by the same center. Multivariate analysis identified head trauma (OR = 3.216, 95%CI 1.296-7.979, P =.012), a platelet count ≤ 15,000/µL at the time of ITP diagnosis (OR = 1.679, 95%CI 1.044-2.698, P =.032) and severe/life-threatening bleeding (severe bleeding vs. mild bleeding, OR = 1.910, 95%CI 1.088-3.353, P =.024; life-threatening bleeding vs. mild bleeding, OR = 2.620, 95%CI 1.360-5.051, P =.004) as independent risk factors for ICH. Intraparenchymal hemorrhage (OR = 5.191, 95%CI 1.717-15.692, P =.004) and a history of severe bleeding (OR = 4.322, 95%CI 1.532-12.198, P =.006) were associated with the 30-day outcome of ICH. These findings may facilitate ICH risk stratification and outcome prediction in patients with ITP.

Development and validation of a prediction model (AHC) for early identification of refractory thrombotic thrombocytopenic purpura using nationally representative data.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological emergency. Although therapeutic plasma exchange together with corticosteroids achieve successful outcomes, a considerable number of patients remain refractory to this treatment and require early initiation of intensive therapy. However, a method for the early identification of refractory iTTP is not available. To develop and validate a model for predicting the probability of refractory iTTP, a cohort of 265 consecutive iTTP patients from 17 large medical centres was retrospectively identified. The derivation cohort included 94 patients from 11 medical centres. For the validation cohort, we included 40 patients from the other six medical centres using geographical validation. An easy-to-use risk score system was generated, and its performance was assessed using internal and external validation cohorts. In the multivariable logistic analysis of the derivation cohort, three candidate predictors were entered into the final prediction model: age, haemoglobin and creatinine. The prediction model had an area under the curve of 0.886 (95% CI: 0.679-0.974) in the internal validation cohort and 0.862 (95% CI: 0.625-0.999) in the external validation cohort. The calibration plots showed a high agreement between the predicted and observed outcomes. In conclusion, we developed and validated a highly accurate prediction model for the early identification of refractory iTTP. It has the potential to guide tailored therapy and is a step towards more personalized medicine.

RARß acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells.

This study investigates the mechanism and consequences of microRNA-22 ( miR-22) induction. Our data revealed for the first time that retinoic acid (RA) and histone deacetylase (HDAC) inhibitors, including short-chain fatty acids and suberanilohydroxamic acid (SAHA), could individually or in combination induce miR-22. This induction was mediated via RA receptor ß (RARß) binding to a direct repeat 5 (DR5) motif. In addition, we uncovered HDAC1 as a novel miR-22 target. In an miR-22-dependent manner, HDAC inhibitors and RA reduced HDAC1, HDAC4, and sirtuin 1 (SIRT1), which were involved in chromatin remodeling of the RARß and nerve growth factor IB ( NUR77). Thus, HDAC inhibitors and RA-induced miR-22 resulted in simultaneous induction of cytoplasmic RARß and NUR77, leading to apoptosis of colon cancer cells. In mice, miR-22 and its inducers inhibited the growth of xenograft colon cancer. Moreover, tumor size reduction was accompanied by elevated miR-22, NUR77, and RARß and by reduced HDACs. In human colon polyps and adenocarcinomas, miR-22 and RARß were consistently reduced, which was associated with elevated HDAC1, HDAC4, and SIRT1 in colon adenocarcinomas. Results from this study revealed a novel anticancer mechanism of RARß via miR-22 induction to epigenetically regulate itself and NUR77, providing a promising cancer treatment modality using miR-22 and its inducers.-Hu, Y., French, S. W., Chau, T., Liu, H.-X., Sheng, L., Wei, F., Stondell, J., Garcia, J. C., Du, Y., Bowlus, C. L., Wan, Y.-J. Y. RARß acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells.

Comparison of different cytomegalovirus diseases following haploidentical hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) can cause end-organ diseases including pneumonia, gastroenteritis, retinitis, and encephalitis in hematopoietic stem cell transplantation recipients. Potential differences among different CMV diseases remain uncertain. This study aimed to compare the clinical characteristics, risk factors, and mortality among different CMV diseases. A retrospective nested case-control study was performed based on a cohort of 3862 patients who underwent haploidentical hematopoietic stem cell transplantation at a single-center. CMV diseases occurred in 113 (2.92%) of 3862 haplo-HSCT recipients, including probable CMV pneumonia (CMVP, n = 34), proven CMV gastroenteritis (CMVG, n = 34), CMV retinitis (CMVR, n = 31), probable CMV encephalitis (CMVE, n = 7), and disseminated CMV disease (Di-CMVD, n = 7). Most (91.2%) cases of CMVG developed within 100 days, while most (90.3%) cases of CMVR were late onset. Refractory CMV infection and CMV viral load at different levels were associated with an increased risk of CMVP, CMVG, and CMVR. Compared with patients without CMV diseases, significantly higher non-relapse mortality at 1 year after transplantation was observed in patients with CMVP and CMVR, rather than CMVG. Patients with CMVP, Di-CMVD, and CMVE had higher overall mortality after diagnosis than that of patients with CMVG and CMVR (61.7%, 57.1%, 40.0% vs 27.7%, 18.6%, P = 0.001). In conclusion, the onset time, viral dynamics, and mortality differ among different CMV diseases. The mortality of CMV diseases remains high, especially for CMVP, Di-CMVD, and CMVE.

A novel supramolecular polymer gel-based long-alkyl-chain-functionalized coumarin acylhydrazone for the sequential detection and separation of toxic ions.

A novel approach for the detection and separation of toxic ions was successfully developed via the introduction of competitive reactions into a long-alkyl-chained acylhydrazone-based coumarin supramolecular polymer, chemosensor OGC (3%, n-BuOH/H2O), which showed sequential detection and separation of CN-, Fe3+ and S2-, Ag+ in the gel state with high selectivity and sensitivity. Moreover, the ion-responsive films were prepared for the convenient and continuous detection of CN-, Fe3+ and S2-, Ag+ in water solution.

Obesity treatment by epigallocatechin-3-gallate-regulated bile acid signaling and its enriched Akkermansia muciniphila.

Dysregulated bile acid (BA) synthesis is accompanied by dysbiosis, leading to compromised metabolism. This study analyzes the effect of epigallocatechin-3-gallate (EGCG) on diet-induced obesity through regulation of BA signaling and gut microbiota. The data revealed that EGCG effectively reduced diet-increased obesity, visceral fat, and insulin resistance. Gene profiling data showed that EGCG had a significant impact on regulating genes implicated in fatty acid uptake, adipogenesis, and metabolism in the adipose tissue. In addition, metabolomics analysis revealed that EGCG altered the lipid and sugar metabolic pathways. In the intestine, EGCG reduced the FXR agonist chenodeoxycholic acid, as well as the FXR-regulated pathway, suggesting intestinal FXR deactivation. However, in the liver, EGCG increased the concentration of FXR and TGR-5 agonists and their regulated signaling. Furthermore, our data suggested that EGCG activated Takeda G protein receptor (TGR)-5 based on increased GLP-1 release and elevated serum PYY level. EGCG and antibiotics had distinct antibacterial effects. They also differentially altered body weight and BA composition. EGCG, but not antibiotics, increased Verrucomicrobiaceae, under which EGCG promoted intestinal bloom of Akkermansia muciniphila. Excitingly, A. muciniphila was as effective as EGCG in treating diet-induced obesity. Together, EGCG shifts gut microbiota and regulates BA signaling thereby having a metabolic beneficial effect.-Sheng, L., Jena, P. K., Liu, H.-X., Hu, Y., Nagar, N., Bronner, D. N., Settles, M. L., Bäumler, A. J. Wan, Y.-J. Y. Obesity treatment by epigallocatechin-3-gallate-regulated bile acid signaling and its enriched Akkermansia muciniphila.

Western Diet-Induced Dysbiosis in Farnesoid X Receptor Knockout Mice Causes Persistent Hepatic Inflammation after Antibiotic Treatment.

Patients who have liver cirrhosis and liver cancer also have reduced farnesoid X receptor (FXR). The current study analyzes the effect of diet through microbiota that affect hepatic inflammation in FXR knockout (KO) mice. Wild-type and FXR KO mice were on a control (CD) or Western diet (WD) for 10 months. In addition, both CD- and WD-fed FXR KO male mice, which had hepatic lymphocyte and neutrophil infiltration, were treated by vancomycin, polymyxin B, and Abx (ampicillin, neomycin, metronidazole, and vancomycin). Mice were subjected to morphological analysis as well as gut microbiota and bile acid profiling. Male WD-fed FXR KO mice had the most severe steatohepatitis. FXR KO also had reduced Firmicutes and increased Proteobacteria, which could be reversed by Abx. In addition, Abx eliminated hepatic neutrophils and lymphocytes in CD-fed, but not WD-fed, FXR KO mice. Proteobacteria and Bacteroidetes persisted in WD-fed FXR KO mice even after Abx treatment. Only polymyxin B could reduce hepatic lymphocytes in WD-fed FXR KO mice. The reduced hepatic inflammation by antibiotics was accompanied by decreased free and conjugated secondary bile acids as well as changes in gut microbiota. Our data revealed that Lactococcus, Lactobacillus, and Coprococcus protect the liver from inflammation.

A thumb-size electrochemical system for portable sensors.

To enable electrochemistry-based sensors to be applied under size and cost sensitive conditions, we developed a thumb-size electrochemistry instrument system (MiniEC) with integrated components including an electrochemical sensing interface, signal transduction, amplification, filtering, processing and transmission with a cost of around only $15. We showed its potential application for electrochemical studies and on-site environmental monitoring in a wide range of environments such as laboratory, household, countryside, industry or wild settings. By using the MiniEC with screen printed electrodes, the LOD (limit of detection) for Cd2+ and Pb2+ is as low as 1 µg L-1 and 0.5 µg L-1, respectively.

Hepatic inflammation caused by dysregulated bile acid synthesis is reversible by butyrate supplementation.

Dysregulated bile acid (BA) synthesis or reduced farnesoid X receptor (FXR) levels are found in patients having metabolic diseases, autoimmune hepatitis, and liver cirrhosis or cancer. The objective of this study was to establish the relationship between butyrate and dysregulated BA synthesis-induced hepatitis as well as the effect of butyrate in reversing the liver pathology. Wild-type (WT) and FXR knockout (KO) male mice were placed on a control (CD) or western diet (WD) for 15 months. In the presence or absence of butyrate supplementation, feces obtained from 15-month-old WD-fed FXR KO mice, which had severe hepatitis and liver tumors, were transplanted to 7-month-old WD-fed FXR KO for 3 months. Hepatic phenotypes, microbiota profile, and BA composition were analyzed. Butyrate-generating bacteria and colonic butyrate concentration were reduced due to FXR inactivation and further reduced by WD intake. In addition, WD-fed FXR KO male mice had the highest concentration of hepatic ß-muricholic acid (ß-MCA) and bacteria-generated deoxycholic acid (DCA) accompanied by serious hepatitis. Moreover, dysregulated BA and reduced SCFA signaling co-existed in both human liver cancers and WD-fed FXR KO mice. Microbiota transplantation using butyrate-deficient feces derived from 15-month-old WD-fed FXR KO mice increased hepatic lymphocyte numbers as well as hepatic ß-MCA and DCA concentrations. Furthermore, butyrate supplementation reduced hepatic ß-MCA as well as DCA and eliminated hepatic lymphocyte infiltration. In conclusion, reduced butyrate contributes to the development of hepatitis in the FXR KO mouse model. In addition, butyrate reverses dysregulated BA synthesis and its associated hepatitis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

MiR-22-silenced cyclin A expression in colon and liver cancer cells is regulated by bile acid receptor.

Because of the significant tumor-suppressive role of microRNA-22 (miR-22), the current study was designed to understand the regulation of miR-22 and to identify additional downstream miR-22 targets in liver and colon cells. The data showed that miR-22 was transcriptionally regulated by bile acid receptor farnesoid X receptor (FXR) through direct binding to an invert repeat 1 motif located at -1012 to -1025 bp upstream from miR-22. Among the studied primary and secondary bile acids, chenodeoxycholic acid, which has the highest binding affinity to FXR, induced miR-22 level in both Huh7 liver and HCT116 colon cells in a dose- and time-dependent manner. In addition, cyclin A2 (CCNA2) was identified as a miR-22 novel target in liver and colon cancer cells. The sequence of miR-22, which is conserved in mice, rats, humans, and other mammalians, aligns with the sequence of 3'-UTR of CCNA2. Chenodeoxycholic acid treatment and miR-22 mimics reduced CCNA2 protein and increased the number of G0/G1 Huh7 and HCT116 cells. In FXR KO mice, reduction of miR-22 was accompanied by elevated hepatic and ileal CCNA2 protein, as well as an increased number of hepatic and colonic Ki-67-positive cells. In humans, the expression levels of miR-22 and CCNA2 are inversely correlated in liver and colon cancers. Taken together, our data showed that bile acid-activated FXR stimulates miR-22-silenced CCNA2, a novel pathway for FXR to exert its protective effect in the gastrointestinal tract.

Functional analysis of the relationship between intestinal microbiota and the expression of hepatic genes and pathways during the course of liver regeneration.

BACKGROUND & AIMS: The pathways regulating liver regeneration have been extensively studied within the liver. However, the signaling contribution derived from the gut microbiota to liver regeneration is poorly understood. METHODS: Microbiota and expression of hepatic genes in regenerating livers obtained from mice at 0h to 9days post 2/3 partial hepatectomy were temporally profiled to establish their interactive relationships. RESULTS: Partial hepatectomy led to rapid changes in gut microbiota that was reflected in an increased abundance of Bacteroidetes S24-7 and Rikenellaceae and decreased abundance of Firmicutes Clostridiales, Lachnospiraceae, and Ruminococcaceae. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to infer biological functional changes of the shifted microbiota. RNA-sequencing data revealed 6125 genes with more than a 2-fold difference in their expression levels during regeneration. By analyzing their expression pattern, six uniquely expressed patterns were observed. In addition, there were significant correlations between hepatic gene expression profiles and shifted bacterial populations during regeneration. Moreover, hepatic metabolism and immune function were closely associated with the abundance of Ruminococcacea, Lachnospiraceae, and S24-7. Bile acid profile was analyzed because bacterial enzymes produce bile acids that significantly impact hepatocyte proliferation. The data revealed that specific bacteria were closely associated with the concentration of certain bile acids and expression of hepatic genes. CONCLUSIONS: The presented data established, for the first time, an intimate relationship between intestinal microbiota and the expression of hepatic genes in regenerating livers.

Evaluation of Six Recombinant Proteins for Serological Diagnosis of Lyme Borreliosis in China.

OBJECTIVE: In this study, we evaluated the diagnostic efficiency of six recombinant proteins for the serodiagnosis of Lyme borreliosis (LB) and screened out the appropriate antigens to support the production of a Chinese clinical ELISA (enzyme-linked immunosorbent assay) kit for LB. METHODS: Six recombinant antigens, Fla B.g, OspC B.a, OspC B.g, P39 B.g, P83 B.g, and VlsE B.a, were used for ELISA to detect serum antibodies in LB, syphilis, and healthy controls. The ELISA results were used to generate receiver operating characteristic (ROC) curves, and the sensitivity and specificity of each protein was evaluated. All recombinant proteins were evaluated and screened by using logistic regression models. RESULTS: Two IgG (VlsE and OspC B.g) and two IgM (OspC B.g and OspC B.a) antigens were left by the logistic regression model screened. VlsE had the highest specificity for syphilis samples in the IgG test (87.7%, P<0.05). OspC B.g had the highest diagnostic value in the IgM test (AUC=0.871). Interactive effects between OspC B.a and Fla B.g could reduce the specificity of the ELISA. CONCLUSION: Three recombinant antigens, OspC B.g, OspC B.a, and VlsE B.a, were useful for ELISAs of LB. Additionally, the interaction between OspC B.a and Fla B.g should be examined in future research.

A Novel Isothermal Assay of Borrelia burgdorferi by Recombinase Polymerase Amplification with Lateral Flow Detection.

A novel isothermal detection for recombinase polymerase amplification with lateral flow (LF-RPA) was established for Borrelia burgdorferi (B. burgdorferi) detection in this study. This assay with high sensitivity and specificity can get a visible result without any additional equipment in 30 min. We designed a pair of primers according to recA gene of B. burgdorferi strains and a methodology evaluation was performed. The results showed that the RPA assay based on the recA gene was successfully applied in B. burgdorferi detection, and its specific amplification was only achieved from the genomic DNA of B. burgdorferi. The detection limit of the new assay was about 25 copies of the B. burgdorferi genomic DNA. Twenty Lyme borreliosis patients' serum samples were detected by LF-RPA assay, real-time qPCR and nested-PCR. Results showed the LF-RPA assay is more effective than nested-PCR for its shorter reaction time and considerably higher detection rate. This method is of great value in clinical rapid detection for Lyme borreliosis. Using the RPA assay might be a megatrend for DNA detection in clinics and endemic regions.

Implications of microbiota and bile acid in liver injury and regeneration.

Studies examining the mechanisms by which the liver incurs injury and then regenerates usually focus on factors and pathways directly within the liver, neglecting the signaling derived from the gut-liver axis. The intestinal content is rich in microorganisms as well as metabolites generated from both the host and colonizing bacteria. Through the gut-liver axis, this complex "soup" exerts an immense impact on liver integrity and function. This review article summarizes data published in the past 30 years demonstrating the signaling derived from the gut-liver axis in relation to liver injury and regeneration. Due to the intricate networks of implicated pathways as well as scarcity of available mechanistic data, it seems that nutrigenomic, metabolomics, and microbiota profiling approaches are warranted to provide a better understanding regarding the interplay and impact between nutrition, bacteria, and host response in influencing liver function and healing. Therefore elucidating the possible molecular mechanisms that link microbiota alteration to host physiological response and vice versa.

Accelerated partial hepatectomy-induced liver cell proliferation is associated with liver injury in Nur77 knockout mice.

Nur77, encoded by Nr4a1 (alias Nur77), plays roles in cell death, survival, and inflammation. To study the role of Nur77 in liver regeneration, wild-type (WT) and Nur77 knockout (KO) mice were subjected to standard two-thirds partial hepatectomy (PH). Nur77 mRNA and protein levels were markedly induced at 1 hour after PH in WT livers, coinciding with ERK1/2 activation. Surprisingly, Nur77 KO mice exhibited a higher liver-to-body weight ratio than WT mice at 24, 48, and 72 hours after PH. Nur77 KO livers exhibited increase in Ki-67-positive hepatocytes at 24 hours, with early induction of cell-cycle genes. Despite accelerated regeneration, Nur77 KO livers paradoxically incurred necrosis, hepatocyte apoptosis, elevated serum alanine aminotransferase activity, and Kupffer cell accumulation. Microarray analysis revealed up-regulation of genes modulating inflammation, cell proliferation, and apoptosis but down-regulation (due to Nur77 deficiency) of glucose and lipid homeostasis genes. Levels of proinflammatory cytokines IL-6, IL-12, IL-23, and CCL2 were increased and levels of anti-inflammatory IL-10 were decreased, compared with WT. Activated NF-κB and STAT3 and mRNA levels of target genes Myc and Bcl2l1 were elevated in Nur77 KO livers. Overall, Nur77 appears essential for regulating early signaling of liver regeneration by modulating cytokine-mediated inflammatory, apoptotic, and energy mobilization processes. The accelerated liver regeneration observed in Nur77 KO mice is likely due to a compensatory effect caused by injury.

NURBS: a database of experimental and predicted nuclear receptor binding sites of mouse.

SUMMARY: Nuclear receptors (NRs) are a class of transcription factors playing important roles in various biological processes. An NR often impacts numerous genes and different NRs share overlapped target networks. To fulfil the need for a database incorporating binding sites of different NRs at various conditions for easy comparison and visualization to improve our understanding of NR binding mechanisms, we have developed NURBS, a database for experimental and predicted nuclear receptor binding sites of mouse (NURBS). NURBS currently contains binding sites across the whole-mouse genome of 8 NRs identified in 40 chromatin immunoprecipitation with massively parallel DNA sequencing experiments. All datasets are processed using a widely used procedure and same statistical criteria to ensure the binding sites derived from different datasets are comparable. NURBS also provides predicted binding sites using NR-HMM, a Hidden Markov Model (HMM) model. AVAILABILITY: The GBrowse-based user interface of NURBS is freely accessible at http://shark.abl.ku.edu/nurbs/. NR-HMM and all results can be downloaded for free at the website. CONTACT: jwfang@ku.edu

The Prevalence of HIV Drug Resistance among Treatment-failure Individuals and Treatment-naïve Individuals in China: A Meta-analysis.

OBJECTIVE: To understand drug resistance prevalence among treatment-failure and treatment-naïve HIV-positive individuals in China. METHODS: We searched five electronic databases (Wanfang, CNKI, CQVIP, SinoMed, and Pubmed) for studies of HIV drug resistance. Random-effects models were carried out to estimate the prevalence of drug resistance among treatment-failure and treatment-naïve individuals, respectively. RESULTS: The estimated nationwide rates of HIV drug resistance to any-class drugs among treatment-failure and treatment-naïve individuals were 57% (95% CI: 49%-65%) and 3.23% (95% CI: 2.47%-4.07%), respectively. Among the drug classes, the prevalence of resistance to PIs was low (1.45%; 95% CI: 0.73%-2.33%) in treatment-failure individuals, although high rates of resistance to NNRTIs (54%; 95% CI: 45%-63%) and NRTIs (40%; 95% CI: 32%-49%) were found. Resistance to any-class drugs, NNRTIs and NRTIs manifested regional differences, but resistance to PIs did not. Positive correlations were observed between resistance to NNRTIs and NRTIs among treatment-failure and treatment-naïve individuals, respectively. CONCLUSION: The prevalence of HIV drug resistance to NNRTIs and NRTIs among treatment-failure individuals was high. In contrast, the prevalence of drug resistance among treatment-naïve individuals was low. The epidemics of drug resistance matched current treatment strategies and interventions in China. Surveillance for HIV drug resistance is necessary to assess the sustainability and durability of current treatment regimens.