Background/Aims: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1–3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. Methods: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. Results: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. Conclusions Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

The radical resection is the most important treatment for primary liver cancer, but the high recurrence rate is the main obstacle to the survival of postoperative patients.According to the time of tumor recurrence, the postoperative recurrence of liver cancer is divided into the early recurrence and late recurrence. The former is mainly related to the invasion and metastasis of liver cancer, and the latter is mainly caused by multicenter tumor occurrence based on the background of liver disease. The early prediction of postoperative recurrence risk contributes to the timely and effective intervention and improved the prognosis of the patients. In the past ten years, the clinical research on the recurrence of liver cancer has been systematically studied. The molecular mechanism of the metastasis and recurrence has been newly recognized: the metastatic potential of liver cancer begins in the early stage of primary tumor; the imbalance of micro-environmental inflammatory response promotes the metastasis of cancer. At the same time, a variety of molecular markers for predicting the recurrence of liver cancer were identified, and a molecular prediction model for the metastasis of liver cancer was created and optimized. These research results lay the foundation for more accurately understanding of the recurrence and metastasis of liver cancer and developing the more precise prevention and treatment strategies.

Myasthenia gravis (MG) is a prototypical antibody-mediated neurological autoimmune disease with the involvement of humoral immune responses in its pathogenesis. T follicular helper (Tfh) cells have been implicated in many autoimmune diseases. However, whether and how Tfh cells are involved in MG remain unclear. Here, we established and studied a widely-used and approved animal model of human MG, the rat model with acetylcholine receptor alpha (AChRα) subunit (R-AChR)-induced experimental autoimmune myasthenia gravis (EAMG). This model presented mild body-weight loss 10 days after the first immunization (representing the early stage of disease) and more obvious clinical manifestations and body-weight loss 7 days after the second immunization (representing the late stage of disease). AChR-specific pre-Tfh cells and mature Tfh cells were detected in these two stages, respectively. In co-cultures of Tfh cells and B cells, the number of IgG2b-secreting B cells and the level of anti-AChR antibodies in the supernatant were higher in the cultures containing EAMG-derived Tfh cells. In immunohistochemistry and immunofluorescence assays, a substantial number of CD4/Bcl-6 T cells and a greater number of larger germinal centers were observed in lymph node tissues resected from EAMG rats. Based on these results, we hypothesize that an AChR-specific Tfh cell-mediated humoral immune response contributes to the development of EAMG.
Animals ; B-Lymphocytes ; immunology ; Disease Models, Animal ; Female ; Immunity, Humoral ; Lymph Nodes ; immunology ; Myasthenia Gravis, Autoimmune, Experimental ; immunology ; Protein Subunits ; immunology ; Proto-Oncogene Proteins c-bcl-6 ; immunology ; Rats, Inbred Lew ; Receptor Cross-Talk ; Receptors, Cholinergic ; immunology ; T-Lymphocytes, Helper-Inducer ; immunology

Prostaglandin E2 (PGE2) is a cyclooxygenase metabolite of arachidonic acid. It acts as a bioactive lipid and plays an important role in regulating many biological processes. PGE2 binds to 4 different G protein-coupled receptors including prostaglandin E2 receptor subtypes EP1, EP2, EP3 and EP4. The EP4 receptor is widely expressed in most of human organs and tissues. Increasing evidence demonstrates that EP4 is essential for cardiovascular homeostasis and participates in the pathogenesis of many cardiovascular diseases. Here we summarize the role of EP4 in the regulation of cardiovascular function and discuss potential mechanisms by which EP4 is involved in the development of cardiovascular disorders with a focus on its effect on inflammation.
Cardiovascular Diseases ; physiopathology ; Cyclooxygenase 2 ; Dinoprostone ; physiology ; Humans ; Receptors, Prostaglandin E, EP4 Subtype ; physiology

BACKGROUND: Posterior screw rod system reduction and internal fixation is often used to treat thoracolumbar fractures (T11-L2). However, the "shell" phenomenon is focused on imaging findings and lacks of in-depth clinical research. OBJECTIVE: To explore the new method of "shell" volume measurement of vertebral body after thoracolumbar fractures reduction, and to evaluate the effect of different "shell" sizes on clinical treatment. METHODS: From January 2013 to December 2015, 72 patients with thoracolumbar fractures were treated in the No. 4 People's Hospital of Zigong City retrospectively. The patients with vertebral "shell" were retrospectively analyzed. Clinical and imaging data (X ray, CT and MRI) were collected. Compression degree of anterior border of the vertebral body, Cobb angle, Visual Analogue Scale score and reduction-related complication were recorded and analyzed. The volumes of vertebral "shell" and the injured vertebral body were measured by Mimics software. The volume ratio of shell/injured vertebral body was calculated. The healing of vertebral "shell" was followed up and observed. RESULTS AND CONCLUSION: (1) Among the 72 patients, there were 16 cases with a shell/injured vertebral volume ratio of < 5% (group A), 30 cases with the volume ratio of 5%-10% (group B), and 26 cases with volume ratio of > 10% (group C). (2) The "shell" healing: The "shell"nonunion rate was significantly lower in the groups A and B than in the group C (P < 0.05); and significant differences were not determined between groups A and B (P > 0.05). (3) Compression degree of the anterior border of the injured vertebral body: No significant difference was found in groups A, B and C before and right after reduction (P > 0.05). The compression was significantly higher in the groups A and B than in group C at final follow-up (P < 0.05). (4) Cobb angle was not significantly different in groups A, B and C before and right after reduction and during final follow-up (P > 0.05). (5) Visual Analogue Scale score was not significantly different between groups A and B and group C right after reduction (P > 0.05). The Visual Analogue Scale score was significantly better in the groups A and B than in the group C (P < 0.05). (6) Occurrence of complications: In the group A, one case affected incision exudate. In the group B, one case experienced incision infection and one case suffered from screw loosening. In the group C, two cases affected screw loosening, and one case experienced unilateral connecting rod fracture. No significant difference in complications was detected among groups A, B and C (P > 0.05). (7) Results indicate that the "shell"nonunion rate was high when vertebral shell/injured vertebral body volume ratio > 10%; loss of posterior vertebral height and chronic lumbago and back pain easily appeared. The measurement of the volume of vertebral "shell" plays an important role in clinical prognosis and treatment options of thoracolumbar judgment.

Objective Xuanwei, Yunnan, is one of the areas with the highest incidence of lung cancer in China and in the world as well. This study was to explore the differential expressions of lncRNAs and mRNAs, establish a competing endogenous RNA (ceRNA) coexpression network, and find some new ideas for the diagnosis and treatment of lung cancer in the Xuanwei area.Methods Using the gene chip of the lncRNA + mRNA expression profile, we examined 10 pairs of samples of lung cancer and adjacent normal tissues from the patients in the Xuanwei area and analyzed differentially expressed mRNAs with such bioinformatics Methods as gene ontology (GO), Kyoto Encyclopedia Genomes (KEGG) pathway and network analyses.Results By comparison between the lung cancer and adjacent normal tissues, 384 differentially expressed lncRNAs were identified (fold change≥2.0, P<0.05), in which 78 were upregulated, with abParts as the most differentially expressed (fold change=7.522, and 306 downregulated, with XLOG-012046 as the most differentially expressed (fold change=9.001). Among the 946 differentially expressed mRNAs identified (fold change≥2.0, P<0.05), SPP1 was the most significantly upregulated (fold change=16.500) and AGER was the most significantly downregulated (fold change=14.377). Both up- and downregulated expressions of lncRNA and mRNA were found in the lung cancer tissue of the patients, the upregulated expression of mRNA involved mainly the calcium ion signaling pathway, phagosomes and hematopoietic cell lineage, while the downregulated expression of mRNA chiefly involved in the hematopoietic cell lineage and calcium ion signaling pathway. lncRNAs were correlated with mRNAs in a one-to-one or one-to-many manner, with the coexpression of p14245 (LINC00472) with Q9H8W2 and XLOG-005764. The expressions of SEMA5A and SEMA6A regulated by ENSG00000244513.2 (ceRNA score=0.461) and ENSG00000257424.1 (ceRNA score=0.372) were both decreased in the mRNA expression profile. SEMA5A participated mainly in cell adhesion, bioadhesion, and vasculature development, while SEMA6A chiefly in cell-surface receptor signal transduction, cell movement, and cytoskeleton.Conclusion The expression profile of differentially expressed lncRNAs was identified by microarray in the lung cancer tissue of the patients in Xuanwei, which may become a novel biomarker or therapeutic target of lung cancer in this area.

BACKGROUNDThe efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for immunoglobulin A nephropathy (IgAN) are unclear. This study was designed to evaluate the efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for IgAN.

METHODSIt is a multicenter, prospective, double-dummy randomized controlled trial. Primary IgAN patients were recruited in 13 renal units across Beijing, China, from July 2010 to June 2012. After a 4-week telmisartan (80 mg/d) wash-in, 400 patients continuing on 80 mg/d telmisartan were randomly assigned to additionally receive placebo (Group A), 50 mg/d clopidogrel (Group B), 20 mg/d leflunomide (Group C), or 50 mg/d clopidogrel and 20 mg/d leflunomide (Group D). The 24-week intervention was completed by 360 patients. The primary endpoint was change in 24-h proteinuria at 24 weeks. A linear mixed-effect model was used to analyze the changes at 4, 12, and 24 weeks. Generalized estimating equations were used to evaluate changes in hematuria grade. This trial was registered at the Chinese Clinical Trial Registry.

RESULTSThe effects of telmisartan combined with leflunomide on changes in proteinuria (0.36 [95% confidence interval (CI) 0.18-0.55] g/d, P < 0.001), in serum uric acid (76.96 [95% CI 57.44-96.49] μmol/L, P < 0.001), in serum creatinine (9.49 [95% CI 6.54-12.44] μmol/L, P < 0.001), and in estimated glomerular filtration rate (-6.72 [95% CI-9.46 to -3.98] ml·min-1·1.73 m-2, P < 0.001) were statistically significant, whereas they were not statistically significant on changes in systolic and diastolic blood pressure and weight (P > 0.05). Telmisartan combined with clopidogrel had no statistical effect on any outcome, and there was no interaction between the interventions. No obvious adverse reactions were observed.

CONCLUSIONSTelmisartan combined with leflunomide, not clopidogrel, is safe and effective for decreasing proteinuria in certain IgAN patients.

TRIAL REGISTRATIONchictr.org.cn, ChiCTR-TRC-10000776; http://www.chictr.org.cn/showproj.aspx?proj=8760.

Adolescent ; Adult ; Benzimidazoles ; adverse effects ; therapeutic use ; Benzoates ; adverse effects ; therapeutic use ; Blood Pressure ; drug effects ; China ; Creatinine ; blood ; Female ; Glomerular Filtration Rate ; drug effects ; Glomerulonephritis, IGA ; blood ; drug therapy ; Humans ; Isoxazoles ; adverse effects ; therapeutic use ; Kidney Function Tests ; Male ; Middle Aged ; Prospective Studies ; Ticlopidine ; adverse effects ; analogs & derivatives ; therapeutic use ; Treatment Outcome ; Uric Acid ; blood ; Young Adult

To investigate the molecular mechanism of hydroxycamptothecin (HCPT)-mediated anti-hepatic fibrosis by evaluting its effects on expression of tumor growth factor-beta 1 (TGFb1), alpha-smooth muscle actin (a-SMA) and collagen I (Col I) in hepatic satellite cells (HSCs). Cultured HSCs were treated with different concentrations of HCPT: low-dose group, 0.25 mg/L; middle-dose group, 0.5 mg/L; high-dose group, 0.75 mg/L; and control group, 0 mg/L. Cell proliferation was assessed by the MTT assay. The mRNA expressions of TGFb1, a-SMA and Col I were determined by reverse transcription-polymerase chain reaction. The protein expressions of TGFb1 and a-SMA were detected by Western blot. The content of Col I in the cultured HSCs' supernatant was measured by enzyme-linked immunosorbent assay. The MTT absorbance values of the low-dose group (0.631+/-0.074), middle-dose group (0.469+/- 0.012) and high-dose group (0.204+/- 0.001) were significantly lower than that of the control group (0.793+/-0.098; F = 82.86, P less than 0.01). Compared with the control group, the HCPT-treated groups showed significantly down-regulated gene expressions of TGFb1 (control: 0.716+/-0.064 vs. low: 0.611+/-0.040, middle: 0.510+/-0.014, high: 0.403+/-0.026), a-SMA (control: 0.696+/-0.075 vs. low: 0.579+/-0.037, middle: 0.470+/-0.024, high: 0.299+/-0.017), and Col I (control: 1.019+/-0.056 vs. low: 0.835+/-0.022, middle: 0.696+/-0.055, high: 0.322+/-0.104) (all, P less than 0.01). Meanwhile, HCPT-treated HSCs showed significantly reduced protein expressions of TGFb1 (control: 0.872+/-0.053 vs. low: 0.654+/-0.047, middle: 0.545+/-0.042, high: 0.436+/-0.039) and a-SMA (control: 0.858+/-0.050 vs. low: 0.620+/-0.045, middle: 0.525+/-0.042, high: 0.434+/-0.052) (all, P less than 0.01). The Col I levels secreted by HSCs were significantly lower in the HCPT-treated groups (low: 168.367+/-16.453 ng/ml; middle: 141.284+/-11.731 ng/ml; high: 132.910+/-10.048 ng/ml) than in the control group (188.733 +/-18.299 ng/ml) (all, P less than 0.01). The mechanism of HCPT-mediated anti-hepatic fibrosis may involve down-regulation of TGFb1 expression to inhibit HSC proliferation and activation, as well as reduction of Col I synthesis and secretion.
Actins ; metabolism ; Animals ; Camptothecin ; analogs & derivatives ; pharmacology ; Cell Proliferation ; Cells, Cultured ; Collagen Type I ; metabolism ; Hepatic Stellate Cells ; cytology ; drug effects ; metabolism ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1 ; metabolism

OBJECTIVETo evaluate the relationship between PAR1 (Protease-Activated Receptor 1) expression and the clinicopathologic features and to investigate the prognostic value of PAR1 expression in hepatocellular carcinoma (HCC) in early stage after curative resection.

METHODSReal-time PCR was used to detect PAR1 expression in 41 pairs of tumors and matched peritumoral samples of HCC in early stage. Prognostic value of PAR1 mRNA expression was evaluated. Meanwhile, another 49 tissue paraffin slices of HCC were tested using immunohistochemistry (Envision) and the prognostic value of PAR1 expression and other clinicopathologic factors were evaluated.

RESULTSPeritumoral PAR1 mRNA expression was significantly increased in HCCs from the patients with tumor recurrence as compared with those without recurrence (P < 0.05). Peritumoral PAR1 protein expression was related to tumor differentiation (P < 0.05). Kaplan-Meier analysis showed that Peritumoral PAR1 protein expression was associated with the overall survival (OS) (P < 0.05) of HCC patients and the time to recurrence (TTR) (P < 0.05). The 1, 3 and 5 -year overall survival time and the cumulative recurrence time in the high PAR1 protein expression group were significantly lower as compared to the low PAR1 expression group in the peritumoral liver tissue.

CONCLUSIONSPeritumoral PAR1 expression is closely associated with the prognosis of early stage HCC patients after curable surgery. PAR1 may be involved in thrombin-mediated invasion process and may be used as a prognostic marker for HCC.

Carcinoma, Hepatocellular ; metabolism ; pathology ; Female ; Humans ; Liver Neoplasms ; metabolism ; pathology ; Male ; Middle Aged ; Postoperative Period ; Prognosis ; Receptor, PAR-1 ; metabolism

The aim of this study was to explore the clinical effect and toxicity of bortezomib combined with methylprednisolone in treatment of relapsed or refractory multiple myeloma (MM). Clinical data of 33 patients (23 male, 10 female; aged from 38 to 85 years old) were analyzed retrospectively. The median diagnosis time was 25 (2 - 120) months. 33 patients received bortezomib (0.9 - 1.1) mg/m(2) on days 1, 4, 8, 11, in combination with methylprednisolone 40 mg/d (4 cases), 80mg/d (13 cases), 120 mg/d (2 cases), 200 mg/d (9 cases), 300 mg/d (5 cases) respectively. The median follow-up time was 10(3-60) months. The used therapy courses were 1 - 8 (mean 4 courses). The results indicated that 24 cases showed the response of different degree, the overall response rate (ORR) was 72.7% (24/33). 32 patients received ≥ 2 therapy courses, and ORR was 71.9% (23/32). 16 patients received 4 therapy courses, and ORR was 93.8% (15/16 cases). 7 patients received 6 therapy courses and the ORR was 100% (7/7 cases). Main side-effects were thrombocytopenia, infection and peripheral neuropathy. The median survival time was 41.5 (2 - 120) months and the 2-year, 3-year and 5-year overall survival rate were 80%, 59.1% and 21.1%, respectively. It is concluded that bortezomib combined with methylprednisolone is an effective therapy with higher response rate, and safe in treatment of relapsed or refractory multiple myeloma.
Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Boronic Acids ; administration & dosage ; Bortezomib ; Female ; Humans ; Male ; Methylprednisolone ; administration & dosage ; Middle Aged ; Multiple Myeloma ; drug therapy ; pathology ; Neoplasm Recurrence, Local ; drug therapy ; Pyrazines ; administration & dosage ; Retrospective Studies ; Treatment Outcome