Cytokine receptor-like factor 1 (CRLF1) promotes cardiac fibrosis via ERK1/2 signaling pathway. / ç»†èƒžå› å­å—ä½“æ ·å› å­1(CRLF1)通过ERK1/2信号通路促进心脏纤维化.

Cardiac fibrosis is a cause of morbidity and mortality in people with heart disease. Anti-fibrosis treatment is a significant therapy for heart disease, but there is still no thorough understanding of fibrotic mechanisms. This study was carried out to ascertain the functions of cytokine receptor-like factor 1 (CRLF1) in cardiac fibrosis and clarify its regulatory mechanisms. We found that CRLF1 was expressed predominantly in cardiac fibroblasts. Its expression was up-regulated not only in a mouse heart fibrotic model induced by myocardial infarction, but also in mouse and human cardiac fibroblasts provoked by transforming growth factor-|ß1 (TGF|-|ß1). Gain- and loss-of-function experiments of CRLF1 were carried out in neonatal mice cardiac fibroblasts (NMCFs) with or without TGF-|ß1 stimulation. CRLF1 overexpression increased cell viability, collagen production, cell proliferation capacity, and myofibroblast transformation of NMCFs with or without TGF|-|ß1 stimulation, while silencing of CRLF1 had the opposite effects. An inhibitor of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and different inhibitors of TGF-|ß1 signaling cascades, comprising mothers against decapentaplegic homolog (SMAD)|-dependent and SMAD-independent pathways, were applied to investigate the mechanisms involved. CRLF1 exerted its functions by activating the ERK1/2 signaling pathway. Furthermore, the SMAD-dependent pathway, not the SMAD-independent pathway, was responsible for CRLF1 up-regulation in NMCFs treated with TGF-|ß1. In summary, activation of the TGF-|ß1/SMAD signaling pathway in cardiac fibrosis increased CRLF1 expression. CRLF1 then aggravated cardiac fibrosis by activating the ERK1/2 signaling pathway. CRLF1 could become a novel potential target for intervention and remedy of cardiac fibrosis.

TMT-based quantitative proteomic analysis of spheroid cells of endometrial cancer possessing cancer stem cell properties.

BACKGROUND: Cancer stem cells (CSCs) play an important role in endometrial cancer progression and it is potential to isolate CSCs from spheroid cells. Further understanding of spheroid cells at protein level would help find novel CSC markers. METHODS: Spheroid cells from endometrial cancer cell lines, Ishikawa and HEC1A, exhibited increased colony forming, subsphere forming, chemo-drug resistance, migration, invasion ability and tumorigenicity, verifying their cancer stem-like cell properties. The up-regulated CD90, CD117, CD133 and W5C5 expression also indicated stemness of spheroid cells. TMT-based quantitative proteomic analysis was performed to explore the potential alterations between parent cells and cancer stem-like spheroid cells. HK2-siRNA was transfected to Ishikawa and HEC1A cells to explore the roles and molecular mechanism of HK2 in endometrial cancer. RESULTS: We identified and quantified a total of 5735 proteins and 167 overlapped differentially expressed proteins of two cell types, 43 proteins were up-regulated and 124 were down-regulated in spheroid cells comparing with parent cells. KEGG pathway revealed a significant role of HIF-1 pathway in spheroid cells. qRT-PCR and western blot results of GPRC5A, PFKFB3 and HK2 of HIF-1 pathway confirmed their elevated expressions in spheroid cells which were consistent with proteomic results. HK2 promoted cancer stemness in endometrial cancer. CONCLUSION: These findings indicate that spheroid cells from endometrial cancer cell lines possess cancer stem-like cell properties and enrich CSCs. HIF-1 pathway is activated in endometrial cancer stem-like spheroid cells.

Mendelian randomization suggests a potential causal effect of eosinophil count on influenza vaccination responsiveness.

Currently, the clinical factors affecting immune responses to influenza vaccines have not been systematically explored. The mechanism of low responsiveness to influenza vaccination (LRIV) is complicated and not thoroughly elucidated. Thus, we integrate our in-house genome-wide association studies (GWAS) analysis result of LRIV (N = 111, Ncase [Low Responders] = 34, Ncontrol [Responders] = 77) with the GWAS summary of 10 blood-based biomarkers (sample size ranging from 62 076-108 794) deposited in BioBank Japan (BBJ) to comprehensively explore the shared genetics between LRIV and blood-based biomarkers to investigate the causal relationships between blood-based biomarkers and LRIV by Mendelian randomization (MR). The applications of four MR approaches (inverse-variance-weighted [IVW], weighted median, weighted mode, and generalized summary-data-based MR [GSMR]) suggested that the genetically instrumented LRIV was associated with decreased eosinophil count (ß = -5.517 to -4.422, p = 0.004-0.039). Finally, we conclude that the low level of eosinophil count is a suggestive risk factor for LRIV.

Predictive value of live birth rate based on different intrauterine adhesion evaluation systems following TCRA.

OBJECTIVE: The aim of this study was to assess the predictive value of five different intrauterine adhesion (IUA) evaluation systems for live birth rate following transcervical resection of adhesion (TCRA). METHOD: This retrospective study included 128 women with IUA who desired for spontaneous conception after TCRA. All the patients were retrospectively scored by the American Fertility Society (AFS) classification, European Society of Gynecological Endoscopy (ESGE) classification, March's classification (March), Nasr classification (Nasr) and Chinese IUA diagnosis classification criteria (Chinese). The predictive value of these evaluation systems was determined by receiver operating characteristic (ROC) curves and area under a ROC curve (AUC). RESULTS: The correlation coefficients of AFS, ESGE, March, Nasr and Chinese classification and the live birth rate were 0.313, 0.313, 0.288, 0.380, and 0.336, respectively. Among women with hypomenorrhea and amenorrhea, as well as women with no infertility, the severities determined by all five evaluation systems were correlated with live birth rate (P <  0.001). All five scoring systems were efficient to predict live birth rate. Among them, Nasr classification showed the highest AUC (0.748) with the best predictive value. Multivariate logistic regression analyses showed that Nasr classification had the highest OR (OR, 6.523; 95% CI, 2.612, 18.263). And, Nasr's classification system also showed highest sensitivity (81.8%) and negative predictive value (96.7%) when divide the system into mild IUA vs. moderate and severe IUA. CONCLUSION: AFS, ESGE, March, Nasr and Chinese classification were demonstrated to be capable of predicting live birth following TCRA although the predictive capacities might be limited, and Nasr classification showed the highest predictive value of live birth.

Development and Validation of a Prognostic Prediction Model for Postoperative Ovarian Sex Cord-Stromal Tumor Patients.

BACKGROUND We developed a nomogram for prognostic prediction of overall survival (OS) in postoperative ovarian sex cord-stromal tumor (SCST) patients and discuss the effect of chemotherapy at various FIGO stages. MATERIAL AND METHODS SCST patients after surgery from 2004 to 2015 were enrolled from the Surveillance, Epidemiology and End-Results (SEER) database, matched into pairs by propensity score matching (PSM), and divided into a training set and a validation set. Univariate and multivariate Cox analyses were conducted to identify significant variables for the development of the nomogram. The nomogram model was validated by concordance index (C-index), receiver operating characteristics (ROCs) curve, calibration plot, and decision curve analysis (DCA). Survival curves showed the integrative ability of prognostic prediction and the efficacy of chemotherapy. RESULTS A total of 913 SCST patients were initially enrolled, and after PSM, 506 patients were included. Age, marital status, CA125 levels, tumor size, FIGO stage, grade, and chemotherapy were indicators for building the OS nomogram. The C-index was 0.850 in the training set and 0.786 in the validation set. Calibration plots were satisfactory and the nomogram had relatively better clinical utility than FIGO stage. The survival analysis showed that the low-risk group had generally longer survival than the high-risk group based on the prognostic score, and chemotherapy had an overall reverse effect on OS. CONCLUSIONS The nomogram model displays the potential to provide individualized prognosis probability of SCSTs and to aid in clinical decision-making. The unfavorable results of chemotherapy in all stages shows the need for further exploration.

Research Progress on the Animal Models of Drug-Induced Liver Injury: Current Status and Further Perspectives.

Drug-induced liver injury (DILI) is a major concern in clinical studies as well as in postmarketing surveillance. It is necessary to establish an animal model of DILI for thorough investigation of mechanisms of DILI and searching for protective medications. This article reviews the current status and future perspective on establishment of DILI models based on different hepatotoxic drugs, as well as the underlying mechanisms of liver function damage induced by specific medicine. Therefore, information from this article can help researchers make a suitable selection of animal models for further study.

Pharmacological mechanism of roflumilast in the treatment of asthma-COPD overlap.

Asthma-COPD overlap (ACO) is a type of incomplete obstructive airway disease that has a high incidence and mortality. Nevertheless, there is currently no clear definition of ACO and no effective intervention. The newly discovered phosphodiesterase-4 inhibitor, roflumilast, has shown initial efficacy for treating asthma, COPD, and ACO. The mechanism of roflumilast, however, remains unclear, and there has been no interpretation through systematic review to date. The determination of a definite mechanism of roflumilast will guide the clinician's decisions regarding medication use, standardized diagnosis, and treatment guidelines. For this reason, we have systematically reviewed the therapeutic mechanism of roflumilast for ACO and provided reference for the clinical application of roflumilast in ACO.

The efficacy and safety of alectinib in the treatment of ALK+ NSCLC: a systematic review and meta-analysis.

BACKGROUND: Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the US Food and Drug Administration to treat crizotinib-refractory non-small cell lung cancer. We performed this meta-analysis to synthesize the results of different clinical trials to evaluate the efficacy and safety of alectinib. METHODS: A search of 3 databases, including PubMed, Web of Science, and the Cochrane Library, was performed from the inception of each database through September 5, 2017. We have pooled the overall response rate (ORR), disease control rate, progression-free survival, and intracranial ORR to evaluate the efficacy of alectinib. Discontinuation rate, rate of dose reduction or interruption due to adverse events as well as the incidence of several adverse events were aggregated to evaluate its safety. RESULTS: A total of 8 studies with 626 patients have been included in our study. The pooled efficacy parameters are as follows: ORR 70% (95% CI: 57% to 82%), disease control rate 88% (95% CI: 82% to 94%), progression-free survival 9.36 months (95% CI: 7.38% to 11.34%), and intracranial ORR 52% (95% CI: 45% to 59%). ALK inhibitor-naïve patients tend to have better responses than crizotinib-pretreated patients. The aggregate discontinuation rate is 7% (95% CI: 4% to 10%), and the pooled rate of dose reduction or interruption is 33% (95% CI: 24% to 42%). The incidences of most adverse events were relatively low, while the incidences of 2 frequently reported adverse events, myalgia (18%) and anemia (25%), were even higher than with the first-generation ALK inhibitor crizotinib. CONCLUSION: Generally, alectinib is a drug with preferable efficacy and tolerable adverse effects, and it is suitable for the treatment of intracranial metastases.