Prediction of Advanced Fibrosis in Nonalcoholic Fatty Liver Disease: An Enhanced Model of BARD Score.

UNLABELLED: BACKGROUNDAIMS: The BARD score is a model to detect advanced liver fibrosis in nonalcoholic fatty liver disease (NAFLD) patients. The aims of this study were to identify additional factors and then to build an enhanced version of the BARD score. METHODS: One hundred seven patients with biopsy-proven NAFLD were enrolled retrospectively. Logistic regressions were performed to identify independent risk factors for advanced liver fibrosis (stage 3 or 4). An enhanced model of the BARD score (BARDI score) was built and evaluated with a receiver operating characteristic (ROC) curve. RESULTS: In multivariate analysis, age (odds ratio [OR], 0.89; p=0.04), aspartate aminotransferase/alanine aminotransferase ratio (OR, 1.73; p CONCLUSIONS: The BARDI score had an improved PPV over the BARD score and maintained an excellent NPV. Further study is warranted for its external validation and comparison with other models

GOChase-II: correcting semantic inconsistencies from Gene Ontology-based annotations for gene products

<p>Abstract</p> <p>Background</p> <p>The Gene Ontology (GO) provides a controlled vocabulary for describing genes and gene products. In spite of the undoubted importance of GO, several drawbacks associated with GO and GO-based annotations have been introduced. We identified three types of semantic inconsistencies in GO-based annotations; semantically redundant, biological-domain inconsistent and taxonomy inconsistent annotations.</p> <p>Methods</p> <p>To determine the semantic inconsistencies in GO annotation, we used the hierarchical structure of GO graph and tree structure of NCBI taxonomy. Twenty seven biological databases were collected for finding semantic inconsistent annotation.</p> <p>Results</p> <p>The distributions and possible causes of the semantic inconsistencies were investigated using twenty seven biological databases with GO-based annotations. We found that some evidence codes of annotation were associated with the inconsistencies. The numbers of gene products and species in a database that are related to the complexity of database management are also in correlation with the inconsistencies. Consequently, numerous annotation errors arise and are propagated throughout biological databases and GO-based high-level analyses. GOChase-II is developed to detect and correct both syntactic and semantic errors in GO-based annotations.</p> <p>Conclusions</p> <p>We identified some inconsistencies in GO-based annotation and provided software, GOChase-II, for correcting these semantic inconsistencies in addition to the previous corrections for the syntactic errors by GOChase-I.</p

Homeobox gene Dlx-2 is implicated in metabolic stress-induced necrosis

<p>Abstract</p> <p>Background</p> <p>In contrast to tumor-suppressive apoptosis and autophagic cell death, necrosis promotes tumor progression by releasing the pro-inflammatory and tumor-promoting cytokine high mobility group box 1 (HMGB1), and its presence in tumor patients is associated with poor prognosis. Thus, necrosis has important clinical implications in tumor development; however, its molecular mechanism remains poorly understood.</p> <p>Results</p> <p>In the present study, we show that Distal-less 2 (Dlx-2), a homeobox gene of the Dlx family that is involved in embryonic development, is induced in cancer cell lines dependently of reactive oxygen species (ROS) in response to glucose deprivation (GD), one of the metabolic stresses occurring in solid tumors. Increased Dlx-2 expression was also detected in the inner regions, which experience metabolic stress, of human tumors and of a multicellular tumor spheroid, an <it>in vitro </it>model of solid tumors. Dlx-2 short hairpin RNA (shRNA) inhibited metabolic stress-induced increase in propidium iodide-positive cell population and HMGB1 and lactate dehydrogenase (LDH) release, indicating the important role(s) of Dlx-2 in metabolic stress-induced necrosis. Dlx-2 shRNA appeared to exert its anti-necrotic effects by preventing metabolic stress-induced increases in mitochondrial ROS, which are responsible for triggering necrosis.</p> <p>Conclusions</p> <p>These results suggest that Dlx-2 may be involved in tumor progression via the regulation of metabolic stress-induced necrosis.</p

Blockade of Airway Inflammation by Kaempferol via Disturbing Tyk-STAT Signaling in Airway Epithelial Cells and in Asthmatic Mice

Asthma is characterized by bronchial inflammation causing increased airway hyperresponsiveness and eosinophilia. The interaction between airway epithelium and inflammatory mediators plays a key role in the asthmatic pathogenesis. The in vitro study elucidated inhibitory effects of kaempferol, a flavonoid found in apples and many berries, on inflammation in human airway epithelial BEAS-2B cells. Nontoxic kaempferol at ≤20 μM suppressed the LPS-induced IL-8 production through the TLR4 activation, inhibiting eotaxin-1 induction. The in vivo study explored the demoting effects of kaempferol on asthmatic inflammation in BALB/c mice sensitized with ovalbumin (OVA). Mouse macrophage inflammatory protein-2 production and CXCR2 expression were upregulated in OVA-challenged mice, which was attenuated by oral administration of ≥10 mg/kg kaempferol. Kaempferol allayed the airway tissue levels of eotaxin-1 and eotaxin receptor CCR3 enhanced by OVA challenge. This study further explored the blockade of Tyk-STAT signaling by kaempferol in both LPS-stimulated BEAS-2B cells and OVA-challenged mice. LPS activated Tyk2 responsible for eotaxin-1 induction, while kaempferol dose-dependently inhibited LPS- or IL-8-inflamed Tyk2 activation. Similar inhibition of Tyk2 activation by kaempferol was observed in OVA-induced mice. Additionally, LPS stimulated the activation of STAT1/3 signaling concomitant with downregulated expression of Tyk-inhibiting SOCS3. In contrast, kaempferol encumbered STAT1/3 signaling with restoration of SOCS3 expression. Consistently, oral administration of kaempferol blocked STAT3 transactivation elevated by OVA challenge. These results demonstrate that kaempferol alleviated airway inflammation through modulating Tyk2-STAT1/3 signaling responsive to IL-8 in endotoxin-exposed airway epithelium and in asthmatic mice. Therefore, kaempferol may be a therapeutic agent targeting asthmatic diseases

Role of interleukin-10 in endochondral bone formation in mice: Anabolic effect via the bone morphogenetic protein/Smad pathway

Objective: Interleukin-10 (IL-10) is a pleiotropic immunoregulatory cytokine with a chondroprotective effect that is elevated in cartilage and synovium in patients with osteoarthritis. However, the role of IL-10 during endochondral bone formation and its mechanism of action have not been elucidated. Methods: IL-10-/- mice and IL-10-treated tibial organ cultures were used to study loss and gain of IL-10 functions, respectively, during endochondral bone formation. Primary chondrocytes from the long bones of mouse embryos were cultured with and without IL-10. To assess the role of IL-10 in chondrogenic differentiation, we conducted mesenchymal cell micromass cultures. Results: The lengths of whole skeletons from IL-10-/- mice were similar to those of their wild-type littermates, although their skull diameters were smaller. The tibial growth plates of IL-10-/- mice showed shortening of the proliferating zone. Treatment with IL-10 significantly increased tibial lengths in organ culture. IL-10 also induced chondrocyte proliferation and hypertrophic differentiation in primary chondrocytes in vitro. Mechanistically, IL-10 activated STAT-3 and the Smad1/5/8 and ERK-1/2 MAP kinase pathways and induced the expression of bone morphogenetic protein 2 (BMP-2) and BMP-6 in primary chondrocytes. Furthermore, the blocking of BMP signaling attenuated the IL-10-mediated induction of cyclin D1 and RUNX-2 in primary chondrocytes and suppressed Alcian blue and alkaline phosphatase staining in mesenchymal cell micromass cultures. Conclusion: These results indicate that IL-10 acts as a stimulator of chondrocyte proliferation and chondrogenic or hypertrophic differentiation via activation of the BMP signaling pathway. © 2013, American College of Rheumatology

Brigatinib Versus Crizotinib in ALK Inhibitor–Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial

ALK tyrosine kinase inhibitor; Brigatinib; Non–small cell lung cancerInhibidor de la tirosina quinasa ALK; Brigatinib; Cáncer de pulmón de células no pequeñasInhibidor de la tirosina cinasa ALK; Brigatinib; Càncer de pulmó de cèl·lules no petitesIntroduction In the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor–naive advanced ALK-positive NSCLC, brigatinib exhibited superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results. Methods Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. Results A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed. Conclusions In the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study

Efficacy and Safety of Brigatinib Compared With Crizotinib in Asian vs. Non-Asian Patients With Locally Advanced or Metastatic ALK–Inhibitor-Naive ALK+ Non–Small Cell Lung Cancer: Final Results From the Phase III ALTA-1L Study

Anaplastic lymphoma kinase; First line; Tyrosine kinase inhibitorCinasa del linfoma anaplásico; Primera línea; Inhibidor de la tirosina quinasaQuinasa del limfoma anaplàsic; Primera línia; Inhibidor de la tirosina quinasaBackground Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor with demonstrated efficacy in locally advanced and metastatic non–small cell lung cancer (NSCLC) in crizotinib-refractory and ALK inhibitor-naive settings. This analysis assessed brigatinib in Asian vs. non-Asian patients from the first-line ALTA-1L trial. Patients and Methods This was a subgroup analysis from the phase III ALTA-1L trial of brigatinib vs. crizotinib in ALK inhibitor–naive ALK+ NSCLC. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review committee (BIRC). Secondary endpoints included confirmed objective response rate (ORR) and overall survival (OS) in the overall population and BIRC-assessed intracranial ORR and PFS in patients with brain metastases. Results Of the 275 randomized patients, 108 were Asian. Brigatinib showed consistent superiority in BIRC-assessed PFS vs. crizotinib in Asian (hazard ratio [HR]: 0.35 [95% CI: 0.20-0.59]; log-rank P = .0001; median 24.0 vs. 11.1 months) and non-Asian (HR: 0.56 [95% CI: 0.38-0.84]; log-rank P = .0041; median 24.7 vs. 9.4 months) patients. Results were consistent with investigator-assessed PFS and BIRC-assessed intracranial PFS. Brigatinib was well tolerated. Toxicity profiles and dose modification rates were similar between Asian and non-Asian patients. Conclusion Efficacy with brigatinib was consistently better than with crizotinib in Asian and non-Asian patients with locally advanced or metastatic ALK inhibitor-naive ALK-+ NSCLC. There were no clinically notable differences in overall safety in Asian vs. non-Asian patients.This study was supported by ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. The sponsor designed and conducted the study and collected the data together with the authors. The sponsor managed and analyzed the data. Data were interpreted by the authors and the sponsor. The sponsor together with the authors prepared, reviewed, and approved the manuscript and made the decision to submit the manuscript for publication

Association between dyslipidemia and asthma in children: a systematic review and multicenter cohort study using a common data model

Background The association between dyslipidemia and asthma in children remains unclear. Purpose This study investigated the association between dyslipidemia and cholesterol levels in children. Methods A systematic literature review was performed to identify studies investigating the association between dyslipidemia and asthma in children. The PubMed database was searched for articles published from January 2000–March 2022. Data from a cohort study using electronic health records from 5 hospitals, converted to the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM), were used to identify the association between total cholesterol (TC) levels and asthma in children. This cohort study used the Cox proportional hazards model to examine hazard ratio (HR) of asthma after propensity score matching, and included an aggregate meta-analysis of HR. Results We examined 11 studies reporting an association between dyslipidemia and asthma in children. Most were cross-sectional; however, their results were inconsistent. In OMOP-CDM multicenter analysis, the high TC (>170 mg/dL) group included 29,038 children, while the normal TC (≤170 mg/dL) group included 88,823 children including all hospital datasets. In a meta-analysis of this multicenter cohort, a significant association was found between high TC levels and later development of asthma in children <15 years of age (pooled HR, 1.30; 95% confidence interval, 1.12–1.52). Conclusion Elevated TC levels in children may be associated with asthma

Clinical MetaData ontology: a simple classification scheme for data elements of clinical data based on semantics

Background The increasing use of common data elements (CDEs) in numerous research projects and clinical applications has made it imperative to create an effective classification scheme for the efficient management of these data elements. We applied high-level integrative modeling of entire clinical documents from real-world practice to create the Clinical MetaData Ontology (CMDO) for the appropriate classification and integration of CDEs that are in practical use in current clinical documents. Methods CMDO was developed using the General Formal Ontology method with a manual iterative process comprising five steps: (1) defining the scope of CMDO by conceptualizing its first-level terms based on an analysis of clinical-practice procedures, (2) identifying CMDO concepts for representing clinical data of general CDEs by examining how and what clinical data are generated with flows of clinical care practices, (3) assigning hierarchical relationships for CMDO concepts, (4) developing CMDO properties (e.g., synonyms, preferred terms, and definitions) for each CMDO concept, and (5) evaluating the utility of CMDO. Results We created CMDO comprising 189 concepts under the 4 first-level classes of Description, Event, Finding, and Procedure. CMDO has 256 definitions that cover the 189 CMDO concepts, with 459 synonyms for 139 (74.0%) of the concepts. All of the CDEs extracted from 6 HL7 templates, 25 clinical documents of 5 teaching hospitals, and 1 personal health record specification were successfully annotated by 41 (21.9%), 89 (47.6%), and 13 (7.0%) of the CMDO concepts, respectively. We created a CMDO Browser to facilitate navigation of the CMDO concept hierarchy and a CMDO-enabled CDE Browser for displaying the relationships between CMDO concepts and the CDEs extracted from the clinical documents that are used in current practice. Conclusions CMDO is an ontology and classification scheme for CDEs used in clinical documents. Given the increasing use of CDEs in many studies and real-world clinical documentation, CMDO will be a useful tool for integrating numerous CDEs from different research projects and clinical documents. The CMDO Browser and CMDO-enabled CDE Browser make it easy to search, share, and reuse CDEs, and also effectively integrate and manage CDEs from different studies and clinical documents.This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number:HI18C2386). KHIDI had no participation in the study design or data collection and analysis process. KHIDI did not participate in the writing of the manuscript