Widespread GLI expression but limited canonical hedgehog signaling restricted to the ductular reaction in human chronic liver disease

Canonical Hedgehog (Hh) signaling in vertebrate cells occurs following Smoothened activation/translocation into the primary cilia (Pc), followed by a GLI transcriptional response. Nonetheless, GLI activation can occur independently of the canonical Hh pathway. Using a murine model of liver injury, we previously identified the importance of canonical Hh signaling within the Pc+ liver progenitor cell (LPC) population and noted that SMO-independent, GLI-mediated signals were important in multiple Pc-ve GLI2+ intrahepatic populations. This study extends these observations to human liver tissue, and analyses the effect of GLI inhibition on LPC viability/gene expression. Human donor and cirrhotic liver tissue specimens were evaluated for SHH, GLI2 and Pc expression using immunofluorescence and qRT-PCR. Changes to viability and gene expression in LPCs in vitro were assessed following GLI inhibition. Identification of Pc (as a marker of canonical Hh signaling) in human cirrhosis was predominantly confined to the ductular reaction and LPCs. In contrast, GLI2 was expressed in multiple cell populations including Pc-ve endothelium, hepatocytes, and leukocytes. HSCs/myofibroblasts (gt;99%) expressed GLI2, with only 1.92% displaying Pc. In vitro GLI signals maintained proliferation/viability within LPCs and GLI inhibition affected the expression of genes related to stemness, hepatocyte/biliary differentiation and Hh/Wnt signaling. At least two mechanisms of GLI signaling (Pc/SMOdependent and Pc/SMO-independent) mediate chronic liver disease pathogenesis. This may have significant ramifications for the choice of Hh inhibitor (anti-SMO or anti-GLI) suitable for clinical trials. We also postulate GLI delivers a pro-survival signal to LPCs whilst maintaining stemness

Incidence of acute cerebrovascular events in patients with rheumatic or calcific mitral stenosis: a systematic review and meta-analysis

Background Patients with mitral stenosis (MS) may be predisposed to acute cerebrovascular events (ACE) and peripheral thromboembolic events (TEE). Concomitant atrial fibrillation (AF), mitral annular calcification (MAC) and rheumatic heart disease (RHD) are independent risk factors. Our aim was to evaluate the incidence of ACEs in MS patients and the implications of AF, MAC, and RHD on thromboembolic risks. Methods This systematic review was registered on PROSPERO (CRD42021291316). Six databases were searched from inception to 19th December 2021. The clinical outcomes were composite ACE, ischaemic stroke/transient ischaemic attack (TIA), and peripheral TEE. Results We included 16 and 9 papers, respectively, in our qualitative and quantitative analyses. The MS cohort with AF had the highest incidence of composite ACE (31.55%; 95%CI 3.60-85.03; I 2 =99%), followed by the MAC (14.85%; 95%CI 7.21-28.11; I 2 =98%), overall MS (8.30%; 95%CI 3.45-18.63; I 2 =96%) and rheumatic MS population (4.92%; 95%CI 3.53-6.83; I 2 =38%). Stroke/TIA were reported in 29.62% of the concomitant AF subgroup (95%CI 2.91-85.51; I 2 =99%) and in 7.11% of the overall MS patients (95%CI 1.91-23.16; I 2 =97%). However, the heterogeneity of the pooled incidence of clinical outcomes in all groups, except the rheumatic MS group, were substantial and significant. The logit-transformed proportion of composite ACE increased by 0.0141 (95% CI 0.0111-0.0171; p<0.01) per year of follow-up. Conclusion In the MS population, MAC and concomitant AF are risk factors for the development of ACE. The scarcity of data in our systematic review reflects the need for further studies to explore thromboembolic risks in all MS subtypes

A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma.

c-MET receptors are activated in cancers through genomic events like tyrosine kinase domain mutations, juxtamembrane splicing mutation and amplified copy numbers, which can be inhibited by c-MET small molecule inhibitors. Here, we discover that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables METN375S to interact with HER2 in a ligand-independent fashion. The resultant METN375S/HER2 dimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis. Accordingly, HER2 blockers, but not c-MET inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing METN375S. These results establish METN375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies

Ontology for Cultural Variations in Interpersonal Communication: Building on Theoretical Models and Crowdsourced Knowledge

The domain of cultural variations in interpersonal communication is becoming increasingly important in various areas, including human-human interaction (e.g. business settings) and human-computer interaction (e.g. during simulations, or with social robots). User generated content (UGC) in social media can provide an invaluable source of culturally diverse viewpoints for supporting the understanding of cultural variations. However, discovering and organizing UGC is notoriously challenging and laborious for humans, especially in ill-defined domains such as culture. This calls for computational approaches to automate the UGC sensemaking process by using tagging, linking and exploring. Semantic technologies allow automated structuring and qualitative analysis of UGC, but are dependent on the availability of an ontology representing the main concepts in a specific domain. For the domain of cultural variations in interpersonal communication, no ontological model exists. This paper presents the first such ontological model, called AMOn+, which defines cultural variations and enables tagging culture-related mentions in textual content. AMOn+ is designed based on a novel interdisciplinary approach that combines theoretical models of culture with crowdsourced knowledge (DBpedia). An evaluation of AMOn+ demonstrated its fitness-for-purpose regarding domain coverage for annotating culture-related concepts mentioned in text corpora. This ontology can underpin computational models for making sense of UGC

The Efficacy of Energy-Restricted Diets in Achieving Preoperative Weight Loss for bariatric Pateints: A Systematic Review

The final publication is available at Springer via https://doi.org/10.1007/s11695-018-3451-1In bariatric practice, a preoperative weight loss of at least 5% is recommended. However, the hypocaloric diets prescribed vary and no consensus exists. This study examined the efficacy of preoperative diets in achieving 5% weight loss. From a systematic literature search, eight randomised controlled trials (n = 862) were identified. Half of the trials used a Bvery-low-calorie diet^ whilst the rest employed a Blow-calorie diet^. Only five diets achieved ≥ 5% weight loss over varying durations and energy intakes. By inference, compliance with a 700–1050 kcal (2929–4393 kJ) diet, consisting of moderate carbohydrate, high protein and low/moderate fat, for 3 weeks is likely to achieve 5% weight loss. A low-carbohydrate diet (< 20 g/day) may achieve this target within a shorter duration. Additional research is required to validate these conclusions

Antimicrobial Peptides As Biologic and Immunotherapeutic Agents against Cancer: A Comprehensive Overview

Antimicrobial peptides (AMPs) are a pervasive and evolutionarily ancient component of innate host defense which is present in virtually all classes of life. In recent years, evidence has accumulated that parallel or de novo mechanisms by which AMPs curb infectious pathologies are also effective at restraining cancer cell proliferation and dissemination, and have consequently stimulated significant interest in their deployment as novel biologic and immunotherapeutic agents against human malignancies. In this review, we explicate the biochemical underpinnings of their tumor-selectivity, and discuss results of recent clinical trials (outside of oncologic indications) which substantiate their safety and tolerability profiles. Next, we present evidence for their preclinical antitumor activity, systematically organized by the major and minor classes of natural AMPs. Finally, we discuss the barriers to their clinical implementation and envision directions for further development