Evolution provides the unifying framework with which to understand biology. The coherent investigation of genic and genomic data often requires comparative genomics analyses based on whole-genome alignments, sets of homologous genes and other relevant datasets in order to evaluate and answer evolutionary-related questions. However, the complexity and computational requirements of producing such data are substantial: this has led to only a small number of reference resources that are used for most comparative analyses. The Ensembl comparative genomics resources are one such reference set that facilitates comprehensive and reproducible analysis of chordate genome data. Ensembl computes pairwise and multiple whole-genome alignments from which large-scale synteny, per-base conservation scores and constrained elements are obtained. Gene alignments are used to define Ensembl Protein Families, GeneTrees and homologies for both protein-coding and non-coding RNA genes. These resources are updated frequently and have a consistent informatics infrastructure and data presentation across all supported species. Specialized web-based visualizations are also available including synteny displays, collapsible gene tree plots, a gene family locator and different alignment views. The Ensembl comparative genomics infrastructure is extensively reused for the analysis of non-vertebrate species by other projects including Ensembl Genomes and Gramene and much of the information here is relevant to these projects. The consistency of the annotation across species and the focus on vertebrates makes Ensembl an ideal system to perform and support vertebrate comparative genomic analyses. We use robust software and pipelines to produce reference comparative data and make it freely available.Database URL: http://www.ensembl.org.

Database: The Journal of Biological Databases and Curation

Tumors often show, compared to normal tissues, a markedly decreased extracellular pH resulting from anaerobic or aerobic glycolysis in combination with a reduced removal of acidic metabolites. Several studies indicate that acidosis induces (independently from hypoxia) hematogenous and lymphatic spread of tumor cells worsening the long-term prognosis of tumor patients. This review gives an overview on the impact of low pH on different steps of metastasis including (a) local tumor cell invasion and angiogenesis, (b) intravasation of tumor cells and detachment into the circulation, and (c) adherence of circulating tumor cells, transmigration and invasion in the new host tissue. The review describes pH-dependent cellular mechanisms fostering these steps such as epithelial-to-mesenchymal transition (EMT), activation of cell migration, degradation of the extracellular matrix, or angiogenesis. The review discusses mechanisms of tumor cells for proton sensing including acid-sensitive ion channels (ASICs, TRPs) or ion transporters (NHE1) and G protein coupled H+-sensors. Finally, the review describes several intracellular signaling cascades activated by H+ sensing mechanisms leading to transcriptional, post-transcriptional, or functional changes in the cell relevant for the metastatic spread. From these studies, different therapeutical approaches are described to overcome tumor acidosis or to interfere with the signaling cascades to reduce the metastatic potential of tumors.

Tumor pH and metastasis: a malignant process beyond hypoxia

A novel, selective, and efficacious GPR4 antagonist 13 was developed starting from lead compound 1a. While compound 1a showed promising efficacy in several disease models, its binding to a H3 receptor as well as a hERG channel prevented it from further development. Therefore, a new round of optimization addressing the key liabilities was performed and led to discovery of compound 13 with an improved profile. Compound 13 showed significant efficacy in the rat antigen induced arthritis as well as in the hyperalgesia and angiogenesis model at a well-tolerated dose of 30 mg/kg.

Development of Selective, Orally Active GPR4 Antagonists with Modulatory Effects on Nociception, Inflammation, and Angiogenesis.

Adult neurogenesis is one of the most important mechanisms contributing to brain development, learning, and memory. Alterations in neurogenesis underlie a wide spectrum of brain diseases. Neurogenesis takes place in highly specialized neurogenic niches. The concept of neurogenic niches is becoming widely accepted due to growing evidence of the important role of the microenvironment established in the close vicinity to stem cells in order to provide adequate control of cell proliferation, differentiation, and apoptosis. Neurogenic niches represent the platform for tight integration of neurogenesis and angiogenesis supported by specific properties of cerebral microvessel endothelial cells contributing to establishment of partially compromised blood-brain barrier (BBB) for the adjustment of local conditions to the current metabolic needs of stem and progenitor cells. Here, we review up-to-date data on microvascular dynamics in activity-dependent neurogenesis, specific properties of BBB in neurogenic niches, endothelial-driven mechanisms of clonogenic activity, and future perspectives for reconstructing the neurogenic niches in vitro.

Blood-brain barrier-supported neurogenesis in healthy and diseased brain

The evolution and mechanism of GPCR proton sensing

Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor survival and is the sixth most common cancer worldwide. Gastroesophageal reflux is a common event in SCCHN patients. GPR4 is a proton-sensing G-protein coupled receptor, which can be activated by acidosis. The objective of this study was to explore the role of GPR4 in acid exposure and tumor angiogenesis in SCCHN. In this study, we confirmed that overexpressing GPR4 in SCCHN cells could increase the expression and secretion of IL6, IL8 and VEGFA at pH 5.9. This effect could be inhibited by SB203580 (a p38 inhibitor). Western blot analysis indicated that phosphorylation of p38 increased in GPR4 infected cells at pH 5.9, which could be inhibited by SB203580. In tube formation assay, HMEC-1 cells were incubated with conditioned medium (CM, pH 5.9, 6.5, 7.4) derived from control and GPR4 infected SCCHN cells. Tube length was significantly increased in HMEC-1 cells incubated with CM from GPR4 infected cells compared with control cells at pH5.9, which indicated the pro-angiogenic effect of GPR4 in acidic pH. The neutralizing antibodies of IL6, IL8 and VEGFA could inhibit tube formation of HMEC-1 cells. In vivo, the effect of GPR4 on angiogenesis was investigated with the chick chorioallantoic membrane (CAM) model. Control and GPR4 infected SCCHN cells were seeded onto the upper CAM surface (n = 5 in each group) and 5 μL DMEM/F12 (pH 5.9, 6.5, 7.4) was added to the surface of the cell every 24 h. Four days later, the upper CAM were harvested and the ratio of the vascular area to the CAM area was quantified using Image-Pro Plus 6.0 software. GPR4 infected cells could recruit more vascular than control cells at pH5.9. In conclusion, we suggested that GPR4 induces angiogenesis via GPR4-induced p38-mediated IL6, IL8 and VEGFA secretion at acidic extracellular pH in SCCHN.

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0152789&type=printable

The Proton-Sensing G-Protein Coupled Receptor GPR4 Promotes Angiogenesis in Head and Neck Cancer

Basic transcription factor 3 (BTF3), a transcription factor and modulator of apoptosis, is differentially expressed in carcinoma. To acquire further understanding of the involvement of BTF3 in carcinoma, the present study analyzed the expression of BTF3, as well as its role in cell function in nasopharyngeal carcinoma (NPC). BTF3 transcription rates in human NPC samples (n=46) and adjacent normal tissue samples (n=46) were analyzed using reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. BTF3-silencing in NPC cells was performed via specific small interfering RNA molecules. The function of BTF3 was analyzed by proliferation assays and colony forming assays using a Cellomic assay system. The positive expression rates of BTF3 were significantly increased in cancerous tissues compared with those in adjacent tissues (P<0.05). In addition, BTF3-silencing decreased cell proliferation and colony formation (P<0.01) in TCA-8113 and 5-8F cells. BTF3 is overexpressed in NPC, and its silencing is associated with decreased cell proliferation and colony formation, enhanced apoptosis and cell cycle regulation of TCA-8113 and 5-8F cells.

/pdf/expression-and-clinical-significance-of-basic-transcription-2lbov83ay9.pdf

Expression and clinical significance of basic transcription factor 3 in nasopharyngeal carcinoma

// Ping Chen 1, * , Wenbin Yu 2, * , Junwei Huang 1 , Hongbo Xu 1 , Guojun Li 3, 4 , Xiaohong Chen 1 , Zhigang Huang 1 1 Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China 2 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Head and Neck surgery, Peking University Cancer Hospital & Institute, Houston, TX 77030, USA 3 Department of Head and Neck Surgery, Houston, TX 77030, USA 4 Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA * These authors contributed equally to this work and co-first authors Correspondence to: Zhigang Huang, email: enthzg@trhos.com Xiaohong Chen, email: trchxh@163.com Keywords: differentiation, laryngeal carcinoma, prognosis, staging, survival Received: November 18, 2016      Accepted: January 11, 2017      Published: January 20, 2017 ABSTRACT To compare survival outcomes between patients with poorly differentiated versus well-differentiated glottic squamous cell carcinoma (GSCC). Fifty-five patients with well-differentiated newly diagnosed GSCC were pair-matched to 55 patients with poorly differentiated GSCC according to age, sex, year of diagnosis, overall stage, treatment (surgery type, neck dissection, surgical margin, and chemoradiation), smoking, and alcohol use. Survival analysis was performed using Kaplan-Meier estimates, and matched-pair survival was estimated using the Cox proportional hazards regression model. Patients with well-differentiated GSCC had significantly better overall survival (OS) ( P = 0.001), disease-specific survival (DSS) ( P < 0.001), and disease-free survival (DFS) ( P = 0.003) than patients with poorly differentiated GSCC. Moreover, matched-pair analysis indicated that increased differentiation was associated with a significantly reduced risk of overall death (HR, 0.18; 95% confidence interval [CI], 0.07–0.46), death owing to disease (HR, 0.16; 95% CI, 0.05–0.45), and disease recurrence (HR, 0.17; 95% CI, 0.07–0.41), and these risks were reduced approximately 4-fold, 3.7-fold, and 9-fold, respectively, after adjustment for cancer-associated variables. Survival differed significantly between the well-differentiated and poorly differentiated GSCC patients after adjustment for cancer prognosis-associated variables. Thus, identifying potential differences in the molecular characteristics between these two groups of patients would help to further stratify these patients and ensure appropriate individualized treatment decisions. Basing treatment strategies on the level of differentiation may improve survival.

/pdf/matched-pair-analysis-of-survival-in-patients-with-poorly-1xqqkls806.pdf

Matched-pair analysis of survival in patients with poorly differentiated versus well-differentiated glottic squamous cell carcinoma.

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The Proton-Sensing G-Protein Coupled Receptor GPR4 Promotes Angiogenesis in Head and Neck Cancer

Expression and clinical significance of basic transcription factor 3 in nasopharyngeal carcinoma

Matched-pair analysis of survival in patients with poorly differentiated versus well-differentiated glottic squamous cell carcinoma.