Design and synthesis of novel 1H-tetrazol-5-amine based potent antimicrobial agents: DNA topoisomerase IV and gyrase affinity evaluation supported by molecular docking studies.

Eur J Med Chem. 2018 Jul 17;156:631-640

Authors: Szulczyk D, Dobrowolski MA, Roszkowski P, Bielenica A, Stefańska J, Koliński M, Kmiecik S, Jóźwiak M, Wrzosek M, Olejarz W, Struga M

Abstract
A total of 14 of 1,5-disubstituted tetrazole derivatives were prepared by reacting appropriate thiourea and sodium azide in the presence of mercury (II) chloride and triethylamine. All compounds were evaluated in vitro for their antimicrobial activity. Derivatives 10 and 11 showed the highest inhibition against Gram-positive and Gram-negative strains (standard and hospital strains). The observed minimal inhibitory concentrations values were in the range of 1-208 μM (0.25-64 μg/ml). Inhibitory activity of 1,5-tetrazole derivatives 10 and 11 against gyrase and topoisomerase IV isolated from S. aureus was studied. Evaluation was supported by molecular docking studies for all synthesized derivatives and reference ciprofloxacin. Moreover, selected tetrazoles (2, 3, 5, 6, 8, 9, 10 and 11) were evaluated for their cytotoxicity. All tested compounds are non-cytotoxic against HaCaT and A549 cells (CC50 ≤ 60 μM).

PMID: 30031974 [PubMed - as supplied by publisher]

The inhibitory role of purinergic P2Y receptor on Mg2+ transport across intestinal epithelium-like Caco-2 monolayer.

J Physiol Sci. 2018 Jul 21;:

Authors: Thongon N, Chamniansawat S

Abstract
The mechanism of proton pump inhibitors (PPIs) suppressing intestinal Mg2+ uptake is unknown. The present study aimed to investigate the role of purinergic P2Y receptors in the regulation of Mg2+ absorption in normal and omeprazole-treated intestinal epithelium-like Caco-2 monolayers. Omeprazole suppressed Mg2+ transport across Caco-2 monolayers. An agonist of the P2Y2 receptor, but not the P2Y4 or P2Y6 receptor, suppressed Mg2+ transport across control and omeprazole-treated monolayers. Omeprazole enhanced P2Y2 receptor expression in Caco-2 cells. Forskolin and P2Y2 receptor agonist markedly enhanced apical HCO3- secretion by control and omeprazole-treated monolayers. The P2Y2 receptor agonist suppressed Mg2+ transport and stimulated apical HCO3- secretion through the Gq-protein coupled-phospholipase C (PLC) dependent pathway. Antagonists of cystic fibrosis transmembrane conductance regulator (CFTR) and Na+-HCO3- cotransporter-1 (NBCe1) could nullify the inhibitory effect of P2Y2 receptor agonist on Mg2+ transport across control and omeprazole-treated Caco-2 monolayers. Our results propose an inhibitory role of P2Y2 on intestinal Mg2+ absorption.

PMID: 30032468 [PubMed - as supplied by publisher]

MendelProb: Probability and sample size calculations for Mendelian studies of exome and whole genome sequence data.

Bioinformatics. 2018 Jul 19;:

Authors: He Z, DeWan AT, Leal SM

Abstract
Motivation: For the design of genetic studies, it is necessary to perform power calculations. Although for Mendelian traits the power of detecting linkage for pedigree(s) can be determined, it is also of great interest to determine the probability of identifying multiple pedigrees or unrelated cases with variants in the same gene. For many diseases, due to extreme locus heterogeneity this probability can be small. If only one family is observed segregating a variant classified as likely pathogenic or of unknown significance, the gene cannot be implicated in disease etiology. The probability of identifying several disease families or cases is dependent on the gene-specific disease prevalence and the sample size. The observation of multiple disease families or cases with variants in the same gene as well as evidence of pathogenicity from other sources, e.g., in silico prediction, expression, and functional studies, can aid in implicating a gene in disease etiology. MendelProb can determine the probability of detecting a minimum number of families or cases with variants in the same gene. It can also calculate the probability of detecting genes with variants in different data types, e.g., identifying a variant in at least one family that can establish linkage and more the two additional families regardless of their size. Additionally, for a specified probability MendelProb can determine the number of probands which need to be screened to detect a minimum number of individuals with variants within the same gene.
Summary: A single Mendelian disease family is not sufficient to implicate a gene in disease etiology. It is necessary to observe multiple families or cases with potentially pathogenic variants in the same gene. MendelProb, an R library, was developed to determine the probability of observing multiple families and cases with variants within a gene and to also establish the numbers of probands to screen to detect multiple observations of variants within a gene.
Program and documentation: https://github.com/statgenetics/mendelprob.

PMID: 30032240 [PubMed - as supplied by publisher]

Mutational Intratumor Heterogeneity is a Complex and Early Event in the Development of Adult T-cell Leukemia/Lymphoma.

Neoplasia. 2018 Jul 19;20(9):883-893

Authors: Farmanbar A, Firouzi S, Makałowski W, Kneller R, Iwanaga M, Utsunomiya A, Nakai K, Watanabe T

Abstract
The clonal architecture of tumors plays a vital role in their pathogenesis and invasiveness; however, it is not yet clear how this clonality contributes to different malignancies. In this study we sought to address mutational intratumor heterogeneity (ITH) in adult T-cell leukemia/lymphoma (ATL). ATL is a malignancy with an incompletely understood molecular pathogenesis caused by infection with human T-cell leukemia virus type-1 (HTLV-1). To determine the clonal structure through tumor genetic diversity profiles, we investigated 142 whole-exome sequencing data of tumor and matched normal samples from 71 ATL patients. Based on SciClone analysis, the ATL samples showed a wide spectrum of modes over clonal/subclonal frequencies ranging from one to nine clusters. The average number of clusters was six across samples, but the number of clusters differed among different samples. Of these ATL samples, 94% had more than two clusters. Aggressive ATL cases had slightly more clonal clusters than indolent types, indicating the presence of ITH during earlier stages of disease. The known significantly mutated genes in ATL were frequently clustered together and possibly coexisted in the same clone. IRF4, CCR4, TP53, and PLCG1 mutations were almost clustered in subclones with a moderate variant allele frequency (VAF), whereas HLA-B, CARD11, and NOTCH1 mutations were clustered in subclones with lower VAFs. Taken together, these results show that ATL displays a high degree of ITH and a complex subclonal structure. Our findings suggest that clonal/subclonal architecture might be a useful measure for prognostic purposes and personalized assessment of the therapeutic response.

PMID: 30032036 [PubMed - as supplied by publisher]

MoDentify: phenotype-driven module identification in metabolomics networks at different resolutions.

Bioinformatics. 2018 Jul 19;:

Authors: Do KT, Rasp DJN, Kastenmüller G, Suhre K, Krumsiek J

Abstract
Summary: Associations of metabolomics data with phenotypic outcomes are expected to span functional modules, which are defined as sets of correlating metabolites that are coordinately regulated. Moreover, these associations occur at different scales, from entire pathways to only a few metabolites; an aspect that has not been addressed by previous methods. Here we present MoDentify, a free R package to identify regulated modules in metabolomics networks at different layers of resolution. Importantly, MoDentify shows higher statistical power than classical association analysis. Moreover, the package offers direct interactive visualization of the results in Cytoscape. We present an application example using complex, multifluid metabolomics data. Due to its generic character, the method is widely applicable to other types of data.
Availability and Implementation: https://github.com/krumsieklab/MoDentify (vignette includes detailed workflow).
Supplementary Information: Supplementary materials are available at Bioinformatics online.

PMID: 30032270 [PubMed - as supplied by publisher]

Editorial: Plant Chemical Biology.

Plant Cell Physiol. 2018 Jul 19;:

Authors: Kinoshita T, McCourt P, Asami T, Torii KU

PMID: 30032233 [PubMed - as supplied by publisher]

Thrombospondin 2 promotes tumor metastasis by inducing matrix metalloproteinase-13 production in lung cancer cells.

Biochem Pharmacol. 2018 Jul 19;:

Authors: Liu JF, Lee CW, Tsai MH, Tang CH, Chen PC, Lin LW, Lin CY, Lu CH, Lin YF, Yang SH, Chao CC

Abstract
Thrombospondin (TSP)-2, a matricellular glycoprotein of the TSP family, regulates multiple biological functions, including proliferation, angiogenesis, cell adhesion, and extracellular matrix (ECM) modeling. The clinical relevance of TSP-2 has been explored in many different cancers. TSP-2 expression levels vary between different cancer types, and their role in tumor progression remains controversial. Although previous studies have reported higher serum TSP-2 levels in patients with non-small cell lung cancer, the role of TSP-2 in lung cancer progression remains to be addressed. A total of 585 lung adenocarcinoma datasets, including mRNA sequencing and clinical data, were retrieved from The Cancer Genome Atlas (TCGA). Forty paired adjacent normal tissues and lung tumor tissue datasets were used to examine TSP-2 expression levels. Tumor microarray were performed with immunohistochemical staining to examine TSP-2 expression in lung cancer patients. Transwell migration assay, quantitative real-time PCR and western blot were used to investigate molecular mechanism of TSP-2 in lung cancer cell. TSP-2 promotes MMP-13 expression, cell migration, and cell invasion by mediating integrin αvβ3/FAK/Akt/NF-κB signal transduction. Using TSP-2 knockdown stable cell lines, we found that TSP-2 knockdown reduces MMP-13 expression and cell mobility. When we manipulated the tumor tissue microarray and TCGA datasets to investigate the clinical relevance of TSP-2, we found high TSP-2 expression levels in lung cancer specimens. The present study demonstrates that TSP-2 regulates cell mobility through matrix metalloproteinase (MMP)-13 expression in lung cancer cells. In addition, TSP-2 expression was associated with MMP-13 expression and poor prognosis in lung cancer. TSP-2 may therefore be a promising novel target for lung cancer treatment.

PMID: 30031810 [PubMed - as supplied by publisher]

Genome-Scale Oscillations in DNA Methylation during Exit from Pluripotency.

Cell Syst. 2018 Jul 12;:

Authors: Rulands S, Lee HJ, Clark SJ, Angermueller C, Smallwood SA, Krueger F, Mohammed H, Dean W, Nichols J, Rugg-Gunn P, Kelsey G, Stegle O, Simons BD, Reik W

Abstract
Pluripotency is accompanied by the erasure of parental epigenetic memory, with naïve pluripotent cells exhibiting global DNA hypomethylation both in vitro and in vivo. Exit from pluripotency and priming for differentiation into somatic lineages is associated with genome-wide de novo DNA methylation. We show that during this phase, co-expression of enzymes required for DNA methylation turnover, DNMT3s and TETs, promotes cell-to-cell variability in this epigenetic mark. Using a combination of single-cell sequencing and quantitative biophysical modeling, we show that this variability is associated with coherent, genome-scale oscillations in DNA methylation with an amplitude dependent on CpG density. Analysis of parallel single-cell transcriptional and epigenetic profiling provides evidence for oscillatory dynamics both in vitro and in vivo. These observations provide insights into the emergence of epigenetic heterogeneity during early embryo development, indicating that dynamic changes in DNA methylation might influence early cell fate decisions.

PMID: 30031774 [PubMed - as supplied by publisher]

'Ropy' phenotype, exopolysaccharides and metabolism: Study on food isolated potential probiotics LAB.

Microbiol Res. 2018 Sep;214:137-145

Authors: Cirrincione S, Breuer Y, Mangiapane E, Mazzoli R, Pessione E

Abstract
Lactic acid bacteria are fully recognized for their industrial applications among which the production and release of exopolysaccharides. In the present investigation, we screened fifteen Lactobacilli in order to find ropy strains, quantify exopolysaccharides and detect proteins specifically associated with the ropy-exopolysaccharide production. The highest ropy-exopolysaccharide producer (L. helveticus 6E8), was grown in stimulating and basal condition (10% and 2% lactose) and subjected to comparative proteomic analysis. The levels of 4 proteins were found significantly increased in the membrane fraction under stimulating conditions: a specific exopolysaccharide biosynthetic protein, a stress-induced protein, a protein involved in secretion and an ATP-synthase subunit. Conversely, several enzymes involved in anabolism and protein synthesis were decreased. These results suggest a general shift from growth to exopolysaccharide-mediated protection from the hyperosmotic environment. Due to the great interest in exopolysaccharides with novel features, the identification of these proteins could have implications for future improvements of industrial strains.

PMID: 30031476 [PubMed - in process]

Perspectives in melanoma: Meeting report from the Melanoma Bridge (30 November-2 December, 2017, Naples, Italy).

J Transl Med. 2018 Jul 21;16(1):207

Authors: Ascierto PA, Puzanov I, Agarwala SS, Bifulco C, Botti G, Caracò C, Ciliberto G, Davies MA, Dummer R, Ferrone S, Gajewski TF, Garbe C, Luke JJ, Marincola FM, Masucci G, Mehnert JM, Mozzillo N, Palmieri G, Postow MA, Schoenberger SP, Wang E, Thurin M

Abstract
Metastatic melanoma represents a challenging clinical situation and, until relatively recently, there was an absence of effective treatment options. However, in 2011, the advanced melanoma treatment landscape was revolutionised with the approval of the anti-cytotoxic T-lymphocyte-associated protein-4 checkpoint inhibitor ipilimumab and the selective BRAF kinase inhibitor vemurafenib, both of which significantly improved overall survival. Since then, availability of new immunotherapies, especially the anti-programmed death-1 checkpoint inhibitors, as well as other targeted therapies, have further improved outcomes for patients with advanced melanoma. Seven years on from the first approval of these novel therapies, evidence for the use of various immune-based and targeted approaches is continuing to increase at a rapid rate. Improved understanding of the tumour microenvironment and tumour immuno-evasion strategies has resulted in different approaches to target and harness the immune response. These new immune-based approaches offer the opportunity for various approaches with distinct modes of action being used in combination with one another, as well as combined with other treatment modalities such as targeted therapy, electrochemotherapy and surgery. The increasing number of treatment options that are now available has resulted in a growing need to identify which patients will derive most benefit from which treatments. Much research is now focused on the identification of biomarkers that can be utilised to help select patients for treatment. These and other recent advances in the management of melanoma were the focus of discussions at the third Melanoma Bridge meeting (30 November-2 December, 2017, Naples, Italy), which is summarised in this report.

PMID: 30031393 [PubMed - in process]

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"systems biology"

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("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

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Lateral inhibition: Two modes of non-autonomous negative autoregulation by neuralized.

PLoS Genet. 2018 Jul 20;14(7):e1007528

Authors: Miller SW, Posakony JW

Abstract
Developmental patterning involves the progressive subdivision of tissue into different cell types by invoking different genetic programs. In particular, cell-cell signaling is a universally deployed means of specifying distinct cell fates in adjacent cells. For this mechanism to be effective, it is essential that an asymmetry be established in the signaling and responding capacities of the participating cells. Here we focus on the regulatory mechanisms underlying the role of the neuralized gene and its protein product in establishing and maintaining asymmetry of signaling through the Notch pathway. The context is the classical process of "lateral inhibition" within Drosophila proneural clusters, which is responsible for distinguishing the sensory organ precursor (SOP) and non-SOP fates among adjacent cells. We find that neur is directly regulated in proneural clusters by both proneural transcriptional activators and Enhancer of split basic helix-loop-helix repressors (bHLH-Rs), via two separate cis-regulatory modules within the neur locus. We show that this bHLH-R regulation is required to prevent the early, pre-SOP expression of neur from being maintained in a subset of non-SOPs following SOP specification. Lastly, we demonstrate that Neur activity in the SOP is required to inhibit, in a cell non-autonomous manner, both neur expression and Neur function in non-SOPs, thus helping to secure the robust establishment of distinct cell identities within the developing proneural cluster.

PMID: 30028887 [PubMed - as supplied by publisher]

The positive inotropic agent DPI-201106 selectively reverses ABCB1-mediated multidrug resistance in cancer cell lines.

Cancer Lett. 2018 Jul 18;:

Authors: Hsiao SH, Murakami M, Yeh N, Li YQ, Hung TH, Wu YS, Ambudkar SV, Wu CP

Abstract
The overexpression of ABCB1 in cancer cells is a major factor contributing to the development of multidrug resistance (MDR) and treatment failure in cancer patients. Therefore, re-sensitization of MDR cancer cells to anticancer drugs remains an important aspect in chemotherapy. The progress in developing clinically applicable synthetic inhibitors of ABCB1 has been slow, mostly due to complications associated with intrinsic toxicities and unforeseen drug-drug interactions. Here, we explored the drug-repositioning approach for cancer therapy by targeting ABCB1-mediated MDR in human cancer cells. We found that DPI-201106, a positive inotropic agent, selectively inhibits the drug efflux function of ABCB1, and in doing so, re-sensitizes ABCB1-overexpressing MDR cancer cells to conventional anticancer drugs. Furthermore, the ATPase activity of ABCB1 and docking analysis of DPI-201106 in the drug-binding pocket of ABCB1 were determined to confirm the interaction between DPI-201106 and ABCB1 protein. In summary, we revealed an additional action and a potential clinical application of DPI-201106 to reverse ABCB1-mediated MDR in human cancer cells, which may be beneficial for cancer patients who have developed multidrug resistance and no longer respond to conventional chemotherapy, and should be further investigated.

PMID: 30031116 [PubMed - as supplied by publisher]