Patient-driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a Novel AKT1 Fusion-driven Cancer.

Cancer Discov. 2019 Mar 15;:

Authors: Slotkin EK, Diolaiti D, Shukla NN, Dela Cruz FS, Clark JJ, Gundem G, Yellapantula VD, Levine MF, You D, Ma P, Pachhal S, Ibanez Sanchez G, Benayed R, Jungbluth AA, Smyth LM, Mauguen A, Gushterova I, Ding H, Spraggon L, Darnell R, Califano A, Ladanyi M, Papaemmanuil E, Kung AL, Hyman DM, Roberts SS

Abstract
Despite the important role of the PI3K/AKT/mTOR axis in the pathogenesis of cancer, to date there have been few functional oncogenic fusions identified involving the AKT genes. A 12-year-old female with a histopathologically indeterminate epithelioid neoplasm was found to harbor a novel fusion between the LAMTOR1 and AKT1 genes. Through expanded use access, she became the first pediatric patient to be treated with the oral ATP-competitive pan-AKT inhibitor ipatasertib. Treatment resulted in dramatic tumor regression demonstrating through patient-driven discovery that the fusion resulted in activation of AKT1, was an oncogenic driver, and could be therapeutically targeted with clinical benefit. Post-clinical validation using patient-derived model systems corroborated these findings, confirmed a membrane-bound and constitutively active fusion protein, and identified potential mechanisms of resistance to single-agent treatment with ipatasertib.

PMID: 30877085 [PubMed - as supplied by publisher]

Chemical Characterization and DNA Fingerprinting of Griffonia simplicifolia Baill.

Molecules. 2019 Mar 15;24(6):

Authors: Vigliante I, Mannino G, Maffei ME

Abstract
BACKGROUND: Griffonia simplicifolia Baill. (Caesalpiniaceae) is a medicinal plant whose seeds are widely used in traditional medicine for their high content of 5-hydroxy-l-tryptophan (5-HTP), a direct precursor and enhancer of the activity of the brain hormone serotonin (5-HT). The plant extracts are used in dietary supplements aimed to alleviate serotonin-related disorders.
METHODS: In order to characterize the chemical components of G. simplicifolia seeds and their identity, we used a combined methodology by using HPLC-DAD-ESI-MS/MS for the qualitative and quantitative determination of the N-containing compounds, GC-FID and GC-MS for the characterization of the major fatty acids, and DNA fingerprinting based on PCR⁻RFLP for the unequivocal identification of the plant.
RESULTS: 5-HTP was the most representative compound, followed by lower percentages of the β-carboline alkaloid derivative griffonine and other alkaloids. Fatty acids were dominated by the unsaturated fatty acids linoleic acid and oleic acid, followed by the saturated fatty acids stearic and palmitic acids. PCR analysis of the internal transcribed spacer amplified sequence showed a major band at about 758 bp, whereas the PCR⁻RFLP analysis of this sequence using three different restriction enzymes (MspI, HhaI, and HaeIII) generated a specific fingerprinting useful for the plant identification.
CONCLUSIONS: The combined chemical and molecular analysis of G. simplicifolia provided an interesting integrated approach for the unequivocal identification of commercial G. simplicifolia seeds.

PMID: 30875930 [PubMed - in process]

Cellular Gene Expression during Hepatitis C Virus Replication as Revealed by Ribosome Profiling.

Int J Mol Sci. 2019 Mar 15;20(6):

Authors: Gerresheim GK, Bathke J, Michel AM, Andreev DE, Shalamova LA, Rossbach O, Hu P, Glebe D, Fricke M, Marz M, Goesmann A, Kiniry SJ, Baranov PV, Shatsky IN, Niepmann M

Abstract
BACKGROUND: Hepatitis C virus (HCV) infects human liver hepatocytes, often leading to liver cirrhosis and hepatocellular carcinoma (HCC). It is believed that chronic infection alters host gene expression and favors HCC development. In particular, HCV replication in Endoplasmic Reticulum (ER) derived membranes induces chronic ER stress. How HCV replication affects host mRNA translation and transcription at a genome wide level is not yet known.
METHODS: We used Riboseq (Ribosome Profiling) to analyze transcriptome and translatome changes in the Huh-7.5 hepatocarcinoma cell line replicating HCV for 6 days.
RESULTS: Established viral replication does not cause global changes in host gene expression-only around 30 genes are significantly differentially expressed. Upregulated genes are related to ER stress and HCV replication, and several regulated genes are known to be involved in HCC development. Some mRNAs (PPP1R15A/GADD34, DDIT3/CHOP, and TRIB3) may be subject to upstream open reading frame (uORF) mediated translation control. Transcriptional downregulation mainly affects mitochondrial respiratory chain complex core subunit genes.
CONCLUSION: After establishing HCV replication, the lack of global changes in cellular gene expression indicates an adaptation to chronic infection, while the downregulation of mitochondrial respiratory chain genes indicates how a virus may further contribute to cancer cell-like metabolic reprogramming ("Warburg effect") even in the hepatocellular carcinoma cells used here.

PMID: 30875926 [PubMed - in process]

28 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2019/03/16

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37 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

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"systems biology"

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"systems biology"

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"systems biology"

These pubmed results were generated on 2019/03/13

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28 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

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28 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2019/03/12

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The metabolic network coherence of human transcriptomes is associated with genetic variation at the cadherin 18 locus.

Hum Genet. 2019 Mar 09;:

Authors: Schlicht K, Nyczka P, Caliebe A, Freitag-Wolf S, Claringbould A, Franke L, Võsa U, BIOS Consortium, Kardia SLR, Smith JA, Zhao W, Gieger C, Peters A, Prokisch H, Strauch K, KORA Study Group, Baurecht H, Weidinger S, Rosenstiel P, Hütt MT, Knecht C, Szymczak S, Krawczak M

Abstract
Metabolic coherence (MC) is a network-based approach to dimensionality reduction that can be used, for example, to interpret the joint expression of genes linked to human metabolism. Computationally, the derivation of 'transcriptomic' MC involves mapping of an individual gene expression profile onto a gene-centric network derived beforehand from a metabolic network (currently Recon2), followed by the determination of the connectivity of a particular, profile-specific subnetwork. The biological significance of MC has been exemplified previously in the context of human inflammatory bowel disease, among others, but the genetic architecture of this quantitative cellular trait is still unclear. Therefore, we performed a genome-wide association study (GWAS) of MC in the 1000 Genomes/ GEUVADIS data (n = 457) and identified a solitary genome-wide significant association with single nucleotide polymorphisms (SNPs) in the intronic region of the cadherin 18 (CDH18) gene on chromosome 5 (lead SNP: rs11744487, p = 1.2 × 10- 8). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n = 2661; lead SNP), but failed in two additional studies (KORA, Germany, n = 711; GENOA, USA, n = 411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis.

PMID: 30852652 [PubMed - as supplied by publisher]

Synthesis and evaluation of solid lipid nanoparticles loaded with bovine serum albumin prepared by different methods.

Pak J Pharm Sci. 2019 Jan;32(1(Special)):397-405

Authors: Saleem M, Qadir MA, Mahmood N, Shahzadi SK, Shahid S

Abstract
.We evaluated the effect of different synthesis methods of solid lipid nanoparticles (SLNs) loaded with bovine serum albumin (BSA) on parameters including particle size, polydispersity index, loading capacity and % entrapment efficiency including release study. We investigated the binary fatty acids mixtures for test protein BSA. Different techniques were used as micro emulsion, ultrasound homogenization and double emulsification-evaporation for the BSA loading of SLNs. With the increase in BSA content from 0-10%, indicated an increase in the size and decrease in polydispersity index. The stability of SLNs loaded with BSA was examined by measuring the zeta potential and all formulations were found to be quite stable. Release study and kinetic models were applied to assess BSA release profile from different formulations of SLNs. The particle size of BSA loaded SLNs was reduced to 89.67 ± 4.88 nm when PEG 6000 and Brij were used as 0.25% and 1.5% of total formulation (F5). Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and Fourier-transform infrared spectroscopy (FTIR) indicated the chemical stability of BSA which was used to load SLNs in different formulations. SLNs from the combinations of solid and liquid lipids had enhanced the physicochemical properties and permitted controlled release of BSA for up to 10 days. The study also evaluated the addition of polyethylene glycol which reduced the particles size and enhanced % entrapment efficiency. The release of BSA from SLNs was followed zero order rate kinetics and diffusion-controlled. Different mathematical models, i.e., zero order, first order, Higuchi and Korsmeyer-Peppas models were found best fit to BSA release profile of all formulations of SLNs.

PMID: 30852476 [PubMed - in process]

ColocalizR: An open-source application for cell-based high-throughput colocalization analysis.

Comput Biol Med. 2019 Mar 02;107:227-234

Authors: Sauvat A, Leduc M, Müller K, Kepp O, Kroemer G

Abstract
The microscopic assessment of the colocalization of fluorescent signals has been widely used in cell biology. Although imaging techniques have drastically improved over the past decades, the quantification of colocalization by measures such as the Pearson correlation coefficient or Manders overlap coefficient, has not changed. Here, we report the development of an R-based application that allows to (i) automatically segment cells and subcellular compartments, (ii) measure morphology and texture features, and (iii) calculate the degree of colocalization within each cell. Colocalization can thus be studied on a cell-by-cell basis, permitting to perform statistical analyses of cellular populations and subpopulations. ColocalizR has been designed to parallelize tasks, making it applicable to the analysis of large data sets. Its graphical user interface makes it suitable for researchers without specific knowledge in image analysis. Moreover, results can be exported into a wide range of formats rendering post-analysis adaptable to statistical requirements. This application and its source code are freely available at https://github.com/kroemerlab/ColocalizR.

PMID: 30852249 [PubMed - as supplied by publisher]

Treatment Avenues in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Split-gender Pharmacogenomic Study of Gene-expression Modules.

Clin Ther. 2019 Mar 06;:

Authors: Jeffrey MG, Nathanson L, Aenlle K, Barnes ZM, Baig M, Broderick G, Klimas NG, Fletcher MA, Craddock TJA

Abstract
PURPOSE: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisymptom illness impacting up to 1 million people in the United States. As the pathogenesis and etiology of this complex condition are unclear, prospective treatments are limited. Identifying US Food and Drug Administration-approved drugs that may be repositioned as treatments for ME/CFS may offer a rapid and cost-effective solution.
METHODS: Here we used gene-expression data from 33 patients with Fukuda-defined ME/CFS (23 females, 10 males) and 21 healthy demographically comparable controls (15 females, 6 males) to identify differential expression of predefined gene-module sets based on nonparametric statistics. Differentially expressed gene modules were then annotated via over-representation analysis using the Consensus Pathway database. Differentially expressed modules were then regressed onto measures of fatigue and cross-referenced with drug atlas and pharmacogenomics databases to identify putative treatment agents.
FINDINGS: The top 1% of modules identified in males indicated small effect sizes in modules associated with immune regulation and mitochondrial dysfunction. In females, modules identified included those related to immune factors and cardiac/blood factors, returning effect sizes ranging from very small to intermediate (0.147 < Cohen δ < 0.532). Regression analysis indicated that B-cell receptors, T-cell receptors, tumor necrosis factor α, transforming growth factor β, and metabolic and cardiac modules were strongly correlated with multiple composite measures of fatigue. Cross-referencing identified genes with pharmacogenomics data indicated immunosuppressants as potential treatments of ME/CFS symptoms.
IMPLICATIONS: The findings from our analysis suggest that ME/CFS symptoms are perpetuated by immune dysregulation that may be approached via immune modulation-based treatment strategies. (Clin Ther. 2019;41:XXX-XXX) © 2019 Elsevier Inc.

PMID: 30851951 [PubMed - as supplied by publisher]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2019/03/10

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"systems biology"

These pubmed results were generated on 2019/03/09

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34 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2019/03/09

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"systems biology"

These pubmed results were generated on 2019/03/08

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"systems biology"

These pubmed results were generated on 2019/03/08

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"systems biology"

These pubmed results were generated on 2019/03/07

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