Bioinformatic and clinical experimental assay uncovers resistance and susceptibility mechanisms of human glioblastomas to temozolomide and identifies new combined and individual survival biomarkers outperforming promoter methylation.

Background: Glioblastoma (GBM) is the most aggressive and lethal central nervous system (CNS) tumor. The treatment strategy is mainly surgery and/or radiation therapy, both combined with adjuvant temozolomide (TMZ) chemotherapy. Historically, methylation of gene promoter is used as the major biomarker predicting individual tumor response to TMZ.

The Association of Adipokines and Myokines in the Blood of Obese Children and Adolescents with Lipoprotein Lipase rs328 Gene Variants.

Obesity develops largely due to genetic factors, with the genetic polymorphism of lipid metabolism enzymes being of particular importance. However, it is still unclear how the genetic variants of one of the key enzymes in lipid transport, lipoprotein lipase (LPL), are associated with the endocrine function of mesenchymal tissues in obesity. The current study was aimed at the investigation of the rs328 gene variant association with adipokines and myokines levels, as well as lipid metabolism indices in the blood of children and adolescents of both genders with obesity.

Alkylresorcinols as New Modulators of the Metabolic Activity of the Gut Microbiota.

Alkylresorcinols (ARs) are polyphenolic compounds with a wide spectrum of biological activities and are potentially involved in the regulation of host metabolism. The present study aims to establish whether ARs can be produced by the human gut microbiota and to evaluate alterations in content in stool samples as well as metabolic activity of the gut microbiota of C57BL, , and LDLR (-/-) mice according to diet specifications and olivetol (5-n-pentylresorcinol) supplementation to estimate the regulatory potential of ARs. Gas chromatography with mass spectrometric detection was used to quantitatively analyse AR levels in mouse stool samples; faecal microbiota transplantation (FMT) from human donors to germ-free mice was performed to determine whether the intestinal microbiota could produce AR molecules; metagenome sequencing analysis of the mouse gut microbiota followed by reconstruction of its metabolic activity was performed to investigate olivetol's regulatory potential.

Mutation Enrichment and Transcriptomic Activation Signatures of 419 Molecular Pathways in Cancer.

Carcinogenesis is linked with massive changes in regulation of gene networks. We used high throughput mutation and gene expression data to interrogate involvement of 278 signaling, 72 metabolic, 48 DNA repair and 47 cytoskeleton molecular pathways in cancer. Totally, we analyzed 4910 primary tumor samples with individual cancer RNA sequencing and whole exome sequencing profiles including ~1.

Pathway Instability Is an Effective New Mutation-Based Type of Cancer Biomarkers.

DNA mutations play a crucial role in cancer development and progression. Mutation profiles vary dramatically in different cancer types and between individual tumors. Mutations of several individual genes are known as reliable cancer biomarkers, although the number of such genes is tiny and does not enable differential diagnostics for most of the cancers.

Gene expression and molecular pathway activation signatures of -amplified neuroblastomas.

Neuroblastoma is a pediatric cancer arising from sympathetic nervous system. Remarkable heterogeneity in outcomes is one of its widely known features. One of the traits strongly associated with the unfavorable subtype is the amplification of oncogene .

Activation of homologous recombination DNA repair in human skin fibroblasts continuously exposed to X-ray radiation.

Molecular and cellular responses to protracted ionizing radiation exposures are poorly understood. Using immunofluorescence microscopy, we studied the kinetics of DNA repair foci formation in normal human fibroblasts exposed to X-rays at a dose rate of 4.5 mGy/min for up to 6 h.

A method for predicting target drug efficiency in cancer based on the analysis of signaling pathway activation.

A new generation of anticancer therapeutics called target drugs has quickly developed in the 21st century. These drugs are tailored to inhibit cancer cell growth, proliferation, and viability by specific interactions with one or a few target proteins. However, despite formally known molecular targets for every "target" drug, patient response to treatment remains largely individual and unpredictable.

Combinatorial high-throughput experimental and bioinformatic approach identifies molecular pathways linked with the sensitivity to anticancer target drugs.

Effective choice of anticancer drugs is important problem of modern medicine. We developed a method termed OncoFinder for the analysis of new type of biomarkers reflecting activation of intracellular signaling and metabolic molecular pathways. These biomarkers may be linked with the sensitivity to anticancer drugs.

Low doses of X-rays induce prolonged and ATM-independent persistence of γH2AX foci in human gingival mesenchymal stem cells.

Diagnostic imaging delivering low doses of radiation often accompany human mesenchymal stem cells (MSCs)-based therapies. However, effects of low dose radiation on MSCs are poorly characterized. Here we examine patterns of phosphorylated histone H2AX (γH2AX) and phospho-S1981 ATM (pATM) foci formation in human gingiva-derived MSCs exposed to X-rays in time-course and dose-response experiments.

New bioinformatic tool for quick identification of functionally relevant endogenous retroviral inserts in human genome.

Endogenous retroviruses (ERVs) and LTR retrotransposons (LRs) occupy ∼8% of human genome. Deep sequencing technologies provide clues to understanding of functional relevance of individual ERVs/LRs by enabling direct identification of transcription factor binding sites (TFBS) and other landmarks of functional genomic elements. Here, we performed the genome-wide identification of human ERVs/LRs containing TFBS according to the ENCODE project.

Signaling pathway activation drift during aging: Hutchinson-Gilford Progeria Syndrome fibroblasts are comparable to normal middle-age and old-age cells.

For the past several decades, research in understanding the molecular basis of human aging has progressed significantly with the analysis of premature aging syndromes. Progerin, an altered form of lamin A, has been identified as the cause of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), and may be a contributing causative factor in normal aging. However, the question of whether HGPS actually recapitulates the normal aging process at the cellular and organismal level, or simply mimics the aging phenotype is widely debated.

Signaling pathways activation profiles make better markers of cancer than expression of individual genes.

Identification of reliable and accurate molecular markers remains one of the major challenges of contemporary biomedicine. We developed a new bioinformatic technique termed OncoFinder that for the first time enables to quantatively measure activation of intracellular signaling pathways basing on transcriptomic data. Signaling pathways regulate all major cellular events in health and disease.

Novel robust biomarkers for human bladder cancer based on activation of intracellular signaling pathways.

We recently proposed a new bioinformatic algorithm called OncoFinder for quantifying the activation of intracellular signaling pathways. It was proved advantageous for minimizing errors of high-throughput gene expression analyses and showed strong potential for identifying new biomarkers. Here, for the first time, we applied OncoFinder for normal and cancerous tissues of the human bladder to identify biomarkers of bladder cancer.

Interactome analysis of myeloid-derived suppressor cells in murine models of colon and breast cancer.

In solid cancers, myeloid derived suppressor cells (MDSC) infiltrate (peri)tumoral tissues to induce immune tolerance and hence to establish a microenvironment permissive to tumor growth. Importantly, the mechanisms that facilitate such infiltration or a subsequent immune suppression are not fully understood. Hence, in this study, we aimed to delineate disparate molecular pathways which MDSC utilize in murine models of colon or breast cancer.

A role for G-CSF and GM-CSF in nonmyeloid cancers.

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) modulate progression of certain solid tumors. The G-CSF- or GM-CSF-secreting cancers, albeit not very common are, however, among the most rapidly advancing ones due to a cytokine-mediated immune suppression and angiogenesis. Similarly, de novo angiogenesis and vasculogenesis may complicate adjuvant use of recombinant G-CSF or GM-CSF thus possibly contributing to a cancer relapse.

The OncoFinder algorithm for minimizing the errors introduced by the high-throughput methods of transcriptome analysis.

The diversity of the installed sequencing and microarray equipment make it increasingly difficult to compare and analyze the gene expression datasets obtained using the different methods. Many applications requiring high-quality and low error rates cannot make use of available data using traditional analytical approaches. Recently, we proposed a new concept of signalome-wide analysis of functional changes in the intracellular pathways termed OncoFinder, a bioinformatic tool for quantitative estimation of the signaling pathway activation (SPA).

A systematic experimental evaluation of microRNA markers of human bladder cancer.

Background: MicroRNAs (miRNAs) are a class of small RNAs that regulate gene expression. They are aberrantly expressed in many human cancers and are potential therapeutic targets and molecular biomarkers.

Methods: In this study, we for the first time validated the reported data on the entire set of published differential miRNAs (102 in total) through a series of transcriptome-wide experiments.

Human-specific endogenous retroviral insert serves as an enhancer for the schizophrenia-linked gene PRODH.

Using a systematic, whole-genome analysis of enhancer activity of human-specific endogenous retroviral inserts (hsERVs), we identified an element, hsERVPRODH, that acts as a tissue-specific enhancer for the PRODH gene, which is required for proper CNS functioning. PRODH is one of the candidate genes for susceptibility to schizophrenia and other neurological disorders. It codes for a proline dehydrogenase enzyme, which catalyses the first step of proline catabolism and most likely is involved in neuromediator synthesis in the CNS.

Characteristic patterns of microRNA expression in human bladder cancer.

MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression. Their altered expression and functional activity have been observed in many human cancers. miRNAs represent promising diagnostic and prognostic molecular biomarkers, and also serve as novel therapeutic targets.

Non-invasive prenatal diagnostics of aneuploidy using next-generation DNA sequencing technologies, and clinical considerations.

Rapidly developing next-generation sequencing (NGS) technologies produce a large amount of data across the whole human genome and allow a large number of DNA samples to be analyzed simultaneously. Screening cell-free fetal DNA (cffDNA) obtained from maternal blood using NGS technologies has provided new opportunities for non-invasive prenatal diagnosis (NIPD) of fetal aneuploidies. One of the major challenges to the analysis of fetal abnormalities is the development of accurate and reliable algorithms capable of analyzing large numbers of short sequence reads.

Non-Markovian Population Dynamics: Does it Help to Optimize the Chemotherapeutic Strategy?

A non-Markovian theory of population dynamics is to simulate the anti-cancer drug distribution between malignant and the hosting normal cell pools. The model takes into account both the cell life span and the proliferation rate differences. This new simulation approach looks promising for its potential to optimize a chemotherapeutic strategy by choosing the scheme with a higher degree of the drug-tumor selectivity.