Tumor gene expression is predictive of patient prognosis in some cancers. However, RNA-seq and whole genome sequencing data contain not only reads from host tumor and normal tissue, but also reads ...from the tumor microbiome, which can be used to infer the microbial abundances in each tumor. Here, we show that tumor microbial abundances, alone or in combination with tumor gene expression, can predict cancer prognosis and drug response to some extent-microbial abundances are significantly less predictive of prognosis than gene expression, although similarly as predictive of drug response, but in mostly different cancer-drug combinations. Thus, it appears possible to leverage existing sequencing technology, or develop new protocols, to obtain more non-redundant information about prognosis and drug response from RNA-seq and whole genome sequencing experiments than could be obtained from tumor gene expression or genomic data alone.
The phenotype of human STK4 deficiency Abdollahpour, Hengameh; Appaswamy, Giridharan; Kotlarz, Daniel ...
Blood,
04/2012, Letnik:
119, Številka:
15
Journal Article
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We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred. Their clinical histories ...included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses. Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apoptosis. STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis. STK4 deficiency is a novel human primary immunodeficiency syndrome.
Decreased gut microbiome diversity has been associated with negative outcome in allogeneic hematopoietic stem cell transfer (HCT). A study published in this issue of Cell identifies associations ...between non-antibiotic drug administration, microbiome state transitions, and response to HCT, highlighting the potential impact of such drugs on microbiome and HCT outcome.
Decreased gut microbiome diversity has been associated with negative outcome in allogeneic hematopoietic stem cell transfer (HCT). A study published in this issue of Cell identifies associations between non-antibiotic drug administration, microbiome state transitions, and response to HCT, highlighting the potential impact of such drugs on microbiome and HCT outcome.
Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and ...autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
Genetic analyses showed that mutations affecting the interleukin-10 receptor are associated with early-onset colitis. Further molecular analyses showed that the mutations abrogated interleukin-10 ...signaling. Treatment of one of the affected children by means of allogeneic hematopoietic stem-cell transplantation was successful.
Genetic analyses showed that mutations affecting the interleukin-10 receptor are associated with early-onset colitis. Treatment of an affected child by means of allogeneic hematopoietic stem-cell transplantation was successful.
Inflammatory bowel disease is a heterogeneous group of disorders, classified as Crohn's disease, ulcerative colitis, and indeterminate colitis.
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In most patients, these disorders are manifested in adolescence or adulthood; however, they may present in infancy and may be inherited as an autosomal recessive trait.
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The genetic causes of inflammatory bowel disease are only partly understood. Studies in transgenic murine models
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and genomewide genetic-linkage and association studies have provided insights into the genetic complexity underlying these inflammatory conditions.
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Investigators using these approaches have implicated several genes in the pathogenesis of inflammatory bowel disease; the identity of these genes suggests . . .
Intestinal first-pass metabolism may contribute to low oral drug bioavailability and drug-drug interactions, particularly for CYP3A substrates. The current analysis predicted intestinal availability ...(F(G)) from in vitro metabolic clearance and permeability data of 25 drugs using the Q(Gut) model. The drug selection included a wide range of physicochemical properties and in vivo F(G) values (0.07-0.94). In vitro clearance data (CLu(int)) were determined in human intestinal (HIM) and three liver (HLM) microsomal pools (n = 105 donors) using the substrate depletion method. Apparent drug permeability (P(app)) was determined in Caco-2 and Madin-Darby canine kidney cells transfected with human MDR1 gene (MDCK-MDR1 cells) under isotonic conditions (pH = 7.4). In addition, effective permeability (P(eff)) data, estimated from regression analyses to P(app) or physicochemical properties were used in the F(G) predictions. Determined CLu(int) values ranged from 0.022 to 76.7 microl/min/pmol of CYP3A (zolpidem and nisoldipine, respectively). Differences in CLu(int) values obtained in HIM and HLM were not significant after normalization for tissue-specific CYP3A abundance, supporting their interchangeable usability. The F(G) predictions were most successful when P(app) data from Caco-2/MDCK-MDR1 cells were used directly; in contrast, the use of physicochemical parameters resulted in significant F(G) underpredictions. Good agreement between predicted and in vivo F(G) was noted for drugs with low to medium intestinal extraction (e.g., midazolam predicted F(G) value 0.54 and in vivo value 0.51). In contrast, low prediction accuracy was observed for drugs with in vivo F(G) <0.5, resulting in considerable underprediction in some instances, as for saquinavir (predicted F(G) is 6% of the observed value). Implications of the findings are discussed.
Primary immunodeficiencies (PIDs) represent exquisite models for studying mechanisms of human host defense. In this study, we report on two unrelated kindreds, with two patients each, who had ...cryptosporidial infections associated with chronic cholangitis and liver disease. Using exome and candidate gene sequencing, we identified two distinct homozygous loss-of-function mutations in the interleukin-21 receptor gene (IL21R; c.G602T, p.Arg201Leu and c.240_245delCTGCCA, p.C81_H82del). The IL-21R(Arg201Leu) mutation causes aberrant trafficking of the IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5. We observed impaired IL-21-induced proliferation and immunoglobulin class-switching in B cells, cytokine production in T cells, and NK cell cytotoxicity. Our study indicates that human IL-21R deficiency causes an immunodeficiency and highlights the need for early diagnosis and allogeneic hematopoietic stem cell transplantation in affected children.
TBLASTN is a mode of operation for BLAST that aligns protein sequences to a nucleotide database translated in all six frames. We present the first description of the modern implementation of TBLASTN, ...focusing on new techniques that were used to implement composition-based statistics for translated nucleotide searches. Composition-based statistics use the composition of the sequences being aligned to generate more accurate E-values, which allows for a more accurate distinction between true and false matches. Until recently, composition-based statistics were available only for protein-protein searches. They are now available as a command line option for recent versions of TBLASTN and as an option for TBLASTN on the NCBI BLAST web server.
We evaluate the statistical and retrieval accuracy of the E-values reported by a baseline version of TBLASTN and by two variants that use different types of composition-based statistics. To test the statistical accuracy of TBLASTN, we ran 1000 searches using scrambled proteins from the mouse genome and a database of human chromosomes. To test retrieval accuracy, we modernize and adapt to translated searches a test set previously used to evaluate the retrieval accuracy of protein-protein searches. We show that composition-based statistics greatly improve the statistical accuracy of TBLASTN, at a small cost to the retrieval accuracy.
TBLASTN is widely used, as it is common to wish to compare proteins to chromosomes or to libraries of mRNAs. Composition-based statistics improve the statistical accuracy, and therefore the reliability, of TBLASTN results. The algorithms used by TBLASTN are not widely known, and some of the most important are reported here. The data used to test TBLASTN are available for download and may be useful in other studies of translated search algorithms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Almost all protein database search methods use amino acid substitution matrices for scoring, optimizing, and assessing the statistical significance of sequence alignments. Much care and effort has ...therefore gone into constructing substitution matrices, and the quality of search results can depend strongly upon the choice of the proper matrix. A long‐standing problem has been the comparison of sequences with biased amino acid compositions, for which standard substitution matrices are not optimal. To address this problem, we have recently developed a general procedure for transforming a standard matrix into one appropriate for the comparison of two sequences with arbitrary, and possibly differing compositions. Such adjusted matrices yield, on average, improved alignments and alignment scores when applied to the comparison of proteins with markedly biased compositions.
Here we review the application of compositionally adjusted matrices and consider whether they may also be applied fruitfully to general purpose protein sequence database searches, in which related sequence pairs do not necessarily have strong compositional biases. Although it is not advisable to apply compositional adjustment indiscriminately, we describe several simple criteria under which invoking such adjustment is on average beneficial. In a typical database search, at least one of these criteria is satisfied by over half the related sequence pairs. Compositional substitution matrix adjustment is now available in NCBI's protein–protein version of blast.
Abstract
Motivation
Computational reconstruction of clonal evolution in cancers has become a crucial tool for understanding how tumors initiate and progress and how this process varies across ...patients. The field still struggles, however, with special challenges of applying phylogenetic methods to cancers, such as the prevalence and importance of copy number alteration (CNA) and structural variation events in tumor evolution, which are difficult to profile accurately by prevailing sequencing methods in such a way that subsequent reconstruction by phylogenetic inference algorithms is accurate.
Results
In this work, we develop computational methods to combine sequencing with multiplex interphase fluorescence in situ hybridization to exploit the complementary advantages of each technology in inferring accurate models of clonal CNA evolution accounting for both focal changes and aneuploidy at whole-genome scales. By integrating such information in an integer linear programming framework, we demonstrate on simulated data that incorporation of FISH data substantially improves accurate inference of focal CNA and ploidy changes in clonal evolution from deconvolving bulk sequence data. Analysis of real glioblastoma data for which FISH, bulk sequence and single cell sequence are all available confirms the power of FISH to enhance accurate reconstruction of clonal copy number evolution in conjunction with bulk and optionally single-cell sequence data.
Availability and implementation
Source code is available on Github at https://github.com/CMUSchwartzLab/FISH_deconvolution.
Supplementary information
Supplementary data are available at Bioinformatics online.
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