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https://www.readbyqxmd.com/read/28720843/clinical-study-of-genomic-drivers-in-pancreatic-ductal-adenocarcinoma
#1
Michael T Barrett, Ray Deiotte, Elizabeth Lenkiewicz, Smriti Malasi, Tara Holley, Lisa Evers, Richard G Posner, Timothy Jones, Haiyong Han, Mark Sausen, Victor E Velculescu, Jeffrey Drebin, Peter O'Dwyer, Gayle Jameson, Ramesh K Ramanathan, Daniel D Von Hoff
BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials. METHODS: Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples...
July 18, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28720700/hitchhiking-and-epistasis-give-rise-to-cohort-dynamics-in-adapting-populations
#2
Sean W Buskirk, Ryan Emily Peace, Gregory I Lang
Beneficial mutations are the driving force of adaptive evolution. In asexual populations, the identification of beneficial alleles is confounded by the presence of genetically linked hitchhiker mutations. Parallel evolution experiments enable the recognition of common targets of selection; yet these targets are inherently enriched for genes of large target size and mutations of large effect. A comprehensive study of individual mutations is necessary to create a realistic picture of the evolutionarily significant spectrum of beneficial mutations...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28720581/hit-ndrive-patient-specific-multi-driver-gene-prioritization-for-precision-oncology
#3
Raunak Shrestha, Ermin Hodzic, Thomas Sauerwald, Phuong Dao, Kendric Wang, Jake Yeung, Shawn Anderson, Fabio Vandin, Gholamreza Haffari, Colin C Collins, Cenk Sahinalp
Prioritizing molecular alterations that act as drivers of cancer remains a crucial bottleneck in therapeutic development. Here we introduce HIT'nDRIVE, a computational method that integrates genomic and transcriptomic data to identify a set of patient-specific, sequence-altered genes, with sufficient collective influence over dysregulated transcripts. HIT'nDRIVE aims to solve the "random walk facility location" (RWFL) problem in a gene (or protein) interaction network, which differs from the standard facility location problem by its use of an alternative distance measure: "multi-hitting time", the expected length of the shortest random walk from any one of the set of sequence-altered genes to an expression-altered target gene...
July 18, 2017: Genome Research
https://www.readbyqxmd.com/read/28719033/identification-of-driver-copy-number-alterations-in-diverse-cancer-types-and-application-in-drug-repositioning
#4
Wenbin Zhou, Zhangxiang Zhao, Ruiping Wang, Yue Han, Chengyu Wang, Fan Yang, Ya Han, Haihai Liang, Lishuang Qi, Chenguang Wang, Zheng Guo, Yunyan Gu
Results from numerous studies suggest an important role for somatic copy number alterations (SCNAs) in cancer progression. Our work aimed to identify the drivers (oncogenes or tumor suppressor genes) that reside in recurrently aberrant genomic regions, including a large number of genes or non-coding genes, which remain a challenge for decoding the SCNAs involved in carcinogenesis. Here, we propose a new approach to comprehensively identify drivers, using 8740 cancer samples involving 18 cancer types from The Cancer Genome Atlas (TCGA)...
July 18, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28718431/racial-differences-in-cancer-susceptibility-and-survival-more-than-the-color-of-the-skin
#5
REVIEW
Berna C Özdemir, Gian-Paolo Dotto
Epidemiological studies point to race as a determining factor in cancer susceptibility. In US registries recording cancer incidence and survival by race (distinguishing 'black versus white'), individuals of African ancestry have a globally increased risk of malignancies compared with Caucasians and Asian Americans. Differences in socioeconomic status and health-care access play a key role. However, the lesser disease susceptibility of Hispanic populations with comparable lifestyles and socioeconomic status as African Americans (Hispanic paradox) points to the concomitant importance of genetic determinants...
March 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28718365/tmem88-ccl14-and-clec3b-as-prognostic-biomarkers-for-prognosis-and-palindromia-of-human-hepatocellular-carcinoma
#6
Xin Zhang, Jin-Xiang Wan, Zun-Ping Ke, Feng Wang, Hai-Xia Chai, Jia-Qiang Liu
Hepatocellular carcinoma is one of the most mortal and prevalent cancers with increasing incidence worldwide. Elucidating genetic driver genes for prognosis and palindromia of hepatocellular carcinoma helps managing clinical decisions for patients. In this study, the high-throughput RNA sequencing data on platform IlluminaHiSeq of hepatocellular carcinoma were downloaded from The Cancer Genome Atlas with 330 primary hepatocellular carcinoma patient samples. Stable key genes with differential expressions were identified with which Kaplan-Meier survival analysis was performed using Cox proportional hazards test in R language...
July 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28715921/the-role-of-secreted-heat-shock-protein-90-hsp90-in-wound-healing-how-could-it-shape-future-therapeutics
#7
Jiacong Guo, Cheng Chang, Wei Li
Defects in tissue repair or wound healing pose a clinical, economic and social problem worldwide. Despite decades of studies, there have been few effective therapeutic treatments. Areas covered: We discuss the possible reasons for why growth factor therapy did not succeed. We point out the lack of human disorder-relevant animal models as another blockade for therapeutic development. We summarize the recent discovery of secreted heat shock protein-90 (Hsp90) as a novel wound healing agent. Expert commentary: Wound healing is a highly complex and multistep process that requires participations of many cell types, extracellular matrices and soluble molecules to work together in a spatial and temporal fashion within the wound microenvironment...
July 18, 2017: Expert Review of Proteomics
https://www.readbyqxmd.com/read/28715416/signatures-of-inflammation-and-impending-multiple-organ-dysfunction-in-the-hyperacute-phase-of-trauma-a-prospective-cohort-study
#8
Claudia P Cabrera, Joanna Manson, Joanna M Shepherd, Hew D Torrance, David Watson, M Paula Longhi, Mimoza Hoti, Minal B Patel, Michael O'Dwyer, Sussan Nourshargh, Daniel J Pennington, Michael R Barnes, Karim Brohi
BACKGROUND: Severe trauma induces a widespread response of the immune system. This "genomic storm" can lead to poor outcomes, including Multiple Organ Dysfunction Syndrome (MODS). MODS carries a high mortality and morbidity rate and adversely affects long-term health outcomes. Contemporary management of MODS is entirely supportive, and no specific therapeutics have been shown to be effective in reducing incidence or severity. The pathogenesis of MODS remains unclear, and several models are proposed, such as excessive inflammation, a second-hit insult, or an imbalance between pro- and anti-inflammatory pathways...
July 2017: PLoS Medicine
https://www.readbyqxmd.com/read/28715138/microbial-functional-diversity-covaries-with-permafrost-thaw-induced-environmental-heterogeneity-in-tundra-soil
#9
Mengting M Yuan, Jin Zhang, Kai Xue, Liyou Wu, Ye Deng, Jie Deng, Lauren Hale, Xishu Zhou, Zhili He, Yunfeng Yang, Joy D Van Nostrand, Edward A G Schuur, Konstantinos T Konstantinidis, C Ryan Penton, James R Cole, James M Tiedje, Yiqi Luo, Jizhong Zhou
Permafrost soil in high latitude tundra is one of the largest terrestrial carbon (C) stocks and is highly sensitive to climate warming. Understanding microbial responses to warming induced environmental changes are critical to evaluating their influences on soil biogeochemical cycles. In this study, a functional gene array (i.e. GeoChip 4.2) was used to analyze the functional capacities of soil microbial communities collected from a naturally degrading permafrost region in Central Alaska. Varied thaw history was reported to be the main driver of soil and plant differences across a gradient of minimally, moderately and extensively thawed sites...
July 17, 2017: Global Change Biology
https://www.readbyqxmd.com/read/28714987/comparison-of-algorithms-for-the-detection-of-cancer-drivers-at-subgene-resolution
#10
Eduard Porta-Pardo, Atanas Kamburov, David Tamborero, Tirso Pons, Daniela Grases, Alfonso Valencia, Nuria Lopez-Bigas, Gad Getz, Adam Godzik
Understanding genetic events that lead to cancer initiation and progression remains one of the biggest challenges in cancer biology. Traditionally, most algorithms for cancer-driver identification look for genes that have more mutations than expected from the average background mutation rate. However, there is now a wide variety of methods that look for nonrandom distribution of mutations within proteins as a signal for the driving role of mutations in cancer. Here we classify and review such subgene-resolution algorithms, compare their findings on four distinct cancer data sets from The Cancer Genome Atlas and discuss how predictions from these algorithms can be interpreted in the emerging paradigms that challenge the simple dichotomy between driver and passenger genes...
July 17, 2017: Nature Methods
https://www.readbyqxmd.com/read/28713819/differential-analysis-of-genetic-epigenetic-and-cytogenetic-abnormalities-in-aml
#11
Mirazul Islam, Zahurin Mohamed, Yassen Assenov
Acute myeloid leukemia (AML) is a haematological malignancy characterized by the excessive proliferation of immature myeloid cells coupled with impaired differentiation. Many AML cases have been reported without any known cytogenetic abnormalities and carry no mutation in known AML-associated driver genes. In this study, 200 AML cases were selected from a publicly available cohort and differentially analyzed for genetic, epigenetic, and cytogenetic abnormalities. Three genes (FLT3, DNMT3A, and NPMc) are found to be predominantly mutated...
2017: International Journal of Genomics
https://www.readbyqxmd.com/read/28713672/bap1-a-tumor-suppressor-gene-driving-malignant-mesothelioma
#12
REVIEW
Mitchell Cheung, Joseph R Testa
Like cancer generally, malignant mesothelioma (MM) is a genetic disease at the cellular level. DNA copy number analysis of mesothelioma specimens has revealed a number of recurrent sites of chromosomal loss, including 3p21.1, 9p21.3, and 22q12.2. The key inactivated driver genes located at 9p21.1 and 22q12.2 were discovered two decades ago as being the tumor suppressor loci CDKN2A and NF2, respectively. Only relatively recently was the BAP1 gene determined to be the driver gene at 3p21.1 that is somatically inactivated...
June 2017: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/28713249/crispr-cas9-mediated-zebrafish-knock-in-as-a-novel-strategy-to-study-midbrain-hindbrain-boundary-development
#13
Gokul Kesavan, Avinash Chekuru, Anja Machate, Michael Brand
The midbrain-hindbrain boundary (MHB) acts as an organizer and controls the fate of neighboring cells to develop into either mesencephalic (midbrain) or metencephalic (hindbrain) cells by secreting signaling molecules like Wnt1 and Fgf8. The zebrafish is an excellent vertebrate model for studying MHB development due to the ease of gene manipulation and the possibility of following cellular dynamics and morphogenetic processes using live imaging. Currently, only very few reporter and/or Cre-driver lines are available to study gene expression at the MHB, hampering the understanding of MHB development, and traditional transgenic technologies using promoter/enhancer fragments or bacterial artificial chromosome (BAC)-mediated transgenesis often do not faithfully recapitulate endogenous expression patterns...
2017: Frontiers in Neuroanatomy
https://www.readbyqxmd.com/read/28713152/metastatic-anaplastic-lymphoma-kinase-1-alk-1-rearranged-inflammatory-myofibroblastic-sarcoma-to-the-brain-with-leptomeningeal-involvement-favorable-response-to-serial-alk-inhibitors-a-case-report
#14
Cai Yuan, Muchou J Ma, John V Parker, Tarek M Mekhail
BACKGROUND ALK gene rearrangements as oncogenic drivers have been described in many cancers, including inflammatory myofibroblastic sarcoma (IMS). The first-generation ALK inhibitor was limited in its ability to cross the blood-brain-barrier to treat brain metastasis. Drug-resistance invariably develops over time in ALK-rearranged tumors, which leads to disease progression. The newer generations of ALK inhibitors are designed to have higher potency in ALK inhibition and improved CNS penetration. CASE REPORT We report a rare case of pulmonary IMS with ALK-1 gene rearrangement and multiple brain metastases as initial presentation...
July 17, 2017: American Journal of Case Reports
https://www.readbyqxmd.com/read/28712565/circadian-clock-involvement-in-zooplankton-diel-vertical-migration
#15
N Sören Häfker, Bettina Meyer, Kim S Last, David W Pond, Lukas Hüppe, Mathias Teschke
Biological clocks are a ubiquitous ancient and adaptive mechanism enabling organisms to anticipate environmental cycles and to regulate behavioral and physiological processes accordingly [1]. Although terrestrial circadian clocks are well understood, knowledge of clocks in marine organisms is still very limited [2-5]. This is particularly true for abundant species displaying large-scale rhythms like diel vertical migration (DVM) that contribute significantly to shaping their respective ecosystems [6]. Here we describe exogenous cycles and endogenous rhythms associated with DVM of the ecologically important and highly abundant planktic copepod Calanus finmarchicus...
July 4, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28711961/heat-shock-protein-70-nitric-oxide-effect-on-stretched-tubular-epithelial-cells-linked-to-wt-1-cytoprotection-during-neonatal-obstructive-nephropathy
#16
Luciana Mazzei, Fernando Darío Cuello-Carrión, Neil Docherty, Walter Manucha
BACKGROUND: Mechanical stress is a key pathogenic driver of apoptosis in the tubular epithelium in obstructive nephropathy. Heat shock protein 70 (Hsp70) and Wilms' tumor (WT-1) have been proposed to represent linked downstream effectors of the cytoprotective properties of NO. In the present study, we sought to evaluate whether the cytoprotective effects of L-arginine in neonatal obstructive nephropathy may be associated with NO-dependent increases in WT-1 and Hsp70 expression. METHODS: Neonatal Wistar-Kyoto rats were submitted to complete unilateral ureteral obstruction (UUO) and treated thereafter with vehicle, L-NAME or L-arginine by daily gavage for 14 days to block or augment NO levels, respectively...
July 15, 2017: International Urology and Nephrology
https://www.readbyqxmd.com/read/28710389/continuation-of-the-genetic-divergence-of-ecological-speciation-by-spatial-environmental-heterogeneity-in-island-endemic-plants
#17
Bing-Hong Huang, Chih-Wei Huang, Chia-Lung Huang, Pei-Chun Liao
Divergent selection plays a critical role not only as a speciation driver but also in maintaining post-speciation divergence. In the absence of direct evidence, ancestral interspecific gene flow between incipient species can reflect ancient selective pressure for ecological speciation. In the present study, two late-Pleistocene diverged species endemic to Taiwan, Scutellaria playfairii and S. tashiroi, were spatially and ecologically partitioned with partial overlap. Multilocus genome-scan analyses and in silico evaluation revealed ancestral interspecific gene flow but distinct genetic compositions, implying that adaptive divergence contributed to their speciation...
July 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28710314/sarcomatoid-renal-cell-carcinoma-has-a-distinct-molecular-pathogenesis-driver-mutation-profile-and-transcriptional-landscape
#18
Zixing Wang, Tae Beom Kim, Bo Peng, Jose A Karam, Chad J Creighton, Aron Y Joon, Fumi Kawakami, Patricia Trevisan, Eric Jonasch, Chi-Wan Chow, Jaime Rodriguez-Canales, Pheroze Tamboli, Nizar M Tannir, Christopher G Wood, Federico A Monzon, Keith A Baggerly, Marileila Varella-Garcia, Bogdan Czerniak, Ignacio I Wistuba, Gordon B Mills, Kenna Shaw, Ken Chen, Kanishka Sircar
Sarcomatoid renal cell carcinoma (SRCC) ranks among the most aggressive clinicopathologic phenotypes of RCC. However, the paucity of high-quality, genome-wide molecular examinations of SRCC has hindered our understanding of this entity.<br /><br />Experimental Design: We interrogated the mutational, copy number, and transcriptional characteristics of SRCC and compared these data with those of non-sarcomatoid RCC (RCC). We evaluated whole exome sequencing, single nucleotide polymorphism, and RNA sequencing data from patients with SRCC (n=65) and RCC (n=598) across different parent RCC subtypes, including clear cell RCC, papillary RCC, and chromophobe RCC subtypes...
July 14, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28710117/genetic-and-epigenetic-drivers-of-neuroendocrine-tumors-net
#19
Annunziata Di Domenico, Tabea Wiedmer, Ilaria Marinoni, Aurel Perren
Neuroendocrine tumors (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumors. The molecular characterization and the clinical classification of these tumors have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging...
July 14, 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/28710116/expression-and-mutational-status-of-usp8-in-tumors-causing-ectopic-acth-secretion-syndrome
#20
Luis Gustavo Pérez-Rivas, Andrea Oßwald, Thomas Knösel, Kristin Lucia, Christian Schaaf, Michael Hristov, Julia Fazel, Thomas Kirchner, Felix Beuschlein, Martin Reincke, Marily Theodoropoulou
The ectopic ACTH secretion syndrome (EAS) is the clinical consequence of the paraneoplastic secretion of ACTH by non-pituitary tumors. The mechanisms responsible for the pathogenesis of these tumors are still unknown. Recently, we and others detected hotspot heterozygous driver mutations in the gene coding for the ubiquitin-specific protease 8 (USP8) in almost half of ACTH-secreting pituitary corticotroph tumors causing Cushing's disease. Mutant USP8 was also found to stimulate proopiomelanocortin (POMC) transcription and ACTH synthesis...
July 14, 2017: Endocrine-related Cancer
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