scholarly journals A pan‐cancer analysis reveals genetic alterations, molecular mechanisms, and clinical relevance of m 5 C regulators

2020 ◽  
Vol 10 (5) ◽  
Author(s):  
E Du ◽  
Jingxian Li ◽  
Fei Sheng ◽  
Shuai Li ◽  
Jianqiang Zhu ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Molecular Mechanisms ◽  
Genetic Alterations ◽  
Pan Cancer

scholarly journals Molecular Mechanisms of PD-1 and PD-L1 Activity on a Pan-Cancer Basis: A Bioinformatic Exploratory Study

2021 ◽  
Vol 22 (11) ◽  
pp. 5478
Author(s):  
Siddarth Kannan ◽  
Geraldine Martina O’Connor ◽  
Emyr Yosef Bakker
Keyword(s):  
Clinical Relevance ◽  
Molecular Mechanisms ◽  
Patient Survival ◽  
Drug Repurposing ◽  
Immune Checkpoint Blockade ◽  
Multiple Cancers ◽  
Significant Survival ◽  
Cancer Types ◽  
Repurposed Drugs ◽  
Pan Cancer

Immune checkpoint blockade targeting PD-1 (PDCD1)/PD-L1 (CD274) is increasingly used for multiple cancers. However, efficacy and adverse-related events vary significantly. This bioinformatic study interrogated molecular differences pertaining to PDCD1/CD274 and their correlated genes on a pan-cancer basis to identify differences between cancer types. Patient RNA-seq data from fifteen cancer types were accessed on cBioPortal to determine the role of PDCD1/CD274 in patient survival and to identify positively and negatively correlated genes, which were also assessed for clinical relevance. Genes correlating with PDCD1/CD274 across multiple cancers were taken forward for drug repurposing via DRUGSURV and microRNA analysis using miRDB and miRabel. MicroRNAs were also screened for clinical relevance using OncomiR. Forty genes were consistently correlated with PDCD1/CD274 across multiple cancers, with the cancers themselves exhibiting a differential role for the correlated genes in terms of patient survival. Esophageal and renal cancers in particular stood out in this regard as having a unique survival profile. Forty-nine putative microRNAs were identified as being linked to the PDCD1/CD274 network, which were taken forward and further assessed for clinical relevance using OncomiR and previously published literature. One hundred and thirty significant survival associations for 46 microRNAs across fourteen groups of cancers were identified. Finally, a total of 23 putative repurposed drugs targeting multiple components of the PDCD1/CD274 network were identified, which may represent immunotherapeutic adjuvants. Taken together, these results shed light on the varying PDCD1/CD274 networks between individual cancers and signpost a need for more cancer-specific investigations and treatments.

scholarly journals Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy

2020 ◽  
Vol 31 (4) ◽  
pp. 799-816 ◽  
Author(s):  
Barbara Mara Klinkhammer ◽  
Sonja Djudjaj ◽  
Uta Kunter ◽  
Runolfur Palsson ◽  
Vidar Orn Edvardsson ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Molecular Mechanisms ◽  
Granulomatous Inflammation ◽  
Kidney Injury ◽  
Rare Condition ◽  
Therapeutic Interventions ◽  
Renal Tubules ◽  
Rodent Models ◽  
Adenine Phosphoribosyltransferase ◽  
Reparative Process

BackgroundHereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown.MethodsUsing animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies.ResultsAdenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy.ConclusionsRodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.

scholarly journals Tumor cell total mRNA expression shapes the molecular and clinical phenotype of cancer

2021 ◽  
Author(s):  
Shaolong Cao ◽  
Jennifer Wang ◽  
Shuangxi Ji ◽  
Peng Yang ◽  
Matthew Montierth ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Mrna Expression ◽  
Genetic Alterations ◽  
Individual Variability ◽  
Cancer Type ◽  
Sequencing Data ◽  
Increased Risk ◽  
Mrna Content ◽  
Risk Of Disease ◽  
Pan Cancer

Abstract Cancers can vary greatly in their transcriptomes. In contrast to alterations in specific genes or pathways, differences in tumor cell total mRNA content have not been comprehensively assessed. Technical and analytical challenges have impeded examination of total mRNA expression at scale across cancers. To address this, we developed a model for quantifying tumor-specific total mRNA expression (TmS) from bulk sequencing data, which performs transcriptomic deconvolution while adjusting for mixed genomes. We used single-cell RNA sequencing data to demonstrate total mRNA expression as a feature of tumor phenotype. We estimated and validated TmS in 5,015 patients across 15 cancer types identifying significant inter-individual variability. At a pan-cancer level, high TmS is associated with increased risk of disease progression and death. Cancer type-specific patterns of genetic alterations, intra-tumor genetic heterogeneity, as well as pan-cancer trends in metabolic dysregulation and hypoxia contribute to TmS. Taken together, our results suggest that measuring cell-type specific total mRNA expression offers a broader perspective of tracking cancer transcriptomes, which has important biological and clinical implications.

scholarly journals Widespread alteration of protein autoinhibition in human cancers

2018 ◽  
Author(s):  
Ashwani Jha ◽  
Jennifer M. Bui ◽  
Dokyun Na ◽  
Jörg Gsponer
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Signal Propagation ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Pathway Activation ◽  
Tumorigenic Potential ◽  
Significant Enrichment ◽  
Cancer Types ◽  
Cancer Drivers

ABSTRACTAutoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins as it prevents spurious pathway activation and primes for signal propagation only under appropriate inputs. Altered functioning of inhibitory allosteric switches underlies the tumorigenic potential of numerous cancer drivers. However, whether protein autoinhibition is altered generically in cancer cells remains elusive. Here, we reveal that cancer-associated missense mutations and fusion breakpoints are found with significant enrichment within inhibitory allosteric switches across all cancer types, which in the case of the fusion breakpoints is specific to cancer and not present in other diseases. Recurrently disrupted or mutated allosteric switches identify established and new cancer drivers. Cancer-specific mutations in allosteric switches are associated with distinct changes in signaling, and suggest molecular mechanisms for altered protein regulation, which in the case of ASK1, DAPK2 and EIF4G1 were supported by biophysical simulations. Our results demonstrate that autoinhibition-modulating genetic alterations are positively selected for by cancer cells, and that their study provides valuable insights into molecular mechanisms of cancer misregulation.

scholarly journals LncTarD: a manually-curated database of experimentally-supported functional lncRNA–target regulations in human diseases

2019 ◽  
Author(s):  
Hongying Zhao ◽  
Jian Shi ◽  
Yunpeng Zhang ◽  
Aimin Xie ◽  
Lei Yu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Sequence Data ◽  
Human Diseases ◽  
Regulatory Mechanisms ◽  
Biological Functions ◽  
Functional Dynamics ◽  
Disease Associations ◽  
Non Coding Rnas ◽  
User Friendly ◽  
Pan Cancer

Abstract Long non-coding RNAs (lncRNAs) are associated with human diseases. Although lncRNA–disease associations have received significant attention, no online repository is available to collect lncRNA-mediated regulatory mechanisms, key downstream targets, and important biological functions driven by disease-related lncRNAs in human diseases. We thus developed LncTarD (http://biocc.hrbmu.edu.cn/LncTarD/ or http://bio-bigdata.hrbmu.edu.cn/LncTarD), a manually-curated database that provides a comprehensive resource of key lncRNA–target regulations, lncRNA-influenced functions, and lncRNA-mediated regulatory mechanisms in human diseases. LncTarD offers (i) 2822 key lncRNA–target regulations involving 475 lncRNAs and 1039 targets associated with 177 human diseases; (ii) 1613 experimentally-supported functional regulations and 1209 expression associations in human diseases; (iii) important biological functions driven by disease-related lncRNAs in human diseases; (iv) lncRNA–target regulations responsible for drug resistance or sensitivity in human diseases and (v) lncRNA microarray, lncRNA sequence data and transcriptome data of an 11 373 pan-cancer patient cohort from TCGA to help characterize the functional dynamics of these lncRNA–target regulations. LncTarD also provides a user-friendly interface to conveniently browse, search, and download data. LncTarD will be a useful resource platform for the further understanding of functions and molecular mechanisms of lncRNA deregulation in human disease, which will help to identify novel and sensitive biomarkers and therapeutic targets.

scholarly journals Exploiting evolutionary trade-offs for posttreatment management of drug-resistant populations

2020 ◽  
Vol 117 (30) ◽  
pp. 17924-17931
Author(s):  
Sergey V. Melnikov ◽  
David L. Stevens ◽  
Xian Fu ◽  
Hui Si Kwok ◽  
Jin-Tao Zhang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Genetic Alterations ◽  
Trna Synthetase ◽  
Molecular Defect ◽  
Antibiotic Resistant ◽  
Resistance Evolution ◽  
Growth Defects ◽  
Trade Offs ◽  
Resistant Cells

Antibiotic resistance frequently evolves through fitness trade-offs in which the genetic alterations that confer resistance to a drug can also cause growth defects in resistant cells. Here, through experimental evolution in a microfluidics-based turbidostat, we demonstrate that antibiotic-resistant cells can be efficiently inhibited by amplifying the fitness costs associated with drug-resistance evolution. Using tavaborole-resistantEscherichia colias a model, we show that genetic mutations in leucyl-tRNA synthetase (that underlie tavaborole resistance) make resistant cells intolerant to norvaline, a chemical analog of leucine that is mistakenly used by tavaborole-resistant cells for protein synthesis. We then show that tavaborole-sensitive cells quickly outcompete tavaborole-resistant cells in the presence of norvaline due to the amplified cost of the molecular defect of tavaborole resistance. This finding illustrates that understanding molecular mechanisms of drug resistance allows us to effectively amplify even small evolutionary vulnerabilities of resistant cells to potentially enhance or enable adaptive therapies by accelerating posttreatment competition between resistant and susceptible cells.

scholarly journals Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 114
Author(s):  
Lisa Linck-Paulus ◽  
Claus Hellerbrand ◽  
Anja K. Bosserhoff ◽  
Peter Dietrich
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
The Future ◽  
Associated Proteins ◽  
Cancer Types ◽  
Novel Therapeutic Strategies

In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs—melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these—at first sight—dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.

scholarly journals Multiple Molecular Mechanisms Contribute to a Stepwise Development of Fluconazole Resistance in Clinical Candida albicans Strains

1998 ◽  
Vol 42 (12) ◽  
pp. 3065-3072 ◽  
Author(s):  
Renate Franz ◽  
Steven L. Kelly ◽  
David C. Lamb ◽  
Diane E. Kelly ◽  
Markus Ruhnke ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Candida Albicans ◽  
Molecular Mechanisms ◽  
Multiple Drug Resistance ◽  
Genetic Alterations ◽  
Mutant Form ◽  
Mrna Levels ◽  
Fluconazole Resistance ◽  
Stepwise Development ◽  
Target Enzyme

ABSTRACT From each of two AIDS patients with oropharyngeal candidiasis, fiveCandida albicans isolates from recurrent episodes of infection which became gradually resistant against fluconazole during antimycotic treatment were analyzed for molecular changes responsible for drug resistance. In both patients, a single C. albicans strain was responsible for the recurrent infections, but the CARE-2 fingerprint pattern of the isolates exhibited minor genetic alterations, indicating that microevolution of the strains took place during fluconazole therapy. In the isolates from patient 1, enhanced mRNA levels of theMDR1 gene, encoding a multiple drug resistance protein from the superfamily of major facilitators, and constitutive high expression of the ERG11 gene, coding for the drug target enzyme sterol 14α-demethylase, correlated with a stepwise development of fluconazole resistance. The resistant strains exhibited reduced accumulation of fluconazole and, for the last in the series, a slight increase in drug needed to inhibit sterol 14α-demethylation in vitro. In the isolates from patient 2, increasedMDR1 mRNA levels and the change from heterozygosity to homozygosity for a mutant form of the ERG11 gene correlated with continuously decreased drug susceptibility. In this series, reduced drug accumulation and increased resistance in the target enzyme activity, sterol 14α-demethylase, were observed. These results demonstrate that different molecular mechanisms contribute to a gradual development of fluconazole resistance in C. albicans.

scholarly journals Primary and Secondary Metabolic Effects of a Key Gene Deletion (ΔYPL062W) in Metabolically Engineered Terpenoid-ProducingSaccharomyces cerevisiae

2019 ◽  
Vol 85 (7) ◽  
Author(s):  
Yan Chen ◽  
Ying Wang ◽  
Ming Liu ◽  
Junze Qu ◽  
Mingdong Yao ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Gene Deletion ◽  
Core Promoter ◽  
Strain Improvement ◽  
Genetic Alterations ◽  
Metabolic Effects ◽  
Industrial Biotechnology ◽  
Cell Factory ◽  
Content Type ◽  
Genetic Function

ABSTRACTSaccharomyces cerevisiaeis an established cell factory for production of terpenoid pharmaceuticals and chemicals. Numerous studies have demonstrated that deletion or overexpression of off-pathway genes in yeast can improve terpenoid production. The deletion ofYPL062WinS. cerevisiae, in particular, has benefitted carotenoid production by channeling carbon toward carotenoid precursors acetyl coenzyme A (acetyl-CoA) and mevalonate. The genetic function ofYPL062Wand the molecular mechanisms for these benefits are unknown. In this study, we systematically examined this gene deletion to uncover the gene function and its molecular mechanism. RNA sequencing (RNA-seq) analysis uncovered thatYPL062Wdeletion upregulated the pyruvate dehydrogenase bypass, the mevalonate pathway, heterologous expression of galactose (GAL) promoter-regulated genes, energy metabolism, and membrane composition synthesis. Bioinformatics analysis and serial promoter deletion assay revealed thatYPL062Wfunctions as a core promoter forALD6and that the expression level ofALD6is negatively correlated to terpenoid productivity. We demonstrate that ΔYPL062Wincreases the production of all major terpenoid classes (C10, C15, C20, C30, and C40). Our study not only elucidated the biological function ofYPL062Wbut also provided a detailed methodology for understanding the mechanistic aspects of strain improvement.IMPORTANCEAlthough computational and reverse metabolic engineering approaches often lead to improved gene deletion mutants for cell factory engineering, the systems level effects of such gene deletions on the production phenotypes have not been extensively studied. Understanding the genetic and molecular function of such gene alterations on production strains will minimize the risk inherent in the development of large-scale fermentation processes, which is a daunting challenge in the field of industrial biotechnology. Therefore, we established a detailed experimental and systems biology approach to uncover the molecular mechanisms ofYPL062Wdeletion inS. cerevisiae, which is shown to improve the production of all terpenoid classes. This study redefines the genetic function ofYPL062W, demonstrates a strong correlation betweenYPL062Wand terpenoid production, and provides a useful modification for the creation of terpenoid production platform strains. Further, this study underscores the benefits of detailed and systematic characterization of the metabolic effects of genetic alterations on engineered biosynthetic factories.

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