In vitro activity of seven hospital biocides against Mycobacterium abscessus: Implications for patients with cystic fibrosis.

Int J Mycobacteriol. 2018 Jan-Mar;7(1):45-47

Authors: Caskey S, Moore JE, Rendall JC

Abstract
Background: Mycobacterium abscessus pulmonary infection has recently emerged as a significant pathogen in patients with cystic fibrosis (CF) and is associated with significant morbidity and accelerated pulmonary decline. There is a paucity of data describing the activity of hospital biocides against this organism.
Methods: M. abscessus isolates (n = 13) were recovered from CF and non-CF respiratory specimens. Seven commonly employed hospital biocides with generic ingredients as follows: acetone, propan-2-ol, diethylene glycol, 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one, chlorine dioxide, 4% chlorhexidine, alcohol, and disodium carbonate, compound with hydrogen peroxide, 10% sodium hypochlorite were assayed for their biocidal activity against M. abscessus. Fresh cultures of M. abscessus were exposed to biocide in liquid medium as per manufacturers' instruction and were immediately plated following the completion of the contact period. The mean concentration of M. abscessus plated was 9.82 × 106 colony-forming units (range: 1.63 × 105-1.12 × 108). In addition, the remaining bacteria/biocide solution was enriched nonselectively in Mueller Hinton broth (37°C/1 week) and then plated.
Results: All M. abscessus isolates survived in alkyl dimethyl benzyl ammonium chloride, 5-chloro-2-methyl-2H-isothiazol-3-one (EC No. 247-500-7) and 2-methyl-2H-isothiazol-3-one, 4% Chlorhexidine™, O-phenylphenol and Sodium Lauryl Sulfate™ and disodium carbonate, compound with hydrogen peroxide. One out of 13 M. abscessus cultures was killed by Chlorine Dioxide™ and one by Sodium Dichloroisocyanurate™, representing a 5-log kill. Two isolates were killed by Alcohol™ again representing a 5 log kill. Following enrichment, O-phenylphenol and Sodium Lauryl Sulfate™ showed the greatest biocidal activity with 11/13 isolates, whereas 2/13 cultures were killed by sodium dichloroisocyanurate™. All other biocide/culture combinations yielded growth.
Conclusion: These data indicate that M. abscessus may persist after exposure to several common hospital biocides. Further work is urgently needed to define unequivocal biocide contact treatments to prevent cross-infection with this mycobacterial species in this patient population and thus ensure effective infection control and prevention.

PMID: 29516885 [PubMed - in process]

Exploring the need for Transition Readiness Scales within Cystic Fibrosis Services: A Qualitative Descriptive Study.

J Clin Nurs. 2018 Mar 08;:

Authors: Bourke M, Houghton C

Abstract
AIMS AND OBJECTIVES: The aim of this study was to explore health care professionals' (HCP) and patients' perceptions of the potential use of a Transition Readiness Scale (TRS) in cystic fibrosis care. This included an examination of barriers and facilitators to its implementation along with the identification of key items to include in a TRS.
BACKGROUND: Due to increasing life expectancy and improved quality of life, more adolescents with cystic fibrosis are transitioning from paediatric to adult health care. In order to assess and correctly manage this transition a more structured approach to transition is advocated. This can be achieved using a Transition Readiness Scale (TRS) to potentially identify or target areas of care in which the adolescent may have poor knowledge. These key items include education, developmental readiness taking in to account relationships, reproduction, future plans and self-management skills. Existing tools to gauge readiness concentrate mainly on education and self-care needs assessment as their key items. Currently there is no specific CF TRS in use in Ireland or internationally.
DESIGN: The study used a descriptive qualitative design.
METHODS: Data were collected using semi-structured interviews (n=8) and analysed using a thematic approach.
RESULTS: The findings identified the potential benefits of this tool and secondly the resources which need to be in place before its development and implementation in to cystic fibrosis services.
CONCLUSION: Transition Readiness Scales have substantial relevance with cystic fibrosis services emphasising the importance of establishing the necessary resources prior to its implementation. These were identified as more staff, a dedicated private space, and staff training and education.
RELEVANCE TO CLINICAL PRACTICE: Significant resources are needed to fully integrate transition readiness scales in practice. The study findings suggest multidisciplinary collaborations and patient engagement are pivotal in planning and easing the transition process for adolescents with cystic fibrosis. This article is protected by copyright. All rights reserved.

PMID: 29516552 [PubMed - as supplied by publisher]

Assembly 3: Basic and Translational Sciences.

Breathe (Sheff). 2018 Mar;14(1):67-68

Authors: Greene CM, Hiemstra PS

Abstract
Meet @ERStalk Assembly 3: Basic and Translational Sciences http://ow.ly/66E830hFi7U.

PMID: 29515672 [PubMed]

Cystic Fibrosis-Related Diabetes.

Front Endocrinol (Lausanne). 2018;9:20

Authors: Kayani K, Mohammed R, Mohiaddin H

Abstract
Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasian populations. Individuals with CF have seen significant increases in life expectancy in the last 60 years. As a result, previously rare complications are now coming to light. The most common of these is cystic fibrosis-related diabetes (CFRD), which affects 40-50% of CF adults. CFRD significantly impacts the pulmonary function and longevity of CF patients, yet a lack of consensus on the best methods to diagnose and treat CFRD remains. We begin by reviewing our understanding of the pathogenesis of CFRD, as emerging evidence shows the cystic fibrosis transmembrane conductance regulator (CFTR) also has important roles in the release of insulin and glucagon and in the protection of β cells from oxidative stress. We then discuss how current recommended methods of CFRD diagnosis are not appropriate, as continuous glucose monitoring becomes more effective, practical, and cost-effective. Finally, we evaluate emerging treatments which have narrowed the mortality gap within the CF patient group. In the future, pharmacological potentiators and correctors directly targeting CFTR show huge promise for both CFRD and the wider CF patient groups.

PMID: 29515516 [PubMed]

Defective mitochondrial protease LonP1 can cause classical mitochondrial disease.

Hum Mol Genet. 2018 Mar 06;:

Authors: Peter B, Waddington CL, Oláhová M, Sommerville EW, Hopton S, Pyle A, Champion M, Ohlson M, Siibak T, Chrzanowska-Lightowlers ZMA, Taylor RW, Falkenberg M, Lightowlers RN

Abstract
LonP1 is a mitochondrial matrix protease whose selective substrate specificity is essential for maintaining mitochondrial homeostasis. Recessively-inherited, pathogenic defects in LonP1 have been previously reported to underlie cerebral, ocular, dental, auricular and skeletal anomalies (CODAS) syndrome, a complex multisystemic and developmental disorder. Intriguingly, although classical mitochondrial disease presentations are well-known to exhibit marked clinical heterogeneity, the skeletal and dental features associated with CODAS syndrome are pathognomonic. We have applied whole exome sequencing to a patient with congenital lactic acidosis, muscle weakness, profound deficiencies in mitochondrial oxidative phosphorylation associated with loss of mtDNA copy number and MRI abnormalities consistent with Leigh syndrome, identifying biallelic variants in the LONP1 (NM_004793.3) gene; c.1693T>C predicting p.(Tyr565His) and c.2197G>A predicting p.(Glu733Lys); no evidence of the classical skeletal or dental defects observed in CODAS syndrome patients were noted in our patient. In vitro experiments confirmed the p.(Tyr565His) LonP1 mutant alone could not bind or degrade a substrate, consistent with the predicted function of Tyr565, whilst a second missense (p.(Glu733Lys)) variant had minimal effect. Mixtures of p.(Tyr565His) mutant and wild type LonP1 retained partial protease activity but this was severely depleted when the p.(Tyr565His) mutant was mixed with the p.(Glu733Lys) mutant, data consistent with the compound heterozygosity detected in our patient. In summary, we conclude that pathogenic LONP1 variants can lead to a classical mitochondrial disease presentations associated with severe biochemical defects in oxidative phosphorylation in clinically-relevant tissues.

PMID: 29518248 [PubMed - as supplied by publisher]

Mitochondrial oxodicarboxylate carrier deficiency is associated with mitochondrial DNA depletion and spinal muscular atrophy-like disease.

Genet Med. 2018 Mar 08;:

Authors: Boczonadi V, King MS, Smith AC, Olahova M, Bansagi B, Roos A, Eyassu F, Borchers C, Ramesh V, Lochmüller H, Polvikoski T, Whittaker RG, Pyle A, Griffin H, Taylor RW, Chinnery PF, Robinson AJ, Kunji ERS, Horvath R

Abstract
PurposeTo understand the role of the mitochondrial oxodicarboxylate carrier (SLC25A21) in the development of spinal muscular atrophy-like disease.MethodsWe identified a novel pathogenic variant in a patient by whole-exome sequencing. The pathogenicity of the mutation was studied by transport assays, computer modeling, followed by targeted metabolic testing and in vitro studies in human fibroblasts and neurons.ResultsThe patient carries a homozygous pathogenic variant c.695A>G; p.(Lys232Arg) in the SLC25A21 gene, encoding the mitochondrial oxodicarboxylate carrier, and developed spinal muscular atrophy and mitochondrial myopathy. Transport assays show that the mutation renders SLC25A21 dysfunctional and 2-oxoadipate cannot be imported into the mitochondrial matrix. Computer models of central metabolism predicted that impaired transport of oxodicarboxylate disrupts the pathways of lysine and tryptophan degradation, and causes accumulation of 2-oxoadipate, pipecolic acid, and quinolinic acid, which was confirmed in the patient's urine by targeted metabolomics. Exposure to 2-oxoadipate and quinolinic acid decreased the level of mitochondrial complexes in neuronal cells (SH-SY5Y) and induced apoptosis.ConclusionMitochondrial oxodicarboxylate carrier deficiency leads to mitochondrial dysfunction and the accumulation of oxoadipate and quinolinic acid, which in turn cause toxicity in spinal motor neurons leading to spinal muscular atrophy-like disease.GENETICS in MEDICINE advance online publication, 8 March 2018; doi:10.1038/gim.2017.251.

PMID: 29517768 [PubMed - as supplied by publisher]

Genetic Alterations in Essential Thrombocythemia Progression to Acute Myeloid Leukemia: A Case Series and Review of the Literature.

Front Oncol. 2018;8:32

Authors: Ayres-Silva JP, Bonamino MH, Gouveia ME, Monte-Mor BCR, Coutinho DF, Daumas AH, Solza C, Braggio E, Zalcberg IR

Abstract
The genetic events associated with transformation of myeloproliferative neoplasms (MPNs) to secondary acute myeloid leukemia (sAML), particularly in the subgroup of essential thrombocythemia (ET) patients, remain incompletely understood. Deep studies using high-throughput methods might lead to a better understanding of genetic landscape of ET patients who transformed to sAML. We performed array-based comparative genomic hybridization (aCGH) and whole exome sequencing (WES) to analyze paired samples from ET and sAML phases. We investigated five patients with previous history of MPN, which four had initial diagnosis of ET (one case harboring JAK2 p.Val617Phe and the remaining three CALR type II p.Lys385fs*47), and one was diagnosed with MPN/myelodysplastic syndrome with thrombocytosis (SF3B1 p.Lys700Glu). All were homogeneously treated with hydroxyurea, but subsequently transformed to sAML (mean time of 6 years/median of 4 years to transformation). Two of them have chromosomal abnormalities, and both acquire 2p gain and 5q deletion at sAML stage. The molecular mechanisms associated with leukemic progression in MPN patients are not clear. Our WES data showed TP53 alterations recurrently observed as mutations (missense and frameshift) and monoallelic loss. On the other hand, aCGH showed novel chromosome abnormalities (+2p and del5q) potentially associated with disease progression. The results reported here add valuable information to the still fragmented molecular basis of ET to sAML evolution. Further studies are necessary to identify minimal deleted/amplified region and genes relevant to sAML transformation.

PMID: 29515972 [PubMed]

Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant.

JCI Insight. 2018 Mar 08;3(5):

Authors: Jacoby MA, Duncavage EJ, Chang GS, Miller CA, Shao J, Elliott K, Robinson J, Fulton RS, Fronick CC, O'Laughlin M, Heath SE, Pusic I, Welch JS, Link DC, DiPersio JF, Westervelt P, Ley TJ, Graubert TA, Walter MJ

Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment for myelodysplastic syndromes (MDS), but patients who relapse after transplant have poor outcomes. In order to understand the contribution of tumor clonal evolution to disease progression,we applied exome and error-corrected targeted sequencing coupled with copy number analysis to comprehensively define changes in the clonal architecture of MDS in response to therapy using 51 serially acquired tumor samples from 9 patients who progressed after an alloHCT. We show that small subclones before alloHCT can drive progression after alloHCT. Notably, at least one subclone expanded or emerged at progression in all patients. Newly acquired structural variants (SVs) were present in an emergent/expanding subclone in 8 of 9 patients at progression, implicating the acquisition of SVs as important late subclonal progression events. In addition, pretransplant therapy with azacitidine likely influenced the mutation spectrum and evolution of emergent subclones after alloHCT. Although subclone evolution is common, founding clone mutations are always present at progression and could be detected in the bone marrow as early as 30 and/or 100 days after alloHCT in 6 of 8 (75%) patients, often prior to clinical progression. In conclusion, MDS progression after alloHCT is characterized by subclonal expansion and evolution, which can be influenced by pretransplant therapy.

PMID: 29515031 [PubMed - as supplied by publisher]

Homozygous CHST11 mutation in chondrodysplasia, brachydactyly, overriding digits, clino-symphalangism and synpolydactyly.

J Med Genet. 2018 Mar 07;:

Authors: Shabbir RMK, Nalbant G, Ahmad N, Malik S, Tolun A

Abstract
BACKGROUND: Carbohydrate sulfotransferase 11 (CHST11) is a membrane protein of Golgi that catalyses the transfer of sulfate to position 4 of the N-acetylgalactosamine residues of chondroitin. Chondroitin sulfate is the predominant proteoglycan in cartilage, and its sulfation is important in the developing growth plate of cartilage. A homozygous deletion encompassing part of the gene and the embedded miRNA MIR3922 had been detected in a woman with hand/foot malformation and malignant lymphoproliferative disease. Chst11-deficient mouse has severe chondrodysplasia, congenital arthritis and neonatal lethality. We searched for the causative variant for the unusual combination of limb malformations with variable expressivity accompanied by skeletal defects in a consanguineous Pakistani kindred.
METHODS: We performed detailed clinical investigations in family members. Homozygosity mapping using SNP genotype data was performed to map the disease locus and exome sequencing to identify the underlying molecular defect.
RESULTS: The limb malformations include brachydactyly, overriding digits and clino-symphalangism in hands and feet and syndactyly and hexadactyly in feet. Skeletal defects include scoliosis, dislocated patellae and fibulae and pectus excavatum. The disease locus is mapped to a 1.6 Mb region at 12q23, harbouring a homozygous in-frame deletion of 15 nucleotides in CHST11. Novel variant c.467_481del (p.L156_N160del) is deduced to lead to the deletion of five evolutionarily highly conserved amino acids and predicted as damaging to protein by in silico analysis. Our findings confirm the crucial role of CHST11 in skeletal morphogenesis and show that CHST11 defects have variable manifestations that include a variety of limb malformations and skeletal defects.

PMID: 29514872 [PubMed - as supplied by publisher]

Life-threatening drug interactions: what the physician needs to know.

Intern Med J. 2017 May;47(5):501-512

Authors: Day RO, Snowden L, McLachlan AJ

Abstract
Adverse drug-drug interactions are a significant cause of adverse events and outcomes. Their incidence is rising, with more patients taking more drugs, and newer, more precise but often more hazardous drugs becoming available. Despite considerable information, including computerised alerts about potential adverse drug-drug interactions, prescribers increasingly override alerts, possibly symptomatic of the immense problem of evaluating the risk of an interaction in a particular patient. Many reports emanate from small studies often of normal and young volunteers, entirely different from the real world where, more often, older patients with multiple health conditions are receiving many more than the two drugs identified in the drug interaction report. Focusing on those drug-drug interactions that are clinically relevant is necessary, and increasingly, tools and reliable sources of this information are easily accessible.

PMID: 28503886 [PubMed - indexed for MEDLINE]

A decade of adverse drug events in Portuguese hospitals: space-time clustering and spatial variation in temporal trends.

BMC Pharmacol Toxicol. 2017 May 10;18(1):34

Authors: Scripcaru G, Mateus C, Nunes C

Abstract
BACKGROUND: The aim of this study is to identify the distribution by municipalities of adverse drug events (ADE) in Portugal, including adverse drug reactions (ADR) and accidental poisoning by drugs (AP), on municipality/years ADE rate clustering. Also we identify areas with different trends in time.
METHODS: We used a national dataset of public hospital discharges in Continental Portugal from 2004 to 2013. Events were identified based on codes: from E930 to E949.9 (ADR) and from E850 to E858.9 (AP). Space-time clustering and spatial variation in temporal trends methods were applied in three different time-periods: globally, by year and grouped in 2 classes (periods of 5 years).
RESULTS: A total of 9,320,076 patients were discharged within this period, with 133,688 patients (1.46%) having at least one ADE, 4% of them related with AP. Critical space-time identified clusters (p < 0.001) were the municipalities from Lisbon metropolitan area and Centro region area. The global rate increased at a 7.8% mean annual percentage change, with high space-time heterogeneity and variation in time trends clusters (p < 0.001). For whole period, 2004-2013, all clusters presented increasing trends. However when analyzed by period of 5 years we identified two clusters with decreasing trends in time in 2004-2008.
CONCLUSION: The impact of ADE is huge, with widely variations within country and in time, and represents an increasing challenge. Future research using individual and contextual risk factors are urgently needed to understand this spatiotemporal variability in order to promote local tailored and updated actions of prevention.

PMID: 28486949 [PubMed - indexed for MEDLINE]

A Bayesian analysis of quantal bioassay experiments incorporating historical controls via Bayes factors.

Stat Med. 2017 May 30;36(12):1907-1923

Authors: León Novelo LG, Womack A, Zhu H, Wu X

Abstract
This paper addresses model-based Bayesian inference in the analysis of data arising from bioassay experiments. In such experiments, increasing doses of a chemical substance are given to treatment groups (usually rats or mice) for a fixed period of time (usually 2 years). The goal of such an experiment is to determine whether an increased dosage of the chemical is associated with increased probability of an adverse effect (usually presence of adenoma or carcinoma). The data consists of dosage, survival time, and the occurrence of the adverse event for each unit in the study. To determine whether such relationship exists, this paper proposes using Bayes factors to compare two probit models, the model that assumes increasing dose effects and the model that assumes no dose effect. These models account for the survival time of each unit through a Poly-k type correction. In order to increase statistical power, the proposed approach allows the incorporation of information from control groups from previous studies. The proposed method is able to handle data with very few occurrences of the adverse event. The proposed method is compared with a variation of the Peddada test via simulation and is shown to have higher power. We demonstrate the method by applying it to the two bioassay experiment datasets previously analyzed by other authors. Copyright © 2017 John Wiley & Sons, Ltd.

PMID: 28106916 [PubMed - indexed for MEDLINE]

Long-term (52-week) safety and efficacy of Sacubitril/valsartan in Asian patients with hypertension.

Hypertens Res. 2017 May;40(5):472-476

Authors: Supasyndh O, Sun N, Kario K, Hafeez K, Zhang J

Abstract
Sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor-neprilysin inhibitor, demonstrated significant reductions in office and 24 h ambulatory blood pressure (BP) over 8 weeks in Asian patients with hypertension. This 52-week extension to the 8-week core study was aimed at evaluating the long-term safety, tolerability and efficacy of sacubitril/valsartan. Patients who completed an 8-week randomized study (the core study) were enrolled in this 52-week open-label study and received sacubitril/valsartan 200 mg QD. The sacubitril/valsartan dose was uptitrated to 400 mg QD if BP was uncontrolled (>140/90 mm Hg) after 4 weeks. Subsequently, in patients with uncontrolled BP, treatment was intensified every 4 weeks with amlodipine 5-10 mg followed by hydrochlorothiazide 6.25-25 mg. Of the 341 patients enrolled, 7 (2.1%) discontinued the study drug due to adverse events (AEs). The incidence of AEs and serious AEs were 63.9 and 3.8%, respectively, and no deaths were reported in this study. The most frequent AEs were nasopharyngitis (18.2%) and dizziness (8.8%). Events that were potentially indicative of low BP were infrequent. One patient reported mild transient angioedema (lasting 2.5 h) that resolved without treatment but led to study drug discontinuation. The sacubitril/valsartan-based regimen provided clinically significant mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) reductions from baseline (-24.7/-16.2 mm Hg). The overall BP control, msSBP and msDBP response rates were 75.3, 90.6 and 87.6%, respectively. Long-term use of sacubitril/valsartan was generally safe and well-tolerated in patients with hypertension and provided significant BP reductions from baseline.

PMID: 27853163 [PubMed - indexed for MEDLINE]

Assessment of Drug Therapy-Related Issues in an Outpatient Heart Failure Population and the Potential Impact of Pharmacist-Driven Intervention.

J Pharm Pract. 2017 Jun;30(3):318-323

Authors: Dempsey JT, Matta LS, Carter DM, Stevens CA, Stevenson LW, Desai AS, Cheng JW

Abstract
BACKGROUND: The Ambulatory Cardiac Triage, Intervention, and Education (ACTIVE) infusion unit is an outpatient center that aims to provide heart failure (HF) patients with comprehensive multidisciplinary interventions.
OBJECTIVE: To describe the patient population served in ACTIVE and to document the prevalence of comorbidities and drug therapy-related issues (DRIs) in order to define the most effective role of a pharmacist in the unit.
METHODS: Patients who have been interviewed by a pharmacist in ACTIVE were included. Comprehensive medical and medication profile reviews were performed. Patient comorbidities were documented, and DRIs were classified.
RESULTS: Sixty patients were included. Most prevalent cardiac comorbidities included hypertension (73%) and hyperlipidemia (62%). Top 3 noncardiac comorbidities included chronic kidney disease (60%), diabetes (50%), and obesity (35%). The prevalence of DRI was reported as follows: (1) needs additional/alternative therapy (untreated indication [37] or suboptimal therapeutic choice [46]), (2) wrong drug (major drug-drug interaction [90], contraindication [11], or duplicate therapy [1]), (3) suboptimal dosing (17), (4) dose exceeds recommended maximum (9), and (5) adverse drug reaction (93). In 63 (22%) of the DRIs, a pharmacist made recommendations to modify the regimen.
CONCLUSION: The prevalence of DRI is high even among HF patients managed in a subspecialty cardiovascular practice. Pharmacists in this setting play a vital role in more effectively resolving DRI.

PMID: 27080398 [PubMed - indexed for MEDLINE]

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Next generation sequencing-based emerging trends in molecular biology of gastric cancer.

Am J Cancer Res. 2018;8(2):207-225

Authors: Verma R, Sharma PC

Abstract
Gastric cancer (GC) is one of the leading causes of cancer related mortality in the world. Being asymptomatic in nature till advanced stage, diagnosis of gastric cancer becomes difficult in early stages of the disease. The onset and progression of gastric cancer has been attributed to multiple factors including genetic alterations, epigenetic modifications, Helicobacter pylori and Epstein-Barr Virus (EBV) infection, and dietary habits. Next Generation Sequencing (NGS) based approaches viz. Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES), RNA-Seq, and targeted sequencing have expanded the knowledge base of molecular pathogenesis of gastric cancer. In this review, we highlight recent NGS-based advances covering various genetic alterations (Microsatellite Instability, Single Nucleotide Variations, and Copy Number Variations), epigenetic changes (DNA methylation, histone modification, microRNAs) and differential gene expression during gastric tumorigenesis. We also briefly discuss the current and future potential biomarkers, drugs and therapeutic approaches available for the management of gastric cancer.

PMID: 29511593 [PubMed]