scholarly journals Applying a Weight-of-Evidence Approach to Evaluate Relevance of Molecular Landscapes in the Exposure-Disease Paradigm

2015 ◽  
Vol 2015 ◽  
pp. 1-11
Author(s):  
Sherilyn A. Gross ◽  
Kristen M. Fedak
Keyword(s):  
Molecular Mechanisms ◽  
Molecular Data ◽  
Weight Of Evidence ◽  
Molecular Characteristics ◽  
Environmental Carcinogens ◽  
Environmental Carcinogen ◽  
Cell Counts ◽  
Disease Outcomes ◽  
Dna Repair Gene ◽  
Increased Risk

Information on polymorphisms, mutations, and epigenetic events has become increasingly important in our understanding of molecular mechanisms associated with exposures-disease outcomes. Molecular landscapes can be developed to illustrate the molecular characteristics for environmental carcinogens as well as associated disease outcomes, although comparison of these molecular landscapes can often be difficult to navigate. We developed a method to organize these molecular data that uses a weight-of-evidence approach to rank overlapping molecular events by relative importance for susceptibility to an exposure-disease paradigm. To illustrate the usefulness of this approach, we discuss the example of benzene as an environmental carcinogen and myelodysplastic syndrome (MDS) as a causative disease endpoint. Using this weight-of-evidence method, we found overlapping polymorphisms in the genes for the metabolic enzymesGSTandNQO1, both of which may infer risk of benzene-induced MDS. Polymorphisms in the tumor suppressor gene,TP53, and the inflammatory cytokine gene,TNF-α, were also noted, albeit inferring opposing outcomes. The alleles identified in the DNA repair geneRAD51indicated an increased risk for MDS in MDS patients and low blood cell counts in benzene-exposed workers. We propose the weight-of-evidence approach as a tool to assist in organizing the sea of emerging molecular data in exposure-disease paradigms.

scholarly journals DNA Repair Gene Polymorphisms and Susceptibility to Urothelial Carcinoma in a Southeastern European Population

2021 ◽  
Vol 28 (3) ◽  
pp. 1879-1885
Author(s):  
Maria Samara ◽  
Maria Papathanassiou ◽  
Lampros Mitrakas ◽  
George Koukoulis ◽  
Panagiotis J. Vlachostergios ◽  
...  
Keyword(s):  
Dna Repair ◽  
Urothelial Carcinoma ◽  
European Population ◽  
Nucleotide Polymorphisms ◽  
Environmental Carcinogens ◽  
Repair Gene ◽  
High Exposure ◽  
Dna Repair Gene ◽  
Increased Risk ◽  
Xrcc3 Thr241met

Single nucleotide polymorphisms (SNPs) in DNA repair genes may predispose to urothelial carcinoma of the bladder (UCB). This study focused on three specific SNPs in a population with high exposure to environmental carcinogens including tobacco and alcohol. A case-control study design was used to assess for presence of XPC PAT +/−, XRCC3 Thr241Met, and ERCC2 Lys751Gln DNA repair gene SNPs in peripheral blood from patients with UCB and healthy individuals. One hundred patients and equal number of healthy subjects were enrolled. The XPC PAT +/+ genotype was associated with a 2-fold increased risk of UCB (OR = 2.16; 95%CI: 1.14–4; p = 0.01). The −/+ and +/+ XPC PAT genotypes were more frequently present in patients with multiple versus single tumors (p = 0.01). No association was detected between ERCC2 Lys751Gln genotypes/alleles, and risk for developing UCB. Presence of the XRCC3 TT genotype (OR = 0.14; 95%CI:0.07–0.25; p < 0.01) and of the T allele overall (OR = 0.26; 95%CI:0.16–0.41; p < 0.01) conferred a protective effect against developing UCB. The XPC PAT −/+ and XRCC3 Thr241Met SNPs are associated with predisposition to UCB. The XPC PAT −/+ SNP is also an indicator of bladder tumor multiplicity, which might require a more individualized surveillance and treatment.

scholarly journals Longitudinal profiling of human blood transcriptome in healthy and lupus pregnancy

2019 ◽  
Vol 216 (5) ◽  
pp. 1154-1169 ◽  
Author(s):  
Seunghee Hong ◽  
Romain Banchereau ◽  
Bat-Sheva L. Maslow ◽  
Marta M. Guerra ◽  
Jacob Cardenas ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Embryo Implantation ◽  
Adverse Outcomes ◽  
Healthy Women ◽  
Cell Counts ◽  
Increased Risk ◽  
Pregnancy And Postpartum ◽  
Blood Transcriptome

Systemic lupus erythematosus carries an increased risk of pregnancy complications, including preeclampsia and fetal adverse outcomes. To identify the underlying molecular mechanisms, we longitudinally profiled the blood transcriptome of 92 lupus patients and 43 healthy women during pregnancy and postpartum and performed multicolor flow cytometry in a subset of them. We also profiled 25 healthy women undergoing assisted reproductive technology to monitor transcriptional changes around embryo implantation. Sustained down-regulation of multiple immune signatures, including interferon and plasma cells, was observed during healthy pregnancy. These changes appeared early after embryo implantation and were mirrored in uncomplicated lupus pregnancies. Patients with preeclampsia displayed early up-regulation of neutrophil signatures that correlated with expansion of immature neutrophils. Lupus pregnancies with fetal complications carried the highest interferon and plasma cell signatures as well as activated CD4+ T cell counts. Thus, blood immunomonitoring reveals that both healthy and uncomplicated lupus pregnancies exhibit early and sustained transcriptional modulation of lupus-related signatures, and a lack thereof associates with adverse outcomes.

The Role of Revascularisation in Patients Undergoing Non-cardiac Surgery

2010 ◽  
Vol 5 (1) ◽  
pp. 104
Author(s):  
Daniel S Menees ◽  
Eric R Bates ◽  
◽  
Keyword(s):  
Cardiac Surgery ◽  
Prediction Models ◽  
Cardiovascular Complications ◽  
Weight Of Evidence ◽  
Beta Blockade ◽  
Cardiac Morbidity ◽  
Increased Risk ◽  
Reduction Strategies ◽  
Artery Disease ◽  
Risk Reduction Strategies

Coronary artery disease (CAD) affects millions of US citizens. As the population ages, an increasing number of people with CAD are undergoing non-cardiac surgery and face significant peri-operative cardiac morbidity and mortality. Risk-prediction models can be used to help identify those patients at increased risk of peri-operative cardiovascular complications. Risk-reduction strategies utilising pharmacotherapy with beta blockade and statins have shown the most promise. Importantly, the benefit of prophylactic coronary revascularisation has not been demonstrated. The weight of evidence suggests reserving either percutaneous or surgical revascularisation in the pre-operative setting for those patients who would otherwise meet independent revascularisation criteria.

The Role of Vascular Aging in Atherosclerotic Plaque Development and Vulnerability

2019 ◽  
Vol 25 (29) ◽  
pp. 3098-3111 ◽  
Author(s):  
Luca Liberale ◽  
Giovanni G. Camici
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Plaque Burden ◽  
Vascular Aging ◽  
Age Related ◽  
Plaque Development ◽  
Increased Risk ◽  
The Impact ◽  
Over Time

Background: The ongoing demographical shift is leading to an unprecedented aging of the population. As a consequence, the prevalence of age-related diseases, such as atherosclerosis and its thrombotic complications is set to increase in the near future. Endothelial dysfunction and vascular stiffening characterize arterial aging and set the stage for the development of cardiovascular diseases. Atherosclerotic plaques evolve over time, the extent to which these changes might affect their stability and predispose to sudden complications remains to be determined. Recent advances in imaging technology will allow for longitudinal prospective studies following the progression of plaque burden aimed at better characterizing changes over time associated with plaque stability or rupture. Oxidative stress and inflammation, firmly established driving forces of age-related CV dysfunction, also play an important role in atherosclerotic plaque destabilization and rupture. Several genes involved in lifespan determination are known regulator of redox cellular balance and pre-clinical evidence underlines their pathophysiological roles in age-related cardiovascular dysfunction and atherosclerosis. Objective: The aim of this narrative review is to examine the impact of aging on arterial function and atherosclerotic plaque development. Furthermore, we report how molecular mechanisms of vascular aging might regulate age-related plaque modifications and how this may help to identify novel therapeutic targets to attenuate the increased risk of CV disease in elderly people.

scholarly journals NCMP-17. MISMATCH REPAIR MUTATIONS AND THE CENTRAL NERVOUS SYSTEM: A CASE SERIES OF GERMLINE MUTATIONS AND CNS MALIGNANCY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii126-ii126
Author(s):  
Amber Ruiz ◽  
Jerome Graber
Keyword(s):  
Treatment Response ◽  
Mismatch Repair ◽  
Case Series ◽  
Germline Mutations ◽  
Molecular Characteristics ◽  
Loss Of Function ◽  
Dna Mismatch ◽  
Mutational Burden ◽  
Increased Risk ◽  
Tumor Mutational Burden

Abstract Our understanding of genetic predispositions for malignancy is continually evolving. One family of germline mutations well described in the literature is that of the DNA mismatch repair mechanism (MMR). Lynch syndrome (LS) is due to a loss of function mutation of several MMR genes- MSH2, MLH1, MSH6, and PMS2. Germline MMR mutations lead to microsatellite instability and loss of genomic integrity resulting in an increased risk for various cancers (colorectal, genitourinary, etc). LS may be as common as 1 in 400 people and some MMR mutations have been associated with gliomas. There is a paucity of information regarding frequency of glioma subtypes as well as tumor genetic and molecular characteristics which have important clinical implications. We describe a case series of 6 individuals with germline MMR mutations and brain tumors. Those with MSH2 and PMS2 mutations (n=3) developed glioblastomas at a mean age at diagnosis of 48 years. These tumors expressed MGMT hyper-methylation and high tumor mutational burden. Only one had IDH-1 mutation. Those with MLH1 mutations (n=3), did not develop gliomas. This raises the question of differential glioma subtype development based on MMR gene. It also highlights the possibility of Lynch-associated gliomas having more favorable treatment response due to MGMT methylation and potential response to immunotherapy based on high tumor mutational burden. Though the sample size is small, there appears to be a preponderance of women compared to men (5:1 respectively). Larger studies are needed to verify CNS involvement in germline MMR mutations. In doing so, we hope to identify factors that may influence clinical management and lead to a better understanding of treatment response and disease prognosis.

Redescription and synonymization of Oscheius citri Tabassum, Shahina, Nasira and Erum, 2016 (Rhabditida, Rhabditidae) from India and its taxonomical consequences

2021 ◽  
Vol 95 ◽  
Author(s):  
A. Rana ◽  
A.H. Bhat ◽  
A.K. Chaubey ◽  
V. Půža ◽  
J. Abolafia
Keyword(s):  
Indian Population ◽  
Uttar Pradesh ◽  
Nematode Species ◽  
Molecular Data ◽  
Molecular Characteristics ◽  
Morphometric Characteristics ◽  
High Similarity ◽  
Rdna Sequences ◽  
Indian Strain ◽  
28S Rdna Sequences

Abstract A population of a nematode species belonging to the genus Oscheius was isolated in western Uttar Pradesh, India. Morphological and morphometrical studies on this species showed its high similarity with six species described previously from Pakistan (Oscheius citri, O. cobbi, O. cynodonti, O. esculentus, O. punctatus and O. sacchari). The molecular analysis of the ITS1-5.8S-ITS2 rDNA sequences of the Indian population and the six species described from Pakistan showed that all the sequences are almost identical. Thus, based on morphological and molecular characteristics, all of the six above-mentioned Pakistani species and Indian strain do not differ from each other, hence can be considered synonyms. The correct name for this taxon is the first described species O. citri. Additionally, the phylogenetic analysis of the 18S rDNA and the 28S rDNA sequences showed that Oscheius citri is sister to the clade formed by O. chongmingensis and O. rugaoensis from China. The high similarity of morphological and morphometric characteristics of O. citri and other species, O. maqbooli, O. nadarajani, O. niazii, O. shamimi and O. siddiqii, suggest their conspecificity; however, lack of molecular data for these species does not allow this hypothesis to be tested.

scholarly journals DNA Repair Gene Polymorphism and the Risk of Mitral Chordae Tendineae Rupture

2015 ◽  
Vol 2015 ◽  
pp. 1-6
Author(s):  
Aysel Kalayci Yigin ◽  
Mehmet Bulent Vatan ◽  
Ramazan Akdemir ◽  
Muhammed Necati Murat Aksoy ◽  
Mehmet Akif Cakar ◽  
...  
Keyword(s):  
Dna Repair ◽  
Fragment Length Polymorphism ◽  
Control Group ◽  
Chordae Tendineae ◽  
Repair Gene ◽  
Repair Capacity ◽  
Dna Repair Capacity ◽  
Dna Repair Gene ◽  
Increased Risk ◽  
Polymerase Chain

Polymorphisms in Lys939Gln XPC gene may diminish DNA repair capacity, eventually increasing the risk of carcinogenesis. The aim of the present study was to evaluate the significance of polymorphism Lys939Gln in XPC gene in patients with mitral chordae tendinea rupture (MCTR). Twenty-one patients with MCTR and thirty-seven age and sex matched controls were enrolled in the study. Genotyping of XPC gene Lys939Gln polymorphism was carried out using polymerase chain reaction- (PCR-) restriction fragment length polymorphism (RFLP). The frequencies of the heterozygote genotype (Lys/Gln-AC) and homozygote genotype (Gln/Gln-CC) were significantly different in MCTR as compared to control group, respectively (52.4% versus 43.2%,p=0.049; 38.15% versus 16.2%,p=0.018). Homozygote variant (Gln/Gln) genotype was significantly associated with increased risk of MCTR (OR = 2.059; 95% CI: 1.097–3.863;p=0.018). Heterozygote variant (Lys/Gln) genotype was also highly significantly associated with increased risk of MCTR (OR = 1.489; 95% CI: 1.041–2.129;p=0.049). The variant allele C was found to be significantly associated with MCTR (OR = 1.481; 95% CI: 1.101–1.992;p=0.011). This study has demonstrated the association of XPC gene Lys939Gln polymorphism with MCTR, which is significantly associated with increased risk of MCTR.

scholarly journals Molecular Mechanisms of Drug Resistance in Glioblastoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6385
Author(s):  
Maya A. Dymova ◽  
Elena V. Kuligina ◽  
Vladimir A. Richter
Keyword(s):  
Drug Resistance ◽  
Brain Tumor ◽  
Molecular Mechanisms ◽  
Primary Brain Tumor ◽  
Therapeutic Resistance ◽  
Molecular Characteristics ◽  
Blood Brain ◽  
Conventional Radiation ◽  
The Brain ◽  
Made In

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, is highly resistant to conventional radiation and chemotherapy, and is not amenable to effective surgical resection. The present review summarizes recent advances in our understanding of the molecular mechanisms of therapeutic resistance of GBM to already known drugs, the molecular characteristics of glioblastoma cells, and the barriers in the brain that underlie drug resistance. We also discuss the progress that has been made in the development of new targeted drugs for glioblastoma, as well as advances in drug delivery across the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB).

Molecular determination of the origin of acephalic cysticercus

Parasitology ◽  
2004 ◽  
Vol 130 (2) ◽  
pp. 239-246 ◽  
Author(s):  
J.-Y. CHUNG ◽  
W.-G. KHO ◽  
S.-Y. HWANG ◽  
E.-Y. JE ◽  
Y.-T. CHUNG ◽  
...  
Keyword(s):  
Nadh Dehydrogenase ◽  
Fatal Outcome ◽  
Constitutive Expression ◽  
Molecular Data ◽  
Molecular Characteristics ◽  
Nadh Dehydrogenase Subunit ◽  
Subarachnoidal Space ◽  
Species Specific ◽  
Molecular Determination

Acephalic cysticercus (Ac), a rarely developed multilobulated and nonencysted form of larval Taenia, causes hydrocephalus or adhesive arachnoiditis in the ventricles and subarachnoidal space that often lead to fatal outcome in affected patients. Ac has been proposed to originate from T. solium on the basis of morphological features, while no molecular data supporting the presumption have been available. In the present study, we investigated the immunological properties as well as molecular characteristics of Ac that was obtained surgically from 6 patients. Immunoblotting of the cyst fluid from Ac samples demonstrated the constitutive expression of a T. solium metacestode (TsM) 10 kDa protein. Specific antibodies against the truncated 10 kDa protein, which appears to be species specific for TsM cysticercosis, were detected in both serum and cerebrospinal fluid samples of Ac patients. Nucleotide sequences of mitochondrial cytochrome c oxidase subunit I (COI) and NADH dehydrogenase subunit 1 (ND1) genes of Ac were almost identical to those of T. solium but differed substantially from those of the other Taenia species. In phylogenetic analysis, Ac clustered with T. solium in a well-supported clade. Our results strongly suggest that Ac may have originated from T. solium.

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