Note on the utility of the st mus302 test for chromosome loss in a blind test of an environmental compound for chromosome breakage in Drosophila.
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Animals↗
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Results for “genetic test utilization”
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Genetic background influences metabolic response to dietary phosphorus restriction.
Dietary phosphorus (P) is essential to bone growth and turnover; however, little research has focused on the genetic mechanisms controlling P utilization. Understanding the interactions between genetics and dietary P that optimize bone integrity could provide novel interventions for osteoporosis. Thirty-six pigs from two sire lines known to differ in bone structure [heavier boned (HB) and lighter boned (LB)] were assigned to one of the three diets (P adequate, P repletion or P deficient). After 14 days, bone marrow and intact radial bones were collected. Differences between these lines in growth rate, bone integrity and gene expression within bone marrow were observed. In HB, but not LB, pigs, the P-deficient diet decreased weight gain (P<.01). For both lines, P deficiency caused a reduction in radial bone strength (P<.01), but HB P-deficient animals had greater (P<.10) bone integrity than P-deficient LB pigs. In HB, but not LB, pigs, dietary treatment affected the expression of CALCR (calcitonin receptor) (P<.05), VDR (vitamin D receptor) (P<.04) and IGFBP3 (insulin-like growth factor binding protein 3) (P<.06). There was also a trend of increased IL6 (interleukin-6), TFIIB (transcription initiation factor IIB) and SOX9 (sex determining region Y-box 9) expression with P deficiency in HB, but not LB, pigs. Both genetic backgrounds responded similarly to P deficiency with an increase in the expression of OXTR (oxytocin receptor) and IGF1 (insulin-like growth factor 1). Differences in growth rate, bone integrity and gene expression within the bone marrow suggest a difference in the homeorhetic control of P utilization between these genetic lines. Understanding these differences could lead to novel treatments for osteoporosis and aid in the development of tests for identifying those at risk for this disease.
Animals↗
Elevated serum type IV collagen: a sensitive indicator of the presence of cirrhosis in haemochromatosis.
BACKGROUND/AIM: Hereditary haemochromatosis can now be diagnosed by genetic testing, although determining the presence or absence of cirrhosis remains crucial to patient management. While many studies have investigated the utility of various serum markers of cirrhosis in chronic liver diseases, few have examined specifically patients with hereditary haemochromatosis. The aim of this study was to assess the utility of serum type IV collagen and serum laminin in diagnosing hepatic fibrosis and cirrhosis in patients with hereditary haemochromatosis. METHODS: The study group consisted of 42 patients with hereditary haemochromatosis and 19 Caucasian controls. Serum type IV collagen, laminin, matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase (TIMP-1) concentrations were measured by enzyme-linked immunosorbant assay in serum from patients with haemochromatosis and control subjects. Liver biopsies from patients with haemochromatosis were graded for fibrosis and correlated with serum markers of hepatic fibrosis. RESULTS: Serum type IV collagen concentration was significantly increased in haemochromatosis patients compared to controls (130+/-79 ng/ml vs 81 +/- 17 ng/ml, p<0.05) and was significantly correlated with both the grade of histological fibrosis (r=0.67, p<0.0001) and serum MMP-2 levels (r=0.42, p<0.05). A serum type IV collagen concentration > 115 ng/ml (mean+2 SD of controls) was 100% sensitive and 69% specific in detecting severe (grade 3) fibrosis and cirrhosis. The sensitivity results of serum laminin and TIMP-1 were 11% and 56% respectively. CONCLUSIONS: Elevated serum type IV collagen is a sensitive indicator of the presence of severe fibrosis and cirrhosis in patients with haemochromatosis. Useful markers of hepatic fibrosis in other chronic liver diseases may not be applicable to haemochromatosis.
Biomarkers↗
An infrared fluorescent dATP for labeling DNA.
Near-infrared fluorescence provides a nonradioactive method of detection with high sensitivity and low background. An infrared fluorophore has been attached covalently to the nucleotide deoxyadenosine triphosphate (dATP) to provide a reagent for enzymatic labeling of various types of DNA molecules and for facilitating their detection with an automated DNA sequencing and analysis system. DNA sequencing reaction products can be labeled internally by performing limited polymerization utilizing infrared-labeled dATP (IR-dATP) as the sole source of adenine deoxynucleotide prior to a dideoxy-specific termination reaction. PCR products can be labeled fluorescently by the addition of limited quantities of IR-dATP to the amplification reaction. This latter strategy has been utilized for detection of short tandem repeat polymorphisms (STRPs) which are useful for gene mapping, genetic diagnostics, forensic analysis, and paternity testing. Restriction fragments can be labeled also by fill-in reactions of appropriate 5' overhangs. Diminutive amounts of such fluorescently labeled DNA molecules can be visualized rapidly and conveniently using infrared detection technology.
Adenosine Triphosphate↗
A diagnostic approach to hemochromatosis.
In the present clinical review, a diagnostic approach to hemochromatosis is discussed from the perspective of two clinicians with extensive experience in this area. The introduction of genetic testing and large-scale population screening studies have broadened our understanding of the clinical expression of disease and the utility of biochemical iron tests for the detection of disease and for the assessment of disease severity. Liver biopsy has become more of a prognostic test than a diagnostic test. The authors offer a stepwise, diagnostic algorithm based on current evidence-based data, that they regard as most cost-effective. An early diagnosis can lead to phlebotomy therapy to prevent the development of cirrhosis.
Hemochromatosis↗
Genetic engineering of Serratia marcescens with bacterial hemoglobin gene: effects on growth, oxygen utilization, and cell size.
The bacterial hemoglobin from Vitreoscilla has been shown to increase growth yield and yield of genetically engineered product in Escherichia coli. To test the generality of this phenomenon, the approximately 560-bp bacterial (Vitreoscilla) hemoglobin gene (vgb) (including the native promoter), cloned into the vector pUC8 in two constructs containing about 1650 and 850 bp, respectively, of Vitreoscilla DNA downstream of vgb, was transformed into Serratia marcescens. After several transfers of the transformants on selective media, both plasmids became stable in this host and the resulting strains produced hemoglobin. Both transformants were compared, regarding growth in liquid Luria-Bertani (LB) medium, with untransformed S. marcescens and S. marcescens transformed with pUC8. The vgb-bearing strains had about 5 times lower maximum viable cell numbers than the strains without hemoglobin, but the former also had late log or early stationary phase cells that were 5-10 times larger than those of the latter. Further, on a dry cell mass basis the presence of vgb inhibited cell growth in liquid media. In contrast, growth of the vgb-bearing strains on LB plates based on cell mass (determined from colony size) was markedly enhanced compared with that of the pUC8 transformant. Respiration of the vgb-bearing strains was lower than that of the strains without vgb on a cell mass basis. These results show that the presence of vgb can have idiosyncratic effects and is not always an aid to cell growth so that its use for genetic engineering must be tested on a case by case basis.
Bacterial Proteins↗
Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing.
Atthe International Workshop on Genotoxicity Test Procedures (IWGTP) held in Washington, DC, March 25-26, 1999, an expert panel met to develop guidelines for the use of the single-cell gel (SCG)/Comet assay in genetic toxicology. The expert panel reached a consensus that the optimal version of the Comet assay for identifying agents with genotoxic activity was the alkaline (pH > 13) version of the assay developed by Singh et al. [1988]. The pH > 13 version is capable of detecting DNA single-strand breaks (SSB), alkali-labile sites (ALS), DNA-DNA/DNA-protein cross-linking, and SSB associated with incomplete excision repair sites. Relative to other genotoxicity tests, the advantages of the SCG assay include its demonstrated sensitivity for detecting low levels of DNA damage, the requirement for small numbers of cells per sample, its flexibility, its low costs, its ease of application, and the short time needed to complete a study. The expert panel decided that no single version of the alkaline (pH > 13) Comet assay was clearly superior. However, critical technical steps within the assay were discussed and guidelines developed for preparing slides with agarose gels, lysing cells to liberate DNA, exposing the liberated DNA to alkali to produce single-stranded DNA and to express ALS as SSB, electrophoresing the DNA using pH > 13 alkaline conditions, alkali neutralization, DNA staining, comet visualization, and data collection. Based on the current state of knowledge, the expert panel developed guidelines for conducting in vitro or in vivo Comet assays. The goal of the expert panel was to identify minimal standards for obtaining reproducible and reliable Comet data deemed suitable for regulatory submission. The expert panel used the current Organization for Economic Co-operation and Development (OECD) guidelines for in vitro and in vivo genetic toxicological studies as guides during the development of the corresponding in vitro and in vivo SCG assay guidelines. Guideline topics considered included initial considerations, principles of the test method, description of the test method, procedure, results, data analysis and reporting. Special consideration was given by the expert panel to the potential adverse effect of DNA degradation associated with cytotoxicity on the interpretation of Comet assay results. The expert panel also discussed related SCG methodologies that might be useful in the interpretation of positive Comet data. The related methodologies discussed included: (1) the use of different pH conditions during electrophoreses to discriminate between DNA strand breaks and ALS; (2) the use of repair enzymes or antibodies to detect specific classes of DNA damage; (3) the use of a neutral diffusion assay to identify apoptotic/necrotic cells; and (4) the use of the acellular SCG assay to evaluate the ability of a test substance to interact directly with DNA. The alkaline (pH > 13) Comet assay guidelines developed by the expert panel represent a work in progress. Additional information is needed before the assay can be critically evaluated for its utility in genetic toxicology. The information needed includes comprehensive data on the different sources of variability (e.g., cell to cell, gel to gel, run to run, culture to culture, animal to animal, experiment to experiment) intrinsic to the alkaline (pH > 3) SCG assay, the generation of a large database based on in vitro and in vivo testing using these guidelines, and the results of appropriately designed multilaboratory international validation studies.
Animals↗
Defining the genetics of osteoporosis: using the mouse to understand man.
Very low bone mineral density (BMD) is now considered as diagnostic of osteoporosis. Moreover, many women who are osteopenic eventually develop osteoporotic fractures. Hence, bone density testing has occupied center stage in the diagnosis and treatment of this disorder. In addition, over the last several years, BMD has been utilized as the phenotype of choice for defining heritable markers for osteoporotic fractures. However, genetic studies in humans have been limited to some degree by the tremendous heterogeneity among populations, as well as multiple genetic, heritable and environmental determinants of the BMD phenotype. Recent advances in technology have afforded investigators the opportunity to study acquisition and maintenance of BMD in small animals. Along with newer knockout and transgenic strategies, quantification of mouse bone mass has advanced our understanding of both the biologic and genetic determinants of bone density. In this review, we will examine the use of the mouse to map the heritable factors that regulate bone acquisition. We will also examine the role of newer technology to decompose the bone density phenotype into components that are amenable to genetic studies. This review will focus on three models: (1) healthy inbred (2) recombinant inbred, and (3) congenic strains of mice. Progress in this area with these strains has been rapid, and a summary of several quantitative trait loci (QTLs) is provided. The future of the mouse as a tool to map the genes that define the osteoporosis syndrome is extremely promising.
Animals↗
Comfort care interventions in a preimplantation genetic testing program.
The fields of human genetics and assisted reproductive technology (ART) have experienced many scientific advances over the past 50 years. The integration of these two clinical specialties has resulted in the ability to perform preimplantation genetic testing (PGT) on an embryo created through ART. This is a technology that can be used by individuals at risk for the transmission of a genetic disorder to prevent occurrence of the disorder in their child. Both the process of PGT and the life experiences that lead to the decision to use PGT stimulate many levels and types of discomfort. Holistic comfort care interventions performed by the nurse are uniquely designed to eliminate or reduce discomfort and to enable those at risk to utilize the available technologies to create healthy families.
Adult↗
Pharmacogenetics of antiretroviral therapy: genetic variation of response and toxicity.
The application of a pharmacogenetic approach to antiretroviral drug therapy represents a significant challenge, as treatment involves multiple drugs and drug classes with the potential for significant variability in drug-host, as well as drug-drug, interactions. However, despite this inherent complexity, considerable gains have been made in understanding how genetic factors influence the efficacy and toxicity of HIV therapy. In this review the available evidence regarding genetic variation in drug disposition will be examined, including the potential for relatively polymorphic drug-metabolizing enzymes (e.g., cytochrome P450 isoforms) and drug transporters (e.g., P-glycoprotein) to influence the disposition of HIV protease inhibitor and non-nucleoside reverse transcriptase inhibitor drugs. In addition, the role of genetic variation in determining the immune response to drug-specific antigens will be considered as a potentially significant determinant of susceptibility to idiosyncratic drug reactions (e.g., major histocompatibility complex alleles associated with abacavir hypersensitivity). The current and potential clinical utility of pharmacogenetic testing in HIV management will also be emphasized.
Anti-Retroviral Agents↗
Cytogenetic markers of susceptibility: influence of polymorphic carcinogen-metabolizing enzymes.
Polymorphisms of xenobiotic-metabolizing enzymes, responsible for individual differences in metabolic activation and detoxification reactions, may profoundly modulate the effects of chemical carcinogens. In the case of genotoxic carcinogens, differences in biological effects due to genetic polymorphisms can be evaluated by cytogenetic methods such as the analysis of chromosomal aberrations (CAs), sister chromatid exchanges (SCEs), micronuclei (MN), and changes in chromosome number. These techniques can be applied to any exposure known to induce such alterations, without additional method development for each exposing agent. The influence of polymorphic genes on the cytogenetic effects of a carcinogen can quickly be tested in vitro using metabolically competent cells collected from donors representing different genotypes or phenotypes. For instance, erythrocytes from individuals positive for glutathione S-transferase T1 (GSTT1) express GSTT1, whereas GSTT1-null donors, having a homozygous deletion of the GSTT1 gene, completely lack this detoxification enzyme. This deficiency results in highly increased sensitivity to SCE induction in whole-blood lymphocyte cultures by 1,2:3,4-diepoxybutane, a reactive metabolite of 1,3-butadiene. The same cytogenetic techniques can also be applied as effect biomarkers in studies of human populations exposed to genotoxic carcinogens. For example, elevated rates of chromosome damage have been detected among smokers lacking glutathione S-transferase M1 (GSTM1-null genotype), and the baseline level of SCEs seems to be increased in GSTT1-null individuals. Information obtained from cytogenetic studies of genetic polymorphisms can be used, for example, to recognize the genotoxically relevant substrates of the polymorphic enzymes, to identify genotypes that are susceptible to these genotoxins, to improve in vitro genotoxicity tests utilizing human cells, to increase the sensitivity of cytogenetic endpoints as biomarkers of genotoxic effects in humans, and to direct mechanistic studies and cancer epidemiology.
Carcinogens↗
Application of transmission disequilibrium tests to nonsyndromic oral clefts: including candidate genes and environmental exposures in the models.
Extensive epidemiological and genetic studies of the cause of oral clefts have demonstrated strong familial aggregation but have failed to yield definitive evidence of any single genetic mechanism. We used the transmission/disequilibrium test (TDT) to investigate the relationship between oral clefts and markers associated with five candidate genes by utilizing 160 parent-offspring trios. Conditional logistic regression models extended the TDT to include covariates as effect modifiers, thus permitting tests for gene-environment interactions. For four of these candidates [transforming growth factor alpha (TGFA), transforming growth factor beta 3 (TGFB3), retinoic acid receptor (RARA), and the proto-oncogene BCL3], we detected modestly elevated odds ratios for the transmission of one marker allele to cleft probands when all the trios were analyzed together. These odds ratios increased when information on type of cleft, race, family history, or maternal smoking were incorporated as effect modifiers. We detected significant interaction between maternal smoking and the transmission of alleles for markers near TGFA and TGFB3; excess transmission of allele 3 at BCL3 was most significant among cleft lip probands; and the odds ratios for transmission of alleles at D19S178 and THRA1 were significant when ethnic group was included in the model. We suggest that utilizing an analytical strategy that allows for stratification of data and incorporating environmental effects into a single analysis may be more effective for detecting genes of small effect.
B-Cell Lymphoma 3 Protein↗
Genetic predisposition to systemic inflammatory proteins is causally associated with inflammatory bowel disease: Insights from multi-omics association study and single-cell RNA-sequencing analysis.
Systemic inflammatory proteins have been reported to be related to inflammatory bowel disease (IBD) in previous observational research. However, their causal links remain obscure. Herein, we performed a Mendelian randomization (MR) analysis to analyze the causality between systemic inflammatory proteins and IBD. Genetic variants related to systemic inflammatory proteins were extracted from a meta-analysis of genome-wide association study (GWAS) data of 8293 European participants. Summary statistics of IBD diverse subtypes were obtained from the international IBD genetic consortium (IIBDGC). We conducted multi-omics method and MR study to detect the causal links through integrating GWAS and protein quantity trait loci (pQTL) data. Inverse variance weighted (IVW) approach was utilized as the dominated analysis method. Moreover, complementary approaches such as MR-Egger intercept test, Cochran Q test and leave-one-out analysis were utilized to validate pleiotropy and heterogeneity. Finally, single-cell RNA-sequencing analysis was performed to detect the expression of significant genes. For IBD, IVW estimates suggested that genetically predicted IL-10 and IL-13 were suggestively associated with an elevated risk of IBD (IL-10: OR: 1.12, 95% CI: 1.00-1.24, P = .04; IL-13: OR: 1.09, 95% CI: 1.01-1.18, P = .023), while CXCL10 was suggestively linked to a lower risk of IBD (CXCL10: OR: 0.90, 95% CI: 0.82-0.99, P = .037). For Crohn disease (CD), the IVW approach provided evidence to sustain that genetically determined IL-13 and CCL3 had a suggestive association with a higher risk of CD (IL-13: OR: 1.13, 95% CI: 1.02-1.26, P = .023; CCL3: OR: 1.22, 95% CI: 1.03-1.45, P = .018). Sensitivity analysis did not explore any heterogeneity and pleiotropy. Our findings supported the causal relationships between 4 specific inflammatory proteins (IL-10, IL-13, CXCL10, and CCL3) and the risk of IBD and CD, thereby providing promising biomarkers of various subtypes stratification and new insights for the prevention and therapeutic target of IBD.
Humans↗
[Prediction of insulin-dependent diabetes mellitus in children of first-degree relatives of diabetic patients].
BACKGROUND: Individuals at risk for insulin dependent diabetes mellitus (IDDM) can be identified using a combination of genetic, immunological and metabolic markers. Our study was aimed at prediction of IDDM in a cohort of children having a first-degree relative with IDDM. METHODS AND RESULTS: In the period of three years, we investigated 208 non-diabetic children and adolescents, aged 10.0 +/- 5.3 (mean +/- SD), mostly siblings of diabetic children. The genetic risk was determined by the HLA-DQB1, -DQA1 genotyping and subtyping of the DRB1*04 alleles carried on the DQB1*0302 haplotypes. Insulitis was detected using a combination of autoantibody tests against three molecular-defined antigens (insulin, GAD65, IA-2). Prevalence of insulitis (defined as confirmed positivity of at least one autoantibody) was 9/208 (4.3%). In children carrying the IDDM highest-risk genotype (HLA-DQB1*0201-DQA1*05/DQB1*0302-DQA1*03), insulitis was almost 10 times more frequent (5/24, 21%) than in children with other genotypes (4/184, 2.2%, P = 0.003). In all subjects with insulitis, the first phase insulin response (FPIR) was determined by the intravenous glucose tolerance test. Three of the nine children had decreased FPIR, of whom two were later diagnosed with IDDM. None of the remaining children developed IDDM. CONCLUSIONS: We present the first IDDM prediction study in the Czech population, emphasising the utility of genetic risk investigation in the prediction scheme.
Adolescent↗
Choline-o-sulphate utilization in Aspergillus nidulans.
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Aspergillus nidulans↗
Nuclear export inhibition activates TP53 pathways and is a potent therapeutic strategy in atypical teratoid rhabdoid tumors.
BACKGROUND: Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor mostly affecting young children. Improved and less toxic therapies for children with ATRT are imperative due to the toxicities associated with current treatments. Furthermore, existing therapies do not address the underlying genetic drivers of ATRT. In this study, we sought to determine whether exportin-1 (XPO1) is a genetic dependency and therapeutic target in ATRT. METHODS: We utilized an integrative approach harnessing patient-derived ATRT cell lines, functional genomics, pharmacologic assays, transcriptomics, and in vivo intracranial xenograft models to systematically test the hypothesis that XPO1 is a novel dependency in ATRT. RESULTS: Analysis of RNA-sequencing datasets revealed high XPO1 expression in ATRT cells compared to other pediatric brain tumor cell lines. Both CRISPR/Cas9 genetic knockdown and pharmacologic inhibition of XPO1 using 6 selective inhibitors of nuclear export (SINEs) in patient-derived atypical teratoid/rhabdoid tumor (ATRT) cells led to significant reduction in cell viability and proliferation. Furthermore, we observed increased apoptosis, G0 phase cell cycle arrest, and upregulation of TP53 signaling pathways in cells treated with the SINE selinexor. Consistently, our transcriptomic data revealed the upregulation of apoptosis and TP53 signaling pathways and concomitant depletion of cell cycle gene sets. In vivo, selinexor in combination with radiation and cyclophosphamide led to significant reduction in tumor volume and increased animal survival in intracranial ATRT xenograft models. CONCLUSIONS: Our data reveals XPO1 as a novel genetic dependency and potent therapeutic target in ATRT.
atypical teratoid rhabdoid tumor↗
The genetic toxicology of organic compounds in natural waters and wastewaters.
This review was drawn from the literature describing genotoxic organic compounds in natural water (rivers, lakes, streams) and wastewater, as well as from recent discussions with industrial scientists and environmental regulators. Testing of wastewaters for genotoxicity may become a routine requirement for some industrial wastewater discharge permits, not unlike the more common requirement for routine aquatic toxicity tests. The stimuli for this are concerns that aquatic organisms inhabiting waters impacted by wastewater discharges suffer an increased risk of genetic damage or cancer, and that humans utilizing these waters for recreational and drinking water purposes may suffer similar genetic or carcinogenic risks. Some evidence suggests that neoplasia in aquatic organisms is related to habitat contamination, yet field evaluations fail to substantiate adequately a cause-and-effect relationship. Because aquatic organisms respond like mammals to the same genotoxic compounds, the increased burden of genotoxic compounds to the environment may impact certain endemic species. Wastewater discharges may be one source of genotoxic organic compounds in those impacted areas. With respect to potential human health impacts, evidence is supportive of increased cancer risk to individuals drinking water from surface sources; however, this risk may or may not relate to whether the drinking water source received input of wastewater discharges or known carcinogens. Throughout the published literature reviewed herein, the Salmonella/Ames gene mutation test was widely used to assess genotoxic activity, although studies using indigenous plants and aquatic organisms as in vivo monitors of genotoxic activity exist. No "standard" or frequently followed protocols for sample collection, sample processing, selection of tests or their conduct, or interpretation of data exist for most of the genotoxicity studies reviewed. For the Salmonella/Ames test, the aqueous samples were concentrated usually on XAD resin or by liquid:liquid extraction, and without this concentration step few samples exhibited genotoxic activity. Hence, in most instances, the ambient concentration of the compounds causing this activity is below that which is readily detectable by this test, a finding not new to this review. In contrast, aquatic organisms in laboratory and field studies responded to ambient concentrations of genotoxic compounds, thus alleviating the need for sample concentration. However, there appears to be a reluctance to utilize this information for extrapolation to potential human health effects. Unfortunately, no generally accepted and scientifically validated protocol for preparing aqueous samples for genotoxicity testing exists. Developing such a protocol is necessary before embarking on widespread genotoxicity testing of wastewaters, especially if results are to be used for permit compliance.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Enhancement of field stability and utility of future biologicals through prior accelerated degradation testing.
The scepticism about the future utility of newer biologicals towards reducing disease morbidity or mortality at the public health or application level can be regarded as appropriate. The financial or research inputs into producing anti-idiotypic, subunit, cloned or genetically engineered products may not be transcribed to the field level due to political or economic impediments and the putative breakdown of any specific activity at the application level, as with the conventional immunobiologicals, may also negate the utility of the newer products. Such an eventuality should be overcome by planning, during the pre-licensure phase, appropriate accelerated degradation tests on newer biologicals.
DNA, Recombinant↗