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1.
Trop Anim Health Prod ; 55(3): 200, 2023 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-37188905

RESUMO

Data on Egyptian buffalo first lactation records (n = 1167) available at Mehalet Mousa Farm (between 2002 and 2015) of the Animal Production Research Institute (APRI), Cairo, Egypt, were used to analyse the genetic parameters of total milk yield (TMY), lactation time (LP), and age at first calving (AFC). Additionally, four selection indices were created by using a single phenotypic standard derivation as relevant economic values. The data were evaluated using multiple-trait derivative-free restricted maximum likelihood (MTDFREML). The estimated heritabilities for TMY, LP, and AFC were 0.22, 0.17, and 0.08 respectively and the phenotypic and genetic correlations between TMY and LP were 0.76 and 0.56, respectively, and between AFC with TMY and LP were nеgаtivеs. Using a selection index that incorporates TMY, LP, and AFC (RIH = 0.68) looks to be optimum for increased genetic gain and a shorter generation interval; as a result, selection should thus be exercised near the end of the first lactation.


Assuntos
Búfalos , Feminino , Animais , Búfalos/genética , Egito
2.
Crit Rev Food Sci Nutr ; 60(20): 3461-3474, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31760761

RESUMO

This article compares and contrasts microbial and chemical risk assessment methodologies in order to evaluate the potential for a common framework for ranking of risk of chemical and microbiological hazards, and developments needed for such a framework. An overview of microbial (MRA) and chemical (CRA) risk assessment is presented and important differences are highlighted. Two microbiological and two chemical hazard-food combinations were ranked based on both a margin of exposure and a risk assessment approach. The comparisons illustrated that it is possible to rank chemical and microbiological hazard-food combinations with traditional approaches from each domain and indicated that the rank order but not the absolute measures is similar using either approach. Including severity in the assessment using DALY reduced differences between hazards and affected the outcome more than which approach was used. Ranking frameworks should include assessment of uncertainty as an integral part of the ranking, and be based on assessment of risk, not safety, and expressed in a common health metric such as disease burden. Necessary simplifications to address data gaps can involve the use of default scenarios. Challenges include comparisons of case-based vs. non-case-based health-endpoints, e.g. biomarker concentration, and integration of the severity of health effects into ranking.


Assuntos
Microbiologia de Alimentos , Alimentos , Contaminação de Alimentos , Medição de Risco
3.
Clin Genet ; 84(5): 464-72, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23323793

RESUMO

Studies suggest that patients carrying a BRCA variant of uncertain significance (VUS) may have lingering confusion concerning results interpretation. Counseling for uninformative BRCA-negative (UN) results is thought to be more straightforward, despite the fact that both results lead to similar methods of empiric cancer risk counseling. This study compared surgical choices and perceptions between 71 patients with VUS results and 714 patients with UN results. All patients underwent genetic counseling because of a personal or family history of breast or ovarian cancer between 1997 and 2010, and completed a 2-year follow-up survey. Risk-reducing mastectomy rates in both groups were 7% (p = 1.00) and risk-reducing oophorectomy rates were 5% and 3%, respectively (p = 0.42). The VUS group reported less cancer distress reduction than the UN group (23.0% vs 35.8%, respectively, p = 0.043). Over 90% of both groups found the counseling process helpful. Overall, the study suggests that VUS results disclosed in genetic counseling did not cause excessive surgery or exaggerated cancer distress, though patients with a VUS found counseling somewhat less informative or reassuring. Future research on communication of VUS results, including pre-and post-test counseling, is essential for full realization of the potential for genomic medicine.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/psicologia , Variação Genética , Neoplasias Ovarianas/psicologia , Estresse Psicológico , Adulto , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Feminino , Seguimentos , Aconselhamento Genético/psicologia , Predisposição Genética para Doença , Humanos , Mastectomia/psicologia , Mastectomia/estatística & dados numéricos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Ovariectomia/psicologia , Ovariectomia/estatística & dados numéricos , Medição de Risco , Incerteza
4.
Braz J Microbiol ; 42(2): 480-8, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24031659

RESUMO

Resistant bacteria in animal can be spread to environment and to humans. Poultry feed and infections caused by Eimeria spp. are important factors in determining the intestinal microbial communities. The aim of this study was to verify the prevalence of species and antimicrobial susceptibility of Enterococcus isolated from broilers fed with different supplements and infected experimentally with Eimeria spp. Broilers were divided in eight groups, fed with diets supplemented with a combination of antimicrobial, ionophore-coccidiostatics, probiotic, essential oil. At 14 days old all birds, except the control, received a solution containing oocysts of Eimeria spp. Samples of cloacal swabs from broilers were collected. A total of 240 Enterococcus sp. strains were isolated, confirmed genus by PCR, classified as species, tested for antimicrobial susceptibility and screened by PCR for the presence of tet(L), tet(M) and erm(B) genes. The overall distribution of species isolated from fecal samples was E. faecalis (40%), followed by E. casseliflavus/E. gallinarum (10.8%), E. mundtii (10.8%), E. faecium (10.8%), E. columbae (5.8%) and E. gallinarum (4.2%). Changes in the composition or frequency of Enterococcus species were observed in all dietary supplementation. Antimicrobial susceptibility tests showed resistance phenotypes a range of antibiotics, especially used in humans such as, streptomycin, penicillin, rifampicin and vancomycin. There was no correlation between different supplementation for broilers and antimicrobial resistance and the presence of tet(M), tet(L) and erm(B) genes. Dietary supplementation had effect on the Enterococcus sp. colonization, but did not have significant effect on the phenotype and genotype of antimicrobial resistance in enterococci.

5.
Science ; 204(4389): 179-80, 1979 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-17738089

RESUMO

Fraction 1 protein has been isolated from leaves of a male sterile Nicotiana tabacum plant containing an extra N. debneyichromosome. The extra chromosome induces appearance of a third polypeptide composing the small subunit of fraction 1 protein, which otherwise contains two polypeptides as is shown by analysis of numerous different cultivars of N. tabacum.

6.
Curr Microbiol ; 58(2): 153-8, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18953604

RESUMO

Bipolaris sorokiniana is a phytopathogenic fungus that causes diseases of cereal crops, such as leaf-spot disease, common root rot, and black point of grain. Because of its great morphological, physiological, and genetic variability, this fungus is difficult to control. The aim of this investigation was to study the variability of isolates of B. sorokiniana by means of vegetative incompatibility. Thirty-five isolates of B. sorokiniana from different geographical regions in Brazil and other countries were used. The vegetative incompatibility between the isolates and the influences of different culture media on these reactions were evaluated. The total protein profile of the isolates was analyzed when the isolates were cultured separately, and in cultures of compatibility and incompatibility reactions. Eighteen of 31 confrontations showed vegetative incompatibility. The results obtained with different culture media for the vegetative compatibility/incompatibility genotypes suggested that the type of substratum influences these reactions. No differences in protein profiles among the isolates were observed. This result suggests that there is no induction of expression of different proteins in vegetative incompatibility reactions.


Assuntos
Ascomicetos/crescimento & desenvolvimento , Doenças das Plantas/microbiologia , Esporos Fúngicos/crescimento & desenvolvimento , Triticum/microbiologia , Ascomicetos/classificação , Ascomicetos/genética , Ascomicetos/isolamento & purificação , Brasil , Meios de Cultura/química , Meios de Cultura/metabolismo , Genótipo , Técnicas de Tipagem Micológica , Esporos Fúngicos/classificação , Esporos Fúngicos/genética , Esporos Fúngicos/isolamento & purificação
7.
Curr Microbiol ; 59(3): 267-73, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19484298

RESUMO

Bipolaris sorokiniana is a phytopathogenic fungus that causes diseases in cereal crops. The high morphological, physiological, and genetic variability makes the control of this fungus a difficult task. The aim of this work was to study the virulence, morphological, and physiological variability of B. sorokiniana isolates. For this, 35 B. sorokiniana isolates from different geographic regions in Brazil and other countries were used. The isolates were evaluated for their morphological variability, considering mycelium color, sector formation, and growth rate. Based on these morphological characteristics, the isolates were grouped in five different morphological groups. Extracellular enzymes activity in solid medium, virulence in wheat seeds and seedlings, and analysis of total proteins by SDS-PAGE were evaluated for all isolates. Variations among the isolates were found for enzymatic activity, and esterase was the enzyme that showed the highest activity indices. The results obtained from infection of seeds and seedlings showed that isolates from the same geographical region and morphological group had different degrees of virulence. The total protein profile shown by the isolates varied in the number of bands and intensity, where some of them may be used to characterize the specie.


Assuntos
Ascomicetos/isolamento & purificação , Ascomicetos/patogenicidade , Doenças das Plantas/microbiologia , Triticum/microbiologia , Ascomicetos/citologia , Ascomicetos/crescimento & desenvolvimento , Brasil , Eletroforese em Gel de Poliacrilamida , Enzimas/análise , Proteínas Fúngicas/análise , Proteoma/análise , Sementes/microbiologia , Virulência
8.
Sci Total Environ ; 672: 525-535, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30965265

RESUMO

Inorganic arsenic (iAs) and total arsenic (tAs) were determined in common food from the Swedish market. Special focus was on rice, fish and shellfish products. For the speciation of iAs the European standard EN:16802 based on anion exchange chromatography coupled to ICP-MS was used. The two market basket food groups cereals (including rice), and sweets and condiments (a mixed group of sugar, sweets, tomato ketchup and dressings), contained the highest iAs levels (means 9 and 7 µg iAs/kg), whereas other food groups, including fish, did not exceed 2 µg iAs/kg. Varying levels of iAs were found in separate samples of tomato ketchup, 2.4-26 µg/kg, and is suggested to be one reason of the rather high average level of iAs in the food group sweets and condiments. Some specific food products revealed iAs levels much higher, i.e. rice crackers 152 and Norway lobster 89 µg iAs/kg. The intake of iAs via food was estimated by data from two national consumption surveys, performed in 2010-11 (1797 adults) and 2003 (2259 children). The estimated median iAs intakes in adults and children were 0.047 and 0.095 µg/kg body weight and day, respectively. The iAs intake for rice eaters was about 1.4 times higher than for non-rice eaters. Validation of the consumption survey-based iAs intake, using food purchase and market basket data mainly from 2015, resulted in a per capita intake of a similar magnitude, i.e. 0.056 µg/kg body weight and day. The estimated cancer risk for adults using low-dose linear extrapolation is <1 per 100,000 per year.


Assuntos
Arsênio/análise , Exposição Dietética/análise , Poluentes Ambientais/análise , Contaminação de Alimentos/estatística & dados numéricos , Arsenicais/análise , Exposição Dietética/estatística & dados numéricos , Grão Comestível/química , Alimentos/estatística & dados numéricos , Oryza/química , Medição de Risco , Alimentos Marinhos/estatística & dados numéricos , Suécia
9.
EFSA J ; 16(Suppl 1): e160813, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32626063

RESUMO

Risk ranking is a versatile tool used to prioritise activities performed by public health regulatory bodies. It also allows efficient communication between all stakeholders in the process of risk analysis. However, risk ranking methods are still not optimal. Because of the different approaches employed in the risk assessment of microbiological agents and chemicals, it is difficult to rank them together using the same metrics. In our work, we first discuss differences and commonalities between chemical and microbiological risk assessment to provide a starting point for consideration of a common risk ranking platform. In the second part, we perform risk ranking of contaminants and regulated chemicals using the recently developed Risk Thermometer tool. In this approach, chemicals are not ranked solely on the basis of the margin of exposure between a reference value and the exposure, but also by considering the severity of the critical health effects used. The results show that ranking using both methods provides different results from the use of either method alone. Overall, specific chemical groups (i.e. heavy metals, pesticides, etc.) do not generally rank higher or lower, but individual compounds are scattered in the rankings from low to high. Risk ranking methods demand further development to gain wide acceptability and recognition.

10.
J Lasers Med Sci ; 9(2): 113-120, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30026896

RESUMO

Introduction: Polycystic ovarian syndrome (PCOS) is one of the most widely recognized reasons for infertility. The aim of this study was to examine the impact of laser acupuncture on PCOS women. Methods: Twenty-five PCOS women were randomly allocated to either the study group (SG; n=13), treated by laser acupuncture, or the control group (CG; n = 12). Blood hormonal levels and insulin resistance were measured at baseline and after 12 weeks of intervention. Results: The pre-intervention levels showed no statistically significant differences between SG and CG for baseline characteristics (P>0.05). After 12 weeks of intervention, within-group analyses showed that body mass index (BMI), blood hormonal levels, and insulin resistance were significantly decreased (P<0.05), while no significant changes in follicle-stimulating hormone (P>0.05) were recorded in the 2 groups. Between-groups analyses showed that most outcomes measures were significantly decreased (P<0.05) in SG compared with CG, with no significant changes in FSH and BMI (P>0.05). Conclusion: Laser acupuncture can be suggested as an effective management for PCOS women.

11.
Genetics ; 83(4): 719-36, 1976 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17248729

RESUMO

New information has resulted from studies comparing the genetic behavior of two experimental cultures, termed variegated-3 and variegated-1, which arose earlier following an interspecific cross. Phenotypic expression in the plant material involves distinctive variegation patterns of anthocyanin distribution in floral tissues.-The data are consistent with the hypothesis that the genetic constitution of variegated-3 includes a unique and independently segregating regulator component, Flt(3), in addition to the v locus element held in common with variegated-1. Flt(3) has not been generated anew within the variegated-1 genotypes among more than 10,000 observed progeny. Presence of Flt(3) modifies the timing of somatic sectoring events, and is correlated with the capability to produce, in germ cell lines of phenotypically flecked plants, frequent changes at the v locus to a stable, non-variegating, dominant allelic form, V.-The latter process is of special interest because progeny tests of mutant individuals, containing newly-arisen V alleles, fail to reveal continued presence of Flt(3). Thus the mechanism generating V from v appears to be correlated invariably with loss or inactivation of the controllingelement inducing this class of mutations, which is located initially on a different chromosome from that bearing v.

12.
Genetics ; 75(1): 93-111, 1973 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-4762878

RESUMO

Somatic effects of radiation intensity on the mutable V and stable R genes were detected in plants of a heterozygous clone (v(S3)/v(s), R/r) subjected to the same dose at four rates. The effects were compared by counting speckled and purple sectors in flowers from irradiated and control plants. Response curves were estimated from the mutant sector averages, observed over a period of transient response for successive mature flowers. A structure for integrating the mutational contributions from different flowers was provided by models. The average control mutation rates are 8,110 per 10(7) cells for the V gene, and 49.45 for R. At a constant intensity of 4320 roentgens/hour, average induced mutation rates per 10(7) cells per roentgen for V increase from 194 (at 24 r total dose) to 1,116 (at 3 r dose); the corresponding rates for R increase from 7.24 to 27.65. With these responses as standards, both genes at corresponding total doses yield lower rates at lower intensities. For the series of intensities 1.2, 0.6, 0.3 and 0.15 roentgens/hour, the decreases in mutation rate for the V gene are, respectively, 66, 148, 315, and 617 per 10(7) cells per roentgen. The corresponding decrements for R are 4.86, 8.70, 14.61, and 23.51. These effects are non-linear functions of intensity for both genes, but V is at least 13 times as sensitive as R. Radiation operating to extinguish a buffering system against final mutation can account for the dose and dose-rate effects observed.


Assuntos
Genes Dominantes , Mutação/efeitos da radiação , Plantas/efeitos da radiação , Radiogenética , Divisão Celular , Células Clonais , Radioisótopos de Cobalto , Cor , Relação Dose-Resposta à Radiação , Heterozigoto , Plantas Tóxicas , Fatores de Tempo , Nicotiana
13.
Genetics ; 90(1): 151-9, 1978 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17248855

RESUMO

Previously, it was shown that a fragment chromosome, apparently derived from the Nicotiana repanda chromosomal complement, restores to normal the morphology and fertility of the abortive and feminized anthers produced by plants that possess the N. tabacum genome in cytoplasm from N. repanda. Furthermore, that restorer chromosome organizes the nucleolus and inhibits the nucleolus-forming activity of the nucleolar organizers of N. tabacum chromosomes present in the same cells, particularly in pollen mother cells. To determine whether these relations are basic or only coincidental, restorer chromosomes for other cytoplasms are now being investigated. The present paper describes a study of a chromosome, presumably derived from N. debneyi, with partial restoring power. Acting in the cytoplasm of N. debneyi, it directs formation of morphologically normal anthers, without, however, restoring pollen fertility. We find that this chromosome also has a functioning nucleolar organizer, but only slightly inhibits the nucleolus-forming capacity of N. tabacum chromosomes. The suggestion of a relationship between the nucleolar apparatus and restoration of normal anthers is thus strengthened by the observation that restorers are found on nucleolus-forming chromosomes from two very distinct Nicotiana species, as well as in several comparable cases cited from the Triticinae. The manner in which the nucleolus, or its organizer, may direct defeminization and restoration of anther morphology is not known; suggestions were offered in the preceding paper in this series (Gerstel, Burns and Burk 1978).

14.
Genetics ; 96(1): 223-35, 1980 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17249061

RESUMO

Plants combining the cytoplasm of Nicotiana debneyi and the 48 chromosomes from N. tabacum are male sterile. Early backcross generations of the amphidiploid hybrid to male N. tabacum produced a great variety of plants from which a series of phenotypes with characteristic flower forms and transmission rates have been isolated. Type 1A possesses completely feminized stamens and deeply split corollas, breeds true when backcrossed to normal males and carries 48 N. tabacum chromosomes. Other phenotypes, 2C, 3E and 4H, range toward normal morphology of corollas and stamens. Like 1A, 2C forms no anther tissue and has 48 chromosomes. This type is transmitted to 36.3% of the backcross progeny, the remainder being of type 1A; presumably 2C carries a chromosome segment from N. debneyi that is responsible for the partial restoration of flower structure. In contrast, both 3E and 4H produce anthers and possess an extra chromosome. The extra chromosomes are transmitted to only 19.9% and 7.1% of the progeny, respectively. Significantly, the extra chromosomes found in the anther-forming types are nucleolus organizing and carry a satellite from N. debneyi. On the basis of these observations, we surmise that differentiation of anthers in plants with N. debneyi cytoplasm may depend on the presence of a nucleolus-organizing chromosome from that species. This chromosome is unstable; unaltered, it conditions a highly restored phenotype (4H), but when structurally modified, it may control different phenotypic expressions. Other examples of satellited restorer chromosomes had been reported for different cytoplasmically male-sterile combinations; therefore, the phenomenon may have more general significance.

15.
J Med Genet ; 41(7): 518-22, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15235022

RESUMO

BACKGROUND: Many clinicians lack adequate knowledge about emerging standards of care related to genetic cancer risk assessment and the features of hereditary cancer needed to identify patients at risk. OBJECTIVE: To determine how a clinical cancer genetics education programme for community based clinicians affected participant knowledge and changed clinical practice. METHODS: The effects of the programme on participant knowledge and changes in clinical practice were measured through pre and post session knowledge questionnaires completed by 710 participants and practice impact surveys completed after one year by 69 out of 114 eligible annual conference participants sampled. RESULTS: Respondents showed a 40% average increase in specific cancer genetics knowledge. Respondents to the post course survey reported that they used course information and materials to counsel and refer patients for hereditary cancer risk assessment (77%), shared course information with other clinicians (83%), and wanted additional cancer genetics education (80%). CONCLUSIONS: There was a significant immediate gain in cancer genetics knowledge among participants in a targeted outreach programme, and subset analysis indicated a positive long term effect on clinical practice. Clinician education that incorporates evidence based content and case based learning should lead to better identification and care of individuals with increased cancer risk.


Assuntos
Genética/educação , Conhecimentos, Atitudes e Prática em Saúde , Neoplasias/genética , Currículo , Estudos de Avaliação como Assunto
16.
Braz J Microbiol ; 45(1): 327-32, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24948952

RESUMO

The present report aimed to perform a molecular epidemiological survey by investigating the presence of virulence factors in E. faecalis isolated from different human clinical (n = 57) and food samples (n = 55) in Porto Alegre, Brazil, collected from 2006 to 2009. In addition, the ability to form biofilm in vitro on polystyrene and the ß-haemolytic and gelatinase activities were determined. Clinical strains presented a higher prevalence of aggregation substance (agg), enterococcal surface protein (esp) and cytolysin (cylA) genes when compared with food isolates. The esp gene was found only in clinical strains. On the other hand, the gelatinase (gelE) and adherence factor (ace) genes had similar prevalence among the strains, showing the widespread occurrence of these virulence factors among food and clinical E. faecalis strains in South Brazil. More than three virulence factor genes were detected in 77.2% and 18.2% of clinical and food strains, respectively. Gelatinase and ß-haemolysin activities were not associated with the presence of gelE and cylA genes. The ability to produce biofilm was detected in 100% of clinical and 94.6% of food isolates, and clinical strains were more able to form biofilm than the food isolates (Student's t-test, p < 0.01). Results from the statistical analysis showed significant associations between strong biofilm formation and ace (p = 0.015) and gelE (p = 0.007) genes in clinical strains. In conclusion, our data indicate that E. faecalis strains isolated from clinical and food samples possess distinctive patterns of virulence factors, with a larger number of genes that encode virulence factors detected in clinical strains.


Assuntos
Proteínas de Bactérias/genética , Enterococcus faecalis/genética , Microbiologia de Alimentos , Infecções por Bactérias Gram-Positivas/microbiologia , Fatores de Virulência/genética , Biofilmes/crescimento & desenvolvimento , Brasil , Enterococcus faecalis/isolamento & purificação , Enterococcus faecalis/fisiologia , Gelatinases/análise , Hemólise , Humanos
18.
Braz J Biol ; 72(2): 323-9, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22735140

RESUMO

Adenovirus (AdV), enterovirus (EV), genogroup A rotaviruses (GARV) and Torque teno virus (TTV) are non-enveloped viral agents excreted in feces and so may contaminate water bodies. In the present study, the molecular detection of these viruses was performed in samples of surface water collected from the Arroio Dilúvio, a waterstream that crosses the city of Porto Alegre, RS, Brazil, receiving great volumes of non-treated sewage from a large urban area. Sampling was performed during 2009, in three different occasions (January, April and September). The highest detection rate was observed for EV (64.28%), followed by TTV (28.57%) and AdV (21.43%). Rotaviruses were not detected. More than on kind of tested virus was detected in five (35. 71%) of 14 samples. January was the month with the highest viral detection rate, being all samples, collected in this month, positive for at least one group of tested virus. The correlation between the detection of these different viral agents and environmental factors is discussed. To the knowledge of the authors, this is the first description of viral genomes in water samples taken from the Arroio Dilúvio, Porto Alegre (Brazil).


Assuntos
Adenoviridae/isolamento & purificação , Enterovirus/isolamento & purificação , Rotavirus/isolamento & purificação , Torque teno virus/isolamento & purificação , Microbiologia da Água , Adenoviridae/genética , Brasil , DNA Viral/genética , Enterovirus/genética , Reação em Cadeia da Polimerase , Rios , Rotavirus/genética , Torque teno virus/genética
19.
Oncogene ; 31(42): 4559-66, 2012 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-22139083

RESUMO

Germline variants in the 3' untranslated region (3'UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3'UTR of the KRAS oncogene, referred to as the KRAS variant, is associated with both cancer risk and altered tumor biology. Here, we test the hypothesis that the KRAS variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS variant-positive EOC patients. As this variant seems to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival. EOC patients with complete clinical data were genotyped for the KRAS variant and analyzed for outcome (n=536), response to neoadjuvant chemotherapy (n=125) and platinum resistance (n=306). Outcome was separately analyzed for women with known BRCA mutations (n=79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were used to confirm altered sensitivity to chemotherapy associated with the KRAS variant. Finally, the KRAS variant was directly targeted through small-interfering RNA/miRNA oligonucleotides in cell lines and survival was measured. Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of ovarian cancer by multivariate analysis (hazard ratio=1.67, 95% confidence interval: 1.09-2.57, P=0.019, n=279). Perhaps explaining this finding, EOC patients with the KRAS variant were significantly more likely to be platinum resistant (odds ratio=3.18, confidence interval: 1.31-7.72, P=0.0106, n=291). In addition, direct targeting of the KRAS variant led to a significant reduction in EOC cell growth and survival in vitro. These findings confirm the importance of the KRAS variant in EOC, and indicate that the KRAS variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this study supports the hypothesis that these tumors have continued dependence on such 3'UTR lesions, and that direct targeting may be a viable future treatment approach.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Regiões 3' não Traduzidas/genética , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/metabolismo , Carboplatina/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Prognóstico , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Interferência de RNA , Resultado do Tratamento , Proteínas ras/metabolismo
20.
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