Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
1.
Mil Med ; 186(1-2): 119-126, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33005931

RESUMO

INTRODUCTION: Retention is a top priority for the U.S. Navy. However, our understanding of factors influencing retention of Navy personnel is limited. Current research implies that poor mental health, low appraisals of unit cohesion, low leadership satisfaction, and low social support may adversely affect retention. There is a need to understand how these and other factors influence retention in U.S. Navy personnel. We evaluated a broad range of factors influencing job satisfaction and career intentions (proxies of retention) in a large sample of Navy service members. MATERIALS AND METHODS: Seven hundred and ninety-eight U.S. Navy men and women participated in this study as part of the Naval Unit Behavioral Health Needs Survey (NHRC.2014.0006). Independent variables included personal and unit morale, unit cohesion, affective organizational commitment, social support, behavioral health, sleep, leadership satisfaction, and perceived stress. Dependent variables include job satisfaction and career intentions. Separate multivariate regression models examined the unique and combined associations of independent and demographic variables with each dependent variable, respectively. RESULTS: Regression models accounted for 48% of variance in job satisfaction and 55% of variance in career intentions, respectively. The most robust predictors of job satisfaction were affective organizational commitment (i.e., one's emotional attachment to, identification with, and involvement in an organization), depressive symptoms, unit cohesion, and perceived stress; primary predictors of career intentions included affective organizational commitment, years of military service, marital status, and race/ethnicity. CONCLUSION: In this study, we identified diverse predictors of job satisfaction and career intentions of Navy men and women, with overall models accounting for substantial variance in both outcomes. This study informs evidence-based policies, programs, practices, and processes designed to influence job satisfaction, career intentions, and retention in U.S. Navy service members. These study findings also inform the development of a dashboard indicator of retention of U.S. Navy men and women.

2.
Health Educ Res ; 31(3): 405-15, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27107432

RESUMO

Adaptation of evidence-based interventions by implementers is widespread. Although frequently viewed as departures from fidelity, adaptations may be positive in impact and consistent with fidelity. Research typically catalogs adaptations but rarely includes the implementers' perspectives on adaptation. We report data on individuals implementing an evidence-based teen dating violence prevention curriculum. Key informant interviews (n = 20) and an online focus group (n = 10) addressed reasons for adaptations, adaptation processes and kinds of adaptations. All implementers described making adaptations, which they considered necessary to achieving intended outcomes. Adaptations were tailored to needs of individual students or learning opportunities presented by current events, fine-tuned over repeated applications and shared with colleagues. Adaptations modified both content and delivery and included both planned and in-the-moment changes. Implementers made adaptations to increase student engagement, and to fit students' learning needs, learning style, social maturity and culture. Student engagement served as an indicator that adaptation might be needed and provided feedback about the immediate effects of the adaptation. These findings underscore the value of fidelity assessments that measure participant response, intervention-specific guidance to implementers and evaluation of the impact of adaptations on participant response and intervention outcomes.


Assuntos
Prática Clínica Baseada em Evidências/métodos , Educação em Saúde/métodos , Violência por Parceiro Íntimo/prevenção & controle , Grupos Focais , Humanos , Entrevistas como Assunto , Violência por Parceiro Íntimo/psicologia , Desenvolvimento de Programas
3.
Transl Behav Med ; 6(1): 115-24, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27012259

RESUMO

Concepts of culture and diversity are necessary considerations in the scientific application of theory generation and developmental processes of preventive interventions; yet, culture and/or diversity are often overlooked until later stages (e.g., adaptation [T3] and dissemination [T4]) of the translational science process. Here, we present a conceptual framework focused on the seamless incorporation of culture and diversity throughout the various stages of the translational science process (T1-T5). Informed by a community-engaged research approach, this framework guides integration of cultural and diversity considerations at each phase with emphasis on the importance and value of "citizen scientists" being research partners to promote ecological validity. The integrated partnership covers the first phase of intervention development through final phases that ultimately facilitate more global, universal translation of changes in attitudes, norms, and systems. Our comprehensive model for incorporating culture and diversity into translational research provides a basis for further discussion and translational science development.


Assuntos
Cultura , Pesquisa Translacional Biomédica , Humanos , Modelos Teóricos , Participação do Paciente , Pesquisa Translacional Biomédica/métodos
4.
Bone Marrow Transplant ; 51(1): 2-12, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26191950

RESUMO

Increased use of novel agents and autologous stem cell transplantation has led to a significant improvement in PFS and overall survival in patients with multiple myeloma. Despite improved treatment strategies, most patients eventually relapse due to persistent low levels of disease in the bone marrow. Increasingly sensitive methods to measure or detect such disease have been evaluated, including multi-parametric flow cytometry, PCR, next-generation sequencing and imaging modalities. The following literature review examines current methods for detecting and monitoring minimal or measurable residual disease (MRD) in the post-transplant setting. Improved methods for detecting MRD will refine the current definitions of remission and could guide treatment approaches.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Mieloma Múltiplo , Reação em Cadeia da Polimerase Multiplex , Transplante de Células-Tronco , Animais , Autoenxertos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Reação em Cadeia da Polimerase Multiplex/métodos , Neoplasia Residual
5.
Pharmacogenomics J ; 13(5): 410-6, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22664478

RESUMO

The phase III CONFIRM clinical trials demonstrated that metastatic colorectal cancer patients with elevated serum lactate dehydrogenase (LDH) had improved outcome when the vascular endothelial growth factor receptor (VEGFR) inhibitor PTK/ZK (Vatalanib) was added to FOLFOX4 chemotherapy. We investigated the hypothesis that high intratumoral expression of genes regulated by hypoxia-inducible factor-1 alpha (HIF1α), namely LDHA, glucose transporter-1 (GLUT-1), VEGFA, VEGFR1, and VEGFR2, were predictive of outcome in CONFIRM-1. Tumor tissue was isolated by laser-capture microdissection from 85 CONFIRM-1 tumor specimens; FOLFOX4/placebo n=42, FOLFOX4/PTK/ZK n=43. Gene expression was analyzed using quantitative RT-PCR. In univariate analyses, elevated mRNA expression of LDHA, GLUT-1, and VEGFR1 were associated with response to FOLFOX4/PTK/ZK. In univariate and multivariate analyses, elevated LDHA and VEGFR1 mRNA levels were associated with improved progression-free survival in FOLFOX4/PTK/ZK patients. Furthermore, increased HIF1α and VEGFR2 mRNA levels were associated with decreased survival in FOLFOX/placebo patients but not in patients who received FOLFOX4/PTK/ZK. These are the first data suggesting intratumoral mRNA expression of genes involved in angiogenesis/HIF pathway may predict outcome to VEGFR-inhibitors. Biomarkers that assist in directing VEGFR-inhibitors toward patients with an increased likelihood of benefit will improve the cost-effectiveness of these promising agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Transportador de Glucose Tipo 1/biossíntese , Transportador de Glucose Tipo 1/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Compostos Organoplatínicos/administração & dosagem , Ftalazinas/administração & dosagem , Piridinas/administração & dosagem , RNA Mensageiro/genética , Transcriptoma , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
6.
Mil Med ; 177(10): 1178-83, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23113444

RESUMO

Deployment represents a significant potential strain on military families. The impact of postdeployment stresses may be increased if family coping resources are diminished by returning service members' physical injuries, mental health issues, or substance abuse. This article examines the health and mental health correlates of self-reported concerns regarding interpersonal conflict among married soldiers following return from deployment and the likelihood that soldiers acknowledging such concerns are referred to counseling services. Among 20,166 married Army soldiers completing Post-Deployment Health Reassessments, 18% reported having experienced serious interpersonal conflict with their spouse, family members, close friends, or coworkers. Results indicate that interpersonal conflict was more common among those who reported health problems, depression, post-traumatic stress disorder, and alcohol abuse. Among soldiers reporting interpersonal conflict and not already receiving services, 11% were referred to service. Findings support the need to communicate with soldiers and their spouses about the availability of services following return from deployment and to continue efforts to reduce stigma associated with seeking treatment.


Assuntos
Conflito Psicológico , Aconselhamento , Relações Interpessoais , Casamento , Adolescente , Adulto , Campanha Afegã de 2001- , Humanos , Guerra do Iraque 2003-2011 , Modelos Logísticos , Masculino , Militares , Encaminhamento e Consulta/estatística & dados numéricos , Estados Unidos , Adulto Jovem
7.
J Occup Environ Med ; 52(8): 819-26, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20657305

RESUMO

OBJECTIVE: To describe intimate partner violence (IPV) services available through employee assistance programs (EAPs) and determine women's satisfaction with these services. METHODS: A mixed-methods study consisting of semistructured telephone interviews with 28 EAPs about IPV-related services and a national web-based survey of 1765 women regarding their interactions with EAPs when seeking IPV-related assistance. Data were collected in the fall of 2008. RESULTS: EAPs provide fairly extensive services to individuals experiencing IPV. Satisfaction with EAP services for IPV was significantly associated with annual income and the type of help received from the EAP, but not with type of IPV experienced. EAP representatives described challenges with accurately identifying IPV victims and women expressed concerns with confidentiality. CONCLUSIONS: Future efforts to enhance the ability of EAPs to respond effectively to IPV should address confidentially and strengthen how IPV-related assistance is delivered.


Assuntos
Serviços de Saúde do Trabalhador/métodos , Satisfação do Paciente , Maus-Tratos Conjugais/terapia , Adolescente , Adulto , Idoso , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Internet , Pessoa de Meia-Idade , Adulto Jovem
8.
Int J Inj Contr Saf Promot ; 17(3): 177-85, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20373194

RESUMO

Child maltreatment (CM) and intimate partner violence (IPV) take a tremendous toll on communities around the world. Despite the impact of CM and IPV, data on their incidence are drawn from disparate sources of varying quality. To improve data resources in these areas, the Centers for Disease Control and Prevention's (CDC) Division of Violence Prevention funded state-based IPV and CM surveillance activities in nine states between 1994 and 2005. This article describes reported outcomes of these surveillance programmes; assesses factors affecting their sustainability; and provides recommendations for similar programmes through document review and interviews with state representatives. Findings indicate that states achieved outcomes with these surveillance initiatives; however, states noted concerns with sustaining systems because of a lack of resources and ineffective collaborations. Highlighted in this article are several lessons that other countries can learn from the experiences of these states in testing CM and IPV surveillance systems.


Assuntos
Maus-Tratos Infantis/prevenção & controle , Vigilância da População/métodos , Parceiros Sexuais , Violência/prevenção & controle , Adolescente , Centers for Disease Control and Prevention, U.S. , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Entrevistas como Assunto , Masculino , Estados Unidos
9.
Health Promot Pract ; 10(1 Suppl): 19S-28S, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19136442

RESUMO

This study extends past research by examining factors associated with changes in attitudes, knowledge, and intended behaviors related to sexual assault. This study included 1,182 participants from four unique multiple-session school-based sexual violence interventions. Implementation and participant factors examined include single- versus mixed-gender groups, group setting versus classroom lecture setting, and participant gender. Participants completed self-administered, paper-and-pencil pre- and postsurveys. A significant desired overall effect was found on participants' reports of positive attitudes, beliefs, and behavior regarding sexual harassment and personal boundaries and positive dating relationship norms (from pretest to posttest). There were steeper increases over time in both measures, with larger mixed-gender/single-gender differences among boys than among girls. Differences in the impact of participating in mixed- versus single-gender groups depended on classroom versus small group settings. The implications of these findings are discussed for sexual assault prevention programs.


Assuntos
Serviços de Saúde Escolar/organização & administração , Delitos Sexuais/prevenção & controle , Violência/prevenção & controle , Adolescente , Criança , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Funções Verossimilhança , Masculino , Avaliação de Programas e Projetos de Saúde , Inquéritos e Questionários , Estados Unidos
10.
Health Promot Pract ; 10(1 Suppl): 29S-37S, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19136443

RESUMO

Sexual violence is a growing public health problem, and there is an urgent need to develop sexual violence prevention programs. Logic models have emerged as a vital tool in program development. The Centers for Disease Control and Prevention funded an empowerment evaluation designed to work with programs focused on the prevention of first-time male perpetration of sexual violence, and it included as one of its goals, the development of program logic models. Two case studies are presented that describe how significant positive changes can be made to programs as a result of their developing logic models that accurately describe desired outcomes. The first case study describes how the logic model development process made an organization aware of the importance of a program's environmental context for program success; the second case study demonstrates how developing a program logic model can elucidate gaps in organizational programming and suggest ways to close those gaps.


Assuntos
Serviços de Saúde Comunitária/organização & administração , Promoção da Saúde/organização & administração , Modelos Logísticos , Delitos Sexuais/prevenção & controle , Violência/prevenção & controle , Currículo , Humanos , Masculino , Poder Psicológico , Desenvolvimento de Programas , Estupro/prevenção & controle
11.
Health Promot Pract ; 10(1 Suppl): 38S-44S, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19136444

RESUMO

Although empowerment evaluation has gained widespread currency, few reports have described its outcomes. This article combines perspectives of participants and technical assistance providers to describe the process and outcomes of the Evaluation Assistance for Sexual Violence Programs project. Participating programs reported substantial enhancements in evaluation capacity, resources devoted to evaluation, and the extent and sophistication of their evaluation practice, as well as numerous examples of the application of evaluation findings to program improvement. Experiences from evaluation technical assistance providers identified aspects of the process that were particularly useful in achieving these outcomes, including investing in collaborative relationships, maximizing participation among program staff, tailoring the content and form of technical assistance to program preferences, and combining structured learning with program-specific technical assistance.


Assuntos
Promoção da Saúde/organização & administração , Avaliação de Processos e Resultados em Cuidados de Saúde , Poder Psicológico , Delitos Sexuais/prevenção & controle , Violência/prevenção & controle , Adolescente , Humanos , Entrevistas como Assunto , Avaliação de Programas e Projetos de Saúde
12.
J Interpers Violence ; 22(12): 1567-80, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17993642

RESUMO

This study extends past research by examining predictors of different types of sexual assault perpetration in a community sample. Computer-assisted self-interviews were conducted with a representative sample of 163 men in one large urban community. As hypothesized, many variables that are significant predictors of sexual assault perpetration in college student samples were also significant predictors in this sample, including empathy, adult attachment, attitudes about casual sex, sexual dominance, alcohol consumption in sexual situations, and peer approval of forced sex. For most measures, the strongest differences were between nonassaulters and men who committed acts that met standard legal definitions of rape. Men who committed forced sexual contact and verbal coercion tended to have scores that fell in between those of the other two groups. The implications of these findings are discussed for community-based sexual assault prevention programs.


Assuntos
Agressão/psicologia , Coerção , Estupro/psicologia , Maus-Tratos Conjugais/psicologia , População Urbana , Adulto , Humanos , Relações Interpessoais , Masculino , Avaliação de Programas e Projetos de Saúde , Medição de Risco , Fatores de Risco , Autoimagem , Inquéritos e Questionários , Estados Unidos
13.
Aggress Behav ; 32(1): 54-67, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26435555

RESUMO

Computer-assisted self-interviews were completed with a random sample of 163 unmarried Caucasian and African American men in a large metropolitan area. Almost a quarter (24.5%) of these men acknowledged committing an act since the age of 14 that met standard legal definitions of attempted or completed rape; an additional 39% had committed another type of sexual assault involving forced sexual contact or verbal coercion. An expanded version of the Malamuth et al. [1991] confluence model was examined using path analysis. The number of sexual assaults perpetrated by participants was associated with the direct or indirect effects of childhood sexual abuse, adolescent delinquency, alcohol problems, sexual dominance, positive attitudes about casual sexual relationships, and pressure from peers to engage in sexual relationships. Additionally, empathy buffered the relationship between sexual dominance and perpetration. The pattern of results was highly similar for African American and Caucasian men. The implications of these findings for sexual assault measurement are discussed and suggestions are made for alternative treatment programs.

14.
Alcohol Clin Exp Res ; 29(2): 263-9, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15714049

RESUMO

This article summarizes the proceedings of a symposium presented at the 2004 meeting of the Research Society on Alcoholism (RSA) in Vancouver, British Columbia, Canada. There were four presentations and a discussant. The symposium was co-chaired by Tina Zawacki and Jeanette Norris. The first presentation was made by Jeanette Norris, who found that alcohol consumption and preexisting alcohol expectancies affected women's hypothetical responses to a vignette depicting acquaintance sexual aggression. The second presentation was made by Joel Martell, who reported that alcohol-induced impairment of executive cognitive functioning mediated the effect of intoxication on men's perceptions of a sexual assault vignette. In the third presentation, Antonia Abbey found that the experiences of women whose sexual assault involved intoxication or force were more negative than were the experiences of women whose sexual assault involved verbal coercion. The fourth presentation was made by Tina Zawacki, who reported that men who perpetrated sexual assault only in adolescence differed from men who continued perpetration into adulthood in terms of their drinking patterns and attitudes toward women. William H. George discussed these findings in terms of their implications for theory development and prevention programming.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Delitos Sexuais/psicologia , Consumo de Bebidas Alcoólicas/psicologia , Feminino , Humanos , Masculino , Delitos Sexuais/prevenção & controle
15.
Psychol Women Q ; 28(4): 323-332, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26257466

RESUMO

Only a few studies have examined the characteristics of sexual assault based on the tactics used by the perpetrator. In this study we compared the experiences of women who were forced to engage in vaginal, anal, or oral intercourse due to verbal coercion, physical force, or intoxication. Random-digit dialing was used to obtain a sample of 272 single African American and Caucasian women between the ages of 18 and 49 from the Detroit metropolitan area. Participants completed a computer-assisted self-interview that asked detailed questions about a past sexual assault and their reactions to it. Among the 139 women who were forced to engage in vaginal, anal, or oral intercourse, sexual assaults that involved physical force produced the most severe negative outcomes. Situations that involved the woman being too intoxicated to resist differed from others primarily in terms of how much alcohol the man and woman consumed. Although all types of sexual assault were perceived as being at least moderately serious, verbally coerced assaults were on average perceived as being least serious. These findings suggest that the perpetrators' tactics affect women's responses to sexual assault.

16.
J Interpers Violence ; 18(7): 813-33, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-14675511

RESUMO

Researchers have suggested that intoxicated perpetrators may act more violently than other perpetrators, although empirical findings have been mixed. Past research has focused on whether or not alcohol was consumed, rather than the quantity consumed, and this may explain these inconsistent findings. The authors hypothesized that the quantity of alcohol consumed would have a curvilinear relationship to the severity of the assault. Data were collected from 113 college men who reported that they had committed a sexual assault since the age of 14. The quantity of alcohol that perpetrators consumed during the assault was linearly related to how much aggression they used and was curvilinearly related to the type of sexual assault committed. The quantity of alcohol that victims consumed during the assault was linearly related to the type of sexual assault committed. Strategies for improving assessment of alcohol consumption in sexual assault research are discussed.


Assuntos
Consumo de Bebidas Alcoólicas , Delitos Sexuais/psicologia , Estudantes , Adolescente , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Fatores de Risco
17.
Aggress Behav ; 29(4): 366-380, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26430287

RESUMO

Approximately 50% of sexual assaults involve alcohol. Researchers have documented situational characteristics that distinguish between sexual assaults that do and do not involve alcohol, but little attention has been paid to differences between the perpetrators of these two types of assault. In this study, discriminant function analysis was used to distinguish between college men (N = 356) who reported perpetrating sexual assault that involved alcohol, sexual assault that did not involve alcohol, or no sexual assault. Predictors of sexual assault perpetration that have been documented in past research differentiated nonperpetrators from both types of perpetrators. Perpetrators of sexual assaults that involved alcohol were in most ways similar to perpetrators of sexual assaults that did not, although they did differ on impulsivity, alcohol consumption in sexual situations, and beliefs about alcohol. These findings suggest mechanisms through which alcohol is involved in sexual assault that are relevant to theory and prevention.

18.
Pharmacogenomics J ; 1(1): 65-70, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11913730

RESUMO

Thymidylate synthase (TS) catalyses the conversion of deoxy-uridylate to deoxy-thymidylate and is essential for DNA synthesis. The human TS gene promoter is polymorphic, having either double or triple tandem repeats of a 28-bp sequence. Here we determined the significance of this polymorphism in humans and its prediction for clinical outcome of patients with metastatic colorectal cancer treated with 5-fluorouracil. The TS mRNA level was analyzed using RT-PCR. Individuals homozygous for the triple repeat variant (L/L) had 3.6 times higher TS mRNA levels compared to those homozygous for the double repeat variant (S/S) in tumor tissue (P = 0.004). We tested 50 patients with disseminated colorectal cancer who received 5-FU treatment to determine whether this TS polymorphism will predict clinical outcome. We found individuals with S/S genotype had a response rate of 50% (4/8) when compared to 9% (2/22) in those with L/L and 15% (3/20) in those with S/L genotype (P = 0.041). Patients with L/L had less severe side effects to 5-FU (P = 0.008). The data suggest that genotyping for the TS polymorphism may have the potential to identify patients more likely to respond to 5-FU based chemotherapy.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Fluoruracila/efeitos adversos , Polimorfismo Genético , Timidilato Sintase/genética , Adulto , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise
19.
Cancer Res ; 60(13): 3493-503, 2000 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-10910061

RESUMO

Aberrant dUTP metabolism plays a significant role in the underlying molecular mechanisms of cell killing mediated by inhibitors of thymidylate biosynthesis. dUTP nucleotidohydrolase (dUTPase) is the key regulator of dUTP pools, and significant evidence exists suggesting that the expression of this enzyme may be an important determinant of cytotoxicity mediated by inhibitors of thymidylate synthase (TS). In this study, we have determined the expression patterns of dUTPase in normal and neoplastic tissues and examined the association between dUTPase expression and response to 5-fluorouracil (5-FU)-based chemotherapy and overall survival in colorectal cancer. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections using a monoclonal antibody (MAb), DUT415, that cross-reacts with both nuclear and mitochondrial isoforms of human dUTPase. Nuclear and cytoplasmic staining was observed in both normal and neoplastic tissues. In normal tissues, nuclear dUTPase staining was observed exclusively in replicating cell types. This observation is in agreement with cell culture studies where expression of the nuclear isoform (DUT-N) is proliferation dependent In contrast, cytoplasmic expression of dUTPase does not correlate with proliferation status and was observed in tissues rich in mitochondria. Consistent with this observation, cell culture studies reveal that the mitochondrial isoform (DUT-M) is expressed constitutively, independent of cell cycle status. These data suggest that in normal tissues, nuclear staining with the DUT415 antibody represents the DUT-N isoform, whereas cytoplasmic staining represents the DUT-M isoform. In colon cancer tumor specimens, expression of dUTPase was shown to be highly variable in both amount and intracellular localization. Patterns of dUTPase protein expression observed included exclusive nuclear, exclusive cytoplasmic, and combined nuclear and cytoplasmic staining. Thus, immunohistochemical detection of dUTPase in colon cancers provides distinct intracellular phenotypes of expression that may be of significant prognostic value. To examine the association between dUTPase expression and response to 5-FU-based chemotherapy and overall survival, we initiated a retrospective study including tumor specimens from 20 patients who had received protracted infusion of 5-FU and leucovorin for treatment of metastatic colon cancer. Positive nuclear staining was found in 8 patients, whereas 12 lacked nuclear expression. Of the patients lacking nuclear dUTPase expression, 6 responded to 5-FU-based chemotherapy, 4 had stable disease, and 2 had progressive disease. Of the patients presenting positive nuclear dUTPase expression, 0 responded to chemotherapy, 1 had stable disease, and 7 had progressive disease (P = 0.005). The median survival for patients with tumors lacking nuclear staining was 8.5 months and 6.9 months for patients with tumors demonstrating positive nuclear dUTPase expression (P = 0.09). Time to progression was significantly longer for patients with tumors lacking nuclear staining (P = 0.017). Variable cytoplasmic dUTPase expression was observed in these tumors; however, there was no apparent association with clinical response or survival in this limited study. Nuclear dUTPase staining within these tumors was also associated with TS gene expression (P = 0.06). This study demonstrates that low intratumoral levels of nuclear dUTPase protein expression is associated with response to 5-FU-based chemotherapy, greater time to progression, and greater overall survival in colorectal cancer. Conversely, high levels of nuclear dUTPase protein expression predict for tumor resistance to chemotherapy, shorter time to progression, and shorter overall survival. This report represents the first clinical study implicating dUTPase overexpression as a mechanism of resistance to TS inhibitor-based chemotherapy.


Assuntos
Neoplasias do Colo/patologia , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/patologia , Fluoruracila/toxicidade , Fluoruracila/uso terapêutico , Pirofosfatases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Colo/enzimologia , Neoplasias do Colo/enzimologia , Neoplasias Colorretais/tratamento farmacológico , Etnicidade , Feminino , Células HeLa , Humanos , Mucosa Intestinal/enzimologia , Isoenzimas/metabolismo , Linfócitos/enzimologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Valores de Referência , Células Tumorais Cultivadas , Estados Unidos
20.
Ann Diagn Pathol ; 2(2): 93-102, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9845725

RESUMO

We report 29 cases of adenocarcinomas whose clinical, gross, and microscopic appearance resembled diffuse malignant pleural mesothelioma. Initial criteria for inclusion in the study included availability of an open pleural biopsy or decortication specimen and microscopic evidence of neutral (periodic acid-Schiff positive) mucin in the tumor. The median age of the patients was 63 years (range, 31 to 78 years), with a peak age in the seventh decade. There were 24 men and five women. Thirteen of them had a history of smoking; six (21%) had possible or definite occupational exposure to asbestos. Three (21%) of 14 lung specimens showed ferruginous bodies and two (14%) showed microscopic evidence of asbestosis. At least 25 patients had pleural effusion, most typically unilateral. Needle biopsy of pleura showed malignancy in 10 (77%) of 13 cases. Most (20 of 29) patients underwent pleural stripping. Radiotherapy and chemotherapy was each given to three patients without effect. Median survival by Kaplan-Meier estimate was 8 months, with an 18-month survival of 13%. Histologically, glands (23 cases), nests (13 cases), tubulopapillary arrays (12 cases), or sheets (eight cases) of tumor cells were found. Spindling of neoplastic cells was seen in 10% of cases. Three (21%) of 14 lung specimens showed a subpleural adenocarcinoma. Antibodies to polyclonal CEA, Ber-EP4, Leu-M1, and B72.3 were positive in 94%, 56%, 50%, and 44% of cases, respectively. All but one of the cases stained with two or more of the antibodies CEA, Ber-EP4, Leu-M1, or B72.3. This study indicates that adenocarcinomas simulating mesothelioma are aggressive variants of peripheral adenocarcinomas with a poor prognosis, that they can show pathological evidence of asbestos exposure in a subset of cases, and that immunohistochemical and histochemical stains are useful in their differential diagnosis with diffuse malignant mesotheliomas.


Assuntos
Adenocarcinoma/patologia , Neoplasias Pulmonares/patologia , Mesotelioma/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Adenocarcinoma Bronquioloalveolar/patologia , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Mesotelioma/tratamento farmacológico , Mesotelioma/radioterapia , Pessoa de Meia-Idade , Coloração e Rotulagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...