889 resultados para translation initiation


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by Henry A. Franklin

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by Marcus Nathan Adler

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by Adolf Hitler

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Bortezomib (VELCADE™, formerly known as PS-341) is a selective and potent inhibitor of the proteasome that was recently FDA-approved for the treatment of multiple myeloma. Despite its success in multiple myeloma and progression into clinical trials for other malignancies, bortezomib's exact mechanism of action remains undefined. The major objective of this study was to evaluate the anticancer activity of this drug using in vitro and in vivo pancreatic cancer models and determine whether bortezomib-induced apoptosis occurs via induction of endoplasmic reticular (ER) stress. The investigation revealed that bortezomib inhibited tumor cell proliferation via abrogation of cdk activity and induced apoptosis in pancreatic cancer cell lines. I hypothesized that bortezomib-induced apoptosis was triggered by a large accumulation ubiquitin-conjugated proteins that resulted in ER stress. My data demonstrated that bortezomib induced a unique type of ER stress in that it inhibited PKR-like ER kinase (PERK) and subsequent phosphorylation of eukaryotic initiation factor 2α (eif2α), a key event in translational suppression. The combined effects of proteasome inhibition and the failure to attenuate translation resulted in an accumulation of aggregated proteins (proteotoxicity), JNK activation, cytochrome c release, caspase-3 activation, and DNA fragmentation. Bortezomib also enhanced apoptosis induced by other agents that stimulated the unfolded protein response (UPR), demonstrating that translational suppression is a critical cytoprotective mechanism during ER stress. Tumor cells attempt to survive bortezomib-induced ER stress by sequestering aggregated proteins into large structures, termed aggresomes. Since histone deacetylase 6 (HDAC6) is essential for aggresome formation, tumor cells may be sensitized to bortezomib-induced apoptosis by blocking HDAC function. My results demonstrated that HDAC inhibitors disrupted aggresome formation and synergized with bortezomib to induce apoptosis in pancreatic cancer or multiple myeloma cells in vitro and in orthotopic pancreatic tumors in vivo. Taken together, my data establish a mechanistic link between bortezomib-induced aggresome formation, ER stress, and apoptosis and identify a novel therapeutic strategy for the treatment of pancreatic cancer and other hematologic and solid malignancies. ^

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Background/significance. The scarcity of reliable and valid Spanish language instruments for health related research has hindered research with the Hispanic population. Research suggests that fatalistic attitudes are related to poor cancer screening behaviors and may be one reason for low participation of Mexican-Americans in cancer screening. This problem is of major concern because Mexican-Americans constitute the largest Hispanic subgroup in the U.S.^ Purpose. The purposes of this study were: (1) To translate the Powe Fatalism Inventory, (PFI) into Spanish, and culturally adapt the instrument to the Mexican-American culture as found along the U.S.-Mexico border and (2) To test the equivalence between the Spanish translated, culturally adapted version of the PFI and the English version of the PFI to include clarity, content validity, reading level and reliability.^ Design. Descriptive, cross-sectional.^ Methods. The Spanish language translation used a translation model which incorporates a cultural adaptation process. The SPFI was administered to 175 bilingual participants residing in a midsize, U.S-Mexico border city. Data analysis included estimation of Cronbach's alpha, factor analysis, paired samples t-test comparison and multiple regression analysis using SPSS software, as well as measurement of content validity and reading level of the SPFI. ^ Findings. A reliability estimate using Cronbach's alpha coefficient was 0.81 for the SPFI compared to 0.80 for the PFI in this study. Factor Analysis extracted four factors which explained 59% of the variance. Paired t-test comparison revealed no statistically significant differences between the SPFI and PFI total or individual item scores. Content Validity Index was determined to be 1.0. Reading Level was assessed to be less than a 6th grade reading level. The correlation coefficient between the SPFI and PFI was 0.95.^ Conclusions. This study provided strong psychometric evidence that the Spanish translated, culturally adapted SPFI is an equivalent tool to the English version of the PFI in measuring cancer fatalism. This indicates that the two forms of the instrument can be used interchangeably in a single study to accommodate reading and speaking abilities of respondents. ^

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Background/significance. Mental illness stigma is a matter of great concern to family caregivers. Few research studies have been conducted in the Arab World on family caregivers' perception of stigma associated with caring for a mentally ill relative. Review of the literature on measurement of the concept of stigma related to caring for a mentally ill relative yielded no instrument appropriate for use in a Jordanian sample. Reliable and valid instruments to measure stigma perception among family caregivers are needed for research and practice, particularly in Arabic speaking populations. ^ Purpose. The purposes of this study were: (1) translate the Stigma-Devaluation scale (SDS) into Arabic, modifying it to accurately reflect the cultural parameters specific to Jordan, and (2) test the reliability, the content and construct validity of the Arabic version of the SDS for use among a sample of family members of mentally ill relatives in Jordan. ^ Design. Methodologic, cross-sectional. ^ Methods. The SDS was translated into Arabic language, modified and culturally adapted to the Jordanian culture by a translation model which incorporates a cultural adaptation process. The Arabic SDS was evaluated in a sample of 164 family caregivers in the outpatient mental health clinic in Irbid-Jordan. Cronbach's alpha estimation of internal consistency was used to assess the reliability of the SDS. Construct validity was determined by confirmatory factor analysis (CFA). Measurements of content validity and reading level of the Arabic SDS were included. ^ Findings. Content Validity Index was determined to be 1.0. Reading level of the Arabic SDS was considered at a 6th grade or lower Cronbach's alpha coefficient of the modified Arabic SDS total scale was .87. Initial results of CFA did not fully support the proposed factor structures of the SDS or its subscales. After modifications, the indices indicated that the modified model of each subscale had satisfactory fit. ^ Conclusion. This study provided psychometric evidence that the modified Arabic SDS translated and culturally adapted instrument, is valid and conceptually consistent with the content of the original English SDS in measuring stigma perception among families of mentally ill relatives in Jordan. ^

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The general research question for this dissertation was: do the data on adolescent sexual experiences and sexual initiation support the explicit or implicit adolescent sexuality theories informing the sexual health interventions currently designed for youth? To respond to this inquiry, three different studies were conducted. The first study included a conceptual and historical analysis of the notion of adolescence introduced by Stanley Hall, the development of an alternative model based on a positive view of adolescent sexuality, and the rationale for introducing to adolescent sexual health prevention programs the new definitions of sexual health and the social determinants of health approach. The second one was a quantitative study aimed at surveying not only adolescents' risky sexual behaviors but also sexual experiences associated with desire/pleasure which have been systematically neglected when investigating the sexual and reproductive health of the youth. This study was conducted with a representative sample of the adolescents attending public high schools in the State of Caldas in the Republic of Colombia. The third study was a qualitative analysis of 22 interviews conducted with male and female U.S. Latino adolescents on the reasons for having had or having not had vaginal sex. The more relevant results were: most current adolescent sexual health prevention programs are still framed in a negative approach to adolescent sexuality developed a century ago by Stanley Hall and Sigmund Freud which do not accept the adolescent sexual experience and propose its sublimation. In contrast, the Colombian study indicates that, although there are gender differences, adolescence is for males and females a normal period of sexual initiation not limited to coital activity, in which sexual desire/pleasure is strongly associated with sexual behavior. By the same token, the study about the reasons for having had or not had initiated heterosexual intercourse indicated that curiosity, sexual desire/pleasure, and love are basic motivations for deciding to have vaginal sexual intercourse for the first time and that during adolescence, young women and men reach the cognitive development necessary for taking conscious decisions about their sexual acts. The findings underline the importance of asking pertinent questions about desire/pleasure when studying adolescent sexuality and adopting an evidence-based approach to sexual health interventions.^

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Background. Among Hispanics, the HPV vaccine has the potential to eliminate disparities in cervical cancer incidence and mortality but only if optimal rates of vaccination are achieved. Media can be an important information source for increasing HPV knowledge and awareness of the vaccine. Very little is known about how media use among Hispanics affects their HPV knowledge and vaccine awareness. Even less is known about what differences exist in media use and information processing among English- and Spanish-speaking Hispanics.^ Aims. Examine the relationships between three health communication variables (media exposure, HPV-specific information scanning and seeking) and three HPV outcomes (knowledge, vaccine awareness and initiation) among English- and Spanish-speaking Hispanics.^ Methods. Cross-sectional data from a survey administered to Hispanic mothers in Dallas, Texas was used for univariate and multivariate logistic regression analyses. Sample used for analysis included 288 mothers of females aged 8-22 recruited from clinics and community events. Dependent variables of interest were HPV knowledge, HPV vaccine awareness and initiation. Independent variables were media exposure, HPV-specific information scanning and seeking. Language was tested as an effect modifier on the relationship between health communication variables and HPV outcomes.^ Results. English-speaking mothers reported more media exposure, HPV-specific information scanning and seeking than Spanish-speakers. Scanning for HPV information was associated with more HPV knowledge (OR = 4.26, 95% CI = 2.41 - 7.51), vaccine awareness (OR = 10.01, 95% CI = 5.43 - 18.47) and vaccine initiation (OR = 2.54, 95% CI = 1.09 - 5.91). Seeking HPV-specific information was associated with more knowledge (OR = 2.27, 95% CI = 1.23 - 4.16), awareness (OR = 6.60, 95% CI = 2.74 - 15.91) and initiation (OR = 4.93, 95% CI = 2.64 - 9.20). Language moderated the effect of information scanning and seeking on vaccine awareness.^ Discussion. Differences in information scanning and seeking behaviors among Hispanic subgroups have the potential to lead to disparities in vaccine awareness.^ Conclusion. Findings from this study underscore health communication differences among Hispanics and emphasize the need to target Spanish language media as well as English language media aimed at Hispanics to improve knowledge and awareness.^

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The female reproductive tract (FRT) develops midway through embryogenesis, and consists of oviducts, uterine horns, cervix and upper part of the vagina. The uterine horns are composed of an epithelial layer, luminal (LE) and glandular epithelium (GE), surrounded by a mesenchymal layer, the stroma and myometrium. Interestingly, in most mammals the GE forms after birth and it only becomes fully differentiated as the female reaches sexual maturity. Uterine glands (UG) are made up of GE and are present in all mammals. They secrete nutrients, cytokines and several other proteins, termed histotroph, that are necessary for embryo implantation and development. Experiments in ewes and mice have revealed that females who lack UGs are infertile mainly due to impaired implantation and early pregnancy loss, suggesting that UGs are essential for fertility. Fortunately for us, UGs develop after birth allowing us to peer into the genetic mechanism of tubulogenesis and branching morphogenesis; two processes that are disrupted in various adenocarcinomas (cancer derived from glands). We created 3D replicas of the epithelium lining the FRT using optical projection tomography and characterized UG development in mice using lineagetracing experiments. Our findings indicate that mouse UGs develop as simple tubular structures and later grow multiple secretory units that stem from the main duct. The main aim of this project was to study the role of SOX9 in the UGs. Preliminary studies revealed that Sox9 is mostly found in the nucleus of the GE. vii This observation led to the hypothesis that Sox9 plays a role in the formation and/or differentiation of the GE. To study the role of Sox9 in UGs differentiation, we conditionally knocked out and overexpressed Sox9 in both the LE and GE using the progesterone receptor (Pgr) promoter. Overexpressing Sox9 in the uterine epithelium, parts of the stroma, and myometrium led to formation of multiple cystic structures inside the endometrium. Histological analysis revealed that these structures appeared morphologically similar to structures present in histological tissue sections obtained from patients with endometrial polyps. We have accounted for the presence of simple and complex hyperplasia with atypia, metaplasia, thick-walled blood vessels, and stromal fibrosis; all “hallmarks” that indicate overexpressing Sox9 leads to development of a polyp-like morphology. Therefore, we can propose the use of Sox9-cOE mice to study development of endometrial cystic lesions and disease progression into hyperplastic lesions.

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Smoking is often initiated in adolescence through trying or experimenting with cigarettes. Smoking initiation is the beginning critical stage in the smoking trajectory often resulting in addiction. This dissertation examined the effect of parenting variables on smoking initiation behavior among 11–14 year old Mexican origin adolescents, a largely understudied group. The participants in this study were part of a population-based cohort of Mexican origin adolescents residing in Houston, Texas. ^ Aim 1 of this study assessed the appropriateness of the Family Life Questionnaire (FLQ) among Mexican origin adolescents. Second order confirmatory factor analysis (CFA) was performed to examine the factor structure of the FLQ and measurement invariance testing was conducted to evaluate the cross-cultural validity of this scale. Aim 2 analyzed cross-sectional associations between parenting variables and adolescent ever tried smoking behavior while aim 3 focused on prospective examination of changes in parenting variables from baseline to final follow-up on ever tried smoking behavior among never smokers. ^ Overall, the results of the CFA indicated that the original factor structure of the FLQ, with alterations, was a good fit for the Mexican origin adolescents. The measurement invariance analysis of the modified FLQ scale indicated adequate measurement invariance. The aim 2 cross-sectional analyses indicated that family cohesion was significantly associated with lower odds of ever tried smoking. Authoritarian parenting was significantly associated with smoking initiation only at the baseline while family conflict was significantly associated with smoking initiation only at the two-year final home visit. The findings from the aim 3 prospective analysis indicated that changes in levels of family cohesion and conflict are important predictors of smoking initiation among those who have never tried smoking. Specifically, perceiving low levels of family cohesion and a decrease in the family cohesion over two years, as well as perceiving high levels of family conflict and an increase in conflict over two years was associated with smoking initiation among never smokers. ^ In general, the findings of this study provide important insights on the links between parenting and adolescent smoking and assist in designing prevention and intervention programs that emphasize the role of family bonding to prevent adolescent smoking behavior. Family education programs for Mexican culture could also highlight the positive effects of authoritarian practices and good family communication to prevent family conflict and subsequent smoking behavior.^

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We examined the practice of initiating Cholinesterase Inhibitors (ChEI) in a Veterans Affairs Medical Center. Patients hospitalized in FY 2008 and prescribed ChEI were identified. We reviewed electronic medical records, comparing those started on ChEI during hospitalization with those continuing ChEI from outpatient status. Of 282 patients receiving ChEI during hospitalization, 15.6% (44) were new-starts and 84.3% (238) were continuing medication. Median length of stay was 16 days in new-starts vs. 6 days in continuation patients (P<0.05). 38.6% new-starts were also treated for infection, which is a delirium risk factor. Chart review also suggested possible treatment for delirium by initiation of benzodiazepines and antipsychotics in 11.4% and 22.7% new-starts respectively. We observed a substantive practice of initiating ChEIs in hospitalized elderly who were at risk of delirium. Though there was no difference in 30-day mortality and readmission rates, new-starts were more likely to have a prolonged hospital stay than continuation patients.^

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Because Hispanic women are even less likely than women of other ethnic groups to receive early prenatal care, the purpose of this study was to identify factors that may influence these women to initiate care. After giving consent, 300 Hispanic women (100 who initiated first trimester care, 100 who initiated second trimester care, and 100 who initiated third trimester care or received no care) were interviewed in the post partum unit of a local public hospital. The interview included recollection of events leading to the first prenatal appointment, including first physical indicators of pregnancy, confirmation of pregnancy, feelings about the pregnancy, appointment making behavior, and system barriers encountered. The Health Belief Model was used as the theoretical framework for determining psychosocial variables. Using this model, perceived susceptibility to problems during pregnancy, perceived seriousness of possible problems, perceived benefits of prenatal care, perceived barriers to care, and cues to action were assessed. Time of entry into prenatal care was assessed by interview.^ In this sample of low-income Hispanic women, a higher perception of barriers to care was associated with later initiation of care and non-use of care, higher perceived benefits of care for the baby were associated with earlier care, especially in women without a card to access hospital district services, and having a card to access hospital district services was associated with earlier care. Several barriers to care were mentioned by women on open-ended questioning including long waiting times, embarrassment, and lack of transportation.^ Recommendations for practice included decreasing the number of visits for low-risk women while increasing the time spent with the provider, decreasing the number of vaginal exams for low-risk women, increasing the use of midwives, training lay workers to do risk assessment, giving specific messages about benefits of care to baby, and increasing general health motivation through community intervention methods. More research on the psychosocial and cultural factors associated with initiation of care is needed. In the meantime, the recommendations for practice can be implemented now to increase the use of prenatal care by low-income Hispanic women. ^