BAD: a good therapeutic target?

The major goal in cancer treatment is the eradication of tumor cells. Under stress conditions, normal cells undergo apoptosis; this property is fortunately conserved in some tumor cells, leading to their death as a result of chemotherapeutic and/or radiation-induced stress. Many malignant cells, however, have developed ways to subvert apoptosis, a characteristic that constitutes a major clinical problem. Gilmore et al. recently described the ability of ZD1839, a small-molecule inhibitor of the epidermal growth factor receptor (EGFR), to induce apoptosis of mammary cells that are dependent upon growth factors for survival. Furthermore, they showed that the major effector of the EGFR-targeted therapy is BAD, a widely expressed BCL-2 family member. These results are promising in light of the role of the EGFR in breast cancer development

Runx1 Loss Minimally Impacts Long-Term Hematopoietic Stem Cells

RUNX1 encodes a DNA binding subunit of the core-binding transcription factors and is frequently mutated in acute leukemia, therapy-related leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia. Mutations in RUNX1 are thought to confer upon hematopoietic stem cells (HSCs) a pre-leukemic state, but the fundamental properties of Runx1 deficient pre-leukemic HSCs are not well defined. Here we show that Runx1 deficiency decreases both apoptosis and proliferation, but only minimally impacts the frequency of long term repopulating HSCs (LT-HSCs). It has been variously reported that Runx1 loss increases LT-HSC numbers, decreases LT-HSC numbers, or causes age-related HSC exhaustion. We attempt to resolve these discrepancies by showing that Runx1 deficiency alters the expression of several key HSC markers, and that the number of functional LT-HSCs varies depending on the criteria used to score them. Finally, we identify genes and pathways, including the cell cycle and p53 pathways that are dysregulated in Runx1 deficient HSCs

Genome-Wide Local Ancestry Approach Identifies Genes and Variants Associated with Chemotherapeutic Susceptibility in African Americans

Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5′-deoxyfluorouridine (5′-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−4). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5′-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10−3). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information

An evaluation of three self-report physical activity instruments for older adults

Objective: To investigate the reliability and validity of a Wechsler Abbreviated Scale of Intelligence-based Wechsler Adult Intelligence Scale - third edition (WAIS-III) short form (SF) in a sample of individuals with mild to borderline intellectual disability (MBID) (N=117; M-IQ=71.34; SDIQ=8.00, range: 52-85). Methods: A full WAIS-III was administered as a standard procedure in the diagnostic process. Results: The results indicate an excellent reliability (r=0.96) and a strong, positive correlation with the full WAIS-III (r=0.89). The SF correctly identified ID in general and the correct IQ category more specifically in the majority of cases (97.4% and 86.3% of cases, respectively). In addition, 82.1% of the full scale IQ (FSIQ) estimates fell within the 95% confidence interval of the original score. Conclusions: We conclude that the SF is a reliable and valid measure to estimate FSIQ. It can be used in clinical and research settings when global estimates of intelligence are sufficient

Social Responsibility and Cultural Competence Among Physical Therapists With International Experience

Background and Purpose: Physical therapists, particularly those involved in educating doctors of physical therapy (DPTs), are often confronted with the following question: What is the educational priority for entry-level students? To become socially responsible professionals? To become culturally competent providers? How is the physical therapy profession maintaining social responsibility and cultural competence as core values of the profession? The purpose of this study was to investigate whether existing measures of social responsibility and cultural competence capture a potential association between 2 groups of physical therapists with international experiences. The hypothesis was that physical therapists with multiple international experiences would demonstrate a positive relationship between social responsibility and the Inventory for Assessing the Process of Cultural Competence Among Healthcare Professionals-Revised (IAPCC-R) survey tool. Therefore, potential partnership between educators and physical therapists with multiple international experiences could be possible with instructional technology in the classroom. Subjects: Purposive sampling consisted of 2 physical therapist groups, a few international experiences group (n = 32) and a multiple international experiences group (n = 23), retrieved from the American Physical Therapy Association\u27s online member directory. Methods: Quantitative data, generated by using APTAs Professionalism in Physical Therapy: Core Values Self-Assessment and the IAPCC-R online survey, were collected. Results: Study outcomes indicated a statistically significant difference in IAPCCR total scores between the 2 groups. Social responsibility was moderately and positively correlated with IAPCC-R (r = .627, P = .001) for the multiple international experiences group. Discussion and Conclusion: The findings suggest that social responsibility and cultural competence may not be mutually exclusive. Physical therapists with multiple international experiences may help model social responsibility and cultural competence to physical therapist students. Overall, the process of social responsibility and cultural competence is seen as a life-long continuum that should be considered mainstream in the physical therapy profession

Development of the Department of Veterans Affairs Centers of Excellence in Primary Care Education Trainee Participant Survey: Measuring Trainees’ Perceptions of an Interprofessional Education Curriculum

Background: The Trainee Participant Survey was developed for the evaluation of the Department of Veterans Affairs, Centers of Excellence in Primary Care Education (VA CoEPCE), which developed and delivered an interprofessional education (IPE) postgraduate curriculum to learners of multiple professions at seven geographically diverse VA facilities across the United States.Methods and findings: Perceptions of the curriculum by learners across professions were assessed to identify differences in curricular perceptions and unmet needs to inform programmatic changes. The comparison of responses by profession revealed no statistically significant differences across the core domains; precepting, supervising, mentoring; or program practices. Trainee professions differed significantly on satisfaction and system impacts.Conclusion: The Trainee Participant Survey has excellent psychometric properties and can serve as a model for evaluating future IPE programs