Translational Research Principles Research Articles

Therapeutic Strategies for the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Positive (HR+/HER2+) Breast Cancer: A Review of the Current Literature.

Simple SummaryIn the last decades, tremendous advances have been made in understanding HER2-positive breast cancer biology, with a progressive improvement in survival rates of patients with this breast cancer subtype. However, a not negligible proportion of patient with HER2-positive breast cancer will eventually relapse, and metastatic HER2-positive disease is still to be considered an incurable condition, thus highlighting the imperative need to further improve our understanding in this regard. In this context, there is growing knowledge that HER2-overexpressing breast tumors are highly heterogeneous, and the co-expression of hormone-receptors may account, at least in part, for this heterogeneity. The aim of the present work is to review preclinical and clinical evidence on HER2-positive/hormone-receptor positive breast cancer, focusing on studies investigating both activity and efficacy of various combination of treatment strategies, including anti-HER2 drugs, hormonal treatments and other targeted agents, such as CDK inhibitors, both in the early and advanced setting.Enormous advances have been made in the understanding and treatment of human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) in the last 30 years that have resulted in survival gains for affected patients. A growing body of evidence suggests that hormone receptor-positive (HR+)/HER2+ BC and HR-negative (HR−)/HER2+ BC are biologically different, with complex molecular bidirectional crosstalk between the estrogen receptor and HER2 pathway potentially affecting sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ BC. Subgroup analyses from trials enrolling patients with HER2+ BC and the results of clinical trials specifically designed to evaluate therapy in patients with HR+/HER2+ BC are helping to guide treatment decisions. In this context, encouraging results with strategies aimed at delaying or reversing drug resistance, including extended adjuvant therapy and the addition of drugs targeting alternative pathways, such as cyclin-dependent kinase (CDK) 4 and 6 inhibitors, have recently emerged. We have reached the point where tailoring the treatment according to risk and biology has become the paradigm in early BC. However, further clinical trials are needed that integrate translational research principles and identify and consider specific patient subgroups and biomarkers.

Small Talk: A Community Research Collaboration to Increase Parental Provision of Language to Children

Early language input contributes to children’s healthy brain development and sets the stage for life-long achievement and wellness. Parents vary in their ability to offer rich language support within the home environment due to social and contextual factors. There is a lack of research on the effectiveness of a universal prevention approach to equip all parents to provide an enriching home language environment. A team including university researchers, a public library, and a community non-profit agency worked together to test the effectiveness of a universal, community-based intervention to increase parents’ child-directed speech, back-and-forth interactions with their child, and knowledge of child development. Over a period of 2 years, three cohorts of parents and caregivers completed the program (n = 153). Using translational research principles, a pre/post longitudinal repeated measures data analytic strategy examined the growth in parent talk (total number of adult words and conversational turns directed to the child) and parent knowledge of child development. This objective quantitative language data was collected automatically, with innovative wearable technology that was a part of the intervention and data collection. In each of the cycles of the intervention, a significant increase in the amount of child-directed speech and in the number of conversational turns between the caregiver and child was demonstrated. In addition, parents significantly increased their knowledge of child development. Conclusion: Universal programs delivered in the community have potential to help parents provide the type of enriching language environments that lead to optimal brain development for young children.

Prevention of Trauma and Stressor-Related Disorders: A Review.

Posttraumatic stress disorder (PTSD) is a common, frequently chronic, and disabling condition which, along with acute stress disorder (ASD), is categorized as a trauma- and stressor-related disorder by the DSM-5. These disorders are unique in requiring exposure to a severe stressor, which implies that potential sufferers could be identified and helped before developing a disorder. Research on prevention strategies for stress-related disorders has taken a number of avenues, including intervention before and after trauma and the use of both psychosocial and somatic approaches. Despite advances in neurobiological understanding of response to trauma, clinical evidence for preventive interventions remains sparse. This review provides an overview of prevention approaches and summarizes the existing literature on prevention of ASD and PTSD, including clinical and preclinical studies. Given the potential benefits to trauma survivors and society, the development of effective preventive interventions should be given greater priority. Resources should be directed to adequately test promising interventions in clinical trials, and research should be conducted according to translational research principles in which preclinical research informs the design of clinical studies.

Translational research principles applied to education: the mapping educational specialist knowhow (MESH) initiative

MESH is a part of a research project applying knowledge management principles which are well known in other sectors, public and private, to the education sector (Leask and Preston 2010; Leask 2011,...

Nexus of poverty, energy balance and health

Since the inception of planning process in India, health planning was an integral component of socio-economic planning. Recommendations of several committees, policy documents and Millennium development goals were instrumental in development of impressive health infrastructure. Several anti-poverty and employment generation programmes were instituted to remove poverty. Spectacular achievements took place in terms of maternal and child health indicators and expectancy of life at birth. However, communicable diseases and undernutrition remain cause of serious concern and non-communicable diseases are imposing unprecedented challenge to planners and policy makers. Estimates of poverty based on different criteria point that it has remained a sustained problem in the country and emphasizes on revisiting anti-poverty programmes, economic policies and social reforms. Poverty affects purchasing power and thereby, food consumption. Energy intake data has inherent limitations. It must be assessed in terms of energy expenditure. Energy balance has been least explored area of research. The studies conducted in three different representative population group of Eastern Uttar Pradesh revealed that 69.63% rural adolescent girls (10-19 years), 79.9% rural reproductive age group females and 62.3% rural geriatric subjects were in negative energy balance. Negative energy balance was significantly less in adolescent girls belonging to high SES (51.37%), having main occupation of family as business (55.3%), and highest per capita income group (57.1%) with respect to their corresponding sub-categories. In case of rural reproductive age groups, this was maximum (93.0%) in SC/ST category and least (65.7%) in upper caste group. In case of geriatric group, higher adjusted Odd's Ratio for negative energy balance for subjects not cared by family members (AOR 23.43, CI 3.93-139.56), not kept money (AOR 5.27, CI 1.58-17.56), belonging to lower and upper middle SES by Udai Pareekh Classification (AOR 3.73, CI 1.22-11.41), with lowest per capita income (AOR 15.14, CI 2.44-94.14) and in age group >80 years (AOR 5.76, CI 1.03-32.39). Of those in negative energy balance, 70.21% rural adolescent girls and 7 out of 10 geriatric subjects (activity based) were victims of CED. Extent of undernutrition and CED in rural reproductive age group females were more in those caste groups where energy deficit was also of higher magnitude. Energy balance must be visualized giving due consideration to the importance of exercise on human health. The evidence thus generated needs to be translated to the masses based on principles of translational research.

New treatment approaches in metastatic renal cell carcinoma

Recent developments in the understanding of the molecular biology of renal cell carcinoma have led to the development of several biologic agents with different mechanisms of action. In 2005, promising results have been observed especially in second-line therapy following cytokine failures and in 2006 more mature data with regard to time to progression and overall survival should be available. This review, analyzing basic translational research principles, will summarize the available evidence with a glimpse of the future therapeutic approaches in renal cell carcinoma. Vascular endothelial growth factor- and platelet-derived growth factor receptor-inhibiting drugs (SU11248, Bay 43-9006, Bevacizumab, AG-013736, etc.) report time to progression ranging between 4 and 9 months and variable benefits in overall survival. Confirmatory studies are ongoing regarding other novel treatments (CCI-779, Infliximab, PTK-787). In renal cell carcinoma, there is a strong rationale for targeting multiple pathways and particularly angiogenesis. Vascular endothelial growth factor- and platelet-derived growth factor receptor-inhibiting drugs have been rapidly approved in the second-line setting and will soon be used as first-line therapy. In the next years, translational/clinical research will provide evidence for combination strategies to improve upon the results of the biologic agents and hopefully offer more hope to patients with renal cell carcinoma.

Pharmacogenomics: catechol O-methyltransferase to thiopurine S-methyltransferase.

1. Pharmacogenomics is the study of the role of inheritance in variation in the drug response phenotype-a phenotype that can vary from adverse drug reactions at one end of the spectrum to lack of therapeutic efficacy at the other. 2. The thiopurine S-methyltransferase (TPMT) genetic polymorphism represents one of the best characterized and most clinically relevant examples of pharmacogenomics. This polymorphism has also served as a valuable "model system" for studies of the ways in which variation in DNA sequence might influence function. 3. The discovery and characterization of the TPMT polymorphism grew directly out of pharmacogenomic studies of catechol O-methyltransferase (COMT), an enzyme discovered by Julius (Julie) Axelrod and his coworkers. 4. This review will outline the process by which common, functionally significant genetic polymorphisms for both COMT and TPMT were discovered and will use these two methyltransferase enzymes to illustrate general principles of pharmacogenomic research-both basic mechanistic and clinical translational research-principles that have been applied to a series of genes encoding methyltransferase enzymes.

Translational research principles of an effectiveness trial for diabetes care in an urban African American population.

Large-scale effectiveness trials designed to translate evidence-based diabetes care to community settings are few. Studies describing these methods among high-risk minority populations are particularly limited. The authors describe Project Sugar, a randomized controlled trial conducted in 2 phases: Project Sugar 1 (1994-1999), which piloted a 4-arm clinic and home-based intervention using nurse case management and community health workers in 186 urban African Americans with type 2 diabetes, and Project Sugar 2 (2000-2005), which examined effectiveness of this intervention among 542 diabetic, urban African Americans. Results and Conclusions Project Sugar had success with regard to recruitment and retention, both in phase 1 (80% rate at 24 months) and phase 2 (>90% at 24 months). Using the RE-AIM framework, planning and research design for Project Sugar 2 is described in detail for elements that contributed to the reach, effectiveness, adoption, implementation, and maintenance of this study within a minority community setting. In addition to successful strategies, challenges to conducting effectiveness trials in an inner-city African American community are identified.