Single nucleotide polymorphisms (SNPs) in the promoter and untranslated region of cyclooxygenase (COX)-2, an inducible enzyme responsible for the synthesis of prostaglandins, have been reported to modulate the risk for many human cancers. We performed comprehensive linkage disequilibrium (LD) and haplotype analyses of 13 single nucleotide polymorphisms of the COX-2 gene and examined its susceptibility to adenoma development in 72 African American cases and 142 controls. Results revealed significant variation in LD patterns with consequence for adenoma development. Two distinct haplotype blocks were identified; one block covered the coding regions of exon 1, introns and a section of the 3′-unstranslated region (3′-UTR), whereas the second block resided solely in the 3′-UTR region. A haplotype in block 1 increased the risk of adenoma development by threefold (odds ratio [OR] = 2.9, confidence interval [CI] = 1.8–3.7, P = 0.002). Regression analysis showed, increase in copies of minor alleles of 6,064(T>C) polymorphism associated with increased odds of adenoma development by 80% (OR = 1.80, CI = 1.09–3.21, P = 0.034), 10,848(G>A) by 84% (OR = 1.84, CI = 1.05–3.23, P = 0.034) and 10,935(A>G) by 32% (OR = 1.32, CI = 1.12–3.69, P = 0.036). These results support the hypothesis that COX-2 gene might play a role in the etiology of colon cancer and warrant further investigation in other cancers. Besides, these variations should be taken into account for disease-based association studies in which the COX-2 polymorphism is considered as a candidate gene. Clin Trans Sci 2011; Volume #: 1–5
Abdominal aortic aneurysm (AAA) is a common condition with high mortality when ruptured. Most clinicians agree that small AAAs are best managed by ultrasonographic surveillance. However, it has been stated in recent reviews that a serum/plasma biomarker that predicts AAA rupture risk would be a powerful tool in stratifying patients with small AAA. Identification of such circulating biomarkers has been to date unsuccessful. In this study, we used a proteomic approach to find new, potential plasma AAA biomarker candidates. Prefractionated plasma samples were analyzed by two-dimensional differential in-gel electrophoresis to identify differentially expressed proteins between four patients with small AAA and four controls without aneurysm. Protein spots that differed significantly between patients and controls were selected and identified by mass spectrometry. Three protein spots had significantly different expression between patients and controls. The most interesting finding was that patients with small AAA had increased levels of the enzyme glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) compared with the controls without aneurysm. In conclusion, by using a proteomic approach, this pilot-study provides evidence of GPI-PLD as a novel potential plasma biomarker for AAA. Clin Trans Sci 2011; Volume #: 1–4
This commentary is germane for clinical and translational researchers. Basic scientists may face different obstacles to developing their research careers. Over the past several years, the federal government has seen reductions in funding for extramural research. It seems that under the adverse economic forecasts, things are going to get worse. It might seem logical for the federal government to stretch whatever limited resources exist, by asking the institutions to cost-share greater fractions of the actual research costs, and as an incentive, avoid the imposition of unfunded mandates. But alas, although well intended, there have been expensive requirements imposed by the government, making it difficult for investigators and institutions to adequately fund and conduct their research and for scientific journals to maintain paying subscribers. Five prominent and costly changes, which are the focus of this commentary are (1) HIPAA, (2) ClinicalTrials. Gov, (3) Clinical and Translational Science Awards, (4) Upcoming rule changes for IRBs, and (5) PubMedCentral, each of which will be discussed in the ensuing paragraphs. Clin Trans Sci 2011; Volume #: 1–2
Hibernation is an extreme physiological challenge for the brown bear (Ursus arctos) in which metabolism is based mainly on lipids. The study objective was to compare plasma lipids in hibernating and active free-ranging brown bears and relate them to arterial histopathology. Blood was drawn from seven immobilized free-ranging brown bears (three females, 2–3 years old) during hibernation in February and from the same bears while active in June and analyzed by enzymatic and automated hematology methods within 48 hours of sampling. Left anterior descending coronary arteries and aortic arches from 12 bears (six females, 1.5–12 years old) killed in hunting were examined by histopathology. Total plasma cholesterol decreased from hibernation to the active period (11.08 ± 1.04 mmol/L vs. 7.89 ± 1.96 mmol/L, P = 0.0028) as did triglyceride (3.16 ± 0.62 mmol/L vs. 1.44 ± 0.27 mmol/L, P = 0.00012) and LDL cholesterol (4.30 ± 0.71 mmol/L vs. 2.02 ± 1.03 mmol/L, P = 0.0075), whereas HDL cholesterol was unchanged. No atherosclerosis, fatty streaks, foam cell infiltration, or inflammation were seen in any arterial samples. Brown bears tolerate elevated cholesterol levels, obesity, physical inactivity, and circulatory slow flow during hibernation without signs of atherosclerosis. This species might serve as a reverse translational model for atherosclerosis resistance. Clin Trans Sci 2011; Volume #: 1–4
Although the importance of research mentorship has been well established, the role of mentors of junior clinical and translational science investigators is not clearly defined. The authors attempt to derive a list of actionable competencies for mentors from a series of complementary methods. We examined focus groups, the literature, competencies derived for clinical and translational scholars, mentor training curricula, mentor evaluation forms and finally conducted an expert panel process in order to compose this list. These efforts resulted in a set of competencies that include generic competencies expected of all mentors, competencies specific to scientists, and competencies that are clinical and translational research specific. They are divided into six thematic areas: (1) Communication and managing the relationship, (2) Psychosocial support, (3) Career and professional development, (4) Professional enculturation and scientific integrity, (5) Research development, and (6) Clinical and translational investigator development. For each thematic area, we have listed associated competencies, 19 in total. For each competency, we list examples that are actionable and measurable. Although a comprehensive approach was used to derive this list of competencies, further work will be required to parse out how to apply and adapt them, as well future research directions and evaluation processes. Clin Trans Sci 2011; Volume #: 1–8
The rates of obesity, diabetes, and heart disease in Native Americans and Alaska Natives far exceed that of the general US population. There are many postulating reasons for these excessive rates including the transition from a traditional to a contemporary diet. Although information on the dietary intakes of Native American and Alaska Native communities are limited, there seems to be a consensus that the Native American and Alaska Native diet is high in total fat, saturated fat, cholesterol, and sodium. Further information on the diet needs to be attained so that dietary interventions can effectively be implemented in these communities. An approach that is community based is proposed as the best solution to understanding the Native diet and developing culturally tailored interventions to sustainably improve diet. Clin Trans Sci 2011; Volume #: 1–6
Alpha1-antitrypsin (AT) deficiency is the most common genetic cause of liver disease in children and is also a cause of chronic hepatic fibrosis, cirrhosis, and hepatocellular carcinoma in adults. Recent advances in understanding how mutant AT molecules accumulate within hepatocytes and cause liver cell injury have led to a novel strategy for chemoprophylaxis of this liver disease. This strategy involves a class of drugs, which enhance the intracellular degradation of mutant AT and, because several of these drugs have been used safely in humans for other indications, the strategy can be moved immediately into clinical trials. In this review, we will also report on advances that provide a basis for several other strategies that could be used in the future for treatment of the liver disease associated with AT deficiency. Clin Trans Sci 2011; Volume #: 1–6
Pancreatic cyst detection is increasing largely due to increasing use of cross-sectional imaging. The management of pancreatic cysts differs for true cysts, pseudocysts, mucinous cysts, nonmucinous cysts, and malignant lesions. Depending on the setting, diagnostic tests, such as cross-sectional imaging, endoscopic ultrasound, cyst fluid chemistry, and cytology, have moderate accuracy in characterizing the cyst subtype. Molecular analysis of cyst fluid aspirates has shown promise in preliminary studies and may require smaller fluid volumes than is needed for carcinoembryonic antigen level and cytology. This article reviews published studies in which molecular analysis was performed in the evaluation of pancreatic cysts. The molecular studies are compared with the conventional tests. Most studies have had moderate sample sizes (16–124) and have characterized a high proportion of patients with malignant cysts. Evaluation of molecular analysis as a diagnostic tool merits larger prospective trials with long-term follow-up of patients who are not sent to surgery. Larger cysts may meet size criteria for resection, and it is the smaller cysts for which molecular analysis may be of benefit if additional molecular testing results in a change in management. Clin Trans Sci 2011; Volume #: 1–6
Disseminated intravascular coagulation (DIC) profoundly increases the morbidity and mortality of patients who have sepsis. Both laboratory and clinical research advanced the understanding of the biology and pathophysiology of DIC. This, in turn, gave rise to improved therapies and patient outcomes. Beginning with a stimulus causing disruption of vascular integrity, cytokines and chemokines cause activation of systemic coagulation and inflammation. Seemingly paradoxically, the interplay between coagulation and inflammation also inhibits endogenous anticoagulants, fibrinolytics, and antiinflammatory pathways. The earliest documented and best-studied microbial cause of DIC is the lipopolysaccharide endotoxin of Gram-negative bacteria. Extensive microvascular thrombi emerge in the systemic vasculature due to dysregulation of coagulation. The result of this unrestrained, widespread small vessel thromboses multiorgan system failure. Consumption of platelets and coagulation factors during this process can lead to an elevated risk of hemorrhage. The management of these patients with simultaneous hemorrhage and thrombosis is complex and challenging. Definitive treatment of DIC, and attenuation of end-organ damage, requires control of the inciting cause. Currently, activated protein C is the only approved therapy in the United States for sepsis complicated by DIC. Further research is needed in this area to improve clinical outcomes for patients with sepsis. Clin Trans Sci 2011; Volume #: 1–8
Acute kidney injury (AKI) is a common, heterogeneous, and detrimental clinical condition that has significant attributable morbidity and mortality. Despite major advances in understanding the epidemiology, pathogenesis, and outcomes of AKI, preventive measures remain inadequate and therapeutic approaches (except for renal replacement therapy) have largely proven futile so far. Critical to the process of designing rational therapies is translational research, which involves the transition between the basic research discoveries and everyday clinical applications to prevent, diagnose, and treat human diseases. Progress in innovative approaches has been hampered due in part to the reliance on functional markers (serum creatinine and blood urea nitrogen) that are neither sensitive nor specific to diagnose AKI. This limitation has created a great deal of interest and intense investigation to identify a “troponin-like marker” that would facilitate recognition of AKI and allow for timely implementation of the precise therapeutic agent. The other major obstacle in this field is the diverse and complex nature of AKI that involves multiple independent and overlapping pathways, making it difficult to cure AKI with a single approach. In this review, we will summarize the advances, ongoing studies, and future perspectives in the field of translational research of AKI. Clin Trans Sci 2011; Volume #: 1–9
A comprehensive mentoring program includes a variety of components. One of the most important is the ongoing assessment of and feedback to mentors. Scholars need strong active mentors who have the expertise, disposition, motivation, skills, and the ability to accept feedback and to adjust their mentoring style. Assessing the effectiveness of a given mentor is no easy task. Variability in learning needs and academic goals among scholars makes it difficult to develop a single evaluation instrument or a standardized procedure for evaluating mentors. Scholars, mentors, and program leaders are often reluctant to conduct formal evaluations, as there are no commonly accepted measures. The process of giving feedback is often difficult and there is limited empirical data on efficacy. This article presents a new and innovative six-component approach to mentor evaluation that includes the assessment of mentee training and empowerment, peer learning and mentor training, scholar advocacy, mentee–mentor expectations, mentor self-reflection, and mentee evaluation of their mentor. Clin Trans Sci 2011; Volume #: 1–7.
(-)-Epicatechin (Epi), a flavanol in cacao stimulates mitochondrial volume and cristae density and protein markers of skeletal muscle (SkM) mitochondrial biogenesis in mice. Type 2 diabetes mellitus (DM2) and heart failure (HF) are diseases associated with defects in SkM mitochondrial structure/function. A study was implemented to assess perturbations and to determine the effects of Epi-rich cocoa in SkM mitochondrial structure and mediators of biogenesis. Five patients with DM2 and stage II/III HF consumed dark chocolate and a beverage containing approximately 100 mg of Epi per day for 3 months. We assessed changes in protein and/or activity levels of oxidative phosphorylation proteins, porin, mitofilin, nNOS, nitric oxide, cGMP, SIRT1, PGC1α, Tfam, and mitochondria volume and cristae abundance by electron microscopy from SkM. Apparent major losses in normal mitochondria structure were observed before treatment. Epi-rich cocoa increased protein and/or activity of mediators of biogenesis and cristae abundance while not changing mitochondrial volume density. Epi-rich cocoa treatment improves SkM mitochondrial structure and in an orchestrated manner, increases molecular markers of mitochondrial biogenesis resulting in enhanced cristae density. Future controlled studies are warranted using Epi-rich cocoa (or pure Epi) to translate improved mitochondrial structure into enhanced cardiac and/or SkM muscle function. Clin Trans Sci 2011; Volume #: 1–5
Introduction: Participants’ perceptions of their research experiences provide valuable measures of ethical treatment, yet no validated instruments exist to measure these experiences. We conducted focus groups of research participants and professionals as the initial step in developing a validated instrument.
Methods: Research participants enrolled in 12 focus groups, consisting of: (1) individuals with disorders undergoing interventions; (2) in natural history studies; or (3) healthy volunteers. Research professionals participated in six separate groups of: (1) institutional review board members, ethicists, and Research Subject Advocates; (2) research nurses/coordinators; or (3) investigators. Focus groups used standard methodologies.
Results: Eighty-five participants and 29 professionals enrolled at eight academic centers. Altruism and personal relevance of the research were commonly identified motivators; financial compensation was less commonly mentioned. Participants were satisfied with informed consent processes but disappointed if not provided test results, or study outcomes. Positive relationships with research teams were valued highly. Research professionals were concerned about risks, undue influence, and informed consent.
Conclusions: Participants join studies for varied, complex reasons, notably altruism and personal relevance. They value staff relationships, health gains, new knowledge, and compensation, and expect professionalism and good organization. On the basis of these insights, we propose specific actions to enhance participant recruitment, retention, and satisfaction. Clin Trans Sci 2011; Volume 4: 403–413
Insulin resistance and type 2 diabetes are associated with low HDL-cholesterol (HDL-c) levels, which would impair reverse cholesterol transport (RCT). A promising therapeutic strategy is to raise HDL with cholesteryl ester transfer protein (CETP) inhibitors, but their effects on RCT remains to be demonstrated in vivo. We therefore evaluated the effects of CETP inhibitor torcetrapib in CETP-apolipoprotein (apo)B100 mice made obese and insulin resistant with a 60% high-fat diet. High-fat diet over 3 months increased body weight and homeostasis model of insulin resistance index by 30% and 846%, respectively (p < 0.01 for both vs. chow-fed mice). Total cholesterol (TC) increased by 46% and HDL-c/TC ratio decreased by 28% (both p < 0.05). Compared to vehicle, high-fat-fed mice treated with torcetrapib (30 mg/kg/day, 3 weeks) showed increased HDL-c levels and HDL-c/TC ratio by 41% and 37% (both p < 0.05). Torcetrapib increased in vitro macrophage cholesterol efflux by 22% and in vivo RCT through a 118% increase in 3H-bile acids fecal excretion after 3H-cholesterol labeled macrophage injection (p < 0.01 for both). Fecal total bile acids mass was also increased by 158% (p < 0.001). In conclusion, CETP inhibition by torcetrapib improves RCT in CETP-apoB100 mice. These results emphasize the potential of CETP inhibition to prevent cardiovascular diseases. Clin Trans Sci 2011; Volume 4: 414–420
Clinical research nursing is a specialty nursing practice focused on the care of research subjects and implementation of clinical research. A five-dimensional model (Clinical Practice [CP], Study Management, Care Coordination and Continuity, Contributing to the Science [CS], Human Subjects Protection) has been validated nationally to represent the domain of clinical research nursing practice. The purpose of this study was to describe the frequency and importance of activities within each dimension as performed by nurses in clinical research and to describe differences between roles. One thousand and four nurses from the NIH Intramural Campus in Bethesda, Maryland, were invited to participate in an anonymous web-based survey. Participants (N = 412) were predominantly female (90%) with ≥11 years research experience (70%). Two hundred eighty-eight respondents (70%) identified themselves as clinical research nurses (CRNs) and 74 (18%) as research nurse coordinators (RNCs). CP activities were reported most frequent and important whereas CS activities were least frequent and important. CRN and RNC activity frequency differed across all dimensions (p < 0.001) with CRNs reporting significantly higher levels of CP activities and significantly lower levels in other dimensions. Delineating specialty activities and practice across roles enhances the understanding of nurses’ role in clinical research and provides groundwork for role-based training. Clin Trans Sci 2011; Volume 4: 421–427
Introduction: Community-based participatory research (CBPR) adds community perspectives to research and aids translational research aims. There is a need for increased capacity in CBPR but few models exist for how to support the development of community/university partnerships.
Objective: Evaluate an approach to promote nascent CBPR partnerships.
Methods: Design was a mixed–methods evaluation using interviews, process notes, and open- and close-ended survey questions. We trained 10 community scholars, matched them with prepared researchers to form seven partnerships, and supported their developing partnerships. Sequential mixed–methods analysis assessed research and partnership processes and identified integrated themes.
Results: Four of seven partnerships were funded within 15 months; all self-reported their partnerships as successful. Themes were: (1) motivators contributed to partnership development and resiliency; (2) partners took on responsibilities that used individuals’ strengths; (3) partners grappled with communication, decision making, and power dynamics; and (4) community–university infrastructure was essential to partnership development.
Conclusions: This program for developing nascent partnerships between academicians and community members may guide others in increasing capacity for CBPR. Clin Trans Sci 2011; Volume 4: 428–433
Health disparities may affect any person in any community in the world, resulting from a multitude of factors including socioeconomic status, race, ethnicity, environment, and genetics. The impact of health disparities is felt by affected individuals, their families, communities, and the greater health care system.
There is a critical need to increase health disparities research activities. This may be achieved by expanding and strengthening the training, education and career development of motivated clinicians, physicians and basic scientists, engaging them in clinical and translational research. Translational research relies on collaboration across disciplines, facilitating the dissemination and transfer of knowledge to populations for the overall improvement of health while decreasing the economic burden of health care.
The University of Puerto Rico Medical Sciences Campus (UPR-MSC), Schools of Health Professions and Medicine joint initiatives, Clinical Research Education and Career Development (CRECD) and Hispanics in Research Capability (HiREC) programs, convened health disparities experts, faculty and scholars from multiple disciplines, cultural backgrounds and institutions. Together, they created a model for teaching translational research in health disparities that spans disciplines without boundaries. This work was presented at the 2011 Clinical and Translational Research and Education Meeting, ACRT/AFMR/SCTS Joint Annual Meeting in Washington, DC. Clin Trans Sci 2011; Volume 4: 434–438.
The mentoring relationship between a scholar and their primary mentor is a core feature of research training. Anecdotal evidence suggests this relationship is adversely affected when scholar and mentor expectations are not aligned. We examined three questions: (1) What is the value in assuring that the expectations of scholars and mentors are mutually identified and aligned? (2) What types of programmatic interventions facilitate this process? (3) What types of expectations are important to identify and align? We addressed these questions through a systematic literature review, focus group interviews of mentors and scholars, a survey of Clinical and Translational Science Award (CTSA) KL2 program directors, and review of formal programmatic mechanisms used by KL2 programs. We found broad support for the importance of identifying and aligning the expectations of scholars and mentors and evidence that mentoring contracts, agreements, and training programs facilitate this process. These tools focus on aligning expectations with respect to the scholar’s research, education, professional development and career advancement as well as support, communication, and personal conduct and interpersonal relations. Research is needed to assess test the efficacy of formal alignment activities. Clin Trans Sci 2011; Volume 4: 439–447
Research training has enabled academic clinicians to contribute significantly to the body of medical research literature. Biostatistics represents a critical methodological skill for such researchers, as statistical methods are increasingly a necessary part of medical research. However, there is no validated knowledge and skills assessment for graduate level biostatistics for academic medical researchers. In this paper, I review graduate level statistical competencies and existing instruments intended to assess physicians’ ability to read the medical literature and for undergraduate statistics for their alignment with core competencies necessary for successful use of statistics. This analysis shows a need for a new instrument to assess biostatistical competencies for medical researchers. Clin Trans Sci 2011; Volume 4: 448–454
Translational Science Search (TSS; http://tscience.nlm.nih.gov) is a web application for finding MEDLINE/PubMed journal articles that are regarded by their authors as novel, promising, or may have potential clinical application. A set of “translational” filters and related terms was created by reviewing journal articles published in clinical and translational science (TS) journals. Through E-Utilities, a user’s query and TS filters are submitted to PubMed, and then, the retrieved PubMed citations are matched with a database of MeSH terms (for disease conditions) and RxNorm (for interventions) to locate the search term, translational filters found, and associated interventions in the title and abstract. An algorithm ranks the interventions and conditions, and then highlights them in the results page for quick reading and evaluation. Using previously searched terms and standard formulas, the precision and recall of TSS were 0.99 and 0.47, compared to 0.58 and 1.0 for PubMed Entrez, respectively. Clin Trans Sci 2011; Volume 4: 455–459
Autosomal recessive polycystic kidney disease (ARPKD) is a developmental disorder that mainly affects the kidneys and the biliary tract. Affected patients often have massively enlarged cystic kidneys as well as congenital hepatic fibrosis (CHF) characterized by dilated bile ducts and associated peribiliary fibrosis. This review will examine what is known about ARPKD-associated liver disease and will highlight areas of ongoing research into its pathogenesis and potential treatment. Clin Trans Sci 2011; Volume 4: 460–465
Microarray technologies enable the simultaneous interrogation of expressions from thousands of genes from a biospecimen sample taken from a patient. This large set of expressions generates a genetic profile of the patient that may be used to identify potential prognostic or predictive genes or genetic models for clinical outcomes. The aim of this article is to provide a broad overview of some of the major statistical considerations for the design and analysis of microarrays experiments conducted as correlative science studies to clinical trials. An emphasis will be placed on how the lack of understanding and improper use of statistical concepts and methods will lead to noise discovery and misinterpretation of experimental results. Clin Trans Sci 2011; Volume 4: 466–477