James K.M.,Biomedical Ethics Research Unit |
Cowl C.T.,Mayo Medical School |
Tilburt J.C.,Biomedical Ethics Research Unit |
Tilburt J.C.,Mayo Medical School |
And 5 more authors.
Mayo Clinic Proceedings | Year: 2011
OBJECTIVE: To assess the impact of direct-to-consumer (DTC) predictive genomic risk information on perceived risk and worry in the context of routine clinical care. PATIENTS AND METHODS: Patients attending a preventive medicine clinic between June 1 and December 18, 2009, were randomly assigned to receive either genomic risk information from a DTC product plus usual care (n=74) or usual care alone (n=76). At intervals of 1 week and 1 year after their clinic visit, participants completed surveys containing validated measures of risk perception and levels of worry associated with the 12 conditions assessed by the DTC product. RESULTS: Of 345 patients approached, 150 (43%) agreed to participate, 64 (19%) refused, and 131 (38%) did not respond. Compared with those receiving usual care, participants who received genomic risk information initially rated their risk as higher for 4 conditions (abdominal aneurysm [P=.001], Graves disease [P=.04], obesity [P=.01], and osteoarthritis [P=.04]) and lower for one (prostate cancer [P=.02]). Although differences were not significant, they also reported higher levels of worry for 7 conditions and lower levels for 5 others. At 1 year, there were no significant differences between groups. CONCLUSION: Predictive genomic risk information modestly influences risk perception and worry. The extent and direction of this influence may depend on the condition being tested and its baseline prominence in preventive health care and may attenuate with time. © 2011 Mayo Foundation for Medical Education and Research.
Wieland M.L.,Mayo Medical School |
Weis J.A.,Center for Translational Science Activities |
Olney M.W.,Hawthorne Education Center |
Sullivan S.,Winona State University |
And 4 more authors.
American Journal of Public Health | Year: 2011
Objectives: We used a community-based participatory research (CBPR) approach to plan and implement free TB skin testing at an adult education center to determine the efficacy of CBPR with voluntary tuberculosis (TB) screening and the prevalence of TB infection among immigrant and refugee populations. Methods: We formed a CBPR partnership to address TB screening at an adult education center that serves a large immigrant and refugee population in Rochester, Minnesota. We conducted focus groups involving educators, health providers, and students of the education center, and used this input to implement TB education and TB skin testing among the center's students. Results: A total of 259 adult learners volunteered to be skin-tested in April 2009;48 (18.5%) had positive TB skin tests. Conclusions: Our results imply that TB skin testing at adult education centers that serve large foreign-born populations may be effective. Our findings also show that a participatory process may enhance the willingness of foreign-born persons to participate in TB skin-testing efforts.
Greenberg A.J.,Center for Translational Science Activities |
Greenberg A.J.,Mayo Medical School |
Walters D.K.,Mayo Medical School |
Kumar S.K.,Mayo Medical School |
And 2 more authors.
European Journal of Haematology | Year: 2013
The introduction of novel immunomodulatory drugs (IMiDs) has dramatically improved the survival of patients with multiple myeloma (MM). While it has been shown that patients with specific cytogenetic subtypes, namely t(4;14), have the best outcomes when treated with bortezomib-based regimens, the relationship between cytogenetic subtypes and response to IMiDs remains unclear. Using DNA synthesis assays, we investigated the relationship between cytogenetic subtype and lenalidomide response in a representative panel of human myeloma cell lines (HMCLs). We examined HMCL protein expression levels of the lenalidomide target cereblon (CRBN) and its downstream target interferon regulatory factor-4 (IRF4), which have previously been shown to be predictive of lenalidomide response in HMCLs. Our results reveal that lenalidomide response did not correlate with specific cytogenetic translocations. There were distinct groups of lenalidomide-responsive and non-responsive HMCLs, as defined by inhibition of cellular proliferation; notably, all of the hyperdiploid HMCLs fell into the latter category. Repeated dosing of lenalidomide significantly lowered the IC50 of the responsive HMCL ALMC-1 (IC50 = 2.6 μm vs. 0.005 μm, P < 0.0001), but did not have an effect on the IC50 of the non-responsive DP-6 HMCL (P > 0.05). Moreover, no association was found between lenalidomide responsiveness and CRBN and IRF4 expression. Our data indicate that lenalidomide sensitivity is independent of cytogenetic subtype in HMCLs. While CRBN and IRF4 have been shown to be associated with response to lenalidomide in patients, these findings do not translate back to HMCLs, which could be attributable to factors present in the bone marrow microenvironment. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Boczek N.J.,Center for Translational Science Activities |
Boczek N.J.,Mayo Medical School |
Best J.M.,University of Wisconsin - Madison |
Tester D.J.,Molecular Therapeutics |
And 6 more authors.
Circulation: Cardiovascular Genetics | Year: 2013
Background-Long QT syndrome (LQTS) is the most common cardiac channelopathy with 15 elucidated LQTSsusceptibility genes. Approximately 20% of LQTS cases remain genetically elusive. Methods and Results-We combined whole-exome sequencing and bioinformatic/systems biology to identify the pathogenic substrate responsible for nonsyndromic, genotype-negative, autosomal dominant LQTS in a multigenerational pedigree, and we established the spectrum and prevalence of variants in the elucidated gene among a cohort of 102 unrelated patients with "genotype-negative/phenotype-positive" LQTS. Whole-exome sequencing was used on 3 members within a genotype-negative/phenotype-positive family. Genomic triangulation combined with bioinformatic tools and ranking algorithms led to the identification of a CACNA1C mutation. This mutation, Pro857Arg-CACNA1C, cosegregated with the disease within the pedigree, was ranked by 3 disease-network algorithms as the most probable LQTS-susceptibility gene and involves a conserved residue localizing to the proline, gltamic acid, serine, and threonine (PEST) domain in the II-III linker. Functional studies reveal that Pro857Arg-CACNA1C leads to a gain of function with increased I Ca,L and increased surface membrane expression of the channel compared to wild type. Subsequent mutational analysis identified 3 additional variants within CACNA1C in our cohort of 102 unrelated cases of genotype-negative/phenotype-positive LQTS. Two of these variants also involve conserved residues within Cav1.2's PEST domain. Conclusions-This study provides evidence that coupling whole-exome sequencing and bioinformatic/systems biology is an effective strategy for the identification of potential disease-causing genes/mutations. The identification of a functional CACNA1C mutation cosegregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome. © 2013 American Heart Association, Inc.
Harrison A.M.,Mayo Medical School |
Thalji N.M.,Mayo Medical School |
Greenberg A.J.,Center for Translational Science Activities |
Tapia C.J.,Center for Translational Science Activities |
And 2 more authors.
Clinical and Translational Science | Year: 2014
Translational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non-Hodgkin's lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation. © 2013 Wiley Periodicals, Inc.
Veldhuis J.,Rochester College |
Yang R.,Rochester College |
Roelfsema F.,Leiden University |
Takahashi P.,Center for Translational Science Activities
Journal of Clinical Endocrinology and Metabolism | Year: 2016
Context: In the experimental animal, inflammatory signals quench LH's feedforward drive of testosterone (T) secretion and appear to impair GnRH-LH output. The degree to which such suppressive effects operate in the human is not known. Objective: To test the hypothesis that IL-2 impairs LH's feedforward drive on T and T's feedback inhibition of LH secretion in healthy men. Setting: Mayo Center for Translational Science Activities. Patients or Other Participants: A total of 35 healthy men, 17 young and 18 older. Interventions: Randomized prospective double-blind saline-controlled study of IL-2 infusion in 2 doses with concurrent 10-minute blood sampling for 24 hours. Main Outcome Measures: Deconvolution analysis of LH and T secretion. Results:After saline injection, older compared with young men exhibited reduced LH feedforward drive on T secretion (P.001), and decreased T feedback inhibition of LH secretion (P.01). After IL-2 injection, LH's feedforward onto T secretion declined markedly especially in young subjects (P.001). Concomitantly, IL-2 potentiated T's proportional feedback on LH secretion especially in older volunteers. Conclusion: This investigation confirms combined feedforward and feedback deficits in older relative to young men given saline and demonstrates 1) joint mechanisms by which IL-2 enforces biochemical hypogonadism, viz, combined feedforward block and feedback amplification; and 2) unequal absolute inhibition of T and LH secretion by IL-2 in young and older men. These outcomes establish that the male gonadal axis is susceptible to dual-site suppression by a prototypic inflammatory mediator. Thus, we postulate that selected ILs might also enforce male hypogonadism in chronic systemic inflammation.
Hawley N.C.,Center for Translational Science Activities |
Wieland M.L.,Center for Translational Science Activities |
Weis J.A.,Center for Translational Science Activities |
Sia I.G.,Center for Translational Science Activities
Progress in Community Health Partnerships: Research, Education, and Action | Year: 2014
Background: Human subjects protection training (HSPT) is a requirement of institutional review boards (IRBs) for individuals who engage in research. The lack of HSPT among community partners may contribute to power imbalance between community and academic members of communitybased participatory research (CBPR) partnerships. The Rochester Healthy Community Partnership (RHCP) is an established CBPR partnership in Minnesota that works primarily with immigrant and refugee populations.Objective: We sought to describe the implementation and evaluation of HSPT among community members of a CBPR partnership.Methods: Seven community partners participated in HSPT through adaptation of an existing institutional program. Evaluation of program acceptability was measured through a 5-item survey (5-point Likert scales). A focus group with all seven participants was conducted to evaluate the impact of training on perceptions of research, characteristics of a successful program, and potential value of training to CBPR partnerships. Coding and inductive analysis were done on the transcript with NVIVO-9 software.Results: The HSPT program was highly acceptable (mean score, 4.5 ± 0.2). Focus groups revealed that training implementation should be done as a cohesive group with the opportunity to discuss concepts as they pertain to partnership projects. Training fostered an encouraging and safe environment, accommodated diverse learning styles, and promoted interaction. Participants reported improved trust in research as a result of the training. Perceived impact of the training on the CBPR partnership included improved transparency and enhanced camaraderie while establishing essential knowledge required for community leaders.Conclusions: HSPT is feasible among community members of a CBPR partnership, and may improve perceptions of research while strengthening capacity of partnerships to impact community health. © 2014 The Johns Hopkins University Press.
McCormick J.B.,Center for Translational Science Activities |
Sharp R.R.,Cleveland Clinic |
Ottenberg A.L.,Mayo Medical School |
Reider C.R.,Ohio State University |
And 3 more authors.
Clinical and Translational Science | Year: 2013
Emphasis on translational research to facilitate progression from the laboratory into the community also creates a dynamic in which ethics and social policy questions and solutions are ever pressing. In response, academic institutions are creating Research Ethics Consultation Services (RECS). All Clinical Translational Science Award institutions were surveyed in early 2010 to determine which institutions have a RECS in operation and what is their composition and function. Of the 46 institutions surveyed, 33 (70%) have a RECS. Only 15 RECS have received any consult requests in the last year. Issues that are common among these relatively nascent services include relationships with institutional oversight committees, balancing requestor concerns about confidentiality with research integrity and human subjects protection priorities, tracking consult data and outcomes, and developing systems for internal evaluation. There is variability in how these issues are approached. It will be important to be attentive to the institutional context to develop an appropriate approach. Further data about the issues raised by requestors and the recommendations provided are necessary to build a community of scholars who can navigate and resolve ethical issues encountered along the translational research pathway. © 2012 Wiley Periodicals, Inc.
Campbell J.M.,Center for Translational Science Activities |
Hartjes K.A.,Center for Regenerative Medicine |
Hartjes K.A.,Molecular Therapeutics |
Nelson T.J.,Center for Regenerative Medicine |
And 6 more authors.
Circulation Research | Year: 2013
Recent advances in the burgeoning field of genome engineering are accelerating the realization of personalized therapeutics for cardiovascular disease. In the postgenomic era, sequence-specific gene-editing tools enable the functional analysis of genetic alterations implicated in disease. In partnership with high-throughput model systems, efficient gene manipulation provides an increasingly powerful toolkit to study phenotypes associated with patient-specific genetic defects. Herein, this review emphasizes the latest developments in genome engineering and how applications within the field are transforming our understanding of personalized medicine with an emphasis on cardiovascular diseases. © 2013 American Heart Association, Inc.
Veldhuis J.D.,Center for Translational Science Activities |
Veldhuis J.D.,Mayo Medical School |
Bondar O.P.,Mayo Medical School |
Dyer R.B.,Mayo Medical School |
And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014
Context: SHBG concentrations correlate inconsistently with metabolic parameters. Hypothesis: SHBG assay platforms contribute to nonuniformities according to the literature. Design: The design of the study was a noninterventional quantification of SHBG by two immunoand two mass spectrometric assays and abdominal visceral fat by computed tomography scan. Setting: The study was conducted at the Center for Translational Science Activities. Participants: Healthy men (n = 120) aged 18-80 years with a body mass index of 20-43 kg/m2 participated I the study. Outcomes: Outcomes of the study included a correlation of log SHBG with age, metabolic surrogates [body mass index, albumin, glucose, insulin, abdominal (total and visceral) fat, homeostasis model assessment insulin resistance index], sex steroids (estrone, 17β-estradiol, T, and dihydrotestosterone by mass spectrometry), and adipocytokines (IL-1β, IL-6, IL-8, IL-10 and IL-12, TNF-α, and adiponectin). Results: By univariate regression, age (P < 10-4), dihydrotestosterone (P < 10-4), T (P ≤ .00022), and adiponectin (P ≤ .0084) were positive correlates, and insulin and homeostasis model assessment insulin resistance index were negative correlates (P ≤ .0060) of SHBG in all four assays. Stepwise multivariate analysis unveiled that age and T together could explain 38.1%-52.5% of the statistical variance in SHBG in all assays (P < 10-11). Multivariate regression without sex steroids unveiled that age (P < 10-5) and insulin (P < 10-3) are jointly associated with SHBG levels in the four assays with overall R2 = 0.215-0.293 and P < 10-6. In one immunological SHBG assay each, abdominal visceral fat and adiponectin were weak multivariates also. Conclusion: Immunological and mass spectrometric SHBG assays yield both consistent and inconsistent correlations with key metabolic variables in healthy men, thereby potentially explaining earlier inconsistencies in the literature. (J Clin Endocrinol Metab 99: 184-193, 2014). © Copyright 2014 by The Endocrine Society.