Clinical and Translational Science via MedWorm.com

Dynamic Changes in Lymphocyte GRK2 Levels in Cardiac Transplant Patients: A Biomarker for Left Ventricular Function

Clinical and Translational Science — Thu, 25 Feb 2010 00:00:00 +0100

This study represents an attempt to define the role for GRK2 as a potential biomarker of left ventricular function in HF patients. We obtained blood from 24 HF patients before and after heart transplantation and followed them for up to 1 year, also recording hemodynamic data and histological results from endomyocardial biopsies. We determined blood GRK2 protein by Western blotting and enzyme-linked immunosorbent assay. GRK2 levels were obtained before transplant and at first posttransplant biopsy. GRK2 levels significantly declined after transplant and remained low over the course of the study period. After transplantation, we found that blood GRK2 signifi cantly dropped and remained low consistent with improved cardiac function in the transplanted heart. Blood GRK2 has potential as a biom...

The Clinical and Translational Science "Tent"

Clinical and Translational Science — Wed, 24 Feb 2010 00:00:00 +0100

(Source: Clinical and Translational Science)

Fostering Collaboration in Treatment and Discovery

Clinical and Translational Science — Wed, 24 Feb 2010 00:00:00 +0100

(Source: Clinical and Translational Science)

White Paper on CTSA Consortium Role in Facilitating Comparative Effectiveness Research

Clinical and Translational Science — Wed, 24 Feb 2010 00:00:00 +0100

(Source: Clinical and Translational Science)

Interest in Conflicts

Clinical and Translational Science — Wed, 24 Feb 2010 00:00:00 +0100

(Source: Clinical and Translational Science)

Survey of Community Engagement in NIH-Funded Research

Clinical and Translational Science — Wed, 24 Feb 2010 00:00:00 +0100

This study assessed baseline prevalence of community engagement activities among NIH-funded studies at a large Midwestern university with a CTSA. An online survey was e-mailed to principal investigators of recent NIH-funded studies (N = 480). Investigators were asked to identify what types of community engagement activities had occurred for each study. Responses were received for 40.4% (194/480) of studies. Overall, 42.6% reported any community engagement activities. More collaborative types of engagement (e.g., community advisory board) were less common than activities requiring less engagement (e.g., sharing study results with community members). Studies with more collaborative community engagement were less likely to be described as basic or preclinical research compared to all other st...

Changes in NIH Criteria for Tenure to Reward Clinical/Translational Teams

Clinical and Translational Science — Wed, 24 Feb 2010 00:00:00 +0100

(Source: Clinical and Translational Science)

Transforming Research Environments through Institutional Partnerships:

Clinical and Translational Science — Wed, 24 Feb 2010 00:00:00 +0100

(Source: Clinical and Translational Science)

The European and American Use of Exploratory Approaches for First-in-Human Studies*

Clinical and Translational Science — Wed, 24 Feb 2010 00:00:00 +0100

Exploratory approaches for first-in-human clinical studies have evolved over the last few years and have stimulated the issuance of national regulatory guidances in some European countries as well as the United States. With the increasing implementation of these approaches and the recent preparation of a multiregional regulatory guidance (ICH M3 rev2), an exchange of experiences on the opportunities and challenges of exploratory clinical trials was desirable; thus, a workshop focusing on the use of this clinical approach was planned and conducted in Lisbon, Portugal, March 18[ndash]19, 2009 sponsored by the Portuguese Health Authority (INFARMED) and DIA. The structure of the workshop focused in three main areas. Regulatory representatives from Portugal, Belgium, Germany, the United Kingdom...

Principles of Human Subjects Protections Applied in an Opt-Out, De-identified Biobank

Clinical and Translational Science — Wed, 24 Feb 2010 00:00:00 +0100

BioVU, the Vanderbilt DNA Databank, is one of few biobanks that qualifies as non-human subjects research as determined by the local IRB and the federal Office of Human Research Protections (OHRP). BioVU accrues DNA samples extracted from leftover blood remaining from routine clinical testing. The resource is linked to a de-identified version of data extracted from an Electronic Medical Record (EMR) system, termed the Synthetic Device (SD), in which all personal identifiers have been removed. Thus, there is no identifiable private information attached to the records. The Belmont Report enumerates the importance of the boundary between practice and research, and three principles: Respect for Persons, Beneficence, and Justice, which constitute the essential ethical framework by which IRBs and...

Team Building: Electronic Management-Clinical Translational Research (eM-CTR) Systems

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

We describe a novel, integrated strategy, whose focus is to support and manage a study using an Information Hub, Communication Hub, and Data Hub design. This design is illustrated by an application to a series of varied projects sponsored by Special Clinical Centers of Research in chronic obstructive pulmonary disease at the University of Pittsburgh. In contrast to classical informatics support, it is readily scalable to large studies. Our experience suggests the culture consequences of research group self-empowerment is not only economically efficient but transformative to the research process. (Source: Clinical and Translational Science)

Willem Dicke. Brilliant Clinical Observer and Translational Investigator. Discoverer of the Toxic Cause of Celiac Disease

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

We can admire and learn from physicians with acute clinical acumen and superb approaches to translational research. The observations and studies of Dr. Willem Dicke, a Dutch pediatrician, on the toxic effects of a protein component of wheat and rye demonstrate the highest quality of such investigations. From a clinical observation of one child with celiac disease, through years of historical questioning and empirical dietary suggestions of patient families, he concluded that such foods were toxic. When research became possible after the second world war and fecal fat measures as a hard end point became available he studied 5 children in detail to establish the validity of his clinical clues. (Source: Clinical and Translational Science)

Comparative Effectiveness Research: An Approach to Avoiding "Overgeneralized Medicine"

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

(Source: Clinical and Translational Science)

Pharmacotherapy and Pregnancy: Highlights from the Second International Conference for Individualized Pharmacotherapy in Pregnancy

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

To address provider struggles to provide evidence-based, rational drug therapy to pregnant women, a second conference was convened to highlight the current research in the field. Speakers from academic centers and institutions spoke about: the unique physiology and pathology of pregnancy; pharmacokinetic changes in pregnancy; thyroid disorders in pregnancy; pharmacogenetics in pregnancy; the role of CYP2D6 in pregnancy; treating addiction in pregnancy; the power of teratology networks to inform clinical decisions; the use of anti-depressants in pregnancy; and how to utilize computer-based modeling to aid with individualized pharmacotherapy in pregnancy. The Conference highlighted several areas of collaboration with the current Obstetrics Pharmacology Research Units Network (OPRU) and hoped...

Correlates of Valvular Ossification in Patients with Aortic Valve Stenosis

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

Valvular calcification may include a regulated process of active ossification; however, the determinants of ossification are unclear. The aim of this study was to identify subject and disease characteristics associated with valvular ossification among patients with calcified aortic valves. Medical records were reviewed for variables associated with aortic stenosis and skeletal bone in a series of 195 patients requiring aortic valve excision. Thirty patients had valvular bone on histopathology. Univariate analyses suggested that warfarin therapy (p= 0.004), African American race (p= 0.006), height (p= 0.03), and male sex (p= 0.07) were associated with greater odds of valvular ossification while diabetes was associated with lower odds (p= 0.07). Multivariate analysis demonstrated that warfar...

Divergent Effects of Losartan and Metoprolol on Cardiac Remodeling, C-kit+ Cells, Proliferation and Apoptosis in the Left Ventricle after Myocardial Infarction

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

There is strong evidence for the use of angiotensin converting enzyme inhibitors and beta-blockers to reduce morbidity and mortality in patients with myocardial infarction (MI), whereas the effect of angiotensin receptor blockers is less clear. We evaluated the effects of an angiotensin receptor blocker losartan and a beta-blocker metoprolol on left ventricular (LV) remodeling, c-kit+ cells, proliferation, fibrosis, apoptosis, and angiogenesis using a model of coronary ligation in rats. Metoprolol treatment for 2 weeks improved LV systolic function. In contrast, losartan triggered deleterious structural remodeling and functional deterioration of LV systolic function, ejection fraction being 41% and fractional shortening 47% lower in losartan group than in controls 2 weeks after MI. The num...

Family Networks of Obesity and Type 2 Diabetes in Rural Appalachia

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

In conclusion, the poorest counties of rural Appalachia are at crisis level with the prevalence of obesity and diabetes. The distribution of age-corrected obesity and family diabetes risk potential are not normally distributed. We suggest that targeting individual family units at greatest risk offers the most efficient strategy for ameliorating this epidemic. (Source: Clinical and Translational Science)

Magnesium Carbonate-Containing Phosphate Binder Prevents Connective Tissue Mineralization in Abcc6−/− Mice–Potential for Treatment of Pseudoxanthoma Elasticum

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

In this study, we tested oral phosphate binders for treatment of a mouse model of PXE which we have developed by targeted ablation of the corresponding mouse gene (Abcc6[minus]/[minus]). This "knock-out" (KO) mouse model recapitulates features of PXE and demonstrates mineralization of a number of tissues, including the connective tissue capsule surrounding vibrissae in the muzzle skin which serves as an early biomarker of the mineralization process. Treatment of these mice with a magnesium carbonate-enriched diet (magnesium concentration being 5-fold higher than in the control diet) completely prevented mineralization of the vibrissae up to 6 months of age, as demonstrated by computerized morphometric analysis of histopathology as well as by calcium and phosphate chemical assays. The magne...

The University of Chicago Institute for Translational Medicine

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

(Source: Clinical and Translational Science)

Exciting Interventions in Individualized Medicine

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

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A Novel Tool for Translational Research Discovery

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

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Towards a Unifying Theory of Clinical Research

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

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In the NEWS A QUICK ROUNDUP OF NEWS AND INFORMATION FROM OUR COMMUNITY

Clinical and Translational Science — Fri, 18 Dec 2009 00:00:00 +0100

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Inclusion of a Nitric Oxide Congener in the Insufflation Gas Repletes S-Nitrosohemoglobin and Stabilizes Physiologic Status During Prolonged Carbon Dioxide Pneumoperitoneum

Clinical and Translational Science — Wed, 16 Dec 2009 00:00:00 +0100

A method to maintain organ blood flow during laparoscopic surgery has not been developed. Here we determined if ethyl nitrite, an S-nitrosylating agent that would maintain nitric oxide bioactivity (the major regulator of tissue perfusion), might be an effective intervention to preserve physiologic status during prolonged pneumoperitoneum. The study was conducted on appropriately anesthetized adult swine; the period of pneumoperitoneum was 240 minutes. Cohorts consisted of an anesthesia control group and groups insufflated with CO2 alone or CO2 containing fixed amounts of ethyl nitrite (1[ndash]300 ppm). Insufflation with CO2 alone produced declines in splanchnic organ blood flows and it reduced circulating levels of S-nitrosohemoglobin (i.e., nitric oxide bioactivity); these reductions wer...

Sailing From Bench to Bedside

Clinical and Translational Science — Tue, 01 Dec 2009 00:00:00 +0100

(Source: Clinical and Translational Science)

Community-Based Participatory Clinical Research in Obesity by Adolescents: Pipeline for Researchers of the Future

Clinical and Translational Science — Mon, 26 Oct 2009 00:00:00 +0100

We describe a pilot model in which adolescents apply principles of Community-Based Participatory Research (CBPR) at the epicenter of the obesity diabetes epidemic in rural Appalachia in West Virginia. The model invites minority, financially disadvantaged, and educationally disadvantaged adolescents to become educated on ethics, then provides infrastructure to support study design and conduct of CBPR. This experience demonstrates that these adolescents can effi ciently, with quality and integrity, reach into the most vulnerable of communities and their own families to show that the prevalence of obesity is at 50% and diabetes 10.4% (n= 989). Our experience illustrates the infrastructure requirements for this strategy to be successful and emphasizes the substantial benefit that could accrue ...

Feasibility of Adolescents to Conduct Community-Based Participatory Research on Obesity and Diabetes in Rural Appalachia

Clinical and Translational Science — Mon, 26 Oct 2009 00:00:00 +0100

We describe a novel approach applied to obesity management and diabetes prevention. This takes advantage of a network of science clubs organized by the Health Sciences and Technology Academy (HSTA) for extracurricular activity of disadvantaged high school students in rural Appalachia. Physician scientists and educators provided an intensive summer course on CBPR, ethics, and study design on obesity management and diabetes prevention. Ethical certification for CBPR investigation was obtained for 210 students and 18 mentors for a study on the prevalence of obesity and Type II diabetes within their community. Over a 6-month period, 989 had a collection of complete analyzable data, of which 103 had diabetes. The proportion with obesity (BMI [ge] 30) was over 50%. The frequency of diabetes was ...

The Washington University Institute for Clinical and Translational Sciences

Clinical and Translational Science — Mon, 26 Oct 2009 00:00:00 +0100

(Source: Clinical and Translational Science)

The Future of Biotechnology Funding

Clinical and Translational Science — Mon, 26 Oct 2009 00:00:00 +0100

(Source: Clinical and Translational Science)

What Can Be Done to Protect the Translational Investigator?

Clinical and Translational Science — Mon, 26 Oct 2009 00:00:00 +0100

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In the NEWS A QUICK ROUNDUP OF NEWS AND INFORMATION FROM OUR COMMUNITY

Clinical and Translational Science — Mon, 26 Oct 2009 00:00:00 +0100

(Source: Clinical and Translational Science)

Bring Business Lessons to CTS

Clinical and Translational Science — Mon, 26 Oct 2009 00:00:00 +0100

(Source: Clinical and Translational Science)

Thrombotic Microangiopathies: Multimers, Metalloprotease, and Beyond

Clinical and Translational Science — Wed, 07 Oct 2009 23:00:00 +0100

The pathophysiology of various types of thrombotic microangiopathies is coming progressively into focus. Therapeutic advances are likely to follow at a quickening pace. This discussion focuses on thrombotic thrombocytopenic purpura (TTP), the hemolytic-uremic syndrome (HUS), thrombotic microangiopathies associated with transplantation-immunosuppression or anti-angiogenesis therapy, and the preeclampsia/hemolysis-elevated liver enzymes and low platelets syndrome (HELLP). (Source: Clinical and Translational Science)

Meta-analysis: A Brief Introduction

Clinical and Translational Science — Tue, 06 Oct 2009 23:00:00 +0100

Meta-analysis is the process of combining data from multiple sources and analyzing it together to increase power and provide a clearer picture of the effect of intervention or exposure on an outcome. The process is not complicated, but requires a great deal of attention to detail. A specific set of inclusion criteria for studies must be defined. Published or available study results may be affected by publication bias of several different types, so the researcher should be sure to conduct a thorough search of available databases in order to include unpublished findings. Following selection, the group of studies should be examined using funnel plots or statistical tests. Meta-analysis models themselves must be selected to properly reflect the combined studies. Both fixed- and random-effects ...

From Research to Public Policy: An Essential Extension of the Translation Research Agenda

Clinical and Translational Science — Mon, 05 Oct 2009 23:00:00 +0100

Research translation typically includes translation from basic science into clinical research and from clinical research into everyday clinical practice. In this essay, we propose a greater emphasis on applying research findings, both basic and clinical, into effective public policies that promote health. Research can have important influences on policy by providing a scholarly basis for action research, and translation science units within academic health centers are in powerful positions to build bridges between the research and policy making communities to promote the development of evidence based policy. The results will benefit the researcher and the decision maker, as well as the research itself. (Source: Clinical and Translational Science)

Targeted Disruption of KATP Channels Aggravates Cardiac Toxicity in Cocaine Abuse

Clinical and Translational Science — Mon, 05 Oct 2009 23:00:00 +0100

This study therefore reveals a previously unrecognized role of Kir6.2-encoded KATP channels in determining cardiovascular outcome in chronic cocaine abuse, identifying a novel molecular determinant of cocaine cardiotoxicity. (Source: Clinical and Translational Science)

Experimental Therapeutics: A Paradigm for Personalized Medicine

Clinical and Translational Science — Mon, 05 Oct 2009 23:00:00 +0100

(Source: Clinical and Translational Science)

Creating an Ontology-Based Human Phenotyping System: The Rockefeller University Bleeding History Experience

Clinical and Translational Science — Mon, 05 Oct 2009 23:00:00 +0100

The lack of standardized methods for human phenotyping is a major obstacle in translational science. We have developed a bleeding history phenotyping system comprising an ontology, a questionnaire, a Web-based phenotype recording instrument (PRI), and a database. The ontology facilitates transparency, collaboration, aggregation of data, and data analysis. The integrated system allows investigators worldwide to use the PRI, add their de-identified data to the database, and query the aggregated data. Thus, this system can increase the power to detect genotype[ndash]phenotype[ndash]environment relationships and help new investigators begin their studies. We anticipate that this approach may be applicable to other disorders. (Source: Clinical and Translational Science)

Imprinting Status of GαS, NESP55, and XLαs in Cell Cultures Derived from Human Embryonic Germ Cells: GNAS Imprinting in Human Embryonic Germ Cells

Clinical and Translational Science — Mon, 05 Oct 2009 23:00:00 +0100

GNAS is a complex gene that through use of alternative first exons encodes signaling proteins G[alpha]s and XL[alpha]s plus neurosecretory protein NESP55. Tissue-specific expression of these proteins is regulated through reciprocal genomic imprinting in fully differentiated and developed tissue. Mutations in GNAS account for several human disorders, including McCune-Albright syndrome and Albright hereditary osteodystrophy, and further knowledge of GNAS imprinting may provide insights into variable phenotypes of these disorders. We therefore analyzed expression of G[alpha]s, NESP55, and XL[alpha]s prior to tissue differentiation in cell cultures derived from human primordia germ cells. We found that the expression of G[alpha]s was biallelic (maternal allele: 52.6%± 2.5%; paternal allele: 4...

Neutrophil Elastase Increases Airway Epithelial Nonheme Iron Levels

Clinical and Translational Science — Mon, 05 Oct 2009 23:00:00 +0100

Alpha-1-antitrypsin (A1AT) deficiency is characterized by increased neutrophil elastase (NE) activity and oxidative stress in the lung. We hypothesized that NE exposure generates reactive oxygen species by increasing lung nonheme iron. To test this hypothesis, we measured bronchoalveolar lavage (BAL) iron and ferritin levels, using inductively coupled plasma (ICP) optical emission spectroscopy and an ELISA, respectively, in A1AT-deficient patients and healthy subjects. To confirm the role of NE in regulating lung iron homeostasis, we administered intratracheally NE or control buffer to rats and measured BAL and lung iron and ferritin. Our results demonstrated that A1AT-deficient patients and rats postelastase exposure have elevated levels of iron and ferritin in the BAL. To investigate the...

Increased Phosphorylation-Dependent Nuclear Export of Class II Histone Deacetylases in Failing Human Heart

Clinical and Translational Science — Thu, 10 Sep 2009 23:00:00 +0100

In this study, human left ventricular tissue from nonfailing and failing adult hearts was analyzed for the presence of MEF2, HDACs 4 and 5. CaMK and HDAC kinase activities were measured in tissue homogenates. In nuclear fractions from failing ventricles, HDAC4 and HDAC5 protein was decreased versus nonfailing controls. MEF2 was not reduced in failing nuclear fractions. CaMK and HDAC kinase activities were increased in failing versus nonfailing hearts. PKC[mu] (PKD1) activity was increased in nuclear fractions from failing human LVs. These data provide support for decreased nuclear compartment class II HDACs in the FHH, associated with increased activities of kinases known to phosphorylate class II HDACs. (Source: Clinical and Translational Science)

Isosorbide Dinitrate and Hydralazine as Therapy for African Americans with Heart Failure; a Failed Paradigm?

Clinical and Translational Science — Thu, 06 Aug 2009 23:00:00 +0100

(Source: Clinical and Translational Science)

Lymphocyte-Bound Complement Activation Products as Biomarkers for Diagnosis of Systemic Lupus Erythematosus

Clinical and Translational Science — Fri, 31 Jul 2009 23:00:00 +0100

Systemic lupus erythematosus (SLE) is frequently misdiagnosed due to the lack of definitive diagnostic tests. The purpose of this study was to determine specifically whether complement activation products (CAP) are deposited on lymphocytes of SLE patients and whether lymphocyte-bound CAP (LB-CAP) may serve as novel biomarkers for the diagnosis of SLE. We conducted a cross-sectional study of 224 patients with SLE, 179 patients with other diseases, and 114 healthy controls. LB-CAP on peripheral blood lymphocytes was measured by flow cytometry. Diagnostic utility of LB-CAP was determined by receiver operating characteristic (ROC) analysis. Significantly elevated levels of C4d and C3d were detected specifically on T and B lymphocytes (designated T-C4d, T-C3d, B-C4d, and B-C3d) of SLE patients....

Phenotyping the Right Ventricle in Patients with Pulmonary Hypertension

Clinical and Translational Science — Thu, 30 Jul 2009 23:00:00 +0100

Right ventricular (RV) failure is associated with poor outcomes in pulmonary hypertension (PH). We sought to phenotype the RV in PH patients with compensated and decompensated RV function by quantifying regional and global RV structural and functional changes. Twenty-two patients (age 51 ± 11, 14 females, mean pulmonary artery (PA) pressure range 13[ndash]79 mmHg) underwent right heart catheterization, echocardiography, and ECG-gated multislice computed tomography of the chest. Patients were divided into three groups: Normal, PH with hemodynamically compensated, and decompensated RV function (PH-C and PH-D, respectively). RV wall thickness (WT) was measured at end-diastole (ED) and end-systole (ES) in three regions: infundibulum, lateral free wall, and inferior free wall. Globally, RV vol...

Trachea Epithelium as a "Canary" for Cigarette Smoking-Induced Biologic Phenotype of the Small Airway Epithelium

Clinical and Translational Science — Wed, 29 Jul 2009 23:00:00 +0100

The initial site of smoking-induced lung disease is the small airway epithelium, which is difficult and time consuming to sample by fiberoptic bronchoscopy. We developed a rapid, office-based procedure to obtain trachea epithelium without conscious sedation from healthy nonsmokers (n= 26) and healthy smokers (n= 19, 27 ± 15 pack-year). Gene expression differences (fold change >1.5, p < 0.01, Benjamini[ndash]Hochberg correction) were assessed with Affymetrix microarrays. A total of 1,057 probe sets were differentially expressed in healthy smokers versus nonsmokers, representing >500 genes. Trachea gene expression was compared to an independent group of small airway epithelial samples (n= 23 healthy nonsmokers, n= 19 healthy smokers, 25 ± 12 pack-year). The trachea epithelium is more sensi...

Single Cell Analysis of Complex Thymus Stromal Cell Populations: Rapid Thymic Epithelia Preparation Characterizes Radiation Injury

Clinical and Translational Science — Wed, 15 Jul 2009 23:00:00 +0100

We present a new rapid separation technique that yields consistent viable TEC numbers in a quarter of the prior preparation time. Using this new procedure, we identify changes in stromal populations following total body irradiation (TBI). By flow cytometry, we show that TBI significantly depletes UEA+ medullary TEC, while sparing Ly51+ CD45[minus] cells. Further characterization of the Ly51+ subset reveals enrichment of fibroblasts (CD45[minus] Ly51+ MHCII[minus]), while cortical TECs (CD45[minus] Ly51+ MHCII+) were markedly reduced. Dendritic cells (CD11c+ CD45+) were also decreased following TBI. These data suggest that cytotoxic preparative regimens may impair thymic renewal by reducing critical populations of cortical and medullary TEC, and that such thymic damage can be assessed by th...

Defining the Components of the Research Pipeline

Clinical and Translational Science — Tue, 14 Jul 2009 23:00:00 +0100

The National Institutes of Health (NIH) has proposed that research moves from "bench to bedside" through a Pipeline consisting of distinct research categories bridged by bidirectional translation. The original NIH Pipeline has now been expanded to include practice- and community-based research. We developed operational definitions for the elements along the expanded NIH Pipeline. The proposed definitions were pilot-tested and refined using the Computer Retrieval of Information on Scientific Projects (CRISP) and the Secure Internet-Linked Web Technologies (SILK) database containing funding information for individual NIH awards. Using our definitions, two reviewers independently agreed on the categorization of 94% of 866 National Heart, Lung, and Blood Institute (NHLBI)-funded projects, and ...

Identification of Biomarkers in Human Head and Neck Tumor Cell Lines That Predict For In Vitro Sensitivity to Gefitinib

Clinical and Translational Science — Wed, 24 Jun 2009 23:00:00 +0100

Potential biomarkers were identified for in vitro sensitivity to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in head and neck cancer. Gefitinib sensitivity was determined in cell lines, followed by transcript profiling coupled with a novel pathway analysis approach. Eleven cell lines were highly sensitive to gefitinib (inhibitor concentration required to give 50% growth inhibition [GI50] < 1 [mu]M), three had intermediate sensitivity (GI50 1[ndash]7 [mu]M), and six were resistant (GI50 > 7 [mu]M); an exploratory principal component analysis revealed a separation between the genomic profiles of sensitive and resistant cell lines. Subsequently, a hypothesis-driven analysis of Affymetrix data (Affymetrix, Inc., Santa Clara, CA, USA) revealed higher mRNA lev...

Stem Cell Platforms for Regenerative Medicine

Clinical and Translational Science — Thu, 07 May 2009 23:00:00 +0100

The pandemic of chronic degenerative diseases associated with aging demographics mandates development of effective approaches for tissue repair. As diverse stem cells directly contribute to innate healing, the capacity for de novo tissue reconstruction harbors a promising role for regenerative medicine. Indeed, a spectrum of natural stem cell sources ranging from embryonic to adult progenitors has been recently identified with unique characteristics for regeneration. The accessibility and applicability of the regenerative armamentarium has been further expanded with stem cells engineered by nuclear reprogramming. Through strategies of replacement to implant functional tissues, regeneration to transplant progenitor cells or rejuvenation to activate endogenous self-repair mechanisms, the ove...

Ca2+-Binding Proteins in Dogs with Heart Failure: Effects of Cardiac Contractility Modulation Electrical Signals

Clinical and Translational Science — Thu, 07 May 2009 23:00:00 +0100

Conclusion: CCM therapy restores LV expression of S100A1, PS2, and sorcin. Normalization of CBPs may partly contribute to improved LV function in HF following CCM therapy. (Source: Clinical and Translational Science)

Tissue-Level Modeling of Xenobiotic Metabolism in Liver: An Emerging Tool for Enabling Clinical Translational Research

Clinical and Translational Science — Fri, 13 Mar 2009 00:00:00 +0100

This review summarizes some of the recent developments and identifies critical challenges associated with in vitro and in silico representations of the liver and assesses the translational potential of these models in the quest of rationalizing the process of evaluating drug efficacy and toxicity. It discusses a wide range of research efforts that have produced, during recent years, quantitative descriptions and conceptual as well as computational models of hepatic processes such as biotransport and biotransformation, intra- and intercelular signal transduction, detoxification, etc. The abovementioned research efforts cover multiple scales of biological organization, from molecule[ndash]molecule interactions to reaction network and cellular and histological dynamics, and have resulted in a...

Inhibition of Protein 4.1 R and NuMA Interaction by Mutagenization of Their Binding-Sites Abrogates Nuclear Localization of 4.1 R

Clinical and Translational Science — Sat, 31 Jan 2009 00:00:00 +0100

Protein 4.1R(4.1R) is a multifunctional structural protein recently implicated in nuclear assembly and cell division. We earlier demonstrated that 4.1R forms a multiprotein complex with mitotic spindle and spindle pole organizing proteins, such as NuMA, dynein, and dynactin, by binding to residues 1788[ndash]1810 of NuMA through amino acids encoded by exons 20 and 21 in 24 kD domain. Employing random-and site-directed mutagenesis combined with glycine- and alanine-scanning, we have identified amino acids of 4.1 R and NuMA that sustain their interaction, and have analyzed the effect of mutating the binding sites on their intracellular colocalization. We found that V762, V765, and V767 of 4.1 R, and 11800, 11801,11803, Tl 804, and M1805 of NuMA are necessary for their interaction. GST-fusion...

Molecular Diagnostics at the Nexus of Individualized Medicine, Healthcare Delivery, and Public Policy

Clinical and Translational Science — Thu, 23 Oct 2008 23:00:00 +0100

(Source: Clinical and Translational Science)