http://www.translational-medicine.com The latest research articles published by Journal of Translational Medicine 2010-03-16T00:00:00Z This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ Correlative studies are a primary mechanism through which insights can be obtained about the bioactivity and potential efficacy of candidate therapeutics evaluated in early-stage clinical trials. Accordingly, well designed and performed early-stage correlative studies have the potential to strongly influence further clinical development of candidate therapeutic agents, and correlative data obtained from early stage trials has the potential to provide important guidance on the design and ultimate successful evaluation of products in later stage trials, particularly in the context of emerging clinical trial paradigms such as adaptive trial design.Historically the majority of early stage trials have not generated meaningful correlative data sets that could guide further clinical development of the products under evaluation. In this review article we will discuss some of the potential limitations with the historical approach to performing correlative studies that might explain at least in part the to-date overall failure of such studies to adequately support clinical trial development, and present emerging thought and approaches related to comprehensiveness and quality that hold the promise to support the development of correlative plans which will provide meaningful correlative data that can effectively guide and support the clinical development path for candidate therapeutic agents. http://www.translational-medicine.com/content/8/1/26 Michael Kalos Journal of Translational Medicine 2010, 8:26 2010-03-16T00:00:00Z doi:10.1186/1479-5876-8-26 Journal of Translational Medicine 1479-5876 8 26 2010-03-16T00:00:00Z PDF There are countless reasons nearly every scientist should learn how to communicate effectively with the media, including increased understanding of critical research findings to attract or sustain funding and build new professional partnerships that will further propel forward research. But where do scientists begin? Bridging the Divide between Science and Journalism offers practical tips for any scientist looking to work with the media.Given the traditional and internet-based sources for medical research and healthcare-related news now available, it is imperative that scientists know how to communicate their latest findings through the appropriate channels. The credible media channels are managed by working journalists, so learning how to package vast, technical research in a form that is appetizing and "bite-sized" in order to get their attention, is an art. Reducing years of research into a headline can be extremely difficult and certainly doesn't come naturally to every scientist, so this article provides suggestions on how to work with the media to communicate your findings. http://www.translational-medicine.com/content/8/1/25 Laura Van Eperen Francesco Marincola Jennifer Strohm Journal of Translational Medicine 2010, 8:25 2010-03-10T00:00:00Z doi:10.1186/1479-5876-8-25 Journal of Translational Medicine 1479-5876 8 25 2010-03-10T00:00:00Z PDF Human stem cells from adult sources have been shown to contribute to the regeneration of muscle, liver, heart, and vasculature. The mechanisms by which this is accomplished are, however, still not well understood. We tested the engraftment and regenerative potential of human umbilical cord blood-derived ALDHhiLin-, and ALDHloLin- cells following transplantation to NOD/SCID or NOD/SCID beta2m null mice with experimentally induced acute myocardial infarction. We used combined nanoparticle labeling and whole organ fluorescent imaging to detect human cells in multiple organs 48 hours post transplantation. Engraftment and regenerative effects of cell treatment were assessed four weeks post transplantation. We found that ALDHhiLin- stem cells specifically located to the site of injury 48 hours post transplantation and engrafted the infarcted heart at higher frequencies than ALDHloLin- committed progenitor cells four weeks post transplantation. We found no donor derived cardiomyocytes and few endothelial cells of donor origin. Cell treatment was not associated with any detectable functional improvement at the four week endpoint. There was, however, a significant increase in vascular density in the central infarct zone of ALDHhiLin- cell-treated mice, as compared to PBS and ALDHloLin- cell-treated mice. Conclusions: Our data indicate that adult human stem cells do not become a significant part of the regenerating tissue, but rapidly home to and persist only temporarily at the site of hypoxic injury to exert paracrine effects on tissue repair thereby enhancing vascular recovery. http://www.translational-medicine.com/content/8/1/24 Claus Sondergaard David Hess Dustin Maxwell Carla Weinheimer Ivana Rosova Michael Creer David Piwnica-Worms Attila Kovacs Lene Pederson Jan Nolta Journal of Translational Medicine 2010, 8:24 2010-03-09T00:00:00Z doi:10.1186/1479-5876-8-24 Journal of Translational Medicine 1479-5876 8 24 2010-03-09T00:00:00Z PDF Background: ZAP-70 is an independent negative prognosticator in chronic lymphocytic leukemia (CLL). Usually, its expression is investigated by flow cytometric protocols in which the percentage of ZAP-70 positive CLL cells is determined in respect to isotypic control (ISO-method) or residual ZAP-70 positive T cells (T-method). These methods, however, beside suffering of an inherent subjectivity in their application, may give discordant results in some cases. The aim of this study was to assess the prognostic significance of these methods in comparison with another in which ZAP-70 expression was evaluated as a Mean-Fluorescence-Intensity Ratio between gated T and CLL cells (T/B Ratio-method). Methods: Cytometric files relative to ZAP-70 determination according to the three readouts were retrospectively reviewed on a cohort of 173 patients (test set), all with complete clinical and biological prognostic assessment and time-to-treatment (TTT) available. Findings were then validated in an independent cohort of 341 cases from a different institution (validation set). Results: The optimal prognostic cut-offs for ZAP-70 expression were selected at 11% (ISO-method) or 20% of positive cells (T-method), as well as at 3.0 (T/B Ratio-method) in the test set; these cut-offs yielded 66, 60 and 73 ZAP-70+ cases, respectively. Univariate analyses resulted in a better separation of ZAP-70+ vs. ZAP-70- CLL patients utilizing the T/B-Ratio, compared to T- or ISO-methods. In multivariate analyses which included the major clinical and biological prognosticators for CLL, the prognostic impact of ZAP-70 appeared stronger when the T/B Ratio-method was applied. These findings were confirmed in the validation set, in which ZAP-70 expression, evaluated by the T- (cut-off = 20%) or T/B Ratio (cut-off = 3.0) methods, yielded 180 or 127 ZAP-70+ cases, respectively. ZAP-70+ patients according to the T/B Ratio-method had shorter TTT, both if compared to ZAP-70- CLL, and to cases classified ZAP-70+ by the T-method only. Conclusions: We suggest to evaluate ZAP-70 expression in routine settings using the T/B Ratio-method, given the operator and laboratory independent feature of this approach. We propose the 3.0 T/B Ratio value as optimal cut-off to discriminate ZAP-70+ (T/B Ratio less than 3.0) from ZAP-70- (T/B Ratio more/equal than 3.0) cases. http://www.translational-medicine.com/content/8/1/23 Francesca Rossi Maria Ilaria Del Principe Davide Rossi Maria Irno Consalvo Fabrizio Luciano Antonella Zucchetto Pietro Bulian Riccardo Bomben Michele Dal Bo Marco Fangazio Dania Benedetti Massimo Degan Gianluca Gaidano Giovanni Del Poeta Valter Gattei Journal of Translational Medicine 2010, 8:23 2010-03-08T00:00:00Z doi:10.1186/1479-5876-8-23 Journal of Translational Medicine 1479-5876 8 23 2010-03-08T00:00:00Z PDF Biomedical informatics involves a core set of methodologies that can provide a foundation for crossing the "translational barriers" associated with translational medicine. To this end, the fundamental aspects of biomedical informatics (e.g., bioinformatics, imaging informatics, clinical informatics, and public health informatics) may be essential in helping improve the ability to bring basic research findings to the bedside, evaluate the efficacy of interventions across communities, and enable the assessment of the eventual impact of translational medicine innovations on health policies. Here, a brief description is provided for a selection of key biomedical informatics topics (Decision Support, Natural Language Processing, Standards, Information Retrieval, and Electronic Health Records) and their relevance to translational medicine. Based on contributions and advancements in each of these topic areas, the article proposes that biomedical informatics practitioners ("biomedical informaticians") can be essential members of translational medicine teams. http://www.translational-medicine.com/content/8/1/22 Indra Sarkar Journal of Translational Medicine 2010, 8:22 2010-02-26T00:00:00Z doi:10.1186/1479-5876-8-22 Journal of Translational Medicine 1479-5876 8 22 2010-02-26T00:00:00Z XML Background: According to the scientific literature, less than 30 borderline ovarian tumors have been karyotyped and less than 100 analyzed for genomic imbalances by CGH. Methods: We report a series of borderline ovarian tumors (n = 23) analyzed by G-banding and karyotyping as well as high resolution CGH; in addition, the tumors were analyzed for microsatellite stability status and by FISH for possible 6q deletion. Results: All informative tumors were microsatellite stable and none had a deletion in 6q27. All cases with an abnormal karyotype had simple chromosomal aberrations with +7 and +12 as the most common. In three tumors with single structural rearrangements, a common breakpoint in 3q13 was detected. The major copy number changes detected in the borderline tumors were gains from chromosome arms 2q, 6q, 8q, 9p, and 13q and losses from 1p, 12q, 14q, 15q, 16p, 17p, 17q, 19p, 19q, and 22q. The series included five pairs of bilateral tumors and, in two of these pairs, informative data were obtained as to their clonal relationship. In both pairs, similarities were found between the tumors from the right and left side, strongly indicating that bilaterality had occurred via a metastatic process. The bilateral tumors as a group showed more aberrations than did the unilateral ones, consistent with the view that bilaterality is a sign of more advanced disease. Conclusion: Because some of the imbalances found in borderline ovarian tumors seem to be similar to imbalances already known from the more extensively studied overt ovarian carcinomas, we speculate that the subset of borderline tumors with detectable imbalances or karyotypic aberrations may contain a smaller subset of tumors with a tendency to develop a more malignant phenotype. The group of borderline tumors with no imbalances would, in this line of thinking, have less or no propensity for clonal evolution and development to full-blown carcinomas. http://www.translational-medicine.com/content/8/1/21 Francesca Micci Lisbeth Haugom Terje Ahlquist Hege Andersen Vera Abeler Ben Davidson Claes Trope Ragnhild Lothe Sverre Heim Journal of Translational Medicine 2010, 8:21 2010-02-26T00:00:00Z doi:10.1186/1479-5876-8-21 Journal of Translational Medicine 1479-5876 8 21 2010-02-26T00:00:00Z XML Background: To test the hypothesis that modulation of Bcl-2 with 13-cis retinoic acid (CRA)/interferon-alpha2b (IFN) with paclitaxel (TAX), or mitoxantrone, estramustine and vinorelbine (MEV) will have clinical activity in men with metastatic castrate-resistant prostate cancer (CRPC). Methods: 70 patients were treated with either MEV (Arm A) in a 3-week cycle or CRA/IFN/TAX with an 8-week cycle (Arm B). Patients were assessed for response, toxicity, quality of life (QOL), and the effect of treatment on Bcl-2 levels in peripheral blood mononuclear cells (PBMC). Results: The PSA response rates were 50% and 23%, measurable disease response rates (CR+PR) 14% and 15%, and median overall survival 19.4 months and 13.9 months on Arm A and Arm B respectively. Transient grade 4 neutropenia occurred in 18 and 2 patients, and grade 3 to 4 thrombosis in 7 patients and 1 patient in Arm A and Arm B respectively. Patients on Arm B reported a clinically significant decline in QOL between baseline and week 9/10 (.71 s.d.), and a significantly lower level of QOL than Arm A (p = 0.01). As hypothesized, Bcl-2 levels decreased with CRA/IFN therapy only in Arm B (p = 0.03). Conclusions: Treatment with MEV was well tolerated and demonstrated clinical activity in patients with CRPC. Given the adverse effect of CRA/IFN/TAX on QOL, the study of other novel agents that target Bcl-2 family proteins is warranted. The feasibility of measuring Bcl-2 protein in a cooperative group setting is hypothesis generating and supports further study as a marker for Bcl-2 targeted therapy.Trial RegistrationClinical Trials Registration number: CDR0000067865 http://www.translational-medicine.com/content/8/1/20 Robert DiPaola Yu-Hui Chen Mark Stein David Vaughn Linda Patrick-Miller Michael Carducci Bruce Roth Eileen White George Wilding Journal of Translational Medicine 2010, 8:20 2010-02-24T00:00:00Z doi:10.1186/1479-5876-8-20 Journal of Translational Medicine 1479-5876 8 20 2010-02-24T00:00:00Z XML Background: Increased levels of cryptic collagen epitope HU177 in the sera of melanoma patients have been shown to be associated with thicker primary melanomas and with the nodular histologic subtype. In this study, we investigate the association between HU177 shedding in the sera and clinical outcome in terms of disease-free survival (DFS) and overall survival (OS). Methods: Serum samples from 209 patients with primary melanoma prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group at the New York University Langone Medical Center (mean age = 58, mean thickness = 2.09 mm, stage I = 136, stage II = 41, stage III = 32, median follow-up = 54.9 months) were analyzed for HU177 concentration using a validated ELISA assay. HU177 serum levels at the time of diagnosis were used to divide the study cohort into two groups: low and high HU177. DFS and OS were estimated by Kaplan-Meier survival analysis, and the log-rank test was used to compare DFS and OS between the two HU177 groups. Multivariate Cox proportional hazards regression models were employed to examine the independent effect of HU177 category on DFS and OS. Results: HU177 sera concentrations ranged from 0-139.8 ng/ml (mean and median of 6.2 ng/ml and 3.7 ng/ml, respectively). Thirty-eight of the 209 (18%) patients developed recurrences, and 34 of the 209 (16%) patients died during follow-up. Higher HU177 serum level was associated with an increased rate of melanoma recurrence (p = 0.04) and with increasing mortality (p = 0.01). The association with overall survival remained statistically significant after controlling for thickness and histologic subtype in a multivariate model (p = 0.035). Conclusions: Increased shedding of HU177 in the serum of primary melanoma patients is associated with poor prognosis. Further studies are warranted to determine the clinical utility of HU177 in risk stratification compared to the current standard of care. http://www.translational-medicine.com/content/8/1/19 Heather Hamilton Amy Rose Paul Christos Richard Shapiro Russell Berman Madhu Mazumdar Michelle Ma Daniel Krich Leonard Liebes Peter Brooks Iman Osman Journal of Translational Medicine 2010, 8:19 2010-02-23T00:00:00Z doi:10.1186/1479-5876-8-19 Journal of Translational Medicine 1479-5876 8 19 2010-02-23T00:00:00Z XML Hepatitis C virus (HCV) is one of the major risk factors for chronic hepatitis, which may progress to cirrhosis and hepatocellular carcinoma, as well as for type II mixed cryoglobulinemia (MC), which may further evolve into an overt B-cell non-Hodgkin's lymphoma (NHL).It has been previously shown that B-cell receptor (BCR) repertoire, expressed by clonal B-cells involved in type II MC as well as in HCV-associated NHL, is constrained to a limited number of variable heavy (VH)- and light (VL)-chain genes. Among these, the VK3-20 light chain idiotype has been selected as a possible target for passive as well as active immunization strategy.In the present study, we describe the results of a multiparametric analysis of the innate and early adaptive immune response after ex vivo stimulation of human immune cells with the VK3-20 protein. This objective has been pursued by implementing high-throughput technologies such as multiparameter flow cytometry and multiplex analysis of cytokines and chemokines. http://www.translational-medicine.com/content/8/1/18 Luigi Buonaguro Annacarmen Petrizzo Marialina Tornesello Maria Napolitano Debora Martorelli Giuseppe Castello Gerardo Beneduce Amalia De Renzo Oreste Perrella Luca Romagnoli Vitor Sousa Valli De Re Riccardo Dolcetti Franco Buonaguro Journal of Translational Medicine 2010, 8:18 2010-02-19T00:00:00Z doi:10.1186/1479-5876-8-18 Journal of Translational Medicine 1479-5876 8 18 2010-02-19T00:00:00Z XML Background: Type-1 T cells are critical for effective anti-tumor immune responses. The recently discovered microRNAs (miRs) are a large family of small regulatory RNAs that control diverse aspects of cell function, including immune regulation. We identified miRs differentially regulated between type-1 and type-2 T cells, and determined how the expression of such miRs is regulated. Methods: We performed miR microarray analyses on in vitro differentiated murine T helper type-1 (Th1) and T helper type-2 (Th2) cells to identify differentially expressed miRs. We used quantitative RT-PCR to confirm the differential expression levels. We also used WST-1, ELISA, and flow cytometry to evaluate the survival, function and phenotype of cells, respectively. We employed mice transgenic for the identified miRs to determine the biological impact of miR-17-92 expression in T cells. Results: Our initial miR microarray analyses revealed that the miR-17-92 cluster is one of the most significantly over-expressed miR in murine Th1 cells when compared with Th2 cells. RT-PCR confirmed that the miR-17-92 cluster expression was consistently higher in Th1 cells than Th2 cells. Disruption of the IL-4 signaling through either IL-4 neutralizing antibody or knockout of signal transducer and activator of transcription (STAT)6 reversed the miR-17-92 cluster suppression in Th2 cells. Furthermore, T cells from tumor bearing mice and glioma patients had decreased levels of miR-17-92 when compared with cells from non-tumor bearing counterparts. CD4+ T cells derived from miR-17-92 transgenic mice demonstrated superior type-1 phenotype with increased IFN-γ production and very late antigen (VLA)-4 expression when compared with counterparts derived from wild type mice. Human Jurkat T cells ectopically expressing increased levels of miR-17-92 cluster members demonstrated increased IL-2 production and resistance to activation-induced cell death (AICD). Conclusion: The type-2-skewing tumor microenvironment induces the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor control. Genetic engineering of T cells to express miR-17-92 may represent a promising approach for cancer immunotherapy. http://www.translational-medicine.com/content/8/1/17 Kotaro Sasaki Gary Kohanbash Aki Hoji Ryo Ueda Heather McDonald Todd Reinhart Jeremy Martinson Michael Lotze Francesco Marincola Ena Wang Mitsugu Fujita Hideho Okada Journal of Translational Medicine 2010, 8:17 2010-02-18T00:00:00Z doi:10.1186/1479-5876-8-17 Journal of Translational Medicine 1479-5876 8 17 2010-02-18T00:00:00Z XML