http://www.translational-medicine.com The most accessed research articles published by Journal of Translational Medicine 2012-05-09T00:00:00Z Background: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) is an etiologically unexplained disorder characterised by irregularities in various aspects of the immunological function. Presently, it is unknown whether these immunological changes remain consistent over time. This study investigates Natural Killer (NK) cell cytotoxic activity, NK cell subsets (CD56brightCD16- and CD56dimCD16+) and cytokines, over the course of a12 month period in patients with CFS/ME. Methods: The participants in the study comprised 65 (47.2+/-11.5 years) CFS/ME participants and 21 (45.2 +/-9.3 years) non-fatigued controls. Flow cytometry protocols were used to assess NK subsets and NK cytotoxic activity at various time points that included baseline (T1), 6 (T2) and 12 months (T3). Cytokine secretions were measured following mitogenic stimulation of peripheral blood mononuclear cells. Results: NK cytotoxic activity was significantly decreased in the CFS/ME patients at T1, T2 and T3 compared to the non-fatigued group. Additionally, in comparison to the non-fatigued controls, the CFS/ME group had significantly lower numbers of CD56brightCD16- NK cells at both T1 and T2. Interestingly, following mitogenic stimulation, cytokine secretion revealed significant increases in IL-10, IFN-gamma and TNF-alpha at T1 in the CFS/ME group. A significant decrease was observed at T2 in the CFS/ME group for IL-10 and IL-17A while at T3, IL-2 was increased in the CFS/ME group in comparison to the non- fatigued controls. Overall cytotoxic activity was significantly decreased at T3 compared to T1 and T2. CD56brightCD16- NK cells were much lower at T2 compared to the T1 and T3. IL-10 and IL-17A secretion was elevated at T2 in comparison to the T1 and T3. Conclusion: These results confirm decreases in immune function in CFS/ME patients, suggesting an increased susceptibility to viral and other infections. Furthermore NK cytotoxic activity may be a suitable biomarker for diagnosing CFS/ME as it was consistently decreased during the course of the 12 months study. http://www.translational-medicine.com/content/10/1/88 Ekua Brenu Mieke van Driel Donald Staines Kevin Ashton Sharni Hardcastle James Keane Lotti Tajouri Daniel Peterson Sandra Ramos Sonya Marshall-Gradisnik Journal of Translational Medicine 2012, null:88 2012-05-09T00:00:00Z doi:10.1186/1479-5876-10-88 /content/figures/1479-5876-10-88-toc.gif Journal of Translational Medicine 1479-5876 ${item.volume} 88 2012-05-09T00:00:00Z PDF BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50% of melanomas harbors activating BRAF mutations (over 90% V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naive patients (BRIM-3). The study results showed a relative reduction of 63% in risk of death and 74% in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA4 inhibitor mAb Ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors. http://www.translational-medicine.com/content/10/1/85 Paolo Ascierto John Kirkwood Jean-Jacques Grob Ester Simeone Antonio Grimaldi Michele Maio Giuseppe Palmieri Alessandro Testori Francesco Marincola Nicola Mozzillo Journal of Translational Medicine 2012, null:85 2012-05-03T00:00:00Z doi:10.1186/1479-5876-10-85 /content/figures/1479-5876-10-85-toc.gif Journal of Translational Medicine 1479-5876 ${item.volume} 85 2012-05-03T00:00:00Z PDF Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions whose incidence is reaching epidemic proportions, afflicting approximately 1 in 166 children. Autistic disorder, or autism is the most common form of ASD. Although several neurophysiological alterations have been associated with autism, immune abnormalities and neural hypoperfusion appear to be broadly consistent. These appear to be causative since correlation of altered inflammatory responses, and hypoperfusion with symptology is reported. Mesenchymal stem cells (MSC) are in late phases of clinical development for treatment of graft versus host disease and Crohn's Disease, two conditions of immune dysregulation. Cord blood CD34+ cells are known to be potent angiogenic stimulators, having demonstrated positive effects in not only peripheral ischemia, but also in models of cerebral ischemia. Additionally, anecdotal clinical cases have reported responses in autistic children receiving cord blood CD34+ cells. We propose the combined use of MSC and cord blood CD34+cells may be useful in the treatment of autism. http://www.translational-medicine.com/content/5/1/30 Thomas Ichim Fabio Solano Eduardo Glenn Frank Morales Leonard Smith George Zabrecky Neil Riordan Journal of Translational Medicine 2007, null:30 2007-06-27T00:00:00Z doi:10.1186/1479-5876-5-30 /content/figures/1479-5876-5-30-toc.gif Journal of Translational Medicine 1479-5876 ${item.volume} 30 2007-06-27T00:00:00Z XML The development of cancer has historically been attributed to genomic alterations of normal host cells. Accordingly, the aim of most traditional cancer therapies has been to destroy the transformed cells themselves. There is now widespread appreciation that the progressive growth and metastatic spread of cancer cells requires the cooperation of normal host cells (endothelial cells, fibroblasts, other mesenchymal cells, and immune cells), both local to, and at sites distant from, the site at which malignant transformation occurs. It is the balance of these cellular interactions that both determines the natural history of the cancer, and influences its response to therapy. This active tumor-host dynamic has stimulated interest in the tumor microenvironment as a key target for both cancer diagnosis and therapy. Recent data has demonstrated both that the presence of CD8+ T cells within a tumor is associated with a good prognosis, and that the eradication of all malignantly transformed cells within a tumor requires that the intra-tumoral concentration of cytolytically active CD8+ effector T cells remain above a critical concentration until every tumor cell has been killed. These findings have stimulated two initiatives in the field of cancer immunotherapy that focus on the tumor microenvironment. The first is the development of the immune score as part of the routine diagnostic and prognostic evaluation of human cancers, and the second is the development of combinatorial immune-based therapies that reduce tumor-associated immune suppression to unleash pre-existing or therapeutically-induced tumor immunity. In support of these efforts, the Society for the Immunotherapy of Cancer (SITC) is sponsoring a workshop entitled "Focus on the Target: The Tumor Microenvironment" to be held October 24-25, 2012 in Bethesda, Maryland. This meeting should support development of the immune score, and result in a position paper highlighting opportunities for the development of integrative cancer immunotherapies that sculpt the tumor microenvironment to promote definitive tumor rejection. http://www.translational-medicine.com/content/10/1/70 Leisha Emens Samuel Silverstein Samir Khleif Francesco Marincola Jerome Galon Journal of Translational Medicine 2012, null:70 2012-04-10T00:00:00Z doi:10.1186/1479-5876-10-70 /content/figures/1479-5876-10-70-toc.gif Journal of Translational Medicine 1479-5876 ${item.volume} 70 2012-04-10T00:00:00Z XML Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer. http://www.translational-medicine.com/content/9/1/214 Bernard Fox Dolores Schendel Lisa Butterfield Steinar Aamdal James Allison Paolo Antonio Ascierto Michael Atkins Jirina Bartunkova Lothar Bergmann Neil Berinstein Cristina Bonorino Ernest Borden Jonathan Bramson Cedrik Britten Xuetao Cao William Carson Alfred Chang Dainius Characiejus A.Raja Choudhury George Coukos Tanja de Gruijl Robert Dillman Harry Dolstra Glenn Dranoff Lindy Durrant James Finke Jerome Galon Jared Gollob Cecile Gouttefangeas Fabio Grizzi Michele Guida Leif Hakansson Kristen Hege Ronald Herberman F.Stephen Hodi Axel Hoos Christoph Huber Patrick Hwu Kohzoh Imai Elizabeth Jaffee Sylvia Janetzki Carl June Pawel Kalinski Howard Kaufman Koji Kawakami Yutaka Kawakami Ulrich Keilholtz Samir Khleif Rolf Kiessling Beatrix Kotlan Guido Kroemer Rejean Lapointe Hyam Levitsky Michael Lotze Cristina Maccalli Michele Maio Jens-Peter Marschner Michael Mastrangelo Giuseppe Masucci Ignacio Melero Cornelius Nelief William Murphy Brad Nelson Andrea Nicolini Michael Nishimura Kunle Odunsi Pamela Ohashi Jill O'Donnell-Tormey Lloyd Old Christian Ottensmeier Michael Papamichail Giorgio Parmiani Graham Pawelec Enrico Proietti Shukui Qin Robert Rees Antoni Ribas Ruggero Ridolfi Gerd Ritter Licia Rivoltini Pedro Romero Mohamed Salem Rik Scheper Barbara Seliger Padmanee Sharma Hiroshi Shiku Harpreet Singh-Jasuja Wenru Song Per Thor Straten Hideaki Tahara Zhigang Tian Sjoerd van Der Burg Paul von Hoegen Ena Wang Marij Welters Hauke Winter Tara Withington Jedd Wolchok Weihua Xiao Laurence Zitvogel Heinz Zwierzina Francesco Marincola Thomas Gajewski Jon Wigginton Mary Disis Journal of Translational Medicine 2011, null:214 2011-12-14T00:00:00Z doi:10.1186/1479-5876-9-214 /content/figures/1479-5876-9-214-toc.gif Journal of Translational Medicine 1479-5876 ${item.volume} 214 2011-12-14T00:00:00Z XML Background: Over-diagnosis and treatment of prostate cancer has been a major problem in prostate cancer care and management. Currently the most relevant prognostic factor to predict a patient's risk of death due to prostate cancer is the Gleason score of the biopsied tissue samples. However, pathological analysis is subjective, and the Gleason score is only a qualitative estimate of the cancer malignancy. Molecular biomarkers and diagnostic tests that can accurately predict prostate tumor aggressiveness are rather limited.MethodWe report here for the first time the development of a nanoparticle test that not only can distinguish prostate cancer from normal and benign conditions, but also has the potential to predict the aggressiveness of prostate cancer quantitatively. To conduct the test, a prostate tissue lysate sample is spiked into a blood serum or human IgG solution and the spiked sample is incubated with a citrate-protected gold nanoparticle solution. IgG is known to adsorb to citrate-protected gold nanoparticles to form a "protein corona" on the nanoparticle surface. From this study, we discovered that certain tumor-specific molecules can interact with IgG and change the adsorption behavior of IgG to the gold nanoparticles. This change is reflected in the nanoparticle size of the assay solution and detected by a dynamic light scattering technique. Assay data were analyzed by one-way ANOVA for multiple variant analysis, and using the Student t-test or nonparametric Mann-Whitney U-tests for pairwise analyses. Results: An inverse, quantitative correlation of the average nanoparticle size of the assay solution with tumor status and histological diagnostic grading was observed from the nanoparticle test. IgG solutions spiked with prostate tumor tissue exhibit significantly smaller nanoparticle size than the solutions spiked with normal and benign tissues. The higher grade the tumor is, the smaller the nanoparticle size is. The test particularly revealed large differences among the intermediate Grade 2 tumors, and suggested the need to treat them differently. Conclusion: Development of a new nanoparticle test may provide a quantitative measure of the prostate cancer aggressiveness. If validated in a larger study of patients with prostate cancer, this test could become a new diagnostic tool in conjunction with Gleason Score pathology diagnostics to better distinguish aggressive cancer from indolent tumor. http://www.translational-medicine.com/content/10/1/44 Qun Huo Sally Litherland Shannon Sullivan Hillari Hallquist David Decker Inoel Rivera-Ramirez Journal of Translational Medicine 2012, null:44 2012-03-09T00:00:00Z doi:10.1186/1479-5876-10-44 /content/figures/1479-5876-10-44-toc.gif Journal of Translational Medicine 1479-5876 ${item.volume} 44 2012-03-09T00:00:00Z XML A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naive and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies. http://www.translational-medicine.com/content/10/1/48 David Stroncek Carolina Berger Martin Cheever Richard Childs Mark Dudley Peter Flynn Luca Gattinoni James Heath Micheal Kalos Francesco Marincola Jeffery Miller Gustavo Mostoslavsky Daniel Powell Mahendra Rao Nicholas Restifo Steven Rosenberg John O'Shea Cornelis Melief Journal of Translational Medicine 2012, null:48 2012-03-15T00:00:00Z doi:10.1186/1479-5876-10-48 /content/figures/1479-5876-10-48-toc.gif Journal of Translational Medicine 1479-5876 ${item.volume} 48 2012-03-15T00:00:00Z PDF After more than 30 years, landmark progress has been made in the treatment of cancer and, melanoma in particular, with the success of new molecules such as ipilimumab, vemurafenib and active specific immunization.After the first congress in December 2010, the second edition of "Melanoma Research: a bridge from Naples to the World" meeting, organized by Paolo A. Ascierto (INT, Naples, Italy), Francesco M. Marincola (NIH, Bethesda, USA), and Nicola Mozzillo (INT, Naples, Italy) took place in Naples, on 5-6 December 2011. We have identified four new topics of discussion: Innovative Approaches in Prevention, Diagnosis and Surgical Treatment, New Pathways and Targets in Melanoma: An Update about Immunotherapy, and Combination Strategies.This international congress gathered more than 30 international faculty members and was focused on recent advances in melanoma molecular biology, immunology and therapy, and created an interactive atmosphere which stimulated discussion of new approaches and strategies in the field of melanoma. http://www.translational-medicine.com/content/10/1/83 Paolo Ascierto Antonio Grimaldi Brendan Curti Mark Faries Soldano Ferrone Keith Flaherty Bernard Fox Thomas Gajewski Jeffrey Gershenwald Helen Gogas Kenneth Grossmann Axel Hauschild F Stephen Hodi Richard Kefford John Kirkwood Sancy Leachmann Michele Maio Richard Marais Giuseppe Palmieri Donald Morton Antoni Ribas David Stroncek Rodney Stewart Ena Wang Nicola Mozzillo Francesco Marincola Journal of Translational Medicine 2012, null:83 2012-05-02T00:00:00Z doi:10.1186/1479-5876-10-83 /content/figures/1479-5876-10-83-toc.gif Journal of Translational Medicine 1479-5876 ${item.volume} 83 2012-05-02T00:00:00Z PDF Background: Liver fibrosis is a major health problem worldwide and poses a serious obstacle for cell basedtherapies. Mesenchymal stem cells (MSCs) are multipotent and important candidate cells forfuture clinical applications however success of MSC therapy depends upon their homing andsurvival in recipient organs. This study was designed to improve the repair potential of MSCsby transplanting them in sodium nitroprusside (SNP) pretreated mice with CCl4 induced liverfibrosis. Methods: SNP 100 mM, a nitric oxide (NO) donor, was administered twice a week for 4 weeks toCCl4-injured mice. MSCs were isolated from C57BL/6 wild type mice and transplanted in theleft lateral lobe of the liver in experimental animals. After 4 weeks, animals were sacrificedand liver improvement was analyzed. Analysis of fibrosis by qRT-PCR and sirius redstaining, homing, bilirubin and alkaline phosphatase (ALP) serum levels between differenttreatment groups were compared to control. Results: Liver histology demonstrated enhanced MSCs homing in SNP-MSCs group compared toMSCs group. The gene expression of fibrotic markers; alphaSMA, collagen 1alpha1, TIMP, NFkappaBand iNOS was down regulated while cytokeratin 18, albumin and eNOS was up-regulated inSNP-MSCs group. Combine treatment sequentially reduced fibrosis in SNP-MSCs treatedliver compared to the other treatment groups. These results were also comparable withreduced serum levels of bilirubin and ALP observed in SNP-MSCs treated group. Conclusion: This study demonstrated that NO effectively augments MSC ability to repair liver fibrosisinduced by CCl4 in mice and therefore is a better treatment regimen to reduce liver fibrosis. http://www.translational-medicine.com/content/10/1/75 Gibran Ali Sadia Mohsin Mohsin Khan Ghazanfar Nasir Suleiman Shams Shaheen Khan Sheikh Riazuddin Journal of Translational Medicine 2012, null:75 2012-04-25T00:00:00Z doi:10.1186/1479-5876-10-75 /content/figures/1479-5876-10-75-toc.gif Journal of Translational Medicine 1479-5876 ${item.volume} 75 2012-04-25T00:00:00Z PDF Background: The unique features of human embryonic stem (hES) cells make them the best candidate resource for both cell replacement therapy and development research. However, the molecular mechanisms responsible for the simultaneous maintenance of their self-renewal properties and undifferentiated state remain unclear. Non-coding microRNAs (miRNA) which regulate mRNA cleavage and inhibit encoded protein translation exhibit temporal or tissue-specific expression patterns and they play an important role in development timing. Results: In this study, we analyzed miRNA and gene expression profiles among samples from 3 hES cell lines (H9, I6 and BG01v), differentiated embryoid bodies (EB) derived from H9 cells at different time points, and 5 adult cell types including Human Microvascular Endothelial Cells (HMVEC), Human Umbilical Vein Endothelial Cells (HUVEC), Umbilical Artery Smooth Muscle Cells (UASMC), Normal Human Astrocytes (NHA), and Lung Fibroblasts (LFB). This analysis rendered 104 miRNAs and 776 genes differentially expressed among the three cell types. Selected differentially expressed miRNAs and genes were further validated and confirmed by quantitative real-time-PCR (qRT-PCR). Especially, members of the miR-302 cluster on chromosome 4 and miR-520 cluster on chromosome 19 were highly expressed in undifferentiated hES cells. MiRNAs in these two clusters displayed similar expression levels. The members of these two clusters share a consensus 7-mer seed sequence and their targeted genes had overlapping functions. Among the targeted genes, genes with chromatin structure modification function are enriched suggesting a role in the maintenance of chromatin structure. We also found that the expression level of members of the two clusters, miR-520b and miR-302c, were negatively correlated with their targeted genes based on gene expression analysis Conclusion: We identified the expression patterns of miRNAs and gene transcripts in the undifferentiation of human embryonic stem cells; among the miRNAs that are highly expressed in undifferentiated embryonic stem cells, the miR-520 cluster may be closely involved in hES cell function and its relevance to chromatin structure warrants further study. http://www.translational-medicine.com/content/7/1/20 Jiaqiang Ren Ping Jin Ena Wang Francesco Marincola David Stroncek Journal of Translational Medicine 2009, null:20 2009-03-23T00:00:00Z doi:10.1186/1479-5876-7-20 /content/figures/1479-5876-7-20-toc.gif Journal of Translational Medicine 1479-5876 ${item.volume} 20 2009-03-23T00:00:00Z XML