JTM's Tumor immunology goes broad: announcing the Immunobiology and Immunotherapy section.

For the last four years the Journal of Translational Medicine (JTM) has hosted the Section of Tumor Immunology and Biological Cancer Therapy. Under the editorial leadership of Dr. Pedro Romero and with the direct support of the Society for Immunotherapy of Cancer (SITC), this section enriched the communication between basic immunological sciences and the clinical investigation arena in oncology. We are re-launching this Section of JTM, now entitled Immunobiology and Immunotherapy, succeeding Tumor Immunology and Biological Cancer Therapy. While aiming to build on the editorial success and focus of its predecessor, this novel Section will have a broader scope, hosting translational immunology topics pertaining to immunotherapy beyond oncology, including disciplines such as inflammation, autoimmunity, transplantation, metabolic disorders and others. As the vision of this re-launched Section of JTM broadens up to serve a communication need for translational immunologists involved with immunotherapy irrespectively of the therapeutic area, a novel and focused journal entitled Journal for Immunotherapy of Cancer (JITC) has just been initiated, sponsored by the SITC

Rewarding patient-directed research: Excellence in Translational Medicine Award

The Editorial Board of Journal of Translational Medicine is pleased to announce a prize to recognize outstanding contributions in the field of translational medicine. The prize is sponsored by Pfizer Global Research and Development, Global Translational Medicine and supported by the Journal of Translational Medicine Editorial Board

MicroRNA and gene expression patterns in the differentiation of human embryonic stem cells

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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</p> <p>Conclusion</p> <p>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.</p

Gene expression profiling of cutaneous wound healing

BACKGROUND: Although the sequence of events leading to wound repair has been described at the cellular and, to a limited extent, at the protein level this process has yet to be fully elucidated. Genome wide transcriptional analysis tools promise to further define the global picture of this complex progression of events. STUDY DESIGN: This study was part of a placebo-controlled double-blind clinical trial in which basal cell carcinomas were treated topically with an immunomodifier – toll-like receptor 7 agonist: imiquimod. The fourteen patients with basal cell carcinoma in the placebo arm of the trial received placebo treatment consisting solely of vehicle cream. A skin punch biopsy was obtained immediately before treatment and at the end of the placebo treatment (after 2, 4 or 8 days). 17.5K cDNA microarrays were utilized to profile the biopsy material. RESULTS: Four gene signatures whose expression changed relative to baseline (before wound induction by the pre-treatment biopsy) were identified. The largest group was comprised predominantly of inflammatory genes whose expression was increased throughout the study. Two additional signatures were observed which included preferentially pro-inflammatory genes in the early post-treatment biopsies (2 days after pre-treatment biopsies) and repair and angiogenesis genes in the later (4 to 8 days) biopsies. The fourth and smallest set of genes was down-regulated throughout the study. Early in wound healing the expression of markers of both M1 and M2 macrophages were increased, but later M2 markers predominated. CONCLUSION: The initial response to a cutaneous wound induces powerful transcriptional activation of pro-inflammatory stimuli which may alert the host defense. Subsequently and in the absence of infection, inflammation subsides and it is replaced by angiogenesis and remodeling. Understanding this transition which may be driven by a change from a mixed macrophage population to predominately M2 macrophages, may help the interpretation of the cellular and molecular events occurring in the microenvironment of serially biopsied tissues

Comparison of proteomic profiles of serum, plasma, and modified media supplements used for cell culture and expansion

BACKGROUND: The culture and expansion of human cells for clinical use requires the presence of human serum or plasma in culture media. Although these supplements have been extensively characterized in their chemical composition, only recently it has been possible to provide by high throughput protein analysis, a comprehensive profile of the soluble factors contributing to cell survival. This study analyzed and compared the presence of 100 proteins including chemokines, cytokines and soluble factors in six different types of media supplements: serum, plasma, recalcified plasma, heat inactivated serum, heat inactivated plasma and heat inactivated recalcified plasma. METHODS: Serum, plasma, recalcified plasma, and heat inactivated supplements were prepared from ten healthy subjects. The levels of 100 soluble factors were measured in each sample using a multiplexed ELISA assay and compared by Eisen hierarchical clustering analysis. RESULTS: A comparison of serum and plasma levels of soluble factors found that 2 were greater in plasma but 18 factors were greater in serum including 11 chemokines. The levels of only four factors differed between recalcified plasma and plasma. Heat inactivation had the greatest effect on soluble factors. Supervised Eisen hierarchical clustering indicated that the differences between heat inactivated supplements and those that were not were greater than the differences within these two groups. The levels of 36 factors differed between heat inactivated plasma and plasma. Thirty one of these factors had a lower concentration in heat inactivated plasma including 12 chemokines, 4 growth factors, 4 matrix metalloproteases, and 3 adhesion molecules. Heat inactivated decalcified plasma is often used in place of heat inactivated serum and the levels of 19 soluble factors differed between these two supplements. CONCLUSION: Our report provides a comprehensive protein profile of serum, plasma recalcified plasma, and heat inactivated supplements. This profile represents a qualitative and quantitative database that can aid in the selection of the appropriate blood derived supplement for human cell cultures with special requirements

CMV pp65 and IE-1 T cell epitopes recognized by healthy subjects

BACKGROUND: Adoptive immune and vaccine therapies have been used to prevent cytomegalovirus (CMV) disease in recipients of hematopoietic progenitor cell transplants, but the nature of T cell responses to CMV have not been completely characterized. METHODS: Peptide pools and individual peptides derived from the immune-dominant CMV proteins pp65 and IE-1 and antigen-specific, cytokine flow cytometry were used to characterize the prevalence and frequency of CD4+ and CD8+ memory T cells in 20 healthy CMV-seropositive subjects. RESULTS: CD8+ T cell responses to pp65 were detected in 35% of subjects and to IE-1 in 40% of subjects. CD4+ T cell responses to pp65 were detected in 50% of subjects, but none were detected to IE-1. Several new IE-1 HLA class I epitopes were identified, including 4 restricted to HLA-C antigens. One region of IE-1 spanning amino acids 300 to 327 was rich in class I epitopes. The HLA class I restrictions of IE-1 peptides were more promiscuous than those of pp65 peptides. CONCLUSION: Since naturally occurring CD4+ and CD8+ T cell responses to pp65 were detectable in many subjects, but only CD8+ T cell responses to IE-1 were detected, pp65 may be better than IE-1 for use in vaccine and adoptive immune therapies

In support of descriptive studies; relevance to translational research

The contemporary scientific establishment equates hypothesis testing to good science. This stance bypasses the preliminary need to identify a worthwhile hypothesis through rigorous observation of natural processes. If alleviation of human suffering is claimed as the goal of a scientific undertaking, it would be unfair to test a hypothesis whose relevance to human disease has not been satisfactorily proven. Here, we argue that descriptive investigations based on direct human observation should be highly valued and regarded essential for the selection of worthwhile hypotheses while the pursuit of costly scientific investigations without such evidence is a desecration of the cause upon which biomedical research is grounded

Differentiation of two types of mobilized peripheral blood stem cells by microRNA and cDNA expression analysis

<p>Abstract</p> <p>Background</p> <p>Mobilized-peripheral blood hematopoietic stem cells (HSCs) have been used for transplantation, immunotherapy, and cardiovascular regenerative medicine. Agents used for HSC mobilization include G-CSF and the CXCR4 inhibitor AMD3100 (plerixafor). The HSCs cells mobilized by each agent may contain different subtypes and have different functions. To characterize mobilized HSCs used for clinical applications, microRNA (miRNA) profiling and gene expression profiling were used to compare AMD3100-mobilized CD133+ cells from 4 subjects, AMD3100 plus G-CSF-mobilized CD133+ cells from 4 subjects and G-CSF-mobilized CD34+ cells from 5 subjects. The HSCs were compared to peripheral blood leukocytes (PBLs) from 7 subjects.</p> <p>Results</p> <p>Hierarchical clustering of miRNAs separated HSCs from PBLs. miRNAs up-regulated in all HSCs included hematopoiesis-associated miRNA; miR-126, miR-10a, miR-221 and miR-17-92 cluster. miRNAs up-regulated in PBLs included miR-142-3p, -218, -21, and -379. Hierarchical clustering analysis of miRNA expression separated the AMD3100-mobilized CD133+ cells from G-CSF-mobilized CD34+ cells. Gene expression analysis of the HSCs naturally segregated samples according to mobilization and isolation protocol and cell differentiation status.</p> <p>Conclusion</p> <p>HSCs and PBLs have unique miRNA and gene expression profiles. miRNA and gene expression microarrays maybe useful for assessing differences in HSCs.</p

Review of the 25th annual scientific meeting of the International Society for Biological Therapy of Cancer

Led by key opinion leaders in the field, the 25th Annual Meeting of the International Society for Biological Therapy of Cancer (iSBTc, recently renamed the Society for Immunotherapy of Cancer, SITC) provided a scientific platform for ~500 attendees to exchange cutting-edge information on basic, clinical, and translational research in cancer immunology and immunotherapy. The meeting included keynote addresses on checkpoint blockade in cancer therapy and recent advances in therapeutic vaccination against cancer induced by Human Papilloma Virus 16. Participants from 29 countries interacted through oral presentations, panel discussions, and posters on topics that included dendritic cells and cancer, targeted therapeutics and immunotherapy, innate/adaptive immune interplay in cancer, clinical trial endpoints, vaccine combinations, countering negative regulation, immune cell trafficking to tumor microenvironment, and adoptive T cell transfer. In addition to the 50 oral presentations and >180 posters on these topics, a new SITC/iSBTc initiative to create evidence-based Cancer Immunotherapy Guidelines was announced. The SITC/iSBTc Biomarkers Taskforce announced the release of recommendations on immunotherapy biomarkers and a highly successful symposium on Immuno-Oncology Biomarkers that took place on the campus of the National Institutes of Health (NIH) immediately prior to the Annual Meeting. At the Annual Meeting, the NIH took the opportunity to publicly announce the award of the U01 grant that will fund the Cancer Immunotherapy Trials Network (CITN). In summary, the Annual Meeting gathered clinicians and scientists from academia, industry, and regulatory agencies from around the globe to interact and exchange important scientific advances related to tumor immunobiology and cancer immunotherapy