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Background: Image contrast enhanced by exogenous contrast agents plays a crucial role in the early detection, characterization, and determination of the precise location of cancers. Here, we investigate the feasibility of using a non-nutritive sweetener, sucralose (commercial name, Splenda), as magnetic resonance imaging (MRI) contrast agent for cancer studies.Methods: High-resolution nuclear-magnetic-resonance spectroscopy and MR studies on sucralose solution phantom were performed to detect the chemical exchange saturation transfer (CEST) property of sucralose hydroxyl protons with bulk water (sucCEST). For the animal experiments, female Fisher rats (F344/NCR) were used to generate 9L-gliosarcoma model. MRI with CEST experiments were performed on anesthetized rats at 9.4 T MR scanner. Following the baseline CEST scans, sucralose solution was intravenously administered in control and tumor bearing rats. CEST acquisitions were continued during and following the administration of sucralose. Following the sucCEST, Gadolinium-diethylenetriamine pentaacetic acid was injected to perform Gd-enhanced imaging for visualizing the tumor.Results: The sucCEST contrast in vitro was found to correlate positively with the sucralose concentration and negatively with the pH, indicating the potential of this technique in cancer imaging. In a control animal, the CEST contrast from the brain was found to be unaffected following the administration of sucralose, demonstrating its blood-brain barrier impermeability. In a 9L glioma model, enhanced localized sucCEST contrast in the tumor region was detected while the unaffected brain region showed unaltered CEST effect implying the specificity of sucralose toward the tumorous tissue. The CEST asymmetry plots acquired from the tumor region before and after the sucralose infusion showed elevation of asymmetry at 1 ppm, pointing towards the role of sucralose in increased contrast.Conclusions: We show the feasibility of using sucralose and sucCEST in study of preclinical models of cancer. This study paves the way for the potential development of sucralose and other sucrose derivatives as contrast agents for clinical MRI applications. [ABSTRACT FROM AUTHOR]

Background -: Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures. PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906. Methods -: Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of CPT-11 (CPT-11) by PHY906 in a well-characterized pre-clinical model; the administration of PHY906 and CPT-11 to female BDF-1 mice bearing subcutaneous Colon 38 tumors. Results -: We observed that 1) individually PHY906 and CPT-11 induce distinct alterations in tumor, liver and spleen; 2) PHY906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of CPT-11, with prevalent induction of pro-apoptotic and proinflammatory pathways that may favor tumor rejection. Conclusions -: PHY906 together with CPT-11 triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response. [ABSTRACT FROM AUTHOR]

Background In the recent years there have been major advances in the field of cancer immunology and the existence of a dichotomy between immunologically active and quiescent tumor phenotypes has been recognized in several cancers. The activation of a Th1 immune signature has been shown to confer better prognosis and likelihood to respond to immunotherapy. However, whether such dichotomy depends on the genetic make-up of individual cancers is not known yet. In melanoma, BRAF and NRAS mutations are commonly acquired during tumor progression. Although the oncogenic potential of BRAF and NRAS alterations has been attributed to reduced apoptosis, increased invasiveness and increased metastatic behavior, the role of BRAF and NRAS in the immunological landscape of cutaneous melanoma has been poorly investigated and the effects of BRAF and NRAS mutations on global gene expression remain to be understood. We explored the role of BRAF and NRAS mutations at the transcriptome level and in influencing the immune phenotype (based on a classification previously identified by our group). Materials and methods One-hundred-thirteen pre-treatment snap frozen tumor biopsies were collected from patients treated at the Surgery Branch, NCI (Bethesda, Maryland) and processed for DNA and RNA isolation. Each sample underwent microarray analysis and BRAF and NRAS genotyping. Allele-specific PCR was also performed in order to exclude low-frequency mutations. Fifteen melanoma cell lines were also tested for BRAF and NRAS mutation by Sanger sequencing and RNA-sequencing. Results Comparison between BRAF and NRAS mutant versus wild type samples identified mostly constituents or regulators of MAPK and related pathways. Initially, we postulated that there might be a common MAPK activation signature resulting from either BRAF or NRAS mutation; however, we found no overabundance of discriminatory genes for the combined group of samples displaying either BRAF or NRAS mutations. This suggests that the transcriptional consequences resulting from mutations of BRAF or NRAS might be different, although there was overlapping of some genes, presumably due to their differential capacity to receive input signals and transduce them through different effectors. When testing gene lists discriminative of BRAF, NRAS and MAPK alterations, we found that 112 BRAF-specific transcripts were able to distinguish the two immunerelated phenotypes already described in melanoma, with the poor phenotype associated mostly with BRAF mutation. Noteworthy, such association was stronger in samples displaying low BRAF mRNA expression. However, when testing NRAS mutation, we were not able to find the same association. Class comparison between BRAF mutant samples with high and low expression of the same gene identified 6296 transcripts. Functional interpretation analysis showed that these 6296 transcripts were associated to IL-2 and JAK/Stat signaling pathways, supporting the immunoregulatory role of BRAF. Additionally, fifteen melanoma cell lines were also tested by BRAF and NRAS DNA genotyping and RNA-sequencing. Interestingly, we found that among 8 cell lines BRAF mutated (V600E), three of them expressed BRAF at low level and may have preferential wild type allele selection at the RNA level. Conclusion In conclusion we provide novel insights into the effect of BRAF and NRAS mutations on gene expression according to the immune classification. However, further deeper analyses are warranted to understand the mechanisms behind the association of BRAF mutation with a poor immune phenotype and also behind BRAF low expression and wild type allele selection at the RNA level. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]