The pan-cancer analysis of whole genomes The expansion of whole-genome sequencing studies from individual ICGC and TCGA working groups presented the opportunity to undertake a meta-analysis of genomic features across tumour types. To achieve this, the PCAWG Consortium was established. A Technical Working Group implemented the informatics analyses by aggregating the raw sequencing data from different working groups that studied individual tumour types, aligning the sequences to the human genome and delivering a set of high-quality somatic mutation calls for downstream analysis (Extended Data Fig. 1). Given the recent meta-analysis

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To perform real-time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection. Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image-guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Sixty-three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range, 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first-line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared with those with the basal-like subtype ( = 0.004). The best progression-free survival was observed in those with classical subtype treated with m-FOLFIRINOX. expression in tumor measured by RNA hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients. Prospective genomic profiling of advanced PDAC is feasible, and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes. .

Abstract:In the present study, we first examined the expression of T-cadherin in human CNS by northern blot analysis, immunohistochemical staining, and in situ hybridization. Northern blot analysis demonstrated expression of T-cadherin in human adult cerebral cortex, medulla, thalamus, and midbrain. Immunohistochemical staining with a newly generated monoclonal antibody, designated MA-511, revealed strong expression of Tcadherin in neural cell surface membrane and neurites in adult cerebral cortex, medulla oblongata, and nucleus olivaris. Little or no expression of T-cadherin was found in spinal cord. We further examined T-cadherin expression in various developing nervous systems, and found that T-cadherin expression was lower in developing brain than in adult brain. In situ hybridization revealed that neural cells in medulla oblongata and nucleus olivaris, but not in spinal cord, possessed T-cadherin molecules. We transfected T-cadherin-negative TGW and NH-12 neuroblastoma cells with a T-cadherin cDNA-containing expression vector. T-cadherin-expressing neuroblastoma cells lost mitogenic proliferative response to epidermal growth factor. Epidermal growth factor is known to be required for proliferation of neural stem cells. This finding, together with those of the present study, suggests that T-cadherin functions as a negative regulator of neural cell growth. Key Words: T-cadherinBrain-Monoclonal antibody-MA-511-Epidermal growth factor-Neuroblastoma.

IntroductionMultiple myeloma appears to arise from initiating chromosomal translocations and duplications in postgerminal center plasma cells with subsequent secondary mutations contributing to disease progression. 1,2 Six unique myeloma variants can be identified by gene expression profiling with 3 of the 6 groups anchored by an initiating chromosome translocation. It is noteworthy that a unifying event of cyclin D dysregulation is identified in all subgroups. 1,2 One of the initiating chromosomal abnormalities in myeloma involves members of the Maf family of oncogenes. 1 Maf proteins are basic leucine zipper transcription factors in the AP1 family and regulate gene transcription by binding DNA sequences known as MAF responsive elements (MAREs). 3,4 Of the Maf family, c-maf was the first endogenous member identified and is probably the best characterized with respect to function. 5 Genes up-regulated by c-maf include cyclin D2, ␤-integrin 7, ARK 5 and CCR1, all of which are important in the pathogenesis of multiple myeloma. [6][7][8] c-maf is dysregulated in multiple myeloma. For example, approximately 25% of myeloma cell lines have a t(14;16) translocation. 6 In patients with myeloma, approximately 6% have a t(14;16) or t(14;20), translocations that juxtapose IgH with c-maf and its homolog mafB, respectively. 9,10 The frequency of c-maf overexpression in patients who lack the t(14;16) has varied from study to study, depending on the method to assess its overexpression and ranges from 5% to 50%. 6,11,12 In malignant cell lines, including multiple myeloma, overexpression of c-maf augments cell proliferation and increases tumor formation in xenograft models. 6,7 Conversely, inhibition of c-maf with dominant-negative constructs decreases cell proliferation, impairs adhesion to marrow stroma, and delays tumor growth. 6 Overexpression of c-maf is also clinically relevant in that patients with myeloma and the t(14;16) c-maf translocation have a shorter overall survival. 13 Although the functional importance of c-maf has been described, the mechanisms that govern its regulation have not been fully elucidated. Therefore, molecules that decrease c-maf and subsequently its downstream targets, particularly cyclin D2, could further our understanding of the regulation of c-maf. Improved understanding of c-maf will help develop therapies that target this protein.To this end, we developed a high-throughput chemical genomics screen to identify compounds that inhibit c-maf-dependent transactivation of the cyclin D2 promoter. With this assay, we screened libraries of off-patent drugs and chemicals and were surprised to identify glucocorticoids as inhibitors of c-mafdependent cyclin D2 transactivation. Subsequent studies demonstrated that glucocorticoids decrease c-maf protein by promoting its ubiquitination through the up-regulation of ubiquitin C mRNA. Thus, this chemical biology approach has provided insights into a novel mechanism of c-maf regulation. The publication costs of this article were defrayed in part by page charge ...