Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing

The Immune Landscape of Cancer

We performed an extensive immunogenomic anal-ysis of more than 10,000 tumors comprising 33diverse cancer types by utilizing data compiled byTCGA. Across cancer types, we identified six im-mune subtypes\u2014wound healing, IFN-gdominant,inflammatory, lymphocyte depleted, immunologi-cally quiet, and TGF-bdominant\u2014characterized bydifferences in macrophage or lymphocyte signa-tures, Th1:Th2 cell ratio, extent of intratumoral het-erogeneity, aneuploidy, extent of neoantigen load,overall cell proliferation, expression of immunomod-ulatory genes, and prognosis. Specific drivermutations correlated with lower (CTNNB1,NRAS,orIDH1) or higher (BRAF,TP53,orCASP8) leukocytelevels across all cancers. Multiple control modalitiesof the intracellular and extracellular networks (tran-scription, microRNAs, copy number, and epigeneticprocesses) were involved in tumor-immune cell inter-actions, both across and within immune subtypes.Our immunogenomics pipeline to characterize theseheterogeneous tumors and the resulting data areintended to serve as a resource for future targetedstudies to further advance the field

Oncogenic Signaling Pathways in The Cancer Genome Atlas

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFb signaling, p53 and beta-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy

Calcium-43 chemical shift and electric field gradient tensor interplay: A sensitive probe of structure, polymorphism, and hydration

Calcium is the 5th most abundant element on earth, and is found in numerous biological tissues, proteins, materials, and increasingly in catalysts. However, due to a number of unfavourable nuclear properties, such as a low magnetogyric ratio, very low natural abundance, and its nuclear electric quadrupole moment, development of solid-state 43Ca NMR has been constrained relative to similar nuclides. In this study, 12 commonly-available calcium compounds are analyzed via43Ca solid-state NMR and the information which may be obtained by the measurement of both the 43Ca electric field gradient (EFG) and chemical shift tensors (the latter of which are extremely rare with only a handful of literature examples) is discussed. Combined with density functional theory (DFT) computations, this 'tensor interplay' is, for the first time for 43Ca, illustrated to be diagnostic in distinguishing polymorphs (e.g., calcium formate), and the degree of hydration (e.g., CaCl2\ub72H2O and calcium tartrate tetrahydrate). For Ca(OH)2, we outline the first example of 1H to 43Ca cross-polarization on a sample at natural abundance in 43Ca. Using prior knowledge of the relationship between the isotropic calcium chemical shift and the calcium quadrupolar coupling constant (CQ) with coordination number, we postulate the coordination number in a sample of calcium levulinate dihydrate, which does not have a known crystal structure. Natural samples of CaCO3 (aragonite polymorph) are used to show that the synthetic structure is present in nature. Gauge-including projector augmented-wave (GIPAW) DFT computations using accepted crystal structures for many of these systems generally result in calculated NMR tensor parameters which are in very good agreement with the experimental observations. This combination of 43Ca NMR measurements with GIPAW DFT ultimately allows us to establish clear correlations between various solid-state 43Ca NMR observables and selected structural parameters, such as unit cell dimensions and average Ca-O bond distances. \ua9 2014 The Owner Societies.Peer reviewed: YesNRC publication: Ye

Hybrid material constructed from Hg(NCS)2and 2,4,6-Tris(2-pyrimidyl)-1,3,5-triazine (TPymT): Coordination of TPymT in a 2,2′-bipyridine-like mode

A unique HgII coordination polymer has been synthesized through the reaction of 2,4,6-tris(2-pyrimidyl)-1,3,5-triazine (TPymT) with a stoichiometric mixture of HgCl2 and NH4NCS, thus leading to the formation of a 1D polymeric heteroleptic hybrid material[{Hg(NCS)2}2TPymT]n (1). Two coordination pockets of TPymT in 1 are each coordinated to two HgII cations in an unprecedented 2,2′-bipyridine-like mode. © 2015 Wiley-VCH Verlag GmbH & Co. KGaA

Linear dicoordinate beryllium: a 9Be solid-state NMR study of a discrete zero-valent s-block beryllium complex

Beryllium-9 quadrupolar coupling and chemical shift tensor data are reported for bis(1-(2,6-diisopropylphenyl)-3,3,5,5-tetramethylpyrrolidine-2-ylidene)beryllium (Be(CAAC)2). These are the first such data for beryllium in a linear dicoordinate environment. TheThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Photophysics of a fluorene co-polymer in solution and films.

The photophysical properties of a new light-emitting co-polymer of fluorene and di-alkoxyphenylene are reported. A range of optical spectroscopies were applied to both solutions and solid films, and comparing the results gives information about the excited states in each phase. Several important differences are observed. The peak of the absorption spectrum is at 350 nm in both solutions and films, but the films show additional absorption features at 450 and 560 nm. The luminescence of the solution phase has a maximum at 420 nm while the films exhibit two maxima with the stronger one located at 420 nm and the weaker one at 540 nm. The photoluminescence quantum yield of the solutions was found to be 45-60%, depending upon the solvent used, and was reduced to 7% for films. Time-resolved luminescence of the solutions revealed a dominant 500 ps decay time upon detection at 420 nm. For redder detection, the excited state decay became bi-exponential with an additional strong nanosecond component that was sensitive to solvent polarity. Time-resolved luminescence of films revealed more complex excited state dynamics. In the blue, the decay is dominated by a similar to40 ps phase followed by weaker 400 ps and 3 ns components. These observations point to the formation of stronger electronic inter-chain interactions aggregate, when going from the liquid to the solid phase. (C) 2002 Elsevier Science B.V. All rights reserved