Large-Scale Profiling of Kinase Dependencies in Cancer Cell Lines

One approach to identifying cancer-specific vulnerabilities and therapeutic targets is to profile genetic dependencies in cancer cell lines. Here, we describe data from a series of siRNA screens that identify the kinase genetic dependencies in 117 cancer cell lines from ten cancer types. By integrating the siRNA screen data with molecular profiling data, including exome sequencing data, we show how vulnerabilities/genetic dependencies that are associated with mutations in specific cancer driver genes can be identified. By integrating additional data sets into this analysis, including protein-protein interaction data, we also demonstrate that the genetic dependencies associated with many cancer driver genes form dense connections on functional interaction networks. We demonstrate the utility of this resource by using it to predict the drug sensitivity of genetically or histologically defined subsets of tumor cell lines, including an increased sensitivity of osteosarcoma cell lines to FGFR inhibitors and SMAD4 mutant tumor cells to mitotic inhibitors

Radiation induced CNS toxicity – molecular and cellular mechanisms

Radiotherapy of tumours proximal to normal CNS structures is limited by the sensitivity of the normal tissue. Prior to the development of prophylactic strategies or treatment protocols a detailed understanding of the mechanisms of radiation induced CNS toxicity is mandatory. Histological analysis of irradiated CNS specimens defines possible target structures prior to a delineation of cellular and molecular mechanisms. Several lesions can be distinguished: Demyelination, proliferative and degenerative glial reactions, endothelial cell loss and capillary occlusion. All changes are likely to result from complex alterations within several functional CNS compartments. Thus, a single mechanism responsible cannot be separated. At least four factors contribute to the development of CNS toxicity: (1) damage to vessel structures; (2) deletion of oligodendrocyte-2 astrocyte progenitors (O-2A) and mature oligodendrocytes; (3) deletion of neural stem cell populations in the hippocampus, cerebellum and cortex; (4) generalized alterations of cytokine expression. Several underlying cellular and molecular mechanisms involved in radiation induced CNS toxicity have been identified. The article reviews the currently available data on the cellular and molecular basis of radiation induced CNS side effects.   http://www.bjcancer.com © 2001 Cancer Research Campaig

RhoGTPase Regulators Orchestrate Distinct Stages of Synaptic Development

Small RhoGTPases regulate changes in post-synaptic spine morphology and density that support learning and memory. They are also major targets of synaptic disorders, including Autism. Here we sought to determine whether upstream RhoGTPase regulators, including GEFs, GAPs, and GDIs, sculpt specific stages of synaptic development. The majority of examined molecules uniquely regulate either early spine precursor formation or later matura- tion. Specifically, an activator of actin polymerization, the Rac1 GEF β-PIX, drives spine pre- cursor formation, whereas both FRABIN, a Cdc42 GEF, and OLIGOPHRENIN-1, a RhoA GAP, regulate spine precursor elongation. However, in later development, a novel Rac1 GAP, ARHGAP23, and RhoGDIs inactivate actomyosin dynamics to stabilize mature synap- ses. Our observations demonstrate that specific combinations of RhoGTPase regulatory pro- teins temporally balance RhoGTPase activity during post-synaptic spine development

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Sequential therapy with ranibizumab and dexamethasone intravitreal implant is better than dexamethasone monotherapy for macular oedema due to retinal vein occlusion

PURPOSE: To evaluate the efficacy and safety of sequential therapy with ranibizumab followed by dexamethasone intravitreal implant compared with dexamethasone monotherapy for macular oedema (MO) secondary to retinal vein occlusion (RVO). METHODS: In this retrospective interventional study, the medical records of subjects with MO due to RVO who received either ranibizumab followed by dexamethasone intravitreal implant (Group 1) or dexamethasone-implant monotherapy (Group 2) were included. Primary outcome was the proportion of subjects who exhibited best-corrected visual acuity (VA) gain and resolution of MO within 6 months. RESULTS: Thirty-three eyes were included (17 in Group 1, 16 in Group 2). More subjects in Group 1 exhibited a VA gain of at least 0.5 (LogMAR units hereafter) than Group 2 (29% vs 0%, p=0.044). The speed of VA gain was greater in Group 1 (1.4+/-0.8 months vs 2.7+/-1.4 months, p=0.020). MO was controlled in more subjects in Group 1 at all measured time intervals, and this difference was statistically significant at 3 months and 4 months. Subjects with branch RVO experienced VA gain more rapidly if they were from Group 1 (p=0.023). CONCLUSIONS: Sequential therapy was found to be more effective than dexamethasone monotherapy in treating MO due to RVO

Sequential therapy with ranibizumab and dexamethasone intravitreal implant is better than dexamethasone monotherapy for macular oedema due to retinal vein occlusion

Purpose To evaluate the efficacy and safety of sequential therapy with ranibizumab followed by dexamethasone intravitreal implant compared with dexamethasone monotherapy for macular oedema (MO) secondary to retinal vein occlusion (RVO). Methods In this retrospective interventional study, the medical records of subjects with MO due to RVO who received either ranibizumab followed by dexamethasone intravitreal implant (Group 1) or dexamethasone-implant monotherapy (Group 2) were included. Primary outcome was the proportion of subjects who exhibited best-corrected visual acuity (VA) gain and resolution of MO within 6 months. Results Thirty-three eyes were included (17 in Group 1, 16 in Group 2). More subjects in Group 1 exhibited a VA gain of at least 0.5 (LogMAR units hereafter) than Group 2 (29% vs 0%, p=0.044). The speed of VA gain was greater in Group 1 (1.4±0.8 months vs 2.7±1.4 months, p=0.020). MO was controlled in more subjects in Group 1 at all measured time intervals, and this difference was statistically significant at 3 months and 4 months. Subjects with branch RVO experienced VA gain more rapidly if they were from Group 1 (p=0.023). Conclusions Sequential therapy was found to be more effective than dexamethasone monotherapy in treating MO due to RVO. © 2014 by the BMJ Publishing Group Ltd