PURPOSE: Cecal ligation and puncture (CLP) has been used as a useful model for the induction of polymicrobial sepsis. Necrotic tissue resection and peritoneal lavage (REL) are the surgical procedures ...for controlling perforated appendicitis. The aim of this study was to evaluate leukocyte-endothelial interactions in the rat mesentery in vivo after CLP and REL. METHODS: Thirty-seven male Wistar rats (250-300 g) underwent laparotomy and were randomly assigned to the following groups: 1) SHAM; 2) CLP: animals submitted to CLP, 3) CLP+REL: animals submitted to CLP and REL. Mesenteric leukocyte-endothelial interactions were studied by intravital microscopy assessed once in each animal (3-5 postcapillary venules, 15-25 µm diameter) 24 hours after intervention. Follow-up was performed in all animals; this included analysis of glycemia, lactate, hematocrit, white blood cell count as well as a functional score that was the sum of scoring on the following parameters: alertness, mobility, piloerection, diarrhea, encrusted eyes, and dirty nose and tail. RESULTS: None of the animals showed significant changes in body weight (265 ± 20 g) or in hematocrit levels (46% ± 2%) during the experimental protocol. Compared to SHAM animals, CLP animals showed an increased number of rolling (2x), adherent, and migrating leukocytes (7x) in the mesenteric microcirculation, an increase in blood glucose (136 ± 8 mg/dL), lactate (3.58 ± 0.94 mmol/L), white cell count (23,570 ± 4,991 cells/mm³) and functional alterations (score 11 ± 1), characterized by impaired alertness and mobility, and presence of piloerection, diarrhea, encrusted eyes, and dirty nose and tail. The REL procedure normalized the number of rolling, adherent, and migrated leukocytes in the mesentery; glycemia; lactate; and white blood cell count. The REL procedure also improved the functional score (7 ± 1). CONCLUSION: Local and systemic inflammation was induced by CLP, while REL completely overcame the inflammatory process.OBJETIVO: O procedimento de ligadura cecal e perfuração (CLP) tem sido usado como um modelo útil de indução de sepse polimicrobiana. A ressecção do tecido necrosado e lavagem peritoneal (REL) são procedimentos cirúrgicos freqüentemente utilizados para controlar uma apendicite perfurada. O objetivo desse estudo foi avaliar in vivo as interações leucócito-endotélio no mesentério de ratos após a CLP e REL. MÉTODOS: Trinta e sete ratos Wistar machos (250-300 g) foram submetidos à laparotomia e aleatoriamente divididos em grupos: 1) SHAM, 2) CLP: ratos submetidos à CLP, 3) CLP+REL: animais submetidos à CLP e REL. As interações leucócito-endotélio no mesentério foram estudadas através de microscopia intravital somente uma vez em cada animal (3-5 vênulas pós-capilares, 15-25 µm diâmetro), 24-horas após as intervenções. A evolução clínica foi realizada em todos os animais, incluindo glicemia, lactato, hematócrito, número total de células brancas e um escore funcional, o qual foi considerado como a somatória dos seguintes parâmetros: estado de alerta, mobilidade, piloereção, diarréia, olhos encrustados, e nariz e cauda sujos. RESULTADOS: Os animais não apresentaram alterações significantes no peso (265 ± 20 g) e hematócrito (46 ± 2%) ao longo do estudo. Comparados ao SHAM, os animais CLP apresentaram aumento no número de leucócitos em rolamento (2x), aderidos (7x) e migrados (7x) na microcirculação mesentérica, aumentos da glicemia (136 ± 8 mg/dL), lactato (3,58 ± 0,94 mmol/L), leucocitose (23.570 ± 4.991 células/mm³) e alterações clínicas (escore 11±1), caracterizadas por comprometimento do estado de alerta e mobilidade, e presença de piloereção, diarréia, olhos encrustados, nariz e cauda sujos. REL normalizou o número de leucócitos em rolamento, aderidos e migrados no mesentério, a glicemia, o lactato e o número de leucócitos circulantes. REL também melhorou o escore clínico (7 ± 1). CONCLUSÃO: A CLP induziu inflamação local e sistêmica. A REL resolveu, por completo, o processo inflamatório.
Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature
. Here, as part of the Pan-Cancer Analysis of Whole ...Genomes (PCAWG) Consortium
of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses
, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.
The evolutionary history of 2,658 cancers Gerstung, Moritz; Jolly, Clemency; Leshchiner, Ignaty ...
Nature (London),
02/2020, Letnik:
578, Številka:
7793
Journal Article
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Cancer develops through a process of somatic evolution
. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the ...changing influence of mutational processes
. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)
, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes
. Here we ...develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types
. Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions-as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2-7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and-in liver cancer-frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.
Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested ...that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.
Clusters of galaxies are the most massive gravitationally bound objects in the Universe and are still forming. They are thus important probes of cosmological parameters and many astrophysical ...processes. However, knowledge of the dynamics of the pervasive hot gas, the mass of which is much larger than the combined mass of all the stars in the cluster, is lacking. Such knowledge would enable insights into the injection of mechanical energy by the central supermassive black hole and the use of hydrostatic equilibrium for determining cluster masses. X-rays from the core of the Perseus cluster are emitted by the 50-million-kelvin diffuse hot plasma filling its gravitational potential well. The active galactic nucleus of the central galaxy NGC 1275 is pumping jetted energy into the surrounding intracluster medium, creating buoyant bubbles filled with relativistic plasma. These bubbles probably induce motions in the intracluster medium and heat the inner gas, preventing runaway radiative cooling--a process known as active galactic nucleus feedback. Here we report X-ray observations of the core of the Perseus cluster, which reveal a remarkably quiescent atmosphere in which the gas has a line-of-sight velocity dispersion of 164 ± 10 kilometres per second in the region 30-60 kiloparsecs from the central nucleus. A gradient in the line-of-sight velocity of 150 ± 70 kilometres per second is found across the 60-kiloparsec image of the cluster core. Turbulent pressure support in the gas is four per cent of the thermodynamic pressure, with large-scale shear at most doubling this estimate. We infer that a total cluster mass determined from hydrostatic equilibrium in a central region would require little correction for turbulent pressure.
Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and-for a subset-whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was ...aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein-Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV; for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and head-and-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer.
About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in ...2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.
Intestinal lymphangiectasia (IL) is a common complication in dogs. This study analyzed intestinal microbiota using 16S rRNA amplicon analysis as candidate factors that strongly influence the small ...intestinal lymphatic vessels in dogs with and without IL. Twelve dogs were included, of which six were diagnosed with lymphoplasmacytic enteritis, four with small-cell lymphoma, and two with large-cell lymphoma. Seven of these dogs had IL, whereas five did not. First, the microbial diversity analyzed by Faith pd index was significantly decreased in dogs with IL compared to dogs without IL. Then, the relative amounts of each bacterial taxa were compared between dogs with and without IL using Linear discriminant analysis effect size analysis. At the genus level, the Ruminococcus gnavus group significantly increased in dogs with IL compared to dogs without IL. A total of four genera, including Ruminococcus torques group and Faecalibacterium, which produce butyrate, significantly decreased in dogs with IL. This study showed decreased intestinal bacterial diversity and several alterations of intestinal microbiota, including a decrease in butyrate-producing bacteria in dogs with IL, compared to dogs without IL.
Genomic basis for RNA alterations in cancer Calabrese, Claudia; Davidson, Natalie R; Demircioğlu, Deniz ...
Nature (London),
02/2020, Letnik:
578, Številka:
7793
Journal Article
Recenzirano
Odprti dostop
Transcript alterations often result from somatic changes in cancer genomes
. Various forms of RNA alterations have been described in cancer, including overexpression
, altered splicing
and gene ...fusions
; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)
. Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed 'bridged' fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.
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