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Microbial signatures in tumours and blood 期刊论文
NATURE, 2020, 579 (7800) : 502-503
作者:  Goodman, Russell P.;  Markhard, Andrew L.;  Shah, Hardik;  Sharma, Rohit;  Skinner, Owen S.;  Clish, Clary B.;  Deik, Amy;  Patgiri, Anupam;  Hsu, Yu-Han H.;  Masia, Ricard;  Noh, Hye Lim;  Suk, Sujin;  Goldberger, Olga;  Hirschhorn, Joel N.;  Yellen, Gary;  Kim, Jason K.;  Mootha, Vamsi K.
收藏  |  浏览/下载:22/0  |  提交时间:2020/07/03

Microbiome signatures as putative cancer diagnostics.


Analysis of nucleic-acid sequences from human cancers, along with samples from adjacent tissue and blood, reveals the presence of microorganisms in tumours and blood across cancers.


  
A pause in Southern Hemisphere circulation trends due to the Montreal Protocol 期刊论文
NATURE, 2020, 579 (7800) : 544-548
作者:  Imai, Yu;  Meyer, Kirsten J.;  Iinishi, Akira;  Favre-Godal, Quentin;  Green, Robert;  Manuse, Sylvie;  Caboni, Mariaelena;  Mori, Miho;  Niles, Samantha;  Ghiglieri, Meghan;  Honrao, Chandrashekhar;  Ma, Xiaoyu;  Guo, Jason J.;  Makriyannis, Alexandros;  Linares-Otoya, Luis;  Boehringer, Nils;  Wuisan, Zerlina G.;  Kaur, Hundeep;  Wu, Runrun;  Mateus, Andre
收藏  |  浏览/下载:20/0  |  提交时间:2020/05/13

Observations show robust near-surface trends in Southern Hemisphere tropospheric circulation towards the end of the twentieth century, including a poleward shift in the mid-latitude jet(1,2), a positive trend in the Southern Annular Mode(1,3-6) and an expansion of the Hadley cell(7,8). It has been established that these trends were driven by ozone depletion in the Antarctic stratosphere due to emissions of ozone-depleting substances(9-11). Here we show that these widely reported circulation trends paused, or slightly reversed, around the year 2000. Using a pattern-based detection and attribution analysis of atmospheric zonal wind, we show that the pause in circulation trends is forced by human activities, and has not occurred owing only to internal or natural variability of the climate system. Furthermore, we demonstrate that stratospheric ozone recovery, resulting from the Montreal Protocol, is the key driver of the pause. Because pre-2000 circulation trends have affected precipitation(12-14), and potentially ocean circulation and salinity(15-17), we anticipate that a pause in these trends will have wider impacts on the Earth system. Signatures of the effects of the Montreal Protocol and the associated stratospheric ozone recovery might therefore manifest, or have already manifested, in other aspects of the Earth system.


  
Mechanisms and therapeutic implications of hypermutation in gliomas 期刊论文
NATURE, 2020, 580 (7804) : 517-+
作者:  Feng, Kaibo;  Quevedo, Raundi E.;  Kohrt, Jeffrey T.;  Oderinde, Martins S.;  Reilly, Usa;  White, M. Christina
收藏  |  浏览/下载:27/0  |  提交时间:2020/07/03

A high tumour mutational burden (hypermutation) is observed in some gliomas(1-5)  however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.


Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.


  
Integrating genomic features for non-invasive early lung cancer detection 期刊论文
NATURE, 2020, 580 (7802) : 245-+
作者:  Wang, Qinyang;  Wang, Yupeng;  Ding, Jingjin;  Wang, Chunhong;  Zhou, Xuehan;  Gao, Wenqing;  Huang, Huanwei;  Shao, Feng;  Liu, Zhibo
收藏  |  浏览/下载:15/0  |  提交时间:2020/07/03

Circulating tumour DNA in blood is analysed to identify genomic features that distinguish early-stage lung cancer patients from risk-matched controls, and these are integrated into a machine-learning method for blood-based lung cancer screening.


Radiologic screening of high-risk adults reduces lung-cancer-related mortality(1,2)  however, a small minority of eligible individuals undergo such screening in the United States(3,4). The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)(5), a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed '  lung cancer likelihood in plasma'  (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.


  
Chiral superconductivity in heavy-fermion metal UTe2 期刊论文
NATURE, 2020, 579 (7800) : 523-527
作者:  Chica, Daniel G.;  He, Yihui;  McCall, Kyle M.;  Chung, Duck Young;  Pak, Rahmi O.;  Trimarchi, Giancarlo;  Liu, Zhifu;  De Lurgio, Patrick M.;  Wessels, Bruce W.;  Kanatzidis, Mercouri G.
收藏  |  浏览/下载:45/0  |  提交时间:2020/07/03

Scanning tunnelling microscopy and spectroscopy measurements show chiral edge states inside the superconducting gap of the heavy-fermion superconductor UTe2, indicating the presence of chiral spin-triplet superconductivity.


Spin-triplet superconductors are condensates of electron pairs with spin 1 and an odd-parity wavefunction(1). An interesting manifestation of triplet pairing is the chiral p-wave state, which is topologically non-trivial and provides a natural platform for realizing Majorana edge modes(2,3). However, triplet pairing is rare in solid-state systems and has not been unambiguously identified in any bulk compound so far. Given that pairing is usually mediated by ferromagnetic spin fluctuations, uranium-based heavy-fermion systems containing f-electron elements, which can harbour both strong correlations and magnetism, are considered ideal candidates for realizing spin-triplet superconductivity(4). Here we present scanning tunnelling microscopy studies of the recently discovered heavy-fermion superconductor UTe2, which has a superconducting transition temperature of 1.6 kelvin(5). We find signatures of coexisting Kondo effect and superconductivity that show competing spatial modulations within one unit cell. Scanning tunnelling spectroscopy at step edges reveals signatures of chiral in-gap states, which have been predicted to exist at the boundaries of topological superconductors. Combined with existing data that indicate triplet pairing in UTe2, the presence of chiral states suggests that UTe2 is a strong candidate for chiral-triplet topological superconductivity.


  
A genomic and epigenomic atlas of prostate cancer in Asian populations 期刊论文
NATURE, 2020: 93-+
作者:  Perry, Rachel J.;  Zhang, Dongyan;  Guerra, Mateus T.;  Brill, Allison L.;  Goedeke, Leigh;  Nasiri, Ali R.;  Rabin-Court, Aviva;  Wang, Yongliang;  Peng, Liang;  Dufour, Sylvie;  Zhang, Ye;  Zhang, Xian-Man;  Butrico, Gina M.;  Toussaint, Keshia;  Nozaki, Yuichi;  Cline, Gary W.;  Petersen, Kitt Falk;  Nathanson, Michael H.;  Ehrlich, Barbara E.;  Shulman, Gerald I.
收藏  |  浏览/下载:33/0  |  提交时间:2020/07/03

Prostate cancer is the second most common cancer in men worldwide(1). Over the past decade, large-scale integrative genomics efforts have enhanced our understanding of this disease by characterizing its genetic and epigenetic landscape in thousands of patients(2,3). However, most tumours profiled in these studies were obtained from patients from Western populations. Here we produced and analysed whole-genome, whole-transcriptome and DNA methylation data for 208 pairs of tumour tissue samples and matched healthy control tissue from Chinese patients with primary prostate cancer. Systematic comparison with published data from 2,554 prostate tumours revealed that the genomic alteration signatures in Chinese patients were markedly distinct from those of Western cohorts: specifically, 41% of tumours contained mutations in FOXA1 and 18% each had deletions in ZNF292 and CHD1. Alterations of the genome and epigenome were correlated and were predictive of disease phenotype and progression. Coding and noncoding mutations, as well as epimutations, converged on pathways that are important for prostate cancer, providing insights into this devastating disease. These discoveries underscore the importance of including population context in constructing comprehensive genomic maps for disease.


Genomic, transcriptomic and DNA methylation data from tissue samples from 208 Chinese patients with prostate cancer define the landscape of alterations in this population, and comparison with data from Western cohorts suggests that the disease may stratify into different molecular subtypes.


  
Strongly correlated electrons and hybrid excitons in a moire heterostructure 期刊论文
NATURE, 2020, 580 (7804) : 472-+
作者:  Banerjee, Antara;  Fyfe, John C.;  Polvani, Lorenzo M.;  Waugh, Darryn;  Chang, Kai-Lan
收藏  |  浏览/下载:28/0  |  提交时间:2020/07/03

Two-dimensional materials and their heterostructures constitute a promising platform to study correlated electronic states, as well as the many-body physics of excitons. Transport measurements on twisted graphene bilayers have revealed a plethora of intertwined electronic phases, including Mott insulators, strange metals and superconductors(1-5). However, signatures of such strong electronic correlations in optical spectroscopy have hitherto remained unexplored. Here we present experiments showing how excitons that are dynamically screened by itinerant electrons to form exciton-polarons(6,7) can be used as a spectroscopic tool to investigate interaction-induced incompressible states of electrons. We study a molybdenum diselenide/hexagonal boron nitride/molybdenum diselenide heterostructure that exhibits a long-period moire superlattice, as evidenced by coherent hole-tunnelling-mediated avoided crossings of an intralayer exciton with three interlayer exciton resonances separated by about five millielectronvolts. For electron densities corresponding to half-filling of the lowest moire subband, we observe strong layer pseudospin paramagnetism, demonstrated by an abrupt transfer of all the (roughly 1,500) electrons from one molybdenum diselenide layer to the other on application of a small perpendicular electric field. Remarkably, the electronic state at half-filling of each molybdenum diselenide layer is resilient towards charge redistribution by the applied electric field, demonstrating an incompressible Mott-like state of electrons. Our experiments demonstrate that optical spectroscopy provides a powerful tool for investigating strongly correlated electron physics in the bulk and paves the way for investigating Bose-Fermi mixtures of degenerate electrons and dipolar excitons.


Optical spectroscopy is used to probe correlated electronic states in a moire heterostructure, showing many-body effects such as strong layer paramagnetism and an incompressible Mott-like state of electrons.


  
Microbiome analyses of blood and tissues suggest cancer diagnostic approach 期刊论文
NATURE, 2020, 579 (7800) : 567-+
作者:  Shao, Zhengping;  Flynn, Ryan A.;  Crowe, Jennifer L.;  Zhu, Yimeng;  Liang, Jialiang;  Jiang, Wenxia;  Aryan, Fardin;  Aoude, Patrick;  Bertozzi, Carolyn R.;  Estes, Verna M.;  Lee, Brian J.;  Bhagat, Govind;  Zha, Shan;  Calo, Eliezer
收藏  |  浏览/下载:55/0  |  提交时间:2020/07/03

Microbial nucleic acids are detected in samples of tissues and blood from more than 10,000 patients with cancer, and machine learning is used to show that these can be used to discriminate between and among different types of cancer, suggesting a new microbiome-based diagnostic approach.


Systematic characterization of the cancer microbiome provides the opportunity to develop techniques that exploit non-human, microorganism-derived molecules in the diagnosis of a major human disease. Following recent demonstrations that some types of cancer show substantial microbial contributions(1-10), we re-examined whole-genome and whole-transcriptome sequencing studies in The Cancer Genome Atlas(11) (TCGA) of 33 types of cancer from treatment-naive patients (a total of 18,116 samples) for microbial reads, and found unique microbial signatures in tissue and blood within and between most major types of cancer. These TCGA blood signatures remained predictive when applied to patients with stage Ia-IIc cancer and cancers lacking any genomic alterations currently measured on two commercial-grade cell-free tumour DNA platforms, despite the use of very stringent decontamination analyses that discarded up to 92.3% of total sequence data. In addition, we could discriminate among samples from healthy, cancer-free individuals (n = 69) and those from patients with multiple types of cancer (prostate, lung, and melanoma  100 samples in total) solely using plasma-derived, cell-free microbial nucleic acids. This potential microbiome-based oncology diagnostic tool warrants further exploration.


  
Peripheral T cell expansion predicts tumour infiltration and clinical response 期刊论文
NATURE, 2020, 579 (7798) : 274-+
作者:  Yasuda, Sayaka;  Tsuchiya, Hikaru;  Kaiho, Ai;  Guo, Qiang;  Ikeuchi, Ken;  Endo, Akinori;  Arai, Naoko;  Ohtake, Fumiaki;  Murata, Shigeo;  Inada, Toshifumi;  Baumeister, Wolfgang;  Fernandez-Busnadiego, Ruben;  Tanaka, Keiji;  Saeki, Yasushi
收藏  |  浏览/下载:18/0  |  提交时间:2020/07/03

Despite the resounding clinical success in cancer treatment of antibodies that block the interaction of PD1 with its ligand PDL1(1), the mechanisms involved remain unknown. A major limitation to understanding the origin and fate of T cells in tumour immunity is the lack of quantitative information on the distribution of individual clonotypes of T cells in patients with cancer. Here, by performing deep single-cell sequencing of RNA and T cell receptors in patients with different types of cancer, we survey the profiles of various populations of T cells and T cell receptors in tumours, normal adjacent tissue, and peripheral blood. We find clear evidence of clonotypic expansion of effector-like T cells not only within the tumour but also in normal adjacent tissue. Patients with gene signatures of such clonotypic expansion respond best to anti-PDL1 therapy. Notably, expanded clonotypes found in the tumour and normal adjacent tissue can also typically be detected in peripheral blood, which suggests a convenient approach to patient identification. Analyses of our data together with several external datasets suggest that intratumoural T cells, especially in responsive patients, are replenished with fresh, non-exhausted replacement cells from sites outside the tumour, suggesting continued activity of the cancer immunity cycle in these patients, the acceleration of which may be associated with clinical response.


  
The repertoire of mutational signatures in human cancer 期刊论文
NATURE, 2020, 578 (7793) : 94-+
作者:  Ciurlo, Anna;  39;Neil, Kelly Kosmo
收藏  |  浏览/下载:7/0  |  提交时间:2020/07/03

Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature(1). Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium(2) 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(3-15), 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.