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Olfactory sniffing signals consciousness in unresponsive patients with brain injuries 期刊论文
NATURE, 2020
作者:  Hellmuth, Susanne;  Gomez-H, Laura;  Pendas, Alberto M.;  Stemmann, Olaf
收藏  |  浏览/下载:10/0  |  提交时间:2020/07/03

After severe brain injury, it can be difficult to determine the state of consciousness of a patient, to determine whether the patient is unresponsive or perhaps minimally conscious(1), and to predict whether they will recover. These diagnoses and prognoses are crucial, as they determine therapeutic strategies such as pain management, and can underlie end-of-life decisions(2,3). Nevertheless, there is an error rate of up to 40% in determining the state of consciousness in patients with brain injuries(4,5). Olfaction relies on brain structures that are involved in the basic mechanisms of arousal(6), and we therefore hypothesized that it may serve as a biomarker for consciousness(7). Here we use a non-verbal non-task-dependent measure known as the sniff response(8-11) to determine consciousness in patients with brain injuries. By measuring odorant-dependent sniffing, we gain a sensitive measure of olfactory function(10-15). We measured the sniff response repeatedly over time in patients with severe brain injuries and found that sniff responses significantly discriminated between unresponsive and minimally conscious states at the group level. Notably, at the single-patient level, if an unresponsive patient had a sniff response, this assured future regaining of consciousness. In addition, olfactory sniff responses were associated with long-term survival rates. These results highlight the importance of olfaction in human brain function, and provide an accessible tool that signals consciousness and recovery in patients with brain injuries.


Odorant-dependent sniff responses predicted the long-term survival rates of patients with severe brain injury, and discriminated between individuals who were unresponsive and in minimally conscious states.


  
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.


  
Mechanical regulation of glycolysis via cytoskeleton architecture 期刊论文
NATURE, 2020, 578 (7796) : 621-+
作者:  Faivre, Emily J.;  McDaniel, Keith F.;  Albert, Daniel H.;  Mantena, Srinivasa R.;  Plotnik, Joshua P.;  Wilcox, Denise;  Zhang, Lu;  Bui, Mai H.;  Sheppard, George S.;  Wang, Le;  Sehgal, Vasudha;  Lin, Xiaoyu;  Huang, Xiaoli;  Lu, Xin;  Uziel, Tamar;  Hessler, Paul;  Lam, Lloyd T.;  Bellin, Richard J.;  Mehta, Gaurav;  Fidanze, Steve;  Pratt, John K.;  Liu, Dachun;  Hasvold, Lisa A.;  Sun, Chaohong;  Panchal, Sanjay C.;  Nicolette, John J.;  Fossey, Stacey L.;  Park, Chang H.;  Longenecker, Kenton;  Bigelow, Lance;  Torrent, Maricel;  Rosenberg, Saul H.;  Kati, Warren M.;  Shen, Yu
收藏  |  浏览/下载:15/0  |  提交时间:2020/07/03

The mechanics of the cellular microenvironment continuously modulates cell functions such as growth, survival, apoptosis, differentiation and morphogenesis via cytoskeletal remodelling and actomyosin contractility(1-3). Although all of these processes consume energy(4,5), it is unknown whether and how cells adapt their metabolic activity to variable mechanical cues. Here we report that the transfer of human bronchial epithelial cells from stiff to soft substrates causes a downregulation of glycolysis via proteasomal degradation of the rate-limiting metabolic enzyme phosphofructokinase (PFK). PFK degradation is triggered by the disassembly of stress fibres, which releases the PFK-targeting E3 ubiquitin ligase tripartite motif (TRIM)-containing protein 21 (TRIM21). Transformed non-small-cell lung cancer cells, which maintain high glycolytic rates regardless of changing environmental mechanics, retain PFK expression by downregulating TRIM21, and by sequestering residual TRIM21 on a stress-fibre subset that is insensitive to substrate stiffness. Our data reveal a mechanism by which glycolysis responds to architectural features of the actomyosin cytoskeleton, thus coupling cell metabolism to the mechanical properties of the surrounding tissue. These processes enable normal cells to tune energy production in variable microenvironments, whereas the resistance of the cytoskeleton in response to mechanical cues enables the persistence of high glycolytic rates in cancer cells despite constant alterations of the tumour tissue.


Glycolysis in normal epithelial cells responds to microenvironmental mechanics via the modulation of actin bundles that sequester the phosphofructokinase-targeting ubiquitin ligase TRIM21, a process superseded by persistent actin bundles in cancer cells.


  
B cells are associated with survival and immunotherapy response in sarcoma 期刊论文
NATURE, 2020, 577 (7791) : 556-+
作者:  Willis, J. P.;  Canning, R. E. A.;  Noordeh, E. S.;  Allen, S. W.;  King, A. L.;  Mantz, A.;  Morris, R. G.;  Stanford, S. A.;  Brammer, G.
收藏  |  浏览/下载:15/0  |  提交时间:2020/07/03

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes(1,2). The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely(3,4). To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8(+) T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.


Immune profiling of the tumour microenvironment of soft-tissue sarcoma identifies a group of patients with high levels of B-cell infiltration and tertiary lymphoid structures that have improved survival and a high response rate to immune checkpoint blockade therapy.


  
Survival rate of China passenger vehicles: A data-driven approach 期刊论文
ENERGY POLICY, 2019, 129: 587-597
作者:  Zheng, Jihu;  Zhou, Yan;  Yu, Rujie;  Zhao, Dongchang;  Lu, Zifeng;  Zhang, Peng
收藏  |  浏览/下载:14/0  |  提交时间:2019/11/26
Scrappage standard  Survival rate  Total fuel consumption  
Tree survival and growth are impacted by increased surface temperature on paved land 期刊论文
LANDSCAPE AND URBAN PLANNING, 2017, 162
作者:  Chen, Yuanyuan;  Wang, Xiaoke;  Jiang, Bo;  Wen, Zhi;  Yang, Ning;  Li, Li
收藏  |  浏览/下载:8/0  |  提交时间:2019/04/09
Tree growth  Pervious pavement  Surface temperature  Soil moisture  Survival rate  Tree spacing  
Shoot and root responses of woody species to silvicultural management for afforestation of degraded croplands in the Sudano-Sahelian zone of Benin 期刊论文
FOREST ECOLOGY AND MANAGEMENT, 2017, 385
作者:  Noulekoun, Florent;  Lamers, John P. A.;  Naab, Jesse;  Khamzina, Asia
收藏  |  浏览/下载:4/0  |  提交时间:2019/04/09
Jatropha curcas  Survival rate  Trait plasticity  Relative growth rate  Rooting depth  West Africa