GSTDTAP

浏览/检索结果: 共6条,第1-6条 帮助

已选(0)清除 条数/页:   排序方式:
Rapid non-uniform adaptation to conformation-specific KRAS(G12C) inhibition 期刊论文
NATURE, 2020, 577 (7790) : 421-+
作者:  Xue, Jenny Y.;  Zhao, Yulei;  Aronowitz, Jordan;  Mai, Trang T.;  Vides, Alberto;  Qeriqi, Besnik;  Kim, Dongsung;  Li, Chuanchuan;  de Stanchina, Elisa;  Mazutis, Linas;  Risso, Davide;  Lito, Piro
收藏  |  浏览/下载:33/0  |  提交时间:2020/07/03

KRAS GTPases are activated in one-third of cancers, and KRAS(G12C) is one of the most common activating alterations in lung adenocarcinoma(1,2). KRAS(G12C) inhibitors(3,4) are in phase-I clinical trials and early data show partial responses in nearly half of patients with lung cancer. How cancer cells bypass inhibition to prevent maximal response to therapy is not understood. Because KRAS(G12C) cycles between an active and inactive conformation(4-6), and the inhibitors bind only to the latter, we tested whether isogenic cell populations respond in a non-uniform manner by studying the effect of treatment at a single-cell resolution. Here we report that, shortly after treatment, some cancer cells are sequestered in a quiescent state with low KRAS activity, whereas others bypass this effect to resume proliferation. This rapid divergent response occurs because some quiescent cells produce new KRAS(G12C) in response to suppressed mitogen-activated protein kinase output. New KRAS(G12C) is maintained in its active, drug-insensitive state by epidermal growth factor receptor and aurora kinase signalling. Cells without these adaptive changes-or cells in which these changes are pharmacologically inhibited-remain sensitive to drug treatment, because new KRAS(G12C) is either not available or exists in its inactive, drug-sensitive state. The direct targeting of KRAS oncoproteins has been a longstanding objective in precision oncology. Our study uncovers a flexible non-uniform fitness mechanism that enables groups of cells within a population to rapidly bypass the effect of treatment. This adaptive process must be overcome if we are to achieve complete and durable responses in the clinic.


  
Extreme rainfall triggered the 2018 rift eruption at Kilauea Volcano 期刊论文
NATURE, 2020, 580 (7804) : 491-+
作者:  Cloutier, Richard;  Clement, Alice M.;  Lee, Michael S. Y.;  Noel, Roxanne;  Bechard, Isabelle;  Roy, Vincent;  Long, John A.
收藏  |  浏览/下载:60/0  |  提交时间:2020/05/13

The May 2018 rift intrusion and eruption of Kilauea Volcano, Hawai'  i, represented one of its most extraordinary eruptive sequences in at least 200 years, yet the trigger mechanism remains elusive(1). The event was preceded by several months of anomalously high precipitation. It has been proposed that rainfall can modulate shallow volcanic activity(2,3), but it remains unknown whether it can have impacts at the greater depths associated with magma transport. Here we show that immediately before and during the eruption, infiltration of rainfall into Kilauea Volcano'  s subsurface increased pore pressure at depths of 1 to 3 kilometres by 0.1 to 1 kilopascals, to its highest pressure in almost 50 years. We propose that weakening and mechanical failure of the edifice was driven by changes in pore pressure within the rift zone, prompting opportunistic dyke intrusion and ultimately facilitating the eruption. A precipitation-induced eruption trigger is consistent with the lack of precursory summit inflation, showing that this intrusion-unlike others-was not caused by the forceful intrusion of new magma into the rift zone. Moreover, statistical analysis of historic eruption occurrence suggests that rainfall patterns contribute substantially to the timing and frequency of Kilauea'  s eruptions and intrusions. Thus, volcanic activity can be modulated by extreme rainfall triggering edifice rock failure-a factor that should be considered when assessing volcanic hazards. Notably, the increasingly extreme weather patterns associated with ongoing anthropogenic climate change could increase the potential for rainfall-triggered volcanic phenomena worldwide.


Immediately before and during the eruption of Ki & x304  lauea Volcano in May 2018, anomalously high rainfall increased the pore pressure in the subsurface to its highest level in 50 years, causing weakening and mechanical failure of the edifice.


  
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I 期刊论文
NATURE, 2020, 581 (7806) : 100-+
作者:  Waszak, Sebastian M.;  Robinson, Giles W.;  Gudenas, Brian L.;  Smith, Kyle S.;  Forget, Antoine;  Kojic, Marija;  Garcia-Lopez, Jesus;  Hadley, Jennifer;  Hamilton, Kayla V.;  Indersie, Emilie;  Buchhalter, Ivo;  Kerssemakers, Jules;  Jager, Natalie;  Sharma, Tanvi;  Rausch, Tobias;  Kool, Marcel;  Sturm, Dominik;  Jones, David T. W.;  Vasilyeva, Aksana;  Tatevossian, Ruth G.;  Neale, Geoffrey;  Lombard, Berangere;  Loew, Damarys;  Nakitandwe, Joy;  Rusch, Michael;  Bowers, Daniel C.;  Bendel, Anne;  Partap, Sonia;  Chintagumpala, Murali;  Crawford, John;  Gottardo, Nicholas G.;  Smith, Amy;  Dufour, Christelle;  Rutkowski, Stefan;  Eggen, Tone;  Wesenberg, Finn;  Kjaerheim, Kristina;  Feychting, Maria;  Lannering, Birgitta;  Schuz, Joachim;  Johansen, Christoffer;  Andersen, Tina V.;  Roosli, Martin;  Kuehni, Claudia E.;  Grotzer, Michael;  Remke, Marc;  Puget, Stephanie;  Pajtler, Kristian W.;  Milde, Till;  Witt, Olaf;  Ryzhova, Marina;  Korshunov, Andrey;  Orr, Brent A.;  Ellison, David W.;  Brugieres, Laurence;  Lichter, Peter;  Nichols, Kim E.;  Gajjar, Amar;  Wainwright, Brandon J.;  Ayrault, Olivier;  Korbel, Jan O.;  Northcott, Paul A.;  Pfister, Stefan M.
收藏  |  浏览/下载:63/0  |  提交时间:2020/07/03

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy(1-3). However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found(5) despite the frequent downregulation of MHC-I expression(6-8). Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8(+) T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.


Inhibition of the autophagy-lysosome system upregulates surface expression of MHC class I proteins and enhances antigen presentation, and evokes a potent anti-tumour immune response that is mediated by CD8(+) T cells.


  
Multispecific drugs herald a new era of biopharmaceutical innovation 期刊论文
NATURE, 2020, 580 (7803) : 329-338
作者:  Gallego, Laura D.;  Schneider, Maren;  Mittal, Chitvan;  Romanauska, Anete;  Carrillo, Ricardo M. Gudino;  Schubert, Tobias;  Pugh, B. Franklin;  Koehler, Alwin
收藏  |  浏览/下载:39/0  |  提交时间:2020/07/03

The modern biopharmaceutical industry traces its roots to the dawn of the twentieth century, coincident with marketing of aspirin-a signature event in the history of modern drug development. Although the archetypal discovery process did not change markedly in the first seven decades of the industry, the past fifty years have seen two successive waves of transformative innovation in the development of drug molecules: the rise of '  rational drug discovery'  methodology in the 1970s, followed by the invention of recombinant protein-based therapeutic agents in the 1980s. An incipient fourth wave is the advent of multispecific drugs. The successful development of prospectively designed multispecific drugs has the potential to reconfigure our ideas of how target-based therapeutic molecules can work, and what it is possible to achieve with them. Here I review the two major classes of multispecific drugs: those that enrich a therapeutic agent at a particular site of action and those that link a therapeutic target to a biological effector. The latter class-being freed from the constraint of having to directly modulate the target upon binding-may enable access to components of the proteome that currently cannot be targeted by drugs.


  
The promise and challenge of therapeutic genome editing 期刊论文
NATURE, 2020, 578 (7794) : 229-236
作者:  Zhong, Suijuan;  Ding, Wenyu;  Sun, Le;  Lu, Yufeng;  Dong, Hao;  Fan, Xiaoying;  Liu, Zeyuan;  Chen, Ruiguo;  Zhang, Shu;  Ma, Qiang;  Tang, Fuchou;  Wu, Qian;  Wang, Xiaoqun
收藏  |  浏览/下载:57/0  |  提交时间:2020/07/03

Genome editing, which involves the precise manipulation of cellular DNA sequences to alter cell fates and organism traits, has the potential to both improve our understanding of human genetics and cure genetic disease. Here I discuss the scientific, technical and ethical aspects of using CRISPR (clustered regularly interspaced short palindromic repeats) technology for therapeutic applications in humans, focusing on specific examples that highlight both opportunities and challenges. Genome editing is-or will soon be-in the clinic for several diseases, with more applications under development. The rapid pace of the field demands active efforts to ensure that this breakthrough technology is used responsibly to treat, cure and prevent genetic disease.


  
Monitoring Soil Erosion on a Burned Site in the Mojave-Great Basin Transition Zone: Final Report for the Jacob Fire Site 科技报告
来源:US Department of Energy (DOE). 出版年: 2013
作者:  Miller, Julianne [DRI];  Etyemezian, Vic [DRI];  Cablk, Mary E. [DRI];  Shillito, Rose [DRI];  Shafer, David [DOE Grand Junction, Colorado]
收藏  |  浏览/下载:10/0  |  提交时间:2019/04/05
A historic return interval of 100 years for large fires in the U.S. southwestern deserts is being replaced by one where fires may reoccur as frequently as every 20 to 30 years. The shortened return interval  which translates to an increase in fires  has i