Abstract:
:Cells that are deficient in homologous recombination, such as those that lack functional breast cancer-associated 1 (BRCA1) or BRCA2, are hypersensitive to inhibition of poly(ADP-ribose) polymerase (PARP). However, BRCA-deficient tumors represent only a small fraction of adult cancers, which might restrict the therapeutic utility of PARP inhibitor monotherapy. Cyclin-dependent kinase 1 (Cdk1) phosphorylates BRCA1, and this is essential for efficient formation of BRCA1 foci. Here we show that depletion or inhibition of Cdk1 compromises the ability of cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA-wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize nontransformed cells or tissues to inhibition of PARP. Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers.
journal_name
Nat Medjournal_title
Nature medicineauthors
Johnson N,Li YC,Walton ZE,Cheng KA,Li D,Rodig SJ,Moreau LA,Unitt C,Bronson RT,Thomas HD,Newell DR,D'Andrea AD,Curtin NJ,Wong KK,Shapiro GIdoi
10.1038/nm.2377subject
Has Abstractpub_date
2011-06-26 00:00:00pages
875-82issue
7eissn
1078-8956issn
1546-170Xpii
nm.2377journal_volume
17pub_type
杂志文章相关文献
NATURE MEDICINE文献大全abstract::Given the variation in the HIV-1 viral load (VL) set point across subjects, as opposed to a fairly stable VL over time within an infected individual, it is important to identify the characteristics of the host and virus that affect VL set point. Although recently infected individuals with multiple phylogenetically lin...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3932
更新日期:2015-10-01 00:00:00
abstract::Mice carrying mutations in both the dystrophin and utrophin genes die prematurely as a consequence of severe muscular dystrophy. Here, we show that intravascular administration of recombinant adeno-associated viral (rAAV) vectors carrying a microdystrophin gene restores expression of dystrophin in the respiratory, car...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1439
更新日期:2006-07-01 00:00:00
abstract::PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140...
journal_title:Nature medicine
pub_type: 杂志文章,随机对照试验
doi:10.1038/s41591-020-0805-8
更新日期:2020-04-01 00:00:00
abstract::The notoriously drug-resistant bug MRSA has made headlines for years, but a whole other class of bacteria may prove even more troublesome. These microbes, Gram-negative bacteria, are increasingly a threat--and yet not a single late-stage drug in development specifically targets them. Christian Torres follows one man's...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0610-628
更新日期:2010-06-01 00:00:00
abstract::Given the associations between chronic inflammation and epithelial cancer, we studied susceptibility to skin carcinogenesis in mice deficient for the pro-inflammatory cytokine TNF-alpha (refs. 5,6). TNF-alpha(-/-) mice were resistant to development of benign and malignant skin tumors, whether induced by initiation wit...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/10552
更新日期:1999-07-01 00:00:00
abstract::Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging suite in a biosafety containment facility, we show th...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3937
更新日期:2015-10-01 00:00:00
abstract::Whereas uncoupling protein 1 (UCP-1) is clearly involved in thermogenesis, the role of UCP-2 is less clear. Using hybridization, cloning techniques and cDNA array analysis to identify inducible neuroprotective genes, we found that neuronal survival correlates with increased expression of Ucp2. In mice overexpressing h...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm903
更新日期:2003-08-01 00:00:00
abstract::Migration inhibitory factor (MIF) is known to exert significant pro-inflammatory effects and has the potential to override the anti-inflammatory action of glucocorticoids. In this study we have identified significant quantities of MIF in the alveolar airspaces of patients with acute respiratory distress syndrome (ARDS...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0397-320
更新日期:1997-03-01 00:00:00
abstract::In chronic kidney disease (CKD), loss of functional nephrons results in metabolic and mechanical stress in the remaining ones, resulting in further nephron loss. Here we show that Akt2 activation has an essential role in podocyte protection after nephron reduction. Glomerulosclerosis and albuminuria were substantially...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3313
更新日期:2013-10-01 00:00:00
abstract::CD4(+) T cells that express the forkhead box P3 (FOXP3) transcription factor function as regulatory T (Treg) cells and hinder effective immune responses against cancer cells. Abundant Treg cell infiltration into tumors is associated with poor clinical outcomes in various types of cancers. However, the role of Treg cel...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.4086
更新日期:2016-06-01 00:00:00
abstract::Parkinson's disease symptoms can be improved by transplanting fetal dopamine cells into the putamen of parkinsonian patients. Because the supply of human donor tissue is limited and variable, an alternative and genetically modifiable non-human source of tissue would be valuable. We have generated cloned transgenic bov...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0598-569
更新日期:1998-05-01 00:00:00
abstract::CD4-unhelped CD8(+) T cells are functionally defective T cells primed in the absence of CD4(+) T cell help. Given the co-stimulatory role of natural-killer group 2, member D protein (NKG2D) on CD8(+) T cells, we investigated its ability to rescue these immunologically impotent cells. We demonstrate that augmented co-s...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2683
更新日期:2012-02-26 00:00:00
abstract::Substantial global effort has been devoted to curtailing the tobacco epidemic over the past two decades, especially after the adoption of the Framework Convention on Tobacco Control1 by the World Health Organization in 2003. In 2015, in recognition of the burden resulting from tobacco use, strengthened tobacco control...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-020-01210-8
更新日期:2021-01-21 00:00:00
abstract::Sepsis remains a global clinical problem. By using the mouse cecal ligation and puncture model of sepsis, here we identify an important aspect of mast cell (MC)-dependent, innate immune defenses against Gram-negative bacteria by demonstrating that MC protease activity is regulated by interleukin-15 (IL-15). Mouse MCs ...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1615
更新日期:2007-08-01 00:00:00
abstract::Copy number variants are a recently discovered source of large-scale genomic diversity present in all individuals. We capitalize on these inherent genomic differences, focusing on deletion polymorphisms, to develop informative fluorescence in situ hybridization probes with the ability to unequivocally distinguish betw...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.1862
更新日期:2009-02-01 00:00:00
abstract::The impact of single-agent antibodies against programmed death-ligand 1 (PD-L1) as maintenance therapy is unknown in patients with metastatic breast cancer. The SAFIR02-BREAST IMMUNO substudy included patients with human epidermal growth factor receptor type 2 (Her2)-negative metastatic breast cancer whose disease did...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-020-01189-2
更新日期:2021-01-18 00:00:00
abstract::Severe malaria is a major cause of childhood mortality in sub-Saharan Africa but the factors predisposing children to severe forms of malaria have not been fully elucidated. In a case-control study of over 1,200 Gambian children hepatitis B virus carriage was significantly increased amongst cases of severe malaria com...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0495-374
更新日期:1995-04-01 00:00:00
abstract::Evolutionary patterns of virus replication and distribution in lymphoid tissue during the early phases of HIV infection have not been delineated. Lymph node (LN) biopsies were excised from patients at different times after the estimated time of primary infection. Within 3 months of the acute viral syndrome, HIV was mo...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm0398-341
更新日期:1998-03-01 00:00:00
abstract::In the Supplementary Information originally published with this article, a lane was missing in the β-actin blot in Supplementary Fig. 2. The lane has been added. The error has been corrected in the Supplementary Information associated with this article. ...
journal_title:Nature medicine
pub_type: 已发布勘误
doi:10.1038/s41591-018-0168-6
更新日期:2018-10-01 00:00:00
abstract::Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wi...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/86507
更新日期:2001-04-01 00:00:00
abstract::Targeting the mammalian target of rapamycin (mTOR) protein is a promising strategy for cancer therapy. The mTOR kinase functions in two complexes, TORC1 (target of rapamycin complex-1) and TORC2 (target of rapamycin complex-2); however, neither of these complexes is fully inhibited by the allosteric inhibitor rapamyci...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.2091
更新日期:2010-02-01 00:00:00
abstract::Despite the central role of the liver in the regulation of glucose and lipid metabolism, there are currently no methods to directly assess hepatic oxidative metabolism in humans in vivo. By using a new (13)C-labeling strategy in combination with (13)C magnetic resonance spectroscopy, we show that rates of mitochondria...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm.3415
更新日期:2014-01-01 00:00:00
abstract::A high-fat diet increases the risk of colon, breast and prostate cancer. The molecular mechanism by which dietary lipids promote tumorigenesis is unknown. Their effects may be mediated at least in part by the peroxisome proliferator-activated receptors (PPARs). These ligand-activated nuclear receptors modulate gene ex...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/2042
更新日期:1998-09-01 00:00:00
abstract::TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition1-8. With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechani...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-019-0542-z
更新日期:2019-09-01 00:00:00
abstract::The rate of expansion of primary prostatic carcinoma is comparatively slow, with tumours frequently taking years or decades to reach clinically relevant size. We now report the presence of an endogenous inhibitor, derived from aqueous extracts of human prostate tissue, which blocks prostatic carcinoma cell proliferati...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/nm1095-1040
更新日期:1995-10-01 00:00:00
abstract::Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymp...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-020-01145-0
更新日期:2021-01-01 00:00:00
abstract::Although programmed death-ligand 1-programmed death 1 (PD-L1-PD-1) inhibitors are broadly efficacious, improved outcomes have been observed in patients with high PD-L1 expression or high tumor mutational burden (TMB). PD-L1 testing is required for checkpoint inhibitor monotherapy in front-line non-small-cell lung canc...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-018-0134-3
更新日期:2018-09-01 00:00:00
abstract::In most cases of sporadic colorectal cancers, tumorigenesis is a multistep process, involving genomic alterations in parallel with morphologic changes. In addition, accumulating evidence suggests that the human gut microbiome is linked to the development of colorectal cancer. Here we performed fecal metagenomic and me...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/s41591-019-0458-7
更新日期:2019-06-01 00:00:00
abstract::Both the risk and the rate of development of atherosclerosis are increased in diabetics, but the mechanisms involved are unknown. Here we report a glucose-mediated increase in CD36 mRNA translation efficiency that results in increased expression of the macrophage scavenger receptor CD36. Expression of CD36 was increas...
journal_title:Nature medicine
pub_type: 杂志文章
doi:10.1038/89969
更新日期:2001-07-01 00:00:00
abstract::Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma1 and colorectal cancer2. In NABUCCO (ClinicalTrials.gov: NCT03387761 ), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two ...
journal_title:Nature medicine
pub_type: 杂志文章,多中心研究
doi:10.1038/s41591-020-1085-z
更新日期:2020-12-01 00:00:00