source_doi stringlengths 13 57 | source_mag_paper_id int64 490k 157M | source_abstract stringlengths 8 10.7k | target_doi stringlengths 14 27 | target_summary stringlengths 42 889 |
|---|---|---|---|---|
10.1101/gad.8.7.855 | 18,565,703 | The first step in the decay of some eukaryotic mRNAs is the shortening of the poly(A) tail. To examine how the transcript body was degraded after deadenylation, we followed the decay of a pulse of newly synthesized MFA2 transcripts while utilizing two strategies to trap intermediates in the degradation pathway. First, ... | 10.1038/nrm2917 | This paper was the first to report that the deadenylation of eukaryotic mRNA triggers cap removal, thereby exposing the 5′ end to exonucleolytic attack by XRN1. |
10.1073/pnas.90.14.6756 | 80,711,313 | Previous work has shown that RNase E-mediated cleavage of RNAI, an antisense repressor of the replication of ColE1-type plasmids, relieves repression in vivo by endonucleolytically converting RNAI to a rapidly decaying product. We report that mutations in the Escherichia coli pcnB gene result in a 10-fold prolongation ... | 10.1038/nrm2917 | This report was the first to reveal the function of bacterial poly(A) tails by showing that they expedite the degradation of RNA decay intermediates in E. coli |
10.1073/pnas.0510928103 | 83,127,135 | MicroRNAs (miRNAs) are ubiquitous regulators of eukaryotic gene expression. In addition to repressing translation, miRNAs can down-regulate the concentration of mRNAs that contain elements to which they are imperfectly complementary. Using miR-125b and let-7 as representative miRNAs, we show that in mammalian cells thi... | 10.1038/nrm2917 | This report shows that miRNAs accelerate the degradation of partially complementary mRNAs by expediting their deadenylation. |
10.1073/pnas.0306752101 | 45,493,046 | Genes and proteins generate molecular circuitry that enables the cell to process information and respond to stimuli. A major challenge is to identify characteristic patterns in this network of interactions that may shed light on basic cellular mechanisms. Previous studies have analyzed aspects of this network, concentr... | 10.1038/nrm1857 | This work presents a methodology to decompose cellular networks into their constituent basic building blocks, or network motifs. Although the technique can be applied to networks of any type, this study focuses on the analysis of a S. cerevisiae network derived from genome-scale protein–protein- and protein–DNA-interac... |
10.1073/pnas.0409233102 | 80,840,699 | Focused and nontargeted approaches were used to assess the impact associated with introduction of new high-flux pathways in Arabidopsis thaliana by genetic engineering. Transgenic A. thaliana plants expressing the entire biosynthetic pathway for the tyrosine-derived cyanogenic glucoside dhurrin as accomplished by inser... | 10.1038/nrm1857 | This study used omics data integration to diagnose unexpected impacts of genomic manipulations on the phenotype of the organism. Metabolomic and transcriptomic data were integrated to assess the systems-wide impact of introducing exogenous high-flux pathways to A. thaliana |
10.1073/pnas.0500756102 | 42,543,492 | Human neuroendocrine (NE) cancers range from relatively indolent to highly aggressive. In this study, we combine functional genomics with metabolomics to identify features of NE cancers associated with a poor outcome. Analysis of GeneChip datasets of primary prostate tumors, as well as lymph node and liver metastases f... | 10.1038/nrm1857 | The utility of integrating omics data to identify biomarkers is shown in this work, which integrated transcriptomics and metabolomics data to determine a molecular signature that is associated with poor-prognosis human neuroendocrine cancers. |
10.1126/science.1113833 | 83,298,560 | Recent experiments revealed large-scale differences in the transcription programs of related species, yet little is known about the genetic basis underlying the evolution of gene expression and its contribution to phenotypic diversity. Here we describe a large-scale modulation of the yeast transcription program that is... | 10.1038/nrm1857 | Genomics and transcriptomics data are integrated to identify a cis -regulatory element associated with the evolutionary emergence of rapid anaerobic growth capacity in certain yeast species. This study highlights the potential of integrating omics data sets to address fundamental evolutionary questions. |
10.1101/gr.1239303 | 104,407,415 | Cytoscape is an open source software project for integrating biomolecular interaction networks with high-throughput expression data and other molecular states into a unified conceptual framework. Although applicable to any system of molecular components and interactions, Cytoscape is most powerful when used in conjunct... | 10.1038/nrm1857 | One of the most widely used and broadly accessible software packages designed to facilitate omics data integration and analysis, known as Cytoscape, is detailed in this report. |
10.1126/science.1164382 | 20,638,024 | Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-ge... | 10.1038/nrc2981 | Sequencing of the glioblastoma genome in which mutation of IDH1 was identified as a driver mutation. |
10.1126/science.1160809 | 20,879,499 | Fuel Economy for Growing Cells Sophisticated 21st-century analyses of the signaling pathways that control cell growth have led researchers back to the seminal work of Otto Warburg, who discovered in the 1920s that tumor cells generate their energy in an unusual way—by switching from mitochondrial respiration to glycoly... | 10.1038/nrc2981 | Provocative review advancing the concept that glycolytic metabolism supports biosynthetic pathways. |
10.4049/jimmunol.175.10.6551 | 110,259,540 | Abstract Immunity and tumor protection in mice transgenic for human MUC.1, a glycoprotein expressed in the majority of cancers of epithelial origin in humans, were induced by vaccination with B lymphocytes genetically programmed to activate MUC.1-specific CD4 T cells. Their activation required a functional cooperation ... | 10.1038/nrc2326 | Weak CD4 + T-cell responses can themselves be helped by parallel CD4 + T-cell responses to foreign epitopes. This phenomenon of T H –T H cooperation might be particularly important in overcoming regulation and again informs vaccine design. |
10.4049/jimmunol.169.7.3908 | 58,149,034 | Abstract DNA vaccines can activate immunity against tumor Ags expressed as MHC class I-associated peptides. However, priming of CD8+ CTL against weak tumor Ags may require adjuvant molecules. We have used a pathogen-derived sequence from tetanus toxin (fragment C (FrC)) fused to tumor Ag sequences to promote Ab and CD4... | 10.1038/nrc2326 | A DNA vaccine design using a minimized microbial sequence to provide non-immunodominating T-cell help, together with a single tumour-derived epitope to generate focused CD8 + T-cell responses, appears effective. It is now in clinical trials. |
10.4049/jimmunol.179.7.4741 | 60,317,306 | Abstract The mechanisms by which in vivo electroporation (EP) improves the potency of i.m. DNA vaccination were characterized by using the hepatitis C virus nonstructural (NS) 3/4A gene. Following a standard i.m. injection of DNA with or without in vivo EP, plasmid levels peaked immediately at the site of injection and... | 10.1038/nrc2326 | The perceived difficulty in translating the effectiveness of DNA vaccination from pre-clinical rodents to large animals, including human subjects, appears to have been overcome by the use of electroporation. The mechanisms of amplification of performance include increased antigen expression and development of inflammat... |
10.1182/blood-2005-08-3255 | 22,091,114 | Abstract Human subjects maintain long-term immunologic memory against infective organisms but the mechanism is unclear. CD4+ T-helper memory (Thmem) cells are pivotal in controlling humoral and cellular responses, therefore their longevity and response to vaccination are critical for maintenance of protective immunity.... | 10.1038/nrc2326 | A surprising finding emerging from simple studies of CD4 + T-cell responses in normal human subjects to conventional vaccines was that vaccination co-stimulates memory CD4 + T cells against non-vaccine antigens. This 'bystander' stimulation is relevant for the maintenance of T-cell memory and for evaluating vaccine-ind... |
10.4049/jimmunol.171.11.5908 | 102,095,092 | Abstract We analyzed whether the immunobiology of vaccinating plasmid DNA containing a transcription unit for OVA is influenced by immunostimulatory CpG motifs in the plasmid backbone. Indeed, plasmid DNA differentially activated in vitro myeloid and plasmacytoid dendritic cells (DCs) provided they expressed the CpG-DN... | 10.1038/nrc2326 | The assumption, derived largely from data on synthetic CpG oligonucleotides, that sequences in the backbone of DNA plasmid vaccines operated solely through TLR9 was challenged by the finding that DNA vaccines functioned well in Tlr −/− mice. |
10.1002/ijc.20569 | 82,306,208 | Abstract Recombinant plasmid DNA and attenuated poxviruses are under development as cancer and infectious disease vaccines. We present the results of a phase I clinical trial of recombinant plasmid DNA and modified vaccinia Ankara (MVA), both encoding 7 melanoma tumor antigen cytotoxic T lymphocyte (CTL) epitopes. HLA‐... | 10.1038/nrc2326 | The concept that delivery of weak antigens by viral vectors will succeed has many theoretical problems. This paper illustrates that immunodomination from virus-specific CTL is one, and this is evident in a clinical trial in patients with melanoma. |
10.1126/science.1142364 | 20,264,295 | The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analys... | 10.1038/nrg2796 | One of the earliest examples of the use of imputation in meta-analysis. This paper combined three GWA studies and was able to identify several novel associations. |
10.1073/pnas.96.10.5698 | 45,448,659 | The β-chemokine receptor CCR5 is considered to be an attractive target for inhibition of macrophage-tropic (CCR5-using or R5) HIV-1 replication because individuals having a nonfunctional receptor (a homozygous 32-bp deletion in the CCR5 coding region) are apparently normal but resistant to infection with R5 HIV-1. In t... | 10.1038/nrd795 | The first small-molecule CCR5 antagonist to be disclosed in the peer-reviewed literature. Single-digit nanomolar binding affinity to CCR5 translates into potent anti-HIV-1 activity. |
10.1084/jem.186.1.121 | 58,945,944 | Interleukin 5 (IL-5) is the key cytokine involved in regulating the production and many of the specialized functions of mature eosinophils including priming, adhesion, and survival. We have generated a point mutant of human IL-5, IL-5 (E12K), which is devoid of agonist activity in both a TF-1 cell proliferation assay a... | 10.1038/nrd795 | Shows that the replacement of a single amino acid in a cytokine can produce a potent antagonist. The cytokine has more than one signal-transduction mechanism, and the mutation antagonizes only one of the responses. |
10.1084/jem.187.8.1215 | 79,679,730 | CCR5, a chemokine receptor expressed on T cells and macrophages, is the principal coreceptor for M-tropic HIV-1 strains. Recently, we described an NH2-terminal modification of the CCR5 ligand regulated on activation, normal T cell expressed and secreted (RANTES), aminooxypentane-RANTES (AOP-RANTES), that showed potent ... | 10.1038/nrd795 | This paper shows differences in signalling pathways that could be crucial for the control of receptor cycling. |
10.1126/science.1130258 | 41,561,474 | We used nuclear magnetic resonance relaxation dispersion to characterize higher energy conformational substates of Escherichia coli dihydrofolate reductase. Each intermediate in the catalytic cycle samples low-lying excited states whose conformations resemble the ground-state structures of preceding and following inter... | 10.1038/nmeth.3324 | CPMG relaxation dispersion experiments characterize the structural dynamics of the catalytic cycle of DHFR as a sequence of ‘linked’ ground and excited states |
10.1126/science.1157092 | 122,973,471 | Protein dynamics are essential for protein function, and yet it has been challenging to access the underlying atomic motions in solution on nanosecond-to-microsecond time scales. We present a structural ensemble of ubiquitin, refined against residual dipolar couplings (RDCs), comprising solution dynamics up to microsec... | 10.1038/nmeth.3324 | A comprehensive, integrative computational procedure reveals the conformational ensemble of ubiquition, validated by comparative crystal structure analysis |
10.1073/pnas.1323440111 | 19,666,754 | Significance Most proteins are inherently flexible and their dynamics play a central role in their biological functions. A molecular level understanding of protein function and mechanism requires an accurate description of the atomic coordinates in both time and space. Here we show, through studies of the enzyme dihydr... | 10.1038/nmeth.3324 | This study establishes that a multiconformer crystallographic ensemble (ref. 85 ) at room temperature accurately reflects fast dynamics in solution by relating B factors to NMR order parameters |
10.1182/blood-2010-12-324210 | 20,645,078 | Abstract Chronic lymphocytic leukemia (CLL) is an incurable adult disease of unknown etiology. Understanding the biology of CLL cells, particularly cell maturation and growth in vivo, has been impeded by lack of a reproducible adoptive transfer model. We report a simple, reproducible system in which primary CLL cells p... | 10.1038/nrc3907 | This study is an in vivo demonstration of the requirement of T cells for the growth of CLL. |
10.1182/blood-2012-07-441030 | 80,730,956 | Abstract Persistence or recurrence of minimal residual disease (MRD) after chemotherapy results in clinical relapse in patients with acute lymphoblastic leukemia (ALL). In a phase 2 trial of B-lineage ALL patients with persistent or relapsed MRD, a T cell–engaging bispecific Ab construct induced an 80% MRD response rat... | 10.1038/nrc3907 | This study documents the long-term efficacy of a novel mechanism of immunotherapeutic action in a traditionally treatment-refractory disease. |
10.1126/scitranslmed.3002842 | 104,325,590 | Adoptively transferred gene-modified T cells expand in vivo, eliminate leukemic cells, and form functional memory cells in patients. | 10.1038/nrc3907 | References 69 and 70 demonstrate that second-generation CAR T cells can mediate sustained tumour regression, undergo massive expansion in vivo and persist for extended periods of time, establishing memory T cells. |
10.1126/scitranslmed.3008226 | 83,497,245 | CD19 CAR T cell therapy induces complete remissions in 88% of 16 adult patients with relapsed or refractory acute lymphoblastic leukemia. | 10.1038/nrc3907 | References 72 and 73 highlight the pronounced sensitivity of relapsed or refractory ALL to CAR T cells using different second-generation CAR designs and demonstrate the durability of remissions with use of the CD137 co-stimulatory domain. |
10.1182/blood-2013-08-523001 | 28,090,314 | Key Points Marrow CD8+ T-cell infiltrates may be a novel predictor of response to donor lymphocyte infusions in patients with relapsed CML. Reversal of T-cell exhaustion is tightly linked to effective antileukemia responses to donor lymphocyte infusions. | 10.1038/nrc3907 | The authors use T cell-derived molecular signatures to explain the mechanism of DLI efficacy and predict DLI responses in a preliminary study cohort. |
10.1126/science.282.5393.1494 | 104,305,028 | Virtually all uropathogenic strains of Escherichia coli encode filamentous surface adhesive organelles called type 1 pili. High-resolution electron microscopy of infected mouse bladders revealed that type 1 pilus tips interacted directly with the lumenal surface of the bladder, which is embedded with hexagonal arrays o... | 10.1038/nri3887 | This study describes how superficial BECs reduce bacterial load following UPEC infection by spontaneous exfoliation into the urine. |
10.1126/science.280.5365.855 | 42,620,509 | Old-age survival has increased substantially since 1950. Death rates decelerate with age for insects, worms, and yeast, as well as humans. This evidence of extended postreproductive survival is puzzling. Three biodemographic insights—concerning the correlation of death rates across age, individual differences in surviv... | 10.1038/nrg1871 | Biodemography is a combination of biology and demography; this paper provides important biodemographical insights into the enigma of increasing longevity. |
10.1126/science.1081447 | 20,582,341 | Reduced signaling of insulin-like peptides increases the life-span of nematodes, flies, and rodents. In the nematode and the fly, secondary hormones downstream of insulin-like signaling appear to regulate aging. In mammals, the order in which the hormones act is unresolved because insulin, insulin-like growth factor–1,... | 10.1038/nrg1871 | Provides an extensive review of the endocrine regulation of ageing by insulin-like signals in mammals and invertebrates. |
10.1126/science.1102587 | 46,186,735 | Human genetic diseases that resemble accelerated aging provide useful models for gerontologists. They combine known single-gene mutations with deficits in selected tissues that are reminiscent of changes seen during normal aging. Here, we describe recent progress toward linking molecular and cellular changes with the p... | 10.1038/nrg1871 | The authors summarize the strengths and weaknesses of the premature ageing syndromes as models for human ageing. |
10.1046/j.1532-5415.2001.49180.x | 16,649,386 | OBJECTIVE: To assess the prevalence of common illnesses in an unselected population of centenarians. DESIGN: A population‐based survey. SETTING: Denmark. PARTICIPANTS: All Danes who celebrated their 100th anniversary between April 1, 1995 and May 31, 1996: 276 persons. MEASUREMENTS: All participants (including proxies)... | 10.1038/nrg1871 | Demonstrates that centenarians are generally not free of diseases, as non-population-based studies have suggested. |
10.1126/science.2200121 | 20,688,056 | High-affinity nucleic acid ligands for a protein were isolated by a procedure that depends on alternate cycles of ligand selection from pools of variant sequences and amplification of the bound species. Multiple rounds exponentially enrich the population for the highest affinity species that can be clonally isolated an... | 10.1038/nrmicro1458 | This paper describes the first use of the term SELEX and explains the basics of the process. |
10.1177/009127000004001217 | 131,430,710 | The pharmacokinetics and tolerability of a chemically stabilized synthetic ribozyme (ANGIOZYME ™ ) targeting the Flt‐1 VEGF receptor mRNA were evaluated in healthy volunteers. In a placebo‐controlled, single‐dose escalation study, ribozyme was administered as a 4‐hour IV infusion of 10 or 30 mg/m 2 or as a SC bolus of ... | 10.1038/nrmicro1458 | This paper outlines the biodistribution, bioavailability and clearance of RNA-based therapeutics. |
10.1016/s0014-5793(02)03275-1 | 122,030,549 | Many signalling proteins involved in diverse functions such as cell growth and differentiation can act as oncogenes and cause cellular transformation. These molecules represent attractive targets for cancer diagnosis or therapy and are therefore subject to intensive investigation. Aptamers are small nucleic acid molecu... | 10.1038/nrmicro1458 | This paper is a short review of the use of aptamers in the treatment of cancers. |
10.1083/jcb.200307137 | 41,715,118 | All ligands of the epidermal growth factor receptor (EGFR), which has important roles in development and disease, are released from the membrane by proteases. In several instances, ectodomain release is critical for activation of EGFR ligands, highlighting the importance of identifying EGFR ligand sheddases. Here, we u... | 10.1038/nrm1548 | Explores the contribution of different ADAMs to the shedding of six EGFR ligands using a loss-of-function approach with cells isolated from different ADAM-knockout mice. |
10.1126/science.282.5392.1281 | 83,243,373 | The ectodomains of numerous proteins are released from cells by proteolysis to yield soluble intercellular regulators. The responsible protease, tumor necrosis factor-α converting enzyme (TACE), has been identified only in the case when tumor necrosis factor-α (TNFα) is released. Analyses of cells lacking this metallop... | 10.1038/nrm1548 | Evaluation of mice lacking ADAM17 that uncovers a crucial role for ADAM17 in activating TGFα and the EGFR during mouse development. |
10.1083/jcb.200307035 | 81,541,224 | Heparin-binding EGF-like growth factor (HB-EGF) is first synthesized as a membrane-anchored form (proHB-EGF), and its soluble form (sHB-EGF) is released by ectodomain shedding from proHB-EGF. To examine the significance of proHB-EGF processing in vivo, we generated mutant mice by targeted gene replacement, expressing e... | 10.1038/nrm1548 | Mice with a knock-in mutation that renders HB-EGF uncleavable have defects in heart-valve development that resemble those in mice that completely lack HB-EGF or ADAM17. This further corroborates the essential role of ectodomain shedding in the functional activation of HB-EGF. |
10.1186/1742-6405-3-13 | 63,125,981 | Abstract The Rev protein of the human immunodeficiency virus (HIV) facilitates the nuclear export of intron containing viral mRNAs allowing formation of infectious virions. Rev traffics through the nucleolus and shuttles between the nucleus and cytoplasm. Rev multimerization and interaction with the export protein CRM1... | 10.1038/nrmicro1597 | Together with other papers from this group, this is groundbreaking research into how disrupting viral–nucleolar interactions can lead to novel and hopefully successful anti-HIV therapeutic strategies. |
10.1242/jcs.02982 | 108,010,909 | When human adenovirus infects human cells there is disruption of rRNA biogenesis. This report examines the effect of adenovirus infection on the nucleolar protein, upstream binding factor (UBF) which plays a major role in regulating rRNA synthesis. We determined that early after infection, UBF associates with the repli... | 10.1038/nrmicro1597 | This work illustrates how a study of viral interactions with the nucleolus can lead to shifts in our understanding of cell biology. |
10.1002/sim.4780140404 | 124,649,453 | Abstract We present a Bayesian approach for monitoring multiple outcomes in single‐arm clinical trials. Each patient's response may include both adverse events and efficacy outcomes, possibly occurring at different study times. We use a Dirichlet‐multinomial model to accommodate general discrete multivariate responses.... | 10.1038/nrd819 | An introduction to the complex topic of novel Bayesian monitoring methods applied to clinical-trial designs in oncology. |
10.1242/jcs.112.14.2453 | 125,136,730 | Ran is an abundant GTPase of the Ras superfamily that is highly conserved in eukaryotes. In interphase cells, Ran is mainly nuclear and thought to be predominantly GTP-bound, but it is also present in the cytoplasm, probably GDP-bound. This asymmetric distribution plays an important role in directing nucleocytoplasmic ... | 10.1038/nrm2410 | References 61–65 demonstrate a role for Ran in the assembly of microtubule asters and mitotic spindles. |
10.1126/science.1057661 | 101,592,074 | The guanosine triphosphatase Ran stimulates assembly of microtubule asters and spindles in mitotic Xenopus egg extracts. A carboxyl-terminal region of the nuclear-mitotic apparatus protein (NuMA), a nuclear protein required for organizing mitotic spindle poles, mimics Ran's ability to induce asters. This NuMA fragment ... | 10.1038/nrm2410 | References 95 and 96, together with reference 75, identify the role of importins in mediating the effects of RanGTP on spindle assembly factors. |
10.1126/science.288.5470.1429 | 102,399,947 | The nuclear envelope (NE) forms a controlled boundary between the cytoplasm and the nucleus of eukaryotic cells. To facilitate investigation of mechanisms controlling NE assembly, we developed a cell-free system made from Xenopus laevis eggs to study the process in the absence of chromatin. NEs incorporating nuclear po... | 10.1038/nrm2410 | References 123 and 124 show that nuclear-envelope assembly is controlled by Ran. |
10.1091/mbc.e03-05-0275 | 28,042,432 | Assembly of a eukaryotic nucleus involves three distinct events: membrane recruitment, fusion to form a double nuclear membrane, and nuclear pore complex (NPC) assembly. We report that importin β negatively regulates two of these events, membrane fusion and NPC assembly. When excess importin β is added to a full Xenopu... | 10.1038/nrm2410 | This paper, together with references 126 and 133, demonstrates roles for importin-β in nuclear-envelope assembly. |
10.1189/jlb.0709518 | 83,409,882 | Abstract The synergistic relationship between URT viruses and bacteria in OM pathogenesis is not fully understood, but overall is predicated on viral impairment of airway defenses. OM, or inflammation of the middle ear, is a highly prevalent infection in children worldwide. OM is a multifactorial disease with multiple ... | 10.1038/nrdp.2016.63 | This comprehensive review discusses the host innate and acquired immune response involved in the pathogenesis of AOM, including information on viral-induced pathological changes in the nasopharynx and the middle ear in animal models. |
10.1542/peds.2012-1988 | 61,119,162 | OBJECTIVE: To assess the effects of electronic health record–based clinical decision support (CDS) and physician performance feedback on adherence to guidelines for acute otitis media (AOM) and otitis media with effusion (OME). METHODS: We conducted a factorial-design cluster randomized trial with primary care practice... | 10.1038/nrdp.2016.63 | This large primary care-based cluster RCT including 140,000 OM visits shows that clinical decision support and performance feedback improve adherence to OM guidelines. |
10.1158/1078-0432.ccr-03-0632 | 97,481,915 | Abstract Purpose: Surgeons treating patients with head and neck squamous cell carcinoma (HNSCC) rely heavily on histology to decide whether the resection margins are tumor free and subsequent adjuvant treatments can be omitted. However, despite the presence of tumor-free margins, 10–30% of HNSCC patients still develop ... | 10.1038/nrc.2017.102 | This study presents the updated concept of field cancerization, which includes a genetic perspective. |
10.1158/1078-0432.ccr-11-2011 | 125,260,537 | Abstract Infection-associated cancers account for a large proportion of human cancers, and gastric cancer, the vast majority of which is associated with Helicobacter pylori infection, is a typical example of such cancers. Epigenetic alterations are known to occur frequently in gastric cancers, and H. pylori infection h... | 10.1038/nrc.2017.102 | This study describes epigenetic fields as a cause of field cancerization in the stomach. |
10.1126/science.aaa6806 | 20,687,641 | Normal skin's curiously abnormal genome Within every tumor, a battle is being waged. As individual tumor cells acquire new mutations that promote their survival and growth, they clonally expand at the expense of tumor cells that are “less fit.” Martincorena et al. sequenced 234 biopsies of sun-exposed but physiological... | 10.1038/nrc.2017.102 | This study identifies an extensive amount of cancer-associated mutations in morphologically normal human skin. |
10.1126/science.1243148 | 20,258,187 | Limiting Tumor Initiation What is the competitive advantage of cells with frequently occurring mutations during tumor development? Vermeulen et al. (p. 995 ; see the Perspective by Bozic and Nowak ) quantified the advantages of Apc -loss, Kras activation, and P53 mutation during tumor initiation in the mouse intestine.... | 10.1038/nrc.2017.102 | This study quantifies the selective advantage of pretumour mutations in the intestine. |
10.1126/science.aaf9011 | 41,609,411 | A substantial fraction of mutations in human cancer are attributable to random errors occurring during DNA replication. | 10.1038/nrc.2017.102 | This study suggests a critical role for pretumour mutation accumulation in cancer development. |
10.1073/pnas.1221068110 | 82,811,334 | Although it has been hypothesized that some of the somatic mutations found in tumors may occur before tumor initiation, there is little experimental or conceptual data on this topic. To gain insights into this fundamental issue, we formulated a mathematical model for the evolution of somatic mutations in which all rele... | 10.1038/nrc.2017.102 | This study suggests that most somatic mutations in cancer accrue prior to the initiation of cancer growth. |
10.1073/pnas.0909797107 | 103,487,490 | The stromal compartment is increasingly recognized to play a role in cancer. However, its role in the transition from preinvasive to invasive disease is unknown. Most gastrointestinal tumors have clearly defined premalignant stages, and Barrett’s esophagus (BE) is an ideal research model. Supervised clustering of gene ... | 10.1038/nrc.2017.102 | This study shows consistent changes in the gene expression profile of cells within the stromal compartment across pre-malignant gastrointestinal diseases. |
10.1073/pnas.0909428106 | 61,382,328 | Chronic inflammation predisposes to a variety of human cancers. Affected tissues slowly accumulate mutations, some of which affect growth regulation and drive successive waves of clonal evolution, whereas a far greater number are functionally neutral and serve only to passively mark expanding clones. Ulcerative colitis... | 10.1038/nrc.2017.102 | This study demonstrates that evidence of recent clonal expansion in patients with colitis indicates increased cancer risk. |
10.1126/science.1099414 | 60,546,218 | The turnover of Jun proteins, like that of other transcription factors, is regulated through ubiquitin-dependent proteolysis. Usually, such processes are regulated by extracellular stimuli through phosphorylation of the target protein, which allows recognition by F box–containing E3 ubiquitin ligases. In the case of c-... | 10.1038/nri1731 | This paper provides genetic and biochemical evidence that JNK signalling modulates the turnover of JUN proteins by phosphorylation and activation of the E3 ligase ITCH. |
10.1126/science.1107107 | 83,481,978 | Activation of the transcription factor NF-κB after engagement of the T cell receptor (TCR) is important for T cell proliferation and activation during the adaptive immune response. Recent reports have elucidated a signaling pathway that involves the protein kinase C θ (PKCθ), the scaffold protein CARD11 (also called CA... | 10.1038/nri1731 | This paper shows that PDK1 has a dual role in NF-κB activation through phosphorylation of PKC-θ and through recruitment of the CARMA1–BCL-10–MALT1 complex. |
10.1182/blood-2009-07-235119 | 18,956,834 | Abstract Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and primary myelofibrosis show an inherent tendency for transformation into leukemia (MPN-blast phase), which is hypothesized to be accompanied by acquisition of additional genomic lesio... | 10.1038/nrc3805 | References 3, 6 and 10 provide compelling evidence that CUX1 is the target of LOH at 7q22.1. Moreover, references 4 and 5 show that CUX1 mRNA and protein expression was reduced approximately twofold in leukaemic cells of affected patients. |
10.1073/pnas.1008403108 | 60,999,796 | Cell populations able to generate a large repertoire of genetic variants have increased potential to generate tumor cells that survive through the multiple selection steps involved in tumor progression. A mechanism for the generation of aneuploid cancer cells involves passage through a tetraploid stage. Supernumerary c... | 10.1038/nrc3805 | This study shows that p110 CUX1 activates expression of genes involved in the spindle assembly checkpoint and promotes bipolar mitosis in cells with more than two centrosomes. However, frequent merotelic chromosome attachments lead to aneuploidy and rapidly generate populations of genetic variants from which tumour cel... |
10.1002/anie.200390233 | 123,028,444 | Abstract Binding events of ligands to receptors are the key for an understanding of biological processes. Gaining insight into protein–protein and protein–ligand interactions in solution has recently become possible on an atomic level by new NMR spectroscopic techniques. These experiments identify binding events either... | 10.1038/nrd2220 | An excellent overview of the numerous applications of NMR in fragment-based screening. |
10.1073/pnas.92.11.4917 | 101,090,801 | Chromosomal rearrangements involving band 12p13 are found in a wide variety of human leukemias but are particularly common in childhood acute lymphoblastic leukemia. The genes involved in these rearrangements, however, have not been identified. We now report the cloning of a t(12;21) translocation breakpoint involving ... | 10.1038/nrc1164 | References 11 and 12 describe the co-discovery of the most common fusion gene in childhood leukaemia. |
10.1073/pnas.070061297 | 107,094,258 | Chromosomal translocations involving the MLL gene occur in about 80% of infant leukemia. In the search for possible agents inducing infant leukemia, we identified bioflavonoids, natural substances in food as well as in dietary supplements, that cause site-specific DNA cleavage in the MLL breakpoint cluster region (BCR)... | 10.1038/nrc1164 | The first experimental demonstration that bioflavonoid substances can induce breaks in the MLL gene. This information underpins current epidemiological studies. |
10.1073/pnas.94.25.13950 | 136,101,731 | Epidemiological evidence has suggested that some pediatric leukemias may be initiated in utero and, for some pairs of identical twins with concordant leukemia, this possibility has been strongly endorsed by molecular studies of clonality. Direct evidence for a prenatal origin can only be derived by prospective or retro... | 10.1038/nrc1164 | A key paper providing the first evidence that leukaemia fusion genes are present and detectable in the archived neonatal blood spots of patients. |
10.1073/pnas.171321298 | 123,295,299 | The t(8;21) is one of the most frequent chromosomal abnormalities associated with acute myeloid leukemia (AML). The translocation, which involves the AML1 gene on chromosome 21 and the ETO gene on chromosome 8, generates an AML1-ETO fusion transcription factor. To examine the effect of the AML1-ETO fusion protein on le... | 10.1038/nrc1164 | An elegant paper showing that common chromosome translocations in leukaemia have to be complemented by other genetic abnormalities to produce overt leukaemias. |
10.1126/science.2406902 | 20,535,001 | In tumor cells from virtually all patients with chronic myelogenous leukemia, the Philadelphia chromosome, a fusion of chromosomes 9 and 22, directs the synthesis of the P210 bcr/abl protein. The protein-tyrosine kinase activity and hybrid structure of P210 bcr/abl are similar to the oncogene product of the Abelson mur... | 10.1038/nrc1164 | Shows that human leukaemia can be mimicked in mice using the appropriate leukaemia gene ( BCR–ABL ) as a transgene. |
10.1073/pnas.112218799 | 20,753,787 | Studies on monozygotic twins with concordant leukemia and retrospective scrutiny of neonatal blood spots of patients with leukemia indicate that chromosomal translocations characteristic of pediatric leukemia often arise prenatally, probably as initiating events. The modest concordance rate for leukemia in identical tw... | 10.1038/nrc1164 | First paper identifying cells carrying common chromosome translocations in blood from normal newborns. |
10.1126/science.1099314 | 41,637,132 | Receptor tyrosine kinase genes were sequenced in non–small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Ir... | 10.1038/nrc2088 | Identified mutations in the kinase domain of EGFR that predict gefitinib response. |
10.1073/pnas.0502860102 | 20,376,547 | Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutatio... | 10.1038/nrc2088 | In vitro data showing that T790M-mediated acquired resistance to gefitinib can be overcome by irreversible EGFR-TKIs. |
10.1101/gad.1417406 | 80,419,872 | Somatic mutations in exons encoding the tyrosine kinase domain of the epidermal growth factor receptor ( EGFR ) gene are found in human lung adenocarcinomas and are associated with sensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib. Nearly 90% of the EGFR mutations are either short, in-frame deletion... | 10.1038/nrc2088 | Modelled NSCLC in mice using transgenic kinase domain mutant EGFR and showed their response to EGFR-TKIs. |
10.1126/science.1101637 | 104,361,617 | Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. We report that these mutant EGFRs selectively a... | 10.1038/nrc2088 | EGFR kinase domain mutations hyperactivate survival pathways such as Akt and STAT 3, and gefitinib attenuates them in sensitive cell lines. |
10.1073/pnas.0409773102 | 4,791,663 | Therapies that target the EGF receptor (EGFR), such as gefitinib (IRESSA), are effective in a subset of patients with advanced non-small cell lung cancer (NSCLC). The differences in intracellular signaling networks between gefitinib-sensitive and -resistant NSCLCs remain poorly understood. In this study, we observe tha... | 10.1038/nrc2088 | Gefitinib sensitivity is correlated with the heterodimerization of EGFR with ERBB2 and the attenuation of Akt activation in gefitinib-treated NSCLC cell lines. |
10.1073/pnas.0504952102 | 60,537,568 | To realize the full potential of targeted protein kinase inhibitors for the treatment of cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the EGF receptor (EGFR) have been found that confer resistance to the drugs imatinib, gefitinib, and erlotin... | 10.1038/nrc2088 | Details the development of second generation TKIs that overcome resistance that arises from mutations of the gatekeeper residue in various tyrosine kinase oncogenes. |
10.1126/science.1133427 | 62,580,409 | The elucidation of the human genome sequence has made it possible to identify genetic alterations in cancers in unprecedented detail. To begin a systematic analysis of such alterations, we determined the sequence of well-annotated human protein-coding genes in two common tumor types. Analysis of 13,023 genes in 11 brea... | 10.1038/nrc2088 | Highlights the genetic complexity and inter-tumour variability of human cancers. |
10.1126/science.1099962 | 62,613,550 | Signaling by the transcription factor nuclear factor kappa B (NF-κB) involves its release from inhibitor kappa B (IκB) in the cytosol, followed by translocation into the nucleus. NF-κB regulation of IκBα transcription represents a delayed negative feedback loop that drives oscillations in NF-κB translocation. Single-ce... | 10.1038/nrm2042 | Live-cell imaging and computational modelling are combined to link pulses of NF-κB nuclear translocation to the level of transcriptional activity. |
10.1126/science.1105809 | 83,350,899 | Machine learning was applied for the automated derivation of causal influences in cellular signaling networks. This derivation relied on the simultaneous measurement of multiple phosphorylated protein and phospholipid components in thousands of individual primary human immune system cells. Perturbing these cells with m... | 10.1038/nrm2042 | A novel method for using flow cytometry data to automatically generate network topology models. |
10.1126/science.1113230 | 19,110,382 | We used fluorescence microscopy to measure global and local concentrations of 28 cytoskeletal and signaling proteins fused to yellow fluorescent protein (YFP) in the fission yeast Schizosaccharomyces pombe . Native promoters controlled the expression of these functional YFP fusion proteins. Fluorescence measured by mic... | 10.1038/nrm2042 | Fluorescence microscopy and flow cytometry of yellow-FP-tagged genes was used to determine the absolute global and local concentrations of ∼ 40 proteins in the yeast cytokinesis network. This is the largest survey of absolute endogenous-protein concentrations so far. |
10.1126/science.1100533 | 20,522,723 | Cell migration initiates by extension of the actin cytoskeleton at the leading edge. Computational analysis of fluorescent speckle microscopy movies of migrating epithelial cells revealed this process is mediated by two spatially colocalized but kinematically, kinetically, molecularly, and functionally distinct actin n... | 10.1038/nrm2042 | Statistical modelling of high-resolution live-cell microscopy data reveals remarkable kinetic differences between subsets of the actin network in migrating cells. |
10.4049/jimmunol.166.5.3151 | 120,864,722 | Abstract Confocal fluorescent microscopy was used to study redistribution of membrane-associated proteins in naive T cells from young and old mice from a transgenic stock whose T cells express a TCR specific for a peptide derived from pigeon cytochrome C. About 50% of the T cells from young mice that formed conjugates ... | 10.1038/nri2318 | This work demonstrates at a single-cell level the existence of age-related proximal defects in T-cell signalling. |
10.1073/pnas.0601040103 | 20,334,085 | Using GFP to mark recent thymic emigrants (RTEs) in mice carrying a GFP transgene driven by the recombination-activating gene 2 promoter, we demonstrate that RTEs are readily detectable even in 2-year-old mice, despite the fact that the proportion of the peripheral T cell pool comprised of RTEs declines with age. Altho... | 10.1038/nri2318 | An elegant insight into the decrease of thymic function with ageing in mice. |
10.4049/jimmunol.151.12.6657 | 139,037,196 | Abstract As mice age, spontaneous changes occur in the receptor repertoire of their T cells. The receptor repertoire of CD4+ T cells does not change with age. By contrast, however, the percentage of alpha beta+, CD8+ T cells bearing particular V elements varies considerably between individual aged mice, although it is ... | 10.1038/nri2318 | This study provides the first description of age-related T-cell clonal expansions. |
10.4049/jimmunol.174.11.7446 | 103,999,662 | Abstract The ability to mount protective immune responses depends on the diversity of T cells. T cell diversity may be compromised by the declining thymic output of new T cells. The aging process imposes a threat to diversity, because thymic function deteriorates. In this study we have examined the relationship between... | 10.1038/nri2318 | References 61 and 62 provide essential evidence for increased turnover and concomitant loss of naive T cells in ageing primates and humans, respectively. |
10.4049/jimmunol.176.4.2645 | 62,297,044 | Abstract The age-associated decrease in functionality of the human immune system is thought to have a negative impact on the capacity to provide protection against infection, in turn leading to increased incidence of mortality. In a previous longitudinal study of octogenarians, we identified an immune risk phenotype (I... | 10.1038/nri2318 | An outstanding longitudinal study of an ageing Swedish population that suggests a strong impact of CMV on the ageing immune system. |
10.4049/jimmunol.180.7.4848 | 8,271,578 | Abstract The immune system devotes substantial resources to the lifelong control of persistent pathogens, which were hypothesized to play an important role in immune aging. Specifically, the presence of latent herpesviruses has been correlated with immune exhaustion and shorter lifespan in octogenarians. But neither th... | 10.1038/nri2318 | This study reveals that localized, niche-limited latent herpesvirus may not have an impact on immune senescence. |
10.4049/jimmunol.179.6.3535 | 37,756,845 | Abstract Increasing age is associated with the development of CD8+ T cell clonal expansions (TCE) that can dominate the peripheral T cell repertoire and interfere with immune responses to infection and vaccination. Some TCE are driven by chronic infections, consistent with dysregulated outgrowth of T cell clones in res... | 10.1038/nri2318 | This study shows that age-related T-cell clonal expansions can be specific for acute, long-cleared pathogens, suggesting that homeostatic disturbances have an important role in the onset of these abnormalities. |
10.1084/jem.20040437 | 46,000,812 | Peripheral T cell diversity is virtually constant in the young, but is invariably reduced in aged mice and humans. CD8+ T cell clonal expansions (TCE) are the most drastic manifestation of, and possible contributors to, this reduced diversity. We show that the presence of TCE results in reduced CD8+, but not CD4+, T ce... | 10.1038/nri2318 | This manuscript shows that constriction of the T-cell repertoire by uncontrolled T-cell clonal expansions can erode protective immunity. |
10.1083/jcb.149.3.591 | 58,551,540 | The eukaryotic chaperonin tailless complex polypeptide 1 (TCP1) ring complex (TRiC) (also called chaperonin containing TCP1 [CCT]) is a hetero-oligomeric complex that facilitates the proper folding of many cellular proteins. To better understand the manner in which TRiC interacts with newly translated polypeptides, we ... | 10.1038/nrm1492 | The results in this paper indicate a tight coupling between translation and chaperone-assisted protein folding. |
10.1083/jcb.201502016 | 104,170,110 | Polyploid cells, which contain more than two genome copies, occur throughout nature. Beyond well-established roles in increasing cell size/metabolic output, polyploidy can also promote nonuniform genome, transcriptome, and metabolome alterations. Polyploidy also frequently confers resistance to environmental stresses n... | 10.1038/nrg.2017.26 | This interesting review discusses how polyploidy (mainly in animals and fungi) frequently confers resistance to environmental stresses that are not tolerated by diploid cells. It also highlights the accumulating evidence that indicates how the study of polyploid cells might improve our understanding of human disease. |
10.1126/science.1240561 | 83,301,014 | Genome duplication (or polyploidization) has occurred throughout plant evolutionary history and is thought to have driven the adaptive radiation of plants. We found that the cytotype of the root, and not the genotype, determined the majority of heritable natural variation in leaf potassium (K) concentration in Arabidop... | 10.1038/nrg.2017.26 | This paper shows that both natural polyploidy and artificially-induced polyploidy in confer increased salt tolerance by regulating leaf potassium levels. |
10.1101/gr.168997.113 | 104,199,694 | Ancient whole-genome duplications (WGDs), also referred to as paleopolyploidizations, have been reported in most evolutionary lineages. Their attributed role remains a major topic of discussion, ranging from an evolutionary dead end to a road toward evolutionary success, with evidence supporting both fates. Previously,... | 10.1038/nrg.2017.26 | This paper provides strong support for a previously suggested, but controversial, correlation between WGDs and the most recent mass extinction. |
10.1073/pnas.1404177111 | 82,030,639 | The role of polyploidy, particularly allopolyploidy, in plant diversification is a subject of debate. Whole-genome duplications precede the origins of many major clades (e.g., angiosperms, Brassicaceae, Poaceae), suggesting that polyploidy drives diversification. However, theoretical arguments and empirical studies sug... | 10.1038/nrg.2017.26 | In this paper, the authors show that a wave of allopolyploidizations in C 4 grasses seems to have coincided with the worldwide expansion of C 4 grasslands. Polyploidy seems to be correlated with the dominance of C 4 grasses over C 3 grasses and large-scale displacement of the latter. |
10.1111/j.1365-2958.2011.07600.x | 125,231,763 | Summary Haloferax volcanii is highly polyploid and contains about 20 copies of the major chromosome. A heterozygous strain was constructed that contained two different types of genomes: the leuB locus contained either the wild‐type leuB gene or a leuB:trpA gene introduced by gene replacement. As the trpA locus is devoi... | 10.1038/nrg.2017.26 | This seminal paper demonstrates the existence of gene conversion, one of the processes that is key to the survival of polyploid prokaryotes. |
10.1534/genetics.106.061929 | 45,485,746 | Abstract Cell competition is a homeostatic mechanism that regulates the size attained by growing tissues. We performed an unbiased genetic screen for mutations that permit the survival of cells being competed due to haplo-insufficiency for RpL36. Mutations that protect RpL36 heterozygous clones include the tumor suppre... | 10.1038/nrm2221 | Shows that mutations in components of the Hippo pathway enable cells to outcompete and eliminate wild-type neighbouring cells. However, the mechanisms that underlie this phenotype remain unclear. |
10.1126/science.275.5300.665 | 122,837,290 | The regulation of the serine-threonine kinase Akt by lipid products of phosphoinositide 3-kinase (PI 3-kinase) was investigated. Akt activity was found to correlate with the amount of phosphatidylinositol-3,4-bisphosphate (PtdIns-3,4-P 2 ) in vivo, and synthetic PtdIns-3,4-P 2 activated Akt both in vitro and in vivo. B... | 10.1038/nrc2842 | This study described regulation of Akt by PtdIns(3, 4)P 2 |
10.1038/embor.2009.28 | 61,090,722 | Akt is a crucial phosphoinositide 3‐kinase (PI(3)K) effector that regulates cell proliferation and survival. PI(3)K‐generated signals, PtdIns(3,4,5)P 3 and PtdIns(3,4)P 2 , direct Akt plasma membrane engagement. Pathological Akt plasma membrane association promotes oncogenesis. PtdIns(3,4)P 2 is degraded by inositol po... | 10.1038/nrc2842 | This study shows that phosphoinositide 4-phosphatase can control the activation of Akt and thereby cell proliferation, survival and tumourigenesis. |
10.1083/jcb.200405156 | 41,114,938 | The epidermal growth factor (EGF)–induced increase in free barbed ends, resulting in actin polymerization at the leading edge of the lamellipodium in carcinoma cells, occurs as two transients: an early one at 1 min and a late one at 3 min. Our results reveal that phospholipase (PLC) is required for triggering the early... | 10.1038/nrc2842 | This study described the connection between cofilin-regulation and activation of PLC. |
10.1126/science.274.5284.99 | 62,116,299 | Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein containing a Lys 670 → Asn, Met 671 → Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increas... | 10.1038/nri1843 | This article shows a correlation between amyloid-β load and cognitive memory deficits in APP -transgenic mice. |
10.1073/pnas.94.8.4109 | 121,844,087 | In Alzheimer disease, β-amyloid peptide accumulates in the brain as insoluble amyloid plaques. Amyloid filaments, similar to those found in amyloid plaques, can be assembled in vitro from chemically synthesized β-peptides. In this study, we report that antibodies raised against the N-terminal region (1–28) of the β-amy... | 10.1038/nri1843 | A demonstration that antibody can reduce amyloid-β fibril formation in vitro |
10.1073/pnas.0506209103 | 124,117,771 | Vaccination against amyloid β-peptide (Aβ) has been shown to be successful in reducing Aβ burden and neurotoxicity in mouse models of Alzheimer's disease (AD). However, although Aβ immunization did not show T cell infiltrates in the brain of these mice, an Aβ vaccination trial resulted in meningoencephalitis in 6% of p... | 10.1038/nri1843 | Description of meningoencephalitis in APP -transgenic mice and reduction of amyloid-β levels mediated by amyloid-β-specific T cells. |
10.1016/0014-5793(91)81017-3 | 81,460,713 | The serine protease α‐thrombin (thrombin) potently stimulates G‐protein‐coupled signaling pathways and DNA synthesis in CCL39 hamster lung fibroblasts. To clone a thrombin receptor cDNA, selective amplification of mRNA sequences displaying homology to the transmembrane domains of G‐protein‐coupled receptor genes was pe... | 10.1038/nrd3615 | This was one of the first reports to describe the cloning and functional expression of the thrombin receptor in mammalian cells. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.