MET exon 14 alterations are oncogenic drivers of non-small-cell lung cancers (NSCLCs)
. These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition
. ...Crizotinib is a multikinase inhibitor with potent activity against MET
. The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations. Objective response rate was 32% (95% confidence interval (CI), 21-45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by splice-site region and mutation type of the MET exon 14 alteration, concurrent increased MET copy number or the detection of a MET exon 14 alteration in circulating tumor DNA. The median duration of response was 9.1 months (95% CI, 6.4-12.7). The median progression-free survival was 7.3 months (95% CI, 5.4-9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations and adds to an expanding list of genomically driven therapies for oncogenic subsets of NSCLC.
In addition to maintaining the GenBank(R) nucleic acid sequence database, the National Center for Biotechnology Information (NCBI) provides data retrieval systems and computational resources for the ...analysis of data in GenBank and other biological data made available through NCBI's website. NCBI resources include Entrez, Entrez Programming Utilities, PubMed, PubMed Central, Entrez Gene, the NCBI Taxonomy Browser, BLAST, BLAST Link (BLink), Electronic PCR, OrfFinder, Spidey, RefSeq, UniGene, HomoloGene, ProtEST, dbMHC, dbSNP, Cancer Chromosomes, Entrez Genomes and related tools, the Map Viewer, Model Maker, Evidence Viewer, Clusters of Orthologous Groups (COGs), Retroviral Genotyping Tools, HIV-1/Human Protein Interaction Database, SAGEmap, Gene Expression Omnibus (GEO), Online Mendelian Inheritance in Man (OMIM), the Molecular Modeling Database (MMDB), the Conserved Domain Database (CDD) and the Conserved Domain Architecture Retrieval Tool (CDART). Augmenting many of the Web applications are custom implementations of the BLAST program optimized to search specialized datasets. All of the resources can be accessed through the NCBI home page at http://www.ncbi.nlm.nih.gov.
Abstract
The National Center for Biotechnology Information (NCBI) produces a variety of online information resources for biology, including the GenBank® nucleic acid sequence database and the PubMed® ...database of citations and abstracts published in life science journals. NCBI provides search and retrieval operations for most of these data from 35 distinct databases. The E-utilities serve as the programming interface for the most of these databases. Resources receiving significant updates in the past year include PubMed, PMC, Bookshelf, RefSeq, SRA, Virus, dbSNP, dbVar, ClinicalTrials.gov, MMDB, iCn3D and PubChem. These resources can be accessed through the NCBI home page at https://www.ncbi.nlm.nih.gov.
Transition metal catalysts, particularly those derived from the group VIII−X metals, display remarkable efficiency for the formation of carbon−carbon and carbon−heteroatom bonds through the reactions ...of suitable nucleophiles with organic electrophilic partners. Within this subset of the periodic table, palladium and nickel complexes offer the broadest utility, while additionally providing the deepest mechanistic insight into thus-termed “cross-coupling reactions”. The mammoth effort devoted to palladium and nickel catalysts over the past 30 years has somewhat obscured reports of alternative metal complexes in this arena. As cross-coupling reactions have evolved into a critical support for modern synthetic chemistry, the search for alternative catalysts has been taken up with renewed vigor. When the current generation of synthetic chemists reflects back to the origins of cross coupling for inspiration, the well-documented effect of iron salts on the reactivity of Grignard reagents with organic electrophiles surfaces as a fertile ground for alternative catalyst development. Iron possesses the practical benefits more befitting an alkali or alkaline earth metal, while displaying the unique reactivity of a d-block element. Therefore the search for broadly applicable iron catalysts for cross coupling is an increasingly important goal in modern synthetic organic chemistry. This Account describes the evolution of iron-catalyzed cross coupling from its inception in the work of Kochi to the present. Specific emphasis is placed on reactivity and synthetic applications, with selected examples from acyl-, alkenyl-, aryl-, and alkyl halide/pseudohalide cross coupling included. The typical reaction partners are Grignard reagents, though organomanganese, -copper, and -zinc derivatives have also been used in certain cases. Such iron-catalyzed processes occur very rapidly even at low temperature and therefore are distinguished by broad functional group compatibility. Furthermore, recent advances in carbon−heteroatom bond formation and studies relevant to the general reactivity of in situ generated and structurally defined “low-valent” iron catalysts are presented. The preparative aspects of iron-catalyzed cross coupling are encouraging, but the inclination to classify these processes within the characteristic reaction manifold is premature, as mechanistic studies have evolved at a comparatively slow pace. A typical protocol for cross coupling employs an Fe(+2) or Fe(+3) precatalyst, which is reduced in situ by the organometallic nucleophile. The nature of the resulting active component(s) is still best described, more than 30 years later, in Kochi’s original terms as a “reduced form of soluble iron”. Despite huge gaps in our current knowledge, three distinct mechanisms have been formulated, largely based on empirical evidence: a “canonical” cross-coupling process, a manifold wherein alkylation of an organoiron intermediate replaces transmetalation as a key step, and finally a proposal reliant on the formation of nucleophilic ate complexes. Conjecture and speculation abound, but precisely what constitutes the catalytic cycle in iron-catalyzed cross coupling remains an extremely challenging unanswered question.
Objectives This study sought to investigate whether the everolimus-eluting stent (EES) is superior to the paclitaxel-eluting stent (PES) with respect to long-term individual clinical outcomes. ...Background Individual studies have indicated a clinical advantage of coronary EES compared with PES with respect to restenosis and the composite endpoint of major adverse cardiac events. However, these trials were not powered for superiority in low-frequency event rates and have reported limited data beyond 1-year follow-up. Methods We conducted a meta-analysis of the final 3-year results from the international SPIRIT (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) II, III, and IV clinical trials. Individual patient data from 4,989 patients who were prospectively randomized to treatment with EES (n = 3,350) or PES (n = 1,639) were pooled for analysis. Results At 3-year follow-up, EES was superior to PES in reducing the following event rates: target lesion failure (8.9% vs. 12.5%, hazard ratio HR: 0.71, 95% confidence interval CI: 0.59 to 0.85; p = 0.0002), all-cause mortality (3.2% vs 5.1%, HR: 0.65, 95% CI: 0.49 to 0.86; p = 0.003), myocardial infarction (3.2% vs. 5.1%, HR: 0.64, 95% CI: 0.48 to 0.85; p = 0.002), cardiac death or myocardial infarction (4.4% vs. 6.3%, HR: 0.70, 95% CI: 0.54 to 0.90; p = 0.005), ischemia-driven target lesion revascularization (6.0% vs. 8.2%, HR: 0.72, 95% CI: 0.58 to 0.90; p = 0.004), stent thrombosis (0.7% vs. 1.7%, HR: 0.45, 95% CI: 0.26 to 0.78; p = 0.003), and major adverse cardiac events (9.4% vs. 13.0%, HR: 0.71, 95% CI: 0.60 to 0.85; p = 0.0002). No interaction was present between stent type and the 3-year relative rates of target lesion failure across a broad range of subgroups, with the exception of diabetes and vessel (left anterior descending vs. other). Conclusions In this large dataset with 3-year follow-up, coronary implantation of EES compared with PES resulted in reduced rates of all-cause mortality, myocardial infarction, ischemia-driven target lesion revascularization, stent thrombosis, and target lesion failure. Further research is warranted to characterize possible interactions between stent type, diabetes, and vessel.
Abstract
The National Center for Biotechnology Information (NCBI) provides a large suite of online resources for biological information and data, including the GenBank® nucleic acid sequence database ...and the PubMed® database of citations and abstracts published in life science journals. The Entrez system provides search and retrieval operations for most of these data from 34 distinct databases. The E-utilities serve as the programming interface for the Entrez system. Custom implementations of the BLAST program provide sequence-based searching of many specialized datasets. New resources released in the past year include a new PubMed interface and NCBI datasets. Additional resources that were updated in the past year include PMC, Bookshelf, Genome Data Viewer, SRA, ClinVar, dbSNP, dbVar, Pathogen Detection, BLAST, Primer-BLAST, IgBLAST, iCn3D and PubChem. All of these resources can be accessed through the NCBI home page at https://www.ncbi.nlm.nih.gov.
Abstract
GenBank® (https://www.ncbi.nlm.nih.gov/genbank/) is a comprehensive, public database that contains 15.3 trillion base pairs from over 2.5 billion nucleotide sequences for 504 000 formally ...described species. Recent updates include resources for data from the SARS-CoV-2 virus, including a SARS-CoV-2 landing page, NCBI Datasets, NCBI Virus and the Submission Portal. We also discuss upcoming changes to GI identifiers, a new data management interface for BioProject, and advice for providing contextual metadata in submissions.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus attacks multiple organs of coronavirus disease 2019 (COVID-19) patients, including the brain. There are worldwide descriptions ...of neurological deficits in COVID-19 patients. Central nervous system (CNS) symptoms can be present early in the course of the disease. As many as 55% of hospitalized COVID-19 patients have been reported to have neurological disturbances three months after infection by SARS-CoV-2. The mutability of the SARS-COV-2 virus and its potential to directly affect the CNS highlight the urgency of developing technology to diagnose, manage, and treat brain injury in COVID-19 patients. The pathobiology of CNS infection by SARS-CoV-2 and the associated neurological sequelae of this infection remain poorly understood. In this review, we outline the rationale for the use of blood biomarkers (BBs) for diagnosis of brain injury in COVID-19 patients, the research needed to incorporate their use into clinical practice, and the improvements in patient management and outcomes that can result. BBs of brain injury could potentially provide tools for detection of brain injury in COVID-19 patients. Elevations of BBs have been reported in cerebrospinal fluid (CSF) and blood of COVID-19 patients. BB proteins have been analyzed in CSF to detect CNS involvement in patients with infectious diseases, including human immunodeficiency virus and tuberculous meningitis. BBs are approved by the U.S. Food and Drug Administration for diagnosis of mild versus moderate traumatic brain injury and have identified brain injury after stroke, cardiac arrest, hypoxia, and epilepsy. BBs, integrated with other diagnostic tools, could enhance understanding of viral mechanisms of brain injury, predict severity of neurological deficits, guide triage of patients and assignment to appropriate medical pathways, and assess efficacy of therapeutic interventions in COVID-19 patients.
Summary Background Uveal melanoma is a rare tumour with no established treatments once metastases develop. Although a variety of immune-based therapies have shown efficacy in metastatic cutaneous ...melanoma, their use in ocular variants has been disappointing. Recently, adoptive T-cell therapy has shown salvage responses in multiple refractory solid tumours. Thus, we sought to determine if adoptive transfer of autologous tumour-infiltrating lymphocytes (TILs) could mediate regression of metastatic uveal melanoma. Methods In this ongoing single-centre, two-stage, phase 2, single-arm trial, patients (aged ≥16 years) with histologically confirmed metastatic ocular melanoma were enrolled. Key eligibility criteria were an Eastern Cooperative Oncology Group performance status of 0 or 1, progressive metastatic disease, and adequate haematological, renal, and hepatic function. Metastasectomies were done to procure tumour tissue to generate autologous TIL cultures, which then underwent large scale ex-vivo expansion. Patients were treated with lymphodepleting conditioning chemotherapy (intravenous cyclophosphamide 60 mg/kg daily for 2 days followed by fludarabine 25 mg/m2 daily for 5 days, followed by a single intravenous infusion of autologous TILs and high-dose interleukin-2 720 000 IU/kg every 8 h). The primary endpoint was objective tumour response in evaluable patients per protocol using Response to Evaluation Criteria in Solid Tumors, version 1.0. An interim analysis of this trial is reported here. The trial is registered at ClinicalTrials.gov , number NCT01814046. Findings From the completed first stage and ongoing expansion stage of this trial, a total of 21 consecutive patients with metastatic uveal melanoma were enrolled between June 7, 2013, and Sept 9, 2016, and received TIL therapy. Seven (35%, 95% CI 16–59) of 20 evaluable patients had objective tumour regression. Among the responders, six patients achieved a partial response, two of which are ongoing and have not reached maximum response. One patient achieved complete response of numerous hepatic metastases, currently ongoing at 21 months post therapy. Three of the responders were refractory to previous immune checkpoint blockade. Common grade 3 or worse toxic effects were related to the lymphodepleting chemotherapy regimen and included lymphopenia, neutropenia, and thrombocytopenia (21 100% patients for each toxicity); anaemia (14 67% patients); and infection (six 29% patients). There was one treatment-related death secondary to sepsis-induced multiorgan failure. Interpretation To our knowledge, this is the first report describing adoptive transfer of autologous TILs to mediate objective tumour regression in patients with metastatic uveal melanoma. These initial results challenge the belief that metastatic uveal melanoma is immunotherapy resistant and support the further investigation of immune-based therapies for this cancer. Refinement of this T-cell therapy is crucial to improve the frequency of clinical responses and the general applicability of this treatment modality. Funding Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.
The National Center for Biotechnology Information (NCBI) provides online information resources for biology, including the GenBank® nucleic acid sequence database and the PubMed® database of citations ...and abstracts published in life science journals. NCBI provides search and retrieval operations for most of these data from 35 distinct databases. The E-utilities serve as the programming interface for most of these databases. New resources include the Comparative Genome Resource (CGR) and the BLAST ClusteredNR database. Resources receiving significant updates in the past year include PubMed, PMC, Bookshelf, IgBLAST, GDV, RefSeq, NCBI Virus, GenBank type assemblies, iCn3D, ClinVar, GTR, dbGaP, ALFA, ClinicalTrials.gov, Pathogen Detection, antimicrobial resistance resources, and PubChem. These resources can be accessed through the NCBI home page at https://www.ncbi.nlm.nih.gov.
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