Showing papers by "University of Kansas published in 2018"
Emory University1, University of Pittsburgh2, Riverside Methodist Hospital3, University of Miami4, Autonomous University of Barcelona5, Centre Hospitalier Universitaire de Toulouse6, Baptist Health7, Case Western Reserve University8, University at Buffalo9, Royal Melbourne Hospital10, Rush University Medical Center11, California Pacific Medical Center12, University Health Network13, University Of Tennessee System14, University of Kansas15, University of Barcelona16, Capital District Health Authority17, Kaiser Permanente18, University of California, Los Angeles19, University of California, San Francisco20
TL;DR: Among patients with acute stroke who had last been known to be well 6 to 24 hours earlier and who had a mismatch between clinical deficit and infarct, outcomes for disability at 90 days were better with thrombectomy plus standard care than with standard care alone.
Abstract: BackgroundThe effect of endovascular thrombectomy that is performed more than 6 hours after the onset of ischemic stroke is uncertain. Patients with a clinical deficit that is disproportionately severe relative to the infarct volume may benefit from late thrombectomy. MethodsWe enrolled patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery who had last been known to be well 6 to 24 hours earlier and who had a mismatch between the severity of the clinical deficit and the infarct volume, with mismatch criteria defined according to age (<80 years or ≥80 years). Patients were randomly assigned to thrombectomy plus standard care (the thrombectomy group) or to standard care alone (the control group). The coprimary end points were the mean score for disability on the utility-weighted modified Rankin scale (which ranges from 0 [death] to 10 [no symptoms or disability]) and the rate of functional independence (a score of 0, 1, or 2 on the modified Rankin scale, whic...
3,331 citations
Yale Cancer Center1, Princess Margaret Cancer Centre2, University of Toronto3, Osaka University4, University of Kansas5, University of Pittsburgh6, Indiana University7, NewYork–Presbyterian Hospital8, Pontifical Catholic University of Chile9, Sheba Medical Center10, Tel Aviv University11, University of California, Los Angeles12, University of Chicago13, Tel Aviv Sourasky Medical Center14, Sanford Health15, University of California, San Francisco16, Memorial Sloan Kettering Cancer Center17, Harvard University18, New Generation University College19, Merck & Co.20, Mayo Clinic21
TL;DR: Pembrolizumab monotherapy demonstrated promising activity and manageable safety in patients with advanced gastric or gastroesophageal junction cancer who had previously received at least 2 lines of treatment.
Abstract: Importance Therapeutic options are needed for patients with advanced gastric cancer whose disease has progressed after 2 or more lines of therapy. Objective To evaluate the safety and efficacy of pembrolizumab in a cohort of patients with previously treated gastric or gastroesophageal junction cancer. Design, Setting, and Participants In the phase 2, global, open-label, single-arm, multicohort KEYNOTE-059 study, 259 patients in 16 countries were enrolled in a cohort between March 2, 2015, and May 26, 2016. Median (range) follow-up was 5.8 (0.5-21.6) months. Intervention Patients received pembrolizumab, 200 mg, intravenously every 3 weeks until disease progression, investigator or patient decision to withdraw, or unacceptable toxic effects. Main Outcomes and Measures Primary end points were objective response rate and safety. Objective response rate was assessed by central radiologic review per Response Evaluation Criteria in Solid Tumors, version 1.1, in all patients and those with programmed cell death 1 ligand 1 (PD-L1)–positive tumors. Expression of PD-L1 was assessed by immunohistochemistry. Secondary end points included response duration. Results Of 259 patients enrolled, most were male (198 [76.4%]) and white (200 [77.2%]); median (range) age was 62 (24-89) years. Objective response rate was 11.6% (95% CI, 8.0%-16.1%; 30 of 259 patients), with complete response in 2.3% (95% CI, 0.9%-5.0%; 6 of 259 patients). Median (range) response duration was 8.4 (1.6+ to 17.3+) months (+ indicates that patients had no progressive disease at their last assessment). Objective response rate and median (range) response duration were 15.5% (95% CI, 10.1%-22.4%; 23 of 148 patients) and 16.3 (1.6+ to 17.3+) months and 6.4% (95% CI, 2.6%-12.8%; 7 of 109 patients) and 6.9 (2.4 to 7.0+) months in patients with PD-L1–positive and PD-L1–negative tumors, respectively. Forty-six patients (17.8%) experienced 1 or more grade 3 to 5 treatment-related adverse events. Two patients (0.8%) discontinued because of treatment-related adverse events, and 2 deaths were considered related to treatment. Conclusions and Relevance Pembrolizumab monotherapy demonstrated promising activity and manageable safety in patients with advanced gastric or gastroesophageal junction cancer who had previously received at least 2 lines of treatment. Durable responses were observed in patients with PD-L1–positive and PD-L1–negative tumors. Further study of pembrolizumab for this group of patients is warranted. Trial Registration clinicaltrials.gov Identifier: NCT02335411
1,203 citations
Henry Ford Health System1, Harvard University2, Stanford University3, University of Hasselt4, University of Texas MD Anderson Cancer Center5, Nencki Institute of Experimental Biology6, École Polytechnique Fédérale de Lausanne7, Sage Bionetworks8, Université libre de Bruxelles9, Poznan University of Medical Sciences10, George Washington University11, Cold Spring Harbor Laboratory12, University of Kansas13, University of California, Santa Cruz14, University of North Carolina at Chapel Hill15, Van Andel Institute16
TL;DR: Novel stemness indices for assessing the degree of oncogenic dedifferentiation are provided and it is found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors.
1,099 citations
Oregon Health & Science University1, Howard Hughes Medical Institute2, Oregon State University3, University of Florida4, University of Texas Southwestern Medical Center5, Fox Chase Cancer Center6, University of Utah7, National Institutes of Health8, University of Colorado Denver9, University of Kansas10, University of Miami11, Stanford University12
TL;DR: Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.
Abstract: The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset—accessible through the Beat AML data viewer (Vizome)—that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML. Analyses of samples from patients with acute myeloid leukaemia reveal that drug response is associated with mutational status and gene expression; the generated dataset provides a basis for future clinical and functional studies of this disease.
763 citations
University of South Florida1, Washington University in St. Louis2, University of Texas MD Anderson Cancer Center3, Oregon Health & Science University4, University of Kansas5, Cornell University6, Medical University of South Carolina7, Vanderbilt University8, Northside Hospital9, Harvard University10, University of Michigan11, University of California, Los Angeles12, University of California, San Diego13, University of Rochester14, Fred Hutchinson Cancer Research Center15, Stanford University16
TL;DR: CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML, and improved outcomes were observed across age-groups and AML subtypes.
Abstract: Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML) Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen The primary end point was overall survival Results CPX-351 significantly improved median overall survival versus 7+3 (956 v 595 months; hazard ratio, 069; 95% CI, 052 to 090; one-sided P = 003) Overall remission rate was also significantly higher with CPX-351 versus 7+3 (477% v 333%; two-sided P = 016) Improved outcomes were observed across age-groups and AML subtypes The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351 Early mortality rates with CPX-351 and 7+3 were 59% and 106% (two-sided P = 149) through day 30 and 137% and 212% (two-sided P = 097) through day 60 Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML The safety profile of CPX-351 was similar to that of conventional 7+3 therapy
619 citations
Vanderbilt University1, Van Andel Institute2, University of North Carolina at Chapel Hill3, Memorial Sloan Kettering Cancer Center4, University of Texas MD Anderson Cancer Center5, Massachusetts Institute of Technology6, Harvard University7, Baylor College of Medicine8, University of Kansas9, Brigham and Women's Hospital10, Washington University in St. Louis11, Mayo Clinic12, Leidos13, Yale University14, Oregon Health & Science University15
TL;DR: Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers.
606 citations
TL;DR: In this paper, the discriminating variables and the algorithms used for heavy-flavour jet identification during the first years of operation of the CMS experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, are presented.
Abstract: Many measurements and searches for physics beyond the standard model at the LHC rely on the efficient identification of heavy-flavour jets, i.e. jets originating from bottom or charm quarks. In this paper, the discriminating variables and the algorithms used for heavy-flavour jet identification during the first years of operation of the CMS experiment in proton-proton collisions at a centre-of-mass energy of 13 TeV, are presented. Heavy-flavour jet identification algorithms have been improved compared to those used previously at centre-of-mass energies of 7 and 8 TeV. For jets with transverse momenta in the range expected in simulated events, these new developments result in an efficiency of 68% for the correct identification of a b jet for a probability of 1% of misidentifying a light-flavour jet. The improvement in relative efficiency at this misidentification probability is about 15%, compared to previous CMS algorithms. In addition, for the first time algorithms have been developed to identify jets containing two b hadrons in Lorentz-boosted event topologies, as well as to tag c jets. The large data sample recorded in 2016 at a centre-of-mass energy of 13 TeV has also allowed the development of new methods to measure the efficiency and misidentification probability of heavy-flavour jet identification algorithms. The b jet identification efficiency is measured with a precision of a few per cent at moderate jet transverse momenta (between 30 and 300 GeV) and about 5% at the highest jet transverse momenta (between 500 and 1000 GeV).
454 citations
Massachusetts Institute of Technology1, University of Texas MD Anderson Cancer Center2, Van Andel Institute3, Baylor College of Medicine4, Royal Institute of Technology5, Ghent University6, University of California, San Francisco7, BC Cancer Agency8, University of São Paulo9, Mayo Clinic10, University of Kansas11, University of Washington12, Medical College of Wisconsin13, University of Oklahoma Health Sciences Center14, University of Alabama at Birmingham15, University of Maryland, Baltimore16, Wake Forest Baptist Medical Center17, University of New South Wales18, Cedars-Sinai Medical Center19, New York University20
TL;DR: Using 16 key molecular features, five prognostic subtypes were identified and a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories was developed, raising potential implications for immunotherapy.
421 citations
TL;DR: This Review highlights prodrug design strategies for improved formulation and pharmacokinetic and targeting properties, with a focus on the most recently marketed prodrugs.
Abstract: Prodrugs are molecules with little or no pharmacological activity that are converted to the active parent drug in vivo by enzymatic or chemical reactions or by a combination of the two. Prodrugs have evolved from being serendipitously discovered or used as a salvage effort to being intentionally designed. Such efforts can avoid drug development challenges that limit formulation options or result in unacceptable biopharmaceutical or pharmacokinetic performance, or poor targeting. In the past 10 years, the US Food and Drug Administration has approved at least 30 prodrugs, which accounts for more than 12% of all approved small-molecule new chemical entities. In this Review, we highlight prodrug design strategies for improved formulation and pharmacokinetic and targeting properties, with a focus on the most recently marketed prodrugs. We also discuss preclinical and clinical challenges and considerations in prodrug design and development.
412 citations
TL;DR: The use of ROBINS-I in GRADE assessments may allow for a better comparison of evidence from randomized controlled trials (RCTs) and nonrandomized studies (NRSs) because they are placed on a common metric for risk of bias.
406 citations
TL;DR: A review of models and recent advances in understanding how microbes might interact with one another using quorum sensing discusses some of these models and the potential to guide studies of microbial sociality in natural settings and the design of new medicines and therapies to treat bacterial infections.
Abstract: Many bacteria use a cell-cell communication system called quorum sensing to coordinate population density-dependent changes in behavior. Quorum sensing involves production of and response to diffusible or secreted signals, which can vary substantially across different types of bacteria. In many species, quorum sensing modulates virulence functions and is important for pathogenesis. Over the past half-century, there has been a significant accumulation of knowledge of the molecular mechanisms, signal structures, gene regulons, and behavioral responses associated with quorum-sensing systems in diverse bacteria. More recent studies have focused on understanding quorum sensing in the context of bacterial sociality. Studies of the role of quorum sensing in cooperative and competitive microbial interactions have revealed how quorum sensing coordinates interactions both within a species and between species. Such studies of quorum sensing as a social behavior have relied on the development of "synthetic ecological" models that use nonclonal bacterial populations. In this review, we discuss some of these models and recent advances in understanding how microbes might interact with one another using quorum sensing. The knowledge gained from these lines of investigation has the potential to guide studies of microbial sociality in natural settings and the design of new medicines and therapies to treat bacterial infections.
TL;DR: Conceptual advances of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group guidance to evaluate the certainty of evidence from network meta-analysis (NMA) are described.
Stanford University1, University of Calgary2, Centers for Disease Control and Prevention3, George Washington University4, Cleveland Clinic5, Johns Hopkins University School of Medicine6, University of California, Los Angeles7, University of Florida Health Science Center8, Kaiser Permanente9, Emory University10, Icahn School of Medicine at Mount Sinai11, Princeton University12, University of Texas Health Science Center at San Antonio13, Harvard University14, Loma Linda University15, Cincinnati Children's Hospital Medical Center16, University of Washington17, St. Louis Children's Hospital18, University of Utah19, Children's Hospital of Philadelphia20, University of North Carolina at Chapel Hill21, John H. Stroger, Jr. Hospital of Cook County22, Vanderbilt University23, University of Pittsburgh24, Nationwide Children's Hospital25, The Ohio State University Wexner Medical Center26, Boston Children's Hospital27, University of Miami28, University of California, San Diego29, American Academy of Neurology30, University of Kansas31, University of Virginia32, Penn State Milton S. Hershey Medical Center33
TL;DR: This guideline identifies the best practices for mTBI based on the current evidence and creates user-friendly guideline implementation materials that are concise and actionable.
Abstract: Importance Mild traumatic brain injury (mTBI), or concussion, in children is a rapidly growing public health concern because epidemiologic data indicate a marked increase in the number of emergency department visits for mTBI over the past decade. However, no evidence-based clinical guidelines have been developed to date for diagnosing and managing pediatric mTBI in the United States. Objective To provide a guideline based on a previous systematic review of the literature to obtain and assess evidence toward developing clinical recommendations for health care professionals related to the diagnosis, prognosis, and management/treatment of pediatric mTBI. Evidence Review The Centers for Disease Control and Prevention (CDC) National Center for Injury Prevention and Control Board of Scientific Counselors, a federal advisory committee, established the Pediatric Mild Traumatic Brain Injury Guideline Workgroup. The workgroup drafted recommendations based on the evidence that was obtained and assessed within the systematic review, as well as related evidence, scientific principles, and expert inference. This information includes selected studies published since the evidence review was conducted that were deemed by the workgroup to be relevant to the recommendations. The dates of the initial literature search were January 1, 1990, to November 30, 2012, and the dates of the updated literature search were December 1, 2012, to July 31, 2015. Findings The CDC guideline includes 19 sets of recommendations on the diagnosis, prognosis, and management/treatment of pediatric mTBI that were assigned a level of obligation (ie, must, should, or may) based on confidence in the evidence. Recommendations address imaging, symptom scales, cognitive testing, and standardized assessment for diagnosis; history and risk factor assessment, monitoring, and counseling for prognosis; and patient/family education, rest, support, return to school, and symptom management for treatment. Conclusions and Relevance This guideline identifies the best practices for mTBI based on the current evidence; updates should be made as the body of evidence grows. In addition to the development of the guideline, CDC has created user-friendly guideline implementation materials that are concise and actionable. Evaluation of the guideline and implementation materials is crucial in understanding the influence of the recommendations.
University of Queensland1, University of Salford2, University of Western Australia3, Queensland University of Technology4, University of Lausanne5, Wildfowl & Wetlands Trust6, Canadian Parks and Wilderness Society7, University of Évora8, University of Freiburg9, University of Melbourne10, University of Plymouth11, Mississippi State University12, Australian Institute of Marine Science13, Griffith University14, Zurich University of Applied Sciences/ZHAW15, University of British Columbia16, Duke University17, Finnish Environment Institute18, University of Adelaide19, King Fahd University of Petroleum and Minerals20, IFREMER21, University of California, Davis22, Technical University of Madrid23, National Institute of Water and Atmospheric Research24, Memorial University of Newfoundland25, Royal Society for the Protection of Birds26, University of Kansas27, University of California, Merced28, University of the Sunshine Coast29, Nelson Mandela Metropolitan University30, Swedish University of Agricultural Sciences31, University of Grenoble32, Oregon State University33, Gulf of Maine Research Institute34, University of Toronto35, University of Georgia36, Newcastle University37, Parks Canada38, Humboldt University of Berlin39
TL;DR: Of high importance is the identification of a widely applicable set of transferability metrics, with appropriate tools to quantify the sources and impacts of prediction uncertainty under novel conditions.
Abstract: Predictive models are central to many scientific disciplines and vital for informing management in a rapidly changing world However, limited understanding of the accuracy and precision of models transferred to novel conditions (their ‘transferability’) undermines confidence in their predictions Here, 50 experts identified priority knowledge gaps which, if filled, will most improve model transfers These are summarized into six technical and six fundamental challenges, which underlie the combined need to intensify research on the determinants of ecological predictability, including species traits and data quality, and develop best practices for transferring models Of high importance is the identification of a widely applicable set of transferability metrics, with appropriate tools to quantify the sources and impacts of prediction uncertainty under novel conditions
University of California, Los Angeles1, King's College London2, University of Florida3, Washington University in St. Louis4, Abbott Northwestern Hospital5, University of Michigan6, University of Kansas7, Columbia University Medical Center8, Indiana University9, Overlook Medical Center10, University of Rochester Medical Center11, Rush University Medical Center12, Rutgers University13, University of Cincinnati14, Hackensack University Medical Center15, University of California, Irvine16, Winthrop-University Hospital17, Rhode Island Hospital18, University of Colorado Hospital19, Henry Ford Health System20, University of Texas Health Science Center at San Antonio21, University of Pennsylvania22, University of North Carolina at Chapel Hill23, City of Hope National Medical Center24, Thomas Jefferson University25, St. Joseph Hospital26, Vanderbilt University27, Beth Israel Deaconess Medical Center28, Baylor University Medical Center29, Medical University of South Carolina30, Mount Sinai Hospital31, Dresden University of Technology32, Tufts University33, Stony Brook University34, Université de Sherbrooke35, University of California, San Diego36, Houston Methodist Hospital37, Geisinger Health System38, Kaiser Permanente39, University of Kentucky40, Montreal Neurological Institute and Hospital41, Hofstra University42, University of Washington43, Northwest Biotherapeutics44
TL;DR: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival, and overall adverse events withDCVax were comparable to standard Therapy alone.
Abstract: Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.
Cleveland Clinic1, Washington University in St. Louis2, University of Manitoba3, Mayo Clinic4, University of California, San Francisco5, University of Kansas6, University of Louisville7, St. Luke's University Health Network8, University of Virginia9, Wayne State University10, University of Southern California11, Kaiser Permanente12, National Multiple Sclerosis Society13, Heart Rhythm Society14, American Academy of Neurology15, University of Calgary16
TL;DR: The development of a guideline covering 23 medications and 143 randomized trials, as well as 30-plus recommendations and multiple development steps, is complex to the point of being overwhelming.
Abstract: Objective To develop recommendations for disease-modifying therapy (DMT) for multiple sclerosis (MS). Methods A multidisciplinary panel developed DMT recommendations, integrating findings from a systematic review; followed an Institute of Medicine–compliant process to ensure transparency and patient engagement; and developed modified Delphi consensus–based recommendations concerning starting, switching, and stopping DMTs pertinent to people with relapsing-remitting MS, secondary progressive MS, primary progressive MS, and clinically isolated syndromes of demyelination. Recommendations were supported by structured rationales, integrating evidence from one or more sources: systematic review, related evidence (evidence not from the systematic review), principles of care, and inference from evidence. Results Thirty recommendations were developed: 17 on starting DMTs, including recommendations on who should start them; 10 on switching DMTs if breakthrough disease develops; and 3 on stopping DMTs. Recommendations encompassed patient engagement strategies and individualization of treatment, including adherence monitoring and disease comorbidity assessment. The panel also discussed DMT risks, including counseling about progressive multifocal leukoencephalopathy risk in people with MS using natalizumab, fingolimod, rituximab, ocrelizumab, and dimethyl fumarate; and made suggestions for future research to evaluate relative merits of early treatment with higher potency DMTs vs standard stepped-care protocols, DMT comparative effectiveness, optimal switching strategies, long-term effects of DMT use, definitions of highly active MS, and effects of treatment on patient-specified priority outcomes. This guideline reflects the complexity of decision-making for starting, switching, or stopping MS DMTs. The field of MS treatment is rapidly changing; the Academy of Neurology development process includes planning for future updates.
University of Minnesota1, Stony Brook University2, University of Notre Dame3, Macquarie University4, University of North Texas5, University at Buffalo6, University of Kentucky7, University of Vermont8, University of Toronto9, University of South Florida10, University of Maryland, Baltimore11, Southern Methodist University12, University of Hawaii13, College of William & Mary14, Ghent University15, University of Utah16, University of Michigan17, Columbia University18, University of Kansas19, Pennsylvania State University20, University of California, Davis21, Georgia State University22, University of Iowa23, University of Georgia24, Texas A&M University25, Oklahoma State University–Stillwater26, University of Groningen27, University of Liverpool28, Florida State University29, Uniformed Services University of the Health Sciences30, Maastricht University31, Bryn Mawr College32, Purdue University33, University of Otago34, University of Maryland, College Park35, University of Arizona36, University of New South Wales37, Northwestern University38, Emory University39, Oak Ridge National Laboratory40, University of Pittsburgh41, Vanderbilt University42
TL;DR: The aims and current foci of the HiTOP Consortium, a group of 70 investigators working together to study empirical classification of psychopathology, are described, which pertain to continued research on the empirical organization of psychopathological constructs; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic.
TL;DR: The regulation of FBXW7, its role in oncogenesis, and the clinical implications and prognostic value of loss of function of FBxW7 in human cancers are discussed.
Abstract: The ubiquitin-proteasome system (UPS) is involved in multiple aspects of cellular processes, such as cell cycle progression, cellular differentiation, and survival (Davis RJ et al., Cancer Cell 26:455-64, 2014; Skaar JR et al., Nat Rev Drug Discov 13:889-903, 2014; Nakayama KI and Nakayama K, Nat Rev Cancer 6:369-81, 2006). F-box and WD repeat domain containing 7 (FBXW7), also known as Sel10, hCDC4 or hAgo, is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. FBXW7 is a critical tumor suppressor and one of the most commonly deregulated ubiquitin-proteasome system proteins in human cancer. FBXW7 controls proteasome-mediated degradation of oncoproteins such as cyclin E, c-Myc, Mcl-1, mTOR, Jun, Notch and AURKA. Consistent with the tumor suppressor role of FBXW7, it is located at chromosome 4q32, a genomic region deleted in more than 30% of all human cancers (Spruck CH et al., Cancer Res 62:4535-9, 2002). Genetic profiles of human cancers based on high-throughput sequencing have revealed that FBXW7 is frequently mutated in human cancers. In addition to genetic mutations, other mechanisms involving microRNA, long non-coding RNA, and specific oncogenic signaling pathways can inactivate FBXW7 functions in cancer cells. In the following sections, we will discuss the regulation of FBXW7, its role in oncogenesis, and the clinical implications and prognostic value of loss of function of FBXW7 in human cancers.
Albert M. Sirunyan1, Robin Erbacher2, C. A. Carrillo Montoya3, Wagner Carvalho4 +2355 more•Institutions (153)
TL;DR: In this paper, the performance of the modified system is studied using proton-proton collision data at center-of-mass energy √s=13 TeV, collected at the LHC in 2015 and 2016.
Abstract: The CMS muon detector system, muon reconstruction software, and high-level trigger underwent significant changes in 2013–2014 in preparation for running at higher LHC collision energy and instantaneous luminosity. The performance of the modified system is studied using proton-proton collision data at center-of-mass energy √s=13 TeV, collected at the LHC in 2015 and 2016. The measured performance parameters, including spatial resolution, efficiency, and timing, are found to meet all design specifications and are well reproduced by simulation. Despite the more challenging running conditions, the modified muon system is found to perform as well as, and in many aspects better than, previously. We dedicate this paper to the memory of Prof. Alberto Benvenuti, whose work was fundamental for the CMS muon detector.
University of California, San Diego1, Oregon Health & Science University2, Tulane Medical Center3, Columbia University4, University of Western Ontario5, University of Washington6, University of Kansas7, University of Pennsylvania8, National Institutes of Health9, University of São Paulo10, McGill University11
TL;DR: Concerted efforts to understand Lp (a) pathophysiology, together with diagnostic and therapeutic advances, are required to reduce Lp(a)-mediated risk of CVD and CAVD.
TL;DR: A historical account of the development of ensemble docking is given and some pertinent methodological advances in conformational sampling are discussed.
TL;DR: This review covers molecules that might act as the biomarkers of Parkinson's disease and suggests that microRNA-based analysis may bring considerable progress, especially if it is combined with α-syn data.
Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder caused mainly by lack of dopamine in the brain. Dopamine is a neurotransmitter involved in movement, motivation, memory, and other functions; its level is decreased in PD brain as a result of dopaminergic cell death. Dopamine loss in PD brain is a cause of motor deficiency and, possibly, a reason of the cognitive deficit observed in some PD patients. PD is mostly not recognized in its early stage because of a long latency between the first damage to dopaminergic cells and the onset of clinical symptoms. Therefore, it is very important to find reliable molecular biomarkers that can distinguish PD from other conditions, monitor its progression, or give an indication of a positive response to a therapeutic intervention. PD biomarkers can be subdivided into four main types: clinical, imaging, biochemical, and genetic. For a long time protein biomarkers, dopamine metabolites, amino acids, etc. in blood, serum, cerebrospinal liquid (CSF) were considered the most promising. Among the candidate biomarkers that have been tested, various forms of α-synuclein (α-syn), i.e., soluble, aggregated, post-translationally modified, etc. were considered potentially the most efficient. However, the encouraging recent results suggest that microRNA-based analysis may bring considerable progress, especially if it is combined with α-syn data. Another promising analysis is the advanced metabolite profiling of body fluids, called "metabolomics" which may uncover metabolic fingerprints specific for various stages of PD. Conventional pharmacological treatment of PD is based on the replacement of dopamine using dopamine precursors (levodopa, L-DOPA, L-3,4 dihydroxyphenylalanine), dopamine agonists (amantadine, apomorphine) and MAO-B inhibitors (selegiline, rasagiline), which can be used alone or in combination with each other. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. This review covers molecules that might act as the biomarkers of PD. Then, PD risk factors (including genetics and non-genetic factors) and PD treatment options are discussed.
TL;DR: In this paper, CdS nanoparticles were deposited on the g-C3N4 nanosheets by photodeposition and chemical deposition methods for comparison, and the results illustrate that the electro...
Abstract: Heterojunction and direct Z-scheme nanostructures are two typical representatives of an efficient photocatalyst, which is composed of two semiconductors. However, it is a great challenge to construct each of them on purpose. The photodeposition technique can be a potentially powerful tool to regulate the electron flow direction for constructing these nanostructures. In this report, CdS nanoparticles were deposited on the g-C3N4 nanosheets by photodeposition and chemical deposition methods for comparison. In the photodeposition case, PL and charge flow tracking demonstrate that a type II heterojunction is constructed because CdS is selectively deposited at the electron transfer site of g-C3N4, which leads to the photoexcited electron from g–C3N4 tending to transfer to CdS in the composites. In the latter, the CdS is randomly deposited onto the g-C3N4 nanosheets through chemical deposition. There is no preferred site for deposition or charge transfer in the composite. The results illustrate that the electro...
University of California, Los Angeles1, University of Bologna2, Taipei Veterans General Hospital3, Chiba University4, Pierre-and-Marie-Curie University5, University of Florida6, Mount Sinai Hospital7, University of Kansas8, Bayer Corporation9, Bayer10, Bayer HealthCare Pharmaceuticals11, University of Barcelona12
TL;DR: Examination of characteristics and outcomes of patients with hepatocellular carcinoma who were treated with regorafenib after they had disease progression during sorafenIB treatment show that regoracenib conferred a clinical benefit regardless of the last sorafanib dose or TTP on prior sorafinib.
TL;DR: This review focuses on the functional use of exosomes in therapy and the potential advantages and challenges in using exosome for therapeutic purposes.
Abstract: Extracellular vesicles (EVs) comprise apoptotic bodies, microvesicles and exosomes, and they perform as key regulators in cell-to-cell communication in normal as well as diseased states. EVs contain natural cargo molecules, such as miRNA, mRNA and proteins, and transfer these functional cargos to neighboring cells or more distant cells through circulation. These functionally active molecules then affect distinct signaling cascades. The message conveyed to the recipient cells is dependent upon the composition of the EV, which is determined by the parent cell and the EV biogenesis. Because of their properties such as increased stability in circulation, biocompatibility, low immunogenicity and toxicity, EVs have drawn attention as attractive delivery systems for therapeutics. This review focuses on the functional use of exosomes in therapy and the potential advantages and challenges in using exosomes for therapeutic purposes.
TL;DR: In this phase 2 trial, cabozantinib treatment significantly prolonged PFS per IRC compared with sunitinib as initial systemic therapy for advanced RCC of poor or intermediate risk.
TL;DR: In this article, a measurement of the H→ττ signal strength is performed using events recorded in proton-proton collisions by the CMS experiment at the LHC in 2016 at a center-of-mass energy of 13TeV.
University of North Carolina at Chapel Hill1, Norwich University2, University of Hamburg3, The Chinese University of Hong Kong4, University of Cyprus5, University College Dublin6, Purdue University7, Hong Kong University of Science and Technology8, University of São Paulo9, Sun Yat-sen University10, Ghent University11, University of Kansas12, China Meteorological Administration13, National Center for Atmospheric Research14, University of Reading15
TL;DR: The World Urban Database and Access Portal Tools (WUDAPT) as mentioned in this paper is an international community-based initiative to acquire and disseminate climate relevant data on the physical geographies of cities for modeling and analysis purposes.
Abstract: The World Urban Database and Access Portal Tools (WUDAPT) is an international community-based initiative to acquire and disseminate climate relevant data on the physical geographies of cities for modeling and analysis purposes. The current lacuna of globally consistent information on cities is a major impediment to urban climate science toward informing and developing climate mitigation and adaptation strategies at urban scales. WUDAPT consists of a database and a portal system; its database is structured into a hierarchy representing different levels of detail, and the data are acquired using innovative protocols that utilize crowdsourcing approaches, Geowiki tools, freely accessible data, and building typology archetypes. The base level of information (L0) consists of local climate zone (LCZ) maps of cities; each LCZ category is associated with a range of values for model-relevant surface descriptors (roughness, impervious surface cover, roof area, building heights, etc.). Levels 1 (L1) and 2 (L2) will provide specific intra-urban values for other relevant descriptors at greater precision, such as data morphological forms, material composition data, and energy usage. This article describes the status of the WUDAPT project and demonstrates its potential value using observations and models. As a community-based project, other researchers are encouraged to participate to help create a global urban database of value to urban climate scientists.
McMaster University1, Ottawa Hospital Research Institute2, University of Geneva3, Geneva College4, Montefiore Medical Center5, Rockyview General Hospital6, University of Calgary7, Indiana University – Purdue University Indianapolis8, University of Illinois at Chicago9, University of Missouri–Kansas City10, Loyola University Medical Center11, University of Kansas12
TL;DR: These evidence-based guidelines are intended to support patients, clinicians, and health care professionals in VTE diagnosis by recommending using D-dimer as the initial test and research is needed on new diagnostic modalities and on clinical decision rules for patients with suspected recurrent VTE.
University of Kentucky1, University of Maryland, College Park2, University of Utah3, Stowers Institute for Medical Research4, Heidelberg University5, University of Kansas6, University of Washington7, University of Cape Town8, University of Oxford9, Francis Crick Institute10, Benaroya Research Institute11, University of California, Merced12
TL;DR: A new assembly of the sea lamprey germline genome identifies genomic regions that are systematically eliminated from somatic tissue during early development and gives new insight into vertebrate evolution.
Abstract: The sea lamprey (Petromyzon marinus) serves as a comparative model for reconstructing vertebrate evolution. To enable more informed analyses, we developed a new assembly of the lamprey germline genome that integrates several complementary data sets. Analysis of this highly contiguous (chromosome-scale) assembly shows that both chromosomal and whole-genome duplications have played significant roles in the evolution of ancestral vertebrate and lamprey genomes, including chromosomes that carry the six lamprey HOX clusters. The assembly also contains several hundred genes that are reproducibly eliminated from somatic cells during early development in lamprey. Comparative analyses show that gnathostome (mouse) homologs of these genes are frequently marked by polycomb repressive complexes (PRCs) in embryonic stem cells, suggesting overlaps in the regulatory logic of somatic DNA elimination and bivalent states that are regulated by early embryonic PRCs. This new assembly will enhance diverse studies that are informed by lampreys' unique biology and evolutionary/comparative perspective.