tbuckley/cabot-search huggingface dataset:
Milestone Analyses of Immune Checkpoint Inhibitors, Targeted Therapy, and Conventional Therapy in Metastatic Non–Small Cell Lung Cancer Trials
Authors: Gideon M. Blumenthal, Lijun Zhang, Hui Zhang, Dickran Kazandjian, Sean Khozin, Shenghui Tang, Kirsten Goldberg, Rajeshwari Sridhara, Patricia Keegan, Richard Pazdur
Journal: JAMA Oncology (2017)

Novel intermediate end points may be useful to detect signals of early activity and prioritize new therapies to treat patients with advanced malignant neoplasms, including metastatic non-small cell lung cancer (mNSCLC).To explore milestone rate, a proposed intermediate end point for immunotherapy trials.Trials submitted to the US Food and Drug Administration with more than 150 patients and in which the intention-to-treat population was assessed were identified.An initial meta-analysis identified 14 randomized clinical trials for treatment of mNSCLC with active controls submitted to the US Food and Drug Administration from January 1, 2003, through December 31, 2013. An additional 11 randomized clinical trials submitted from January 1, 2014, through December 31, 2016 were included.Two investigators abstracted data and pooled data to compare trial-level milestone ratios with conventional end points.Trial-level milestone ratios for milestone rates were calculated for overall response rate (ORR) within 6 months, 9-month progression-free survival (PFS), 9-month overall survival (OS), and 12-month OS. A weighted linear regression model evaluated associations between milestone ratios and hazard ratios (HRs). Experimental and control arms of trials testing immunotherapy, targeted therapy, and other trials were pooled to compare Kaplan-Meier survival estimates in the 3 therapeutic classes.A total of 20 013 unique patients (65.4% male and 34.6% female; mean age, 60 [range, 18-92] years) with advanced lung cancer were identified in 25 unique trials. A moderate association was observed between 12-month OS milestone ratio and OS HR (R2 = 0.80; 95% CI, 0.63-0.91) and 9-month OS milestone ratio and OS HR (R2 = 0.67; 95% CI, 0.49-0.82). No associations were observed between 9-month PFS milestone ratio and OS HR (R2 = 0.19; 95% CI, 0.03-0.49) or 6-month ORR and OS HR (R2 = 0.05; 95% CI, 0.0001-0.31). The aggregated Kaplan-Meier analysis of immunotherapy trials vs chemotherapy revealed an OS HR of 0.69 (95% CI, 0.63-0.75) and PFS HR of 0.82 (95% CI, 0.76-0.89). Targeted therapy trials vs chemotherapy had an OS HR of 0.98 (95% CI, 0.80-1.19) and PFS HR of 0.48 (95% CI, 0.42-0.56).This analysis of milestone rates suggests a moderate association between OS milestones at 12 or 9 months and OS HR but not 9-month PFS or 6-month ORR milestones and OS HR. Although OS at 12 months had the strongest association with OS HR, it may not be the optimal time for future trials, which will increasingly have immunotherapy as the control, deploy new biomarker-enrichment strategies, and likely enroll patients with longer survival. Milestone rates may be useful as a complementary tool to summarize or interpret trial results or as a secondary end point in exploratory studies.
A-PREDICT: A phase II study of axitinib in patients with metastatic renal cell cancer unsuitable for nephrectomy (CRUKE/11/061).
Authors: Rosalie A. Fisher, Andrew Rowan, Mark Stares, Mark F Webster-Smith, Rebecca Lewis, Lucy S Kilburn, David Nicol, Grant Stewart, Agnieszka Michael, Naveen Vasudev, Steve Hazell, Samra Turaljic, Lisa M. Pickering, Martin Eric Gore, Claire Snowdon, Judith M. Bliss, Charles Swanton, James M. G. Larkin
Journal: Journal of Clinical Oncology (2014)

TPS4597 Background: Patients presenting with metastatic renal cell carcinoma (mRCC) who cannot have palliative nephrectomy constitute a poor prognosis group. The vascular endothelial growth factor receptor (VEGFR) inhibitor axitinib has demonstrated a high response rate in mRCC, but its efficacy has not been evaluated in this patient group. Sustained disease control and predicting sensitivity to VEGFR inhibitors may be difficult to achieve in mRCC because of intra-tumour heterogeneity (ITH) and branched, sub-clonal tumour evolution. Methods: A-PREDICT is a single group phase II trial of axitinib in patients with newly diagnosed mRCC not considered suitable for immediate nephrectomy. The primary objective is to assess clinical activity of axitinib in this patient group. The study includes longitudinal sampling of tumour tissue during therapy to investigate the extent of ITH and track evolution of somatic mutational and copy number events. Key inclusion criteria are: clear cell histology and unsuitability for nephrectomy due to locally advanced primary tumour, high burden of metastatic disease or lack of fitness for surgery. Five core biopsies of the primary tumour are taken before the patient starts axitinib (starting dose 5 mg twice daily). After 8 weeks’ treatment, multiple biopsies of the kidney tumour are repeated. Axitinib is continued for as long as the patient benefits. At treatment cessation, the progressing site is biopsied. Nephrectomy is offered to any patient who becomes suitable during the course of the trial and resected specimens are sampled. The primary endpoint is the proportion of participants free from disease progression 6 months from treatment start. The proportion of patients who become operable as a consequence of axitinib will be measured. To end 2013, 17 patients from 7 UK sites were recruited. The target accrual of 99 patients has 90% power to discount an ‘ineffective’ rate of freedom from progression at 6 months of 25% in favour of a rate of at least 40%. Serial tumour & blood samples will be evaluated by a functional genomics approach. Dynamic changes in expression of putative biomarkers during therapy will be compared between patients who respond to axitinib and those who are resistant. Clinical trial information: ISRCTN72679844.
Erratum: Long QT syndrome patients with mutations on the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate: Implications for gene-specific therapy (Circulation (1995) 92 (3381-3386))
Authors: P. J. Schwartz, S. G. Priori, E. H. Locati, C. Napolitano, F. Cantu, J. A. Towbin, M. T. Keating, H. Hammoude, A. M. Brown, L. K. Chen, T. J. Colatsky
Journal: Circulation (1996)
Identifying Genotypes and Phenotypes of Cardiovascular Diseases Using Big Data Analytics
Authors: Chayakrit Krittanawong, Takeshi Kitai
Journal: JAMA Cardiology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Lipogenic transcription factor ChREBP mediates fructose-induced metabolic adaptations to prevent hepatotoxicity
Authors: Deqiang Zhang, Xin Tong, Kyle VanDommelen, Neil Gupta, Kenneth Stamper, Graham F. Brady, Zhuoxian Meng, Jiandie Lin, Liangyou Rui, M. Bishr Omary, Lei Yin
Journal: Journal of Clinical Investigation (2017)

Epidemiologic and animal studies implicate overconsumption of fructose in the development of nonalcoholic fatty liver disease, but the molecular mechanisms underlying fructose-induced chronic liver diseases remain largely unknown. Here, we have presented evidence supporting the essential function of the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP) in mediating adaptive responses to fructose and protecting against fructose-induced hepatotoxicity. In WT mice, a high-fructose diet (HFrD) activated hepatic lipogenesis in a ChREBP-dependent manner; however, in Chrebp-KO mice, a HFrD induced steatohepatitis. In Chrebp-KO mouse livers, a HFrD reduced levels of molecular chaperones and activated the C/EBP homologous protein-dependent (CHOP-dependent) unfolded protein response, whereas administration of a chemical chaperone or Chop shRNA rescued liver injury. Elevated expression levels of cholesterol biosynthesis genes in HFrD-fed Chrebp-KO livers were paralleled by an increased nuclear abundance of sterol regulatory element-binding protein 2 (SREBP2). Atorvastatin-mediated inhibition of hepatic cholesterol biosynthesis or depletion of hepatic Srebp2 reversed fructose-induced liver injury in Chrebp-KO mice. Mechanistically, we determined that ChREBP binds to nuclear SREBP2 to promote its ubiquitination and destabilization in cultured cells. Therefore, our findings demonstrate that ChREBP provides hepatoprotection against a HFrD by preventing overactivation of cholesterol biosynthesis and the subsequent CHOP-mediated, proapoptotic unfolded protein response. Our findings also identified a role for ChREBP in regulating SREBP2-dependent cholesterol metabolism.
DNA Damage and Repair Biomarkers of Immunotherapy Response
Authors: Kent W. Mouw, Michael S. Goldberg, Panagiotis A. Konstantinopoulos, Alan D. D'Andrea
Journal: Cancer Discovery (2017)

DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.
Неалкогольна жирова хвороба печінки: сучасний погляд на патогенез, діагностику та лікування
Authors: V.B. Yagmur
Journal: GASTROENTEROLOGY (2013)

У статті наведені сучасні погляди на причини, механізми розвитку та лікування неалкогольної жирової хвороби печінки (НЖХП). Основними механізмами накопичення жирів у печінці є їх надлишкове надходження, синтез та недостатнє виведення. Крім численних адипоцитокінів, на прогресування жирової хвороби печінки та формування цирозу впливає оксидативний стрес. Для діагностики НЖХП використовують сучасні інструментальні та лабораторні методи дослідження, але найбільш чутливим методом залишається морфологічне дослідження. Головна мета лікування НЖХП — попередження її прогресування. Лікувальні стратегії ґрунтуються на терапії асоційованих метаболічних порушень (діабету, гіперліпідемії), містять рекомендації з модифікації способу життя, застосування інсуліносенситайзерів. У статті розглянуті нові напрямки в патогенетичному лікуванні жирової дистрофії печінки.
Correspondence on Lovell et al.: response to Bornelöv et al.
Authors: Peter V. Lovell, Claudio V. Mello
Journal: Genome biology (2017)

While the analysis of Bornelöv et al. is informative, they provide evidence for the existence of only 3% of the reported avian missing genes set, and thus do not significantly challenge our main findings that specific groups of syntenic protein-coding genes are missing in birds.This is a response to the Correspondence article: https://www.dx.doi.org/10.1186/s13059-017-1231-1.
Robot-assisted Laparoscopic Implantation of Brachytherapy Catheters in Bladder Cancer
Authors: Judith Bosschieter, André N. Vis, Henk G. van der Poel, Luc M. Moonen, Simon Horenblas, Bas W.G. van Rhijn, Bradley R. Pieters, Jakko A. Nieuwenhuijzen, Kees Hendricksen
Journal: European Urology (2017)
Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling
Authors: Mustapha Amyere, Nicole Revencu, Raphaël Helaers, Eleonore Pairet, Eulalia Baselga, Maria Cordisco, Wendy Chung, Josée Dubois, Jean-Philippe Lacour, Loreto Martorell, Juliette Mazereeuw-Hautier, Reed E. Pyeritz, David J. Amor, Annouk Bisdorff, Francine Blei, Hannah Bombei, Anne Dompmartin, David Brooks, Juliette Dupont, Maria Antonia González-Enseñat, Ilona Frieden, Marion Gérard, Malin Kvarnung, Andrea Kwan Hanson-Kahn, Louanne Hudgins, Christine Léauté-Labrèze, Catherine McCuaig, Denise Metry, Philippe Parent, Carle Paul, Florence Petit, Alice Phan, Isabelle Quere, Aicha Salhi, Anne Turner, Pierre Vabres, Asuncion Vicente, Orli Wargon, Shoji Watanabe, Lisa Weibel, Ashley Wilson, Marcia Willing, John B. Mulliken, Laurence M. Boon, Miikka Vikkula
Journal: Circulation (2017)

Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs.We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro.We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs.We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.
Rituximab-containing reduced-intensity conditioning improves progression-free survival following allogeneic transplantation in B cell non-Hodgkin lymphoma
Authors: Narendranath Epperla, Kwang Woo Ahn, Sairah Ahmed, Madan Jagasia, Alyssa DiGilio, Steven M. Devine, Samantha Jaglowski, Vanessa Kennedy, Andrew R. Rezvani, Sonali M. Smith, Anna Sureda, Timothy S. Fenske, Mohamed A. Kharfan-Dabaja, Phillipe Armand, Mehdi Hamadani
Journal: Journal of Hematology & Oncology (2017)

In B cell non-Hodgkin lymphoma (B-NHL), rituximab-containing reduced-intensity conditioning regimens (R-RIC) have been shown to provide favorable outcomes in single-arm studies; however, large multicenter studies comparing R-RIC and non-rituximab-containing reduced-intensity conditioning regimens (nonR-RIC) have not been performed. Using the CIBMTR database, we report the outcomes of R-RIC versus nonR-RIC regimens in B-NHL.We evaluated 1401 adult B-NHL patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who received nonR-RIC (n = 1022) or R-RIC (n = 379) regimens. Graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based approaches.Median follow-up of survivors in the R-RIC and nonR-RIC groups was 47 and 37 months, respectively. On multivariate analysis, no difference was seen between the R-RIC and nonR-RIC cohorts in terms of acute GVHD grade II-IV (RR = 1.14, 95%CI = 0.83-1.56, p = 0.43) or grade III-IV (RR = 1.16, 95%CI = 0.72-1.89, p = 0.54), chronic GVHD (RR = 1.15, 95%CI = 0.92-1.46, p = 0.22), non-relapse mortality (RR = 0.90; 95%CI = 0.67-1.22; p = 0.51), relapse/progression (RR = 0.79; 95%CI = 0.63-1.01; p = 0.055), and mortality (RR = 0.84, 95%CI = 0.69-1.02, p = 0.08) risk. However, R-RIC was associated with a significantly improved progression-free survival (RR = 0.76; 95%CI 0.62-0.92; p = 0.006). On subgroup analysis, mortality benefit was noted in the R-RIC group patients not receiving busulfan-based RIC (RR = 0.76; 95%CI = 0.60-0.96; p = 0.02) and with the use of a higher cumulative rituximab dose (RR = 0.43; 95%CI = 0.21-0.90; p = 0.02).Our analysis shows that inclusion of rituximab in RIC regimens improves progression-free survival in patients with B cell NHL. These data supports the use of R-RIC in B-NHL patients undergoing allo-HCT.
The Dendritic Cell Receptor DNGR-1 Promotes the Development of Atherosclerosis in Mice
Authors: Yacine Haddad, Charlotte Lahoute, Marc Clément, Ludivine Laurans, Sarvenaz Metghalchi, Lynda Zeboudj, Andreas Giraud, Xavier Loyer, Marie Vandestienne, Julien Wain-Hobson, Bruno Esposito, Stephane Potteaux, Hafid Ait-Oufella, Alain Tedgui, Ziad Mallat, Soraya Taleb
Journal: Circulation Research (2017)

Rationale: Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. However, the molecular links between necrosis and the development of atherosclerosis are not completely understood. Clec9a (C-type lectin receptor) or DNGR-1 (dendritic cell NK lectin group receptor-1) is preferentially expressed by the CD8α + subset of dendritic cells (CD8α + DCs) and is involved in sensing necrotic cells. We hypothesized that sensing of necrotic cells by DNGR-1 plays a determinant role in the inflammatory response of atherosclerosis. Objective: We sought to address the impact of total, bone marrow–restricted, or CD8α + DC–restricted deletion of DNGR-1 on atherosclerosis development. Methods and Results: We show that total absence of DNGR-1 in Apoe (apolipoprotein e)–deficient mice ( Apoe −/− ) and bone marrow–restricted deletion of DNGR-1 in Ldlr (low-density lipoprotein receptor)–deficient mice ( Ldlr −/− ) significantly reduce inflammatory cell content within arterial plaques and limit atherosclerosis development in a context of moderate hypercholesterolemia. This is associated with a significant increase of the expression of interleukin-10 (IL-10). The atheroprotective effect of DNGR-1 deletion is completely abrogated in the absence of bone marrow–derived IL-10. Furthermore, a specific deletion of DNGR-1 in CD8α + DCs significantly increases IL-10 expression, reduces macrophage and T-cell contents within the lesions, and limits the development of atherosclerosis. Conclusions: Our results unravel a new role of DNGR-1 in regulating vascular inflammation and atherosclerosis and potentially identify a new target for disease modulation.
Older Adults’ Views and Communication Preferences About Cancer Screening Cessation
Authors: Nancy L. Schoenborn, Kimberley Lee, Craig E. Pollack, Karen Armacost, Sydney M. Dy, John F. P. Bridges, Qian-Li Xue, Antonio C. Wolff, Cynthia Boyd
Journal: JAMA Internal Medicine (2017)

<h3>Importance</h3> Older adults with limited life expectancy are frequently screened for cancer even though it exposes them to risks of screening with minimal benefit. Patient preferences may be an important contributor to continued screening. <h3>Objective</h3> To examine older adults’ views on the decision to stop cancer screening when life expectancy is limited and to identify older adults’ preferences for how clinicians should communicate recommendations to cease cancer screening. <h3>Design, Setting, and Participants</h3> In this semistructured interview study, we interviewed 40 community-dwelling older adults (≥ 65 years) recruited at 4 clinical programs affiliated with an urban academic medical center. <h3>Main Outcomes and Measure</h3> We transcribed the audio recorded discussions and analyzed the transcripts using standard techniques of qualitative content analysis to identify major themes and subthemes. <h3>Results</h3> The participants’ average age was 75.7 years. Twenty-three participants (57.5%) were female; 25 (62.5%) were white. Estimated life expectancy was less than 10 years for 19 participants (47.5%). We identified 3 key themes. First, participants were amenable to stopping cancer screening, especially in the context of a trusting relationship with their clinician. Second, although many participants supported using age and health status to individualize the screening decision, they did not often understand the role of life expectancy. All except 2 participants objected to a Choosing Wisely statement about not recommending cancer screening in those with limited life expectancy, often believing that clinicians cannot accurately predict life expectancy. Third, participants preferred that clinicians explain a recommendation to stop screening by incorporating individual health status but were divided on whether life expectancy should be mentioned. Specific wording of life expectancy was important; many felt the language of “you may not live long enough to benefit from this test” was unnecessarily harsh compared with the more positive messaging of “this test would not help you live longer.” <h3>Conclusions and Relevance</h3> Although research and clinical practice guidelines recommend using life expectancy to inform cancer screening, older adults may not consider life expectancy important in screening and may not prefer to hear about life expectancy when discussing screening. The described communication preferences can help inform future screening discussions. Better delineating patient-centered approaches to discuss screening cessation is an important step toward optimizing cancer screening in older adults.
Network Meta-analysis in Mental Health Research
Authors: Yiftach Roth, Gaby Simon Pell, Abraham Zangen
Journal: JAMA Psychiatry (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Aberrant Phosphorylation of MEF2C Is Dispensable for Hematopoiesis, and Induces Chemotherapy Resistance and Susceptibility to MARK Kinase Inhibition Therapy in Acute Myeloid Leukemia
Authors: Fiona C Brown, Eric Still, Paolo Cifani, Casie Reed, Scott Ficarro, Jie He, Richard Koche, Patrick Bhola, Peter Romanienko, Willie Mark, Andrei V. Krivtsov, Anthony Letai, Nathanael Gray, Jarrod Marto, Scott A. Armstrong, Alex Kentsis
Journal: Blood (2016)