tbuckley/cabot-search huggingface dataset:
Novel carcinoembryonic antigen T-cell bispecific (CEA-TCB) antibody: Preliminary clinical data as a single agent and in combination with atezolizumab in patients with metastatic colorectal cancer (mCRC)
Authors: G. Argilés, J. Saro, N.H. Segal, I. Melero, W. Ros, A. Marabelle, M.E. Rodriguez, J. Albanell, E. Calvo, V. Moreno, J.M. Cleary, P. Eder, L. Paz-Ares, H. Hurwitz, M. Bacac, M. Perro, S. Bouseida, F. Sandoval, D. Sabanes Bove, S. Sreckovic, C. Jamois, A. Silva, C. Klein, P. Umana, V. Karanikas, J. Tabernero
Journal: Annals of Oncology (2017)
Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort.
Journal: Diabetes Care (1999)

OBJECTIVE: The Diabetes Control and Complications Trial (DCCT) demonstrated the powerful impact of glycemic control on the early manifestations of microvascular complications. Contemporary prospective data on the evolution of macrovascular and late microvascular complications of type 1 diabetes are limited. The Epidemiology of Diabetes Interventions and Complications (EDIC) study is a multicenter, longitudinal, observational study designed to use the well-characterized DCCT cohort of &amp;gt; 1,400 patients to determine the long-term effects of prior separation of glycemic levels on micro- and macrovascular outcomes. RESEARCH DESIGN AND METHODS: Using a standardized annual history and physical examination, 28 EDIC clinical centers that were DCCT clinics will follow the EDIC cohort for 10 years. Annual evaluation also includes resting electrocardiogram. Doppler ultrasound measurements of ankle/arm blood pressure, and screening for nephropathy. At regular intervals, a timed 4-h urine is collected, lipid profiles are obtained, and stereoscopic fundus photographs are taken. In addition, dual B-mode Doppler ultrasound scans of the common and internal carotid arteries will be performed at years 1 and 6 and at study end. RESULTS: Written informed consent was obtained from 96% of the DCCT subjects. The participants, compared with nonparticipants, tended to have better glycemic control at the completion of the DCCT and were more likely to have their diabetes care provided by DCCT personnel. The EDIC baseline measurement stratified by sex delineates multiple cardiovascular disease risk factor differences such as age (older in men), waist-to-hip ratio (higher in men). HDL cholesterol (lower in men), hypertension (more prevalent in men), and maximum intimal-medial thickness of common and internal carotid arteries (thicker in men). Of the original conventional treatment group, 69% have changed to continuous subcutaneous insulin infusion or multiple daily injections. Although the mean HbA1c difference between the intensive and conventional treatment groups narrowed at EDIC years 1 and 2, HbA1c remained significantly lower in the intensive group. Of all expected clinic visits, 95% were completed, and the quality of EDIC data is very similar to that observed in the DCCT. CONCLUSIONS: Although obvious problems exist in extended follow-up studies of completed clinical trials, these are balanced by the value of continued systematic observation of the DCCT cohort. In contrast to other epidemiologic studies, EDIC will provide 1) definitive data on type 1 as distinct from type 2 diabetes; 2) reliance on prospective rather than on cross-sectional analysis; 3) long-term follow-up in a large population; 4) consistent use of objective, reliable measures of outcomes and glycemia; and 5) observation of patients from before the onset of complications.
Natural Killing—Present and Future (Summary of Workshop on Natural Killer Cells)
Authors: Hillel S. Koren, Ph.D., Ronald B. Herberman, M.D.
Journal: JNCI Journal of the National Cancer Institute (1983)

Natural Killing—Present and Future (Summary of Workshop on Natural Killer Cells) Get access Hillel S. Koren, Ph.D., Hillel S. Koren, Ph.D. Department of Microbiology and Immunology Duke University Medical Center, Box 3010 Durham, North Carolina 27710 Search for other works by this author on: Oxford Academic PubMed Google Scholar Ronald B. Herberman, M.D. Ronald B. Herberman, M.D. Biologics Response Modifiers Program Biological Therapeutics Branch Division of Cancer Treatment National Cancer Institute National Institutes of Health Public Health Service U.S. Department of Health and Human Services, Frederick, Maryland 21701 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 70, Issue 4, April 1983, Pages 785–786, https://doi.org/10.1093/jnci/70.4.785 Published: 01 April 1983
Trastuzumab in adjuvant breast cancer therapy: A model based cost-effectiveness analysis
Authors: J. Norum, J. A. Olsen
Journal: Journal of Clinical Oncology (2006)

628 Background: Trastuzumab has shown activity in patients with early breast cancer that overexpress HER2. However, significant resources have to be allocated to finance this therapy, therefore its cost-effectiveness is called for and treatment’s value for money should be calculated. We aimed to evaluate the marginal cost effectiveness of trastuzumab in adjuvant treatment of HER2 positive early breast cancer in a model based cost-effectiveness-analysis (CEA). Methods: A breast cancer treatment model was set up. Societal costs were calculated according to Norwegian prices as in September 2005 and converted to Euros at the rate of 1Euro = 7.81 NOK. Life expectancy data were based on the literature and prolonged according to qualified guess (10% and 20% improved overall survival (OS). The comparator was the present practice, the FEC 100 regimen alone. The human capital approach was employed and a sensitivity analysis was added. Results: The median raised cost per patient treated was calculated at Euro16,713 - 35,714. The yielding cost per life year saved was in the range between Euro 5,571 and 32,616, depending on survival gain (10% or 20% improved OS) and discount rate (0% or 3%) employed. The sensitivity analyses documented survival gain, discount rate and price of trastuzumab the major factors influencing cost-effectiveness ratio. Conclusion: The economic evaluation indicates trastuzumab cost effective in adjuvant breast cancer treatment. No significant financial relationships to disclose.
The ubiquitin-conjugating enzyme UBE2O modulates c-Maf stability and induces myeloma cell apoptosis
Authors: Yujia Xu, Zubin Zhang, Jie Li, Jiefei Tong, Biyin Cao, Paul Taylor, Xiaowen Tang, Depei Wu, Michael F. Moran, Yuanying Zeng, Xinliang Mao
Journal: Journal of Hematology & Oncology (2017)

UBE2O is proposed as a ubiquitin-conjugating enzyme, but its function was largely unknown. Mass spectrometry was applied to identify c-Maf ubiquitination-associated proteins. Immunoprecipitation was applied for c-Maf and UBE2O interaction. Immunoblotting was used for Maf protein stability. Luciferase assay was used for c-Maf transcriptional activity. Lentiviral infections were applied for UBE2O function in multiple myeloma (MM) cells. Flow cytometry and nude mice xenografts were applied for MM cell apoptosis and tumor growth assay, respectively. UBE2O was found to interact with c-Maf, a critical transcription factor in MM, by the affinity purification/tandem mass spectrometry assay and co-immunoprecipitation assays. Subsequent studies showed that UBE2O mediated c-Maf polyubiquitination and degradation. Moreover, UBE2O downregulated the transcriptional activity of c-Maf and the expression of cyclin D2, a typical gene modulated by c-Maf. DNA microarray revealed that UBE2O was expressed in normal bone marrow cells but downregulated in MGUS, smoldering MM and MM cells, which was confirmed by RT-PCR in primary MM cells, suggesting its potential role in myeloma pathophysiology. When UBE2O was restored, c-Maf protein in MM cells was significantly decreased and MM cells underwent apoptosis. Furthermore, the human MM xenograft in nude mice showed that re-expression of UBE2O delayed the growth of myeloma xenografts in nude mice in association with c-Maf downregulation and activation of the apoptotic pathway. UBE2O mediates c-Maf polyubiquitination and degradation, induces MM cell apoptosis, and suppresses myeloma tumor growth, which provides a novel insight in understanding myelomagenesis and UBE2O biology.
OOTR-N006: mTOR inhibition with everolimus in invasive breast cancer patients after pre-operative use of anthracycline and/or taxane-based chemotherapy.
Authors: Louis W.C. Chow, Seock-Ah Im, Ting Ying Ng, Min Hyuk Lee, Cheol Wan Lim, Sung Yong Kim
Journal: Journal of Clinical Oncology (2016)

e12507 Background: Inhibition of mTOR, a downstream mediator of the PI3K/AKT signaling pathway, is a significant anti-cancer approach in response to PI3K/AKT activation, as demonstrated clinically with everolimus in the BOLERO-2 study. mTOR inhibition could potentially reverse resistance caused by pTEN mutation/AKT activation to chemotherapeutic agents. Methods: In a randomised controlled pilot-study investigating signals involved in chemotherapy-resistance, 45 evaluable patients in Hong Kong and South Korea with pathologically confirmed invasive breast cancer, a tumour greater than 3 cm at diagnosis, and measurable residual disease after 1 to 2 lines of anthracycline- and/or taxane-based neo-adjuvant chemotherapy (NAT), were randomised 1:1 within 1 week of NAT completion to either undergo observation or receive 3 weeks of everolimus 10mg/d before surgery. Primary objective was to obtain biological samples and analyse biomarkers. Therefor, pre- and post-treatment tissue samples were analysed by Foundation Medicine Next Gene Sequencing (NGS). Results: 29 subjects had evaluable samples for NGS. The mean number of aberrations such as gene copy number amplifications, somatic variations and rearrangements detected in the observation arm at time of surgery (n = 8) was 22.1. A reduction of aberrations compared to observation arm was noted in the everolimus arm (n = 13), where the mean number of aberrations at surgery was 16.2. Reduction in gene aberrations of PIK3 and AKT family was observed in the everolimus arm. Mean Ki67 at time of surgery was similar in both arms. 7 patients had confirmed pathological complete response (observation: 3; everolimus: 4). Adverse events were similar in both arms, though mucositis/stomatitis seemed to have slightly higher incidence in the active group. Conclusions: Three weeks of everolimus after NAT is safe and tolerable. There is a signal that everolimus reduces the overall number of aberrations as well as gene aberrations in PIK3 and AKT family genes upstream of mTor. Further investigation of these genes in relation to mTor inhibition after NAT can provide further clarity on its role in reversing chemotherapy-resistance. Clinical trial information: NCT01088893.
ITACA: A new validated international erythropoietic stimulating agent‐response score that further refines the predictive power of previous scoring systems
Authors: Rena Buckstein, Enrico Balleari, Richard Wells, Valeria Santini, Alessandro Sanna, Chiara Salvetti, Elena Crisà, Bernardino Allione, Paolo Danise, Carlo Finelli, Marino Clavio, Antonella Poloni, Flavia Salvi, Daniela Cilloni, Esther Natalie Oliva, Pellegrino Musto, Brett Houston, Nancy Zhu, Michelle Geddes, Heather Leitch, Brian Leber, Mitchell Sabloff, Thomas J. Nevill, Karen W. Yee, John M. Storring, Janika Francis, Luca Maurillo, Roberto Latagliata, Maria Antonietta Aloe Spiriti, Alessandro Andriani, Anna Lina Piccioni, Luana Fianchi, Susanna Fenu, Svitlana Gumenyuk, Francesco Buccisano
Journal: American Journal of Hematology (2017)

In 'real-life', the Nordic score guides Erythropoietic stimulating agent (ESA) use in lower-risk myelodysplastic syndrome (MDS) with predicted response rates of 25% or 74%. As new treatments emerge, a more discriminating score is needed.To validate existing ESA predictive scores and develop a new score that identifies non-responders.ESA-treated patients were identified in 3 MDS registries in Italy and Canada (FISM 555, GROM 233, and MDS-CAN 208). Clinical and disease-related variables were captured. Nordic, MDS-CAN, and IPSS-R-based ESA scores were calculated and documented ESA responses compared.996 ESA-treated patients were identified. Overall response rate (ORR) was 59%. The database was randomly divided into balanced derivation (n = 463) and validation (n = 462) cohorts. By multivariate analysis, transfusion independence, erythropoietin (EPO) level <100 IU/L, and IPSS low-risk were independently predictive of response. Assigning a score of 1 to each resulted in a scoring system of 0-3 with response rates of 23%, 43%, 67%, and 85%. ORR was concordant in the validation cohort. The 'ITACA' score had the highest discriminating power of response.ITACA is an internally-validated predictive SS of ESA response in real-life 'good risk' MDS patients derived from a large international dataset that surpasses others. The incorporation of biologic markers to better identify non-responders is still needed.
Genetic Deletion of NADPH Oxidase 1 Rescues Microvascular Function in Mice With Metabolic Disease
Authors: Jennifer A. Thompson, Sebastian Larion, James D. Mintz, Eric J. Belin de Chantemèle, David J. Fulton, David W. Stepp
Journal: Circulation Research (2017)

Early vascular changes in metabolic disease that precipitate the development of cardiovascular complications are largely driven by reactive oxygen species accumulation, yet the extent to which excess reactive oxygen species derive from specific NADPH oxidase isoforms remains ill defined.Identify the role of Nox1 in the development of microvascular dysfunction in metabolic disease.Four genotypes were generated by breeding Nox1 knockout mice with db/db mice: lean (HdbWnox1), lean Nox1 knockout (HdbKnox1), obese (KdbWnox1), and obese KK (KdbKnox1). The degree of adiposity, insulin resistance, and dyslipidemia in KW mice was not influenced by Nox1 deletion as determined by nuclear magnetic resonance spectroscopy, glucose tolerance tests, and plasma analyses. Endothelium-dependent responses to acetylcholine in pressurized mesenteric arteries were reduced in KW versus HW (P<0.01), whereas deletion of Nox1 in KW mice normalized dilation. Vasodilator responses after inhibition of NO synthase blunted acetylcholine responses in KK and lean controls, but had no impact in KW, attributing recovered dilatory capacity in KK to normalization of NO. Acetylcholine responses were improved (P<0.05) with Tempol, and histochemistry revealed oxidative stress in KW animals, whereas Tempol had no impact and reactive oxygen species staining was negligible in KK. Blunted dilatory responses to an NO donor and loss of myogenic tone in KW animals were also rescued with Nox1 deletion.Nox1 deletion reduces oxidant load and restores microvascular health in db/db mice without influencing the degree of metabolic dysfunction. Therefore, targeted Nox1 inhibition may be effective in the prevention of vascular complications.
Longitudinal Assessment of Children with Mild Cystic Fibrosis Using Hyperpolarized Gas Lung Magnetic Resonance Imaging and Lung Clearance Index
Authors: Laurie Smith, Helen Marshall, Ina Aldag, Felix Horn, Guilhem Collier, David Hughes, Noreen West, Alex Horsley, Chris J. Taylor, Jim Wild
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
An Unbiased High-Throughput Screen to Identify Novel Effectors That Impact on Cardiomyocyte Aggregate Levels
Authors: Patrick M. McLendon, Gregory Davis, James Gulick, Sonia R. Singh, Na Xu, Nathan Salomonis, Jeffery D. Molkentin, Jeffrey Robbins
Journal: Circulation Research (2017)

Postmitotic cells, such as cardiomyocytes, seem to be particularly susceptible to proteotoxic stimuli, and large, proteinaceous deposits are characteristic of the desmin-related cardiomyopathies and crystallin cardiomyopathic diseases. Increased activity of protein clearance pathways in the cardiomyocyte, such as proteasomal degradation and autophagy, has proven to be beneficial in maintaining cellular and cardiac function in the face of multiple proteotoxic insults, holding open the possibility of targeting these processes for the development of effective therapeutics.Here, we undertake an unbiased, total genome screen for RNA transcripts and their protein products that affect aggregate accumulations in the cardiomyocytes.Primary mouse cardiomyocytes that accumulate aggregates as a result of a mutant CryAB (αB-crystallin) causative for human desmin-related cardiomyopathy were used for a total genome-wide screen to identify gene products that affected aggregate formation. We infected cardiomyocytes using a short hairpin RNA lentivirus library in which the mouse genome was represented. The screen identified multiple candidates in many cell signaling pathways that were able to mediate significant decreases in aggregate levels.Subsequent validation of one of these candidates, Jak1 (Janus kinase 1), a tyrosine kinase of the nonreceptor type, confirmed the usefulness of this approach in identifying previously unsuspected players in proteotoxic processes.
Serum androgen levels and their relation to performance in track and field: mass spectrometry results from 2127 observations in male and female elite athletes
Authors: Stéphane Bermon, Pierre-Yves Garnier
Journal: British Journal of Sports Medicine (2017)

Objective To describe and characterise serum androgen levels and to study their possible influence on athletic performance in male and female elite athletes. Methods 2127 observations of competition best performances and mass spectrometry-measured serum androgen concentrations, obtained during the 2011 and 2013 International Association of Athletics Federations World Championships, were analysed in male and female elite track and field athletes. To test the influence of serum androgen levels on performance, male and female athletes were classified in tertiles according to their free testosterone (fT) concentration and the best competition results achieved in the highest and lowest fT tertiles were then compared. Results The type of athletic event did not influence fT concentration among elite women, whereas male sprinters showed higher values for fT than male athletes in other events. Men involved in all throwing events showed significantly (p&lt;0.05) lower testosterone and sex hormone binding globulin than men in other events. When compared with the lowest female fT tertile, women with the highest fT tertile performed significantly (p&lt;0.05) better in 400 m, 400 m hurdles, 800 m, hammer throw, and pole vault with margins of 2.73%, 2.78%, 1.78%, 4.53%, and 2.94%, respectively. Such a pattern was not found in any of the male athletic events. Conclusion Female athletes with high fT levels have a significant competitive advantage over those with low fT in 400 m, 400 m hurdles, 800 m, hammer throw, and pole vault.
Mortality and acute exacerbation of COPD: a pilot study on the influence of myocardial injury
Authors: Said Laribi, Chris J. Pemberton, Lyndsey Kirwan, Semir Nouira, Kenan Turkdogan, Mehmet Birhan Yilmaz, Richard W. Troughton, Etienne Gayat, Mercedes Rivas-Lasarte, Malha Sadoune, Zaid Sabti, Erwin Hansconrad, Justina Motiejunaite, Patrick Plaisance, Agim Beshiri, Wenjia Chen, Corinne Collet, J. Mark FitzGerald, Christian Mueller, Jean-Marie Launay, Mark Richards, Alexandre Mebazaa
Journal: European Respiratory Journal (2017)

Acute exacerbations of chronic obstructive pulmonary disease (COPD) punctuate important disease progression [1]. In-hospital mortality rates for acute exacerbations of COPD vary between 2.5% to 24.5% [2–4]. An integrated clinical score, CURB-65, has been proposed to predict in-hospital and 30-day mortality in acute exacerbations of COPD [5, 6]. According to death-certificate data the most common proximate cause of death in COPD is cardiac disease [7]. An association between elevated cardiac high-sensitivity troponin (hs-cTn) at admission and mortality has been reported in acute exacerbations of COPD [8, 9]. Copeptin has also been associated with poor clinical outcomes and mortality of acute exacerbations of COPD [10], as well as pneumonia [11] and myocardial infarction [12]. Recently, the combination of elevated copeptin and hs-cTn at admission for acute chest pain has been shown to have better discriminative value for acute myocardial injury [13] than troponin alone, as well as strong prognostic value for major cardiac adverse events [14]. We hypothesised that myocardial injury may be an important cause of death in patients admitted with an acute exacerbations of COPD. Accordingly, we investigated whether circulating markers of myocardial injury at the time of presentation to the emergency department (ED) with acute exacerbations of COPD added prognostic value to the CURB-65 score. Acute exacerbated COPD patients with elevated markers of myocardial injury are at high risk of early mortality <http://ow.ly/aAaM30adU28>
NicE-seq: high resolution open chromatin profiling
Authors: V. K. Chaithanya Ponnaluri, Guoqiang Zhang, Pierre-Olivier Estève, George Spracklin, Stephanie Sian, Shuang-yong Xu, Touati Benoukraf, Sriharsa Pradhan
Journal: Genome biology (2017)

Open chromatin profiling integrates information across diverse regulatory elements to reveal the transcriptionally active genome. Tn5 transposase and DNase I sequencing-based methods prefer native or high cell numbers. Here, we describe NicE-seq (nicking enzyme assisted sequencing) for high-resolution open chromatin profiling on both native and formaldehyde-fixed cells. NicE-seq captures and reveals open chromatin sites (OCSs) and transcription factor occupancy at single nucleotide resolution, coincident with DNase hypersensitive and ATAC-seq sites at a low sequencing burden. OCSs correlate with RNA polymerase II occupancy and active chromatin marks, while displaying a contrasting pattern to CpG methylation. Decitabine-mediated hypomethylation of HCT116 displays higher numbers of OCSs.
Measuring the effects of treatment in patients with PAH: should we image the right ventricle?
Authors: Andrew J. Peacock
Journal: European Respiratory Journal (2017)

Treatment for pulmonary arterial hypertension (PAH) has really only been available for the last 16 years. Progress has been extremely rapid, and both the mortality and the morbidity from this condition have been improved by the application of one or more of three groups of therapy, the endothelin receptor antagonists (ETRA), the agents promoting the nitric oxide pathway (both phosphodiesterase 5 inhibitors (PDE5i) and guanylate cyclase activators) and the prostacyclins. Echocardiography and CMR allow noninvasive, serial examination of right ventricular function in PAH <http://ow.ly/UJPq30bRO86>
Genetic and Epigenetic Defects in the Autophagy Machinery in Myelodysplastic Syndromes
Authors: Valeria Visconte, Bartlomiej P Przychodzen, Steffan T. Nawrocki, Swapna Thota, Kevin R. Kelly, Bhumika Patel, Cassandra M. Hirsch, Hetty E. Carraway, Yvonne Parker, Daniel Lindner, Mikkael A. Sekeres, Heesun J Rogers, Jaroslaw P. Maciejewski, Jennifer S. Carew
Journal: Blood (2016)