tbuckley/cabot-search huggingface dataset:
A phosphokinome‐based screen uncovers new drug synergies for cancer driven by liver‐specific gain of nononcogenic receptor tyrosine kinases
Authors: Yannan Fan, Maria Arechederra, Sylvie Richelme, Fabrice Daian, Chiara Novello, Julien Calderaro, Luca Di Tommaso, Guillaume Morcrette, Sandra Rebouissou, Matteo Donadon, Emanuela Morenghi, Jessica Zucman‐Rossi, Massimo Roncalli, Rosanna Dono, Flavio Maina
Journal: Hepatology (2017)

Genetic mutations leading to oncogenic variants of receptor tyrosine kinases (RTKs) are frequent events during tumorigenesis; however, the cellular vulnerability to nononcogenic RTK fluctuations has not been characterized. Here, we demonstrated genetically that in the liver subtle increases in wild-type Met RTK levels are sufficient for spontaneous tumors in mice (Alb-R26Met ), conceptually illustrating how the shift from physiological to pathological conditions results from slight perturbations in signaling dosage. By analyzing 96 different genes in a panel of tumor samples, we demonstrated that liver tumorigenesis modeled by Alb-R26Met mice corresponds to a subset of hepatocellular carcinoma (HCC) patients, thus establishing the clinical relevance of this HCC mouse model. We elucidated the regulatory networks underlying tumorigenesis by combining a phosphokinome screen with bioinformatics analysis. We then used the signaling diversity results obtained from Alb-R26Met HCC versus control livers to design an "educated guess" drug screen, which led to the identification of new, deleterious synthetic lethal interactions. In particular, we report synergistic effects of mitogen-activated protein kinase kinase, ribosomal S6 kinase, and cyclin-dependent kinase 1/2 in combination with Bcl-XL inhibition on a panel of liver cancer cells. Focusing on mitogen-activated protein kinase kinase and Bcl-XL targeting, we mechanistically demonstrated concomitant down-regulation of phosphorylated extracellular signal-regulated kinase and myeloid cell leukemia 1 levels. Of note, a phosphorylated extracellular signal-regulated kinase+/BCL-XL+ /myeloid cell leukemia 1+ signature, deregulated in Alb-R26Met tumors, characterizes a subgroup of HCC patients with poor prognosis.Our genetic studies highlight the heightened vulnerability of liver cells to subtle changes in nononcogenic RTK levels, allowing them to acquire a molecular profile that facilitates the full tumorigenic program; furthermore, our outcomes uncover new synthetic lethal interactions as potential therapies for a cluster of HCC patients. (Hepatology 2017;66:1644-1661).
Intestinal IFN-γ–producing type 1 regulatory T cells coexpress CCR5 and programmed cell death protein 1 and downregulate IL-10 in the inflamed guts of patients with inflammatory bowel disease
Authors: Johanna Sophie Alfen, Paola Larghi, Federica Facciotti, Nicola Gagliani, Roberto Bosotti, Moira Paroni, Stefano Maglie, Paola Gruarin, Chiara Maria Vasco, Valeria Ranzani, Cristina Frusteri, Andrea Iseppon, Monica Moro, Maria Cristina Crosti, Stefano Gatti, Massimiliano Pagani, Flavio Caprioli, Sergio Abrignani, Richard A. Flavell, Jens Geginat
Journal: Journal of Allergy and Clinical Immunology (2018)
A Randomized Phase III Trial of Busulfan + Melphalan Vs Melphalan Alone for Multiple Myeloma
Authors: Muzaffar H. Qazilbash, Qaiser Bashir, Peter F Thall, Denái R. Milton, Nina Shah, Krina K. Patel, Borje S Andersson, Yago Nieto, Partow Kebriaei, Benigno C. Valdez, Jitesh Kawedia, Simrit Parmar, Ruby Delgado, Sairah Ahmed, Chitra Hosing, Uday Popat, Elizabeth J Shpall, Donna M. Weber, Sheeba K. Thomas, Elisabet E. Manasanch, Hans C. Lee, Robert Z. Orlowski, Richard E Champlin
Journal: Blood (2017)
Enzalutamide for the Treatment of Androgen Receptor–Expressing Triple-Negative Breast Cancer
Authors: Tiffany A. Traina, Kathy Miller, Denise A. Yardley, Janice Eakle, Lee S. Schwartzberg, Joyce O’Shaughnessy, William Gradishar, Peter Schmid, Eric Winer, Catherine Kelly, Rita Nanda, Ayca Gucalp, Ahmad Awada, Laura Garcia-Estevez, Maureen E. Trudeau, Joyce Steinberg, Hirdesh Uppal, Iulia Cristina Tudor, Amy Peterson, Javier Cortes
Journal: Journal of Clinical Oncology (2018)

Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile. This study supports additional development of enzalutamide in advanced TNBC.
Integrated Stress Response and Immune Cell Infiltration in an Ibrutinib-Refractory Mantle Cell Lymphoma Patient Following ONC201 Treatment
Authors: Jorge Enrique Romaguera, Hun Ju Lee, Rohinton Tarapore, Varun Vijay Prabhu, Joshua E. Allen, Lee Schalop, Andrew Zloza, Chi Young Ok, Maria Badillo, Michael Wang
Journal: Blood (2017)
Healthcare utilisation and costs of home mechanical ventilation
Authors: Mika L Nonoyama, Douglas A McKim, Jeremy Road, Denise Guerriere, Peter C Coyte, Marina Wasilewski, Monica Avendano, Sherri L Katz, Reshma Amin, Roger Goldstein, Brandon Zagorski, Louise Rose
Journal: Thorax (2018)

Background Individuals using home mechanical ventilation (HMV) frequently choose to live at home for quality of life, despite financial burden. Previous studies of healthcare utilisation and costs do not consider public and private expenditures, including caregiver time. Objectives To determine public and private healthcare utilisation and costs for HMV users living at home in two Canadian provinces, and examine factors associated with higher costs. Methods Longitudinal, prospective observational cost analysis study (April 2012 to August 2015) collecting data on public and private (out-of-pocket, third-party insurance, caregiving) costs every 2 weeks for 6 months using the Ambulatory and Home Care Record. Functional Independence Measure (FIM) was used at baseline and study completion. Regression models examined variables associated with total monthly costs selected a priori using Andersen and Newman’s framework for healthcare utilisation, relevant literature, and clinical expertise. Data are reported in 2015 Canadian dollars ($C1=US$0.78=₤0.51=€0.71). Results We enrolled 134 HMV users; 95 with family caregivers. Overall median (IQR) monthly healthcare cost was $5275 ($2291–$10 181) with $2410 (58%) publicly funded; $1609 (39%) family caregiving; and $141 (3%) out-of-pocket (&lt;1% third-party insurance). Median healthcare costs were $8733 ($5868–$15 274) for those invasively ventilated and $3925 ($1212–$7390) for non-invasive ventilation. Variables associated with highest monthly costs were amyotrophic lateral sclerosis (1.88, 95% CI 1.09 to 3.26, P&lt;0.03) and lower FIM quintiles (higher dependency) (up to 6.98, 95% CI 3.88 to 12.55, P&lt;0.0001) adjusting for age, sex, tracheostomy and ventilation duration. Conclusions For HMV users, most healthcare costs were publicly supported or associated with family caregiving. Highest costs were incurred by the most dependent users. Understanding healthcare costs for HMV users will inform policy decisions to optimise resource allocation, helping individuals live at home while minimising caregiver burden.
Abstract MP14: Preventable Stroke and Ischaemic Heart Disease Deaths in Argentina Comparative Risk Assessment of Different Levels of Physical Activity
Authors: Rosana Poggio, Adolfo Rubinstein, Vilma Irazola, Ariel Bardach, Goodarz Danaei
Journal: Circulation (2016)

Introduction: In Argentina physical inactivity was the fifth leading risk factor for all-cause mortality in 2010. The aim of this project was to estimate the numbers of ischaemic heart disease (IHD) and stroke deaths in Argentina attributable to different levels of physical activity (PA). Materials and Methods: We conducted a population-level comparative risk assessment for different levels of PA. We obtained data on prevalence of different levels of PA from the Argentinian national survey of risk factors 2013 and used relative risk for stroke and IHD mortality from prior meta-analyses for each category of PA. The number of disease-specific deaths, by age and sex, were obtained from the vital registration system for the year 2010. We considered 4 categories of PA based on the metabolic equivalent tasks per minute per week (MET/minute/week): inactive, &lt;600, ≥ 600 to &lt;1,600 and ≥1,600. We calculated the population attributable fraction for different levels of PA by sex and age group. Results: In Argentina, 76.5% (CI 95%; 75.8-77.7) of the total population engaged &lt;1,600 MET/min/week (72.8% in men and 81.1% in women). This level of insufficient activity was responsible for 26% of all IHD and stroke deaths in 2010 (11,234 of 43,796 deaths; 6,013 in men and 5,221 in women). It was also responsible for 29% (7,292) of the total IHD deaths and 21% (3,942) of the total stroke deaths. Almost half of the population or 52.5% (CI 95%; 51.3-53.7) engaged &lt;600 MET/minutes/week (48.8% in men and 55.7% in women) and this level of inactivity was responsible for 17% (7,278 of 43,796 deaths) of all IHD and stroke deaths in 2010 (3,941 in men and 3,337 in women). It was also responsible for 20% (4,907) of the IHD deaths and 13% (2,371) of the stroke deaths The impact of physical inactivity and insufficient PA was higher in women due to lower level of PA compared to men and in the individuals younger than 70 years old due to a stronger association with the outcomes (higher relative risks), especially for IHD. Conclusions: Physical inactivity and insufficient physical activity contribute substantially to the burden of cardiovascular diseases in Argentina. Interventions to promote PA should be a priority to prevent cardiovascular disease.
Vibegron, a Novel Potent and Selective β3-Adrenoreceptor Agonist, for the Treatment of Patients with Overactive Bladder: A Randomized, Double-blind, Placebo-controlled Phase 3 Study
Authors: Masaki Yoshida, Masayuki Takeda, Momokazu Gotoh, Shinji Nagai, Takafumi Kurose
Journal: European Urology (2018)
Efficient Ex Vivo Expansion of Human Umbilical Cord Blood-Derived Small CD133+lin-CD45- Stem Cells Expressing Pluripotency Markers in Presence of Histone Deacethylase Inhibitors—As a New Challenging Strategy to Obtain Multipotent Cells for Regenerative Medicine
Authors: Janina Ratajczak, Malwina Suszynska, Kamila Bujko, Donald M Miller, Magdalena Kucia, Mariusz Z Ratajczak
Journal: Blood (2017)
Optimizing Checkpoint Blockade As a Treatment for Relapsed Hematologic Malignancies after Allogeneic Hematopoietic Cell Transplantation
Authors: Matthew S. Davids, Haesook T Kim, Caitlin Costello, Alex F. Herrera, Frederick L. Locke, Peter McSweeney, Rodrigo O. Maegawa, Alexandra Savell, Michael Mazzeo, David E. Avigan, Yi-Bin Chen, Nicole R. LeBoeuf, Vincent T Ho, Corey S. Cutler, John Koreth, Edwin Alyea, Joseph H. Antin, Pavan Bachireddy, Catherine J. Wu, Jerome Ritz, Howard Streicher, Edward D Ball, Asad Bashey, Philippe Armand, Robert J. Soiffer
Journal: Blood (2017)
Effective Treatment of Relapsed/Refractory Multiple Myeloma Including Extramedullary Involvement By BCMA-Specific Chimeric Antigen Receptor-Modified T Cells
Authors: Jian-Qing Mi, Xiaohu Fan, Jie Xu, Yuanfang Liu, Yan Zhuang, Shuangshuang Yang, Wu Zhang, Bing Chen, Yueying Wang, Xiangqin Weng, Junmin Li, Weijun Fu, Hua Jiang, Li Zhu, Zhu Chen, Sai-Juan Chen, Jian Hou
Journal: Blood (2017)
Association Between Fluid Balance and Outcomes in Critically Ill Children
Authors: Rashid Alobaidi, Catherine Morgan, Rajit K. Basu, Erin Stenson, Robin Featherstone, Sumit R. Majumdar, Sean M. Bagshaw
Journal: JAMA Pediatrics (2018)

After initial resuscitation, critically ill children may accumulate fluid and develop fluid overload. Accruing evidence suggests that fluid overload contributes to greater complexity of care and worse outcomes.To describe the methods to measure fluid balance, define fluid overload, and evaluate the association between fluid balance and outcomes in critically ill children.Systematic search of MEDLINE, EMBASE, Cochrane Library, trial registries, and selected gray literature from inception to March 2017.Studies of children admitted to pediatric intensive care units that described fluid balance or fluid overload and reported outcomes of interest were included. No language restrictions were applied.All stages were conducted independently by 2 reviewers. Data extracted included study characteristics, population, fluid metrics, and outcomes. Risk of bias was assessed using the Newcastle-Ottawa Scale. Narrative description of fluid assessment methods and fluid overload definitions was done. When feasible, pooled analyses were performed using random-effects models.Mortality was the primary outcome. Secondary outcomes included treatment intensity, organ failure, and resource use.A total of 44 studies (7507 children) were included in this systematic review and meta-analysis. Of those, 27 (61%) were retrospective cohort studies, 13 (30%) were prospective cohort studies, 3 (7%) were case-control studies, and 1 study (2%) was a secondary analysis of a randomized trial. The proportion of children with fluid overload varied by case mix and fluid overload definition (median, 33%; range, 10%-83%). Fluid overload, however defined, was associated with increased in-hospital mortality (17 studies [n = 2853]; odds ratio [OR], 4.34 [95% CI, 3.01-6.26]; I2 = 61%). Survivors had lower percentage fluid overload than nonsurvivors (22 studies [n = 2848]; mean difference, -5.62 [95% CI, -7.28 to -3.97]; I2 = 76%). After adjustment for illness severity, there was a 6% increase in odds of mortality for every 1% increase in percentage fluid overload (11 studies [n = 3200]; adjusted OR, 1.06 [95% CI, 1.03-1.10]; I2 = 66%). Fluid overload was associated with increased risk for prolonged mechanical ventilation (>48 hours) (3 studies [n = 631]; OR, 2.14 [95% CI, 1.25-3.66]; I2 = 0%) and acute kidney injury (7 studies [n = 1833]; OR, 2.36 [95% CI, 1.27-4.38]; I2 = 78%).Fluid overload is common and is associated with substantial morbidity and mortality in critically ill children. Additional research should now ideally focus on interventions aimed to mitigate the potential for harm associated with fluid overload.
HAVEN 2 Updated Analysis: Multicenter, Open-Label, Phase 3 Study to Evaluate Efficacy, Safety and Pharmacokinetics of Subcutaneous Administration of Emicizumab Prophylaxis in Pediatric Patients with Hemophilia A with Inhibitors
Authors: Guy Young, Robert F. Sidonio, Ri Liesner, Johannes Oldenburg, Tiffany Chang, Marianne Uguen, Christophe Dhalluin, Christophe Schmitt, Gallia G. Levy, Midori Shima, Johnny Mahlangu
Journal: Blood (2017)
Differential Diagnosis of Suspected MYD88 Wild-Type Waldenstrom's Macroglobulinemia Includes Other Malignant and Non-Malignant IgM Secreting Entities, Including Frequent Cases of IgM Myeloma
Authors: Steven P Treon, Zachary Hunter, Joshua Gustine, Kirsten Meid, Lian Xu, Xia Liu, Guang Yang, Manit Munshi, Robert Manning, Nickolas Tsakmaklis, Maria Demos, Amanda Kofides, Maria Luisa Guerrera, Jiaji Chen, Gloria Chan, Christopher Patterson, Toni Dubeau, Patricia Severns, Jorge J. Castillo
Journal: Blood (2017)
Everyone is an “Athlete”
Authors: Melissa Novak, Jeff Tanji
Journal: British Journal of Sports Medicine (2018)

Merrian-Webster defines an athlete as: ‘a. a person who is trained or skilled in exercise, sports or games requiring physical strength, agility, or stamina. b. a person who exhibits dexterity or coordination especially an execution of learning physical tasks.’ The term athlete is often confusing for physicians and patients of all ages. As sports medicine physicians we are asked by young physicians in training: ‘Just how much of your practice is real Sports Medicine?' When we look puzzled, the question is often clarified somewhat sheepishly: ‘How much of your practice is in the care of the elite athlete? ’

Each day as a sports medicine physician, we encounter a patient who has set goals and challenged …
CG '806, a First-in-Class Pan-FLT3/BTK Inhibitor, Exhibits Potent Growth Inhibition As a Single Agent and in Combination with a BET Bromodomain Inhibitor or a Bcl2 Inhibitor on Primary AML and CLL Patient Samples
Authors: Stephen E Kurtz, Beth Wilmot, Shannon Mcweeney, Andrea Local, Hongying Zhang, Stephen Howell, William Rice, Brian J. Druker, Jeffrey W. Tyner
Journal: Blood (2017)
Improving Breast Cancer Surgical Treatment Decision Making: The iCanDecide Randomized Clinical Trial
Authors: Sarah T. Hawley, Yun Li, Lawrence C. An, Kenneth Resnicow, Nancy K. Janz, Michael S. Sabel, Kevin C. Ward, Angela Fagerlin, Monica Morrow, Reshma Jagsi, Timothy P. Hofer, Steven J. Katz
Journal: Journal of Clinical Oncology (2018)

Purpose This study was conducted to determine the effect of iCanDecide, an interactive and tailored breast cancer treatment decision tool, on the rate of high-quality patient decisions-both informed and values concordant-regarding locoregional breast cancer treatment and on patient appraisal of decision making. Methods We conducted a randomized clinical trial of newly diagnosed patients with early-stage breast cancer making locoregional treatment decisions. From 22 surgical practices, 537 patients were recruited and randomly assigned online to the iCanDecide interactive and tailored Web site (intervention) or the iCanDecide static Web site (control). Participants completed a baseline survey and were mailed a follow-up survey 4 to 5 weeks after enrollment to assess the primary outcome of a high-quality decision, which consisted of two components, high knowledge and values-concordant treatment, and secondary outcomes (decision preparation, deliberation, and subjective decision quality). Results Patients in the intervention arm had higher odds of making a high-quality decision than did those in the control arm (odds ratio, 2.00; 95% CI, 1.37 to 2.92; P = .0004), which was driven primarily by differences in the rates of high knowledge between groups. The majority of patients in both arms made values-concordant treatment decisions (78.6% in the intervention arm and 81.4% in the control arm). More patients in the intervention arm had high decision preparation (estimate, 0.18; 95% CI, 0.02 to 0.34; P = .027), but there were no significant differences in the other decision appraisal outcomes. The effect of the intervention was similar for women who were leaning strongly toward a treatment option at enrollment compared with those who were not. Conclusion The tailored and interactive iCanDecide Web site, which focused on knowledge building and values clarification, positively affected high-quality decisions largely by improving knowledge compared with static online information. To be effective, future patient-facing decision tools should be integrated into the clinical workflow to improve decision making.
Sixty seconds on . . . the Lansley diaries
Authors: Anne Gulland
Journal: BMJ (2018)

Andrew Lansley—the former health secretary who, in opposition, promised no more top-down reorganisations of the NHS but did just that in office with the introduction of the Health and Social Care Act in 2012.

Unfortunately, they’re not those kinds of diaries—no Adrian Mole-style revelations of secret crushes or details of his calorie intake (vv good) in …
Predictors of Specialized Pediatric Palliative Care Involvement and Impact on Patterns of End-of-Life Care in Children With Cancer
Authors: Kimberley Widger, Rinku Sutradhar, Adam Rapoport, Christina Vadeboncoeur, Shayna Zelcer, Alisha Kassam, Katherine Nelson, Ying Liu, Joanne Wolfe, Craig C. Earle, Jason D. Pole, Sumit Gupta
Journal: Journal of Clinical Oncology (2018)

Purpose The impact of specialized pediatric palliative care (SPPC) teams on patterns of end-of-life care is unknown. We sought to determine (1) which children with cancer access SPPC and (2) the impact of accessing SPPC on the risk of experiencing high-intensity end-of-life care (intensive care unit admission, mechanical ventilation, or in-hospital death). Methods Using a provincial childhood cancer registry, we assembled a retrospective cohort of Ontario children with cancer who died between 2000 and 2012 and received care through pediatric institutions with an SPPC team. Patients were linked to population-based administrative data capturing inpatient, outpatient, and emergency visits. Children were classified as having SPPC, general palliative care, or no palliative care on the basis of SPPC clinical databases, physician billing codes, or inpatient diagnosis codes. Results Of the 572 children, 166 (29%) received care from an SPPC team for at least 30 days before death, and 100 (17.5%) received general palliative care. SPPC involvement was significantly less likely for children with hematologic cancers (OR, 0.3; 95% CI, 0.3 to 0.4), living in the lowest income areas (OR, 0.4; 95% CI, 0.2 to 0.8), and living further from the treatment center (OR, 0.5; 95% CI, 0.4 to 0.5). SPPC was associated with a five-fold decrease in odds of intensive care unit admission (OR, 0.2; 95% CI, 0.1 to 0.4), whereas general palliative care had no impact. Similar associations were seen with all secondary indicators. Conclusion When available, SPPC, but not general palliative care, is associated with lower intensity care at the end of life for children with cancer. However, access remains uneven. These results provide the strongest evidence to date supporting the creation of SPPC teams.
Autologous Stem Cell Transplantation As a Treatment Modality for Type 1 Cryoglobulinemia in Monoclonal Gammopathy of Renal Significance
Authors: Zhen Wang, Noa Biran, Alan P Skarbnik, Andrew L. Pecora, Michele L. Donato, Scott D. Rowley, David S. Siegel, David H. Vesole, Joshua R. Richter
Journal: Blood (2016)
Long-Term Outcome after Haploidentical Hematopoietic Cell Transplantation Utilizing CD34+ Selected/CD3CD19+ Depleted or Tcrαβ+/CD19+ Depleted Grafts in Pediatric Patients with Hemoglobinopathies
Authors: Javid Gaziev, Antonella Isgrò, Pietro Sodani, Katia Paciaroni, Gioia De Angelis, Marco Marziali, Michela Ribersani, Cecilia Alfieri, Marco Andreani, Tiziana Gallucci, Guido Lucarelli
Journal: Blood (2017)
Safety and Activity of the Highly Specific BTK Inhibitor BGB-3111 in Patients with Indolent and Aggressive Non Hodgkin's Lymphoma
Authors: Constantine S. Tam, David Simpson, Stephen Opat, Won Seog Kim, Michael Wang, Gavin Cull, Patrick B Johnston, Javier Munoz, Won-Sik Lee, Paula Marlton, David Gottlieb, Lai Wang, Jane Huang, James Hilger, Ling Xue, Sunhee Ro, Judith Trotman
Journal: Blood (2017)