tbuckley/cabot-search huggingface dataset:
Abstract 782: Human-induced Pluripotent Stem Cell-derived Cardiomyocytes as a Model for Trastuzumab-Induced Cardiac Dysfunction
Authors: Tomoya Kitani, Sang-Ging Ong, Chi K Lam, June-Wha Rhee, Joe Z Zhang, Angelos Oikonomopoulos, Ning Ma, Lei Tian, Jaecheol Lee, Melinda L Telli, Ronald M Witteles, Arun Sharma, Nazish Sayed, Joseph C Wu
Journal: Circulation Research (2019)

Background and Objective: Trastuzumab (Herceptin)-based chemotherapy regimens play a prominent role in treatments of breast cancer, but a significant number of patients develop cardiac disfunction during the therapy. In this study, we examined whether human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) could serve as an effective platform to study this particular cardiotoxicity. Methods and Results: We assessed the effects of trastuzumab on structural and functional properties in three control iPSC-CMs from healthy individuals and found that clinically relevant doses of trastuzumab (1 μM) significantly reduced the contraction velocity (-7.4%, P &lt; 0.01) and calcium amplitude (-14.1%, P &lt; 0.01) in iPSC-CMs without inducing cardiomyocyte death or sarcomeric structural abnormalities. RNA-sequencing analysis revealed mitochondrial dysfunction and altered cardiac energy metabolism pathway as primary causes of this cardiotoxicity. Subsequently, we found that significant reductions in basal, maximal, and ATP-linked oxygen consumption (-19.8%, -10.7%, and -19.0%, respectively, P &lt; 0.01 for all) and cellular ATP content (-10.3%, P &lt; 0.01) in iPSC-CMs after trastuzumab treatment. Next, we recruited seven breast cancer patients with trastuzumab therapy, including five patients diagnosed with trastuzumab-induced cardiac dysfunction and generated iPSCs from these patients. We found that contraction velocity and maximal oxygen consumption were more severely reduced by trastuzumab in iPSC-CMs generated from patients who experienced severe cardiac dysfunction from trastuzumab therapy, compared to iPSC-CMs generated from patients who did not experience cardiac dysfunction (-16.6% vs. -1.4%, and -29.4% vs. -3.7%, respectively, P &lt; 0.01 for all). Lastly, we demonstrated that metabolic modulation with AMPK activators, such as metformin, could avert the detrimental effects of trastuzumab in iPSC-CMs. Conclusion: Our results indicate that human iPSC-CM model can recapitulate the clinical phenotype of trastuzumab-induced cardiac dysfunction, and therefore targeting altered metabolism may be a promising therapeutic approach for treating this cardiotoxicity.
Assessment of Minimal Residual Disease Levels in B-CLL After Front-Line Treatment with FC-R and Rituximab Maintenance
Authors: Jose A. Garcia-Vela, Javier Lopez, Secundino Ferrer, Pilar Giraldo, Eva González-Barca, Eulogio Conde, Marcos González, Jose-Luis Guzman, Javier De la Serna, Mar Osma, Guillermo Deben, Encarna Monzo, Raquel De Paz, Francisco-Javier Penalver, Isidro Jarque, Rafael Martinez, Carmen Burgaleta, Jaime Perez de Oteiza, M.Angeles Andreu, Felix Carbonell, Jose A Garcia-Marco
Journal: Blood (2012)
MYC + Diffuse Large B Cell Lymphomas (DLBCL) Treated in Randomized Prospective Salvage Therapy, RICE or RDHAP Followed by BEAM Plus Autologous Stem Cell Transplantation (ASCT). A BioCORAL Report
Authors: Wendy Cuccuini, Josette Briere, Nicolas Mounier, Hans-Ullrich Voelker, Andreas Rosenwald, Christer Sundstrom, Sergio Cogliatti, Dominique Bron, Edouard Hirchaud, Jean Soulier, Philippe Gaulard, Remi Houlgatte, C. Gisselbrecht, Catherine Thieblemont
Journal: Blood (2011)
Can utilization of clinical pathways (CPs) effectively reduce drug spending (DS) within the Oncology Care Model (OCM)?
Authors: Andrew Allan Hertler, Rani Khetarpal, James Lloyd Wade, Ed Bassin, Sang Chau, Vijay Kumar Damarla
Journal: Journal of Clinical Oncology (2019)

269 Background: It is well known that one of the biggest challenges in the OCM is being able to reduce DS. DS accounts for approximately 50% of episode costs within OCM. New Century Health (NCH) is well known for its value-based care CPs, with a history of successfully controlling DS and taking risk on behalf of commercial payors in oncology. Cancer Care Specialists of Illinois (CCSI), is a community-based oncology private practice spread throughout rural Illinois and is an OCM participant with 14 Medical Oncologists and 4 Mid-Level providers, 6 Radiation Oncologists, and 1 Urologic Oncologist. CCSI engaged NCH in a risk- based relationship to provide support and resources that will allow maximization of OCM episodic cost savings. This included utilization of NCH’s CPs. Methods: Starting in October 2017, CCSI utilized NCHs pathways for OCM attributed patients. NCH CPs were embedded in all CCSI physician computers for rapid access and reference decision making. All treatment plans were submitted in real time to NCH for CP adherence measurement. Analysis was conducted prior to implementation and on an ongoing daily &amp; weekly basis to identify higher cost drugs or regimens. A joint CCSI/ NCH clinical data governance committee met bi-weekly to review CP performance metrics and drug utilization. The goal was to encourage treatment choices favoring both efficacy and value. Results: Post analysis revealed that over a 15-month period (Oct 2017 to Jan 2019), a 13.5% reduction in overall DS, which is equivalent to ~$250k per physician was achieved. This contributed to an overall reduction in total cost of care by 5% as compared to the OCM median. Post analysis also revealed an increase in pathway adherence from a baseline of 69% to 81% at the end of the measurement period. Conclusions: Reduction in DS is possible within a VBC model, through the use of value-based CPs. Important factors contributing to the reduction in DS include physician adherence rates, real time identification of high cost drugs/regimens, availability of immediate peer to peer discussion, rapid desktop access to a catalog of higher value alternate therapies, and continuous collaboration between CCSI and NCH through the governance committee.
ProteinChip Array Profiling and Markers of Inflammation and Thrombin Generation in Plasma Samples from Lung Cancer Patients and Their Modulation by Chemotherapy with or without Warfarin Anticoagulation.
Authors: Muzaffer Demir, A. Ciftci, Debra Hoppensteadt, G. Altiay, Mahemut Tobu, Omer Iqbal, Dan Fareed, Cafer Adiquzel, Michelle Kujawski, Jawed Fareed
Journal: Blood (2007)
Biology and therapeutic potential of interleukin-10
Authors: Margarida Saraiva, Paulo Vieira, Anne O’Garra
Journal: The Journal of Experimental Medicine (2019)

The cytokine IL-10 is a key anti-inflammatory mediator ensuring protection of a host from over-exuberant responses to pathogens and microbiota, while playing important roles in other settings as sterile wound healing, autoimmunity, cancer, and homeostasis. Here we discuss our current understanding of the regulation of IL-10 production and of the molecular pathways associated with IL-10 responses. In addition to IL-10’s classic inhibitory effects on myeloid cells, we also describe the nonclassic roles attributed to this pleiotropic cytokine, including how IL-10 regulates basic processes of neural and adipose cells and how it promotes CD8 T cell activation, as well as epithelial repair. We further discuss its therapeutic potential in the context of different diseases and the outstanding questions that may help develop an effective application of IL-10 in diverse clinical settings.
An NLP tool to identify molecular diagnostic testing in veterans with stage IV NSCLC.
Authors: Julie Ann Lynch, Michael J. Kelley, Kyung Min Lee, Anna Hung, Yanhong Li, Bradley J Hintze, Trudy Pendergraft, Melissa Pavilack, Olga Efimova, Scott L DuVall, Shelby D. Reed
Journal: Journal of Clinical Oncology (2019)

318 Background: ASCO Quality Oncology Practice Initiative (QOPI) encourages hospitals to determine if patients (pts) with stage IV NSCLC adenocarcinoma have activating EGFR mutations. Guidelines recommend tumor testing to identify ALK, BRAF, EGFR, ROS1 and other gene alterations before treatment. Studies have shown EGFR testing underutilization. We developed and tested a tool to identify EGFR tests in Veterans Affairs (VA) electronic health record (EHR). We examined whether Veterans with newly diagnosed NSCLC-IV underwent EGFR testing. We measured EGFR testing trends and analyzed differences by patient, VA Medical Center (VAMC) and region. Methods: VA EHR data identified Veterans with NSCLC-IV diagnosed 2013-2017, who survived 45+ days and had 2+ visits with a VA oncologist within 120 days of diagnosis. All NSCLC histologies were included. Demographics and VAMC were obtained from VA Corporate Data Warehouse. EGFR testing results performed outside VA were from commercial laboratory data. We deployed a natural language processing (NLP) tool to identify EGFR tests in VA EHR clinical notes. Testing rates and characteristics associated with testing were examined by descriptive analysis. Results: Of 3484 pts, 623 (18%) had evidence of EGFR testing. There was a 244% rise in testing. 54 (9%) pts diagnosed in 2013 were tested vs 186 (25%) diagnosed in 2017 ( χ 2 82.3, p-value 0.00). No statistically significant differences by sex, race, or urban/rural address existed. Testing decreased as pts aged ( χ 2 27, p-value 0.00). 35% of pts age ≤49 and 12% of pts age ≥80 were tested. Testing varied widely by VAMC and region (VAMC χ 2 795.6, p-value 0.00; region χ 2 90.3, p-value 0.00). 28% of pts in the Pacific were tested vs 10% of pts in the Southeast. The main contributor to regional variation was VAMC differences. VAMCs that conducted EGFR testing within their own laboratories (64% and 53%), or were co-located with the national precision oncology program (NPOP, 59%) tested the most pts. NPOP was temporally associated with increased testing nationally. 9% of pts diagnosed in 2017 were tested using NPOP. Conclusions: EGFR testing underutilization in the VA persists. QOPI and the NLP tool for this initiative will help system-wide quality improvement initiatives.
Sustained Long-Term MMR to a Reduced Dose of Imatinib in Chronic-Phase CML: A Pilot Study of SLC22A1 Gene Polymorphisms
Authors: Se Ryeon Lee, Seok Young Lee, Dae Sik Kim, Yong Park, Hwa Jung Sung, Chul Won Choi, Jae Sook Ahn, Deok-Hwan Yang, Byung Soo Kim
Journal: Blood (2012)
Randomised controlled trials of traditional Chinese medicine in cancer care published in Chinese: an overview
Authors: Chun-Li Lu, Xun Li, Hong-Mei Zhou, Chi Zhang, Ya-Yue Yang, Ru-Li Feng, Chao-Jun Long, Fang-Yuan Deng, Jing-Chun Li, Ze-Ming Cao, Qi-Yuan Mao, Jin-Pu Zhu, Yan-Fei Hong, Shou-Yu Huang, Jia-Ying Qiu, Yi-Xiu Liu, Ying Wang, Yu-Qian Yan, Jia-MIN Dong, Yu-Xin Luo, Yun-Meng Chen, Ying-Jie Guan, Nicola Robinson, Jian-Ping Liu
Journal: The Lancet (2019)
Abstract 826: Histone Deacetylase Inhibition Improves Heart Failure With Preserved Ejection Fraction Cardiopulmonary Phenotype and Induces Metabolomic Switch
Authors: Deborah M Eaton, Markus Wallner, Remus M Berretta, Natalie Bordag, Jichuan Wu, Mark Y Jeong, Ying H Lin, Giulia Borghetti, Sandy T Baker, Huaqing Zhao, Peter P Rainer, Mark A Oyama, Dirk von Lewinski, Sadia Mohsin, Heiner Post, Christoph Magnes, Elmar Zügner, Timothy A McKinsey, Marla R Wolfson, Steven R Houser
Journal: Circulation Research (2019)

Rationale: Approximately 50% of heart failure patients are diagnosed with Heart Failure with preserved Ejection Fraction (HFpEF), but there are currently no effective treatments. Hypothesis: Treatment of a feline HFpEF animal model with a pan HDAC inhibitor, SAHA, will improve the cardiopulmonary phenotype and mediate changes in the metabolome and skeletal muscle composition. Methods and results: Male domestic short hair cats (n=21, age 2mo) underwent either a sham procedure (n=5) or aortic constriction (n=16) using a customized pre-shaped band causing slow progressive pressure overload during maturation. At 2-months post-banding, banded animals received either daily treatment with 10mg/kg SAHA (b+SAHA) (n=8) or vehicle (b+veh) (n=8) for 2 months. At 4 months post-banding, b+ SAHA animals had significantly reduced LV wall thickness, LA size (LA/Ao), and improved LA function (LA EF) vs. b+ veh animals (fig). Invasive hemodynamics and lung mechanics were performed after 2 months of treatment. Banded animals had significantly increased filling pressures (LVEDP), increased pulmonary arterial pressures (mPAP), decreased lung compliance and arterial oxygenation (A-aDO 2 ). SAHA significantly reduced LVEDP, mPAP, and A-aDO 2 and increased lung compliance (fig). b+SAHA animals had an increase in the percentage of type 1 muscle fibers (increased oxidative capacity) compared to type 2 (fig). Blood-based metabolomics revealed SAHA-induced a metabolic shift towards increased lipolysis and mitochondrial oxidation. Conclusion: Treatment with SAHA improved cardiopulmonary structure and function in banded animals and caused changes in the metabolome and skeletal muscle.
Staining Pattern of Leukemic Lymphoblasts for Coagulation Factor XIII Subunit a Correlates with Clinical Outcome and B-Other Genotype in Childhood Acute Lymphoblastic Leukemia
Authors: Csongor Kiss, Bettina Kárai, Katalin Gyurina, Anikó Ujfalusi, Sędek Łukasz, Gábor Barna, Pál Jáksó, Peter Svec, Gábor Kovács, Alexandra Kolenova, Jerzy Kowalczyk, János Kappelmayer, Zsuzsanna Hevessy, Tomasz Szczepanski
Journal: Blood (2018)
Follow-Up of Patients With Complete Remission of Locally Advanced Basal Cell Carcinoma After Vismodegib Discontinuation: A Multicenter French Study of 116 Patients
Authors: Florian Herms, Jerome Lambert, Jean-Jacques Grob, Luc Haudebourg, Martine Bagot, Sophie Dalac, Caroline Dutriaux, Bernard Guillot, Geraldine Jeudy, Christine Mateus, Sandrine Monestier, Laurent Mortier, Nicolas Poulalhon, Sorilla Prey, Caroline Robert, Pierre Vabres, Celeste Lebbe, Nicolas Meyer, Nicole Basset-Seguin
Journal: Journal of Clinical Oncology (2019)

Vismodegib is a hedgehog pathway inhibitor indicated for the treatment of locally advanced basal cell carcinoma (laBCC), with an objective response rate of 65%, including a 32% complete response (CR). However, adverse effects often lead to drug discontinuation. The objective of our study was to evaluate long-term responses, predictive factors, and management of relapse after vismodegib discontinuation.An observational retrospective study was conducted in nine French oncodermatology units. We included patients with laBCC with CR on vismodegib who discontinued treatment between March 2012 and January 2016; we reviewed charts up to June 2016. The primary objective was to evaluate median relapse-free survival (RFS). Secondary objectives were risk factors associated with RFS, relapse, and death and treatment modalities after relapse and their efficacy.One hundred sixteen patients with laBCC were included. The median RFS was 18.4 months (95% CI, 13.5 to 24.8 months). The RFS rate at 36 months was 35.4% (95% CI, 22.5% to 47.9%) for the total population and 40.0% (95% CI, 25.7% to 53.7%) for patients without Gorlin syndrome. LaBCC to the limbs and trunk was the only variable independently associated with a higher risk of relapse (hazard ratio, 2.77; 95% CI, 1.23 to 6.22; P = .019). Twenty-seven patients (50%) who experienced relapse during follow-up were retreated with vismodegib, with an objective response in 23 (objective response rate, 85%; CR rate, 37%; partial response rate, 48%) and eligibility for surgery in 24 (42%).Long-term response after vismodegib discontinuation is frequent. Most patients who experience a relapse still respond to vismodegib rechallenge.
Comment on Riddle et al. <i>Diabetes Care</i> Editors’ Expert Forum 2018: Managing Big Data for Diabetes Research and Care. Diabetes Care 2019;42:1136–1146
Authors: Laura Lee Hall, Gary A. Puckrein, Jaime A. Davidson
Journal: Diabetes Care (2019)

We commend Riddle et al. (1) for reviewing the potential and challenges of big data in modern health care, given its transformational power in predicting and improving care and outcomes. It is important, however, to recognize additional and evolving data sources as well as the equitable application of big data analytics.

The meeting report focuses on three major sources of big data: the electronic medical record, national surveys and registries, and clinical trial databases. There …
Abstract 917: Actively Blocking Nuclear Localization of G Protein-Couple Receptor 5 Blunts Hypertrophy and Heart Failure After TAC
Authors: Ryan Coleman, Eric W Barr, Kurt Chuprun, Walter J Koch
Journal: Circulation Research (2019)

Introduction: The induction of heart failure (HF) after aortic banding (TAC) in mice encompasses aberrations in gene regulation, leading to maladaptive cardiac hypertrophy and contractile dysfunction. Previously, our lab has shown that the nuclear targeting of GRK5, which is required for maladaptive hypertrophy, is controlled by its N-terminal (NT) calmodulin-binding domain. Hypothesis: We hypothesize that expression of a peptide encoding the NT of GRK5 will act as a GRK5-calmodulin inhibitor preventing the nuclear accumulation of GRK5 and inhibit its pathological activities. Methods: Neonatal rat ventricular cardiomyocytes (NRCM) overexpressing GRK5-NT or control virus were subjected to α-adrenergic stress with 50μM phenylephrine (PE) or vehicle for 30 minutes. Subcellular fractionation and western blotting were used to detect nuclear GRK5. Novel cardiac-specific transgenic mice were generated expressing HA-tagged GRK5-NT and these mice along with their control mice were characterized 8 weeks after TAC or sham surgery. Echocardiography, fibrosis, and lung and heart weight to tibia length metrics were used to evaluate hypertrophy and heart failure response post-TAC. Other cohorts were subjected to TAC for 1 week followed by Western blotting to assess acute signaling and nuclear accumulation of GRK5. Results: In vitro, expression of the GRK5-NT peptide reduced PE-induced nuclear accumulation of GRK5. In both NRCM and tissue, the GRK5-NT peptide was found to bind to calmodulin, which disrupts the endogenous calmodulin-GRK5 interaction. GRK5-NT expression abrogates nuclear GRK5 accumulation following hypertrophic stress in vitro and in vivo. Following 8 weeks of TAC, cardiac function, hypertrophy, and pulmonary congestion were significantly attenuated in GRK5-NT mice compared to NLC mice. Conclusion: We show that the GRK5-NT peptide binds to calmodulin and prevents nuclear accumulation of GRK5 following hypertrophic stress. Our in vivo data show that cardiac-restricted expression of GRK5-NT prevents HF by partially restoring cardiac dysfunction, hypertrophy, and pulmonary congestion following 8 weeks of TAC. Further in vitro work will reveal the calmodulin-dependence of GRK5-NT and the peptide’s effects on G-protein signaling.
Health-Related Quality of Life (HRQL) Trajectories during Treatment for Advanced Stage Pediatric Hodgkin Lymphoma (HL)
Authors: Susan K Parsons, Angie Mae Rodday, Rizvan Bush, Qinglin Pei, Anem Waheed, Frank G Keller, Kara M. Kelly, Tara O. Henderson, Sharon M. Castellino
Journal: Blood (2018)
No Inhibition of Anti-Viral and Anti-Leukemia Effects By Extracorporeal Photopheresis Therapy
Authors: Ming NI, Lei Wang, Angela Hückelhoven, Leopold Sellner, Brigitte Neuber, Jean-Marc Hoffmann, Thomas Luft, Ute Hegenbart, Stefan Schönland, Patrick Wuchter, Volker Eckstein, William Hermann Krüger, Ronit Yerushalmi, Arnon Nagler, Inken Hilgendorf, Carsten Müller-Tidow, Anthony D Ho, Peter Dreger, Michael Schmitt, Anita Schmitt
Journal: Blood (2018)
From guidelines to practice: Patient-focused and evidence-informed update of antiemetic recommendations in Ontario.
Authors: Kathy Vu, David Warr, Leta Marie Forbes, Daniela Gallo-Hershberg, Carlo DeAngelis, Stephanie Yasmin Brule, Dayna Comfort, Lisa Randall, Julie Williams, Sarah Salama
Journal: Journal of Clinical Oncology (2019)

39 Background: Cancer Care Ontario (CCO) last updated their guidance for the management of chemotherapy-induced nausea and vomiting (CINV) in 2013. Since then, new evidence emerged which changed antiemetic recommendations internationally. The CCO Antiemetic Working Group reviewed the current literature and updated existing recommendations for the prevention and management of CINV in adult patients. Methods: Ontario subject matter experts consisting of oncologists, pharmacists and nurses formed the Group. Relevant guidelines published from prominent jurisdictions were assessed. A literature search was done to incorporate the latest evidence. All chemotherapy regimens in the CCO Drug Formulary were reviewed. Ontario Cancer Leads for each disease site were consulted to ensure emetic classifications for all regimens and antiemetic recommendations reflected both the evidence (including gaps in the literature) and clinical practice (including gaps between evidence and practice). Results: Recommendations for antiemetic agents for highly, moderately, low and minimal emetic risk intravenous and oral chemotherapy are outlined. Chemotherapy regimens in the CCO Drug Formulary were reviewed and emetic risks updated. Recommendations differed from those of major international guidelines (including ASCO) around olanzapine dosing, cannabinoids and emetic risk classification. Conclusions: A systematic approach to updating antiemetic recommendations resulted in evidence-informed recommendations that are patient-focused and clinically feasible.
Abstract 604: Doxorubicin-induced microRNA-377 Alters Cardiomyocyte and Endothelial Cell Function
Authors: John Henderson, Hien T Luong, Suresh K Verma, Prasanna Krishnamurthy
Journal: Circulation Research (2019)

Background: microRNAs (miRNA/miR) dysregulation has been implicated in cardiac remodeling after injury or stress. We have previously shown that miR-377 negatively affects bone marrow progenitor cells function in response to inflammation/myocardial ischemia. However, its role in doxorubicin (DOX)-induced cardiotoxicity, cell death and endothelial dysfunction is not known. Objective: The purpose of this study is to evaluate the role of miRNA-377 in DOX-induced cardiomyocytes (CMs) stress and endothelial dysfunction. Methods: miR-377 expression was assessed in myocardial tissue from human patients with heart failure (HF) and mouse model of ischemia-reperfusion injury. In vitro , we determined the effect of pre-miRNA (pre-miR-377, stimulates miRNA) on Dox-induced cardiomyocyte cell death, endothelial cell migration (using modified Boyden chamber), and vascular tube formation (using matrigel assay). Results: Human cardiac biopsies from HF patients show significant increase in miR-377 expression in comparison to non-failing control hearts. Cardiac ischemia-reperfusion (I/R) injury in mice increases myocardial miR-377 expression (vs. sham-operated mice). Interestingly, preparation of single cell suspension of mouse ischemic heart and qPCR analysis show a robust increase in miR-377 expression specifically in the cardiomyocyte as compared to other cardiac cell types. Following DOX-induced cellular stress, miR-377 expression in CMs was elevated, and inhibition of miR-377 attenuates DOX-induced cell death in CMs in vitro . Furthermore, transfection of miR-377 mimics in HUVECs significantly inhibits VEGF induced migration and vascular tube formation. Intriguingly, proteome profile of human CD34 + cells transfected with miR-377 mimics show significant decrease in numerous proangiogenic proteins as compared to nonspecific control transfected cells. Conclusions: These findings suggest that doxorubicin-induced cardiotoxicity is associated with an increase in miR-377 expression in the myocardium and that miR-377 overexpression is detrimental to cardiomyocyte viability and endothelial cell function. Therefore, we anticipate that anti-miR-377 treatment might have a beneficial effect against DOX-induced cardiotoxicity.
Transfusion of Red Cells in Hematopoietic Stem Cell Transplantation (TRIST Study): A Randomized Controlled Trial Evaluating 2 Red Cell Transfusion Thresholds
Authors: Jason Tay, David S. Allan, Elizabeth Chatelain, Doug Coyle, Mohamed Elemary, William Petrcich, Timothy Ramsay, Alan Tinmouth, Irwin Walker, Anargyros Xenocostas, Dean Fergusson
Journal: Blood (2016)