tbuckley/cabot-search huggingface dataset:
Ofatumumab Added To Dexamethasone In Patients With Relapsed Or Refractory Chronic Lymphocytic Leukemia. Results From a Phase II Study Of The Czech Leukemia Study Group For Life
Authors: Michael Doubek, Yvona Brychtova, Anna Panovska, Jakub Trizuljak, Ludmila Sebejova, Olga Stehlikova, Jana Chovancova, Jitka Malcikova, Jana Smardova, Karla Plevova, Pavlina Volfova, Martin Trbusek, Marek Mraz, Denisa Majercakova, Petra Obrtlikova, Josef Karban, Lukas Smolej, Michaela Lindtnerova, Alexandra Oltova, Eva Jelinkova, Sarka Pospisilova, Jiri Mayer
Journal: Blood (2013)
Phase I-IIa Clinical Trial to Assess Safety and Efficacy of MLM-CAR44.1, a CD44v6 Directed CAR-T in Relapsed/Refractory Acute Myeloid Leukemia (AML) and Multiple Myeloma (MM)
Authors: Matteo Giovanni Carrabba, Monica Casucci, Michael Hudecek, Concetta Quintarelli, Javier Briones, Roman Hajek, Jorge Sierra, Franco Locatelli, Hermann Einsele, Claudio Bordignon, Fabio Ciceri, Catia Traversari
Journal: Blood (2018)
Association of Low-Density Lipoprotein Cholesterol With Risk of Aortic Valve Stenosis in Familial Hypercholesterolemia
Authors: Liv J. Mundal, Anders Hovland, Jannicke Igland, Marit B. Veierød, Kirsten B. Holven, Martin Prøven Bogsrud, Grethe S. Tell, Trond P. Leren, Kjetil Retterstøl
Journal: JAMA Cardiology (2019)

Aortic valve stenosis (AS) is the most common valve disease. Elevated levels of low-density lipoprotein (LDL) cholesterol are a risk factor; however, lipid-lowering treatment seems not to prevent progression of AS. The importance of LDL cholesterol in the development of AS thus remains unclear. People with familial hypercholesterolemia (FH) have elevated LDL cholesterol levels from birth and until lipid-lowering treatment starts. Thus, FH may serve as a model disease to study the importance of LDL cholesterol for the development of AS.To compare the incidence of AS per year in all genetically proven patients with FH in Norway with the incidence of these diseases in the total Norwegian population of about 5 million people.This is a registry-based prospective cohort study of all Norwegian patients with FH with regard to first-time AS between 2001 and 2009. All genotyped patients with FH in Norway were compared with the total Norwegian populations through linkage with the Cardiovascular Disease in Norway project and the Norwegian Cause of Death Registry regarding occurrence of first-time AS. Data were analyzed between January 1, 2018, and December 31, 2018.Standardized incidence ratios.In total, 53 cases of AS occurred among 3161 persons (1473 men [46.6%]) with FH during 18 300 person-years of follow-up. Mean age at inclusion and at time of AS were 39.9 years (range, 8-91 years) and 65 years (range, 44-88 years), respectively. Total standardized incidence ratios were 7.9 (95% CI, 6.1-10.4) for men and women combined, 8.5 (95% CI, 5.8-12.4) in women, and 7.4 (95% CI, 5.0-10.9) in men, respectively, indicating marked increased risk of AS compared with the general Norwegian population.In this prospective registry study, we demonstrate a marked increase in risk of AS in persons with FH.
Abstract 840: Epicardial Prestrained Confinement and Residual Stresses: A Newly Observed Heart Ventricle Confinement Interface
Authors: Xiaodan Shi, Yue Liu, Katherine M Copeland, Sara R McMahan, Song Zhang, J. Ryan Butler, Yi Hong, Michael Cho, Pietro Bajona, Huajian Gao, Jun Liao
Journal: Circulation Research (2019)

The heart epicardial layer, with elastin as the dominant component, has not been well investigated, specifically on how it contributes to ventricular biomechanics. In this study, we revealed and quantitatively assessed the overall status of prestraining and residual stresses exerted by the epicardial layer on the heart left ventricle (LV). During porcine heart wall dissection, we discovered that bi-layered LV surface strips, consisting of an epicardial layer and cardiac muscle, always curled towards the epicardial side due to epicardial residual stresses. We hence developed a curling angle characterization technique to intuitively and qualitatively reveal the location-dependency and direction-dependency of epicardial residual stresses. Moreover, by combining prestrain measurement and biaxial mechanical testing, we were able to quantify the epicardial prestrains and residual stresses on the unpressurized intact LV. To investigate the potential mechanical effect of epicardial prestraining, a finite-element (FE) model has been constructed, and we demonstrate that it is the prestraining of the epicardial layer, not the epicardial layer alone, providing an additional resistance mechanism during LV diastolic expansion and ventricular wall protection by reducing myocardial stress. In short, our study on healthy, native porcine hearts has revealed an important phenomenon—the epicardial layer, rich in elastin, acts like a prestrained ‘balloon’ that wraps around the heart and functions as an extra confinement and protection interface. The obtained knowledge fills a gap in ventricular biomechanics and will help design novel biomimicking materials or prosthetic devices to target the maintenance/recreation of this ventricle confinement interface.
Correlation of Thrombosis and Prothrombotic Markers with Outcome in Lung Adenocarcinoma Patients: A Prospective Study.
Authors: Ernesto de Meis, Mauro M. Zamboni, Vera R. Pinheiro, Maria T.S. Guedes, Luize G. Lima, Ilda A.M. Castilho, Amanda F. Sousa, Neura P.R. Silveira, Maria A.L. Loures, Roger A. Levy, Robson Q. Monteiro
Journal: Blood (2007)
Abstract 848: The Iron Chelator Deferiprone Clears Hemorrhagic Byproducts Following Acute Myocardial Infarction in a Swine Model of Ischemia-Reperfusion
Authors: Jill J Weyers, Reuben Thomas, Xiuilng Qi, Jennifer Barry, Vraj Rabadia, Dino Manca, John Connelly, Michael Spino, Bradley H Strauss, Graham A Wright, Nilesh R Ghugre
Journal: Circulation Research (2019)

Current treatments for myocardial infarction (MI) aim to remove the vascular occlusion and reperfuse the infarcted tissue. While reperfusion can salvage myocardium, it can also increase damage to the unsalvageable tissue, one mechanism of which is hemorrhage; the resulting blood and iron deposits increase edema and inflammation. We hypothesize that removing these iron deposits with the iron chelating drug deferiprone (DFP) will reduce inflammation and lead to faster healing post-MI. Using a swine model of ischemia-reperfusion, pigs were administered either DFP or saline for four weeks post-MI. Cardiac MRI tracked heart function, infarct progression (via late gadolinium enhancement), hemorrhage (via T2* imaging), and edema (via T2 imaging) at baseline and 1 day, 1 week, and 4 weeks post-MI. Animals were then sacrificed and hearts were processed for histology. Treatment with DFP decreased the presence of iron in the infarct compared to saline by one week post-MI, as shown by increased T2* values. DFP treatment also decreased end diastolic wall swelling, suggesting less inflammation post-MI. To support this, T2 values and histology both revealed trends toward less edema with DFP. Histology also showed trended increases in fibroblast proliferation and collagen deposition at four weeks post-MI in the treatment group, consistent with a faster resolution to scar. Ventricular remodeling (by ventricular volumes), infarct size (by MRI, histology and blood Troponin I levels), and infarct transmurality were all unaffected, but contractile function improved with DFP treatment: ejection fraction and wall thickening both improved faster. In conclusion, DFP treatment successfully reduced hemorrhagic iron within the infarct as compared to saline, indicating a clearing of the iron byproducts. Treatment also decreased wall swelling, suggesting reduced inflammation, and improved contractile function. In the infarct, reduced swelling could indicate faster remodeling and a faster resolution to scar, and histology confirms a more progressed scar structure with DFP treatment. Overall, iron chelation appears to be a promising therapy that could reduce the negative effects of hemorrhage and speed the functional recovery of patients post-MI.
How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia
Authors: Brian A. Jonas, Daniel A. Pollyea
Journal: Leukemia (2019)

Abstract Acute myeloid leukemia (AML) is associated with poor outcomes, especially in older patients in whom the disease is most common. B-cell lymphoma 2 (BCL-2) is an antiapoptotic protein involved in the survival and maintenance of AML, and it is overexpressed in the leukemia stem cell population. Venetoclax is an oral BCL-2 protein inhibitor recently approved by the United States Food and Drug Administration (FDA) for use in combination with a hypomethylating agent (HMA) (azacitidine or decitabine) or low-dose cytarabine for front-line treatment of AML in older patients or those unfit for induction chemotherapy. Given that its mechanism of action is unique, it is not surprising that this widely effective therapy presents unique challenges, including but not limited to the rapidity of responses, the rate and depth of cytopenias, and issues related to drug–drug interactions. With the recent FDA approval and increasingly widespread use, we aim here to summarize, based on evidence and experience, emerging management strategies for the combination of HMAs and venetoclax in the treatment of AML.
Integration of palliative care into the inpatient oncology service.
Authors: Sasha Waldstein, Benjamin Smith, J. Chris Nunnink
Journal: Journal of Clinical Oncology (2019)

46 Background: Research has demonstrated that early palliative care involvement for patients with advanced cancer has multiple benefits, including improved symptom control/quality of life and reduced readmission rates. Based on this data, the American Society of Clinical Oncology (ASCO) has developed guidelines for early palliative care consultation. At the University of Vermont Medical Center, historically 40% of such patients were evaluated by palliative care during hospital admission. The purpose of this study was to better integrate palliative care into the oncology inpatient setting through the use of a standardized admission template. Methods: A specific oncology H&amp;P template, with inclusion of a drop down menu of ASCO based criteria for palliative care consultation, was created. Providers were educated on template use, and data then were collected for oncology admissions from 2/1-8/31/2018 regarding template usage, if criteria was met for palliative care consultation, and whether consultation occurred. Additionally, 30 day post discharge ED visits and readmissions were recorded, extending data collection for this purpose to 9/30/2018. Results: There were 372 medical oncology admissions during the studied time period, with 284 individual patients. The template was used for 95 (26%) admissions. 267 of those patients admitted qualified for palliative care consultation and, of those in which the template was used, 72% had palliative care consulted versus 50% without the template (p= 0.0013). There was no statistically significant difference in readmission rates between those with palliative care consultation and without. Conclusions: Early palliative care consultation for patients with advanced malignancy has been shown to have multiple benefits on an individual and system-wide basis. It was shown in this study that, though the created template was used for a minority of admissions, with template use a significantly greater proportion of appropriate patients had palliative care consulted. This suggests that, with more widespread practice, this strategy could further promote inpatient palliative care involvement for appropriate oncology patients.
Effects of rising drug costs on efforts to control overall cost at a large academic cancer center.
Authors: Kerin B. Adelson, Maureen Canavan, Susanna N. Supalla, Tannaz Sedghi, Basit Chaudhry, Naralys Sinanis, Cary Philip Gross
Journal: Journal of Clinical Oncology (2019)

2 Background: Value-based payment programs like the Oncology Care Model (OCM) have focused efforts to reduce costly acute care use through improvements in access and coordination rather than targeting the exponential rise in pharmaceutical pricing. We assessed how participation in OCM affected total cost of cancer care at a large academic cancer center. Methods: Using Medicare claims for Yale-Smilow Cancer Hospital, an NCI-designated cancer center with an academic hub and 10 community practices, we identified episodes for chemotherapy initiated during a historical period (pre-OCM, 2012-2015) and performance period (post-OCM, 2016-2017) following OCM criteria to identify total cost of care. We reported frequency of utilization categories, the mean cost per episode, the proportion of total cost attributed to each utilization category and compared pre- and post-participation periods. Results: There were 8,843 episodes during the historical period and 6,679 episodes during the performance period. The mean total cost per episode increased from $28,645 to $32,666, but this was less than the Medicare-defined expected increase (target price). Between the two periods, the percentage of total episodes decreased for emergency department (ED) use from 36% to 33%, inpatient care from 33% to 29%, and post-acute care from 28% to 25% (p &lt; 0.01). Mean costs of drugs per episode increased by 27% between periods, and from 52% to 58% of total cost of care (p &lt; 0.01). While mean cost per episode for ED, inpatient, and post-acute care remained stable, the mean cost per episode for antineoplastics increased 39% from $10,676 to $14,843. Conclusions: After implementing OCM, we beat the Medicare target largely by decreasing acute care use and stabilizing the cost of hospitalizations and ED; however, actual cost increased largely due to pharmaceutical spending. Because drug costs were the largest proportion of overall cost of care, future value-based models must address the rising cost of pharmaceuticals. [Table: see text]
UBR5 Mutations in Mantle Cell Lymphoma Lead to Increased Proliferation through a Cyclin D1-Dependent Mechanism
Authors: Olga Kutovaya, Stacy Hung, Elena Viganò, Adele Telenius, Bruce W Woolcock, Barbara Meissner, Shane Colborne, Randy D. Gascoyne, Diego Villa, Ryan D. Morin, David W. Scott, Gregg B Morin, Christian Steidl
Journal: Blood (2018)
Abstract 847: Adipocyte-specific Pharmacological Inhibition of Adipose Triglyceride Lipase (ATGL) Ameliorates Cardiac Fibrosis in Heart Failure
Authors: Shingo Takahara, Shubham Soni, Nikole J Byrne, Nirmal Parajuli, Zaid H Maayah, Mourad Ferdaoussi, Jody L Levasseur, Anna K Migglautsch, Rolf Breinbauer, Jason R Dyck
Journal: Circulation Research (2019)

Objectives: ATGL is a key enzyme that regulates triglyceride lipolysis in most cells, including the adipocyte and the cardiomyocyte. Recent studies indicate that accelerated adipose tissue lipolysis contributes to worsening heart failure (HF), suggesting that ATGL inhibition specifically in the adipocyte may prevent worsening HF. Indeed, we have shown that the ATGL inhibitor, Atglistatin, which appears to be largely adipocyte-specific, ameliorates cardiac dysfunction and hypertrophy in HF induced by transverse aortic constriction (TAC). However, the mechanisms by which Atglistatin treatment prevents worsening HF in mice remains unknown. Methods: Eight week-old C57BL/6N mice underwent TAC or sham surgery. After 1 week, mice with HF were assigned into 4 groups: 1) vehicle (standard chow)-sham, 2) Atglistain-sham, 3) vehicle-TAC and 4) Atglistatin-TAC. Atglistain was administered in food pellets containing 2mmol Atglistatin/kg for 2 weeks. Thereafter, mice were euthanized and hearts were used for subsequent histological and quantitative PCR analysis. Results: Picro-sirius red staining demonstrated that hearts from the Atglistatin TAC mice had significantly less cardiac fibrosis than the vehicle TAC mice (1.6±0.4 vs 5.3±1.1%, in Atglistatin TAC vs vehicle TAC; p&lt;0.01). Consistent with this finding, Atglistatin treatment of the TAC group reduced transcript levels of fibrosis-related genes, including Col1a1 (-58.7%, p=0.03) and Postn (-54.7%, p&lt;0.01), compared to vehicle-treated hearts. Furthermore, Atglistatin decreased the transcript levels of the macrophage polarization-related genes, including Lgals3 (-55.3%, p&lt;0.01) and Spp1 (-38.7%, p=0.03) , in the hearts from TAC mice compared to controls. Moreover, immunofluorescent analysis showed that Atglistatin reduced infiltration of Galectin-3 positive macrophages in the heart compared to vehicle-TAC mice, suggesting reduced macrophage infiltration and activation and less cardiac fibrosis. Conclusion: Our data indicate that reducing triglyceride lipolysis in the adipose tissue via ATGL inhibition may ameliorate HF via modulation of HF-induced macrophage and fibroblast activation in the heart.
Identification of patients at high risk of recurrent disease development by detection of HER2-positive disseminated tumor cells in bone marrow of patients with HER2-negative tumors.
Authors: Rebecca Aft, Chidananda Mudalagiriyappa, Sreeraj Pillai, Kathryn Trinkaus, Timothy Fleming, Mark Watson
Journal: Journal of Clinical Oncology (2013)

633 Background: A subpopulation of patients with HER2-negative tumors benefit from HER2 therapy. HER2 expression can be discordant between primary tumors and metastases. We have examined the bone marrow (BM) of early stage breast cancer patients for HER2-expression by disseminated tumor cells (DTCs) and the association with disease recurrence. Methods: BM was collected from clinical stage II-III breast cancer prior to treatment between 2007-2011. Gene expression of ERBB2 was determined by multiplex PCR (Fluidigm Biomark [FB]). Positive expression was defined as at least 1.4 fold above a pool of normal BM. Expression was confirmed by single gene PCR and Nanostring nCounter (NC) assays. Cox proportional model was used to estimate hazard ratios (HR). Results: BM from 74 patients was analyzed. Median follow-up was 3.4 years (range 8 months-84 months). 24% of the patients developed metastatic disease. For ERBB2 detection, there was excellent correlation between NC and the FB assays (kappa=0.87, 95% CI [0.62, 1.00]). Nine patients expressed ERBB2 in their BM. Five of the 9 patients had Her2-positive tumors and were treated with trastuzumab. One of 5 (20%) of these patients relapsed whereas 75% (3 of 4) of the patients with HER2-negative tumors but ERBB2-positive DTCs relapsed. Patients with HER2-negative tumors/ERBB2-positive BM were found to have a greater hazard of recurrence than patients with HER2-negative tumors/ERBB2-negative BM or ERBB2-positive DTCs treated with trastuzumab (p=.0069; Table). Those patients with ERBB2-positive BM who did not receive trastuzumab had a decreased disease free survival (p=.016). Conclusions: We have found discordant expression of HER2/ERBB2 in tumors and BM of stage II-III breast cancer patients. The presence of ERBB2 expressing DTCs in patients with HER2-negative tumors identifies a subset of patients at increased risk of recurrence who may benefit from targeted HER2-therapy. [Table: see text] .
Abstract 421: Organ-on-chip Model for Investigating Autonomic Innervation of the Cardiac Microenvironment
Authors: Jonathan R Soucy, Tess Torregrosa, Sanjin Hosic, Sebastian M Arteaga, Abigail N Koppes, Ryan A Koppes
Journal: Circulation Research (2019)

Cardiac sympathovagal imbalance is a dysfunction of the parasympathetic and sympathetic nervous systems (PSNS and SNS) that, in tandem, regulate cardiac output in response to environmental stimuli. This autonomic nervous system (ANS) imbalance increases the risk of cardiac arrhythmias and sudden cardiac failure due to an inability to modulate heart rate following overexertion or excessive stress. Therefore, there is an immediate need to understand the underlying cellular mechanisms of cardiac innervation to develop new strategies to restore ANS balance. Moving away from the complexity and variability of in vivo models, we developed an in vitro microphysiological model of the cardiac ANS. Custom “cut and assembled” microfluidic organ chips were fabricated to support the 3D culture of cardiac cells and ANS neurons within a biomimetic scaffold. Using this system, on-chip innervation of the cardiac microenvironment was confirmed via immunostaining (Figure 1). Further, we demonstrated trending differences in cardiomyocyte beating between those innervated by each ANS neuron population (PSNS vs. SNS: 37.4 ± 6.7 bpm vs. 44.8 ± 7.9 bpm, n = 8, p = 0.0716) via video microscopy and custom software (MATLAB®). Investigations to alter cardiomyocyte function to promote the innervation of different neural populations within the cardiac microenvironment are ongoing. Specifically, beat rate will be increased/decreased with pharmacological agents and innervation quantified using commercial neuron tracing software (Neurolucida®). Altogether, the development and use of this model will enable the systematic investigation of novel therapies to restore cardiac sympathovagal balance.
Declining socioeconomic inequalities in hospital care use and case fatality rates for stroke and ischaemic heart disease in China during 2009–16: a prospective study of 0·5 million adults
Authors: Muriel Levy, Yiping Chen, Robert Clarke, Derrick Bennett, Yunlong Tan, Y Guo, Zheng Bian, Jun Lv, Canqing Yu, Liming Li, Winnie Yip, Zhengming Chen, Borislava Mihaylova
Journal: The Lancet (2019)
Abstract 943: Circulating Mirnome in Obese and Lean Heart Failure Patients: A Case-control Study
Authors: Santiago Alonso L Tobar, Douglas d Soares, Rodrigo H Bueno, Raquel Calloni, Mariana R Mendoza, Michael Andrades, Luis Eduardo P Rohde, Andreia Biolo
Journal: Circulation Research (2019)

Background: Obesity is a risk factor for cardiovascular diseases; however, in obese heart failure (HF) patients live longer than lean HF patients, this observation is known as obesity paradox. MicroRNAs (miRs) regulate processes involved in both cardiac remodeling and obesity. Objective: We investigated whether the levels of circulating miRs in HF patients are influenced by obesity. Methods: In this case–control study, twenty HF patients (10 obese and 10 lean) and 10 healthy control individuals were analyzed using Affymetrix GeneChip miRNA 4.0 Array following manufacturer's instruction. Raw data was normalized using the Robust Multiarray Average method, batch effect was adjusted with Surrogate Variable Analysis, pairwise differential expression analysis was carry-out with Limma R package, and miRPath v3.0 was used to interrogate pathways enriched for the dysregulated miRNAs based on validated targets from Tarbase v7.0 and KEGG pathways annotation database. Bioinformatics and statistical analysis were performed using R and a p-value &lt;0.01 was considered significant. Results and conclusions: We discovered a set of 36 and 48 miRNAs that were differentially expressed in obese HF and lean HF, respectively, in relation to controls. Thirteen miRNAs were commonly dysregulated in both HF groups. In addition, we found hsa-miR-451a to be up-regulated in obese HF in relation to controls, as well as to lean HF patients, suggesting that obesity may accentuate its dysregulation. On the other hand, hsa-miR-4738-5p, hsa-miR-1260a, and hsa-miR-98-5p were differentially expressed in lean HF in relation to both remaining groups. Pathways enrichment analysis suggested that hsa-miR-451a regulates genes from the mTOR signaling pathway (p=0.002), whereas hsa-miR-1260a modulates Hippo (p=0.02) and AMPK (p=0.03) signaling pathways, all of which have been previously related to cardiac hypertrophy. Further investigation and validation of their targets may contribute to a better understanding of the obesity paradox.