tbuckley/cabot-search huggingface dataset:
Abstract 792: Core Cell Survival Requirements of Hypoxia Inducible Factors in Macrophages Dominate Isoform-Specific Function during Cardiac Repair
Authors: Matthew Deberge, Connor Lantz, Lisa Wilsbacher, Edward B Thorp
Journal: Circulation Research (2019)

Objective: Hypoxia inducible factors (HIF) regulate the adaptive response to ischemic injury and enhancement of HIF levels has been proposed as a therapeutic target to improve tissue repair after acute myocardial infarction (MI). HIFs also regulate the inflammatory function of macrophages, the main protagonists of tissue repair after MI, but it is unknown whether changes in macrophage HIF levels will affect outcomes after MI. Using a murine model of acute MI and conditional knockouts, we investigated a role for macrophage HIFs in tissue repair after MI. Methods and Results: In mice subjected to permanent occlusion MI, we observed an accumulation of hypoxic cardiac macrophages and sequential stabilization of HIF-2α followed by HIF-1α, which persisted into the development of heart failure. In patients with ischemic cardiomyopathy, flow cytometry and single-cell transcriptomics revealed a parallel stabilization of HIFs and hypoxia signaling in cardiac macrophages. Since HIFs were stabilized early after MI in cardiac macrophages, we selectively targeted macrophage HIFs using conditional knockouts. Selective deletion of macrophage HIF-2α promoted cardiac macrophage production of IL-10, activating fibroblasts and stimulating collagen deposition, culminating in improved ventricular remodeling and preservation of systolic function. Similarly, selective deletion of macrophage HIF-1α improved cardiac repair; however, this was mechanistically distinct from HIF-2α, inhibiting HIF-1α-dependent proteolytic destruction of MerTK and leading to improved efferocytosis by cardiac macrophages. Contrary to our expectations, loss of both HIF-1α and HIF-2α in hypoxic macrophages enhanced mitochondrial reactive oxygen species and activated necroptosis, leading to increased cell death and cardiac rupture after acute MI. Inhibition of necroptosis with necrostatin-1 attenuated hypoxic macrophage cell death and significantly improved survival after acute MI. Conclusions: These data imply strategies that broadly enhance or inhibit HIFs will lead to catastrophic outcomes after MI, while selective inhibition of macrophage HIF-1α or HIF-2α may enhance tissue repair, preserve systolic function, and limit progression to heart failure.
Phenotipic Heterogeneity Studied By Spade Algorithm in Relapsed/Refractory Acute Myeloid Leukemia
Authors: Giovanni Rossi, Vincenzo Giambra, Francesca Sansico, Francesco Tamiro, Vincenzo Chiello, Patrizio Panelli, Maria Marta Minervini, Nicola Cascavilla, Nicola Pio Sinisi
Journal: Blood (2018)
Emergency department (ED) utilization among patients with cancer receiving intravenous (IV) chemotherapy.
Authors: Ryan David Nipp, Chinenye Azoba, Austin Vyas, Paul Kay, Charn-Xin Fuh, Irene Wang, Minh Mai, Margaret Soriano, Therese Marie Mulvey
Journal: Journal of Clinical Oncology (2019)

22 Background: ED utilization among patients with cancer is often cited as a potential metric to improve the quality of oncology care. However, efforts to understand emergency department (ED) utilization among patients with cancer receiving IV chemotherapy are lacking. We sought to describe sociodemographic and clinical factors associated with ED utilization and explore predictors of ED arrival time. Methods: We conducted a quality improvement assessment of patients who visited the ED within 30-days of receiving IV chemotherapy at Massachusetts General Hospital from October 2017 to January 2018. We used descriptive statistics to describe the sociodemographic and clinical factors associated with ED visits. We used multivariable regression models to explore predictors of the following outcomes: (1) ED visit occurring during normal clinic hours; and (2) ED visit occurring during the weekend. Results: Of the approximately 2,600 patients receiving IV chemotherapy during the assessment period, we identified 500 ED visits (~19.2%). For these ED visits, median patient age was 65 years (range: 22-93), and 49.6% were female. The majority were white race (84.8%), married (63.6%), diagnosed with metastatic disease (70.4%), and 8+ days since receiving most recent chemotherapy (71.4%). The most common cancer types were gastrointestinal (24.2%), lung (13.2%), and lymphomas (11.0%). The most common reason for ED visits included pain (20.4%), fever/cold symptoms (18.0%), and fatigue (11.0%). Over half (50.4%) of ED visits occurred during normal clinic hours and over one-fourth (28.2%) occurred during the weekend. We found that ED visits were less likely to occur during normal clinic hours for patients with lymphomas (OR = 0.44, P = 0.013) compared with other cancer types. ED visits were less likely to occur during the weekend for patients of older age (OR = 0.98, P = 0.020). Conclusions: We identified a substantial number of ED visits among patients with cancer within 30-days of receiving IV chemotherapy, often occurring during normal clinic hours and most commonly for pain, fever/cold symptoms, and fatigue. These findings highlight issues to address when seeking to reduce ED utilization and enhance cancer care quality.
Employer provided health benefits among cancer survivors in the United States.
Authors: Zhiyuan Zheng, Xuesong Han, Matthew P. Banegas, Jingxuan Zhao, Ashish Rai, Reginald Tucker-Seeley, Ahmedin Jemal, K Robin Yabroff
Journal: Journal of Clinical Oncology (2019)

155 Background: Nearly 40% of cancer survivors are of working age in the U.S. Access to high quality diagnosis, treatment, and survivorship care requires both health insurance coverage and sick leave, key components of employer health benefits. This study examines work limitations, paid sick leave, and employer offered health insurance among cancer survivors. Methods: We used the National Health Interview Survey (2001-2017) to identify cancer survivors aged 18-64 years. Work limitations were asked among all cancer survivors regardless of work status (n = 15,247), and categorized into unable to work, limited in type/amount of work, and not limited at all. Paid sick leave and employer offered health insurance offered were asked of cancer survivors who were working in the last week (n = 8741). We used generalized ordinal logistic regressions to examine work limitation and employer health benefits among cancer survivors, controlling for demographic characteristics, time since cancer diagnosis, number of cancer diagnoses, income, and comorbidities. Stratified analyses by type of workplace (private sector, federal/state/local government, and self-employed), and hours worked per week (full time with 35+ hours per week vs part time &lt; 35 hours per week) was conducted. Results: Among cancer survivors aged 18-64 years, 10.7% and 5.3% reported unable to work at all and limited in types/amounts of work, respectively; 57.7% and 67.6% of those working in the last week received paid sick leave and employer offered health insurance, respectively. In stratified analyses, government jobs were associated with the highest paid sick leave and employer insurance (85.7% and 85.6%, respectively), followed by private sector (58.3% and 70.7%, respectively), and self-employed (8.3% and 15.7%), respectively. Moreover, full time jobs had higher paid sick leave (65.2% and 21.9%, respectively) and employer insurance (75.7% and 29.1%, respectively) then part time jobs. Conclusions: Cancer survivors experience work limitations and many working cancer survivors do not receive paid sick leave or health insurance from their employers. Evaluation of the effects of employer-based health benefits on survivorship care and outcomes will be important for future research.
Disulfram/Copper Complex May Enhance Its Cytotoxic Effect on CD34+CD38- KG1-Alpha Cells By Down Regulating the Expression of HIF1-Alpha in the Co-Cultured MSCs
Authors: Guo Xutao, Haiqing Zheng, Shi Pengcheng, Wang Yan, Liang Jiabao, Ru Feng, Bing Xu
Journal: Blood (2018)
Case 32-2019: A 70-Year-Old Woman with Rapidly Progressive Ataxia
Authors: Bart K. Chwalisz, Bradley R. Buchbinder, Jeremy D. Schmahmann, Wesley R. Samore
Journal: New England Journal of Medicine (2019)

A 70-year-old woman presented to the hospital with rapidly progressive ataxia. Imaging of the head and evaluation of the cerebrospinal fluid were unremarkable. Her condition did not improve with immunosuppressive therapy, and memory loss developed. A diagnosis was made.
Non-Myeloablative Allogeneic Stem Cell Transplantation (NMT) Overcomes the Adverse Effects of Treatment Resistance and High Beta-2-Microglobulin in Patients with Mantle Cell Lymphoma (MCL): An Analysis of 123 Transplantations at the MD Anderson Cancer Center.
Authors: Constantine S. Tam, Celina Ledesma, Martin Korbling, Luis E. Fayad, Michael Wang, Amin Alousi, Chitra Hosing, Partow Kebriaei, Gabriela Rondon, Sergio A. Giralt, Paolo Anderlini, Uday Popat, Daniel Couriel, Barbara Pro, Barry Samuels, Frederick Hagemeister, Richard E. Champlin, Issa F. Khouri
Journal: Blood (2007)
Expression Analysis and Prognostic Significance of the PHLPP Gene in Acute Leukemias and Myelodysplastic Syndromes.
Authors: Takaaki Ono, Satoki Nakamura, Shigeno Kazuyuki, Kaori Takeshita, Okinaka Keiji, Isao Hirano, Shinya Fujisawa, Kazunori Ohnishi
Journal: Blood (2007)
A Plant Pathogen Type III Effector Protein Subverts Translational Regulation to Boost Host Polyamine Levels
Authors: Dousheng Wu, Edda von Roepenack-Lahaye, Matthias Buntru, Orlando de Lange, Niklas Schandry, Alvaro L. Pérez-Quintero, Zasha Weinberg, Tiffany M. Lowe-Power, Boris Szurek, Anthony J. Michael, Caitilyn Allen, Stefan Schillberg, Thomas Lahaye
Journal: Cell Host & Microbe (2019)
Clinical and financial outcomes in cancer patients with integration of specialty palliative care versus standard oncology care.
Authors: Sam Gaster, Francine Arneson, Luis Alexander Rojas-Espaillat, Nathan Hruby, Mari Perrenoud
Journal: Journal of Clinical Oncology (2019)

47 Background: Evidence suggests that integrating palliative care into usual oncology care benefits patients with advanced cancer and their caregivers (Ferrell et al., 2017). We evaluated patients with an advanced cancer diagnosis with concurrent palliative care versus standard oncology care to determine how both clinical and financial outcomes differ in our cancer center. Methods: We conducted a retrospective analysis on 340 deceased cancer patients who attended an office visit at a medical/gynecologic oncology clinic between January 2018 and February 2019. Patients who received concurrent palliative care as well as patients that received usual oncologic care were included. Data available in the electronic health record (EHR) were abstracted to quantify patient and practice level data. We compared differences in advance care planning (ACP) documentation, DNR designation, hospice enrollment prior to death, chemotherapy in the last 14 days of life, and health care utilization and cost. Results: Forty-nine patients received a specialty palliative care consultation concurrent with their cancer care. Compared to their counterparts, patients who received a specialty palliative care consultation were more likely to have a completed advanced care plan (57% v 16%, p &lt; .05), have a DNR designation (29% v 4%, p &lt; .05) in the EHR, to enroll in hospice prior to death (78% v 50%, p &lt; .05), and at an earlier time (Mdiff = 14 days, p = .05). Patients who received a specialty palliative care consultation were also less likely to receive chemotherapy in the last 14 days of life (2% v 7%) and end-of-life acute care utilization was lower in patients with a specialty palliative care consultation, including ED visits (50% v 67%) and hospitalizations (20% v 59%), but these results were not statistically significant. Median per patient per month (PPPM) total cost of care was higher pre-consult ($9,307) versus post-consult ($6,088; Diff = -$3,219), but this result was statistically non-significant. Conclusions: These results provide additional support for advantage of concurrent specialty palliative care in patients with advanced cancer versus standard oncologic care.
Abstract 425: Role of MLF1 in Cardiomyocyte Cell Cycle Regulation
Authors: Feng Xiao, Jainy Savla, Alisson C Cardoso, Ana M Periera, Shalini Muralidhar, Diana Canseco, Hesham A Sadek
Journal: Circulation Research (2019)

The neonatal mammalian heart is capable of significant regeneration after cardiac injury. However, that ability is lost in the early postnatal period, coinciding with the development of cardiomyocyte cell cycle arrest. Myeloid leukemia factor 1 (MLF1) is a protein expressed in hematopoietic cells, skeletal muscle and cardiac muscle. In hematopoietic cells, MLF1 is thought to be a negative cell cycle regulator, possibly acting through a p53-dependent mechanism. However, the role of MLF1 in the cardiovascular system is not well understood. Here, we describe MLF1 as a regulator of cardiomyocyte cell cycle progression. We first examined the expression pattern of MLF1 in neonatal mouse heart. MLF1 protein specifically expresses in the nucleus, and the expression level increases from P1 to P7 as revealed by quantitative PCR and Western Blot. To elucidate a potential role of Mlf1 in cardiomyocyte proliferation, we silenced Mlf1 in neonatal rat ventricle myocytes (NRVMs) which showed increased cardiomyocyte proliferation by staining with a mitosis marker phospho-Histone 3 (pH3). Then we generated an inducible cardiac-specific Mlf1 knockout mouse model and assessed for the prolongation of the proliferative window by echocardiography, cell size analysis, and immunostaining for cell cycle markers. Staining the Mlf1 KO hearts with proliferation markers, pH3 to determine mitosis and Aurora B kinase to determine cytokinesis, indicated that deletion of Mlf1 resulted in increased cardiomyocyte proliferation. It also showed improvement in left ventricular systolic function following myocardial infarction by echocardiography. In contrast, overexpression of MLF1 in heart showed decreased cardiac function as quantified by ejection fraction. These results identify MLF1 as a negative cell cycle regulator of cardiomyocyte proliferation.
Abstract 489: CC Chemokine Receptor 5 Protects the Heart from Inflammation in Pressure Overload-induced Cardiac Dysfunction
Authors: Masato Ishizuka, Haruhiro Toko, Mutsuo Harada, Jiaxi Guo, Satoshi Bujo, Haruka Yanagisawa-Murakami, Issei Komuro
Journal: Circulation Research (2019)

Objective: Sustained inflammation is a key pathological process in the development of heart failure and thus suppression of inflammation possibly leads to improvement of cardiac dysfunction. It has been suggested that CC chemokine receptor 5 (CCR5) scavenges pro-inflammatory mediators and resolves inflammation. The aim of this study is to uncover the role of CCR5 in the pathogenesis of heart failure. Methods: Pressure overload heart failure was induced by transverse aortic constriction (TAC). Sham or TAC operation was performed in male 10-week-old CCR5 knockout (KO) mice and wild-type (WT) controls. Cardiac function and morphology were examined by echocardiography 1 week and 4 weeks after TAC surgery. After euthanization, the heart was extracted and embedded in paraffin for the measurements of cardiac fibrosis and cardiomyocyte hypertrophy with EVG stain and immunohistochemistry using WGA, respectively. The extent of inflammation was evaluated by the immunostaining against CD45 and F4/80 antigens, and by qRT-PCR for inflammatory cytokines and chemokines. Results: We found that heart weight was significantly larger and fractional shortening was significantly lower in CCR5 KO mice than those in WT 4 weeks after TAC, indicating CCR5-induced protective effects on heart failure development. Whilst there was no difference observed in the extent of fibrosis, the size of cardiomyocytes from CCR5 KO heart tended to be increased compared to WT. The number of CD45-positive inflammatory cells and F4/80-positive macrophage infiltration was increased 1 week after TAC in KO mice. The RNA expression levels of monocyte chemotactic protein-1, transforming growth factor-β and tumor necrosis factor-α were significantly higher and NFκB p65 was more phosphorylated in KO mice. Conclusions: We revealed that the inflammation in pressure overload-induced heart failure was exacerbated by the deletion of CCR5 and, therefore, CCR5 could contribute to resolution of inflammation and be a potential therapeutic target for the heart failure treatment.
Abstract 447: Development of CD47-nanomedicine as Novel Treatment for Specific Mitigation of Thrombospondin 1-Induced Vascular Dysfunction
Authors: Mingyi Yao, Samayita Ganguly, Aren Ebrahimi, Tamer Elbayoumi
Journal: Circulation Research (2019)

The trans-membrane receptor CD47 is considered a central relay of thrombospondin 1 (TSP-1) mediated responses in human cells/tissues, and ubiquitously serves as a marker of self on hematopoietic cells. Preliminary studies of TSP-1 binding with soluble human CD-47, serving as decoy recombinant protein (rhCD47p), demonstrated molar ratio ≥ 3 folds of rhCD47p abolished all TSP1-vascular CD47 receptor signaling. Accordingly, we attached multiple rh-CD47p ligands onto liposomes (NanoLip), as clinical prototype therapy. Novel rh-CD47p-NanoLip can avoid blood mononuclear cells, while binding many circulating TSP1 molecules, thus eliminating excessive plasma TSP-1, often implicated in pulmonary arterial hypertension (PAH) and ischemia-reperfusion injuries. Direct coupling of rh-CD47p, onto NanoLip surface was achieved using a sulfo-NHS-reaction between amino groups on rh-CD47p and corbodiimide-activated NanoLip, followed by column purification and physico-chemical analysis. Pharmaceutically, rh-CD47p-NanoLip formulation (av. size = 86±6.0nm) engaged 67±11μg/mL of protein, while retaining 86% of native rh-CD47p activity. Western blots and TSP-1-ELISA revealed dosimetric binding of tirmeric human TSP-1: rh-CD47p-NanoLip. Activated macrophages showed substantial decrease in phagocytosis of labeled rh-CD47p-NanoLip, compared to plain- and IgG-NanoLip controls (5- and 4- folds, respectively), indicating self-marker function. Conversely, binding of exogenous TSP-1 caused significant upturn of internalized rh-CD47p-NanoLip (p&lt;0.05, n=4), due to TSP-1/nano-complex formation. Therapeutically, in isolated mouse thoracic aorta model, mimicking high plasma levels of TSP1 in PAH patients, titrated doses of CD47p-NanoLip neutralized TSP1-impaired vasodilation, back to the same level as controls (p&lt;0.001, vs. TSP-1, n=4). This is the first report of its kind about CD47-based immunomodulatory nano-therapy specifically targeting TSP-1. The extracellular domains of native CD47 receptors of TSP1 were successfully “nano-modified” into a candidate systemic decoy pharmaceutical, rh-CD47p-NanoLip, to scavenge and eliminate pathologically elevated TSP-1 plasma levels, to abrogate TSP-1-associated vascular complications.
Cell Surface CXCR4 and BTK Expression Are Associated in Myeloma Cells and Osteoclast Precursors and Mediate Myeloma Cell Homing and Clonogenicity, and Osteoclastogenesis
Authors: Rakesh Bam, Wen Ling, Sharmin Khan, Angela Pennisi, Sathisha Upparahalli Venkateshaiah, Xin Li, Ryan Williams, Frits van Rhee, Bijay Nair, Saad Usmani, Bart Barlogie, John D Shaughnessy, Joshua Epstein, Shmuel Yaccoby
Journal: Blood (2011)
Allogeneic Myelo-Ablative Stem Cell Transplant (SCT) as Salvage Therapy of Reduced-Intensity Conditioned (RIC) SCT: Toxicity and Outcome.
Authors: Catherine Cordonnier, Rose-marie Hamladji, Alois Gratwohl, Per Ljungman, Rodrigo Martino, Pierre Bordigoni, Sylvie François, Eric Deconninck, Agnes Buzyn, Jacques-Olivier Bay, Loic Fouillard, Mathieu Kuentz
Journal: Blood (2005)
Nonalcoholic Fatty Liver Disease in Adults: Current Concepts in Etiology, Outcomes, and Management
Authors: Thomas Marjot, Ahmad Moolla, Jeremy F Cobbold, Leanne Hodson, Jeremy W Tomlinson
Journal: Endocrine Reviews (2019)

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of disease, extending from simple steatosis to inflammation and fibrosis with a significant risk for the development of cirrhosis. It is highly prevalent and is associated with significant adverse outcomes both through liver-specific morbidity and mortality but, perhaps more important, through adverse cardiovascular and metabolic outcomes. It is closely associated with type 2 diabetes and obesity, and both of these conditions drive progressive disease toward the more advanced stages. The mechanisms that govern hepatic lipid accumulation and the predisposition to inflammation and fibrosis are still not fully understood but reflect a complex interplay between metabolic target tissues including adipose and skeletal muscle, and immune and inflammatory cells. The ability to make an accurate assessment of disease stage (that relates to clinical outcome) can also be challenging. While liver biopsy is still regarded as the gold-standard investigative tool, there is an extensive literature on the search for novel noninvasive biomarkers and imaging modalities that aim to accurately reflect the stage of underlying disease. Finally, although no therapies are currently licensed for the treatment of NAFLD, there are interventions that appear to have proven efficacy in randomized controlled trials as well as an extensive emerging therapeutic landscape of new agents that target many of the fundamental pathophysiological processes that drive NAFLD. It is highly likely that over the next few years, new treatments with a specific license for the treatment of NAFLD will become available.
Abstract 657: Long Noncoding RNA Ppp1r1b Regulates Myogenic Differentiation Through Modulating Histone 3 Methylation
Authors: Xuedong Kang, Yan Zhao, Joseph Wu, Stanley F Nelson, Marlin Touma
Journal: Circulation Research (2019)

Introduction: Emerged as critical epigenetic regulators of the transcriptome, the long noncoding RNAs (lncRNAs) play important roles in cardiac development and might be targeted to treat human cardiomyocyte dysfunction in congenital heart disease. In our work, we identified a novel lncRNA that regulates myogenic differentiation. Methods: Antisense oligonucleotides (GapmeR) were used to suppress Ppp1r1b-lncRNA. Chromatin immunoprecipitation (CHIP) and chromatin isolation by RNA purification (CHIRP) were used to analyze gene specific histone modification level and lncRNA:chromatin interaction, respectively. RNA pull-down and RNA immunoprecipitation (RIP) were used to identify the protein molecules that interact with Ppp1r1b-lncRNA. Results: By silencing Ppp1r1b-lncRNA, C2C12, a skeletal myoblast cell line, and human-induced pluripotent stem cell derived cardiomyocytes failed to develop fully differentiated myotubes. Analysis of GapmeR injected neonatal mouse heart ( in vivo ) and siRNA silenced human myoblasts ( in vitro ) further confirmed the role of Ppp1r1b-lncRNA in normal myogenesis. Members of the MyoD family of muscle-specific transcription factors were not induced during myogenic differentiation in C2C12 cells treated with Ppp1r1b-lncRNA specific GapmeR. Proteins essential for striated muscle development were also suppressed in Ppp1r1b-lncRNA- deficient cells. Histone modification analysis revealed enrichment of histone tri-methylation at Myogenin and MyoD1 promoters in GapmeR treated C2C12 cells. Subsequently, lncRNA- protein complex isolation and lncRNA-DNA interaction assays confirmed Ppp1r1b-lncRNA function. Conclusions: Our findings support important role of Ppp1r1b-lncRNA in promoting myogenic differentiation. Ppp1r1b-lncRNA function is mediated by inhibiting histone methylation on promoters of key myogenic genes. Particularly, the identification of EZH2 in pulled Pp1r1b-lncRNA: protein complex supports that Polycomb repressive complex 2 is involved in Ppp1r1b-lncRNA modulated myoblast differentiation. The recovery of MyoD1 promoter DNA in isolated lncRNA: chromatin DNA interactome implies that Ppp1r1b-lncRNA regulates transcription by recruiting PRC2 complex to its target genes.