tbuckley/cabot-search huggingface dataset:
Abstract 135: Hypoxia Induced Defects in 26S Proteasome Machinery Causes Loss Of Immunoprivilege of Allogeneic Mesenchymal Stem Cells
Authors: Ejlal Abu-El-Rub, Weiang Yan, Glen Lester Sequiera, Niketa Sareen, Sanjiv Dhingra
Journal: Circulation Research (2019)

The poor survival of transplanted allogeneic mesenchymal stem cells (MSCs) in the recipient heart has dampened the overall enthusiasm of allogeneic MSCs based clinical trials. Outcome of recent studies suggests that the phenotype of transplanted cells changes from immunoprivileged to immunogenic state that leads to rejection of implanted cells by host immune system. In this study, we present a novel mechanism of immune switch in MSCs. We found that hypoxia/or ischemic environment shifts immunological landscape of MSCs from immunoprivileged to immunogenic state. The immunoprivilege of MSCs is preserved by absence of major histocompatibility complex class II (MHC-II) molecule. Our studies demonstrate that 26S proteasome-mediated degradation of MHC-II prevents its expression on cell surface in MSCs and preserves their immunoprivilege. The exposure to hypoxia results in dissociation of 19S and 20S subunits, and inactivation of 26S proteasome. This promotes accumulation of MHC-II and increases immunogenicity of MSCs. We also found that a chaperon protein HSP90α is responsible for 26S proteasome activity in normoxic MSCs. The level of HSP90α decreases in hypoxic MSCs that leads to increase in immunogenicity. Maintaining HSP90α levels in hypoxic MSCs prevents 26S inactivation and preserves immunoprivilege of MSCs. Therefore, hypoxia-induced defects in 26S proteasome assembly causes loss of immunoprivilege of allogeneic MSCs. Preserving 26S proteasome activity in MSCs maintains immunoprivilege and prevents rejection of allogeneic MSCs in the heart. (This work was supported by CIHR)
FINAL Results of an Phase, Multicenter, Randomied, Controlled OPEN LEVEL Trial: Decitabine Therapy in Patients with Myelodysplastic Syndromes
Authors: Zonghong Shao, Hui Liu, Hao Jiang, Hongyan Tong, Ruixiang Xiang, Linhua Yang, Hongguo Zhao, Jian Ouyang, Hai Bai, Hui Sun, Li Hou, Ming Jiang, Zeng Yun, Zhuogang Liu, Aibin Liang, Yinghua Xie, Kang Yu, Zhimin Zhai, Li Liu
Journal: Blood (2018)
CD34+ Derived Microparticles Regulate Apoptosis in Normal and Acute Myeloid Leukemia Cells
Authors: Angeliki Xagorari, Sarantis Tsetsakos, Zoi Katana, Konstantinos Krikonis, Anastasia Kouvatsi, Katerina Chlichlia, Achilles Anagnostopoulos, Damianos Sotiropoulos
Journal: Blood (2018)
Abstract 863: Pathological Roles of Senometabolites in Cardiovascular Disorders
Authors: Ippei Shimizu, Yohko Yoshida, Ryutaro Ikegami, Tohru Minamino
Journal: Circulation Research (2019)

Mechanisms contributing for the synchronization of aging are yet to be defined. Here, we define “senometabolite” as circulating metabolites having causal roles for the synchronization and progression of aging. Analyzing metabolomic studies in coronary plaque corrected with directional coronary atherectomy (DCA), we found that hydroxyl-metabolite significantly increased in patients with unstable angina compared with stable angina. We generated murine diet induced obese model and found this metabolite increased in aorta and plasma. Administration of this metabolite into human umbilical vein endothelial cells (HUVECs) induced cellular senescence, and immunofluorescence study showed that putative transhydrogenase increased in patients with atherosclerotic disorders. We did metabolomics studies in aged individuals or patients with heart failure and identified another metabolite, oxidized choline, increased under these conditions compared to respective controls. We generated murine left ventricular (LV) pressure overload model and found that oxidized choline increased both in plasma and failing heart. Administration of oxidized choline deteriorated cardiac function, in contrast, genetic model showed suppression of this metabolite ameliorated systolic dysfunction in LV pressure overload model. Proteomic study showed that oxidized choline reduced the expression of cytochrome c oxidase subunit1, and metabolomics study showed that both ATP and phosphocreatine level significantly reduced in cardiac tissues of wild type mice administrated with this metabolite. Administration of oxidized choline also reduced muscle strength, induced fibrosis in skeletal muscle, and electron microscopy showed an increase in dysfunctional mitochondria both in the heart and skeletal muscle. In aged wild type mice, metabolomic study showed oxidized choline increased in plasma. Aging process is still mysterious and continues to be an interesting topic to be explored. Our findings indicate that circulating senometabolites contribute for the progression of pathologies in age related disorders.
Use of a question prompt list (QPL) to facilitate communication between patients with metastatic cancer and their oncologists.
Authors: Tonjeh Mary Stella Bah, Amber McKenna, Anu Paul, Jay M. Marion, Kristina Gambino, Meagan Tinsley, Elizabeth Person, Laci Edwards
Journal: Journal of Clinical Oncology (2019)

187 Background: Difficult conversations require an immense amount of patience. Yet on average doctors allow patients 11 seconds to speak before interrupting, which makes determining the patient’s agenda and goals of care incredibly difficult. Most patients expect their doctor to initiate prognosis and end of life care conversations. An inexpensive, effective way to increase these conversations is with a Question Prompt List (QPL). Our study examines QPL use with patients who are at least three months into treatment for metastatic cancer and includes a pre and post-visit interview to provide a within-group analysis of the QPL’s effect on their understanding of disease state, prognosis, and goals of treatment. Our patient population includes patients of lower socioeconomic background and a higher percentage of African Americans. Methods: 35 out of 155 eligible patients identified by chart review were enrolled in the study. They were interviewed about their diagnosis and prognosis before their oncologists visit. At the end of the interview, patients were given a QPL and encouraged to read it. Once the oncologists completed the visit, the researcher conducted a final interview about their disease state. Results: Before seeing their oncologist, 26 patients (74%) completely read the QPL. Most patients would recommend more physicians use this tool (77%). Of note, patients thought of new questions or concerns (51%), felt more comfortable asking questions (46%), and reported asking more questions compared to prior visits (34%). A staggering majority (68%) of patients reported never having a prognosis discussion prior to today’s visit. Previously, only 15 patients (43%) understood their treatment was palliative compared to 19 patients (54%) after this visit. Conclusions: The QPL was viewed as beneficial by most patients and increased question asking, prognosis conversations, and accuracy of goals of treatment knowledge. The QPL tool is inexpensive and requires minimal work by office staff to implement. We plan to expand our study and if results remain unchanged, we will look at studies to investigate a shortened QPL given at an initial consultation and used at subsequent visits.
Antibiotic efficacy varies based on the infection model and treatment regimen for <i>Pseudomonas aeruginosa</i>
Authors: Cristina Cigana, Serena Ranucci, Alice Rossi, Ida De Fino, Medede Melessike, Alessandra Bragonzi
Journal: European Respiratory Journal (2019)

Antibiotic discovery and preclinical testing are needed to combat the Pseudomonas aeruginosa health threat. Most frequently, antibiotic efficacy is tested in models of acute respiratory infection, with chronic pneumonia remaining largely unexplored. This approach generates serious concerns about the evaluation of treatment for chronically infected patients, and highlights the need for animal models that mimic the course of human disease. In this study, the efficacy of the marketed antibacterial drugs tobramycin (TOB) and colistin (COL) was tested in murine models of acute and chronic P. aeruginosa pulmonary infection. Different administration routes (intranasal, aerosol or subcutaneous) and treatment schedules (soon or 7 days post-infection) were tested. In the acute infection model, aerosol and subcutaneous administration of TOB reduced the bacterial burden and inflammatory response, while intranasal treatment showed modest efficacy. COL reduced the bacterial burden less effectively but dampened inflammation. Mice treated soon after chronic infection for 7 days with daily aerosol or subcutaneous administration of TOB showed higher and more rapid body weight recovery and reduced bacterial burden and inflammation than vehicle-treated mice. COL-treated mice showed no improvement in body weight or change in inflammation. Modest bacterial burden reduction was recorded only with aerosol COL administration. When treatment for chronic infection was commenced 7 days after infection, both TOB and COL failed to reduce P. aeruginosa burden and inflammation, or aid in recovery of body weight. Our findings suggest that the animal model and treatment regimen should be carefully chosen based on the type of infection to assess antibiotic efficacy.
Family caregiver needs assessment in a gynecologic oncology practice: An ASCO quality training program project.
Authors: Heidi AS Donovan, Michelle M. Boisen, Lauren Hand, Young Ji Lee, Nora Lersch, Mary Roberge, Barbara Suchonic, Teresa Thomas, Grace Campbell
Journal: Journal of Clinical Oncology (2019)

178 Background: Family caregiver (CG) demands in gynecologic oncology (gynonc) put CGs at risk for anxiety, depression, and inability to care for loved ones. Resources exist to support patients, but systematic support for CGs is lacking. Fifty percent of CGs in our clinic report 9 or more distressing unmet needs. Thus, an ASCO Quality Training Program (QTP) project aimed to assess and intervene on the needs of 75% of gynonc family CGs (identified in a concurrent QTP project). Methods: An interprofessional team reviewed baseline data, defined the problem and project aim, created process maps, and identified root causes of poor CG documentation. With stakeholder buy-in we implemented eight successive PDSA cycles over 6 months to address root causes. Biweekly team meetings were throughout the PDSA cycles. Outcomes were percent of CGs with 1) needs assessed, and 2) intervention received. Results: Root causes of poor CG assessment included 1) no protocol to assess/respond to CG needs; 2) no designated staff to ‘own’ CG assessment; and 3) lack of understanding of the value of CG support among clinicians. PDSA 1 (pre- launch) included: develop CG assessment/intervention protocol; create CG tracking database; pursue EHR capabilities. PDSA cycle 2-3 prioritized information provision about resources (52-73% of CGs) over individualized assessment (20-23% of CGs) due to the large number of CGs identified. Subsequent PDSAs sought to increase assessment effectiveness by focusing assessment/intervention on CGs of newly diagnosed and high risk patients. While there was variability in outcomes across cycles (Table), by PDSA cycle 8, staff had assessed and intervened on 58% and 50% of CGs, respectively. In addition, multiple potential serious CG and patient mental health crises were avoided from team interventions. Conclusions: CG assessment improved from 28% at baseline to &gt;50% post implementation. Further efforts to more fully integrate assessment and tracking into EHR to reduce the burden of CG tracking over time is underway. [Table: see text]
Durable Responses Observed with JAK Inhibition in T-Cell Lymphomas
Authors: Alison J. Moskowitz, Eric Jacobsen, Jia Ruan, Jonathan H. Schatz, Obadi Obadi, Kristin Motylinski, Christine Jarjies, Natasha Galasso, Helen Hancock, Theresa Davey, Patricia Myskowski, Ahmet Dogan, Giorgio Inghirami, David M Weinstock, Steven M. Horwitz
Journal: Blood (2018)
Stem Cell Transplantation for Congenital Dyserythropoietic Anemia. a Retrospective Study on Behalf of Severe Aplastic Anemia Working Party of the European Blood and Marrow Transplantation Group (EBMT)
Authors: Maurizio Miano, Dirk-Jan Eikema, P.J. Van 't Veer, Mahmoud Aljurf, Johan Maertens, Gülyüz Öztürk, Cristina Diaz de Heredia, Matthias Wölfl, Constantijn J.M. Halkes, Ansgar Schulz, Gerard Socie, Kim Vettenranta, Elena Skorobogatova, Marco Zecca, M Markiewicz, M Rovira, Jorge Sierra, Duygu Cetinkaya, Bulent Antmen, Jean-Hughes Dalle, Stefano Giardino, Amal Al-Seraihy, Rose-Marie Hamladji, Vassiliki Kitra-Roussou, Giorgio La Nasa, Gergely Krivan, Regis Peffault De Latour, Carlo Dufour
Journal: Blood (2017)
Utilizing Y Chromosome FISH to Determine the Origin of Post-Transplant Lymphoproliferative Disease in Solid Organ Transplant Recipients
Authors: James B. Ford, Sanmann N Jennifer, Kelly Erickson, Wendy J Grant, Pamela A Althof, Alan Langnas, Valerie Shostrom, Martin Bast, Timothy C. Greiner, Peter F. Coccia
Journal: Blood (2018)
Abstract 494: Role of Slug / PIP Axis in Pulmonary Hypertension Secondary to Pulmonary Fibrosis
Authors: Gregoire Ruffenach, Mylene Vaillancourt, Jason Hong, Nancy Cao, Christine Cunningham, Rajan Saggar, Srininivasa Reddy, Soban Umar, Gregory Fishbein, Mansoureh Eghbali
Journal: Circulation Research (2019)

Pulmonary hypertension (PH) secondary to pulmonary fibrosis (PF-PH) is the second most common cause of PH. While never studied in detail, pathology reports suggest that vascular remodeling (VR) differs between PF and PF-PH. In PF, VR is mainly limited to fibrotic areas, whereas in PF-PH, it also exist in non-fibrotic areas. These histological differences suggest potential molecular differences. To better understand this mechanism, we investigated the expression of the transcription factor Slug which is known to play a role in PH and PF. Using explanted rat (n=7/group) and human (n=7-14/group) lungs, we compared lung fibrosis, VR and Slug expression between non-fibrotic and fibrotic areas in PF and PF-PH. Online microarray data (GSE24988) were used to find the targets of Slug that are implicated in VR. A new animal model recapitulating our findings in patients was used to test the therapeutic potential of Slug inhibition (n=10/group). This model is based on intra-tracheal instillation of bleomycin (2.5mg/Kg) at day 0 and 2weeks later, an injection of monocrotaline (60mg/kg). PH was assessed by right ventricular systolic pressure (RVSP). P&lt;0.05 are considered significant. In both PF and PF-PH patients, fibrotic areas (PF29±4; PF-PH37±3) exhibit significantly increased VR when compared to non-fibrotic areas of the lung (PF 22±1; PF-PH 31±6). PF-PH patients have increased pulmonary vascular thickening in both areas vs PF patients. This is concomitant with an increased number of Ki67+ vascular cells in PF-PH (12±2%) vs PF (8±1%) as well as an upregulation of Slug in PF-PH patients (2.3±0.5) vs PF (1±0.1). Co-immunolabeling with CD68 demonstrate that macrophages are the main cell type responsible for Slug up-regulation in PF-PH. Human microarray data reveal an up-regulation of the Prolactin-induced protein (PIP) in PF-PH vs PF (9±3 vs 1±0.4). PIP is an extracellular transcriptional target of Slug, known to promote cell proliferation. In-vitro, PIP significantly increases pulmonary arterial smooth muscle cell proliferation in a dose dependent manner. Finally, Slug inhibition decreases RVSP (47±3 vs 62±3mmHg) in an animal model of PF-PH. There are histological differences between PF-PH and PF lungs that are at least in part mediated by a Slug/PIP axis leading to VR.
Cdk4/6 Inhibitor PD 0332991 Demonstrates Cell Cycle Inhibition Via FLT-PET Imaging and Tissue Analysis in Patients with Recurrent Mantle Cell Lymphoma
Authors: John P. Leonard, Ann LaCasce, Mitchell R Smith, Ariela Noy, Jeffrey T Yap, Annick D Van den Abbeele, Jian Q Yu, Selina Chen-Kiang, Scott A Ely, Shankar Vallabhajosula, Lucian R Chirieac, Steven M Larson, Geoffrey I Shapiro, Heiko Schoder
Journal: Blood (2008)
Improving and Expanding Estimates of the Global Burden of Disease Due to Environmental Health Risk Factors
Authors: Rachel M. Shaffer, Samuel P. Sellers, Marissa G. Baker, Rebeca de Buen Kalman, Joseph Frostad, Megan K. Suter, Susan C. Anenberg, John Balbus, Niladri Basu, David C. Bellinger, Linda Birnbaum, Michael Brauer, Aaron Cohen, Kristie L. Ebi, Richard Fuller, Philippe Grandjean, Jeremy J. Hess, Manolis Kogevinas, Pushpam Kumar, Philip J. Landrigan, Bruce Lanphear, Stephanie J. London, Andrew A. Rooney, Jeffrey D. Stanaway, Leonardo Trasande, Katherine Walker, Howard Hu
Journal: Environmental Health Perspectives (2019)

BACKGROUND:The Global Burden of Disease (GBD) study, coordinated by the Institute for Health Metrics and Evaluation (IHME), produces influential, data-driven estimates of the burden of disease and premature death due to major risk factors.Expanded quantification of disease due to environmental health (EH) risk factors, including climate change, will enhance accuracy of GBD estimates, which will contribute to developing costeffective policies that promote prevention and achieving Sustainable Development Goals.OBJECTIVES: We review key aspects of the GBD for the EH community and introduce the Global Burden of Disease-Pollution and Health Initiative (GBD-PHI), which aims to work with IHME and the GBD study to improve estimates of disease burden attributable to EH risk factors and to develop an innovative approach to estimating climate-related disease burden-both current and projected.METHODS: We discuss strategies for improving GBD quantification of specific EH risk factors, including air pollution, lead, and climate change.We highlight key methodological challenges, including new EH risk factors, notably evidence rating and global exposure assessment.DISCUSSION: A number of issues present challenges to the scope and accuracy of current GBD estimates for EH risk factors.For air pollution, minimal data exist on the exposure-risk relationships associated with high levels of pollution; epidemiological studies in high pollution regions should be a research priority.For lead, the GBD's current methods do not fully account for lead's impact on neurodevelopment; innovative methods to account for subclinical effects are needed.Decisions on inclusion of additional EH risk-outcome pairs need to be guided by findings of systematic reviews, the size of exposed populations, feasibility of global exposure estimates, and predicted trends in exposures and diseases.Neurotoxicants, endocrinedisrupting chemicals, and climate-related factors should be high priorities for incorporation into upcoming iterations of the GBD study.Enhancing the scope and methods will improve the GBD's estimates and better guide prevention policy.
Optimization of inpatient chemotherapy administration utilizing evaluation intervals.
Authors: Sabarina Ramanathan, Avani Yenamandra, Aparna Vuppala, Khine Shan, Hugo R. Lara-Martinez, Rabia Khan, Shaun Bryan Hanson, Ahmed Safa, Michael Joseph McCormack, Kristine Marie Ward, Michael Styler
Journal: Journal of Clinical Oncology (2019)

75 Background: Inpatient chemotherapy requires an interdisciplinary approach to achieve shorter hospital stays and decrease cost. A quality improvement project at Hahnemann University Hospital was undertaken to identify delays in the process from admission to chemotherapy initiation in this population. Methods: Time stamps were recorded for patient arrival (door to floor), order placement (floor to order), and administration (order to chemo) to establish a baseline. A multidisciplinary team of pharmacy, nursing, and physicians was developed to address inefficiencies. There were three evaluation intervals: May - October 2015 (Part I), January 2017 - October 2018 (Part II) and October - December 2018 (Part III). Data collected from Part I established a baseline door-to-chemo time (DTC) of 7.2 hrs. Post Part I, prompt communication of patient arrival and delays in chemotherapy hanging were addressed. Part II interventions were outpatient consents and labs, timely order placement, and utilization of order sets. Pharmacy-nurse communication and equal distribution of patients through the week was implemented in Part III. The primary outcome measure was difference in DTC. Results: 200 admissions were reviewed. Results of the evaluation intervals are shown in Table. After the first evaluation interval, DTC improved from 7.18 to 5.96 hrs. DTC further decreased to 5.78 hrs post intervention II. The longest delay was between chemotherapy order and administration. Conclusions: DTC significantly improved between intervals with the above interventions. Utilizing a standardized nursing checklist and biweekly multidisciplinary meetings to emphasize prioritization will further decrease DTC. DTC reduction will decrease cost and increase patient satisfaction. [Table: see text]
Operative technical tricks and 12-month outcomes of diverticular peroral endoscopic myotomy (D-POEM) in patients with symptomatic esophageal diverticula
Authors: Amit Maydeo, Gaurav K. Patil, Ankit Dalal
Journal: Endoscopy (2019)

Submucosal tunneling diverticular septotomy by diverticular peroral endoscopic myotomy (D-POEM) has emerged as an alternative to surgery for symptomatic esophageal diverticula, but its medium to long-term outcomes are currently unexplored.D-POEM for patients with symptomatic esophageal diverticula was prospectively studied to assess its safety and the 12-month outcomes.25 patients (72 % male; median age 61 years [range 48 - 88]) with a Zenker's diverticulum (n = 20) or epiphrenic diverticulum (n = 5) were included. Major indications were dysphagia, recurrent bronchoaspiration, and foreign body sensation in 20 patients (80 %), with a mean symptom duration of 2.5 years (range 1 - : 4). Complete submucosal tunneling septotomy was achieved in a mean of 36 minutes (range 25 - : 45), with 100 % technical success. The median hospitalization was 5 days (range 4 - : 10). The mean (standard deviation) Eckardt Score improved significantly from 13.2 (1.0) at baseline to 3.2 (1.4) at 12 months (P < 0.001) with clinical success in 19/22 patients (86 %) and no long-term adverse events.D-POEM appears safe and durable in patients with esophageal diverticula. Further multicenter studies with a larger patient cohort are warranted.
Pomalidomide 3rd Line Versus 4th Line for RRMM
Authors: Cécile Gruchet, Stephanie Guidez, Valentine Richez, Cyrille Hulin, Eric G. Voog, Aurore Perrot, Margaret Macro, Olivier Decaux, Gueneau Pauline, Denis Caillot, Anne-Marie Stoppa, Pascal Lenain, Pierre Lebreton, Bruno Royer, Charles Lancesseur, Kamel Laribi, Katell Le Du, Charline Moulin, Catalina Montes De Oca, Arnaud Jaccard, Lotfi Benboubker, Carine Chaleteix, Thomas Systchenko, Niels Moya, Florence Sabirou, Anthony Levy, Arthur Bobin, Paul Franques, Helene Gardeney, Cecile Tomowiak, Deborah Desmier, Antoine Machet, Herve Avet Loiseau, Xavier Leleu
Journal: Blood (2018)