tbuckley/cabot-search huggingface dataset:
Abstract 510: Spatial Transcriptomics Unveil ZBTB11 as a Regulator of Cardiomyocyte Degeneration in Arrhythmogenic Cardiomyopathy
Authors: Cornelis J Boogerd, Grégory P Lacraz, Ábel Vértesy, Ilaria Perini, Hesther de Ruiter, Andreas Brodehl, Petra van der Kraak, Manon Huibers, Nicolaas de Jonge, Jan Philip Junker, Aryan Vink, Eva van Rooij
Journal: Circulation Research (2019)

Introduction: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder characterized by progressive loss of contractile myocardium which is replaced by fibrous and adipose tissue, ventricular arrhythmias, and sudden cardiac death. Fibrofatty replacement extends transmurally with an epi-to-endocardial gradient, yet molecular differences between the transition regions are poorly characterized. Methods and Results: To explore molecular mechanisms underlying ACM we obtained an explanted heart of a 35-year-old male with a known pathogenic PKP2 mutation, c.2544G&gt;A. We utilized Tomo-Seq to acquire a genome-wide transcriptional profile with 100μm-spatial resolution, generating a transmural expression atlas of the ACM heart. Tracing transcriptional differences across the ventricular wall enabled us to identify clusters of genes specific to the myocardium and fibrofatty region. In addition, we detected restricted sites of active remodelling within the myocardium with a clearly distinct gene program. Amongst genes specifically enriched in this composite region was the Zinc Finger and BTB Domain-Containing Protein 11 (ZBTB11). Overexpression of ZBTB11 in human cardiomyocytes induced a differential gene expression profile with striking similarities to the composite region from the Tomo-Seq analysis. Most notably, ZBTB11 induced a TP53 mediated stress response including activation of apoptosis and autophagy. The presence of ZBTB11-positive cardiomyocytes flanking fibrofatty islands was confirmed in ACM patients harbouring other PKP2 mutations, as well as ACM and DCM hearts with mutations in non-desmosomal genes. We are currently exploring the ZBTB11 transcriptional network, and its role in disease progression in human cardiomyopathies. Conclusions: Using a spatial transcriptomics approach on a human ACM heart we have identified ZBTB11 as a novel marker of cardiomyocyte degeneration in cardiomyopathies. ZBTB11 induces autophagy and apoptosis and therefore may be relevant for the development of biomarker assays and in identifying novel targets for therapies against cardiomyopathies.
Impact of community practice on providing in-patient oncology and hematology consults via telemedicine to remote rural hospital.
Authors: Natalie R. Dickson, Larry Edward Bilbrey, Mathew John Joseph, Janet A Matheny, Stacey L Poole, Jeffrey Patton
Journal: Journal of Clinical Oncology (2019)

278 Background: A rural oncology/hematology clinic located a far distance from the local community hospital was not able to provide hospital consultation support. Collaboration between the practice and the hospital resulted in a telemedicine pilot study to provide oncology and hematology consults to in-patients using a telemedicine robot that connected patients to a hematologist/oncologist (heme/onc) over the internet. Methods: When an appropriate patient was identified at the hospital, a referring provider contacted the heme/onc for a consult. The heme/onc determined and relayed the appropriate time to schedule and perform the telemedicine consult. The referring provider arranged for hospital staff to deliver the telemedicine robot to the patient’s room at the scheduled time. The heme/onc reviewed clinical data in the hospital EMR and logged into the telemedicine robot to speak in consultation with the patient. Notes and orders were placed in the EMR. Out-patient follow-up at the oncology/hematology clinic was scheduled as needed. Supporting front-office and clinical workflows were developed, and policy and procedure established. Surveys were sent to patients and referring providers. Results: At baseline, hospital consults were not provided. In 2018, there were 27 oncology/hematology consults, of which 89% (24 of 27) were for malignancies. 52% (14 of 27) were seen in the clinic after discharge. To date 40 telemedicine consults have been completed. Patient and referring physician satisfaction are inconclusive due to low survey return. Conclusions: Telemedicine provides an effective means to provide specialty consultative support to rural hospitals by remote community providers. Despite the complexity and sensitive nature of oncology and hematology concerns, the technology has been embraced by referring providers and patients.
Non-invasive score using non-contrast-enhanced MRI for identification of clinically significant portal hypertension (CHESS1802): a prospective, multicentre study
Authors: Yanna Liu, Tianyu Tang, Yifei Huang, Jiansong Ji, Qian Yu, Xiangpan Meng, Jinqiang Liu, Dengxiang Liu, Changchun Liu, Chuan Liu, Ruoyang Shao, Chunqing Zhang, Wenhui Wang, Zhiwei Wang, Weidong Wang, Min Yuan, Lei Li, Changzeng Zuo, Jitao Wang, Zhongwei Zhao, Guangchuan Wang, Mingxing Li, Qingbo Liu, Junqiang Lei, Weimin An, Shenghong Ju, Xiaolong Qi
Journal: The Lancet (2019)
Association of β-Amyloid Burden With Sleep Dysfunction and Cognitive Impairment in Elderly Individuals With Cognitive Disorders
Authors: Jason C. You, Erica Jones, Devon E. Cross, Abigail C. Lyon, Hyunseung Kang, Andrew B. Newberg, Carol F. Lippa
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Evidence shows that sleep dysfunction and β-amyloid (Aβ) deposition work synergistically to impair brain function in individuals with normal cognition, increasing the risk of developing dementia later in life. However, whether Aβ continues to play an integral role in sleep dysfunction after the onset of cognitive decline in individuals with dementia is unclear. <h3>Objective</h3> To determine whether Aβ deposition in the brain is associated with subjective measures of sleep quality and cognition in elderly individuals with cognitive disorders. <h3>Design, Setting, and Participants</h3> A nested survey study was conducted at the Cognitive Disorders and Comprehensive Alzheimer Disease Center of Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. Participants included patients aged 65 years and older with cognitive disorders verified by neuropsychological testing. Eligible participants were identified from a referral center–based sample of patients who underwent fluorine 18–labeled florbetaben positron emission tomography imaging at Thomas Jefferson University Hospital as part of the multicenter Imaging Dementia-Evidence for Amyloid Scanning study. Data collection and analysis occurred between November 2018 and March 2019. <h3>Main Outcomes and Measures</h3> Sleep quality was measured via responses to sleep questionnaires, Aβ deposition was measured via fluorine 18–labeled florbetaben positron emission tomography, and cognition was measured via Mini-Mental State Examination (MMSE) performance. <h3>Results</h3> Of the 67 eligible participants, 52 (77.6%) gave informed consent to participate in the study. Of the 52 enrolled participants (mean [SD] age, 76.6 [7.4] years), 27 (51.9%) were women. Daytime sleepiness was associated with Aβ deposition in the brainstem (<i>B</i> = 0.0063; 95% CI, 0.001 to 0.012;<i>P</i> = .02), but not MMSE performance (<i>B</i> = −0.01; 95% CI, −0.39 to 0.37;<i>P</i> = .96). The number of nocturnal awakenings was associated with Aβ deposition in the precuneus (<i>B</i> = 0.11; 95% CI, 0.06 to 0.17;<i>P</i> &lt; .001) and poor MMSE performance (<i>B</i> = −2.13; 95% CI, −3.13 to −1.13;<i>P</i> &lt; .001). Mediation analysis demonstrated an indirect association between Aβ deposition and poor MMSE performance that relied on nocturnal awakenings as an intermediary (<i>B</i> = −3.99; 95% CI, −7.88 to −0.83;<i>P</i> = .01). <h3>Conclusions and Relevance</h3> Nighttime sleep disruption may mediate the association between Aβ and cognitive impairment, suggesting that there is an underlying sleep-dependent mechanism that links Aβ burden in the brain to cognitive decline. Further elucidation of this mechanism may improve understanding of disease processes associated with Aβ accumulation.
Abstract 615: The Cardiac Myosin Inhibitor, CK-3773274, Reduces Contractility in the R403q Mouse Model of Hypertrophic Cardiomyopathy
Authors: Darren T Hwee, Yangsong Wu, Peadar Cremin, Bradley P Morgan, Fady I Malik, Eva R Chin
Journal: Circulation Research (2019)

Cardiac sarcomere hypercontractility appears to underlie pathological hypertrophy and fibrosis in select genetic hypertrophic cardiomyopathies. The small molecule, CK-3773274, is a novel cardiac myosin inhibitor that decreases contractility in vitro and in healthy animals in vivo . The objective of this study was to evaluate the effect of CK-3773274 in the genetic R403Q mouse model of hypertrophic cardiomyopathy. At approximately 40 weeks of age, left ventricular wall dimensions were determined by echocardiography in male wild type (WT) and heterozygous R403Q mice. As an indicator of cardiac hypertrophy, R403Q mice had significantly greater septal and posterior wall thickness than WT mice (septal wall WT: 0.93 ± 0.03 mm vs. R403Q: 1.22 ± 0.08 mm; posterior wall WT: 0.84 ± 0.04 mm vs. R403Q: 1.09 ± 0.04 mm; mean ± SEM, p&lt; 0.05). R403Q mice were treated with single oral doses of CK-3773274 ranging from 0.25 to 1.5 mg/kg and fractional shortening (FS) and heart rate were assessed at select time points over a 24-hour period. One hour after dose administration, CK-3773274 significantly reduced FS in a dose-related fashion relative to pre-dose baseline values (FS % R403Q baseline: 55.5 ± 2%; 0.25 mg/kg: 43.9 ± 2%; 1 mg/kg: : 27.3 ± 2%; 1.5 mg/kg: 13.7 ± 1%; mean ±SEM, p&lt;0.05 vs. baseline at all doses) without any changes to heart rate. At all dose levels, fractional shortening returned to baseline values by 24 hours. The plasma concentration at 10% and 50% reduction of FS relative to baseline (IC 10 and IC 50 ) was 0.11 and 0.78 μM, respectively. In summary, single oral dose administration of CK-3773274 reduced fractional shortening in a dose and concentration-dependent manner in the genetic R403Q mouse model of hypertrophic cardiomyopathy. Cardiac myosin inhibition may be a viable approach to reduce underlying hypercontractility of the cardiac sarcomere in hypertrophic cardiomyopathies.
IL-35 Suppresses Lipopolysaccharide-Induced Endothelial Cell Activation Through Downregulation of MAPK Signaling-Mediated Upregulation of Adhesion Molecule VCAM-1
Authors: Xiaojin Sha, Shu Meng, Xinyuan Li, Jahaira Lopez Pastrana, Hong Wang, Xiao-Feng Yang
Journal: Blood (2012)
Abstract 864: Mitochondrial Morphology During Stress is Regulated by GJA1-20k Interaction With Actin
Authors: Daisuke Shimura, Rachel Baum, Shaohua Xiao, TingTing Hong, Robin M Shaw
Journal: Circulation Research (2019)

Connexin (Cx) 43 is encoded by the GJA1 gene and GJA1-20k has been identified as an N-terminal truncation of Cx43 generated endogenously by internal translation. Previously we have found GJA1-20k increases with ischemic stress and induces actin organization and, in mice, mitochondrial biogenesis. In this study we explored the acute effect of GJA1-20k on mitochondria. We transfected GFP-tagged GJA1-20k plasmid into HEK293T cells and analyzed mitochondrial morphology by fluorescent microscopy. We found GJA1-20k results in mitochondria that are associated with actin and also are smaller and more circular than in GST-transfected control cells. In addition, quantitative analysis indicated preservation of mitochondrial area and thus enhanced mitochondrial fission in the presence of GJA1-20k. Disruption of actin polymerization inhibited the effect of GJA1-20k on mitochondrial fission as did use of the actin stabilizer phalloidin, indicating the need for robust actin dynamics for GJA1-20k to be effective. These data suggest that the interaction between GJA1-20k and actin cytoskeleton is necessary for stress related mitochondrial fission. The results indicate that, during stress, upregulated GJA1-20k recruits the actin cytoskeleton to directly affect mitochondrial dynamics and cellular metabolic function.
Health-Related Quality of Life and Symptoms in Myelofibrosis Patients Treated with Ruxolitinib Versus Best Available Therapy
Authors: Claire N. Harrison, Jean-Jacques Kiladjian, Haifa Kathrin Al-Ali, Heinz Gisslinger, Laurent Knoops, Roger J. Waltzman, Estella T. Mendelson, Xiaolei Zhou, Catherine Copley-Merriman, Deborah S. Hunter, Richard S. Levy, Francisco Cervantes, Francesco Passamonti, Alessandro M. Vannucchi, Tiziano Barbui, Giovanni Barosi
Journal: Blood (2011)
A Blastic Plasmacytoid Dendritic Cell Neoplasm-like Phenotype Identifies a Subgroup of NPM1-Mutated AML Patients with Worse Prognosis While Has Not Predictive Value in NPM1-Wt AML
Authors: Fabio Guolo, Paola Minetto, Annalisa Kunkl, Elisabetta Tedone, Marino Clavio, Maurizio Miglino, Fabrizio Caviglia, Nicoletta Colombo, Antonia Cagnetta, Michele Cea, Filippo Ballerini, Jean Louis Ravetti, Marco Gobbi, Roberto Massimo Lemoli
Journal: Blood (2018)
Oral (O) versus intravenous (IV) etoposide and platinum in the treatment of extensive-stage small cell lung cancer (SCLC).
Authors: Scott Alan Dorroh, Eric R Siegel, Rangaswamy Govindarajan
Journal: Journal of Clinical Oncology (2013)

7597 Background: Platinum and etoposide chemotherapy is the treatment for patients with SCLC. O etoposide is substituted for IV by many clinicians at twice the dose for bioavailability but the outcome of these subjects has not been studied. To compare the efficacy of O vs. IV etoposide in extensive stage SCLC, a retrospective analysis of subjects treated in the VISN 16 network of 10VA hospitals was undertaken. Methods: Subjects with SCLC diagnosed between 10/1/1996 and 9/30/2010 were identified from the VISN-16 tumor registry. Study was limited to extensive disease by excluding those treated with radiation therapy. Chemotherapy details were obtained from the pharmacy data in the VISN 16 database. Overall survival (OS) was computed as the time in months from the first etoposide issue date to the date of death or last contact. Kaplan-Meier methods were used to compute median OS, and etoposide groups were compared via log-rank test. Results: 300 subjects were eligible for analysis, with median age 67 yrs (range 45-84). 295 deaths were observed during 2,419 total months of follow-up. The median OS of all subjects was 6.3 months (interquartile range (IQR) 2.0-11 months). In addition to platinum, 153 subjects received only O etoposide, 147 received some form of IV etoposide. The median duration (IQR) of therapy for all subjects was 29 (1-110) days; 23 days for those who received any IV etoposide and 43 days for those who received only oral etoposide. The median OS was 7.6 months for those who received only O etoposide vs. 5.4 months for any IV etoposide (P&lt;0.0001). In the latter group, those receiving purely IV etoposide had only 1.5 months’ median OS vs. 8.8 months for those receiving both O and IV etoposide (P&lt;0.0001). Conclusions: Survival of subjects with SCLC treated with O etoposide is comparable to those who received a combination of O and IV therapy. Poor OS for those with only IV therapy may be due to selection bias of poor-performance subjects. [Table: see text]
Co-management of elevated glucose in chemotherapy patients in the community: Working with primary care physicians.
Authors: Ellen Shander, Ellen A. Ronnen, Eileen Ruey-Fun Peng, Melissa Isabel Cruz, Beth Balinski, Sharon Ryan
Journal: Journal of Clinical Oncology (2019)

53 Background: Approximately 8-18% of oncology patients also have diabetes. A diabetes diagnosis increases the risk of recurrence by 21% and decreases both overall and cancer-related 5-year survival. Chemotherapy has also been associated with hyperglycemia in non-diabetic patients. At one office in a multi-site outpatient oncology practice in central New Jersey, 13% of 904 chemotherapy patients treated between August 1, 2018 and October 31, 2018 had blood glucose greater than 200 mg/dL. Community practice models post a challenge to coordinated multidisciplinary care. Methods: Between 12/1/18 and 4/1/19, weekly lab reports were run revealing all active chemotherapy patients with glucose levels greater than 200. The initial run in period was 12/1/18-1/31/19, and follow up for the group (while on chemotherapy) was from 2/1/19-4/1/19. Patients and their primary medical doctors (PMDs) were contacted within 2 weeks of lab draw, labs and recent chemotherapy history shared and all communication was documented. Patients with &gt; one blood glucose above 200 were contacted monthly. Concurrent steroid use with chemotherapy and addition/adjustment of antihyperglycemics was also studied. Results: Of 324 patients who entered into the study between 12/1/18 and 1/3/19, 42 had baseline elevated glucose levels. 36 (85%) of the 42 were on concomitant corticosteroids. During the follow up period, 10 (23%) had elevated glucose levels over 200, 32 (76%) patients had levels under 200 consistently. 12 of the 32 (30%) of those patients had documented diabetic medication adjustments. Oncology/PCP communication was documented in 35 (83%) charts compared with 0% prior to the intervention, amongst our office and PMDs. Percentage of patients who saw their PCP during the intervention time will also be presented. Conclusions: Working more closely with PCPs and better electronic data sharing is needed in the community setting. Accurate medication lists and history sharing are critical to optimal multidisciplinary community care. Management of elevated glucose in oncology patients is challenging and multi factorial.
Mytype: A Capture Based Sequencing Approach to Detect Somatic Mutations, Copy Number Changes and IGH Translocations in Multiple Myeloma
Authors: Venkata Yellapantula, Malin Hultcrantz, Even H Rustad, Heather J. Landau, Christine Iacobuzio-Donahue, Theresia Akhlaghi, Ido Amit, Guy Ledergor, Neha Korde, Sham Mailankody, Dickran Kazandjian, Akshar Patel, Niccolo Bolli, Elli Papaemmanuil, Ola Landgren
Journal: Blood (2018)
A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study
Authors: Robert G. Frykberg, Peter J. Franks, Michael Edmonds, Jonathan N. Brantley, Luc Téot, Thomas Wild, Matthew G. Garoufalis, Aliza M. Lee, Janette A. Thompson, Gérard Reach, Cyaandi R. Dove, Karim Lachgar, Dirk Grotemeyer, Sophie C. Renton
Journal: Diabetes Care (2020)

Topical oxygen has been used for the treatment of chronic wounds for more than 50 years. Its effectiveness remains disputed due to the limited number of robust high-quality investigations. The aim of this study was to assess the efficacy of multimodality cyclical pressure Topical Wound Oxygen (TWO2) home care therapy in healing refractory diabetic foot ulcers (DFUs) that had failed to heal with standard of care (SOC) alone.Patients with diabetes and chronic DFUs were randomized (double-blind) to either active TWO2 therapy or sham control therapy-both in addition to optimal SOC. The primary outcome was the percentage of ulcers in each group achieving 100% healing at 12 weeks. A group sequential design was used for the study with three predetermined analyses and hard stopping rules once 73, 146, and ultimately 220 patients completed the 12-week treatment phase.At the first analysis point, the active TWO2 arm was found to be superior to the sham arm, with a closure rate of 41.7% compared with 13.5%. This difference in outcome produced an odds ratio (OR) of 4.57 (97.8% CI 1.19, 17.57), P = 0.010. After adjustment for University of Texas Classification (UTC) ulcer grade, the OR increased to 6.00 (97.8% CI 1.44, 24.93), P = 0.004. Cox proportional hazards modeling, also after adjustment for UTC grade, demonstrated >4.5 times the likelihood to heal DFUs over 12 weeks compared with the sham arm with a hazard ratio of 4.66 (97.8% CI 1.36, 15.98), P = 0.004. At 12 months postenrollment, 56% of active arm ulcers were closed compared with 27% of the sham arm ulcers (P = 0.013).This sham-controlled, double-blind randomized controlled trial demonstrates that, at both 12 weeks and 12 months, adjunctive cyclical pressurized TWO2 therapy was superior in healing chronic DFUs compared with optimal SOC alone.
Outcomes After Reduced-Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) In 163 Pediatric Patients (&lt;18 years old): A Retrospective Study On Behalf Of The SFGM-TC
Authors: Marion Strullu, Myriam Labopin, Regis Peffaut De La Tour, Alexandra Salmon, Jean-Hugues Dalle, Nathalie Fegueux, Catherine Paillard, Gerard Michel, Pierre Rohrlich, Yves Bertrand, Charlotte Jubert, Yves Beguin, Aude-Marie Cardine, Gaelle Guillerm, Jean-Henri Bourhis, Patrick Lutz, Nicole Raus, Fanny Rialland, Mohamad Mohty, Patrice Chevallier
Journal: Blood (2013)
Abstract 131: Cardiomyocyte Renewal and Cardiac Outcomes Following Injury in Young Swine
Authors: Emma J Agnew, Nivedhitha Velayutham, Victoria Moore, Tarek Alsaied, Richard Scott Baker, Kyle W Riggs, Farhan Zafar, Katherine E Yutzey
Journal: Circulation Research (2019)

Objective: Infants with severe congenital heart defects (CHD) typically require lifesaving cardiac surgery. Performing this surgery during a time when the myocardium can proliferate and repair could improve successful outcomes. The mouse heart can regenerate in the first week post-partum, but the mitotic activity of cardiomyocytes (CM) is extended to 1-2-months post-partum in the pig. Thus, the regulation of CM cell cycling ability and renewal in the hearts of young large mammals after injury was examined. Methods &amp; Results: Pigs at postnatal day 30 (n=6) were subjected to cardiac ischemia (1-hour) by temporary occlusion of the left anterior descending (LAD) artery followed by reperfusion (IR), or to sham operation (n=6, no LAD occlusion). LAD occlusion, below the second diagonal branch, provided an effective injury as indicated by increased circulating cardiac troponin-I 2-hours after injury. In addition, ejection fraction (EF) decreased by 46% (57% to 31%) at 2 hours post-ischemia, which was then maintained to the 4-week study end point. Pigs were sacrificed 4 weeks after surgery and histology demonstrated evidence of scar formation in the area of injury. However, no change in number of proliferating CM or cell death (via pHH3 or TUNEL immunohistochemistry respectively) was detected in IR pigs vs sham, or between regions of the left ventricle. Conclusions: Here we report a successful ischemic injury method, at an age previously not reported in swine. Pigs did not continue to decline towards heart failure following an IR injury at 1 month of life, with preservation of EF up to 4-weeks post-injury. This is also without a change in CM cell cycling activity at 2 months of age. This study highlights that even in the presence of a scar, young, large mammals can adapt to cardiac injury to maintain cardiac function. The pathways regulating scar formation and CM cell cycling are being further investigated by RNA-seq studies. If similar mechanisms operate in humans, it may be beneficial to perform CHD surgeries at a younger age when the heart is able to better tolerate injury, to ultimately improve long term outcomes.