tbuckley/cabot-search huggingface dataset:
Abstract 300: Ischemia and Reperfusion Injury Following Cardioplegic Arrest is Attenuated by Age and Testosterone Deficiency in Male but Not Female Mice
Authors: Anjali Ghimire, Elise S Bisset, Susan E Howlett
Journal: Circulation Research (2019)

Cardiovascular disease increases with age in both sexes and treatment can require cardiac surgery, where the heart is pre-treated with a protective cardioplegic solution before exposure to ischemia and reperfusion (I/R). While endogenous estrogen is thought to be beneficial in I/R, the role of testosterone in cardioprotection is not well understood and whether age modifies responses to I/R is unclear. We investigated sex- and age-specific differences in I/R injury in hearts pre-treated with a clinically relevant cardioplegic solution. Hearts were isolated from adult (6-9 mos) and old (22-28 mos) C57BL/6 mice of both sexes (n=27). They were Langendorff-perfused with Krebs-Henseleit buffer (15 min; 37°C), followed by St. Thomas’2 cardioplegia (6 min; 6-7°C). This was followed by 90 min of global ischemia (room temperature) and 30 min of reperfusion (37°C). Hearts were then perfused with triphenyltetrazolium chloride to quantify infarct area. The role of testosterone was investigated in gonadectomized (GDX; 6-9 mos) male mice and serum testosterone was measured with an ELISA. Functional recovery in reperfusion was significantly better in old males than in adult males. Left ventricular developed pressure (LVDP) recovered to 67.3 ± 7.4% in old compared to 31.6 ± 12.3% in adult male hearts (p&lt;0.05). Similar results were seen for rates of pressure development (+dP/dt; p&lt;0.05) and decay (-dP/dt; p&lt;0.05). Also, infarct areas were markedly smaller in old male hearts (15.5 ± 1.8%) than in younger hearts (48.1 ± 7.7%; p&lt;0.05). By contrast, hearts from adult and old females exhibited a similar degree of post-ischemic functional recovery and showed no age-dependent difference in infarct size. Serum testosterone levels declined with age in males but were low regardless of age in females, which suggested a potential benefit of low testosterone. In support of this, hearts from GDX males exhibited much better recovery of LVDP in reperfusion when compared to hearts from intact males (values were 64.8 ± 7.7% vs. 29.9 ± 12.3%; p&lt;0.05). GDX hearts also had smaller infarcts than hearts from intact males (p&lt;0.05). These results suggest that low testosterone levels may be protective against I/R injury following cardioplegic arrest in the setting of aging, especially in old males.
Abstract 530: Cardiac Fibroblast GSK-3α Contributes to Ventricular Remodeling and Dysfunction of the Failing Heart
Authors: Prachi UMBARKAR, Anand P Singh, Qinkun Zhang, Hind Lal
Journal: Circulation Research (2019)

Background: Heart failure is the leading cause of mortality, morbidity, and healthcare expenditures worldwide. Numerous studies from our lab and others have implicated Glycogen Synthase Kinase-3 (GSK-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms appear to play overlapping, unique and even opposing functions in the heart. Recently our group has identified cardiac fibroblast (CF) GSK-3β as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of CF-GSK-3α in cardiac pathophysiology is poorly understood. Methods and Results: To determine the role of CF-GSK-3α in the pathogenesis of heart failure, GSK -3α was deleted specifically from mouse resident cardiac fibroblast or myofibroblast with tamoxifen-inducible TCF21- or periostin (Postn)- promoter-driven Cre recombinase. At 2 months of age, WT and KO mice were subjected to cardiac injury and heart functions were monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 8 weeks post-injury. In TCF21-KO mice, deletion of GSK-3α from resident cardiac fibroblasts significantly restricted pressure overload-induced adverse cardiac remodeling and improved cardiac function. Consistently, in Postn-KO mice, deletion of GSK-3α from myofibroblasts remarkably reduced LV scar circumference and prevented cardiac dysfunction post-MI. To gain the mechanistic insights of observed GSK-3α mediated fibrotic remodeling, we examined the effect of GSK-3α deletion on myofibroblast transformation and profibrotic TGF-β1-SMAD3 signaling in vitro . WT and GSK-3α KO mouse embryonic fibroblasts (MEFs) were treated with TGF-β1 (10 ng/mL). Indeed, a significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGF-β1 treated GSK-3α KO MEF confirmed that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion had no effect on TGF-β1 induced SMAD3 activation indicating the potential involvement of GSK-3α in eliciting SMAD3 independent profibrotic response. Conclusion: These findings suggest the causal role of CF-GSK3α in the cardiac remodeling of the injured heart that could be a therapeutically targeted for the future clinical applications.
Expansion of an oncology care coordination nurse model to reduce hospitalizations and emergency department utilization.
Authors: Georgina T. Rodgers, Michelle Brusio, Jacob Lindberg, Craig Savage, Joseph Hooley, Ronald Young
Journal: Journal of Clinical Oncology (2019)

82 Background: Comprehensive, coordinated care is a key driver of care transformation within the Oncology Care Model. Care coordination provides deliberate, organized, patient centered care initiatives aimed to improve care transitions, patient education, patient engagement and quality of care throughout the care continuum. Methods: Specialty care coordinator nurses were a part of our heath system’s model of care but over the course of our participation in the OCM we have implemented care coordination in our regional locations across 15 additional sites of care. Standardized templates for initial and follow up education were created for oral and parenteral therapies with an emphasis on symptom management education. A patient education tool was developed through a partnership with nursing, pharmacy and physicians across disease groups to outline when a patient should contact their physician or RN care coordinator with symptom issues. Targeted outreach calls and associated documentation templates were created for symptom assessment and adequate follow up. Templates include a pre-chemo orientation call, post treatment follow up phone call within seven days, and post hospital discharge/ED treat and release follow up calls. A team based huddle guideline was developed to provide a means for interdisciplinary communication to assess patients for high risk based upon medical, functional, social, cognitive and behavioral factors that might lead to a hospitalization. Results: Our teams worked closely with EMR specialists and internal data analysts to build appropriate templates and subsequent reports to monitor compliance with documentation, evaluate the number of outreach touch points and effectiveness of interventions on a reduction of hospitalizations and ED utilization. We have noted an a modest decrease in hospitalizations and ED utilization through OCM feedback reports and reconciliation reports. Conclusions: We continue to monitor our monthly hospital admissions and ED utilization across the health system and drill down into the data to determine if there are any opportunities where care coordination outreach and incoming telephone triage could have prevented the admission.
Post-Transplant High-Dose Cyclophosphamide Overcomes the Detrimental Effect of a Single-Locus HLA Mismatched in Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Patricia Ferraz, Arturo Pereira, María Suárez-Lledó, Gonzalo Gutiérrez-García, Francesc Fernández-Avilés, Laura Rosinol, Teresa Solano, Noemí Llobet, Carla Ramos, Pedro Marín, Alvaro Urbano-Ispizua, Montserrat Rovira, Carmen Martinez
Journal: Blood (2018)
Losartan Rescues Inflammation-related Mucociliary Dysfunction in Relevant Models of Cystic Fibrosis
Authors: Michael D. Kim, Nathalie Baumlin, Makoto Yoshida, Deepika Polineni, Sebastian F. Salathe, Joseph K. David, Charles A. Peloquin, Adam Wanner, John S. Dennis, Juliette Sailland, Philip Whitney, Frank T. Horrigan, Juan R. Sabater, William M. Abraham, Matthias Salathe
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Despite therapeutic progress in treating cystic fibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large-conductance Ca
A proactive approach to assess system safety in clinical operations at a comprehensive cancer center.
Authors: Jeffrey Durney, Lawrence Wong, Alan H. Breaud, Laura Cedro, Shannon Rowell, Caroline Harvey, Audrea H Szabatura, Sarah Kadish, David Frank, Sharon Lane, Hakim Lakhani, Sylvia Bartel
Journal: Journal of Clinical Oncology (2019)

245 Background: Traditional approaches to improve safety in clinical operations focus on reacting to adverse events and intervening at the process level to prevent recurrence. A need exists to proactively explore safety at the system level and evaluate human factors that lead to errors. We developed and piloted a system safety assessment methodology to identify vulnerabilities in the Research Pharmacy at Dana-Farber Cancer Institute. Methods: We developed an interview tool based on the human factors analysis and classification system (HFACS) to obtain staff member perspectives on safety vulnerabilities. Detailed process maps were created for safety critical processes. Policies, procedures, and job aids were evaluated for effectiveness at preventing errors. Interfaces between the Research Pharmacy and other areas were studied to identify potential expectation misalignment. These elements formed a comprehensive methodology to proactively assess safety threats. Results: Based on our application of the assessment methodology, 16 system safety vulnerability themes were identified (table below) and 44 recommendations were generated to address them. From the recommendations, 26 improvement projects were proposed to prevent the occurrence of safety events. To date, 15 projects addressing 13 safety vulnerabilities have been initiated. Conclusions: Vulnerabilities uncovered through our methodology can inform the development of projects to proactively reduce risk and improve system resiliency in any clinical setting. Preliminary data indicate longer average days between safety events in the Research Pharmacy as projects triggered by the assessment are implemented. Further analysis is underway. [Table: see text]
A dyadic study of employment outcomes and quality of life in patients with breast cancer and their support persons.
Authors: Christine M Veenstra, Thomas Braun, Chandler McLeod, Daniela Wittmann, Sarah T. Hawley
Journal: Journal of Clinical Oncology (2019)

176 Background: Many women with breast cancer face job loss related to their diagnosis, but little is known about employment outcomes among their partners and other supporters. Moreover, virtually nothing is known about associations between patients’ quality of life and supporters’ employment outcomes. Methods: Breast cancer patients reported to Georgia and LA SEER registries in 2014-15 (N = 2,502, 68% RR) and their key decision support person (DSP) were surveyed separately. 1234 DSPs responded (71% RR). Patients and DSPs were asked about employment impacts of the patient’s breast cancer. Patients’ quality of life (QOL) was measured with the PROMIS scale for global health. Descriptive analyses of employment outcomes (job loss, missed days due to cancer) were generated for patients and DSPs. Associations between patients’ QOL and employment outcomes of patients and their DSPs were assessed using linear mixed model regression analyses stratified by dyad type (partner vs. non-partner DSP). Results: Among DSPs, 43% were partners. 57% were non-partners (daughters, other family, friends). 67% were employed at time of patient’s diagnosis. Among these, 11% were no longer employed at survey completion. 39% missed &gt;30 days work. Non-partner DSPs were as likely as partners to lose their job or miss work because of the patient’s cancer. 65% patients were employed at diagnosis. Compared to patients whose DSP was a partner, patients with non-partner DSP were more likely to lose their job (39% vs. 24%; p&lt;0.01) or miss &gt;30 days work (55% vs. 45%; p&lt;0.01). For patients with partner and non-partner DSPs, having an employed DSP at diagnosis and having an employed DSP who stays employed were associated with improved patient QOL after adjustment for DSP sociodemographic and patient clinical variables. Conclusions: Both non-partner and partner DSPs faced negative employment impacts related to patients’ breast cancer. Job loss and &gt;30 days of missed work were more likely among patients with non-partner DSPs. Having an employed DSP and having an employed DSP who stays employed positively contributed to patients’ QOL.
GP who dishonestly recorded patients’ vital signs without measuring them is struck off
Authors: Clare Dyer
Journal: BMJ (2019)

A GP has been struck off the UK medical register after a tribunal found that she dishonestly recorded patients’ temperature, pulse, and other key variables without ever actually measuring them or carrying out a proper examination.

Kathleen Bilton was an out-of-hours GP at Royal Glamorgan Hospital in south Wales in early 2018 when two complaints arose from patients she had sent home with antibiotic prescriptions. Both were admitted to hospital soon after and diagnosed with sepsis.

Their medical records showed that Bilton had entered specific figures for their pulse, temperature, respiration, and other variables, but both complainants denied that she had taken such measurements.

Their complaints led Bilton’s employer, the Cwm Taf University Health Board, to refer her to the General Medical Council.

Bilton, who qualified at the University …
Abstract 841: Loss of S-nitrosylation of G Protein-Coupled Receptor Kinase 2 Leads to Cardiovascular Dysfunction With Aging
Authors: Melissa Lieu, Christopher J Traynham, Jennifer Petovic, Gavin P Landesberg, Steven Forrester, Erhe Gao, Satoru Eguchi, Rosario Scalia, Walter J Koch
Journal: Circulation Research (2019)

Nitric oxide (NO) and S-nitrosothiol (SNO) have cardiovascular-protective properties and we have shown that one mechanism is through SNO-modification of G protein-coupled receptor (GPCR) kinase 2 (GRK2). S-nitrosylation at Cys340 (C340S) of GRK2 inhibits its activity on GPCRs such as β-adrenergic receptors in the heart and other GRK2 dependent processes. S-nitrosylation is believed to act as a brake on this pathological kinase. We generated global knock-in (KI) mice that express endogenous levels of GRK2, but with C340 mutated to Ser (GRK2-C340S). The C340 site is the primary site of S-nitrosylation and is largely responsible for eNOS-mediated cardioprotection after acute ischemic injury of the heart. In this study we observed that the loss of SNO-mediated inhibition of GRK2 leads to cardiovascular dysfunction during normal aging. GRK2 has been shown to be up-regulated during several cardiovascular (CV) pathologies including hypertension and heart failure, and aging is a major risk factor of CV disease (CVD). GRK2-C340S KI mice compared to their wild-type (WT) controls showed significant pathology as early as 52 weeks of age and was maintained up to 82 weeks. Maladaptive cardiac hypertrophy was present in aged GRK2-C340S mice with significant perivascular myocardial fibrosis. Fibrosis was prevalent in the kidneys as well. These histological changes were accompanied by reduced systolic function and pulse pressure compared to WT mice. Within the vasculature, aged GRK2-C340S aortas had reduced medial thickness and had reduced contraction in response to PE, KCl, or L-NAME. Acetylcholine-induced relaxation responses remained intact. Consistent with enhanced GRK2 activity in vivo in the heart, we found increased circulating levels of serum catecholamines. Many of these phenotypes we observed in GRK2-C340S mice are also observed in human aging and CVD. These phenotypes predispose patients to developing other diseases. As the US population becomes increasingly older, understanding the dynamic between aging and CVD is important in disease management and therapy. The aged GRK2-C340S mouse model represents a model of higher CVD risk and provides insights into consequences of chronic GRK2 global over-activity when the regulation of this kinase by NO is lost.
TGF-β Neutralizing Antibody 1D11 Inhibits LIF-JAK-Stat3 Signaling and Enhances Cytarabine Induced Apoptosis in AML Cells in Bone Marrow Microenvironment
Authors: Yoko Tabe, Yuexi Shi, Zhihong Zeng, Linhua Jin, Yixin Zhou, Takashi Miida, Michael Andreeff, Marina Konopleva
Journal: Blood (2011)
Abstract 837: Different Disease States in Heart Have Distinct Cardiac Interstitial Cells Contributing to Fibrosis
Authors: Hadi Khalil, Shannon M Jones, Perwez Alam, Bruce J Aronow, Jeffery D Molkentin, Onur Kanisicak
Journal: Circulation Research (2019)

Cardiac fibrosis is a grim consequence for almost all myocardial injuries. In myocardial infarction (MI), what starts as a protective scarring process to prevent ventricular wall rupture becomes a pathological remodeling of the tissue with the accumulation of excess extracellular matrix (ECM) proteins. Eventually, this adaptation impedes the mechanical and electrical properties of the myocardium resulting in heart failure. Recently, we showed that periostin (Postn) expressing resident cardiac fibroblasts (CFs) are a potential therapeutic target since they differentiate into the scar associated, matrix-producing myofibroblasts (MFs) after injury. In fact, deletion of these cells after an acute injury eliminates interstitial fibrosis but results in ventricular rupture which is a hallmark outcome of impaired ECM deposition during the acute phase of MI. On the other hand, ablation of these cells during a chronic injury such as pressure overload-induced cardiac fibrosis model, we observe sustained perivascular fibrosis. Previous studies report heterogeneity of origin and function for ECM producing cells associated with different cardiac diseases. Here we utilized several novel mouse models that permit lineage tracing of all activated MFs as well as perivascular mural cells in the heart to elucidate the role and fate of these distinct cardiac interstitial cells during fibrogenesis. Cells were lineage traced with a tamoxifen-inducible cre recombinase cDNA knock-in alleles (PostnMCM and Gli1CreER) in combination with a Rosa26-eGFP cre-dependent reporter. Hearts subjected to MI, TAC or Angiotensin injury were processed for extensive histological and RNAseq analyses. Results show that interstitial fibrosis in acute MI injury is a result of Postn+ MFs activity, whereas a subset of Gli1+ mural cells are responsible for the perivascular fibrosis observed after pressure overload models. Therefore, we concluded that pathological ECM deposition resulting in fibrosis comes from disease-specific specialized sub-populations of interstitial cells of the heart with distinct gene expressions and require manipulation of alternative cell- and state-specific therapeutic targets.
Abstract 284: Drp1 Protects the Heart Against High Fat Diet-Induced Diabetic Cardiomyopathy
Authors: Mingming Tong, Peiyong Zhai, Wataru Mizushima, Junichi Sadoshima
Journal: Circulation Research (2019)

Type II diabetes induces cardiomyopathy characterized by hypertrophy, diastolic dysfunction and mitochondrial dysfunction. We have shown recently that clearance of damaged mitochondria by mitophagy mediated through an Atg7-dependent mechanism serves as an essential mechanism to maintain the quality of mitochondria during the initial development of diabetic cardiomyopathy. Our previous study showed that disruption of Drp1 inhibits mitophagy and causes mitochondrial dysfunction at baseline and in response to pressure overload. We therefore investigated whether Drp1 is essential for mitophagy during high fat diet (HFD)-induced diabetic cardiomyopathy. Mice were fed either a normal diet (ND) or a HFD (60 kcal % fat). Mitophagy, evaluated with Mito-Keima, was increased after 3 weeks of HFD (p&lt;0.05). However, this increase in mitophagy induced by HFD consumption was abolished in tamoxifen-inducible cardiac-specific Drp1 knockout (Drp1 cKO) mouse hearts (p&lt;0.05), in which both diastolic dysfunction (p&lt;0.05) and systolic dysfunction (p&lt;0.05) were exacerbated. Furthermore, the increase in LC3-dependent general autophagy in response to HFD consumption was also abolished in Drp1 cKO mice (p&lt;0.05). Electron microscopic analyses showed elongated mitochondria and accumulation of lipid droplets in Drp1 cKO mice (p&lt;0.05) in the presence of HFD consumption. Fibrosis and cell death were increased in Drp1 cKO mice during HFD consumption (p&lt;0.05). Thus, Drp1 is essential for mitophagy during HFD consumption and serves as an essential mitochondrial quality control mechanism, thereby protecting the heart against diabetic cardiomyopathy.
Abstract 320: MicroRNA-133a Attenuates the Development of Thoracic Aortic Aneurysm
Authors: Adam W Akerman, Elizabeth N Collins, Jessica K Harrison, Joyce Oh, Lauren B Collins, Jessica Riopedre, Amari DeVaughn, Charles M Raybuck, John S Ikonomidis
Journal: Circulation Research (2019)

Rationale: Thoracic aortic aneurysms (TAA) result from dysregulated remodeling of the vascular extracellular matrix, and may occur as result of altered resident cellular phenotype. MicroRNA-133a is reduced in clinical TAA specimens and plays an inhibitory role in regulation of pathological phenotypic switch of vascular cells. Accordingly, this study tested the hypothesis that miR-133a replacement attenuates the development of TAA. Methods and Results: TAA was induced in wild type mice (0.5M CaCl 2 application, 15 minutes). Following 4 weeks, aortic diameter was increased compared to sham operated controls (1094 ± 38 vs 654 ± 8 μm; p&lt;0.05, n=7). Copy number of miR-133a, quantitated by ddPCR, was reduced in TAA tissue (0.28 ± 0.04 vs 0.68 ± 0.11 copy per U6; p&lt;0.05 vs control, n=7). While no change in smooth muscle cell specific Desmin nor α-smooth muscle actin were detected, an increase in copy number of the fibroblast specific discoidin domain receptor 2 (DDR2) and smooth muscle cell myosin heavy chain 11 (MYH11) were observed in TAA tissue. Combined, these results are consistent with the emergence of a population of myofibroblasts with TAA development. Accordingly, fibroblasts were isolated from TAA and sham operated control tissues (n=10). Copy number of miR-133a was reduced in TAA fibroblasts (0.41 ± 0.14 vs 1.60 ± 0.43 copy per U6; p &lt; 0.05 vs control). TAA fibroblast phenotype was compared to controls; adhesion was reduced (-0.85±0.02 vs -0.77±0.02), migration was increased (63±4% vs 47±4%), and rate of collagen disk contraction over 7 hours was increased (-12.2±1.6 vs -8.5±1.0) (all values, p&lt;0.05 vs control). Finally, after TAA induction in mice, a single tail vein injection of either a miR-133a overexpression or scrambled sequence (control) lentivirus was performed. Following 4 weeks, miR-133a replacement attenuated TAA development (800 ± 18 μm vs 1016 ± 16 μm; p &lt; 0.05 vs control; n=8). Conclusion: Aortic fibroblast phenotype is altered during TAA progression, and miR-133a replacement attenuates the development of TAA in a murine model. These unique findings suggest stable alterations in aortic fibroblasts may be associated with pathological extracellular matrix remodeling, and regulation by miR-133a may lead to a novel therapeutic strategy.