tbuckley/cabot-search huggingface dataset:
Molecular Pathogenesis of Membranous Nephropathy
Authors: Pierre Ronco, Hanna Debiec
Journal: Annual Review of Pathology Mechanisms of Disease (2019)

Membranous nephropathy is a noninflammatory autoimmune disease of the kidney glomerulus, characterized by the formation of immune deposits, complement-mediated proteinuria, and risk of renal failure. Considerable advances in understanding the molecular pathogenesis have occurred with the identification of several antigens [neutral endopeptidase, phospholipase A2 receptor (PLA 2 R), thrombospondin domain-containing 7A (THSD7A)] in cases arising from the neonatal period to adulthood and the characterization of antibody-binding domains (that is, epitopes). Immunization against PLA2R occurs in 70% to 80% of adult cases. The development of highly specific and sensitive assays of circulating antibodies has induced a paradigm shift in diagnosis and treatment monitoring. In addition, several interacting loci in HLA-DQ, HLA-DR, and PLA2R1, as well as classical human leukocyte antigen (HLA)-D alleles have been identified as being risk factors, depending on a patient's ethnicity. Additionally, mechanisms of antibody pathogenicity and pathways of complement activation are now better understood. Further research is mandatory for designing new therapeutic strategies, including the identifying triggering events, the molecular bases of remission and progression, and the T cell epitopes involved.
Abstract 828: The Functional Role of Myofibroblast-Expressed Smooth Muscle Alpha Actin in Post-Myocardial Infarction Tissue Healing
Authors: Xing Fu, Qianglin Liu, Leshan Wang, Jeffery Molkentin
Journal: Circulation Research (2019)

After myocardial infarction (MI), dead cardiomyocytes are permanently replaced by scar tissue due to the lack of cardiomyocyte regeneration. In response to MI, cardiac fibroblasts (CFs) differentiate into myofibroblasts which possess highly organized smooth muscle α-actin (αSMA) stress fibers and secrete a large amount of extracellular matrix (ECM) proteins, essential for the post-MI infarct scar formation. It is well known that the accumulated ECM in the infarct scar stabilize the scar and prevents cardiac rupture. However, the functional role of αSMA stress fiber itself in CF-derived myofibroblasts is still largely unknown besides the wide use of it as a marker of myofibroblast differentiation. Our recent work demonstrated that during myofibroblast differentiation of CFs post-MI, the expression of αSMA reaches a peak a few days earlier than genes encoding ECM proteins. Myofibroblasts then lose αSMA expression and differentiate to the newly identified matrifibrocytes as the infarct scar becomes increasingly stable. These facts suggest a more important role of αSMA stress fibers than ECM proteins in the tissue healing process in early phase post-MI, possibly through providing a support lattice which in turn strengthens the infarcted myocardium. To test our hypothesis, we generated a mouse line with Acta2 (the gene encoding αSMA) flanked by LoxP sites ( Acta2 fl/fl ) to enable cre-mediated Acta2 knockout. Here we show that the loss of Acta2 in CFs leads to enhanced proliferation and reduced contractility upon TGFβ-induced myofibroblast differentiation in vitro . By using a mouse line with tamoxifen-inducible CF-specific Acta2 knockout and CF lineage tracing ( Tcf21 MerCreMer ;Acta2 fl/fl ;R26 GFP ) and a WT control mouse line ( Tcf21 MerCreMer ;R26 GFP ), we identified that CF-specific Acta2 knockout results in significantly exacerbated post-MI cardiac function, increased cardiac rupture incidence, and enhanced fibrosis. More lineage tracing experiments and transcriptome analyses are being conducted to better decipher the impact of Acta2 knockout on CF physiology and post-MI tissue healing.
Abstract 613: Isolating the Pathological Contribution of Detyrosinated Microtubules in Human Myocardial Mechanics
Authors: Matthew A Caporizzo, Christina Y Chen, Kenneth Bedi, Kenneth B Margulies, Benjamin L Prosser
Journal: Circulation Research (2019)

Detyrosinated microtubules (dTyr MTs) provide a viscoelastic resistance to myocyte motion and are proliferated in end-stage heart failure. In isolated myocytes, proliferation of the MT network leads to reduced shortening and relaxation, consistent with an underlying viscoelastic resistance, yet a clear contribution of MTs to the passive mechanical properties of myocytes or myocardium in heart failure remains to be determined. To this end, intact human myocytes were isolated from failing and non-failing hearts and their viscoelasticity was measured using a physiological stretch assay where strain-rates were consistent with diastolic filling. In myocytes from heart failure patients, we find an increase in myocyte viscoelasticity and slowing of passive relaxation during cell stretch compared to myocytes from non-failing hearts. Depolymerizing MTs with colchicine, or suppressing dTyr MTs either pharmacologically with parthenolide or genetically by overexpression of tubulin tyrosine ligase reduces myocyte passive viscoelasticity, accelerates passive relaxation time and leads to consistent improvements in contractile and relaxation dynamics in failing cardiomyocytes. Manipulation of dTyr MT levels does not significantly alter the calcium transient during unloaded contraction, suggesting that the observed gain in function is mechanical in nature. We additionally have begun to assay the MT contribution to mechanics at the tissue level. In intact trabeculae from failing hearts, colchicine treatment to depolymerize MTs reduces passive myocardial viscoelasticity upon diastolic stretch. The results indicate that microtubules contribute to myocardial mechanical properties in the context of end-stage heart failure.
Transcriptome Sequencing Reveals Alternative Splicing Patterns and an Increased Sensitivity to Spliceosome Inhibition Associated MYD88 L265P Mutation in Chronic Lymphocytic Leukemia
Authors: Shuchao Qin, Xinyu Zhang, Qimei Han, Chang-Sheng Chang, Eun-Jeong Park, Lirong Pei, Chandraiah Lagisetti, Thomas R Webb, Jiazhu Wu, Wei Xu, Jianyong Li, Huidong Shi
Journal: Blood (2018)
Abstract 352: Release of 12,13-diHOME From Brown Adipose Tissue Modulates Inotropy and Lusitropy in Old Mice
Authors: Vikram Shettigar, Eaman Abay, Kelsey Pinckard, Lisa A Baer, Kristin I Stanford, Mark T Ziolo
Journal: Circulation Research (2019)

The US demographic is shifting to an elderly population. It is estimated that by 2030, 20% of the population will be comprised of people over 65 years of age. The incidences of cardiovascular and metabolic diseases are increased with aging. A contributor to the age-induced metabolic dysfunction is a decrease in Brown Adipose Tissue (BAT). In addition to being a thermogenic organ, BAT is also an endocrine organ via the release of signaling lipids known as batokines. We have previously shown that there is a significant reduction in the batokine 12,13-diHOME contributing to the metabolic dysfunction with aging. However, the specific role of 12,13-diHOME in the age-induced impairments in cardiac function remains unknown. Thus, we hypothesized that supplementing 12, 13-diHOME would improve cardiac metabolism and function. In this study, we injected 12, 13-diHOME to young (3 months) and old (18months) C57Bl/6 wild type mice either acutely or long term (via an intraperitoneal injection daily for 2 weeks). Cardiac function was measured via echocardiography and hemodynamics via intra-left ventricular catheterization. In young mice, acutely supplementing 12, 13-diHOME greatly enhanced cardiovascular function and hemodynamics (e.g., cardiac output, systolic function, diastolic function, contractility, and relaxation). Similar effects were also observed in old mice that were acutely supplemented with 12,13-diHOME. These data suggest that 12,13-diHOME is a potent inotropic and lusitropic modulator in young and old mice. However, long term (2 weeks) treatment of 12, 13-diHOME on either young or old mice had no chronic effects on cardiac function and/or structure, unlike other inotropic agents. Taken together, these data demonstrate that 12,13-diHOME is a potent regulator of heart function and may be a viable long-term treatment strategy.
Abstract 838: High Molecular Weight FGF2 Contributes to Pressure Overload Induced Systolic Dysfunction by a Mechanism Associated With Modulation of the NR1D1 Orphan Nuclear Receptor Expression
Authors: Navid Koleini, Barbara E Nickel, Raghu S Nagalingam, Natalie M Landry, Robert R Fandrich, Ian M Dixon, Michael Czubryt, Peter A Cattini, Elissavet Kardami
Journal: Circulation Research (2019)

Fibroblast growth factor 2 (FGF2) is implicated in normal cardiac development as well as cardiac pathophysiology; however, FGF2 exist as multiple high and low molecular weight isoforms. While endogenous low molecular weight FGF2 (Lo-FGF2) is cardioprotective during chronic stress, the more prevalent endogenous high molecular weight FGF2 (Hi-FGF2) is proposed to promote maladaptive cardiac remodeling. We have investigated the hypothesis that genetic elimination of Hi-FGF attenuates cardiac dysfunction in mice that have been subjected to pressure overload by transverse aortic constriction (TAC). Two groups of male C57BL/6mice were compared: (1) Wild type (WT) mice, expressing Hi- and Lo-FGF2 (FGF[WT] mice); and (2) Hi-FGF2 knock-out mice, expressing only Lo-FGF2 (FGF[Lo] mice). Echocardiographic assessment of heart function and dimensions was done at baseline and then 4 and 8 weeks after TAC or sham surgery. FGF[WT] mice displayed a decline in systolic function compared to their corresponding sham animals at 4- and 8-weeks post-TAC, which was absent in the FGF[Lo] mice. Relative levels of B-type natriuretic peptide, a marker of cardiac pathology severity, were elevated in FGF[WT] but not FGF[Lo] mice compared to shams. Increased accumulation of the pro-cell death protein BCL2/adenovirus E1B 19 kDa protein-interacting protein-3 was more pronounced in the FGF(WT) compared to FGF(Lo) mice, post TAC. Microarray analysis of the whole transcriptome of hearts in FGF2[WT] and FGF2[Lo] mice indicated the pathway linked to circadian rhythm as a candidate for the most significant differentially regulated. Specifically, upregulation of the circadian rhythm master regulator, Nuclear Receptor Subfamily 1 Group D Member 1 (NR1D1), was validated by qPCR and protein immunoblotting in FGF[Lo] mice versus downregulation of NR1D1in FGF[WT] mice post-TAC, when compared to their sham operated littermates. Taken together these studies suggest that expression of Hi-FGF2 contributes to cardiac systolic dysfunction in left ventricular pressure overloaded WT mice by downregulation of Nr1D1, post-TAC.
The Efficacy of Ultrasound Joint Examination for the Management in Patients with Hemophilia
Authors: Shiho Nishimura, Keita Tomioka, Maiko Shimomura, Yoko Mizoguchi, Shinobu Sasaki, Chihiro Tani, Yoshiko Matsubara, Kazuo Awai, Yuko Nakashima, Nobuo Adachi, Masao Kobayashi
Journal: Blood (2018)
AB0086 Occurrence of giant cell arteritis under methotrexate therapy for rheumatoid arthritis
Authors: J Gerster, I Carey, AM Chamot
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> There is controversy about methotrexate (MTX) as a therapy of giant cell arteritis (GCA). <h3>Objectives</h3> The objective is to present a case who developed GCA during therapy with MTX in association with corticosteroids for rheumatoid arthritis. <h3>Methods</h3> A 66-year-old-woman was diagnosed in 1998 as seronegative rheumatoid arthritis involving knee, shoulder and wrist joints. ESR was 46 mm/1 h, synovial fluid contained 29 G/L leukocytes but no crystals were observed. The patient was treated with MTX at a weekly dose of 7,5 mg, dosage increased to 10 mg/week in February 2000. In addition, she received prednisone 5 mg per day. In November 2000 she started to feel some weakness and to suffer from frontal headaches. The ESR was 120 mm/1 h, CRP 121 mg/l and Hb 80 g/L. The biopsied right temporal artery, which was tender and indurated, demonstrated GCA. The internal elastic lamina was fragmented; there were infiltrates of histiocytes, lymphocytes and giant cells and the lumen was in some places occluded. <h3>Results</h3> <h3>Conclusion</h3> In this case, occurrence of GCA was not prevented by MTX therapy. This suggests that MTX at an average dose is probably insufficient to prevent or treat this disease.
Mutant neuropeptide S receptor reduces sleep duration with preserved memory consolidation
Authors: Lijuan Xing, Guangsen Shi, Yulia Mostovoy, Nicholas W. Gentry, Zenghua Fan, Thomas B. McMahon, Pui-Yan Kwok, Christopher R. Jones, Louis J. Ptáček, Ying-Hui Fu
Journal: Science Translational Medicine (2019)

A human neuropeptide S receptor mutation renders mutant mice to be short sleepers with more resilience to memory deficits caused by sleep deprivation.
Do rural cancer patients receive lower quality cancer care? Assessing the impact of rurality on oncology practice performance measures.
Authors: Catherine R. Fedorenko, Laura Elizabeth Panattoni, Qin Sun, Li Li, Karma L. Kreizenbeck, Scott David Ramsey
Journal: Journal of Clinical Oncology (2019)

166 Background: Rural residents are diagnosed at later stages of cancer compared to urban residents, have poorer survival, and face distinct barriers to receiving quality cancer care. ASCO has developed policy initiatives to address rural cancer care; however, little is known about quality of cancer care among patients residing in rural areas. This study examined the impact of rurality on performance metrics, controlling for socioeconomic status and insurance type. Methods: We linked Washington state cancer registry records from 2015-2017 with claims records for two large commercial insurers, Medicare, and Medicaid. Using claims from this database, we generated eight nationally recognized quality measures. Rurality was measured by the Rural-Urban Commuting Area Codes (RUCAs) categorized into 4 levels (Metro, Metro with commute, Micropolitan, Small Town/Rural). Process and outcome measures were adjusted for age, sex, race, comorbidity score, stage, cancer type, marital status, the Area Deprivation Index, and treatment factors where appropriate. Results were stratified by payer type. Results: The table below lists the effect of a patient’s rurality on the quality metric where significant (p&lt;0.05). Where rurality did not impact the performance measure, results are left blank. Conclusions: After controlling for socioeconomic status and payer type, quality of cancer care for rural cancer patients was not consistently poorer compared to urban patients. These results suggest that lower survival among rural patients may be due to factors beyond quality of care.[Table: see text]
The Transforming Potential of the Homeobox Gene Cdx2 Is Depending on Its N-Terminal Transactivation Domain In Vivo and Can Be Antagonized by the MEK1/2 Inhibitor in a Mouse Model of t(12;13) Positive AML.
Authors: Vijay P.S. Rawat, Natalia Arseni Arseni, Vegi M. Naidu, John P. Lynch, Wolfgang Hiddemann, Michaela Feuring-Buske, Christian Buske
Journal: Blood (2006)
Abstract 307: Chemogenetic Activation of Paraventricular Oxytocin Neurons Reduces Cardiac Dysfunction During Heart Failure
Authors: Jeannette Rodriguez Gonzalez, Jhansi Dyavanapalli, Carla Rocha, Mary Kate Dwyer, John Schloen, Kathryn J Schunke, David M Mendelowitz, Matthew W Kay
Journal: Circulation Research (2019)

There is a distinctive cardiac autonomic imbalance in HF consisting of increased sympathetic activity and decreased parasympathetic tone. Recent work has indicated that activation of paraventricular nucleus (PVN) oxytocin neurons increases co-release of oxytocin with glutamate to elevate cardiac vagal tone yet little is known regarding the long-term (16 week) benefit. We hypothesize that activation of oxytocin neurons in the PVN will blunt the progression of HF by reducing inflammation and fibrosis at 16 weeks post-HF initiation than in untreated counterparts. Rats underwent trans-ascending aortic constriction (TAC) to induce HF. In a subset of HF rats (TAC+OXT), oxytocin neurons were activated by excitatory designer receptors exclusively activated by designer drugs (DREADDs). Rats were implanted with ECG telemetry devices and underwent a treadmill protocol to measure peak effort capacity and heart rate recovery (HRR). Cardiac structural measurements were obtained using echocardiography. After 16 weeks, hearts were rapidly excised, Langendorff perfused to measure mechanical function, and prepared for histology and western blot analysis. Indices of cardiac function (stroke volume, ejection fraction, cardiac output, and fractional shortening) indicated preserved function in TAC+OXT compared to TAC. HRR after peak effort capacity values were lowest in TAC and were significantly greater in TAC+OXT (p≤0.05), indicating preservation of cardiac parasympathetic tone. LV developed pressure was significantly impaired in TAC compared to sham as well as significantly improved in TAC+OXT compared to TAC (p≤0.05). Contractility and relaxation were significantly impaired in TAC compared to sham (p≤0.05), while TAC+OXT animals had values not different from sham. TAC animals had collagen III levels 5X higher than TAC+OXT. Histological analysis indicated increased fibrosis in disease groups compared to sham. TAC+OXT had IL-1β levels significantly lower than TAC (p≤0.05). PVN oxytocin neuron activation slows the decline of cardiac function in 16 week post- TAC rats, likely by reinstating cardioprotective parasympathetic activity. This novel method has translational potential since intranasal oxytocin administration has been used in the clinic.
Burden of varicella complications in secondary care, England, 2004 to 2017
Authors: James Lopez Bernal, Peter Hobbelen, Gayatri Amirthalingam
Journal: Eurosurveillance (2019)

BackgroundStrategies to control varicella vary across Europe. Evidence from established programmes has prompted the United Kingdom to re-evaluate the need for universal vaccination. The burden of complicated varicella is a key parameter in the cost-effectiveness analysis.AimOur objective was to estimate the burden of complicated varicella in England.MethodsThis electronic health record surveillance study used data from all NHS hospitals in England to identify varicella admissions between 2004 and 2017. The incidence of pre-defined complications of varicella was estimated using ICD-10 codes. Inpatient costs were calculated based on the payment rules for providers of NHS services.ResultsThere were 61,024 admissions with varicella between 2004 and 2017 and 38.1% had a recognised varicella complication. Incidence of hospitalisation increased by 25% and the proportion with complicated varicella by 24% from 2004/05 to 2016/17. The most common complications were bacterial skin infections (11.25%), pneumonia (4.82%), febrile convulsions (3.39%) and encephalitis (2.44%). Complication rates were higher in older age groups and the type of complications more severe. Length of stay for complicated varicella was 3.1 times longer than for uncomplicated varicella and inpatient costs were 72% greater.ConclusionComplicated varicella has a substantial health and economic burden. These data together with data on impact on quality of life are important in informing the cost-effectiveness analysis of universal varicella vaccination.
Abstract 18755: Variability in Utilization of Diagnostic Imaging Tests in Patients With Symptomatic Peripheral Arterial Disease - Insights From the International PORTRAIT Registry
Authors: Preetham R Muskula, Krishna K Patel, Jingyan Wang, Laith A Derbas, Kim G Smolderen
Journal: Circulation (2017)

Background: Guidelines recommend diagnostic non-invasive imaging [arterial duplex ultrasound (DUS), MR angiography (MRA) and CT angiography (CTA)] in patients with symptomatic peripheral arterial d...
Enforced Expression Of MiR-24, MiR-126 and MiR-365 Does Not Alter Cellular Viability In TCF3-Rearranged Leukemia
Authors: Farhad Akbari Moqadam, Judith M. Boer, Ellen Lange-Turenhout, Rob Pieters, Monique L. Den Boer
Journal: Blood (2013)
The impact of an electronic medical record alert on code status documentation for hospitalized patients with advanced cancer.
Authors: Benjamin Switzer, Khalid Jazieh, Eden Bernstein, Mohammad Khan, David Harris
Journal: Journal of Clinical Oncology (2019)

319 Background: Cardiopulmonary resuscitation in hospitalized patients with advanced cancer is associated with high rates of morbidity and mortality. Advanced care planning (ACP) in this population has exhibited improvements in quality, patient satisfaction, hospice utilization, rates of harm, and healthcare costs. We have sought to observe the changes in ACP documentation by Internal Medicine residents within a tertiary hospital’s inpatient oncology service following a mandatory caregiver training module and enterprise-wide modification in Epic, as well as identify self-reported barriers in code status documentation. Methods: Patients admitted to the Cleveland Clinic’s oncology service were retrospectively reviewed for 8 weeks before and after the implementation of an ACP caregiver training module and code-status best-practice-alert (BPA) into Epic. ACP documentation was assessed in admission notes and direct orders into Epic. In addition, Internal Medicine residents were surveyed on behaviors and perceived barriers contributing to code status documentation. Results: A total of 551 patients (181 pre and 370 post-BPA) were reviewed, exhibiting a 17.2% (44.2 to 61.4) increase of code status documentation in resident admission notes and a 17.6% (10.5 to 28.1) increase in code status orders by residents into patient Epic charts by the time of discharge. Observed 30, 60, and 90-day mortality rates from the day of admission were 18.2, 24.9, and 32%, respectively. The most common self-reported barrier to resident ACP documentation was “forgetting to discuss during the admission process”, and 58% of first-year residents admitted to feeling “uncomfortable” in orchestrating goals-of-care conversations. Conclusions: Resident ACP documentation continues to be suboptimal in the high-risk cohort of hospitalized advanced cancer patients. However, documentation rates appear to be positively influenced by large-scale and multimodal approaches. Further efforts to improve the current practice and culture of advanced directives and code status for the inpatient oncology patient population remains a crucial aspect in the quality and safety of our approach to patient care.