tbuckley/cabot-search huggingface dataset:
Abstract P154: Focal Adhesion Kinase Plays a Critical Role in Upregulating Fibrogenesis in Load-Induced Cardiac Hypertrophy
Authors: Ana Paula Dalla Costa, Carolina F Clemente, Thais H Theizen, José Roberto Souza, Leandro Cardoso, Kleber G Franchini
Journal: Circulation Research (2011)

Myocardial fibrosis is maladaptive, accelerating the evolution of diseased hearts to failure. The pathogenesis of myocardial fibrosis is critically dependent on complex processes of activation (i.e. enhanced proliferation, production and secretion of soluble factors, collagen and matrix metalloproteinases) and terminal differentiation of cardiac fibroblasts into myofibroblasts, resultant from the mobilization of numerous signaling molecules by physical and humoral stimuli. Noting that Focal Adhesion Kinase (FAK) is activated in areas of ongoing myocardial fibrosis, we sought to examine whether it is a critical mediator of fibrogenesis in load-induced hypertrophic hearts. Isolated fibroblasts from hypertrophic hearts of mice subjected to transverse aortic constriction (TAC; 1 to 8 weeks) were highly activated as recognized by markers that indicate enhanced proliferation (nuclear Ki67), production of collagen and matrix metalloproteinase-2 (MMP-2) and differentiation into myofibroblasts (expression of α-smooth muscle actin - α-SMA). In these cells, FAK was upregulated, as also were its dowstream pathways Src/ERK1/2 and PI3K/AKT/mTOR. Depletion of FAK (∼80%) after treatment with small interfering RNA (siRNA-FAK) markedly attenuated cardiac hypertrophy and fibrosis, and significantly reduced the number of activated fibroblasts harvested from overloaded hearts. Restoration of FAK function by overexpressing a full-length FAK construct in these cells, selectively enhanced the activity of the downstream PI3K/AKT/mTOR and rescued the activated phenotype of fibroblasts. Transfection with an inactive FAK mutant (Tyr397 substituted by phenylalanine) did not rescue the activated phenotype of fibroblasts harvested from overloaded hearts depleted of FAK. However, cells harvested from overloaded hearts depleted of FAK and treated with the mTOR activating aminoacid leucine showed typical phenotype of activated fibroblasts. These findings uncover a role for FAK in regulating the signaling cascade PI3K/AKT/mTOR in cardiac fibroblasts, which seems to be critical for the pathogenesis of myocardial fibrosis in hypertrophic hearts. Targeting this pathway may provide a novel strategy for treating hypertrophic heart diseases.
The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease
Authors: Gerald Burgstaller, Bettina Oehrle, Michael Gerckens, Eric S. White, Herbert B. Schiller, Oliver Eickelberg
Journal: European Respiratory Journal (2017)

The pulmonary extracellular matrix (ECM) determines the tissue architecture of the lung, and provides mechanical stability and elastic recoil, which are essential for physiological lung function. Biochemical and biomechanical signals initiated by the ECM direct cellular function and differentiation, and thus play a decisive role in lung development, tissue remodelling processes and maintenance of adult homeostasis. Recent proteomic studies have demonstrated that at least 150 different ECM proteins, glycosaminoglycans and modifying enzymes are expressed in the lung, and these assemble into intricate composite biomaterials. These highly insoluble assemblies of interacting ECM proteins and their glycan modifications can act as a solid phase-binding interface for hundreds of secreted proteins, which creates an information-rich signalling template for cell function and differentiation. Dynamic changes within the ECM that occur upon injury or with ageing are associated with several chronic lung diseases. In this review, we summarise the available data about the structure and function of the pulmonary ECM, and highlight changes that occur in idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), asthma and lung cancer. We discuss potential mechanisms of ECM remodelling and modification, which we believe are relevant for future diagnosis and treatment of chronic lung disease.
Abstract P155: HSF-1 Deletion Induces MDR1 Gene in the Heart and Protects from Doxorubicin-Induced Cardiotoxicity
Authors: Karthikeyan Krishnamurthy, Lawrence Druhan, Govindasamy Ilangovan
Journal: Circulation Research (2011)

Heat shock factor 1 (HSF-1) has been found to be a frontline responder of different stresses in eukaryotic cells. Deletion of HSF-1 has been reported to develop defects in mice. In the present work we report that deletion of HSF-1 induced multidrug resistance 1 (MDR1) gene and P-glycoprotein (P-gp) expression. Both RT-PCR and western blotting, confirmed the higher level of MDR1 gene expression and P-gp protein in HSF-1 knock out mouse hearts. P-gp is well known ATP binding cassette, which extrudes intracellular drugs upon binding ATP. Hence the phenotype of the P-gp pump in HSF-1 −/− mice was studied in the form of Doxorubicin (Dox) extrusion in the heart. Cardiomyocytes isolated from HSF-1 −/− and HSF-1 +/− mice retained very less intracellular Dox, compared to wild type counterparts. Similarly, both HSF-1 +/− and HSF-1 −/− mice were less susceptible for Dox-induced cardiotoxicity, as seen from reduced cardiac dysfunction in these group against Dox (as confirmed by cardiac MRI and echocardiography). Further confirmatory studies revealed that deletion of HSF-1 enhances NF-B, which subsequently induces MDR1 gene. These results reveal that inactivation of HSF-1 in the heart will be a potential approach to prevent Dox-induced cardiotoxicity.
Effect of siltuximab on lean body mass (LBM) in multicentric Castleman’s disease (MCD) patients (pts).
Authors: Michael B. Sawyer, Corey Casper, Nikhil C. Munshi, Raymond Wong, Jessica Vermeulen, Rajesh Bandekar, Ming Qi, Helgi Van De Velde, Frits Van Rhee
Journal: Journal of Clinical Oncology (2014)

8576 Background: MCD is a rare lymphoproliferative disease with wasting, fever, night sweats, and fatigue. Interleukin-6 (IL-6) plays a pivotal role in MCD and has a major role in cachexia. Siltuximab is a chimeric anti−IL-6 monoclonal antibody being studied for MCD treatment. A randomized, double-blind, placebo-controlled study in MCD showed significant improvement in durable tumor and symptomatic response (34 vs 0% placebo; P = 0.0012), with consistent improvements in major secondary endpoints and no increase in AEs compared with placebo. Methods: Pts with confirmed symptomatic MCD were randomized 2:1 to siltuximab 11 mg/kg (n = 53) or placebo (n = 26) IV q3wk. Mean baseline wt was 77 kg for placebo and 69 kg for siltuximab. Pts received best supportive care, and were treated to treatment failure. Abdominal CT scans suitable for body composition analysis were available for 57 (37 on siltuximab, 20 on placebo)/79 subjects. CT scans for each pt time point were landmarked at the 3rd lumbar vertebra (L3). L3 images were analyzed using Slice-O-Matic with Hounsfield units (HU) set at different levels for each tissue: skeletal muscle range of -29 HU to 150 HU, visceral adipose tissue: within -150 HU to -50 HU, intramuscular adipose tissue: within -190 HU to -30 HU, and subcutaneous adipose tissue: within -190 HU to -30 HU. Results: The median age of 79 treated pts was 48 years and 53M/26F. 58% had previous therapy and 30% were on steroids. 30 % of pts reported weight loss and 38% of pts reported anorexia at baseline. Mean maximal gain in lean body mass (LBM) in siltuximab pts was 2.4 vs. 1.1 kg in placebo (P = 0.04). Mean maximal gain in fat mass (FM) in siltuximab pts was 6.4 vs. 1.4 kg in placebo pts (P = 0.003). At the first CT scan at 9 wks 50% of siltuximab pts had gained 1 kg of LBM, at no point did 50% of placebo pts gain 1 kg. Gain in fat mass preceded gain in LBM. Conclusions: This study has shown that siltuximab caused statistically and clinically meaningful LBM gains compared to placebo pts with MCD. Further study of siltuximab for treating decreases in LBM in IL-6 associated malignancies is warranted. Clinical trial information: NCT01024036. Siltuximab Placebo LBM gain >1 kg 73% 35% Stable LBM (gain/loss <1 kg) 22% 40% LBM loss >1 kg 5% 25% P (Fisher’s Exact test) P = 0.01
Abstract 171: Nkx2-5 Suppresses The Proliferation Of Atrial Cardiomyocytes And Formation Of The Conduction Cells During Cardiac Development
Authors: Yasuhiro Nakashima, Diana A Yanez, Marlin Touma, Maria C Jordan, Kenneth P Roos, Atsushi Nakano
Journal: Circulation Research (2013)

Mutation of human NKX2-5 is linked to atrioventricular conduction abnormalities and atrial septal defects. However, it has been difficult to rigorously examine the primary role of Nkx2-5 during the formation of the atria and cardiac conduction cells due to the concurrent hemodynamic aberration associated with ventricular dysfunction. Here, we examined the role of Nkx2-5 in the formation of the atria and conduction cells. Nkx2-5 was conditionally ablated in the atrial cardiomyocytes using atrial-specific Sln-Cre mouse line. The conditional mutants died shortly after birth, which is earlier and more severe than ventricular-specific knockout of Nkx2-5. While no evidence of ventricular failure was identified, atrial-specific conditional mutants developed congenital heart abnormalities including enlarged foramen ovale and hyperplastic atrial myocardium. Histological analyses revealed that the overproliferation of the atrial myocytes underlies the hyperplastic atrial myocardium prior to the development of the atrial septal enlargement. Moreover, conditional mutants showed massive expansion of SA node, AV node and internodal conduction cells, resulting in atrioventricular blocks that were further exacerbated by catecholamine stimulation. Given that the hemodynamic alteration is minimal during the gestational stages in our model, the misspecification of the conduction cells is not likely due to the alteration of the hemodynamics. Together, these data suggest that Nkx2-5 plays a suppressive role in the proliferation of the atrial cardiomyocytes and the formation of the conduction cells.
Physician Reimbursement in Medicare Advantage Compared With Traditional Medicare and Commercial Health Insurance
Authors: Erin Trish, Paul Ginsburg, Laura Gascue, Geoffrey Joyce
Journal: JAMA Internal Medicine (2017)

Nearly one-third of Medicare beneficiaries are enrolled in a Medicare Advantage (MA) plan, yet little is known about the prices that MA plans pay for physician services. Medicare Advantage insurers typically also sell commercial plans, and the extent to which MA physician reimbursement reflects traditional Medicare (TM) rates vs negotiated commercial prices is unclear.
Functional and Molecular Alterations of Bone Marrow Mesenchymal Stem and Progenitor Cells in Patients with Myelodysplastic Syndrome with Ring Sideroblast
Authors: Monika Dolinska, Pingnan Xiao, Anne-Sofie Johansson, Lakshmi Sandhow, Makoto Kondo, Thibault Bouderlique, Johanna Ungerstedt, Eva Hellstrom-Lindberg, Hong Qian
Journal: Blood (2016)
Late toxicities and clinical outcome at 5 years of the ACCORD 12/0405-PRODIGE 02 trial comparing two neoadjuvant chemoradiotherapy regimens for intermediate-risk rectal cancer
Authors: D. Azria, J. Doyen, M. Jarlier, I. Martel-Lafay, C. Hennequin, P. Etienne, V. Vendrely, E. François, G. de La Roche, O. Bouché, X. Mirabel, B. Denis, L. Mineur, J. Berdah, M. Mahé, Y. Bécouarn, O. Dupuis, G. Lledo, J. Seitz, L. Bedenne, S. Gourgou-Bourgade, B. Juzyna, T. Conroy, J. Gérard
Journal: Annals of Oncology (2017)
Evolocumab reduced CV events in patients with atherosclerotic CV disease taking high- or moderate-intensity statins
Authors: Elizabeth Jackson, Kim A. Eagle
Journal: Annals of Internal Medicine (2017)

Source Citation Sabatine MS, Giugliano RP, Keech AC, et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-22. 28304224
Direct Laser Interference Patterning of CoCr Alloy Surfaces to Control Endothelial Cell and Platelet Response for Cardiovascular Applications
Authors: Romain Schieber, Federico Lasserre, Michael Hans, Marc Fernández‐Yagüe, Maribel Díaz‐Ricart, Ginés Escolar, Maria‐Pau Ginebra, Frank Mücklich, Marta Pegueroles
Journal: Advanced Healthcare Materials (2017)

Abstract The main drawbacks of cardiovascular bare‐metal stents (BMS) are in‐stent restenosis and stent thrombosis as a result of an incomplete endothelialization after stent implantation. Nano‐ and microscale modification of implant surfaces is a strategy to recover the functionality of the artery by stimulating and guiding molecular and biological processes at the implant/tissue interface. In this study, cobalt‐chromium (CoCr) alloy surfaces are modified via direct laser interference patterning (DLIP) in order to create linear patterning onto CoCr surfaces with different periodicities (≈3, 10, 20, and 32 µm) and depths (≈20 and 800 nm). Changes in surface topography, chemistry, and wettability are thoroughly characterized before and after modification. Human umbilical vein endothelial cells' adhesion and spreading are similar for all patterned and plain CoCr surfaces. Moreover, high‐depth series induce cell elongation, alignment, and migration along the patterned lines. Platelet adhesion and aggregation decrease in all patterned surfaces compared to CoCr control, which is associated with changes in wettability and oxide layer characteristics. Cellular studies provide evidence of the potential of DLIP topographies to foster endothelialization without enhancement of platelet adhesion, which will be of high importance when designing new BMS in the future.
Membrane type 1-matrix metalloproteinase (MT1-MMP) targeted antitumor agents
Authors: Jennifer Atkinson, Robert Falconer, Caroline Pennington, Sandie Martin, Dylan Edwards, Laurence Patterson, Jason Gill, Paul Loadman
Journal: Cancer Research (2007)

2453   Matrix metalloproteinase (MMP) activity is required for tumour growth and metastasis. This study assessed the expression of membrane-type MMP1 (MT1-MMP) in human Non Small Cell Lung Cancer (NSCLC) specimens and paired histologically normal lung tissue. Analysis of cell lines, xenografts and 39 NSCLC specimens (representative of all stages and grades), as well as corresponding normal lung tissue, was undertaken by quantitative Real Time PCR (qRT-PCR). MT1-MMP was found to be overexpressed in NSCLC samples relative to normal tissue (p  Following demonstration of selective expression, an MT1-MMP targeted peptide-conjugated anti-tumour agent was synthesised using a combination of solution and solid phase chemistry.  In vitro , this peptide-conjugate is shown to be preferentially cleaved in MT1-MMP expressing tumour homogenates relative to plasma and liver homogenates. Cell lines and xenografts expressing MT1-MMP efficiently cleave this peptide-conjugate to release the active agent whilst those negative for MT1-MMP do not. Clinically derived NSCLC tumours expressing high levels of MT1-MMP also released the active agent whereas the peptide-conjugate was stable in serum from the same patients. Differential cytotoxicity of the peptide conjugate between cell lines positive (IC 50  176 ±39 nM) and negative (IC 50  >5000 nM) for MT1-MMP has also been demonstrated.  In vivo , release of the anti-tumour agent from the peptide-conjugate in human tumour xenografts expressing MT1-MMP was demonstrated by LCMS, with the peptide-conjugate displaying relative stability in plasma and normal tissues. This study shows that MT1-MMP is a therapeutic target in NSCLC and can be used to metabolise agents that are activated selectively by the tumour.
Genetic or CD40L-Mediated Loss of Iκbα Is Associated with Resistance to the Dual SYK/JAK Inhibitor Cerdulatinib in DLBCL Cell Lines
Authors: Greg P Coffey, Jiajia Feng, Sabah Kadri, Y. Lynn Wang, Pin Lu, Shruti Sharma, Jeremy Segal, Glenn Michelson, Anjali Pandey, John T. Curnutte, Pamela B. Conley
Journal: Blood (2016)
PI3KCA and PIM Inhibitors in Peripheral T-Cell Lymphomas
Authors: Esperanza Martin-Sanchez, Socorro M. Rodriguez-Pinilla, Luis Lombardia, Margarita Sanchez-Beato, Beatriz Dominguez-Gonzalez, Diana Romero, Cristina I. Gomez-Abad, PierFrancesco Vargiu, Maria E. Rodriguez, Manuela Mollejo, Javier Alves, Magdalena B. Wozniak, James R. Bischoff, Miguel A. Piris
Journal: Blood (2010)
Early clinical manifestations of Sézary syndrome: A multicenter retrospective cohort study
Authors: Aaron R. Mangold, Agnieszka K. Thompson, Mark D. Davis, Ieva Saulite, Antonio Cozzio, Emmanuella Guenova, Emmilia Hodak, Iris Amitay-Laish, Ramon M. Pujol, Mark R. Pittelkow, Robert Gniadecki
Journal: Journal of the American Academy of Dermatology (2017)
A Young Woman With a New Breast Mass
Authors: Chiara Iacconi, Giulia Vatteroni, Alessandro Ginori
Journal: JAMA Surgery (2017)

A 28-year-old woman without clinical signs of inflammation or infection but with symptoms of fatigue visited the emergency department for a sudden, diffuse, and painful enlargement of the upper quadrants of the left breast with edema and palpable axillary lymph nodes. What is your diagnosis?
Impact of Pre-Transplant Ruxolitinib in Myelofibrosis Patients on Outcome after Allogeneic Stem Cell Transplantation
Authors: Sharifah Shahnaz Syed Abd Kadir, Tatjana Zabelina, Maximilian Christopeit, Gerald G Wulf, Eva Maria Wagner, Martin Bornhäuser, Thomas Schroeder, Martina Crysandt, Karin Mayer, Matthias Stelljes, Anita Badbaran, Christine Wolschke, Francis A. Ayuk, Ioanna N Triviai, Dominik Wolf, Nicolaus Kröger
Journal: Blood (2016)
Abstract 218: Chemical Induced Reductive Stress Causes Cardiomyocyte Hypertrophy
Authors: Sandeep B Shelar, Madhusudhanan Narasimhan, Gobinath Shanmugam, Neelu E Vargees, Ramasamy Sakthivel, Charmaine Brown, Palaniappan Sethu, Wayne E Warner, Victor Darley-Usmar, Namakkal S Rajasekaran
Journal: Circulation Research (2015)

Background: Progressive accumulation of misfolded or unfolded proteins is a symbol of impaired proteostasis and proteotoxicity. Such a chronic proteotoxicity is amenable to cell types that are post mitotically matured with lack of further differentiation or proliferation. Our recent discovery using a mouse model of familial human cardiac disease displayed protuberant shift in the redox state towards reductive stress (RS) in association with accumulation of toxic protein aggregates. Further, sustained trans-activation of Nrf2/antioxidant signaling caused RS in the myopathy hearts. Accordingly, we hypothesized that whether profound activation of Nrf2/antioxidant signaling and subsequent RS may cause pathological remodeling in cardiomyocyte. The aim of this study was to investigate the effect of sustained pharmacological activation of Nrf2 on cardiac remodeling. Methods: HL1 cardiomyocytes were used as an in vitro model to study the RS-mediated cardiac remodeling. They were treated with 2-10 μM of potential Nrf2-inducers; sulforaphane (SF), di-methyl fumarate (DMF) and novel small molecules (C-38, C-50, C-63 and C-66) to establish RS by sustained activation of Nrf2/antioxidant signaling. Next, we investigated the implications of RS in cardiomyocyte remodeling by analyzing transcriptional and translational mechanisms using immunoblotting, qPCR, immunofluorescence, GSH and NADPH redox measurements in HL1 cells. Results: Dose dependent effects for individual small molecules including known Nrf2 inducers (SF and DMF) revealed distinct pro-reductive and reductive intracellular (i.e. reductive stress) environments. In fact, the obligatory activation of Nrf2 signaling was associated with significant upregulation of antioxidant enzymes and small molecular thiols including glutathione (GSH). Surprisingly, while pro-reductive condition in HL1 cells was subdued, the RS induced cardiomyocyte hypertrophy was evident from microscopic examination and molecular signature (increased expression of ANF and BNF) after 24-48 hrs of Nrf2 activation. Conclusion: In summary, the chemical induced sustained activation of Nrf2 leading to formation of reductive stress showed hypertrophic remodeling in HL1 cardiomyocytes.
Symptom distress, quality of life and challenges of illness according to race and income in women with metastatic breast cancer
Authors: M. Rosenzweig, T. Wiehagen, A. M. Brufsky, R. M. Arnold
Journal: Journal of Clinical Oncology (2006)

8609 Background: Response to a diagnosis of metastatic breast cancer (MBC) may vary according to race and income. The aims of this study were: 1) to identify quality of life, symptom distress and challenges of illness during MBC treatment and 2) to determine if these variables differ according to race and income. Methods: The study was a 2×2 prospective design conducted at an urban breast cancer center. Women with MBC were categorized into four groups based on race and income: white low (WL), white high (WH), African American high (AAH) and African American low (AAL). Instruments were 1) Symptom Distress Scale (SDS), (higher scores /worse distress) 2) Functional Assessment of Cancer Therapy (FACT), (higher scores/better QOL) and a 3) semi structured interview assessing patient perspectives of MBC. Interview analysis utilized grounded theory. Results: Preliminary results are for 51 women. Mean age was 58.2 years, with mean 24 months since MBC diagnosis. Quantitative data indicated worse quality of life in AA than white women. (P=0.06), with AALI women exhibiting worse symptom distress (P=0.03) as compared to white women. Qualitative data (n=48) corroborated quantitative data. The most prevalent themes among all sociodemographic groups were of hope (33/48 - 69%), faith (28/48 - 58%) and progressive loss (29/48, 60%). Each racial/economic delineation expressed unique themes: AALI talked about physical (7/7,100%)and social distress (6/7, 86%) as well as uncertainty regarding “whether treatment was worth it” (6/7 - 86%). WLI women verbalized an overall optimism, describing themselves as “lucky” (6/14 - 43%), with minimization of symptoms (10/14 - 71%). WHI women articulated a sense of betrayal at their progressive illness (9/20 - 45%) and fear of physical and economic dependence. Conclusion: Race and economic delineation brings unique symptom experience, quality of life and patient perspective to the metastatic breast cancer experience. These findings will advise tailored intervention. [Table: see text] No significant financial relationships to disclose.