tbuckley/cabot-search huggingface dataset:
Abstract 13521: Cardiac Resynchronization Therapy After Prophylactic Epicardial Leads Implantation During Concomitant Cardiac Surgery: Impact on Left Ventricular Remodeling and Clinical Outcomes
Authors: Mario Senechal, Aude Marceau, François Philippon, Jean-François Sarrazin, Eric Charbonneau, Frederic Jacques, Alexandre Cinq-Mars, François Dagenais, Emilie Leroux, Pierre Voisine
Journal: Circulation (2016)

Introduction: Concomitant prophylactic epicardial leads implantation can be performed in patients with heart failure (HF) and dyssynchrony undergoing cardiac surgery, but the indication and timing of cardiac resynchronization therapy (CRT) remain controversial. Hypothesis: In surgical HF patients with criteria for CRT, most remain eligible for activation at distance from surgery. CRT activation can positively impact left ventricular (LV) remodeling and event-free survival. Methods: Forty-three patients with QRS≥120ms and EF&lt;35% had LV epicardial leads implanted during cardiac surgery (index operation). Twenty-five of them eventually underwent CRT activation (CRT+) while 18 patients did not (CRT-). Echocardiographic data were reviewed at baseline, discharge, prior to CRT activation, and last follow-up. Re-hospitalizations for HF and cardiovascular (CV) deaths were recorded. Results: Clinical characteristics were similar at baseline and prior to CRT activation. At distance from the index operation (9.3±11.9 months) the majority of patients (77%) still had QRS≥120ms and EF&lt;35%. The proportion of resynchronized patients was 25%, 50% and 75% at 1, 6 and 18 months postoperatively. CRT was associated with marked reverse LV remodeling with more pronounced reduction in LVEDV (-74±70ml vs. -14±38ml, p=0.007) and LVESV (-79±66ml vs. -25±34ml, p=0.009) and prominent increase in LVEF (+17±11% vs. +7±8%, p=0.006) at last follow-up (mean 3.5±2.1 years) compared with CRT- patients (mean 1.5±1.3 year). Including the period between index operation and CRT activation, rates per 100-patients-years of re-hospitalization for HF (16.6 vs. 1.5, p&lt;0.0001) and the composite of re-hospitalization and death (31.5 vs. 1.5 p&lt;0.0001) were higher in the CRT- compared to CRT+ group. Freedom from CV death was 100% at 3 years for resynchronized patients, higher than for CRT- patients (89%, 80% and 60% at 1, 2 and 3 years, respectively, p=0.002). Conclusions: The majority of HF patients with QRS≥120ms who undergo prophylactic implantation of epicardial leads during cardiac surgery remain eligible for CRT at distance from surgery. Delaying CRT denies them of reverse LV remodeling and results in significant increases in CV death and re-hospitalizations for HF.
Tissue-specific extracellular matrix scaffolds for the regeneration of spatially complex musculoskeletal tissues
Authors: Gráinne M. Cunniffe, Pedro J. Díaz-Payno, Eamon J. Sheehy, Susan E. Critchley, Henrique V. Almeida, Pierluca Pitacco, Simon F. Carroll, Olwyn R. Mahon, Aisling Dunne, Tanya J. Levingstone, Conor J. Moran, Robert T. Brady, Fergal J. O'Brien, Pieter A.J. Brama, Daniel J. Kelly
Journal: Biomaterials (2018)
Abstract 15850: Sex-specific Transcriptional and Protein Regulation of Calcium Handling Leading to Sex Differences in Cardiomyocyte Death in Heart Failure
Authors: Georgios Kararigas, Cristina E Molina, Holger Summer, Istvan Baczko, Stefan Golz, Vera Regitz-Zagrosek
Journal: Circulation (2015)

Mechanisms underlying sex differences in heart failure (HF) are poorly understood. Women appear to have better prognosis underlain by lower rates of apoptosis and necrosis than men. We hypothesized significant sex differences in left ventricular (LV) transcriptional and protein regulation of end-stage non-ischemic dilated cardiomyopathy (DCM) patients. We compared LV samples of age- and medication-matched male ( n = 5) and female ( n = 5) DCM patients with male ( n = 10) and female ( n = 8) controls. Pathway analysis of genome-wide expression profiling (adjusted P &lt; 0.05) revealed induction of ECM-receptor interaction and several inflammatory pathways in male LVs, while oxidative phosphorylation and proteasome pathways were repressed. In female LVs, the Wnt and Hedgehog signaling pathways were induced, while the mTOR signaling pathway was repressed. Ca2+ signaling pathway was induced in both sexes. However, male LVs had a significantly higher induction of ca. 30% of genes encoding ion channels, accessory beta subunits and regulatory proteins vs. female LVs. Patch-clamp recordings in isolated ventricular myocytes (VMs) from DCM patients showed that while there were no sex differences in sarcoplasmic reticulum Ca2+ load, there was a 2-fold increase in L-type Ca2+ current density in male vs. female VMs ( n = 6-8 cells/group; each cell originated from a different individual; P &lt; 0.05). The cytosolic release of cytochrome c was significantly higher in male vs. female LVs ( P &lt; 0.05). In contrast, the anti-apoptotic protein BCL2 was significantly higher in female vs. male LVs ( P &lt; 0.05). Ca2+-mediated dephosphorylation of pyruvate dehydrogenase was higher in male vs. female LVs ( P &lt; 0.01) indicating higher Ca2+ uptake in male vs. female mitochondria. Given the known reduction of the L-type Ca2+ channel activity by endothelial NO synthase (eNOS), we also show higher eNOS levels in female vs. male LVs ( P &lt; 0.05). We conclude that Ca2+ handling is the target of sex-specific transcriptional and protein regulation, which plays a major role in sex-specific mitochondrial Ca2+ uptake, thereby leading to sex differences in cardiomyocyte death in HF.
Ibuprofen supports macrophage differentiation, T cell recruitment, and tumor suppression in a model of postpartum breast cancer
Authors: Nathan D. Pennock, Holly A. Martinson, Qiuchen Guo, Courtney B. Betts, Sonali Jindal, Takahiro Tsujikawa, Lisa M. Coussens, Virginia F. Borges, Pepper Schedin
Journal: Journal for ImmunoTherapy of Cancer (2018)

Women diagnosed with breast cancer within 5 years postpartum (PPBC) have poorer prognosis than age matched nulliparous women, even after controlling for clinical variables known to impact disease outcomes. Through rodent modeling, the poor prognosis of PPBC has been attributed to physiologic mammary gland involution, which shapes a tumor promotional microenvironment through induction of wound-healing-like programs including myeloid cell recruitment. Previous studies utilizing immune compromised mice have shown that blocking prostaglandin synthesis reduces PPBC tumor progression in a tumor cell extrinsic manner. Given the reported roles of prostaglandins in myeloid and T cell biology, and the established importance of these immune cell populations in dictating tumor growth, we investigate the impact of involution on shaping the tumor immune milieu and its mitigation by ibuprofen in immune competent hosts.In a syngeneic (D2A1) orthotopic Balb/c mouse model of PPBC, we characterized the impact of mammary gland involution and ibuprofen treatment on the immune milieu in tumors and draining lymph nodes utilizing flow cytometry, multiplex IHC, lipid mass spectroscopy and cytokine arrays. To further investigate the impact of ibuprofen on programming myeloid cell populations, we performed RNA-Seq on in vivo derived mammary myeloid cells from ibuprofen treated and untreated involution group mice. Further, we examined direct effects of ibuprofen through in vitro bone marrow derived myeloid cell cultures.Tumors implanted into the mammary involution microenvironment grow more rapidly and display a distinct immune milieu compared to tumors implanted into glands of nulliparous mice. This milieu is characterized by increased presence of immature monocytes and reduced numbers of T cells and is reversed upon ibuprofen treatment. Further, ibuprofen treatment enhances Th1 associated cytokines as well as promotes tumor border accumulation of T cells. Safety studies demonstrate ibuprofen does not impede gland involution, impact subsequent reproductive success, nor promote auto-reactivity as detected through auto-antibody and naïve T cell priming assays.Ibuprofen administration during the tumor promotional microenvironment of the involuting mammary gland reduces overall tumor growth and enhances anti-tumor immune characteristics while avoiding adverse autoimmune reactions. In sum, these studies implicate beneficial prophylactic use of ibuprofen during the pro-tumorigenic window of mammary gland involution.
Brentuximab vedotin for paediatric relapsed or refractory Hodgkin's lymphoma and anaplastic large-cell lymphoma: a multicentre, open-label, phase 1/2 study
Authors: Franco Locatelli, Christine Mauz-Koerholz, Kathleen Neville, Anna Llort, Auke Beishuizen, Stephen Daw, Marta Pillon, Nathalie Aladjidi, Thomas Klingebiel, Judith Landman-Parker, Aurora Medina-Sanson, Keith August, Jessica Sachs, Kristen Hoffman, Judith Kinley, Sam Song, Gregory Song, Stephen Zhang, Ajit Suri, Lia Gore
Journal: The Lancet Haematology (2018)
Neutrophils instruct homeostatic and pathological states in naive tissues
Authors: Maria Casanova-Acebes, José A. Nicolás-Ávila, Jackson LiangYao Li, Susana García-Silva, Akhila Balachander, Andrea Rubio-Ponce, Linnea A. Weiss, José M. Adrover, Kyle Burrows, Noelia A-González, Ivan Ballesteros, Sapna Devi, Juan A. Quintana, Georgiana Crainiciuc, Magdalena Leiva, Matthias Gunzer, Christian Weber, Takashi Nagasawa, Oliver Soehnlein, Miriam Merad, Arthur Mortha, Lai Guan Ng, Hector Peinado, Andrés Hidalgo
Journal: The Journal of Experimental Medicine (2018)

Immune protection relies on the capacity of neutrophils to infiltrate challenged tissues. Naive tissues, in contrast, are believed to remain free of these cells and protected from their toxic cargo. Here, we show that neutrophils are endowed with the capacity to infiltrate multiple tissues in the steady-state, a process that follows tissue-specific dynamics. By focusing in two particular tissues, the intestine and the lungs, we find that neutrophils infiltrating the intestine are engulfed by resident macrophages, resulting in repression of Il23 transcription, reduced G-CSF in plasma, and reinforced activity of distant bone marrow niches. In contrast, diurnal accumulation of neutrophils within the pulmonary vasculature influenced circadian transcription in the lungs. Neutrophil-influenced transcripts in this organ were associated with carcinogenesis and migration. Consistently, we found that neutrophils dictated the diurnal patterns of lung invasion by melanoma cells. Homeostatic infiltration of tissues unveils a facet of neutrophil biology that supports organ function, but can also instigate pathological states.
Abstract 16403: Association Between Dietary Saturated Fat Intake, Coronary Artery Calcification, and Mortality
Authors: Alexandra Lajoie, Yoav Arnson, Heidi Gransar, Louise E Thomson, John D Friedman, Sean W Hayes, Alan Rozanski, Daniel S Berman
Journal: Circulation (2016)

Background: Multiple epidemiologic studies have linked diet to cardiovascular disease (CVD) prevention, with dietary guidelines recommending restricting intake of saturated fats (SatFat) due to obs...
Abstract 13817: Macrophage-Derived Il-18 Evokes a Pro-Inflammatory Positive-Feedback Loop During the Remodeling of the Aging Vasculature
Authors: Roberto Vazquez-Padron, Luis Rodriguez-Menocal, Si M Pham, Hafeez Faridi, Vineet Gupta, Dania Mateu
Journal: Circulation (2011)

Objective: Aging exaggerates neointimal hyperplasia. This study reveals a mechanism by which aging sustains leukocyte adhesion, vascular inflammation and neointima formation. Methods and Results: The effect of aging on vascular remodeling was assessed in the rat balloon injury model using time-course microarray analysis, immunohistochemistry, and LINCOplex immunoassays. As we previously described, the injured arteries in aging rats (22 month-old) developed thicker neointimas than those in their younger counter parts (4 month-old) (I/M: 0.8 ± 0.2 vs. 0.54 ± 0.15, p=0.008). Microarray analysis revealed an early up-regulation of fibrinogen b and γ genes in aging rats which led to an exaggerated focal accumulation of fibrinogen in the injured vascular wall. The accumulation of fibrinogen increased post-injury leukocyte adhesion and extravasation and therefore, exacerbated vascular inflammation. In fact, neointimal hyperplasia in aging rats was associated with an elevated number of tissue macrophages (aging vs...
Deep proteomic network analysis of Alzheimer’s disease brain reveals alterations in RNA binding proteins and RNA splicing associated with disease
Authors: Erik C. B. Johnson, Eric B. Dammer, Duc M. Duong, Luming Yin, Madhav Thambisetty, Juan C. Troncoso, James J. Lah, Allan I. Levey, Nicholas T. Seyfried
Journal: Molecular Neurodegeneration (2018)

The complicated cellular and biochemical changes that occur in brain during Alzheimer's disease are poorly understood. In a previous study we used an unbiased label-free quantitative mass spectrometry-based proteomic approach to analyze these changes at a systems level in post-mortem cortical tissue from patients with Alzheimer's disease (AD), asymptomatic Alzheimer's disease (AsymAD), and controls. We found modules of co-expressed proteins that correlated with AD phenotypes, some of which were enriched in proteins identified as risk factors for AD by genetic studies. The amount of information that can be obtained from such systems-level proteomic analyses is critically dependent upon the number of proteins that can be quantified across a cohort. We report here a new proteomic systems-level analysis of AD brain based on 6,533 proteins measured across AD, AsymAD, and controls using an analysis pipeline consisting of isobaric tandem mass tag (TMT) mass spectrometry and offline prefractionation. Our new TMT pipeline allowed us to more than double the depth of brain proteome coverage. This increased depth of coverage greatly expanded the brain protein network to reveal new protein modules that correlated with disease and were unrelated to those identified in our previous network. Differential protein abundance analysis identified 350 proteins that had altered levels between AsymAD and AD not caused by changes in specific cell type abundance, potentially reflecting biochemical changes that are associated with cognitive decline in AD. RNA binding proteins emerged as a class of proteins altered between AsymAD and AD, and were enriched in network modules that correlated with AD pathology. We developed a proteogenomic approach to investigate RNA splicing events that may be altered by RNA binding protein changes in AD. The increased proteome depth afforded by our TMT pipeline allowed us to identify and quantify a large number of alternatively spliced protein isoforms in brain, including AD risk factors such as BIN1, PICALM, PTK2B, and FERMT2. Many of the new AD protein network modules were enriched in alternatively spliced proteins and correlated with molecular markers of AD pathology and cognition. Further analysis of the AD brain proteome will continue to yield new insights into the biological basis of AD.
Preservation of Blood Vessels with an Oxygen Generating Composite
Authors: Huaifa Zhang, Benjamin Dalisson, Simon Tran, Jake Barralet
Journal: Advanced Healthcare Materials (2018)

Abstract Damage caused by oxygen deficiency (hypoxia) is one of the major factors limiting tissue and organ preservation time. Cooling tissues slows down metabolic rate of cells thereby prolonging tissue and organ survival sufficiently to allow transport and transplantation within a few hours. Although metabolism is slowed, cells and some enzymes continue to consume oxygen that can render cold stored tissues hypoxic. Here, an oxygen‐generating composite (OGC) with sustained oxygen release is reported for ex vivo blood vessel preservation. Aorta segments are cultured under hypothermia for 25 days in vascular preservation media. The presence of OGC increases cell viability from 9 ± 6% to 96 ± 3% and retains 65 ± 8% of original KCl stimulated contractile force after 25 days compared with 25 ± 4% in controls. Culture for 7 days in nitrogen demonstrates proof‐of‐concept for normothermic blood vessel preservation, OGC increases the cell viability from 45 ± 15% to 78 ± 2%, and KCl stimulates contractile force from 49 ± 7% to 95 ± 8%, respectively. Oxygen release materials then may have a role in augmenting current preservation techniques.
Abstract 19008: Biodegradable Multilayered Aligned Nanofiber Cardiac Patch Composed of Human Inducible Pluripotent Stem Cell Derived Cardiomyocytes (hiPSC-CMs) Enhances Cardiac Function and Cell Survival In Vivo
Authors: Mahmood Khan, Jed Johnson, Mark G Angelos
Journal: Circulation (2016)

Introduction: The current obstacles to regenerate ischemic cardiac tissue using the stem-cell based therapies include poor survival of transplanted cells in the ischemic heart, lack of anisotropic structure for alignment of cardiomyocytes and thickness of the engineered cardiac tissue. Hypothesis: We hypothesized that a biodegradable multi-layered hiPSC-CMs aligned nanofiber (PLGA) cardiac patch mimics the anisotropic structure and alignment of transplanted cardiomyocytes, thereby improves cell survival and cardiac function following transplantation onto the ischemic myocardium. Methods: Study was divided into four different groups as follows: 1) Control (no-MI); 2) MI (Permanent LAD ligation); 3) S-CP (Single layer cardiac patch +MI); 4) M-CP (Multilayer cardiac patch+MI). Nude athymic rats (NIHRNU) were used for transplantation of human cardiomyocytes (rFP fluorescence). HiPSC-CMs were cultured for one-week on the aligned nanofiber scaffold. For multilayered patch, three single layers of cardiac patch w...
OSW-1: A novel anticancer agent with potent anticancer activity and unique mechanism of action.
Authors: Yan Zhou, Celia Garcia-Prieto, Li Feng, Helene Pelicano, Zhendong Jin, Michael J. Keating, Peng Huang
Journal: Cancer Research (2004)

2254    Background:  OSW-1 is a naturally occurring compound found in the bulbs of  Ornithogalum saudersiae . Previous  in vitro  study showed that OSW-1 has a potent cytotoxic activity against cancer cells, but the mechanism of the drug action remains unknown. Our present study tested the anticancer activity of OSW-1 against a variety of human cancer cell lines and primary leukemia cells from patients, and investigated the mechanisms responsible for its anticancer activity.  Methods:  The cytotoxic activity of OSW-1 was tested using MTT assay and apoptosis analyses including annexin-V reactivity, loss of mitochondrial transmembrane potential, caspase activation, and loss of DNA integrity. DNA microarray analysis was used to assess changes in gene expression after cancer cells were incubated with OSW-1. Special sub-clones of leukemia cells with mitochondrial DNA alterations and respiration deficiency cells were used to evaluate the role of mitochondrial respiration in OSW-1 action. Electronic microscopy was used to reveal the morphological changes in mitochondria after drug treatment.  Results:  The IC 50  of OSW-1 in several leukemia cell lines, ovarian and pancreatic cancer cells were between 0.03- 0.3 nM. The median IC 50  in primary leukemia cells isolated from 35 patients with chronic lymphocytic leukemia (CLL) is 0.24 nM. Normal lymphocytes and normal ovarian epithelial cells were less sensitive to the cytotoxic action of OSW-1 in comparison with leukemia and ovarian cancer cells, respectively. Microarray assay revealed that OWS-1 induced significant alterations in expression of genes involved in mitochondrial respiration. Cells with respiration deficiency were relatively resistant to OSW-1. Morphological analysis by electronic microscopy revealed that OSW-1 induced significant mitochondrial swelling, flatting of cristae, and decreased matrix density.  Conclusions:  OSW-1 exhibits potent anticancer activity against a wide spectrum of cancer cells and is relatively less toxic to normal cells. Its mechanism of action seems to involve mitochondrial respiration.
Effect of Early Surgery vs Physical Therapy on Knee Function Among Patients With Nonobstructive Meniscal Tears
Authors: Victor A. van de Graaf, Julia C. A. Noorduyn, Nienke W. Willigenburg, Ise K. Butter, Arthur de Gast, Ben W. Mol, Daniel B. F. Saris, Jos W. R. Twisk, Rudolf W. Poolman
Journal: JAMA (2018)

<h3>Importance</h3> Despite recent studies suggesting arthroscopic partial meniscectomy (APM) is not more effective than physical therapy (PT), the procedure is still frequently performed in patients with meniscal tears. <h3>Objective</h3> To assess whether PT is noninferior to APM for improving patient-reported knee function in patients with meniscal tears. <h3>Design, Setting, and Participants</h3> Noninferiority, multicenter, randomized clinical trial conducted in 9 hospitals in the Netherlands. Participants were aged 45 to 70 years with nonobstructive meniscal tears (ie, no locking of the knee joint). Patients with knee instability, severe osteoarthritis, and body mass index greater than 35 were excluded. Recruitment took place between July 17, 2013, and November 4, 2015. Participants were followed up for 24 months (final participant follow-up, October 11, 2017). <h3>Interventions</h3> Three hundred twenty-one participants were randomly assigned to APM (n = 159) or a predefined PT protocol (n = 162). The PT protocol consisted of 16 sessions of exercise therapy over 8 weeks focused on coordination and closed kinetic chain strength exercises. <h3>Main Outcomes and Measures</h3> The primary outcome was change in patient-reported knee function on the International Knee Documentation Committee Subjective Knee Form (range, 0 to 100; from worse to best) from baseline over a 24-month follow-up period. The noninferiority margin was defined as a difference between treatment groups of 8 points and was assessed with a 1-sided α of .025. The primary analysis followed the intention-to-treat principle. <h3>Results</h3> Among 321 patients who were randomized (mean [SD] age, 58 [6.6] years; 161 women [50%]), 289 (90%) completed the trial (161 women and 158 men). In the PT group, 47 participants (29%) had APM during the 24-month follow-up period, and 8 participants randomized to APM (5%) did not have APM. Over a 24-month follow-up period, knee function improved in the APM group by 26.2 points (from 44.8 to 71.5) and in the PT group by 20.4 points (from 46.5 to 67.7). The overall between-group difference was 3.6 points (97.5% CI, −∞ to 6.5;<i>P</i>value for noninferiority = .001). Adverse events occurred in 18 participants in the APM group and 12 in the PT group. Repeat surgery (3 in the APM group and 1 in the PT group) and additional outpatient visits for knee pain (6 in the APM group and 2 in the PT group) were the most frequent adverse events. <h3>Conclusions and Relevance</h3> Among patients with nonobstructive meniscal tears, PT was noninferior to APM for improving patient-reported knee function over a 24-month follow-up period. Based on these results, PT may be considered an alternative to surgery for patients with nonobstructive meniscal tears. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01850719
Passive transfer of anti-HBc after intravenous immunoglobulin administration in patients with cancer: a retrospective chart review
Authors: Huifang Lu, Anna S Lok, Carla L Warneke, Sairah Ahmed, Harrys A Torres, Fernando Martinez, Maria E Suarez-Almazor, Jessica T Foreman, Alessandra Ferrajoli, Jessica P Hwang
Journal: The Lancet Haematology (2018)