tbuckley/cabot-search huggingface dataset:
FLow-Induced PRotrusions (FLIPRs)
Authors: Claudia Tersteeg, Harry F. Heijnen, Anita Eckly, Gerard Pasterkamp, Rolf T. Urbanus, Coen Maas, Imo E. Hoefer, Rienk Nieuwland, Richard W. Farndale, Christian Gachet, Philip G. de Groot, Mark Roest
Journal: Circulation Research (2014)

Platelets are the most important cells in the primary prevention of blood loss after injury. In addition, platelets are at the interface between circulating leukocytes and the (sub)endothelium regulating inflammatory responses.Our aim was to study the dynamic process that leads to the formation of procoagulant and proinflammatory platelets under physiological flow.In the present study, we describe the formation of extremely long, negatively charged membrane strands that emerge from platelets adhered under flow. These flow-induced protrusions (FLIPRs) are formed in vitro on different physiological substrates and are also detected in vivo in a mouse carotid injury model. FLIPRs are formed downstream the adherent and activated platelets and reach lengths of 250 μm. FLIPR formation is shear-dependent and requires cyclophilin D, calpain, and Rac1 activation. It is accompanied by a disassembly of the F-actin and microtubule organization. Monocytes and neutrophils roll over FLIPRs in a P-selectin/P-selectin glycoprotein ligand-1-dependent manner, retrieving fragments of FLIPRs as microparticles on their surface. Consequently, monocytes and neutrophils become activated, as demonstrated by increased CD11b expression and L-selectin shedding.The formation of long platelet membrane extensions, such as the ones presented in our flow model, may pave the way to generate an increased membrane surface for interaction with monocytes and neutrophils. Our study provides a mechanistic model for platelet membrane transfer and the generation of monocyte/neutrophil-microparticle complexes. We propose that the formation of FLIPRs in vivo contributes to the well-established proinflammatory function of platelets and platelet-derived microparticles.
General Health Checks in Adults for Reducing Morbidity and Mortality From Disease
Authors: Lasse T. Krogsbøll, Karsten Juhl Jørgensen, Peter C. Gøtzsche
Journal: JAMA (2013)

What are the benefits and harms of general health checks for adult populations?Compared with usual care, offers of health checks were not associated with lower rates of all-cause mortality, mortality from cardiovascular disease, or mortality from cancer. Health checks may be associated with more diagnoses and more drug treatment. Morbidity was infrequently reported, as were most harms, such as use of diagnostic procedures.
Miami classification for probe-based confocal laser endomicroscopy
Authors: M. Wallace, G. Lauwers, Y. Chen, E. Dekker, P. Fockens, P. Sharma, A. Meining
Journal: Endoscopy (2011)

An essential element for any new advanced imaging technology is standardization of indications, terminology, categorization of images, and research priorities. In this review, we propose a state-of-the-art classification system for normal and pathological states in gastrointestinal disease using probe-based confocal laser endomicroscopy (pCLE). The Miami classification system is based on a consensus of pCLE users reached during a meeting held in Miami, Florida, in February 2009.
Identification of a T cell-derived b cell growth factor distinct from interleukin 2.
Authors: M Howard, J Farrar, M Hilfiker, B Johnson, K Takatsu, T Hamaoka, W E Paul
Journal: The Journal of Experimental Medicine (1982)

We report here a factor (B cell growth factor) found in induced supernatants of the mouse thymoma EL4 that co-stimulates with anti-IgM antibodies in short-term cultures of purified B lymphocytes to induce polyclonal B cell proliferation but not antibody-forming cell production. The factor is not mitogenic for resting B cells and interacts with anti-IgM-activated B cells in a non-H-2-restricted manner. Absorption studies and molecular weight analysis reveal the factor is distinct from interleukin 2. This factor synergises with antigen, interleukin 2, and an interleukin 2-free, B cell growth factor-free T cell supernatant that contains T cell-replacing factor to produce erythrocyte-specific plaque-forming cells in cultures of highly purified B cells.
Lung function tests in severe obese subjects before and one year after bariatric surgery
Authors: Ebymar Arismendi, Eva Rivas, Josep Vidal, Esther Barreiro, Alvar Agusti, Roberto Rodriguez-Roisin
Journal: European Respiratory Journal (2014)

Severe obesity (SO) can be associated with lung function abnormalities, systemic inflammation and arterial deoxygenation.  To determine the functional characteristics and the possible association with systemic and airway inflammation in SO subjects before and 1 year after bariatric surgery (BS). Prevalence of arterial deoxygenation and its correlation with co-morbidities, such as obstructive sleep apnea (OSA) and metabolic syndrome (MS) were also assessed.  We included 129 subjects (46±12 yrs; BMI, 46±6 kg/m 2 ); 87 subjects had OSA and 100 subjects had MS. Twenty healthy subjects with normal weight served as controls.  Before BS, except for low ERV and low PaO 2  (83±12 mmHg according to reference values [predicted mean, 91 mmHg]), obese subjects had normal lung function. Ninety-four (73% of total) patients had low PaO 2  (77±8 mmHg). All serum and exhaled biomarkers in obese were higher than in healthy subjects (p 2  and waist than those without OSA (p 2  (77±9 mmHg). MS subjects had lower FVC, FEV 1 , TLC and 6MWD (p  0.05) than those without MS. Multiple regression analysis showed that biomarkers and co-morbidities were not associated with lower PaO 2 , but FVC and waist were significant factors (r 2 , 0.32, p  0.01). After BS, patients had a 76±18% of excess weight loss with an overall lung function and systemic and airway inflammation improvement (p  0.01). Elderly and low FEV 1  were associated with low PaO 2  (r 2 , 0.28, p  0.01).  In SO subjects low PaO 2  values continue to be common, mostly in those with OSA. However, central obesity can be influential on arterial deoxygenation before BS.  Supported by FIS PI080311, CIBERES and Almirall.
Nuclear factor κB–inducing kinase activation as a mechanism of pancreatic β cell failure in obesity
Authors: Elisabeth K. Malle, Nathan W. Zammit, Stacey N. Walters, Yen Chin Koay, Jianmin Wu, Bernice M. Tan, Jeanette E. Villanueva, Robert Brink, Tom Loudovaris, James Cantley, Shelli R. McAlpine, Daniel Hesselson, Shane T. Grey
Journal: The Journal of Experimental Medicine (2015)

The nuclear factor κB (NF-κB) pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic β cell dysfunction in the metabolic syndrome. Whereas canonical NF-κB signaling is well studied, there is little information on the divergent noncanonical NF-κB pathway in the context of pancreatic islet dysfunction. Here, we demonstrate that pharmacological activation of the noncanonical NF-κB-inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. We identify NIK as a critical negative regulator of β cell function, as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of noncanonical NF-κB components p100 to p52, and accumulation of RelB. TNF and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive β cell-intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the noncanonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to β cell failure. These studies reveal that NIK contributes a central mechanism for β cell failure in diet-induced obesity.
Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study
Authors: Daniel G Healy, Mario Falchi, Sean S O'Sullivan, Vincenzo Bonifati, Alexandra Durr, Susan Bressman, Alexis Brice, Jan Aasly, Cyrus P Zabetian, Stefano Goldwurm, Joaquim J Ferreira, Eduardo Tolosa, Denise M Kay, Christine Klein, David R Williams, Connie Marras, Anthony E Lang, Zbigniew K Wszolek, Jose Berciano, Anthony HV Schapira, Timothy Lynch, Kailash P Bhatia, Thomas Gasser, Andrew J Lees, Nicholas W Wood
Journal: The Lancet Neurology (2008)

Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2-associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2?Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2-associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD.Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2-associated PD were more benign than those of idiopathic PD.Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients.UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.
Making Cuts to Medicare: The Views of Patients, Physicians, and the Public
Authors: Keerthi Gogineni, Katherine Shuman, Derek Chinn, Anita Weber, Carol Cosenza, Mary Ellen Colten, Ezekiel J. Emanuel
Journal: Journal of Clinical Oncology (2015)

Purpose Cancer-related expenditures are increasing health care costs. Determining how patients with cancer, oncologists, and the general public view Medicare spending and whether they would support cost-containment measures is important to identifying acceptable approaches to reducing health care expenditures. Methods Patients with cancer treated at an academic medical center, a random national sample of oncologists, and the general public were surveyed between July 2012 and March 2013 about causes of high health care costs and proposed cost-control measures. Results Three hundred twenty-six patients (response rate, 72%), 250 oncologists (response rate, 55%), and 891 members of the general public (response rate, 50%) completed surveys. The majority thought Medicare spending was a moderate or big problem (75.8% of patients; 97.2% of oncologists; 75.3% of the general public) and thought Medicare could spend less without causing harm (65.6% of patients; 74.0% of oncologists; 69.7% of the general public). There was broad consensus that drug and insurance companies' profits added to costs, although physicians, hospitals, and patients were also perceived as sharing responsibility. More than 75% of respondents supported enabling Medicare to refuse reimbursement for more expensive treatment if less costly, equally effective treatment was available. Respondents generally favored means testing Medicare cost sharing but, except for oncologists, resisted the idea of an independent oversight panel. All groups opposed annual ceilings on Medicare spending per patient. Conclusion The majority of respondents view Medicare costs as a substantial problem and that all players in the system, including providers, contribute to high costs. Most thought Medicare could spend less without causing harm. Overall, respondents strongly favored not paying for more expensive treatments when cheaper ones are equally effective.
Primary prophylaxis of variceal bleeding in children and the role of MesoRex Bypass: Summary of the Baveno VI Pediatric Satellite Symposium
Authors: Benjamin L. Shneider, Jean de Ville de Goyet, Daniel H. Leung, Anshu Srivastava, Simon C. Ling, Mathieu Duché, Patrick McKiernan, Riccardo Superina, Robert H. Squires, Jaime Bosch, Roberto Groszmann, Shiv K. Sarin, Roberto de Franchis, George V. Mazariegos
Journal: Hepatology (2015)

Approaches to the management of portal hypertension and variceal hemorrhage in pediatrics remain controversial, in large part because they are not well informed by rigorous clinical studies. Fundamental biological and clinical differences preclude automatic application of approaches used for adults to children. On April 11‐12, 2015, experts in the field convened at the first Baveno Pediatric Satellite Meeting to discuss and explore current available evidence regarding indications for MesoRex bypass (MRB) in extrahepatic portal vein obstruction and the role of primary prophylaxis of variceal hemorrhage in children. Consensus was reached regarding MRB. The vast majority of children with extrahepatic portal vein obstruction will experience complications that can be prevented by successful MRB surgery. Therefore, children with extrahepatic portal vein obstruction should be offered MRB for primary and secondary prophylaxis of variceal bleeding and other complications, if appropriate surgical expertise is available, if preoperative and intraoperative evaluation demonstrates favorable anatomy, and if appropriate multidisciplinary care is available for postoperative evaluation and management of shunt thrombosis or stenosis. In contrast, consensus was not achieved regarding primary prophylaxis of varices. Although variceal hemorrhage is a concerning complication of portal hypertension in children, the first bleed appears to be only rarely fatal and the associated morbidity has not been well characterized. Conclusion : There are few pediatric data to indicate the efficacy and safety of pharmacologic or endoscopic therapies as primary prophylaxis or that prevention of a sentinel variceal bleed will ultimately improve survival; therefore, no recommendation for primary prophylaxis with endoscopic variceal ligation, sclerotherapy, or nonspecific beta‐blockade in children was proposed. (H epatology 2016;63:1368–1380)
Identification of a Small Molecule with Synthetic Lethality for K-Ras and Protein Kinase C Iota
Authors: Wei Guo, Shuhong Wu, Jinsong Liu, Bingliang Fang
Journal: Cancer Research (2008)

Abstract K-Ras mutations are frequently found in various cancers and are associated with resistance to treatment or poor prognosis. Similarly, poor outcomes have recently been observed in cancer patients with overexpression of protein kinase C iota (PKCι), an atypical protein kinase C that is activated by oncogenic Ras protein and is required for K-Ras–induced transformation and colonic carcinogenesis in vivo. Thus far, there is no effective agent for treatment of cancers with K-Ras mutations or PKCι overexpression. By synthetic lethality screening, we identified a small compound (designated oncrasin-1) that effectively kills various human lung cancer cells with K-Ras mutations at low or submicromolar concentrations. The cytotoxic effects correlated with apoptosis induction, as was evidenced by increase of apoptotic cells and activation of caspase-3 and caspase-8 upon the treatment of oncrasin-1 in sensitive cells. Treatment with oncrasin-1 also led to abnormal aggregation of PKCι in the nucleus of sensitive cells but not in resistant cells. Furthermore, oncrasin-1–induced apoptosis was blocked by siRNA of K-Ras or PKCι, suggesting that oncrasin-1 is targeted to a novel K-Ras/PKCι pathway. The in vivo administration of oncrasin-1 suppressed the growth of K-ras mutant human lung tumor xenografts by &amp;gt;70% and prolonged the survival of nude mice bearing these tumors, without causing detectable toxicity. Our results indicate that oncrasin-1 or its active analogues could be a novel class of anticancer agents, which effectively kill K-Ras mutant cancer cells. [Cancer Res 2008;68(18):7403–8]
Ceruloplasmin functional changes in Parkinson’s disease-cerebrospinal fluid
Authors: Marco Barbariga, Flavio Curnis, Annapaola Andolfo, Alan Zanardi, Massimo Lazzaro, Antonio Conti, Giuseppe Magnani, Maria Antonietta Volontè, Laura Ferrari, Giancarlo Comi, Angelo Corti, Massimo Alessio
Journal: Molecular Neurodegeneration (2015)

Ceruloplasmin, a ferroxidase present in cerebrospinal fluid (CSF), plays a role in iron homeostasis protecting tissues from oxidative damage. Its reduced enzymatic activity was reported in Parkinson's disease (PD) contributing to the pathological iron accumulation. We previously showed that ceruloplasmin is modified by oxidation in vivo, and, in addition, in vitro by deamidation of specific NGR-motifs that foster the gain of integrin-binding function. Here we investigated whether the loss of ceruloplasmin ferroxidase activity in the CSF of PD patients was accompanied by NGR-motifs deamidation and gain of function.We have found that endogenous ceruloplasmin in the CSF of PD patients showed structural changes, deamidation of the (962)NGR-motif which is usually hidden within the ceruloplasmin structure, and the gain of integrin-binding function. These effects occur owing to the presence of abnormal levels of hydrogen peroxide we detected in the CSF of PD patients. Interestingly, the pathological CSF's environment of PD patients promoted the same modifications in the exogenously added ceruloplasmin, which in turn resulted in loss of ferroxidase-activity and acquisition of integrin-binding properties.We show that in pathological oxidative environment of PD-CSF the endogenous ceruloplasmin, in addition to loss-of-ferroxidase function, is modified as to gain integrin-binding function. These findings, beside the known role of ceruloplasmin in iron homeostasis, might have important pathogenic implications due to the potential triggering of signals mediated by the unusual integrin binding in cells of central nervous system. Furthermore, there are pharmacological implications because, based on data obtained in murine models, the administration of ceruloplasmin has been proposed as potential therapeutic treatment of PD, however, the observed CSF's pro-oxidant properties raise the possibility that in human the ceruloplasmin-based therapeutic approach might not be efficacious.
Ca2+ wave probability is determined by the balance between SERCA2-dependent Ca2+ reuptake and threshold SR Ca2+ content
Authors: Mathis K. Stokke, Sarah J. Briston, Guro F. Jølle, Isma Manzoor, William E. Louch, Leiv Øyehaug, Geir Christensen, David A. Eisner, Andrew W. Trafford, Ole M. Sejersted, Ivar Sjaastad
Journal: Cardiovascular Research (2011)

AimsIn this manuscript, we determined the roles of the sarcoendoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and the ryanodine receptor (RyR) in Ca2+ wave development during β-adrenergic stimulation.
A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia
Authors: Naval Daver, Yanis Boumber, Hagop Kantarjian, Farhad Ravandi, Jorge Cortes, Michael E. Rytting, Jitesh D. Kawedia, Jordan Basnett, Kirk S. Culotta, Zhihong Zeng, Hongbo Lu, Mary Ann Richie, Rebecca Garris, Lianchun Xiao, Wenbin Liu, Keith A. Baggerly, Elias Jabbour, Susan O'Brien, Jan Burger, Linda J. Bendall, Deborah Thomas, Marina Konopleva
Journal: Clinical Cancer Research (2015)

Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL).Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD.The median age of patients was 25 years (range, 11-64) and median number of prior treatments was 2 (range, 1-7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P ≤ 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders.The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL.
Minimizing the Inhaled Dose of NO With Breath-by-Breath Delivery of Spikes of Concentrated Gas
Authors: Yoshihiko Katayama, Tim W. Higenbottam, George Cremona, Shinji Akamine, Eric A. G. Demoncheaux, Adrian P. L. Smith, Thomas E. Siddons
Journal: Circulation (1998)

Background —Pulmonary vasodilatation with a 100 ppm concentration of NO given as a short burst of a few milliliters at the beginning of each breath (NO min ) was compared with conventionally inhaled NO, in which a full breath of 40 ppm of NO was inhaled (NO CD ). Methods and Results —NO min was studied in 16 patients with severe pulmonary hypertension and in 16 isolated porcine lungs with experimentally induced pulmonary hypertension. We compared volumes of 8 to 38 mL of 100 ppm NO in N 2 injected at the beginning of each breath with conventional inhalation of 40 ppm NO in air. NO CD and NO min were studied in 4 pigs after inhibition of NO synthase with N G -nitro- l -arginine methyl ester (1 to 2 mg/kg IV) had raised the pulmonary vascular resistance index (PVRI) from 4.4±0.8 to 10.0±1.6 mm Hg · L −1 · min −1 · kg −1 . A similar comparison was made in 7 isolated porcine lungs after the thromboxane analogue U46619 (10 pmol · L −1 · min −1 ) increased the mean PVRI from 4.6±0.8 to 12.2±1.3 mm Hg · L −1 · min −1 · kg −1 . Patients’ mean PVRI was reduced from 29.2±3.7 to 24.0±3.1 with NO min and 24.5±3.3 mm Hg · L −1 · min −1 · m −2 (mean±SEM) with NO CD . In isolated porcine lungs, there was the same reduction of PVRI for NO min and NO CD between 12.7% and 34.8%. Conclusions —A small volume of NO inhaled at the beginning of the breath was equally effective as NO CD but reduced the dose of NO per breath by 40-fold, which ranged from 1.2×10 −8 (0.4 μg) to 1.6×10 −7 mol/L (4.8 μg) compared with 5.3×10 −7 (16 μg) to 1.2×10 −6 mol/L (36 μg) per breath with NO CD .