tbuckley/cabot-search huggingface dataset:
Stroke in Relation to Cardiac Procedures in Patients With Non–ST-Elevation Acute Coronary Syndrome
Authors: Lisa Cronin, Shamir R. Mehta, Feng Zhao, Janice Pogue, Andrzej Budaj, David Hunt, Salim Yusuf
Journal: Circulation (2001)

Background There are few published data on risk factors for stroke in patients with non–ST-elevation acute coronary syndrome (ACS). We investigated prognostic factors for stroke in 2 large cohorts of patients from the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry (8010) and the OASIS-2 trial (10 141) Methods and Results A total of 18 151 patients with non–ST-elevation ACS were enrolled in the OASIS program. Data from these 2 studies were pooled (a test for heterogeneity was nonsignificant, P =0.34). Overall, 238 patients (1.3%) had a stroke over a 6-month follow-up. Those who experienced stroke had a 4-fold increase in 6-month mortality (27.0% versus 6.3%, P &lt;0.001). A Cox multivariate regression analysis identified CABG surgery as the most important predictor of stroke (hazard ratio [HR], 4.6), followed by history of stroke (HR, 2.3), diabetes mellitus (HR, 1.7), older age (HR, 1.6 per 10-year increase), higher heart rate (HR, 1.1 per 10-bpm increase), and on-site catheterization facility (HR, 1.4). There was no significant excess in stroke in patients undergoing percutaneous coronary intervention ( P =0.21). Patients who underwent early CABG surgery were at a substantially increased risk compared with those who had later CABG (3.3% versus 1.6%; HR, 2.1; P =0.003) or who had no surgery (3.3% versus 1.1%; HR, 3.95; P =0.0001). Conclusions In this large cohort of patients with ACS, stroke was an uncommon but serious event associated with high mortality. The performance of early CABG surgery was a powerful independent predictor of stroke.
Trk Receptor Expression and Inhibition in Neuroblastomas
Authors: Garrett M. Brodeur, Jane E. Minturn, Ruth Ho, Anisha M. Simpson, Radhika Iyer, Carly R. Varela, Jennifer E. Light, Venkatadri Kolla, Audrey E. Evans
Journal: Clinical Cancer Research (2009)

Neuroblastoma, the most common and deadly solid tumor in children, exhibits heterogeneous clinical behavior, from spontaneous regression to relentless progression. Current evidence suggests that the TRK family of neurotrophin receptors plays a critical role in these diverse behaviors. Neuroblastomas expressing TrkA are biologically favorable and prone to spontaneous regression or differentiation, depending on the absence or presence of its ligand (NGF) in the microenvironment. In contrast, TrkB-expressing tumors frequently have MYCN amplification and are very aggressive and often fatal tumors. These tumors also express the TrkB ligand (BDNF), resulting in an autocrine or paracrine survival pathway. Exposure to BDNF promotes survival, drug resistance, and angiogenesis of TrkB-expressing tumors. Here we review the role of Trks in normal development, the different functions of Trk isoforms, and the major Trk signaling pathways. We also review the roles these receptors play in the heterogeneous biological and clinical behavior of neuroblastomas, and the activation of Trk receptors in other cancers. Finally we address the progress that has been made in developing targeted therapy with Trk-selective inhibitors to treat neuroblastomas and other tumors with activated Trk expression.
Regulation of glucose turnover during exercise in pancreatectomized, totally insulin-deficient dogs. Effects of beta-adrenergic blockade.
Authors: O Bjorkman, P Miles, D Wasserman, L Lickley, M Vranic
Journal: Journal of Clinical Investigation (1988)

To examine whether glucose metabolic clearance increases and whether catecholamines influence glucose turnover during exercise in total insulin deficiency, 24-h fasted and insulin-deprived pancreatectomized dogs were studied before and during exercise (60 min; 100 m/min; 10% slope) with (n = 8) and without (n = 8) propranolol infusion (PI, 5 micrograms/kg-min). Exercise with or without PI was accompanied by four and fivefold increments in norepinephrine and epinephrine respectively, while glucagon (extrapancreatic) fell slightly. Basal plasma glucose and FFA concentrations and rates of tracer-determined (3[3H]glucose) hepatic glucose production (Ra) and total glucose clearance (including urinary glucose loss) were 459 +/- 24 mg/dl, 1.7 +/- 0.5 mmol/liter, 7.8 +/- 0.9 mg/kg-min and 1.6 +/- 0.1 ml/kg-min, respectively. When corrected for urinary glucose excretion, basal glucose metabolic clearance rate (MCR) was 0.7 +/- 0.1 mg/kg-min and rose twofold (P less than 0.0001) during exercise. Despite lower lactate (3.3 +/- 0.6 vs. 6.6 +/- 1.3 mmol/liter; P less than 0.005) and FFA levels (1.1 +/- 0.2 vs. 2.2 +/- 0.2 mmol/liter; P less than 0.0001) with PI, PI failed to influence MCR during exercise. Ra rose by 3.7 +/- 1.7 mg/kg-min during exercise (P less than 0.02) while with PI the increase was only 1.9 +/- 0.7 mg/kg-min (P less than 0.002). Glucose levels remained unchanged during exercise alone but fell slightly with PI (P less than 0.0001). Therefore, in total insulin deficiency, MCR increases marginally with exercise (13% of normal); the beta adrenergic effects of catecholamines that stimulate both FFA mobilization and muscle glycogenolysis do not regulate muscle glucose uptake. The exercise-induced rise in hepatic glucose production does not require an increase in glucagon levels, but is mediated partially by catecholamines. Present and previous data in normal and alloxan-diabetic dogs, suggest that (a) in total insulin deficiency, control of hepatic glucose production during exercise is shifted from glucagon to catecholamines and that this may involve catecholamine-induced mobilization of peripheral substrates for gluconeogenesis and/or hepatic insensitivity to glucagon, and (b) insulin is not essential for a small exercise-induced increase in muscle glucose uptake, but normal insulin levels are required for the full response. Furthermore, the catecholamines appear to regulate muscle glucose uptake during exercise only when sufficient insulin is available to prevent markedly elevated FFA levels. We speculate that the main role of insulin is not to regulate glucose uptake by the contracting muscle directly, but to restrain lipolysis and thereby also FFA oxidation in the muscle.
Lung-protective mechanical ventilation may be associated with a long-term survival benefit for patients with acute lung injury
Authors: Toni Bryant
Journal: Thorax (2012)

Lung-protective mechanical ventilation may be associated with a long-term survival benefit for patients with acute lung injury Volume and pressure-limited ('lung-protective') mechanical ventilation decreases short-term mortality in patients with acute lung injury (ALI).This multicentre prospective cohort study from the USA evaluated the association of lung-protective mechanical ventilation with a 2-year survival period in patients with ALI.The study included 485 mechanically ventilated patients with ALI diagnosed according to the American-European Consensus criteria.After onset of ALI, twice-daily records of ventilator settings were measured yielding 6240 settings for evaluation.Those with tidal volumes ≤6.5 ml/kg and a plateau pressure ≤30 cm H 2 O were deemed 'adherent' to lung-protective ventilation.In total, only 41% of ventilator settings recorded were adherent.Four hundred and seventeen patients (86%) received 50% or less of their ventilator-settings adherent, and 180 (37%) never received any settings adherent.Overall, 311 patients (64%) died during the 2 years after onset of ALI.Survival was independently associated with several covariates, including age, co-morbidity and organ failure scores.After adjustment for total duration of mechanical ventilation and covariates for each additional adherent ventilator setting, the risk of mortality over 2 years decreased by 3% (HR 0.97, 95% CI 0.95 to 0.99, p=0.002).Statistical modelling estimated an absolute risk reduction in 2-year mortality of 4% (95% CI 0.8% to 7.2%, p=0.012) for 50% ventilator adherence and 7.8% (95% CI 1.6% to 14%, p=0.011) for 100% adherence.Lung-protective ventilation still appears to be under-utilised in clinical practice.Although in this prospective study we cannot be certain that all possible confounding variables were accounted for, there may also be an association between non-adherence to lung-protective ventilation and 2-year mortality.
Prevalence of nontuberculosis mycobacterial in patients with bronchiectasis: A meta-analysis
Authors: Haiqing Chu, Lan Zhao, Heping Xiao, Zhemin Zhang, Jingbo Zhang
Journal: European Respiratory Journal (2014)

Background:Nontuberculous mycobacteria (NTM) have emerged as critical opportunistic pathogens of n lung diseases, recently. Patients with preexisting bronchiectasis are susceptible to NTM. Nevertheless, the data about the geographical difference of NTM prevalence are still not fully understood. Therefore, this study aimed to evaluate the prevalence of NTM in patients with bronchiectasis.  Methods: The relevant data of the prevalence of NTM in patients with bronchiectasis were retrieved by searching the main database such as such as PubMed, MEDLINE, Cochrane Library, and EMBASE. This Meta-analysis was performed by using Rev. Man 5.1 and Stata11.0 software. The collected information of NTM prevalence was chosen as the effect size.  Results:The results of meta-analysis showed that the overall prevalence of NTM was 9.3% in patients with bronchiectasis. The further stratification of subgroup analysis indicated that the combined prevalence of NTM were higher in studies which sample size were more than or equal to 100, in studies which time of study were after or equal to 2002, in studies which participants geographic location were Asian and in studies which method of study were retrospective as well, compared with corresponding groups.  Conclusions: Our finding suggested that the prevalence NTM infection is high in patients with bronchiectasis. Though we advise clinicians to apply anti-NTM therapy in patients with bronchiectasis, a larger number of definitive randomized trials are still need to assess this research issue.
S97 BMPR2 R899X knock-in mice developed age-related pulmonary hypertension
Authors: L. Long, X. Yang, N. W. Morrell, M. Southwood
Journal: Thorax (2011)

<h3>Background</h3> Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor (<i>BMPR2</i>) underlie the majority (&gt;70%) of cases of heritable pulmonary arterial hypertension (hPAH) and a variable proportion of idiopathic PAH (15%–40%). There are also reports of PAH in patients with mutations in the downstream Smad signalling proteins. However, to date there is no mouse model that mimics the genetic mutations in human disease. <h3>Methods</h3> We developed a knock-in mouse harbouring a heterozygous (±) human disease causing mutation in BMPR-II: a nonsense mutation in the cytoplasmic tail (R899X) to determine the in vivo physiologic consequences of this <i>BMPR2</i> mutation. In addition, we crossed this animal with Smad1± knockout mice to determine the effect of additional loss of signalling via this pathway. Haemodynamic, and morphometric data were collected at 3 months and 6 months of age. <h3>Results</h3> At 3 months of age pulmonary haemodynamics and vascular morphometry of R899X± and Smad1± mice were similar to wild-type littermate controls. In contrast, at 6 months of age R899X± and Smad1± mice developed mild pulmonary hypertension with pulmonary vascular remodelling compared with wild-types. Pulmonary artery smooth muscle cells from R899X± mice were hyperproliferative in serum and exhibited defects in Smad signalling in response to BMPs. When R899X± mice were crossed with Smad1± animals, double heterozygous mice had significantly higher right ventricular systolic pressures than single heterozygous mice. <h3>Conclusion</h3> These findings demonstrate that knockin of a human disease causing BMPR-II mutation causes age-related pulmonary hypertension in mice. In addition, we show that the accumulation of defects in the BMP/Smad signalling pathway increases the susceptibility to pulmonary hypertension, highlighting the central role of this pathway in disease.
AZD1152 Rapidly and Negatively Affects the Growth and Survival of Human Acute Myeloid Leukemia Cells <i>In vitro</i> and <i>In vivo</i>
Authors: Adedayo Oke, Daniel Pearce, Robert W. Wilkinson, Claire Crafter, Rajesh Odedra, Jamie Cavenagh, Jude Fitzgibbon, Andrew T. Lister, Simon Joel, Dominique Bonnet
Journal: Cancer Research (2009)

Aurora kinases play a critical role in regulating mitosis and cell division, and their overexpression has been implicated in the survival and proliferation of human cancer. In this study, we report the in vitro and in vivo activities of AZD1152, a compound that has selectivity for aurora B kinase, in acute myeloid leukemia (AML) cell lines, primary AML samples, and cord blood cells. AZD1152 exerted antiproliferative or cytotoxic effects in all cell lines studied, inhibited the phosphorylation of histone H3 (pHis H3) on Ser10 in a dose-dependent manner, and resulted in cells with >4N DNA content. THP-1 cells treated with AZD1152 accumulated in a state of polyploidy and showed a senescent response to the drug, in contrast to the apoptotic response seen in other cell lines. Accordingly, AZD1152 profoundly affected the growth of AML cell lines and primary AML in an in vivo xenotransplantation model. However, concentration-dependent effects on cell growth, apoptosis, and cell cycle progression were also observed when human cord blood and primary lineage-negative stem and progenitor cells were analyzed in vitro and in vivo. These data suggest that the inhibition of aurora B kinase may be a useful therapeutic strategy in the treatment of AML and that further exploration of dosing and treatment schedules is warranted in clinical trials.
Abstract A09: Selector (HaloPlex) targeted resequencing of formalin-fixed paraffin-embedded (FFPE) specimens for mutation diagnostics in NSCLC.
Authors: Johan Botling, Lotte N.J. Moens, Elin Falk-Sorqvist, Linnea LaFleur, Magnus Sundstrom, Patrick Micke, Mats Nilsson
Journal: Clinical Cancer Research (2014)

Abstract In recent years, the advent of massively parallel “next-generation” sequencing technologies (NGS) has enabled substantial advances in the study of cancer. In combination with targeted DNA enrichment methods, high sequence coverage can be obtained for many different genes simultaneously, creating unique opportunities for clinical cancer diagnostics. However, the process of formalin fixation and paraffin embedding (FFPE) of tissue samples results in DNA-fragmentation by cross-linking to other biomolecules, posing a number of technical challenges for downstream mutation analyses. In this study, we have evaluated the HaloPlex target enrichment system for somatic mutation detection in DNA-extracts prepared from surgical non-small cell lung cancer (NSCLC) specimens with available paired tumor and normal tissue in FFPE blocks and matched fresh-frozen tumor and normal samples. In the design of the 56 gene panel, covering the most common mutations in lung colon cancer, several modifications to the standard method were introduced, including a reduced target fragment length, molecular barcoding, and “two strand capturing. We show that FFPE material can be used for HaloPlex based target enrichment and NGS using as little as 50 ng of DNA, i.e. compatible with yields readily available from small biopsies. By specifically capturing both strands for each target fragment, we were able to reduce the number of false positive errors due to FFPE induced artifacts by a factor of 4. Furthermore, the combined approach of molecular barcoding and two strand capturing allowed us to identify two low frequency variants, demonstrating a sensitive and accurate detection of somatic mutations. We believe that the HaloPlex method, provided some modifications are made, will be broadly applicable as a tool for somatic mutation detection. Genetic profiling of NSCLC FFPE tissues will add a new dimension to thoracic tumor pathology and will open vast opportunities for research as large, population-based cohorts of advanced stage NSCLC will be available for comprehensive molecular characterization. Citation Format: Johan Botling, Lotte N.J. Moens, Elin Falk-Sorqvist, Linnea LaFleur, Magnus Sundstrom, Patrick Micke, Mats Nilsson. Selector (HaloPlex) targeted resequencing of formalin-fixed paraffin-embedded (FFPE) specimens for mutation diagnostics in NSCLC. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A09.
Effect of enginereed GOLD nanoparticles targeted to mesenchymal cells on inflammatory response
Authors: Emanuela Cova, Miriam Colombo, Simona Miserere, Jesus Penaranda, Simona Inghilleri, Monica Morosini, Sara Magni, Davide Prosperi, Federica Meloni
Journal: European Respiratory Journal (2013)

In a previous work we proved that gold nanoparticles engineered with a specific anti-CD44 antibody (GNP-HCe) directed against mesenchymal cells (MCs)from BOS patients were able to specifically inhibit their proliferation and increase their apoptosis.  Aim of this work is to prove that GNP-HCe do not stimulate inflammatory cells in vitro since inflammatory process plays a pivotal role in BOS onset and its activation would exacerbate the reactive milieu.  Macrophages were isolated from BAL of three subjects by adhesion procedure. Lymphocytes and neutrophils were obtained from peripheral blood by Lympholyte gradient. IL-8 was assayed by ELISA test while IFN-g, IL-17 and IL-10 by Elispot. Elastase release was evaluated by enzymatic procedure. Apoptosis and proliferation rate were evaluated by flow cytometry (Annexin V and CFSE).  In vitro experiments proved that 24 and 48 h of incubation with GNP-HCe did not increase IL-8 secretion by macrophages but instead a significant (P  This work opens new scenarios on the possibility to target a drug to specific cells without rising a further inflammatory response that would contribute to perpetuate the vicious cycle epithelial damage/inflammatory response/fibroproliferative process.
Increased proteasomal degradation of Bax is a common feature of poor prognosis chronic lymphocytic leukemia
Authors: Samir G. Agrawal, Feng-Ting Liu, Catherine Wiseman, Sima Shirali, Hongxiang Liu, Debra Lillington, Ming-Qing Du, Denise Syndercombe-Court, Adrian C. Newland, John G. Gribben, Li Jia
Journal: Blood (2007)
Urinary C-X-C Motif Chemokine 10 Independently Improves the Noninvasive Diagnosis of Antibody–Mediated Kidney Allograft Rejection
Authors: Marion Rabant, Lucile Amrouche, Xavier Lebreton, Florence Aulagnon, Aurélien Benon, Virginia Sauvaget, Raja Bonifay, Lise Morin, Anne Scemla, Marianne Delville, Frank Martinez, Marc Olivier Timsit, Jean-Paul Duong Van Huyen, Christophe Legendre, Fabiola Terzi, Dany Anglicheau
Journal: Journal of the American Society of Nephrology (2015)

Urinary levels of C-X-C motif chemokine 9 (CXCL9) and CXCL10 can noninvasively diagnose T cell-mediated rejection (TCMR) of renal allografts. However, performance of these molecules as diagnostic/prognostic markers of antibody-mediated rejection (ABMR) is unknown. We investigated urinary CXCL9 and CXCL10 levels in a highly sensitized cohort of 244 renal allograft recipients (67 with preformed donor-specific antibodies [DSAs]) with 281 indication biopsy samples. We assessed the benefit of adding these biomarkers to conventional models for diagnosing/prognosing ABMR. Urinary CXCL9 and CXCL10 levels, normalized to urine creatinine (Cr) levels (CXCL9:Cr and CXCL10:Cr) or not, correlated with the extent of tubulointerstitial (i+t score; all P<0.001) and microvascular (g+ptc score; all P<0.001) inflammation. CXCL10:Cr diagnosed TCMR (area under the curve [AUC]=0.80; 95% confidence interval [95% CI], 0.68 to 0.92; P<0.001) and ABMR (AUC=0.76; 95% CI, 0.69 to 0.82; P<0.001) with high accuracy, even in the absence of tubulointerstitial inflammation (AUC=0.70; 95% CI, 0.61 to 0.79; P<0.001). Although mean fluorescence intensity of the immunodominant DSA diagnosed ABMR (AUC=0.75; 95% CI, 0.68 to 0.82; P<0.001), combining urinary CXCL10:Cr with immunodominant DSA levels improved the diagnosis of ABMR (AUC=0.83; 95% CI, 0.77 to 0.89; P<0.001). At the time of ABMR, urinary CXCL10:Cr ratio was independently associated with an increased risk of graft loss. In conclusion, urinary CXCL10:Cr ratio associates with tubulointerstitial and microvascular inflammation of the renal allograft. Combining the urinary CXCL10:Cr ratio with DSA monitoring significantly improves the noninvasive diagnosis of ABMR and the stratification of patients at high risk for graft loss.
Failure of intradermal skin testing with gluten to produce delayed hypersensitivity reactions in patients with dermatitis herpetiformis
Authors: J.J. GARIOCH, D.J. UNSWORTH, B.S. BAKER, J.N. LEONARD, L. FRY
Journal: British Journal of Dermatology (2006)

Dermatitis herpetiformis (DH) is characterized by a rash and a gluten‐sensitive enteropathy (GSE) indistinguishable from that of coeliac disease. T‐cell‐mediated mechanisms have been implicated in the pathogenesis of GSE. It seems feasible that intradermal injection of gluten, in patients known to have GSE, could lead to an influx of T cells sensitized to gluten, with subsequent development of a delayed hypersensitivity‐type reaction. Six patients with DH and three normal subjects had intradermal injections of‘Frazer's fraction III’ (FFIII; the partial peptic tryptic digest of gluten which is known to be antigenic) and phosphate‐buffered saline (PBS) as a control. Skin biopsies were taken at PBS and FFIII injection sites at 48 h. In addition, two of the patients with DH had biopsies taken of FFIII injection sites at 6 h. Monoclonal antibodies and the avidin‐biotin‐peroxidase technique were used to stain for T cells in the skin biopsies. A monoclonal antibody to a neoepitope exposed in the terminal complement complex and an immunofluorescent method were used to detect the presence of terminal complement component in biopsies taken from two of the control subjects and two of the patients. Both patients and control subjects developed a weal and flare within a few minutes of injecting the FFIII, and this persisted for up to 6 h. No skin reaction was present in either the patients or the control subjects at 48 h. No skin reaction was visible at any time following injection of PBS. There was no increase in T cells in biopsies taken at 6 or 48 h from the FFIII injection sites compared with the PBS injection sites. Terminal complement component was present in the biopsies taken from DH patients at both the PBS and FFIII injection sites (6 and 48 h), but was absent from the biopsies taken from the control subjects. Normal delayed hypersensitivity responses to a battery of common recall antigens showed that the lack of response to FFIII was antigen specific. Thus, this study suggests that the T cells sensitized to gluten in patients with GSE are unable to migrate to the skin.
A Randomized Trial Comparing Preoperative Chemotherapy Plus Surgery with Surgery Alone in Patients with Non-Small-Cell Lung Cancer
Authors: Rafael Rosell, Jose Gomez-Codina, Carlos Camps, Jose Maestre, Jose Padille, Antonio Canto, Jose Luis Mate, Shanrong Li, Jorge Roig, Angel Olazabal, Mercedes Canela, Aurelio Ariza, Zdenek Skacel, Jose Morera-Prat, Albert Abad
Journal: New England Journal of Medicine (1994)

The efficacy of surgery for patients with non-small-cell lung cancer is limited, although recent studies suggest that preoperative chemotherapy may improve survival. We conducted a randomized trial to examine the possible benefit of preoperative chemotherapy and surgery for the treatment of patients with non-small-cell lung cancer.