tbuckley/cabot-search huggingface dataset:
Association of STAT4 polymorphism with systemic sclerosis in a Japanese population
Authors: N Tsuchiya, A Kawasaki, M Hasegawa, M Fujimoto, K Takehara, Y Kawaguchi, M Kawamoto, M Hara, S Sato
Journal: Annals of the Rheumatic Diseases (2009)

Some susceptibility genes are shared by multiple autoimmune diseases. For example, the interferon regulatory factor 5 ( IRF5 ) gene is associated with various autoimmune diseases including systemic lupus erythematosus (SLE) and systemic sclerosis (SSc).1–3 The signal transducer and activator of transcription 4 ( STAT4 ) gene has been shown to be a susceptibility gene for rheumatoid arthritis (RA) and SLE.4 5 STAT4 is a transcription factor involved in interleukin (IL)12 signalling in induction of interferon (IFN)γ production and T helper type 1 (Th1) cell differentiation, type I IFN signalling and IL23-induced IL17 production.6 An association of rs7574864 with SSc was recently reported by a large-scale case-control study in European populations.7 In the present study, we examined the association of a STAT4 intron 3 single nucleotide …
Regulation of T lymphocyte proliferation. Interleukin 2-mediated induction of c-myb gene expression is dependent on T lymphocyte activation state.
Authors: A M Churilla, T J Braciale, V L Braciale
Journal: The Journal of Experimental Medicine (1989)

We previously reported that with time, after antigenic stimulation of antigen-regulated murine T lymphocyte clones, total IL-2-R expression decayed 10-50-fold, commensurate with a decline in the ability of the cells to proliferate to IL-2. However, late after antigenic stimulation, when the cells were refractory to the IL-2-proliferative stimulus, high levels of high affinity IL-2-R remained. In this report we further explore the basis of unresponsiveness to IL-2 in the quiescent clones. We show that the proto-oncogene c-myc is induced in the late cell population by IL-2 to comparable levels observed early after antigen stimulation. IL-2-dependent c-myb induction, however, is seen only early after activation but not in the late-activated population. Analysis of the IL-2-dependent expression of c-myb mRNA with time after antigenic stimulation showed that steadystate c-myb expression declines dramatically with kinetics closely paralleling a decay in IL-2-dependent proliferative ability. In contrast, steadystate c-myc expression remains high throughout this period. Expression of c-myb is critical for proliferation of these cells since antisense oligodeoxy-nucleotide to c-myb can inhibit their IL-2-dependent proliferation. We present evidence for a pathway of c-myb induction via the TCR that is independent of the IL-2/IL-2-R interaction. In addition, the inhibition of IL-2-R-induced c-myb expression by 2-aminopurine and enhanced induction of c-myb via the TCR demonstrate that TCR activation and IL-2-R activation lead to induction of c-myb by different mechanisms.
Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor–related protein
Authors: Manuel Yepes, Maria Sandkvist, Elizabeth G. Moore, Thomas H. Bugge, Dudley K. Strickland, Daniel A. Lawrence
Journal: Journal of Clinical Investigation (2003)

The regulation of cerebrovascular permeability is critical for normal brain homeostasis, and the "breakdown" of the blood-brain barrier (BBB) is associated with the development of vasogenic edema and intracranial hypertension in a number of neurological disorders. In this study we demonstrate that an increase in endogenous tissue-type plasminogen activator (tPA) activity in the perivascular tissue following cerebral ischemia induces opening of the BBB via a mechanism that is independent of both plasminogen (Plg) and MMP-9. We also show that injection of tPA into the cerebrospinal fluid in the absence of ischemia results in a rapid dose-dependent increase in vascular permeability. This activity is not seen with urokinase-type Plg activator (uPA) but is induced in Plg-/- mice, confirming that the effect is Plg-independent. However, the activity is blocked by antibodies to the LDL receptor-related protein (LRP) and by the LRP antagonist, receptor-associated protein (RAP), suggesting a receptor-mediated process. Together these studies demonstrate that tPA is both necessary and sufficient to directly increase vascular permeability in the early stages of BBB opening, and suggest that this occurs through a receptor-mediated cell signaling event and not through generalized degradation of the vascular basement membrane.
Elevated concentration of oxidized LDL together with poor cardiorespiratory and abdominal muscle fitness predicts metabolic syndrome in young men
Authors: Jussi Kosola, Jani P. Vaara, Markku Ahotupa, Heikki Kyröläinen, Matti Santtila, Niku Oksala, Mustafa Atalay, Tommi Vasankari
Journal: Metabolism (2013)
Analysis of <i>KRAS</i>/<i>NRAS</i> Mutations in a Phase III Study of Panitumumab with FOLFIRI Compared with FOLFIRI Alone as Second-line Treatment for Metastatic Colorectal Cancer
Authors: Marc Peeters, Kelly S. Oliner, Timothy J. Price, Andrés Cervantes, Alberto F. Sobrero, Michel Ducreux, Yevhen Hotko, Thierry André, Emily Chan, Florian Lordick, Cornelis J.A. Punt, Andrew H. Strickland, Gregory Wilson, Tudor E. Ciuleanu, Laslo Roman, Eric Van Cutsem, Pei He, Hua Yu, Reija Koukakis, Jan-Henrik Terwey, Andre S. Jung, Roger Sidhu, Scott D. Patterson
Journal: Clinical Cancer Research (2015)

Abstract Purpose: We evaluated the influence of RAS mutation status on the treatment effect of panitumumab in a prospective–retrospective analysis of a randomized, multicenter phase III study of panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) versus FOLFIRI alone as second-line therapy in patients with metastatic colorectal cancer (mCRC; ClinicalTrials.gov, NCT0039183). Experimental Design: Outcomes were from the study's primary analysis. RAS mutations beyond KRAS exon 2 (KRAS exons 3, 4; NRAS exons 2, 3, 4; BRAF exon 15) were detected by bidirectional Sanger sequencing in wild-type KRAS exon 2 tumor specimens. Progression-free survival (PFS) and overall survival (OS) were coprimary endpoints. Results: The RAS ascertainment rate was 85%; 18% of wild-type KRAS exon 2 tumors harbored other RAS mutations. For PFS and OS, the hazard ratio (HR) for panitumumab plus FOLFIRI versus FOLFIRI alone more strongly favored panitumumab in the wild-type RAS population than in the wild-type KRAS exon 2 population [PFS HR, 0.70 (95% confidence interval [CI], 0.54–0.91); P = 0.007 vs. 0.73 (95% CI, 0.59–0.90); P = 0.004; OS HR, 0.81 (95% CI, 0.63–1.03); P = 0.08 vs. 0.85 (95% CI, 0.70–1.04); P = 0.12]. Patients with RAS mutations were unlikely to benefit from panitumumab. Among RAS wild-type patients, the objective response rate was 41% in the panitumumab–FOLFIRI group versus 10% in the FOLFIRI group. Conclusions: Patients with RAS mutations were unlikely to benefit from panitumumab–FOLFIRI and the benefit–risk of panitumumab–FOLFIRI was improved in the wild-type RAS population compared with the wild-type KRAS exon 2 population. These findings support RAS testing for patients with mCRC. Clin Cancer Res; 21(24); 5469–79. ©2015 AACR. See related commentary by Salazar and Ciardiello, p. 5415
Gel-free multiplexed reduced representation bisulfite sequencing for large-scale DNA methylation profiling
Authors: Patrick Boyle, Kendell Clement, Hongcang Gu, Zachary D Smith, Michael Ziller, Jennifer L Fostel, Laurie Holmes, Jim Meldrim, Fontina Kelley, Andreas Gnirke, Alexander Meissner
Journal: Genome biology (2012)

Abstract Sequencing-based approaches have led to new insights about DNA methylation. While many different techniques for genome-scale mapping of DNA methylation have been employed, throughput has been a key limitation for most. To further facilitate the mapping of DNA methylation, we describe a protocol for gel-free multiplexed reduced representation bisulfite sequencing (mRRBS) that reduces the workload dramatically and enables processing of 96 or more samples per week. mRRBS achieves similar CpG coverage to the original RRBS protocol, while the higher throughput and lower cost make it better suited for large-scale DNA methylation mapping studies, including cohorts of cancer samples.
Mucosal T cells. Chemical Immunology. Vol 71.
Authors: A J S MACPHERSON
Journal: Gut (2000)

DiVerential expression of cyclooxygenase 2 in human colorectal cancerEDITOR,-We were puzzled by the recent paper by Dimberg and colleagues (Gut 1999;45:730-732) which reported that upregulation of cyclooxygenase 2 (COX-2) protein expression was prominent in rectal adenocarcinomas compared with that in adenocarcinomas arising from the colon."Low or undetectable levels of COX-2 protein expression" were demonstrated in 15 of 19 colonic adenocarcinomas located proximal to the rectum.Overall, upregulation of COX-2 protein expression was reported in only 56% of colorectal cancers.Previous reports, 1-7 which include one by the current authors on a not dissimilar case series, 1 and two in the joint authorship of the accompanying commentary writer, 2 3 have shown consistent upregulation of COX-2 expression in colonic and rectal adenocarcinomas (in 85-90% of cases) compared with matched normal colonic mucosa using diVerent techniques, including northern blot analysis, RT-PCR, western blot analysis, and immunohistochemistry. Furthermore, four of these studies refer to the distribution of adenocarcinomas throughout the colon without showing evidence of diVerential COX-2 expression between rectal and more proximal tumours. 1 2 4 5 In the one previous study which analysed COX-2 protein expression in human colorectal cancers by western blot analysis, 7 immunoreactive COX-2 was detected in 76% of cases with a 10-fold increase in median tissue COX-2 concentration compared with normal colonic mucosa.In our view, the authors should attempt to explain the discrepancy between their results and previously published data.It is interesting to note that, in the study of Kargman et al, five of six patients taking NSAIDs had low or undetectable COX-2 protein expression. 7Moreover, aspirin has recently been shown to suppress induction of COX-2 mRNA and protein in interleukin-1 and phorbol ester stimulated human endothelial cells and fibroblasts. 8Do the authors have data on NSAID use in their cohort of patients prior to surgery?
Troponin-tropomyosin abnormalities in hamster cardiomyopathy.
Authors: A Malhotra, J Scheuer
Journal: Journal of Clinical Investigation (1990)

Cardiac myofibrils from cardiomyopathic hamsters exhibit elevated Mg2+ ATPase activity and a parallel upward shift of the calcium ATPase dose response curve. To explore the mechanism, myofibrils from control and cardiomyopathic hamster hearts were incubated with isolated troponin-tropomyosin complex (Tn.Tm) from cardiomyopathic and control hamster or from dog hearts. Tn.Tm from control hamster or dog hearts restored normal Mg2+ ATPase activities to myofibrils from myopathic hearts. However, the maximum ATPase response to calcium stimulation was less in cardiomyopathic myofibrils compared to controls, even when control Tn.Tm was included. Electrophoretic patterns of Tn.Tm from myopathic and control hearts were similar. Electrophoresis of the hamster myofibrils mixed with dog cardiac Tn.Tm and then washed demonstrated binding of this complex to myopathic myofibrils. To further confirm that the incubation experiments resulted in binding, 125I troponin-tropomyosin was cross-hybridized with myofibrils, extensively washed, and then analyzed enzymatically and autoradiographically. Autoradiograms demonstrated similar percent binding of 125I Tn.Tm to all myofibrillar preparations and enzymatic effects like those found using cold Tn.Tm. These studies suggest that Tn.Tm from cardiomyopathic hearts inhibits Mg2+ myofibrillar ATPase activity to a lesser degree than Tn.Tm from control hearts. Decreased stimulation by calcium in myopathic preparations may be due to abnormalities in troponin-tropomyosin and/or to the decreased myosin ATPase activity observed previously.
Identification of Comatose Patients at High Risk for Death or Severe Disability
Authors: Mary Beth Hamel
Journal: JAMA (1995)

To develop and validate a simple prognostic scoring system to identify patients in nontraumatic coma at high risk for poor outcomes using data available early in the hospital course.Prospective cohort study.Five geographically diverse academic medical centers.A total of 596 patients in nontraumatic coma enrolled in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT), including 247 in the model derivation set and 349 in the model validation set.Death and severe disability by 2 months.For the 596 patients studied (median age, 67 years; 52% female), the primary cause of coma was cardiac arrest in 31% and cerebral infarction or intracerebral hemorrhage in 36%. At 2 months 69% had died, 20% had survived with known severe disability, 8% were known to have survived without severe disability, and 3% survived with unknown functional status. Five clinical variables available on day 3 after enrollment were associated independently with 2-month mortality: abnormal brain stem response (adjusted odds ratio [OR] = 3.2; 95% confidence interval [CI], 1.3 to 8.1), absent verbal response (OR = 4.6; 95% CI, 1.8 to 11.7), absent withdrawal response to pain (OR = 4.3; 95% CI, 1.7 to 10.8), creatinine level greater than or equal to 132.6 mumol/L (1.5 mg/dL) (OR = 4.5; 95% CI, 1.8 to 11.0), and age of 70 years or older (OR = 5.1; 95% CI, 2.2 to 12.2). Mortality at 2 months for patients with four or five of these risk factors was 97% (58/60; 95% CI, 88% to 100%) in the validation set. Brain stem and motor responses best predicted death or severe disability by 2 months. For patients with either an abnormal brain stem response or absent motor response to pain, the rate of death or severe disability at 2 months was 96% (185/193; 95% CI, 92% to 98%) in the validation set.Five readily available clinical variables identify a large subgroup of patients in nontraumatic coma at high risk for poor outcomes. This risk stratification approach offers physicians, patients, and patients' families information that may prove useful in patient care decisions and resource allocation.
Upfront allogeneic stem-cell transplantation for patients with nonlocalized untreated peripheral T-cell lymphoma: an intention-to-treat analysis from a single center
Authors: M. Loirat, P. Chevallier, C. Leux, A. Moreau, C. Bossard, T. Guillaume, T. Gastinne, J. Delaunay, N. Blin, B. Mahé, V. Dubruille, K. Augeul-Meunier, P. Peterlin, H. Maisonneuve, P. Moreau, N. Juge-Morineau, H. Jardel, M. Mohty, P. Moreau, S. Le Gouill
Journal: Annals of Oncology (2014)
Prediction of Allogeneic Hematopoietic Stem-Cell Transplantation Mortality 100 Days After Transplantation Using a Machine Learning Algorithm: A European Group for Blood and Marrow Transplantation Acute Leukemia Working Party Retrospective Data Mining Study
Authors: Roni Shouval, Myriam Labopin, Ori Bondi, Hila Mishan-Shamay, Avichai Shimoni, Fabio Ciceri, Jordi Esteve, Sebastian Giebel, Norbert C. Gorin, Christoph Schmid, Emmanuelle Polge, Mahmoud Aljurf, Nicolaus Kroger, Charles Craddock, Andrea Bacigalupo, Jan J. Cornelissen, Frederic Baron, Ron Unger, Arnon Nagler, Mohamad Mohty
Journal: Journal of Clinical Oncology (2015)

Purpose Allogeneic hematopoietic stem-cell transplantation (HSCT) is potentially curative for acute leukemia (AL), but carries considerable risk. Machine learning algorithms, which are part of the data mining (DM) approach, may serve for transplantation-related mortality risk prediction. Patients and Methods This work is a retrospective DM study on a cohort of 28,236 adult HSCT recipients from the AL registry of the European Group for Blood and Marrow Transplantation. The primary objective was prediction of overall mortality (OM) at 100 days after HSCT. Secondary objectives were estimation of nonrelapse mortality, leukemia-free survival, and overall survival at 2 years. Donor, recipient, and procedural characteristics were analyzed. The alternating decision tree machine learning algorithm was applied for model development on 70% of the data set and validated on the remaining data. Results OM prevalence at day 100 was 13.9% (n = 3,936). Of the 20 variables considered, 10 were selected by the model for OM prediction, and several interactions were discovered. By using a logistic transformation function, the crude score was transformed into individual probabilities for 100-day OM (range, 3% to 68%). The model's discrimination for the primary objective performed better than the European Group for Blood and Marrow Transplantation score (area under the receiver operating characteristics curve, 0.701 v 0.646; P &lt; .001). Calibration was excellent. Scores assigned were also predictive of secondary objectives. Conclusion The alternating decision tree model provides a robust tool for risk evaluation of patients with AL before HSCT, and is available online ( http://bioinfo.lnx.biu.ac.il/∼bondi/web1.html ). It is presented as a continuous probabilistic score for the prediction of day 100 OM, extending prediction to 2 years. The DM method has proved useful for clinical prediction in HSCT.
S23 Accuracy of contrast enhanced MR lung perfusion compared to perfusion scintigraphy in diagnosing chronic thromboembolic pulmonary hypertension
Authors: S. Rajaram, A. J. Swift, D. Capener, C. Hill, C. Davies, R. Elliot, J. Hurdman, R. Condliffe, J. M. Wild, D. G. Kiely
Journal: Thorax (2011)

<h3>Purpose</h3> The purpose of our study was to assess the diagnostic accuracy and reliability of contrast enhanced MR lung perfusion compared to perfusion scintigraphy in patients with CTEPH. <h3>Methods and Materials</h3> Retrospective analysis of patients investigated for CTEPH who had MR lung perfusion, perfusion scintigraphy and CTPA performed within a time interval of 5 days. The MR images were acquired using a time resolved 3D spoiled gradient echo sequence. The sequence parameters: TE 1.1 ms, TR 2.5 ms, flip angle of 30°, FOV=48 cm<sup>2</sup>, slice thickness of 5 mm, average of 32 slices and frame rate was 2 acquisitions per second. This was a breathhold sequence obtained after 0.05 ml/kg of Gadovist injection at 5 ml/s followed by a 20 ml saline flush. The subtraction images and positive enhancement dataset were analysed in the coronal plane. Four static views perfusion scintigraphy views were obtained. Final diagnosis of CTEPH or non-CTEPH was made at a multidisciplinary meeting following detailed multi-modality assessment. <h3>Results</h3> 27 patients had a diagnosis of CTEPH and 55 patients were diagnosed as non-CTEPH. In the CTEPH group, MRI lung perfusion diagnosed 26 patients as CTEPH and 1 patient with distal surgically inaccessible disease as non-CTEPH. In the non-CTEPH group, four patients were diagnosed as CTEPH and 48 patients were identified as non-CTEPH and three MRI were considered non-diagnostic. MR lung perfusion was not performed in 11 patients due to impaired renal function or patient unable to tolerate breathhold. None of the surgically accessible disease was missed with either modality. The MR lung perfusion had a sensitivity of 96%, specificity of 92%, PPV of 87%, NPV of 98% and accuracy of 94% for diagnosing CTEPH. Perfusion scintigraphy had a sensitivity of 93%, specificity of 90%, PPV of 83%, NPV of 96% and accuracy of 91%. <h3>Conclusion</h3> Our results show that MR lung perfusion compared to 4-view static perfusion scintigraphy has an overall higher accuracy compared to perfusion scintigraphy and has a role in assessment of patients with suspected CTEPH.
Metabolic and ventilatory response pattern to arm elevation in patients with COPD and healthy age-matched subjects
Authors: EM Baarends, AM Schols, DJ Slebos, R Mostert, PP Janssen, EF Wouters
Journal: European Respiratory Journal (1995)

Many patients with chronic obstructive pulmonary disease (COPD) experience problems in those activities of daily living which involve so-called unsupported arm elevations (AE). In this study, possible differences in the metabolic and ventilatory response pattern to three types of arm elevation were compared between 13 COPD patients (forced expiratory volume in one second (FEV1) (mean (SD)) 38 (13)% of predicted) and 13 age-matched healthy subjects. Each subject consecutively performed three types of arm elevation for 2 min, with 3 min rest periods in between. Breath-by-breath metabolic and ventilatory parameters and heart rate (HR) were registered during a 3 min baseline period and throughout the measurement period. Adjusted for significantly greater baseline test results in COPD patients, it was found that AE (arm elevation including recovery) tended to be more demanding with respect to metabolic and ventilatory response for patients with COPD than for the age-matched healthy subjects. Arm elevation resulted in an increase in oxygen consumption (V'O2) (COPD 12%; healthy 6%), carbon dioxide elimination V'CO2 (COPD 15%; healthy 10%), minute ventilation V'E (COPD 13%; healthy 7%) and heart rate (COPD 2%; healthy 5%). A pronounced difference was found in the pattern of metabolic and ventilatory response to arm elevation, i.e. there was an earlier but sluggish V'O2 onset in COPD patients, whereas the healthy subjects demonstrated a sudden peak approximately 30 s after arm elevations. Mutual comparison of the three different types of arm elevation demonstrated a comparable response pattern. Knowledge of the specific response to arm elevations in COPD patients seems essential for interpretation of arm elevation tests in upper extremity rehabilitation programmes.