tbuckley/cabot-search huggingface dataset:
Plasma TGF beta in systemic sclerosis: a cross-sectional study.
Authors: N Snowden, B Coupes, A Herrick, K Illingworth, M I Jayson, P E Brenchley
Journal: Annals of the Rheumatic Diseases (1994)

OBJECTIVES--To determine whether the active 25 kDa form of the fibrogenic cytokine transforming growth factor beta (TGF beta) can be detected in plasma from patients with systemic sclerosis and to examine the relationship between plasma TGF beta and clinical markers of disease severity and serum concentrations of the aminoterminal peptide of type III procollagen (PIIINP) (a laboratory marker of the fibrotic process). METHODS--A cross sectional study was made of 39 patients with systemic sclerosis (11 diffuse and 28 limited), nine patients with primary Raynaud9s disease and 60 healthy controls. TGF beta 1 and TGF beta 2 were measured by enzyme linked immunosorbent assay (ELISA) (sensitivity 100 pg/ml) and PIIINP by radioimmunoassay. RESULTS--TGF beta 1 was detected in plasma from six of 39 patients with systemic sclerosis but not in any patient with primary Raynaud9s disease or healthy controls. TGF beta 2 was not detected in plasma from patients or controls. No clear relationship was demonstrated between TGF beta 1, clinical features or PIIINP concentrations. CONCLUSIONS--The 25 kDa form of TGF beta 1 can be detected in the plasma of some patients with systemic sclerosis. This provides limited support for the hypothesis that this cytokine plays a role in the pathogenesis of this disease. However, longitudinal studies, particularly in early diffuse disease, are required to clarify the relationship between circulating TGF beta 1 and disease activity.
Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption ofSmad4 andPten in mice
Authors: X. Xu
Journal: Journal of Clinical Investigation (2006)

Cholangiocellular carcinoma (CC), the second most common primary liver cancer, is associated with a poor prognosis. It has been shown that CCs harbor alterations of a number of tumor-suppressor genes and oncogenes, yet key regulators for tumorigenesis remain unknown. Here we have generated a mouse model that develops CC with high penetrance using liver-specific targeted disruption of tumor suppressors SMAD4 and PTEN. In the absence of SMAD4 and PTEN, hyperplastic foci emerge exclusively from bile ducts of mutant mice at 2 months of age and continue to grow, leading to tumor formation in all animals at 4-7 months of age. We show that CC formation follows a multistep progression of histopathological changes that are associated with significant alterations, including increased levels of phosphorylated AKT, FOXO1, GSK-3beta, mTOR, and ERK and increased nuclear levels of cyclin D1. We further demonstrate that SMAD4 and PTEN regulate each other through a novel feedback mechanism to maintain an expression balance and synergistically repress CC formation. Finally, our analysis of human CC detected PTEN inactivation in a majority of p-AKT-positive CCs, while about half also lost SMAD4 expression. These findings elucidate the relationship between SMAD4 and PTEN and extend our understanding of CC formation.
Small cell lung cancer cell lines: pure and variant types can be distinguished by their extracellular matrix synthesis
Authors: S Scarpa, G Morstyn, DN Carney, A Modesti, TJ Triche
Journal: European Respiratory Journal (1988)

Variant subclasses of cell lines derived from small cell lung cancers have previously been characterized, having distinctive biochemical, morphological and growth properties compared to the classic lines. Both types of small cell lung cancer express features suggesting that they are derived from neuroectodermal cells. We compared the capacity of these two types of lung cancer cell lines to synthesize the extracellular matrix glycoproteins, fibronectin and laminin, and also analysed a few other non-small cell lung cancer lines, as controls. We found that the cell lines of the pure type did not produce laminin or fibronectin, whereas the cell lines of the variant type synthesized laminin, and the non-small cell lung cancer lines produced either laminin or fibronectin. These findings suggest that the variant form of small cell lung cancer may be derived from a primitive neuroectodermal cell, with both neural and epithelial features, whereas the classic type is derived from a more mature cell with predominantly neuronal features. The differences in extracellular matrix synthesis, and laminin in particular, may explain some of the in vitro and in vivo characteristics of the tumour.
Production of anti-CCP antibodies and matrix metalloproteinase-3 by human rheumatoid arthritis synovial tissues using SCID mice
Authors: S Iwaki-Egawa
Journal: Annals of the Rheumatic Diseases (2005)

The diagnosis of rheumatoid arthritis (RA) remains imprecise, particularly early in the course of the disease. Up to now, rheumatoid factor (RF) has been used as a typical marker for RA; however, RF has a low specificity because it also occurs in many inflammatory diseases as well as in healthy people. It has recently been shown that autoantibodies directed toward cyclic citrullinated peptides (anti-CCP) are potentially important serological markers for diagnosis and prognosis in RA.1

The proteolytic pathways associated with cellular interactions also seem to have an important role in joint cartilage destruction of RA. Matrix metalloproteinase-3 (MMP-3) is secreted by fibroblasts and synovial cells,2 and it has been shown to be increased in RA serum, not only in the late stage but also in the early stage of the disease. Therefore, MMP-3 is a useful marker for predicting bone damage in early RA.3

In many early cases of RA, patients will not always fulfil the American …
Effects of Corneal Thickness, Corneal Curvature, and Intraocular Pressure Level on Goldmann Applanation Tonometry and Dynamic Contour Tonometry
Authors: Brian A. Francis, Amy Hsieh, Mei-Ying Lai, Vikas Chopra, Fernando Pena, Stanley Azen, Rohit Varma
Journal: Ophthalmology (2006)
Human keratinocyte growth factor effects in a porcine model of epidermal wound healing.
Authors: L Staiano-Coico, J G Krueger, J S Rubin, S D'limi, V P Vallat, L Valentino, T Fahey, A Hawes, G Kingston, M R Madden
Journal: The Journal of Experimental Medicine (1993)

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family (hence the alternative designation FGF-7). It is produced by stromal cells, but acts as a mitogen for epithelial cells. We examined the effects of topically applied KGF on healing of wounds in a porcine model. In partial-thickness wounds, KGF stimulated the rate of reepithelialization (p &amp;lt; 0.0002), associated with a thickening of the epidermis (p &amp;lt; 0.0001). Epidermis from KGF-treated full-thickness wound sites was significantly thicker (0.31 +/- 0.22 mm) compared with mirror image control sites (0.18 +/- 0.12 mm) (p &amp;lt; 0.0001). Moreover, the majority (77%) of KGF-treated wounds exhibited epidermis with a deep rete ridge pattern as compared with control sites. These effects were observed as early as 14 d and persisted for at least 4 wk. KGF treatment also increased the number of serrated basal cells associated with increased deposition of collagen fibers in the superficial dermis adjacent to the acanthotic epidermis. Electron microscopy revealed better developed hemidesmosomes associated with thicker bundles of tonofilaments in the serrated cells. The pattern of epidermal thickening observed in KGF-treated wounds resembled psoriasis. Psoriasis is a disease associated with epidermal thickening, parakeratosis as well as hyperproliferation that extends beyond the basal layer. In striking contrast to psoriasis, KGF-treated wounds exhibited normal orthokeratotic maturation, and proliferation was localized to the basal cells. Our present findings have significant implications concerning the role of KGF as a paracrine modulator of epidermal proliferation and differentiation.
Cardiovascular Effects of Halothane in Man
Authors: N. Ty Smith
Journal: JAMA (1968)

The cardiovascular response to induction of anesthesia with halothane-oxygen, as well as to changes in alveolar concentration from one steady-state level to another, was studied in eight subjects. Heart rate, arterial and right atrial pressures, stroke volume, cardiac output, left ventricular minute work, and total peripheral resistance were recorded beat-to-beat. The last four variables were calculated by a ballistocardiograph-analogue computer system. Induction of anesthesia significantly increased all variables except total peripheral resistance and arterial and right atrial pressures. The last two are the variables conventionally measured during anesthesia and surgery. The response to changing concentration was significantly delayed in time and decreased in magnitude late, as compared to early, in anesthesia administration, which indicated an adaptation to halothane anesthesia. The changes noted during induction in our healthy, normal subjects should be transferred with caution to the situation in the operating room.
An Anti‐PSMA Bivalent Immunotoxin Exhibits Specificity and Efficacy for Prostate Cancer Imaging and Therapy
Authors: Fayun Zhang, Liang Shan, Yuanyi Liu, David Neville, Jung‐Hee Woo, Yue Chen, Alexandru Korotcov, Stephen Lin, Sophia Huang, Rajagopalan Sridhar, Wei Liang, Paul C. Wang
Journal: Advanced Healthcare Materials (2012)

Abstract Prostate specific membrane antigen (PSMA) is overexpressed on prostate tumor cells and the neovascular endothelia various solid tumors. A bivalent immunotoxin generated by fusing a fold‐back single‐chain diabody derived from the Fv fragments of an anti‐PSMA monoclonal antibody with a truncated diphtheria toxin (DT) containing the activity and translocation domains [A‐dmDT390‐scfbDb(PSMA)] might be suitable for targeted therapy of tumors that overexpress PSMA. In this study, a PSMA‐positive and a PSMA‐negative prostate cancer cell lines were treated with immunotoxin A‐dmDT390‐scfbDb(PSMA) in order to study the tumor targeting specificity and therapeutic potential of the immunotoxin. The cellular uptake and selective toxicity of the immunotoxin were evident in monolayer cultures of PSMA‐positive LNCaP prostate cancer cells but not in cultures of PSMA‐negative PC‐3 prostate cancer cells. Cellular accumulation of A‐dmDT390‐scfbDb(PSMA) increased with increasing incubation times and concentrations in LNCaP cells. The proportion of apoptotic LNCaP cells increased upon incubation with increasing doses of the fold‐back immunotoxin. Optical imaging and MRI with the Alexa Fluor 680‐labeled A‐dmDT390‐scfbDb(PSMA) confirmed the specific targeting and therapeutic efficacy of this immunotoxin towards PSMA‐positive LNCaP solid tumor xenografts in athymic nude mice.
The effect of mass immunisation campaigns and new oral poliovirus vaccines on the incidence of poliomyelitis in Pakistan and Afghanistan, 2001–11: a retrospective analysis
Authors: Kathleen M O'Reilly, Elias Durry, Obaid ul Islam, Arshad Quddus, Ni'ma Abid, Tahir P Mir, Rudi H Tangermann, R Bruce Aylward, Nicholas C Grassly
Journal: The Lancet (2012)
Progression of lung disease on computed tomography and pulmonary function tests in children and adults with cystic fibrosis
Authors: P A de Jong
Journal: Thorax (2005)

<b>Background:</b> A study was undertaken to compare the ability of computed tomographic (CT) scores and pulmonary function tests to detect changes in lung disease in children and adults with cystic fibrosis (CF). <b>Methods:</b> CT scans and pulmonary function tests were retrospectively studied in a cohort of patients with CF aged 5–52 years for whom two or three CT scans at 3 year intervals were available, together with pulmonary function test results. All CT scans were scored by two observers. Pulmonary function results were expressed as percentage predicted and Z scores. <b>Results:</b> Of 119 patients studied, two CT scans were available in 92 patients and three in 24. CT (composite and component) scores and lung function both deteriorated significantly (p&lt;0.02). Peripheral bronchiectasis worsened by 1.7% per year in children (p&lt;0.0001) and by 1.5% per year in adults (p&lt;0.0001). Bronchiectasis worsened in 68 of 92 patients while forced expiratory volume in 1 second (FEV<sub>1</sub>) worsened in 54 of 92 patients; bronchiectasis also deteriorated in 27 patients with stable or improving FEV<sub>1</sub>. The CT score (and its components) and pulmonary function tests showed similar rates of deterioration in adults and children (p&gt;0.09). <b>Conclusion:</b> The peripheral bronchiectasis CT score deteriorates faster and more frequently than lung function parameters in children and adults with CF, which indicates that pulmonary function tests and CT scans measure different aspects of CF lung disease. Our data support previous findings that the peripheral bronchiectasis CT score has an added value to pulmonary function tests in monitoring CF lung disease.
Intramyocardial, Autologous CD34+ Cell Therapy for Refractory Angina
Authors: Douglas W. Losordo, Timothy D. Henry, Charles Davidson, Joon Sup Lee, Marco A. Costa, Theodore Bass, Farrell Mendelsohn, F. David Fortuin, Carl J. Pepine, Jay H. Traverse, David Amrani, Bruce M. Ewenstein, Norbert Riedel, Kenneth Story, Kerry Barker, Thomas J. Povsic, Robert A. Harrington, Richard A. Schatz
Journal: Circulation Research (2011)

A growing number of patients with coronary disease have refractory angina. Preclinical and early-phase clinical data suggest that intramyocardial injection of autologous CD34+ cells can improve myocardial perfusion and function.Evaluate the safety and bioactivity of intramyocardial injections of autologous CD34+ cells in patients with refractory angina who have exhausted all other treatment options.In this prospective, double-blind, randomized, phase II study (ClinicalTrials.gov identifier: NCT00300053), 167 patients with refractory angina received 1 of 2 doses (1×10(5) or 5×10(5) cells/kg) of mobilized autologous CD34+ cells or an equal volume of diluent (placebo). Treatment was distributed into 10 sites of ischemic, viable myocardium with a NOGA mapping injection catheter. The primary outcome measure was weekly angina frequency 6 months after treatment. Weekly angina frequency was significantly lower in the low-dose group than in placebo-treated patients at both 6 months (6.8±1.1 versus 10.9±1.2, P=0.020) and 12 months (6.3±1.2 versus 11.0±1.2, P=0.035); measurements in the high-dose group were also lower, but not significantly. Similarly, improvement in exercise tolerance was significantly greater in low-dose patients than in placebo-treated patients (6 months: 139±151 versus 69±122 seconds, P=0.014; 12 months: 140±171 versus 58±146 seconds, P=0.017) and greater, but not significantly, in the high-dose group. During cell mobilization and collection, 4.6% of patients had cardiac enzyme elevations consistent with non-ST segment elevation myocardial infarction. Mortality at 12 months was 5.4% in the placebo-treatment group with no deaths among cell-treated patients.Patients with refractory angina who received intramyocardial injections of autologous CD34+ cells (10(5) cells/kg) experienced significant improvements in angina frequency and exercise tolerance. The cell-mobilization and -collection procedures were associated with cardiac enzyme elevations, which will be addressed in future studies.
Early post-bevacizumab progression on contrast-enhanced MRI as a prognostic marker for overall survival in recurrent glioblastoma: results from the ACRIN 6677/RTOG 0625 Central Reader Study
Authors: J. L. Boxerman, Z. Zhang, Y. Safriel, M. Larvie, B. S. Snyder, R. Jain, T. L. Chi, A. G. Sorensen, M. R. Gilbert, D. P. Barboriak
Journal: Neuro-Oncology (2013)

RTOG 0625/ACRIN 6677 is a multicenter, randomized, phase II trial of bevacizumab with irinotecan or temozolomide in recurrent glioblastoma (GBM). This study investigated whether early posttreatment progression on FLAIR or postcontrast MRI assessed by central reading predicts overall survival (OS). Of 123 enrolled patients, 107 had baseline and at least 1 posttreatment MRI. Two central neuroradiologists serially measured bidimensional (2D) and volumetric (3D) enhancement on postcontrast T1-weighted images and volume of FLAIR hyperintensity. Progression status on all posttreatment MRIs was determined using Macdonald and RANO imaging threshold criteria, with a third neuroradiologist adjudicating discrepancies of both progression occurrence and timing. For each MRI pulse sequence, Kaplan-Meier survival estimates and log-rank test were used to compare OS between cases with or without radiologic progression. Radiologic progression occurred after 2 chemotherapy cycles (8 weeks) in 9 of 97 (9%), 9 of 73 (12%), and 11 of 98 (11%) 2D-T1, 3D-T1, and FLAIR cases, respectively, and 34 of 80 (43%), 21 of 58 (36%), and 37 of 79 (47%) corresponding cases after 4 cycles (16 weeks). Median OS among patients progressing at 8 or 16 weeks was significantly less than that among nonprogressors, as determined on 2D-T1 (114 vs 278 days and 214 vs 426 days, respectively; P < .0001 for both) and 3D-T1 (117 vs 306 days [P < .0001] and 223 vs 448 days [P = .0003], respectively) but not on FLAIR (201 vs 276 days [P = .38] and 303 vs 321 days [P = .13], respectively). Early progression on 2D-T1 and 3D-T1, but not FLAIR MRI, after 8 and 16 weeks of anti–vascular endothelial growth factor therapy has highly significant prognostic value for OS in recurrent GBM.
OC-013 How often is upper Gastrointestinal Cancer Missed during Endoscopy?
Authors: D Cheung, T Evans, G Lawrence, N Trudgill
Journal: Gut (2013)

<h3>Introduction</h3> Meta-analysis of published literature suggests that up to 14% of upper gastrointestinal cancer (UGIC) subjects had a negative oesophagogastroduodenoscopy (OGD) up to 3 years prior to diagnosis. We have examined how often UGIC is missed at OGD in our organisation and associated risk factors. <h3>Methods</h3> Computerised OGD records from Sandwell General and City Hospitals between 1999 and 2007 were retrieved and submitted to the West Midlands Cancer Intelligence Unit (WMCIU) for UGIC registrations linkage. Subjects undergoing OGD 3 months to 5 years before diagnosis were identified as potentially missed UGIC cases and those with no OGD 3 months to 5 years before diagnosis served as controls. The influence of age, gender, indication, endoscopist specialty, trainee involvement, sedation use, number of biopsies taken, site and histology of UGIC on missed UGIC were examined by logistic regression analysis. <h3>Results</h3> 36577 OGD records were submitted to WMCIU for cancer linkage and 524 UGIC were linked. 419 control UGIC: 388 (93%) diagnosed at initial OGD; 31 (7%) diagnosed at repeat OGD appropriately (within 90 days, with previous benign histology). 105 (20%) potentially missed UGIC cases: 39 (37%) oesophageal cancer (OC) and 66 (63%) gastric cancer (GC); 42 (40%) had OGD 3 months to 1 year prior to diagnosis; 33 (31%) had OGD 1–3 years prior and 30 (29%) had OGD 3–5 years prior. Furthermore, 30% of missed UGIC cases had OGD where abnormality at site of UGIC was seen but not biopsied or benign histology from an inadequate number of biopsies ( &lt; 4) within 3 months to 1 year prior to diagnosis. Lack of alarm symptoms (2.51, 95%CI 1.58–4.00, p = 0.0001) and female gender (1.79, 1.16–2.79, p = 0.009) were associated with missed UGIC. The number of biopsies taken was significantly lower in the missed UGIC group than in the controls (2.1 ± 0.2 vs 5.4 ± 0.1, p &lt; 0.05). In subjects with OC, mid-oesophageal OC appeared more likely to be missed than lower-oesophageal OC (2.04, 0.99–4.23, p = 0.05). Oesophageal squamous cell carcinoma was much more likely to be missed than oesophageal adenocarcinoma (4.47, 1.88–10.65, p &lt; 0.001). In GC subjects, there was no association between missed UGIC and tumour site (1.10, 0.61–1.97, p = 0.3) or histology subtype (1.10, 0.46–2.67, p = 0.8). Age (1.5, –0.8–3.8, p = 0.2), endoscopist specialty (1.39, 0.70–2.76, p = 0.34), trainee involvement (1.2, 0.78 – 1.86, p = 0.39) and sedation use (0.98, 0.64–1.51, p = 0.9) were not associated with increased risk of missing UGIC. <h3>Conclusion</h3> Missing UGIC at OGD was seen in 14.3% of subjects within 3 years of diagnosis. It was associated with lack of alarm symptoms, female gender, oesophageal squamous cell carcinoma and an insufficient number of biopsies from recognised abnormalities. <h3>Disclosure of Interest</h3> None Declared
A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and Vascular Endothelial Growth Factor Receptor 2
Authors: Joseph Paul Eder, Geoffrey I. Shapiro, Leonard J. Appleman, Andrew X. Zhu, Dale Miles, Harold Keer, Belinda Cancilla, Felix Chu, Suzanne Hitchcock-Bryan, Laurie Sherman, Stewart McCallum, Elisabeth I. Heath, Scott A. Boerner, Patricia M. LoRusso
Journal: Clinical Cancer Research (2010)

Foretinib is an oral multikinase inhibitor targeting Met, RON, Axl, and vascular endothelial growth factor receptor. We conducted a phase I, first-time-in-human, clinical trial using escalating doses of oral foretinib. The primary objectives are to identify a maximum tolerated dose and determine the safety profile of foretinib. Secondary objectives included evaluation of plasma pharmacokinetics, long-term safety after repeated administration, preliminary antitumor activity, and pharmacodynamic activity.Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard measures exist. All patients received foretinib orally for 5 consecutive days every 14 days. Dose escalation followed a conventional "3+3" design.Forty patients were treated in eight dose cohorts. The maximum tolerated dose was defined as 3.6 mg/kg, with a maximum administered dose of 4.5 mg/kg. Dose-limiting toxicities included grade 3 elevations in aspartate aminotransferase and lipase. Additional non-dose-limiting adverse events included hypertension, fatigue, diarrhea, vomiting, proteinuria, and hematuria. Responses were observed in two patients with papillary renal cell cancer and one patient with medullary thyroid cancer. Stable disease was identified in 22 patients. Foretinib pharmacokinetics increased linearly with dose. Pharmacodynamic evaluation indicated inhibition of MET phosphorylation and decreased proliferation in select tumor biopsies at submaximal doses.The recommended dose of foretinib was determined to be 240 mg, given on the first 5 days of a 14-day cycle. This dose and schedule were identified as having acceptable safety and pharmacokinetics, and will be the dose used in subsequent phase II trials.
Adjunctive Pharmacotherapy before Percutaneous Coronary Intervention in Non-ST-Elevation Acute Coronary Syndromes: The Role of Modulating Inflammation
Authors: Dean J. Kereiakes
Journal: Circulation (2003)

Vascular inflammation is central to the pathogenesis of acute coronary syndromes (ACS) and the response to vascular injury after percutaneous coronary intervention (PCI). For both ACS and PCI, the magnitude of vascular inflammation is linked to adverse late clinical outcomes (e.g., death, recurrent myocardial infarction [MI] or ischemia, and restenosis). Many pharmacologic therapies with demonstrated efficacy for the treatment of ACS have anti-inflammatory properties, which are distinct from their perceived primary mechanism of action. The anti-inflammatory effects of aspirin, clopidogrel, low-molecular-weight heparin (LMWH), platelet glycoprotein (GP) IIb/IIIa receptor inhibitors, statins, and angiotensin converting enzyme (ACE) inhibitors are reviewed, and the hypothesis is generated that modulation of vascular inflammation at least in part contributes a common basis for the long-term clinical benefit ascribed to these medications. A therapeutic algorithm based on clinical risk stratification and coronary revascularization strategy is proposed for incorporating the current American College of Cardiology (ACC)/American Heart Association (AHA) guideline recommendations for treatment of patients who present with non-ST-elevation ACS.