tbuckley/cabot-search huggingface dataset:
NKR-P1A is a target-specific receptor that activates natural killer cell cytotoxicity.
Authors: J C Ryan, E C Niemi, M C Nakamura, W E Seaman
Journal: The Journal of Experimental Medicine (1995)

NKR-P1A is a lectinlike surface molecule expressed on rat natural killer (NK) cells. NKR-P1A has structural and functional features of an activating NK cell receptor, but a requirement for NKR-P1A in target cell lysis has not been determined. To define the role of NKR-P1A in natural killing, we have generated a mutant of the rat NK cell line, RNK-16, lacking expression of all members of the NKR-P1 receptor family. Although these NKR-P1-deficient NK cells were able to kill many standard tumor targets, including YAC-1, they were selectively deficient in the lysis of IC-21 macrophage, B-16 melanoma, and C1498 lymphoma targets. Reexpression of a single member of the NKR-P1 family, NKR-P1A, on mutant cells restored lysis of IC-21, and killing of IC-21 targets through rat NKR-P1A was completely blocked by F(ab')2 anti-NKR-P1A. Reexpression of NKR-P1A also restored transmembrane signaling to IC-21, as assessed by the generation of inositol-1,4,5-trisphosphate. The generation of inositol-1,4,5-trisphosphate was also restored in response to B-16 targets, but both B-16 and C1498 cells remained resistant to lysis, indicating that other NK cell molecules, perhaps within the NKR-P1 family, are required for the efficient killing of these tumors. These results are the first to demonstrate that NKR-P1A is a target-specific receptor that activates natural killing.
Familial apolipoprotein E deficiency.
Authors: E J Schaefer, R E Gregg, G Ghiselli, T M Forte, J M Ordovas, L A Zech, H B Brewer
Journal: Journal of Clinical Investigation (1986)

A unique kindred with premature cardiovascular disease, tubo-eruptive xanthomas, and type III hyperlipoproteinemia (HLP) associated with familial apolipoprotein (apo) E deficiency was examined. Homozygotes (n = 4) had marked increases in cholesterol-rich very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL), which could be effectively lowered with diet and medication (niacin, clofibrate). Homozygotes had only trace amounts of plasma apoE, and accumulations of apoB-48 and apoA-IV in VLDL, IDL, and low density lipoproteins. Radioiodinated VLDL apoB and apoE kinetic studies revealed that the homozygous proband had markedly retarded fractional catabolism of VLDL apoB-100, apoB-48 and plasma apoE, as well as an extremely low apoE synthesis rate as compared to normals. Obligate heterozygotes (n = 10) generally had normal plasma lipids and mean plasma apoE concentrations that were 42% of normal. The data indicate that homozygous familial apoE deficiency is a cause of type III HLP, is associated with markedly decreased apoE production, and that apoE is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.
Cytosolic Phospholipase A2: Targeting Cancer through the Tumor Vasculature
Authors: Amanda Linkous, Ling Geng, Andrej Lyshchik, Dennis E. Hallahan, Eugenia M. Yazlovitskaya
Journal: Clinical Cancer Research (2009)

Abstract Purpose: In vascular endothelial cells, low doses of ionizing radiation trigger the immediate activation of cytosolic phospholipase A2 (cPLA2). This event initiates prosurvival signaling that could be responsible for radioresistance of tumor vasculature. Thus, the development of radiosensitizers targeting these survival pathways may enhance tumor response to radiation therapy. Arachidonyltrifluoromethyl Ketone (AACOCF3), a specific cPLA2 inhibitor, was studied as a potential radiosensitizer. Experimental Design: Vascular endothelial cells (3B11 and MPMEC) and lung tumor cells (LLC and H460) were treated with 1 μmol/L AACOCF3 for 30 minutes prior to irradiation. Treatment response was evaluated by clonogenic survival, activation of extracellular signal-regulated kinase 1/2 (ERK1/2), tubule formation, and migration assays. For in vivo experiments, mice with LLC or H460 tumors in the hind limbs were treated for 5 consecutive days with 10 mg/kg AACOCF3 administered daily 30 minutes prior to irradiation. Treatment response was assessed by tumor growth delay, Power Doppler Sonography, and immunohistochemistry. Results: In cell culture experiments, inhibition of cPLA2 with AACOCF3 prevented radiation-induced activation of ERK1/2 and decreased clonogenic survival of irradiated vascular endothelial cells but not the lung tumor cells. Treatment with AACOCF3 also attenuated tubule formation and migration in irradiated vascular endothelial cells. In both tumor mouse models, treatment with AACOCF3 prior to irradiation significantly suppressed tumor growth and decreased overall tumor blood flow and vascularity. Increased apoptosis in both tumor cells and tumor vascular endothelium was determined as a possible mechanism of the observed effect. Conclusion: These findings identify cPLA2 as a novel molecular target for tumor sensitization to radiation therapy through the tumor vasculature.
Interfering with TGFbeta-induced Smad3 nuclear accumulation differentially affects TGFbeta-dependent gene expression.
Authors: Ralph K Lindemann, Alfred Nordheim, Jürgen Dittmer
Journal: Molecular Cancer (2003)

Transforming growth factor-β (TGFβ) plays an important role in late-stage carcinogenesis by stimulating invasive behavior of cancer cells, promoting neo-angiogenesis and by helping cancer cells to escape surveillance by the immune system. It also supports colonization of the bone by metastatic breast cancer cells by increasing expression of osteolytic parathyroid hormone-related protein (PTHrP). Interfering with TGFβ signalling may thus weaken the malignant properties of cancer cells. We investigated to what extent two inhibitors, SB-202190 and SB-203580, interfere with TGFβ-signalling in invasive MDA-MB-231 breast cancer cells. These compounds, formerly used as p38-MAPK-specific inhibitors, were recently also demonstrated to inhibit TGFβ type I receptor kinase. Our results show that these inhibitors delay the onset of TGFβ-induced nuclear accumulation of Smad3 and reduces its amplitude. This effect was accompanied by a strong reduction in TGFβ-responsivess of the slow-responder genes pthrp, pai-1 and upa, while the reactivity of the fast-responder gene smad7 to TGFβ remained almost unchanged. Neither was the TGFβ response of the fast-responder ese-1/esx gene, whose expression we found to be strongly downregulated by TGFβ, affected by the inhibitors. The data show that SB-202190 and SB-203580 suppress TGFβ-dependent activation of genes that are important for the acquisition of invasive behavior, while having no effect on the expression of the natural TGFβ inhibitor Smad7. This suggests that these compounds are potent inhibitors of malignant behavior of cancer cells.
Tissue-specific and reversible RNA interference in transgenic mice
Authors: Ross A Dickins, Katherine McJunkin, Eva Hernando, Prem K Premsrirut, Valery Krizhanovsky, Darren J Burgess, Sang Yong Kim, Carlos Cordon-Cardo, Lars Zender, Gregory J Hannon, Scott W Lowe
Journal: Nature Genetics (2007)
Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies
Authors: L Castera
Journal: Gut (2003)

Steatosis, a frequent histological finding in patients with chronic hepatitis C (CHC), has been suggested to influence liver fibrosis progression. The aim of the present study was to evaluate in patients with CHC and paired liver biopsies the relationship between the evolution of steatosis and that of fibrosis between the two biopsies.Ninety six patients were selected according to the following criteria: absence of treatment; absence of cirrhosis at initial biopsy; and serum hepatitis B surface antigen and human immunodeficiency virus antibody negativity. Degrees of necroinflammatory activity, fibrosis, and steatosis grades were assessed in the two biopsies. In addition to histological lesions, parameters studied included the source of infection, duration of infection, body mass index, alcohol intake, alanine aminotransferase levels, hepatitis C virus genotype, and viral load.The mean interval between the two biopsies was 48 (32) months. Steatosis was found in 54% of patients at first biopsy, and was severe in 9%. Worsening of steatosis was observed in 34% of patients, stability in 50%, and improvement in 16%. Worsening of steatosis was significantly associated with hepatic fibrosis progression in patients with (p=0.03) or without (p<0.03) steatosis at diagnosis. Overall, fibrosis progression was observed in 31% of patients and stability in 69%. In a univariate analysis, fibrosis progression was associated with male sex (p=0.05), worsening of histological activity (p=0.04), and worsening of steatosis (p=0.0003). In a multivariate analysis, the only factor independently associated with fibrosis progression was worsening of steatosis (worsening v improvement/stability: odds ratio 4.7 (95% confidence interval 1.3-10.8); p=0.0001).Our results suggest that in untreated patients with CHC and serial liver biopsies, fibrosis progression is strongly associated with worsening of steatosis.
Serum-free differentiation of functional human coronary-like vascular smooth muscle cells from embryonic stem cells
Authors: Omar El-Mounayri, Anton Mihic, Eric A. Shikatani, Mark Gagliardi, Sarah K. Steinbach, Nicole Dubois, Ralph DaCosta, Ren-Ke Li, Gordon Keller, Mansoor Husain
Journal: Cardiovascular Research (2012)

Despite the diverse developmental origins of vascular smooth muscle cells (VSMCs), recent attempts to generate VSMCs from human embryonic stem cells (hESCs) differentiated along various lineages did not yield distinct cell phenotypes. The aim of this study was to derive and characterize functional coronary-like VSMCs from hESCs using serum-free cardiac-directed differentiation. Embryoid bodies (EBs) from three pluripotent stem cell lines subjected to cardiac-directed differentiation in defined media were characterized over 30 days for VSMC-specific gene expression by qRT–PCR, immunofluorescence microscopy and fluorescence-activated cell sorting (FACS). EBs composed of cardiomyocytes, endothelial cells (ECs), fibroblasts, and VSMCs underwent FACS on d28 to reveal that the VSMCs form a distinct subpopulation, which migrate with ECs in an in vitro angiogenesis assay. To enrich for VSMCs, d28 EBs were dissociated and cultured as monolayers. Over several passages, mRNA and protein levels of cardiomyocyte, endothelial, and fibroblast markers were abolished, whereas those of mature VSMCs were unchanged. Vascular endothelial growth factor and basic fibroblast growth factor were critical for the separation of the cardiac and VSMC lineages in EBs, and for the enrichment of functional VSMCs in monolayer cultures. Calcium cycling and cell shortening responses to vasoconstrictors in hESC-derived VSMCs in vitro were indistinguishable from primary human coronary artery SMCs, and distinct from bladder and aorta SMCs. VSMCs identically derived from green fluorescent protein -expressing hESCs integrated in and contributed to new vessel formation in vivo. The ability to generate hESC-derived functional human coronary-like VSMCs in serum-free conditions has implications for disease modelling, drug screening, and regenerative therapies.
P8 Use of D-dimer: CRP ratio compared to D-dimer alone to predict PE on VQ scanning
Authors: R. Berwick, S. Navalkissoor, J. R. Hurst
Journal: Thorax (2011)

<h3>Introduction</h3> Pulmonary embolism (PE) is a common presentation in the emergency department and in-patient setting. Measurement of D-dimer in conjunction with clinical risk assessment is used to exclude patients at low risk of PE. Some of the conditions that mimic PE, including infection and inflammation, are also associated with elevated D-dimer concentrations such that the test lacks specificity. Most infectious and inflammatory conditions result in an elevated acute-phase serum response which can be quantified using C-Reactive Protein (CRP) assay. We hypothesised, therefore, that patients with isolated PE would have a higher D-dimer: CRP ratio than patients with infectious or inflammatory mimics of PE and therefore that this ratio would be more discriminatory. <h3>Methods</h3> We analysed data from all patients who underwent V/Q scanning to confirm or exclude PE at Royal Free Hampstead NHS Trust, London, UK, during 2010. The CRP and D-dimer results closest, but preceding the V/Q scan were analysed using receiver operator characteristic (ROC) curves to test the hypothesis that the D-dimer: CRP ratio (expressed as ng/ml:mg/l) was a better predictor or PE than D-dimer alone. <h3>Results</h3> 179 patients (mean (SD) age 52.8 (19.7) years) had a V/Q scan for suspected PE during the study period. Of these, 85 had a D-dimer assay, a median (IQR) of 1 (0–1) days prior to the imaging. The median D-dimer concentration was 272 (178–675) ng/ml. 137 patients had CRP assay (12 (3–56) mg/l), measured 1 (0–1) days prior to imaging. It was possible to calculate a D-dimer: CRP ratio in 78 patients (44% of the total), of whom 19 (24%) had a V/Q scan reported as high risk for PE. D-dimer, and the D-dimer: CRP ratio, but not CRP were significantly higher between patients who did and did not have high-risk V/Q scans (Mann–Whitney U test analyses: 764 vs 245 ng/ml, p=0.001; 107 vs 31 units, p=0.020 and 20 vs 10 mg/l, p=0.134 respectively). Biomarker data were log<sub>10</sub> transformed to permit ROC analysis. Area-under-curve (AUC) values using ROC for D-dimer alone, and D-dimer: CRP ratio were 0.74 and 0.68 respectively, both less than the standard criteria for utility of 0.8. <h3>Conclusions</h3> D-dimer: CRP ratio is not superior to D-dimer alone in predicting PE in patients with a clinical suspicion of this diagnosis sufficient to require V/Q scanning.
High-resolution MRI assessment of dactylitis in psoriatic arthritis shows flexor tendon pulley and sheath-related enthesitis
Authors: Ai Lyn Tan, Eiji Fukuba, Nicola Ann Halliday, Steven F Tanner, Paul Emery, Dennis McGonagle
Journal: Annals of the Rheumatic Diseases (2014)

Objective Dactylitis is a hallmark of psoriatic arthritis (PsA) where flexor tenosynovitis is common. This study explored the microanatomical basis of dactylitis using high-resolution MRI (hrMRI) to visualise the small entheses around the digits. Methods Twelve patients with psoriatic dactylitis (4 fingers, 8 toes), and 10 healthy volunteers (6 fingers, 4 toes) had hrMRI of the digits using a ‘microscopy’ coil and contrast enhancement. All structures were evaluated including the tendons and ligaments, related enthesis organs, pulleys, volar/plantar plates and tendon sheaths. Results In dactylitis, collateral ligament enthesitis was seen in nine digits (75%), extensor tendon enthesitis in six digits (50%), functional enthesitis (5 digits, 42%), abnormal enhancement at the volar plates (2/5 joints, 40%) and the plantar plate (1/5 joints, 20%). Nine cases (75%) demonstrated flexor tenosynovitis, with flexor tendon pulley/flexor sheath microenthesopathy observed in 50% of all cases. Less abnormalities which were milder was observed in the normal controls, none of whom had any signal changes in the tendon pulleys or fibrous sheaths. Conclusions This study provides proof of concept for a link between dactylitis and ‘digital polyenthesitis’ including disease of the miniature enthesis pulleys of the flexor tendons, further affirming the concept of enthesitis in PsA.
Evidence of a Sleep-Specific Blunted Cortical Response to Inspiratory Occlusions in Mild Obstructive Sleep Apnea Syndrome
Authors: John Gora, John Trinder, Robert Pierce, Ian M. Colrain
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Obstructive sleep apnea syndrome (OSAS) patients have elevated non-rapid eye movement (REM) sleep arousal thresholds to inspiratory loading. To test the hypothesis that this is due to sleep-specific dampening of cortical responses to inspiratory effort, respiratory-related evoked potentials (RREPs) were evaluated in six mild OSAS patients and six age- and body mass index-matched controls during wakefulness and Stage 2 non-REM sleep. Electroencephalogram was recorded from six scalp sites (Fz, FCz, Cz, CPz, Pz, and O(2)). Electrooculogram, electromyogram, and mask pressure signals were also recorded. During sleep, pharyngeal pressure was recorded using a Millar pressure catheter placed 2 cm below the glottis. The RREP waveform was broadly similar in the two groups during wakefulness, but was markedly different during Stage 2 non-REM sleep. During wakefulness, only the N1 component showed reduced amplitude in the OSAS group. During sleep, the occlusion stimulus elicited fewer K-complexes in the OSAS patients. In addition, the N550 component in the average of K-complex responses was smaller in amplitude in the OSAS group. The data suggest that patients with mild OSAS have a "blunted" response to the respiratory occlusion stimulus. This appears not to be related to compromised mechanoreceptor function, as the RREP was normal in the patients when they were awake.
Indications for arthroscopy in mon- and polyarticular arthritis.
Authors: R A Bots, A M Boerbooms
Journal: Annals of the Rheumatic Diseases (1979)

In many cases clinical and laboratory data and x-rays are insufficient to diagnose the aetiology of synovitis in gonarthritis and to plan adequate treatment. The efficacy of arthroscopy in the management of the knee lesion was studied in mon- and polyarthritis. A classification of 'very useful', 'useful' and 'not useful' was used. On the basis of results reported here we outline the indications for arthroscopy in mon- and polyarthritis.
Immunohistochemical Expression of Basic Fibroblast Growth Factor and Fibroblast Growth Factor Receptors 1 and 2 in the Pathogenesis of Lung Cancer
Authors: Carmen Behrens, Heather Y. Lin, J. Jack Lee, Maria Gabriela Raso, Waun Ki Hong, Ignacio I. Wistuba, Reuben Lotan
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To identify the patterns of protein expression of basic fibroblast growth factor (bFGF) and FGF receptors 1 and 2 in non-small cell lung carcinoma (NSCLC) and their role in the early pathogenesis of squamous cell carcinoma (SCC) of the lung. Experimental Design: Archived tissue from NSCLC (adenocarcinoma and SCC; n = 321) and adjacent bronchial epithelial specimens (n = 426) were analyzed for the immunohistochemical expression of bFGF, FGFR1, and FGFR2, and the findings were correlated with clinicopathologic features of the patients. Results: High expression of bFGF, FGFR1, and FGFR2 was shown in most NSCLC tumors. The pattern of expression for all markers varied according to tumor histologic type and cellular localization. Cytoplasmic expression scores were significantly higher in tumors than in normal epithelia. Nuclear bFGF (P = 0.03) and FGFR1 (P = 0.02) levels were significantly higher in women than in men. Although cytoplasmic FGFR1 expression was significantly higher (P = 0.002) in ever smokers than in never smokers, nuclear FGFR1 (P = 0.0001) and FGFR2 (P = 0.003) expression was significantly higher in never smokers. Different prognostic patterns for the expression of these markers were detected for both NSCLC histologic types. Dysplastic changes showed significantly higher expression of all markers compared with squamous metaplasia. Conclusions: bFGF, FGFR1, and FGFR2 are frequently overexpressed in SCC and adenocarcinoma of the lung. bFGF signaling pathway activation may be an early phenomenon in the pathogenesis of SCC and thus an attractive novel target for lung cancer chemopreventive and therapeutic strategies.
Cloning and sequencing of a cDNA expressing a recombinant house dust mite protein that binds human IgE and corresponds to an important low molecular weight allergen.
Authors: E R Tovey, M C Johnson, A L Roche, G S Cobon, B A Baldo
Journal: The Journal of Experimental Medicine (1989)

A cDNA clone coding for a mite allergen of mol wt approximately 14,000 has been isolated and its DNA sequence determined. The native component from mite extracts encoded by this DNA was identified by immunoprobing blots of mite body extract with human IgE eluted from the electroblotted cloned fusion polypeptides derived from the expressed cDNA clone. The clone encodes a polypeptide with a deduced mol wt of 17,460. The deduced amino acid sequence was not homologous to any known protein sequences and it contains no cysteine or tryptophan. On blots, 21 of 38 sera from mite-allergic subjects recognized the cloned material, and this recognition strongly correlated with IgE-binding to the native component on protein blots of mite extract.
Availability of Inhaled Insulin Promotes Greater Perceived Acceptance of Insulin Therapy in Patients With Type 2 Diabetes
Authors: Nick Freemantle, Lawrence Blonde, Didier Duhot, Marcus Hompesch, Robert Eggertsen, F.D. Richard Hobbs, Luc Martinez, Stuart Ross, Björn Bolinder, Elmar Stridde
Journal: Diabetes Care (2005)

Inhaled insulin (INH, Exubera) is under investigation for preprandial treatment of patients with type 1 and type 2 diabetes (1–3). This dry-powder insulin formulation is delivered by aerosol, permitting the noninvasive administration of rapid-acting insulin (4). Preliminary studies have shown that INH provides reproducible and effective control of glycemia (1,5–7). This randomized controlled trial examined the extent to which the availability of INH affects the perceived acceptability of insulin therapy among patients with type 2 diabetes who failed to achieve target glycemia on current therapy.

Male or female participants ( n = 779) aged 35–80 years with at least 3 months duration of type 2 diabetes and a HbA1c >8%, despite current therapy, were recruited from seven countries. Permitted current therapy included dietary measures and/or oral antidiabetic agents (OADs). Patients receiving insulin injections, smokers, or those who had significant pulmonary diseases were excluded. All patients gave informed consent, and local research ethics review boards approved the study.

Participants were randomly assigned to receive either educational information about the potential risks and benefits of all currently licensed treatment options only (OADs and/or subcutaneous insulin, n = 388) or information about the potential risks and benefits of licensed treatments and INH ( n = 391). …
Nuclear factor-kappa B pathway and response in a phase II trial of bortezomib and docetaxel in patients with recurrent and/or metastatic head and neck squamous cell carcinoma
Authors: C.H. Chung, J. Aulino, N.J. Muldowney, H. Hatakeyama, J. Baumann, B. Burkey, J. Netterville, R. Sinard, W.G. Yarbrough, A.J. Cmelak, R.J. Slebos, Y. Shyr, J. Parker, J. Gilbert, B.A. Murphy
Journal: Annals of Oncology (2009)
Application of a Constant Indicator Dilution Method to the Measurement of Local Venous Flow
Authors: SAMUEL L. KOUNTZ, WILLIAM J. DEMPSTER, JOHN P. SHILLINGFORD, Brian Kastell
Journal: Circulation Research (1964)

A method for measuring local venous flow by a constant indicator dilution technique is described. The optimal conditions have been outlined and the accuracy tested in vitro and found to be within ±3%. When compared with direct measurements of venous flow in dogs, its accuracy was within ±5%. The method is safe, easy to perform and, with the catheters described, flow can be measured over ranges of 20 to 5,700 ml/min in any vein greater than 4 mm inner diameter in which the catheter tips can be introduced.