tbuckley/cabot-search huggingface dataset:
Targeting Endogenous Transforming Growth Factor β Receptor Signaling in SMAD4-Deficient Human Pancreatic Carcinoma Cells Inhibits Their Invasive Phenotype
Authors: Gayathri Subramanian, Roderich E. Schwarz, Linda Higgins, Glenn McEnroe, Sarvajit Chakravarty, Sundeep Dugar, Michael Reiss
Journal: Cancer Research (2004)

Abstract Transforming growth factor-β (TGF-β) suppresses tumor formation by blocking cell cycle progression and maintaining tissue homeostasis. In pancreatic carcinomas, this tumor suppressive activity is often lost by inactivation of the TGF-β-signaling mediator, Smad4. We found that human pancreatic carcinoma cell lines that have undergone deletion of MADH4 constitutively expressed high endogenous levels of phosphorylated receptor-associated Smad proteins (pR-Smad2 and pR-Smad3), whereas Smad4-positive lines did not. These elevated pR-Smad levels could not be attributed to a decreased dephosphorylation rate nor to increased expression of TGF-β type I (TβR-I) or type II (TβR-II) receptors. Although minimal amounts of free bioactive TGF-β1 and TGF-β2 were detected in conditioned medium, treatment with a pan-specific (but not a TGF-β3 specific) TGF-β-neutralizing antibody and with anti-αVβ6 integrin antibody decreased steady-state pSmad2 levels and activation of a TGF-β-inducible reporter gene in neighboring cells, respectively. Thus, activation of TGF-β at the cell surface was responsible for the increased autocrine endogenous and paracrine signaling. Blocking TβR-I activity using a selective kinase inhibitor (SD-093) strongly decreased the in vitro motility and invasiveness of the pancreatic carcinoma cells without affecting their growth characteristics, morphology, or the subcellular distribution of E-cadherin and F-actin. Moreover, exogenous TGF-β strongly stimulated in vitro invasiveness of BxPC-3 cells, an effect that could also be blocked by SD-093. Thus, the motile and invasive properties of Smad4-deficient pancreatic cancer cells are at least partly driven by activation of endogenous TGF-β signaling. Therefore, targeting the TβR-I kinase represents a potentially powerful novel therapeutic approach for the treatment of this disease.
HEREDITARY ANGIO-OEDEMA TREATED WITH E-AMINOCAPROIC ACID
Authors: R. H. CHAMPION, P. J. LACHMANN
Journal: British Journal of Dermatology (1969)

SUMMARY.— Two brothers with hereditary angio-oedema have been studied, the only 2 cases among 227 patients with angio-oedema seen in 10 years. The absence of the inhibitor of the activated first component of complement in their serum confirmed the diagnosis. In a double blind trial their symptoms were partially controlled by ε - aminocaproic acid, although there were no consistent changes in the serum complement levels.
Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart
Authors: Inga Sörensen-Zender, Sagar Bhayana, Nathan Susnik, Veronique Rolli, Sandor Batkai, Arpita Baisantry, Siamak Bahram, Payel Sen, Beina Teng, Robert Lindner, Mario Schiffer, Thomas Thum, Anette Melk, Hermann Haller, Roland Schmitt
Journal: Journal of the American Society of Nephrology (2015)

Zinc-α2-glycoprotein (AZGP1) is a secreted protein synthesized by epithelial cells and adipocytes that has roles in lipid metabolism, cell cycling, and cancer progression. Our previous findings in AKI indicated a new role for AZGP1 in the regulation of fibrosis, which is a unifying feature of CKD. Using two models of chronic kidney injury, we now show that mice with genetic AZGP1 deletion develop significantly more kidney fibrosis. This destructive phenotype was rescued by injection of recombinant AZGP1. Exposure of AZGP1-deficient mice to cardiac stress by thoracic aortic constriction revealed that antifibrotic effects were not restricted to the kidney but were cardioprotective. In vitro, recombinant AZGP1 inhibited kidney epithelial dedifferentiation and antagonized fibroblast activation by negatively regulating TGF-β signaling. Patient sera with high levels of AZGP1 similarly attenuated TGF-β signaling in fibroblasts. Taken together, these findings indicate a novel role for AZGP1 as a negative regulator of fibrosis progression, suggesting that recombinant AZGP1 may have translational effect for treating fibrotic disease.
Geographical distribution of atopic rhinitis in the European Community Respiratory Health Survey I*
Authors: P.‐J. Bousquet, B. Leynaert, F. Neukirch, J. Sunyer, C. M. Janson, J. Anto, D. Jarvis, P. Burney
Journal: Allergy (2008)

Background: No large studies in adults has examined geographical variation in the prevalence of nasal allergy/allergic rhinitis in adults or considered the proportion of reported nasal symptoms on exposure to allergen attributable to atopy. The aim of this report was to describe the geographic distribution of subjects with nasal symptoms who are sensitized as determined by skin prick tests, using data from the European Community Respiratory Health Survey I. Methods: Information on the presence of nasal allergy, nasal symptoms on exposure to allergen and atopy using skin prick tests was collected from 15 394 adults aged 20–44 years living in 35 centres in 15 countries. Age sex standardized prevalence of symptoms and the attributable fraction of IgE sensitization for nasal symptoms on exposure to allergen were determined. Results: The age‐sex standardized prevalence of nasal allergy ranged from 11.8% in Oviedo (Spain) to 46.0% in Melbourne (Australia). The prevalence of atopic nasal allergy ranged from 4.6% in Oviedo to 31.8% in Melbourne (analysis limited on 12 566 subjects). The median attributable fraction for atopy on nasal symptoms on exposure ranged between 12.8% and 65.9% (median 27.2%). Conclusion: In the general population there is a wide variation in the prevalence of nasal allergy in young adults. Many subjects complaining from nasal symptoms on exposure to allergen are not atopic.
Identical Genetic Changes in Different Histologic Components of Wilms' Tumors
Authors: Z. Zhuang, M. J. Merino, A. O. Vortmeyer, B. Bryant, A. E. Lash, C. Wang, M. T. Deavers, W. F. Shelton, S. Kapur, R. S. Chandra
Journal: JNCI Journal of the National Cancer Institute (1997)

In young children and infants, Wilms' tumor is the most common cancer of the kidney. Wilms' tumor exhibits heterogeneous histopathologic features, consisting of rapidly proliferating blastemal and epithelial cells and a stromal component that has heterologous elements (e.g., cartilage, bone, and striated muscle). It is unclear whether the stromal and heterologous components of sporadic Wilms' tumor are neoplastic or should be considered non-neoplastic.Our purpose was twofold: 1) to selectively analyze the different histologic tissue components of sporadic Wilms' tumors, including blastemal, epithelial, stromal, and heterologous elements, for loss of heterozygosity (LOH) of the WT1 gene and for expression of the WT1 gene and 2) to determine the role of WT1 gene expression in the development of these tissues.By use of tissue microdissection techniques, various histologic elements (blastema, stroma, epithelium, and striated muscle) of sporadic Wilms' tumor were obtained from specimens taken from 18 patients. DNA was extracted from the dissected tissue fragments, and DNA solutions were amplified by use of the polymerase chain reaction and the polymorphic genomic markers D11S1392 and D11S904 to detect LOH at the WT1 gene locus (11p13). Three selected specimens with heterologous elements and LOH at 11p13 were analyzed for expression of the WT1 gene by means of the in situ reverse transcription-polymerase chain reaction.Nine (50%) of the 18 specimens showed LOH at the WT1 locus. Although identical WT1 gene deletion was consistently observed in all of the various histologic components of these nine specimens, WT1 gene expression was high in the blastemal and epithelial elements and low in the stromal and heterologous elements.Identical allelic deletion at 11p13 in all components of the sporadic Wilms' tumors examined suggests that the stromal tissue components are neoplastic rather than non-neoplastic. In conjunction with variable WT1 gene expression in the different histologic components, the results raise the possibility that undifferentiated blastemal cells are the precursors of the stromal and heterologous elements. Morphologically benign stromal and heterologous elements may therefore be derived from neoplastic cells. The developmental state of the various tissue components of Wilms' tumor may be attributed to an altered residual WT1 gene that is required for the maturation of blastemal and epithelial cells but that is not required for the maturation of stromal and heterologous elements.
Myocardial Necrosis in Experimental Occlusion of the Portal Vein
Authors: RAUL H. MEJIÍA
Journal: Circulation Research (1960)

Fourteen dogs were subjected to temporary occlusion of the portal vein. Electrocardiographic changes suggestive of epicardial or transmural necrosis of the high lateral region of the left ventricle and of subendocardial ischemia, were found in 55 per cent of the dogs. These electrocardiographic changes were accompanied by a significant rise of plasma GOT. Myocardial sections showed areas of multifocal necrosis, extending from endocardium to epicardium, with predominance in the lateral and anterior wall and pillars of the left ventricle and interventricular septum.
Insulin and Cardiovascular Disease: Paris Prospective Study
Authors: Annick M Fontbonne, Eveline M Eschwège
Journal: Diabetes Care (1991)

The Paris Prospective Study is a long-term investigation of coronary heart disease (CHD) risk factors in a large population of working men. The baseline cohort included 7028 men, 6093 who had a 75-g oral glucose tolerance test with measurement of plasma insulin and glucose levels (0 and 2 h) and 125 who were known non-insulin-treated diabetic patients. After a mean follow-up of 11 yr, 126 deaths ascribed to CHD were reported. Major independent predictors of CHD death were blood pressure, smoking, plasma cholesterol level, and fasting and 2-h postload plasma insulin level. Impairment of glucose tolerance, including overt diabetes, did not rank as an independent predictor when other baseline variables were accounted for. In the subset of the baseline cohort who presented with impaired glucose tolerance or diabetes (n = 943), 26 died from CHD during the follow-up. The strongest independent predictor of subsequent CHD death in this subsample with abnormal glucose tolerance was plasma triglyceride level. In view of the accumulating evidence that hyperinsulinemia and hypertriglyceridemia generally occur in the same type of subjects, in relation to insulin resistance and central obesity, the epidemiological findings of the Paris Prospective Study and of other investigations support the hypothesis that a constellation of mild metabolic abnormalities may play a deleterious role with regard to cardiovascular disease risk.
Identification and Validation of a Blood-Based 18-Gene Expression Signature in Colorectal Cancer
Authors: Ye Xu, Qinghua Xu, Li Yang, Xun Ye, Fang Liu, Fei Wu, Shujuan Ni, Cong Tan, Guoxiang Cai, Xia Meng, Sanjun Cai, Xiang Du
Journal: Clinical Cancer Research (2013)

Abstract Purpose: The early detection of colorectal cancer (CRC) is crucial for successful treatment and patient survival. However, compliance with current screening methods remains poor. This study aimed to identify an accurate blood-based gene expression signature for CRC detection. Experimental Design: Gene expression in peripheral blood samples from 216 patients with CRC tumors and 187 controls was investigated in the study. We first conducted a microarray analysis to select candidate genes that were significantly differentially expressed between patients with cancer and controls. A quantitative reverse transcription PCR assay was then used to evaluate the expression of selected genes. A gene expression signature was identified using a training set (n = 200) and then validated using an independent test set (n = 160). Results: We identified an 18-gene signature that discriminated the patients with CRC from controls with 92% accuracy, 91% sensitivity, and 92% specificity. The signature performance was further validated in the independent test set with 86% accuracy, 84% sensitivity, and 88% specificity. The area under the receiver operating characteristics curve was 0.94. The signature was shown to be enriched in genes related to immune functions. Conclusions: This study identified an 18-gene signature that accurately discriminated patients with CRC from controls in peripheral blood samples. Our results prompt the further development of blood-based gene expression biomarkers for the diagnosis and early detection of CRC. Clin Cancer Res; 19(11); 3039–49. ©2013 AACR.
Circulating Endothelial Cells in Patients with Septic Shock
Authors: MBITHE MUTUNGA, BARBARA FULTON, ROBERT BULLOCK, ANNA BATCHELOR, ALISTER GASCOIGNE, JIM I. GILLESPIE, SIMON V. BAUDOUIN
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

The vascular endothelium has a central role in the control of microvascular tone, and it has been proposed that vascular endothelial damage occurs in septic shock, producing multiorgan failure. We have developed a method of detecting circulating endothelial cells (EC) that provides direct evidence of EC shedding in human sepsis. Human umbilical vein endothelial cells (HUVEC) were seeded in whole blood and recovered by isopycnic centrifugation to validate the technique. Blood samples were subsequently taken from 11 healthy volunteers, nine ventilated intensive care unit (ICU) control patients without sepsis, eight patients with sepsis but without shock, and 15 patients with septic shock. EC were identified by indirect immunofluorescence, using antibodies to von Willebrand factor (vWf) and the vascular endothelial growth factor receptor KDR. Mean HUVEC recovery was 86% for 20 to 100 seeded cells/ml of blood. vWf-positive EC counts per milliliter were significantly higher (analysis of variance [ANOVA], p < 0.0001) in patients with sepsis (16.1 +/- 2.7 [mean +/- SEM]) and septic shock (30.1 +/- 3.3) than in healthy (1.9 +/- 0.5) or ICU controls (2.6 +/- 0.6). KDR-positive EC counts per milliliter were also significantly higher (ANOVA, p < 0.0001) in patients with sepsis (4.2 +/- 1.1/ml) and septic shock (10.4 +/- 1.2/ml) than in healthy (0.7 +/- 0.3/ml) or ICU controls (0.5 +/- 0.2/ml). Cell counts made with anti-vWf antibody were consistently higher than those made with anti KDR antibody, but correlation between the two counts was high (r(2) = 0.93). The number of circulating KDR-positive EC was significantly higher in patients who died of septic shock than in survivors (12.0 +/- 1.6/ml versus 7.1 +/- 1.2/ml, p = 0.026). An increase in circulating EC can be identified during sepsis and septic shock. This supports the hypothesis that endothelial damage occurs in human sepsis.
Variability of within-breath reactance in COPD patients and its association with dyspnoea
Authors: Bernt B. Aarli, Peter M.A. Calverley, Robert L. Jensen, Tomas M.L. Eagan, Per S. Bakke, Jon A. Hardie
Journal: European Respiratory Journal (2014)

The forced oscillation technique can identify expiratory flow limitation (EFL) when a large difference in inspiratory and expiratory reactance (Δ X rs ) occurs. However, flow limitation can vary from breath to breath, and so we compared a multiple-breath Δ X rs approach to the traditional breath-by-breath assessment of EFL. We investigated the within- and between-day reproducibility and the factors that affect the size of Δ X rs when used as a continuous measurement over multiple breaths. In addition, we examined how multiple-breath Δ X rs relates to the sensation of breathlessness. 425 moderate to very severe chronic obstructive pulmonary disease (COPD) patients and 229 controls were included. Spirometry and impedance measurements were performed on a MasterScope CT Impulse Oscillation System. Median Δ X rs approached zero in healthy controls with little variation between measurements. COPD patients generally had higher Δ X rs and higher variability. The COPD patients with Δ X rs &gt;0.1 kPa·L −1 ·s −1 were prone to be more breathless and had a higher modified Medical Research Council dyspnoea scale score. In controls, the 95th percentile of Δ X rs was as low as 0.07 kPa·L −1 ·s −1 . We describe a new method to assess EFL at a patient level and propose a cut-off, mean Δ X rs &gt;0.1 kPa·L −1 ·s −1 , as a way to identify COPD patients who are more likely to report dyspnoea.
LIME, a Novel Transmembrane Adaptor Protein, Associates with p56lck and Mediates T Cell Activation
Authors: Eun Mi Hur, Myoungsun Son, Ok-Hee Lee, Young Bong Choi, Changwon Park, Hyunsook Lee, Yungdae Yun
Journal: The Journal of Experimental Medicine (2003)

In this study, we identify and characterize a novel transmembrane adaptor protein, designated Lck-interacting membrane protein (LIME), as a binding partner of the Lck Src homology (SH)2 domain. LIME possesses a short extracellular domain, a transmembrane domain, and a cytoplasmic tail containing five tyrosine-based motifs. The protein is primarily expressed in hematopoietic cells and lung. Interestingly, LIME expression is up-regulated by TCR stimulation and sustained up to 24 h, suggesting that LIME acts throughout the early to late stages of T cell activation. LIME is localized to membrane rafts and distributed within the T cell–APC contact site. Upon TCR stimulation of Jurkat T cells, LIME associates with Lck as a tyrosine-phosphorylated protein. Experiments using Jurkat T cells expressing CD8–LIME chimera reveal that the protein associates with phosphatidylinositol 3-kinase, Grb2, Gads, and SHP2, and activates ERK1/2 and JNK but not p38. Moreover, overexpression of LIME in Jurkat T cells induces transcriptional activation of the IL-2 promoter. Our data collectively show that LIME is a raft-associated transmembrane adaptor protein linking TCR stimuli to downstream signaling pathways via associations with Lck.
Value of High-Dose Cytarabine During Interval Therapy of a Berlin-Frankfurt-Munster–Based Protocol in Increased-Risk Children With Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma: Results of the European Organization for Research and Treatment of Cancer 58881 Randomized Phase III Trial
Authors: F. Millot, S. Suciu, N. Philippe, Y. Benoit, F. Mazingue, A. Uyttebroeck, P. Lutz, F. Mechinaud, A. Robert, P. Boutard, G. Marguerite, A. Ferster, E. Plouvier, X. Rialland, C. Behard, D. Plantaz, M. F. Dresse, P. Philippet, L. Norton, A. Thyss, N. Dastugue, C. Waterkeyn, E. Vilmer, J. Otten
Journal: Journal of Clinical Oncology (2001)

PURPOSE: The European Organization for Research and Treatment of Cancer 58881 study was designed to test in a prospective multicentric randomized trial the value of high-dose (HD) intravenous (IV) cytarabine (Ara-C) added to HD IV methotrexate (MTX) to reduce the incidence of CNS and systemic relapses in children with increased-risk acute lymphoblastic leukemia (ALL) or stage III and IV lymphoblastic lymphoma treated with a Berlin-Frankfurt-Munster (BFM)–based regimen. PATIENTS AND METHODS: After completion of induction-consolidation phase, children with increased-risk (risk factor &gt; 0.8 or T-lineage) ALL or stage III and IV lymphoblastic lymphoma were randomized to receive four courses of HD MTX (5 g/m 2 over 24 hours every 2 weeks) and four intrathecal administrations of MTX (Arm A) or the same treatment schedule with additional HD IV Ara-C (1 g/m 2 in bolus injection 12 and 24 hours after the start of each MTX infusion) (Arm B). RESULTS: Between January 1990 and January 1996, 653 patients with ALL (593 patients) or lymphoblastic lymphoma (60 patients) were randomized: 323 were assigned to Arm A (without Ara-C) and 330 to Arm B (with Ara-C). A total of 190 events (177 relapses and 13 deaths without relapse) were reported, and the median follow up was 6.5 years (range, 2 to 10 years). The incidence rates of CNS relapse were similar in both arms whether isolated (5.6% and 3.3%, respectively) or combined (5.3% and 4.6%, respectively). The estimated 6-year disease-free survival (DFS) rate was similar (log-rank P = .67) in the two treatment groups: 70.4% (SE = 2.6%) in Arm A and 71.0% (SE = 2.5%) in Arm B. The 6-year DFS rate was similar for ALL and LL patients: 70.2% (SE = 1.9%) versus 76.3% (SE = 5.6%). CONCLUSION: Prevention of CNS relapse was satisfactorily achieved with HD IV MTX and intrathecal injections of MTX in children with increased-risk ALL or stage III and IV lymphoblastic lymphoma treated with our BFM-based treatment protocol in which cranial irradiation was omitted. Disappointingly, with the dose schedule used in this protocol, HD Ara-C added to HD MTX, although well tolerated, failed to further decrease the incidence of CNS relapse or to improve the overall DFS.
Detection of the human endogenous retrovirus ERV3-encoded Env-protein in human tissues using antibody-based proteomics
Authors: Chen Fei, Christina Atterby, Per-Henrik Edqvist, Fredrik Pontén, Wei Wei Zhang, Erik Larsson, Frank P Ryan
Journal: Journal of the Royal Society of Medicine (2013)

Objectives There is growing evidence to suggest that human endogenous retroviruses (HERVs) have contributed to human evolution, being expressed in development, normal physiology and disease. A key difficulty in the scientific evaluation of this potential viral contribution is the accurate demonstration of virally expressed protein in specific human cells and tissues. In this study, we have adopted the endogenous retrovirus, ERV3, as our test model in developing a reliable high-capacity methodology for the expression of such endogenous retrovirus-coded protein. Design Two affinity-purified polyclonal antibodies to ERV3 Env-encoded protein were generated to detect the corresponding protein expression pattern in specific human cells, tissues and organs. Participants Sampling included normal tissues from 144 individuals ranging from childhood to old age. This included more than forty different tissues and organs and some 216 different cancer tissues representing the twenty commonest forms of human cancer. Setting The Rudbeck Laboratory, Uppsala University and Uppsala University Hospital, Uppsala, Sweden. Main Outcome Measures The potential expression at likely physiological level of the ERV3Env encoded protein in a wide range of human cells, tissues and organs. Results We found that ERV3 encoded Env protein is expressed at substantive levels in placenta, testis, adrenal gland, corpus luteum, Fallopian tubes, sebaceous glands, astrocytes, bronchial epithelium and the ducts of the salivary glands. Substantive expression was also seen in a variety of epithelial cells as well as cells known to undergo fusion in inflammation and in normal physiology, including fused macrophages, myocardium and striated muscle. This contrasted strongly with the low levels expressed in other tissues types. These findings suggest that this virus plays a significant role in human physiology and may also play a possible role in disease. Conclusion This technique can now be extended to the study of other HERV genomes within the human chromosomes that may have contributed to human evolution, physiology and disease.