tbuckley/cabot-search huggingface dataset:
Plasma Concentrations and Genetic Variation of Matrix Metalloproteinase 9 and Prognosis of Patients With Cardiovascular Disease
Authors: Stefan Blankenberg, Hans J. Rupprecht, Odette Poirier, Christoph Bickel, Marek Smieja, Gerd Hafner, Jürgen Meyer, François Cambien, Laurence Tiret
Journal: Circulation (2003)

Matrix metalloproteinase (MMP)-9 secretion by macrophages and other inflammatory cells accelerates atherosclerotic progression and destabilizes vulnerable plaque in animal models. However, epidemiological data evaluating the prognostic impact of circulating concentrations and functional genetic variations of MMP-9 are lacking.In a prospective study of 1127 patients with documented coronary artery disease, we measured baseline plasma MMP-9 levels and determined the MMP-9/C-1562T and MMP-9/R279Q genotypes. During the follow-up period (mean of 4.1 years), 97 patients died from cardiovascular (CV) causes. Median concentrations of MMP-9 were significantly higher among patients who experienced a fatal CV event than among those who did not (62.2 versus 47.8 ng/mL; P<0.0001). The crude hazard risk ratio of CV death associated with increasing quartiles of MMP-9 was 1.4 (95% CI, 1.2 to 1.8; P<0.0001), and after adjustment for clinical and therapeutic confounders, it was 1.3 (95% CI, 1.1 to 1.6; P=0.005). Additional adjustment for highly sensitive CRP, interleukin-6, fibrinogen, and interleukin-18 revealed a hazard risk ratio to 1.2 (95% CI, 0.9 to 1.6; P=0.15). The T allele of the C-1562T polymorphism was associated with increased MMP-9 levels in a fairly codominant fashion (P=0.004). Although none of the polymorphisms was significantly related with future CV death, there was a significant association (P=0.02) between the R279Q polymorphism and CV events in patients with stable angina.Plasma MMP-9 concentration was identified as a novel predictor of CV mortality in patients with coronary artery disease. Whether it provides independent prognostic information compared with other inflammatory markers will have to be additionally assessed.
Long‐term follow‐up in optimally treated and stable heart failure patients: primary care vs. heart failure clinic. Results of the <scp>COACH</scp>‐2 study
Authors: Marie Louise A. Luttik, Tiny Jaarsma, Peter Paul van Geel, Maaike Brons, Hans L. Hillege, Arno W. Hoes, Richard de Jong, Gerard Linssen, Dirk J.A. Lok, Marjolein Berge, Dirk J. van Veldhuisen
Journal: European Journal of Heart Failure (2014)
Pulmonary infiltrates and adult acute leukaemia: empirical treatment and survival related to the extent of pulmonary radiological disease.
Authors: A G Wardman, D W Milligan, J A Child, I W Delamore, N J Cooke
Journal: Thorax (1984)

In a retrospective review of 141 consecutive adult patients with acute leukaemia there were 33 local and eight diffuse parenchymal pulmonary abnormalities noted on the first abnormal chest radiograph. Empirical treatment was given without any invasive diagnostic procedures. Twenty of the 41 patients (49%) with radiographic abnormalities died--10 of 31 patients (32%) in the "local" group (excluding two who were not actively treated) and all eight patients in the "diffuse" group. One patient in the local group and six in the diffuse group died within 48 hours of the first abnormal chest radiograph. The results in the local group suggest that failure to respond to the initial treatment prescribed would allow time to perform an invasive procedure in most patients that may lead to a change in management. In the diffuse group, however, an early invasive procedure would be required if the result were to have a chance to influence the outcome.
Stoichiometry of the murine γδ T cell receptor
Authors: Sandra M. Hayes, Paul E. Love
Journal: The Journal of Experimental Medicine (2006)

The T cell receptor for antigen (TCR) complex is organized into two functional domains: the antigen-binding clonotypic heterodimer and the signal-transducing invariant CD3 and TCRζ chains. In most vertebrates, there are two different clonotypic heterodimers (TCRαβ and TCRγδ) that define the αβ and γδ T cell lineages, respectively. αβ- and γδTCRs also differ in their invariant chain subunit composition, in that αβTCRs contain CD3γε and CD3δε dimers, whereas γδTCRs contain only CD3γε dimers. This difference in subunit composition of the αβ- and γδTCRs raises the question of whether the stoichiometries of these receptor complexes are different. As the stoichiometry of the murine γδTCR has not been previously investigated, we used two quantitative immunofluorescent approaches to determine the valency of TCRγδ heterodimers and CD3γε dimers in surface murine γδTCR complexes. Our results support a model of murine γδTCR stoichiometry in which there are two CD3γε dimers for every TCRγδ heterodimer.
Inhibition of tumor growth by DT-A expressed under the control of IGF2 P3 and P4 promoter sequences
Authors: B Ayesh, I Matouk, P Ohana, M.A Sughayer, T Birman, S Ayesh, T Schneider, N de Groot, A Hochberg
Journal: Molecular Therapy (2003)

The human IGF2 P3 and P4 promoters are highly active in a variety of human cancers. We here present an approach for patient oriented therapy of TCC bladder carcinoma by driving the diphtheria toxin A-chain (DT-A) expression under the control of the IGF2 P3 and P4 promoter regulatory sequences. High levels of IGF2 mRNA expression from P3, P4 or both promoters were detected in 18 TCC samples (n = 29) by ISH or RT-PCR. Normal bladder samples (n = 4) showed no expression from either promoter. The activity and specificity of the IGF2 P3 and P4 regulatory sequences were established in human carcinoma cell lines by means of luciferase reporter gene assay. These sequences were used to design DT-A expressing, therapeutic vectors (P3-DT-A and P4-DT-A). The activity of both was determined in cell lines (in vitro) and the activity of P3-DT-A was determined in a heterotopic animal model (in vivo). The treated cell lines highly responded to the treatment in a dose-response manner, and the growth rate of the developed tumors in vivo was highly inhibited (70%) after intratumoraly injection with P3-DT-A compared to non-treated tumors (P < 0.0002) or tumors treated by luciferase gene expressing LucP3 vector (P < 0.002).
Induction of gastric epithelial apoptosis by Helicobacter pylori.
Authors: S F Moss, J Calam, B Agarwal, S Wang, P R Holt
Journal: Gut (1996)

Helicobacter pylori may promote gastric carcinogenesis through increasing gastric epithelial cell proliferation. How H pylori does so is unknown. Programmed, non-necrotic, cell death (apoptosis) occurs throughout the gut and is linked to proliferation. It was hypothesised that H pylori may induce hyper-proliferation through increasing apoptosis.To measure the effect of H pylori infection on gastric epithelial apoptosis in situ.Patients with duodenal ulcers treated to eradicate H pylori and patients with H pylori negative non-ulcer dyspepsia.Retrospective quantification of apoptotic epithelial cells in situ from formalin fixed biopsy specimens, counted after staining by terminal uridine deoxynucleotidyl nick end-labelling.In the uninfected stomach, apoptotic cells were rare and situated in the most superficial portion of gastric glands (mean 2.9% of epithelial cells). In H pylori infection, they were more numerous and were located throughout the depth of gastric glands, comprising 16.8% of epithelial cells, falling to 3.1% after H pylori eradication, p = 0.017. Apoptotic cell number did not correlate with the degree of histological gastritis.These results suggest that H pylori induces epithelial apoptosis in vivo. Increased apoptosis may be the stimulus for a compensatory hyperproliferative and potentially preneoplastic response in chronic H pylori infection.
Identification of Smyd4 as a Potential Tumor Suppressor Gene Involved in Breast Cancer Development
Authors: Liping Hu, Yiwei Tony Zhu, Chao Qi, Yi-Jun Zhu
Journal: Cancer Research (2009)

To identify genes involved in breast tumorigenesis, we applied the retroviral LoxP-Cre system to a nontumorigenic mouse mammary epithelial cell line NOG8 to create random chromosome deletion/translocation. We found that the disruption of one allele of Smyd4 (SET and MYND domain containing 4) gene through chromosome translocation led to tumorigenesis. The expression of Smyd4 was markedly decreased in tumor cells. Re-expression of Smyd4 resulted in growth suppression of tumor cells and inhibition of tumor formation in nude mice. Furthermore, the RNA interference-mediated suppression of Smyd4 expression in human MCF10A mammary epithelial cells caused their growth in soft agar. Microarray studies revealed that platelet-derived growth factor receptor alpha polypeptide (Pdgfr-alpha) was highly expressed in tumor cells compared with NOG8 cells. Re-expression of Smyd4 significantly reduced the expression of Pdgfr-alpha in tumor cells. In human breast cancers, reverse transcription-PCR results revealed that Smyd4 expression was totally silenced in 2 of 10 specimens. These findings indicate that Smyd4, as a potential tumor suppressor, plays a critical role in breast carcinogenesis at least partly through inhibiting the expression of Pdgfr-alpha, and could be a novel target for improving treatment of breast cancer.
Involvements of Rho-Kinase and TGF-β Pathways in Aldosterone-Induced Renal Injury
Authors: Guang-Ping Sun, Masakazu Kohno, Peng Guo, Yukiko Nagai, Kayoko Miyata, Yu-Yan Fan, Shoji Kimura, Hideyasu Kiyomoto, Koji Ohmori, De-Tian Li, Youichi Abe, Akira Nishiyama
Journal: Journal of the American Society of Nephrology (2006)

Recent studies have suggested a role for aldosterone in the pathogenesis of renal injury. This study investigated the potential contributions of Rho-kinase and TGF-beta pathways to aldosterone-induced renal injury. Rats were uninephrectomized and then treated for 5 wk with 1% NaCl in a drinking solution and one of the following: Vehicle (2% ethanol, subcutaneously; n = 9); aldosterone (0.75 microg/h, subcutaneously; n = 9); or aldosterone + fasudil, a specific Rho-kinase inhibitor (10 mg/kg per d, subcutaneously; n = 8). Phosphorylation of myosin phosphate target subunit-1 (MYPT1) and Smad2/3 in renal cortical tissue was measured by Western blotting with anti-phospho MYPT1 and Smad2/3 antibodies, respectively. Rats that received aldosterone infusion exhibited hypertension and severe renal injury characterized by proteinuria, glomerular sclerosis, and tubulointerstitial fibrosis with increases in alpha-smooth muscle actin staining and numbers of monocytes/macrophages in the interstitium. Renal cortical mRNA levels of types I and III collagen, TGF-beta, connective tissue growth factor, and monocyte chemoattractant protein-1 as well as Smad2/3 phosphorylation were significantly increased in rats that received aldosterone infusion. All of these changes were associated with an increase in renal tissue MYPT1 phosphorylation. Treatment with fasudil did not alter BP but significantly ameliorated proteinuria and renal injury in rats that received aldosterone infusion. Furthermore, fasudil prevented MYPT1 phosphorylation and markedly decreased alpha-smooth muscle actin staining, numbers of monocytes/macrophages, mRNA levels of types I and III collagen, TGF-beta, connective tissue growth factor and monocyte chemoattractant protein-1, and Smad2/3 activity in renal cortical tissues. These results provide evidence, for the first time, that Rho-kinase is substantially involved in aldosterone-induced renal injury through activation of a TGF-beta-dependent pathway.
Role of chain pairing for the production of functional soluble IA major histocompatibility complex class II molecules.
Authors: C A Scott, K C Garcia, F R Carbone, I A Wilson, L Teyton
Journal: The Journal of Experimental Medicine (1996)

Structural studies of cellular receptor molecules involved in immune recognition require the production of large quantities of the extracellular domains of these glycoproteins. The murine major histocompatibility complex (MHC) class II-restricted response has been extensively studied by functional means, but the engineering and purification of the native, empty form of the most-studied murine MHC class II molecule, IA, has been difficult to achieve. IA molecules, which are the murine equivalent of human histocompatibility leukocyte antigen-DQ molecules, have a low efficiency of chain pairing, which results in poor transport to the cell surface and in the appearance of mixed isotype pairs. We have engineered soluble IA molecules whose pairing has been forced by the addition of leucine zipper peptide dimers at their COOH-terminus. The molecules are secreted "empty" into the extracellular medium and can be loaded with single peptide after purification. These IA molecules have been expressed in milligram quantity for crystallization as well as for activation of T cells and measurement of MHC class II-T cell receptor interactions.
Ibrutinib Exerts Potent Antifibrotic and Antitumor Activities in Mouse Models of Pancreatic Adenocarcinoma
Authors: Daniel Massó-Vallés, Toni Jauset, Erika Serrano, Nicole M. Sodir, Kim Pedersen, Nesrine I. Affara, Jonathan R. Whitfield, Marie-Eve Beaulieu, Gerard I. Evan, Laurence Elias, Joaquín Arribas, Laura Soucek
Journal: Cancer Research (2015)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense stromal fibroinflammatory reaction that is a major obstacle to effective therapy. The desmoplastic stroma comprises many inflammatory cells, in particular mast cells as key components of the PDAC microenvironment, and such infiltration correlates with poor patient outcome. Indeed, it has been hypothesized that stromal ablation is critical to improve clinical response in patients with PDAC. Ibrutinib is a clinically approved Bruton's tyrosine kinase inhibitor that inhibits mast cells and tumor progression in a mouse model of β-cell tumorigenesis. Here, we show that ibrutinib is highly effective at limiting the growth of PDAC in both transgenic mouse and patient-derived xenograft models of the disease. In these various experimental settings, ibrutinib effectively diminished fibrosis, extended survival, and improved the response to clinical standard-of-care therapy. Our results offer a preclinical rationale to immediately evaluate the clinical efficacy of ibrutinib in patients with PDAC. Cancer Res; 75(8); 1675–81. ©2015 AACR.
Polycystic ovary syndrome and cancer
Authors: A. Balen
Journal: Human Reproduction Update (2001)

The polycystic ovary syndrome (PCOS) is the most common endocrine disturbance affecting women, but disagreements in diagnostic criteria make it difficult to compare epidemiological studies on long-term health risks such as cancer. The association between PCOS and endometrial adenocarcinoma has been reported for many years. Although the degree of risk has not been clearly defined, it is generally accepted that for women with PCOS who experience symptoms of amenorrhoea or oligomenorrhoea, the induction of artificial withdrawal bleeds to prevent endometrial hyperplasia is prudent management. Studies examining the relationship between PCOS and breast carcinoma have not always identified a significantly increased risk, although one recent study examined the standardized mortality rate (SMR) calculated for patients with PCOS compared with the normal population and found that the SMR for all neoplasms was 0.91 (95% CI 0.60–1.32) and for breast cancer 1.48 (95% CI 0.79–2.54). Few studies have addressed the possibility of an association between polycystic ovaries and ovarian cancer, and the results are conflicting and generally reassuring.
A Novel Mechanism for Integrin-Mediated Ras Activation in Breast Carcinoma Cells: The α6β4 Integrin Regulates ErbB2 Translation and Transactivates Epidermal Growth Factor Receptor/ErbB2 Signaling
Authors: Sang-Oh Yoon, Sejeong Shin, Elizabeth A. Lipscomb
Journal: Cancer Research (2006)

Abstract ErbB2 (HER2, Neu) and Ras play key roles in tumor invasion and metastasis. We identified a novel mechanism by which integrin α6β4 regulates ErbB2 expression, Ras activation, and the invasion of breast carcinoma cells. Here we show that integrin α6β4 regulates Ras activity especially in serum-depleted condition. Down-regulation of β4 integrin by β4 short hairpin RNA (shRNA) decreased Ras activity and carcinoma invasion whereas reexpression of this integrin restored Ras activity. ErbB2, a binding partner of epidermal growth factor receptor (EGFR), and EGFR modulated Ras activity, and integrin α6β4 regulated phospho-EGFR level without affecting EGFR expression. We also found that integrin α6β4 is involved in ErbB2 expression. Depletion of β4 by shRNA reduced ErbB2 protein level without affecting ErbB2 mRNA level and reexpression of β4 increased ErbB2 protein level. Reduction of eukaryotic initiation factor 4E, a rate-limiting factor for cap-dependent translation, decreased ErbB2 protein level, and β4 shRNA cells exhibited a shift in ErbB2 mRNA to light polysomes compared with control cells. These results show that integrin α6β4 regulates ErbB2 through translational control. In summary, we propose a novel mechanism for ErbB2 up-regulation and Ras activation in serum-depleted breast cancer cells; integrin α6β4 regulates the expression of ErbB2 and the subsequent phosphorylation of EGFR and activation of Ras. These findings provide a mechanism that substantiates the reported role of α6β4 in carcinoma invasion. (Cancer Res 2006; 66(5): 2732-9)
Effectiveness of antiplatelet drugs against experimental non-alcoholic fatty liver disease
Authors: K Fujita, Y Nozaki, K Wada, M Yoneda, H Endo, H Takahashi, T Iwasaki, M Inamori, Y Abe, N Kobayashi, H Kirikoshi, K Kubota, S Saito, Y Nagashima, A Nakajima
Journal: Gut (2008)

<h3>Objective:</h3> No effective drugs have been developed to date to prevent or treat non-alcoholic fatty liver disease (NAFLD), although diet modification and exercise to improve obesity have been attempted. Therefore, development of a novel drug/strategy to treat NAFLD is urgently needed. In the present study, a novel concept is proposed for the treatment of NAFLD. <h3>Methods:</h3> Fisher 344 male rats were given a choline-deficient, l-amino acid-defined (CDAA) diet or a high-fat high-calorie (HF/HC) diet with or without the antiplatelet agents, aspirin, ticlopidine or cilostazol for 16 weeks. Liver steatosis, inflammation and fibrosis, and the possible mechanisms involved were investigated. <h3>Results:</h3> All three antiplatelet drugs, namely aspirin, ticlopidine and cilostazol, significantly attenuated liver steatosis, inflammation and fibrosis in the CDAA diet group. Of the three agents, cilostazol was the most effective, and the drug also suppressed HF/HC diet-induced liver steatosis. Cilostazol appeared to exert its beneficial effect against NAFLD by suppressing mitogen-activated protein kinase activation induced by oxidative stress and platelet-derived growth factor via intercepting signal transduction from Akt to c-Raf. <h3>Conclusion:</h3> Antiplatelet agents, especially cilostazol, offer the promise of becoming key agents for the treatment of NAFLD.
The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells
Authors: Suzanne Trudel, A. Keith Stewart, Eran Rom, Ellen Wei, Zhi Hua Li, Sarit Kotzer, Irina Chumakov, Yossi Singer, Hong Chang, Sheng-Ben Liang, Avner Yayon
Journal: Blood (2006)
Reduced Levels of IGF-I Mediate Differential Protection of Normal and Cancer Cells in Response to Fasting and Improve Chemotherapeutic Index
Authors: Changhan Lee, Fernando M. Safdie, Lizzia Raffaghello, Min Wei, Federica Madia, Edoardo Parrella, David Hwang, Pinchas Cohen, Giovanna Bianchi, Valter D. Longo
Journal: Cancer Research (2010)

Abstract Inhibitors of the insulin-like growth factor-I (IGF-I) receptor have been widely studied for their ability to enhance the killing of a variety of malignant cells, but whether IGF-I signaling differentially protects the host and cancer cells against chemotherapy is unknown. Starvation can protect mice, but not cancer cells, against high-dose chemotherapy [differential stress resistance (DSR)]. Here, we offer evidence that IGF-I reduction mediates part of the starvation-dependent DSR. A 72-hour fast in mice reduced circulating IGF-I by 70% and increased the level of the IGF-I inhibitor IGFBP-1 by 11-fold. LID mice, with a 70% to 80% reduction in circulating IGF-I levels, were protected against three of four chemotherapy drugs tested. Restoration of IGF-I was sufficient to reverse the protective effect of fasting. Sixty percent of melanoma-bearing LID mice treated with doxorubicin achieved long-term survival whereas all control mice died of either metastases or chemotherapy toxicity. Reducing IGF-I/IGF-I signaling protected primary glia, but not glioma cells, against cyclophosphamide and protected mouse embryonic fibroblasts against doxorubicin. Further, S. cerevisiae lacking homologs of IGF-I signaling proteins were protected against chemotherapy-dependent DNA damage in a manner that could be reversed by expressing a constitutively active form of Ras. We conclude that normal cells and mice can be protected against chemotherapy-dependent damage by reducing circulating IGF-I levels and by a mechanism that involves downregulation of proto-oncogene signals. Cancer Res; 70(4); 1564–72
Clinician-friendly lower extremity physical performance tests in athletes: a systematic review of measurement properties and correlation with injury. Part 2—the tests for the hip, thigh, foot and ankle including the star excursion balance test
Authors: Eric J Hegedus, Suzanne M McDonough, Chris Bleakley, David Baxter, Chad E Cook
Journal: British Journal of Sports Medicine (2015)

To review the quality of literature and measurement properties of physical performance tests (PPTs) of the lower extremity in athletes.Using the PICOS method we established our research question as to whether individual PPTs of the lower extremity have any relationship to injury in competitive athletes ages 12 years to adult (no limit). A search strategy was constructed by combining the terms 'lower extremity' and synonyms for 'performance test' and names of performance tests with variants of the term 'athlete'. After examining the knee in part 1 of this 2 part series, the current report focuses on findings in the rest of the lower extremity. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed and the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist was used to critique the methodological quality of each paper. A second measure was used to analyse the quality of the measurement properties of each test.Thirty-one articles examined the measurement properties of 14 PPTs pertaining to the lower extremity. The terminology used to name and describe the tests and methodology by which the tests were conducted was inconsistent. The star excursion balance test performed in three directions (anterior, posteromedial, and posterolateral) appears to be the only test to be associated with increased injury risk. There is moderate evidence that the one leg hop for distance and the hexagon hop can distinguish between normal and unstable ankles. There is also moderate evidence that the medial hop can distinguish between painful and normal hips in dancers.Currently, there is relatively limited research-backed information on PPTs of the lower extremity in athletes. We would suggest convening an international consortium comprised of experts in sports to standardise the descriptions and methodologies, and to set forth a research agenda to establish definitively the measurement properties of the most common PPTs.