tbuckley/cabot-search huggingface dataset:
Expression of phenotype- and proliferation-related genes in rat aortic smooth muscle cells in primary culture
Authors: A Hultgårdh-Nilsson
Journal: Cardiovascular Research (1997)

Objectives: After endothelial injury, smooth muscle cells (SMCs) in the arterial media are modified from a contractile to a synthetic phenotype. This process includes a prominent structural reorganization and makes the cells able to migrate into the intima, divide, and secrete extracellular matrix components. A similar change occurs in culture and the in vitro system has been established as a useful model in which to study the control of SMC differentiation. The purpose of this study was to analyze the expression of a number of phenotype- and proliferation-related genes in vascular SMCs during the first week in primary culture. Methods: SMCs were enzymatically isolated from rat aorta and seeded on substrates of fibronectin (an adhesive plasma protein) and laminin–collagen type IV (two major basement membrane proteins) in a serum-free medium or in uncoated dishes in a serum-containing medium. Total RNA was isolated from the cells after different times of culture and analyzed by Northern blotting for expression of specific gene transcripts. In part, expression of the corresponding proteins was also explored by Western blotting and indirect immunofluorescence microscopy. Results: The results indicate that the proto-oncogenes c-fos, c-jun and c-ets-1 were already activated during the isolation of the cells and then continued to be strongly expressed for a few days. Especially in the serum-free groups, there was also early activation of the genes for the matrix metalloproteinases, stromelysin (MMP-3) and type IV collagenase (MMP-2). In parallel, an increased expression of the genes for two extracellular matrix components was observed, with an early rise in osteopontin mRNA and a later rise in collagen type I mRNA. At the end of the test period, the corresponding proteins were deposited around the cells in a fibrillar pattern. Among the matrix receptors investigated, the β1 integrin subunit showed a high and persistent expression, whereas the α5 and α1 integrin subunits showed lower and more variable mRNA levels. In support of the existence of an autocrine or paracrine platelet-derived growth factor (PDGF) loop, an early rise in expression of the PDGF A-chain gene and a subsequent rise in expression of the PDGF α-receptor gene were noted. Conclusion: It is proposed that the coordinated shift in gene expression here described to take place in connection with the phenotypic modulation of vascular SMCs in primary culture is part of a predetermined genetic program that normally serves the function to engage the cells in a wound healing response.
<i>BRCA1</i> p.Val1688del Is a Deleterious Mutation That Recurs in Breast and Ovarian Cancer Families From Northeast Italy
Authors: Sandro Malacrida, Simona Agata, Monia Callegaro, Cinzia Casella, Daniela Barana, Maria C. Scaini, Siranoush Manoukian, Cristina Oliani, Paolo Radice, Monica Barile, Chiara Menin, Emma D'Andrea, Marco Montagna
Journal: Journal of Clinical Oncology (2007)

A growing number of sequence changes of unknown clinical significance are being identified in the BRCA1 gene. However, these variants cannot be used for identification and surveillance of at-risk individuals unless their pathogenic role can be demonstrated. The frequency of these variants makes research on this subject a relevant topic in the field of predisposition to breast and ovarian cancers. Herein, we investigate the pathogenicity of the BRCA1 p.Val1688del (c.5181_5183delGTT) variant, which recurs in our population.Recent studies have drawn attention to different strategies that, if considered singly, do not usually provide sufficient power to firmly state for or against causality, thus forcing to a re-evaluation of the literature on each specific variant. To increase the power of our study, we used a recently described strategy that integrates data from multiple independent evidences. By this approach, we analyzed data from the comprehensive study of 12 breast/ovarian cancer families carrying p.Val1688del.We succeeded in integrating five independent evidences of disease causality including segregation, tumor pathology, and evolutionary and epidemiologic data. Under this model, we obtained a final score of 349,000:1 in favor of disease causality. This result largely matches established cutoffs, and thus is readily translatable into a clear clinical message.We show that p.Val1688del is a pathogenic mutation deriving from a common founder. Notably, this study alone increases by 15% the number of BRCA1-positive families in our patients' cohort, thus substantially contributing to explain many of the families wherein prediction of a BRCA1 mutation contrasted with the absence of a molecular recognizable defect.
Enteral human IgG for prevention of necrotising enterocolitis: a placebo-controlled, randomised trial
Authors: Gregor Lawrence, David Tudehope, Kathryn Baumann, Heather Jeffery, Andrew Gill, Michael Cole, John Drew, Andrew McPhee, John Ratcliffe, Graham Reynolds, John Simes, Cheryl Swanson, David Cartwright, Peter Davis, Ian Humphrey, Andrew Berry
Journal: The Lancet (2001)
microRNA Modulation of Circadian-Clock Period and Entrainment
Authors: Hai-Ying M. Cheng, Joseph W. Papp, Olga Varlamova, Heather Dziema, Brandon Russell, John P. Curfman, Takanobu Nakazawa, Kimiko Shimizu, Hitoshi Okamura, Soren Impey, Karl Obrietan
Journal: Neuron (2007)
Panitumumab, a Monoclonal Anti–Epidermal Growth Factor Receptor Antibody in Colorectal Cancer: Another One or the One?
Authors: Wells A. Messersmith, Manuel Hidalgo
Journal: Clinical Cancer Research (2007)

Panitumumab (Vectibix, Amgen, Inc.) is a fully human IgG2 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Panitumumab, formerly called ABX-EGF, was initially developed by Abgenix using the XenoMouse transgenic technology. This methodology is based on inactivating the mouse
Genetic alterations and in vivo tumorigenicity of neurospheres derived from an adult glioblastoma.
Authors: Patrizia Tunici, Lorena Bissola, Elena Lualdi, Bianca Pollo, Laura Cajola, Giovanni Broggi, Gabriella Sozzi, Gaetano Finocchiaro
Journal: Molecular Cancer (2004)

Pediatric brain tumors may originate from cells endowed with neural stem/precursor cell properties, growing in vitro as neurospheres. We have found that these cells can also be present in adult brain tumors and form highly infiltrating gliomas in the brain of immunodeficient mice. Neurospheres were grown from three adult brain tumors and two pediatric gliomas. Differentiation of the neurospheres from one adult glioblastoma decreased nestin expression and increased that of glial and neuronal markers. Loss of heterozygosity of 10q and 9p was present in the original glioblastoma, in the neurospheres and in tumors grown into mice, suggesting that PTEN and CDKN2A alterations are key genetic events in tumor initiating cells with neural precursor properties.
Heat probe thermocoagulation and pure alcohol injection in massive peptic ulcer haemorrhage: a prospective, randomised controlled trial.
Authors: H J Lin, F Y Lee, W M Kang, Y T Tsai, S D Lee, C H Lee
Journal: Gut (1990)

We conducted a prospective randomised controlled trial of 137 patients with massive peptic ulcer haemorrhage over a period of 12 months to compare the haemostatic effects of endoscopic heat probe thermocoagulation and pure alcohol injection. Seventy eight patients (56.9%) were in shock at the time of randomisation to the trial. The age, sex, number of patients in shock, haemoglobin value at the time of entry to the trial, number of patients with severe medical illness, location of bleeders, and stigmata of recent haemorrhage were comparable among the heat probe, pure alcohol, and control groups. The initial haemostatic effect of the heat probe was better than that of the pure alcohol injection (44 of 45 v 31 of 46, p = 0.0004). The ultimate haemostasis achieved by the heat probe group (41 of 45) was better than that of the pure alcohol group (31 of 46, p = 0.012) and of controls (24 of 46, p = 0.0001). The duration of hospital stay was shorter for patients in the heat probe group than for the control group (6.2 days v 13.8 days, p less than 0.05). The incidence of emergency surgery was less for the heat probe than the control group (three of 45 v 12 of 46, p = 0.027). The mortality rate was less in the heat probe than in the control group (one of 45 v seven of 46, p = 0.031). We suggest that heat probe thermocoagulation should be the first treatment of choice for arrest of massive peptic ulcer haemorrhage.
Pancreatic cancer–associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation
Authors: A. Jesse Gore, Samantha L. Deitz, Lakshmi Reddy Palam, Kelly E. Craven, Murray Korc
Journal: Journal of Clinical Investigation (2013)

Pancreatic ductal adenocarcinoma (PDAC) is often associated with overexpression of TGF-β. Given its tumor suppressor functions, it is unclear whether TGF-β is a valid therapeutic target for PDAC. Here, we found that proliferating pancreatic cancer cells (PCCs) from human PDAC patients and multiple murine models of PDAC (mPDAC) often exhibit abundant levels of phosphorylated retinoblastoma 1 (RB) and Smad2. TGF-β1 treatment enhanced proliferation of PCCs isolated from KrasG12D-driven mPDAC that lacked RB (KRC cells). This mitogenic effect was abrogated by pharmacological inhibition of type I TGF-β receptor kinase, combined inhibition of MEK/Src or MEK/PI3K, and restoration of RB expression. TGF-β1 promoted epithelial-to-mesenchymal transition (EMT), invasion, Smad2/3 phosphorylation, Src activation, Wnt reporter activity, and Smad-dependent upregulation of Wnt7b in KRC cells. Importantly, TGF-β1-induced mitogenesis was markedly attenuated by inhibition of Wnt secretion. In an in vivo syngeneic orthotopic model, inhibition of TGF-β signaling suppressed KRC cell proliferation, tumor growth, stroma formation, EMT, metastasis, ascites formation, and Wnt7b expression, and markedly prolonged survival. Together, these data indicate that RB dysfunction converts TGF-β to a mitogen that activates known oncogenic signaling pathways and upregulates Wnt7b, which synergize to promote PCC invasion, survival, and mitogenesis. Furthermore, this study suggests that concomitantly targeting TGF-β and Wnt7b signaling in PDAC may disrupt these aberrant pathways, which warrants further evaluation in preclinical models.
MCP-1 Induces Inflammatory Activation of Human Tubular Epithelial Cells
Authors: Christiane Viedt, Ralph Dechend, Jianwei Fei, Gertrud M. Hänsch, Jörg Kreuzer, Stephan R. Orth
Journal: Journal of the American Society of Nephrology (2002)

Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine synthesized by several cell types, e.g., inflammatory cells, such as monocytes, and resident renal cells, such as human tubular epithelial cells (TECs). Besides induction of monocyte recruitment, MCP-1 has been suggested to induce non-leukocytes to produce cytokines and adhesion molecules. Inflammation of the tubulointerstitium is a hallmark of many renal diseases and contributes to progression of renal failure; the purpose therefore of this study was to investigate the influence of MCP-1 on markers of inflammatory activation in human TECs. MCP-1 stimulated interleukin-6 (IL-6) secretion and intercellular adhesion molecule-1 (ICAM-1) synthesis in a time- and dose-dependent manner. In parallel, MCP-1 increased IL-6 and ICAM-1 mRNA expression in human TECs. Pretreatment with pertussis toxin, GF109203X, BAPTA-AM, and pyrrolidine dithiocarbamate inhibited MCP-1-dependent IL-6 and ICAM-1 synthesis, suggesting the involvement of Gi-proteins, protein kinase C, intracellular Ca(2+), and nuclear factor-kappaB (NF-kappaB) in MCP-1 signaling. Using electrophoretic gel mobility shift assay, we observed that MCP-1 stimulated binding activity of NF-kappaB. Binding activity of the activator protein-1 (AP-1), which has been implicated to regulate induction of the IL-6 gene together with NF-kappaB, was also stimulated by MCP-1. In the present experiments, NF-kappaB and AP-1 were involved in the MCP-1-mediated induction of IL-6, as demonstrated by cis element double-stranded (decoy) oligonucleotides (ODN). In contrast to IL-6 release, MCP-1-induced ICAM-1 expression was predominantly dependent on NF-kappaB activation. These results document for the first time that MCP-1 induces an inflammatory response in human TECs. This may be an important new mechanism in the pathogenesis of tubulointerstitial inflammation.
Comparisons of disparities and risks of HIV infection in black and other men who have sex with men in Canada, UK, and USA: a meta-analysis
Authors: Gregorio A Millett, John L Peterson, Stephen A Flores, Trevor A Hart, William L Jeffries, Patrick A Wilson, Sean B Rourke, Charles M Heilig, Jonathan Elford, Kevin A Fenton, Robert S Remis
Journal: The Lancet (2012)
Expression Evolution Facilitated the Convergent Neofunctionalization of a Sodium Channel Gene
Authors: Ammon Thompson, Derek Vo, Caitlin Comfort, Harold H. Zakon
Journal: Molecular Biology and Evolution (2014)

Ion channels have played a substantial role in the evolution of novel traits across all of the domains of life. A fascinating example of a novel adaptation is the convergent evolution of electric organs in the Mormyroid and Gymnotiform electric fishes. The regulated currents that flow through ion channels directly generate the electrical signals which have evolved in these fish. Here, we investigated how the expression evolution of two sodium channel paralogs (Scn4aa and Scn4ab) influenced their convergent molecular evolution following the teleost-specific whole-genome duplication. We developed a reliable assay to accurately measure the expression stoichiometry of these genes and used this technique to analyze relative expression of the duplicate genes in a phylogenetic context. We found that before a major shift in expression from skeletal muscle and neofunctionalization in the muscle-derived electric organ, Scn4aa was first downregulated in the ancestors of both electric lineages. This indicates that underlying the convergent evolution of this gene, there was a greater propensity toward neofunctionalization due to its decreased expression relative to its paralog Scn4ab. We investigated another derived muscle tissue, the sonic organ of Porichthys notatus, and show that, as in the electric fishes, Scn4aa again shows a radical shift in expression away from the ancestral muscle cells into the evolutionarily novel muscle-derived tissue. This study presents evidence that expression downregulation facilitates neofunctionalization after gene duplication, a pattern that may often set the stage for novel trait evolution after gene duplication.
Randomized study of weekly irinotecan plus high-dose 5-fluorouracil (FUIRI) versus biweekly irinotecan plus 5-fluorouracil/leucovorin (FOLFIRI) as first-line chemotherapy for patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors Study
Authors: E. Aranda, M. Valladares, M. Martinez-Villacampa, M. Benavides, A. Gomez, B. Massutti, E. Marcuello, M. Constenla, J.C. Cámara, A. Carrato, R. Dueñas, M. Reboredo, M. Navarro, E. Díaz-Rubio
Journal: Annals of Oncology (2008)
A global assessment of the oesophageal adenocarcinoma epidemic
Authors: Gustaf Edgren, Hans-Olov Adami, Elisabete Weiderpass, Olof Nyrén
Journal: Gut (2012)

<h3>Objective</h3> About 20 years ago, the scientific community was first alerted to an enigmatic increase of oesophageal adenocarcinomas in the UK and USA. Subsequently, a virtual epidemic—still unexplained—was confirmed in several western countries. Detailed descriptive data might provide clues to its causes. <h3>Design</h3> We collected data on incident cases of oesophageal adenocarcinoma from population-based cancer registries in Australia, Europe, North America and Asia. We calculated age-standardised incidence rates and fitted log-linear Poisson models to assess annual rate of increase and to disentangle age-period-cohort effects, linear spine models to estimate rate of increase since 1985, and Joinpoint models to identify possible inflection points. <h3>Results</h3> With considerable between-registry variation in magnitude and timing, we found a consistent dramatic increase in incidence with an observed or estimated start between 1960 and 1990. The average annual increase ranged from 3.5% in Scotland to 8.1% in Hawaii with similar proportional increase among men and women in most registries and a maintained three to sixfold higher incidence among men. Generally, calendar period was a more important determinant of incidence trends than birth cohort. Where possible to conduct, Joinpoint analyses indicated that the onset of the epidemic varied considerably even between neighbouring countries. <h3>Conclusions</h3> Given the preponderant period effect and the abrupt onset observed or inferred in most populations, the epidemic appears to be caused by some exposure that was first introduced around 1950. At least 30 years9 variation in estimated time of onset opens prospects for hypothesis-generating ecological analyses.
Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial
Authors: M K B Parmar, J A Ledermann, N Colombo, A du Bois, J-F Delaloye, G B Kristensen, S Wheeler, A M Swart, W Qian, V Torri, I Floriani, G Jayson, A Lamont, C Tropé
Journal: The Lancet (2003)
DIFFERENT MECHANISMS OF TUMOR GROWTH INHIBITION BY BLOCKADE OF IGF-IR IN U87-INDUCED AND STEM-LIKE CELL-INDUCED GLIOBLASTOMAS
Authors: M. Westphal, M. Zamykal, T. Martens, K. Lamszus
Journal: Neuro-Oncology (2014)

BACKGROUND: Insulin-like growth factor receptor I (IGF-IR) signaling can contribute to the formation, maintenance, and/or progression of many diverse tumor types, including glioblastomas. We investigated the effect of an IGF-IR blocking antibody (IMC-A12) on tumors derived either from U87 cells or from glioblastoma stem-like (GS) cells in vitro and in vivo. METHODS: Two different xenograft models were established in nude mice. U87 cells were used to generate solid tumors, and the glioblastoma stem-like cell line GS-12 was used to generate diffusely invasive tumors. In both models, IMC-A12 was administered intratumorally via osmotic mini-pumps with catheters for 3-4 weeks. Tumor size, proliferation, apoptosis and angiogenesis were evaluated histologically and immunohistochemically. Receptor expression and activation were analyzed by flow cytometry and immunoprecipitation. Proliferation, apoptosis and migration were studied in vitro. RESULTS: Growth of U87 and of GS-12 tumors was inhibited by 75% and by 50%, respectively. In the solid, non-invasively growing U87 tumors, the intratumoral blood vessel density was reduced significantly, whereas the tumor cell proliferation and apoptosis rates did not differ from controls. In contrast, in the highly invasive GS-12 model, IMC-A12 treatment had no effect on tumor neovascularization, while the proportion of proliferating cells was decreased by 30% compared to controls. We therefore hypothesized that IMC-A12 interfered directly with the stem-like GS-12 glioblastoma cells but not with U87 cells. FACS analyses revealed that only 6% of U87 cells expressed IGF-IR, whereas 87% of GS-12 cells expressed the receptor. IGF-I and IGF-II-induced receptor activation was blocked by IMC-A12 in vitro, and the antibody reduced proliferation of GS-12 cells by 40% and migration by 27%. In contrast, IMC-A12 had no effect on the proliferation or migration of U87 cells. CONCLUSIONS: IGF-IR blockade can inhibit glioblastoma growth in vivo by different mechanisms. In the highly invasive GS-12 model it inhibits proliferation and migration directly. In contrast, in highly angiogenic tumors derived from U87 cells, which barely express IGF-IR, it acts by blocking neovascularization. These findings suggest that the IGF-IR signaling pathway might be useful to target both the highly proliferative angiogenesis-dependent solid tumor component as well as the non-angiogenic infiltrative tumors cells at the invasive edge in glioblastomas. SECONDARY CATEGORY: Tumor Biology.
Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial
Authors: Edwin DeJesus, Jürgen K Rockstroh, Keith Henry, Jean-Michel Molina, Joseph Gathe, Srinivasan Ramanathan, Xuelian Wei, Kitty Yale, Javier Szwarcberg, Kirsten White, Andrew K Cheng, Brian P Kearney
Journal: The Lancet (2012)
Expression of Connective Tissue Growth Factor in Human Renal Fibroblasts
Authors: JULIANE HEUSINGER-RIBEIRO, MICHAEL EBERLEIN, NADIA ABDEL WAHAB, MARGARETE GOPPELT-STRUEBE
Journal: Journal of the American Society of Nephrology (2001)

The induction of connective tissue growth factor (CTGF) was investigated in a human renal fibroblast cell line that exhibited many characteristics of primary human renal fibroblasts. Induction of CTGF mRNA was observed after treatment of the cells with transforming growth factor-beta (TGF-beta) or, even more prominently, lysophosphatidic acid (LPA). LPA induced a rapid transient increase in CTGF mRNA expression, with maximal levels being observed after 1 to 2 h. This increase was accompanied by CTGF protein synthesis. Induction of CTGF was insensitive to pertussis toxin and was not dependent on the activation of p42/44 mitogen-activated protein kinases. Inhibition of the proteins of the Rho family with toxin B from Clostridium difficile abrogated basal and LPA-mediated induction of CTGF. Specific targeting of RhoA with C3 exotoxin or of the Rho kinases with the inhibitor Y-27632 similarly prevented induction of CTGF, implicating RhoA as a signaling module downstream of LPA. Inhibition of RhoA depolymerized the actin cytoskeleton, as did treatment with cytochalasin D. Preincubation of the human renal fibroblasts with cytochalasin D prevented induction of CTGF by LPA, indicating a strong contribution of an intact cytoskeleton. Interference with RhoA signaling similarly inhibited the induction of CTGF by TGF-beta. Elevation of intracellular levels of cAMP and thus activation of protein kinase A prevented induction of CTGF expression. The cytoskeletal effects of cAMP, however, were reversed by LPA. These data indicate complex interactions involving LPA-mediated activation of RhoA- and protein kinase A-dependent signaling pathways. The data thus demonstrate the regulatory functions of the small GTPase RhoA and of an intact cytoskeleton in the expression of CTGF after stimulation with LPA or TGF-beta. Analogous signal transduction pathways were previously demonstrated in rat mesangial cells, suggesting a more general role for RhoA in the regulation of CTGF expression.
Seat belts in pregnancy.
Authors: J. M. Pearce
Journal: BMJ (1992)

Proportion of general practitioners indicating their wish for information in discharge letters conceming various aspects of their patients' attendance at accident and emergency departments No (%) of practitioners requiring information on aspect Aspect of attendance (n= 213) Mode of referral 194 (91) General practitioner diagnosis (prior to referral) 134 (63) Clinical findings in accident and emergency*: All positive findings 115 (54) All negative findings 57 (27) Only relevant findings 109 (51) Results of investigations in accident and emergency: Haematology 187 (88) Biochemistry 183 (86) x Ray 191 (90) Diagnosis in accident and emergency 208 (98) Treatment in accident and emergency 202 (95) Outcome (admit or discharge) 203 (95) Treatment suggested for general practitioner 192 (90) Follow up arrangements 200 (94) Information given to patient 175 (82) Information to general practitioner**: On all patients 160 (75) Only those sent home 53 (25)*Actual question: Would you like to know all positive findings?all negative findings?only "relevant" findings?other (please specify)?Some respondents replied to more than one category.