tbuckley/cabot-search huggingface dataset:
An MDM2 antagonist (MI-319) restores p53 functions and increases the life span of orally treated follicular lymphoma bearing animals
Authors: Ramzi M Mohammad, Jack Wu, Asfar S Azmi, Amro Aboukameel, Angela Sosin, Sherwin Wu, Dajun Yang, Shaomeng Wang, Ayad M Al-Katib
Journal: Molecular Cancer (2009)

MI-319 is a synthetic small molecule designed to target the MDM2-P53 interaction. It is closely related to MDM2 antagonists MI-219 and Nutlin-3 in terms of the expected working mechanisms. The purpose of this study was to evaluate anti-lymphoma activity of MI-319 in WSU-FSCCL, a B-cell follicular lymphoma line. For comparison purpose, MI-319, MI-219 and Nutlin-3 were assessed side by side against FSCCL and three other B-cell hematological tumor cell lines in growth inhibition and gene expression profiling experiments. MI-319 was shown to bind to MDM2 protein with an affinity slightly higher than that of MI-219 and Nutlin-3. Nevertheless, cell growth inhibition and gene expression profiling experiments revealed that the three compounds have quite similar potency against the tumor cell lines tested in this study. In vitro, MI-319 exhibited the strongest anti-proliferation activity against FSCCL and four patient cells, which all have wild-type p53. Data obtained from Western blotting, cell cycle and apoptosis analysis experiments indicated that FSCCL exhibited strong cell cycle arrest and significant apoptotic cell death; cells with mutant p53 did not show significant apoptotic cell death with drug concentrations up to 10 μM, but displayed weaker and differential cell cycle responses. In our systemic mouse model for FSCCL, MI-319 was tolerated well by the animals, displayed effectiveness against FSCCL-lymphoma cells in blood, brain and bone marrow, and achieved significant therapeutic impact (p < 0.0001) by conferring the treatment group a > 28% (%ILS, 14.4 days) increase in median survival days. Overall, MI-319 probably has an anti-lymphoma potency equal to that of MI-219 and Nutlin-3. It is a potent agent against FSCCL in vitro and in vivo and holds the promises to be developed further for the treatment of follicular lymphoma that retains wild-type p53.
Effect of Cell-Based Intercellular Delivery of Transcription Factor GATA4 on Ischemic Cardiomyopathy
Authors: Jing Bian, Zoran B. Popović, Carlos Benejam, Matthew Kiedrowski, L. Leonardo Rodriguez, Marc S. Penn
Journal: Circulation Research (2007)

Recent loss-of-function studies highlight the importance of the transcription factor GATA4 in the myocardial response to injury in the adult heart. However, the potential effects of gain-in-function of GATA4 overexpression, and transcription factors in general, is hindered by the fact that transcription factors are neither secreted nor taken up by cells. Chimeric proteins incorporating motifs of cell-penetrating proteins are secreted from cells and internalized by surrounding cells. We engineered a chimeric protein consisting of GATA4 and the cell-penetrating protein VP22. Cardiac fibroblasts stably transfected with the GATA4:VP22, GFP:VP22, or green fluorescent protein (GFP) constructs were transplanted into Lewis rats 1 month after left anterior descending ligation. GATA4:VP22 expression in the border zone was associated with increased cardiac myosin expression and cardiac myocyte size (30 mum versus 19 mum, P<0.01). Compared with the GFP:VP22 control group, 6 weeks after cardiac fibroblast transplantation (10 weeks after myocardial infarction), animals that received GATA4:VP22-expressing cardiac fibroblasts demonstrated increased cardiac function and less negative remodeling. These data demonstrate a novel strategy for transcription factor delivery to injured myocardium and indicate that the delivery of GATA4 locally to the infarct border zone induces multiple local effects in the border zone cardiac myocytes resulting in beneficial ventricular remodeling and improved global left ventricular function.
Endothelial progenitor cells give rise to pro-angiogenic smooth muscle-like progeny
Authors: Jan-Renier A.J. Moonen, Guido Krenning, Marja G.L. Brinker, Jasper A. Koerts, Marja J.A. van Luyn, Martin C. Harmsen
Journal: Cardiovascular Research (2010)

Reciprocal plasticity exists between endothelial and mesenchymal lineages. For instance, mature endothelial cells adopt a smooth muscle-like phenotype through transforming growth factor beta-1 (TGFβ1)-driven endothelial-to-mesenchymal transdifferentiation (EndMT). Peripheral blood contains circulating endothelial progenitor cells of which the endothelial colony-forming cells (ECFCs) harbour stem cell-like properties. Given the plasticity between endothelial and mesenchymal lineages and the stem cell-like properties of ECFCs, we hypothesized that ECFCs can give rise to smooth muscle-like progeny. ECFCs were stimulated with TGFβ1, after which TGFβ signalling cascades and their downstream effects were investigated. Indeed, EndMT of ECFCs resulted in smooth muscle-like progeniture. TGFβ1-driven EndMT is mediated by ALK5 kinase activity, increased downstream Smad2 signalling, and reduced protein levels of inhibitor of DNA-binding protein 3. ECFCs lost expression of endothelial markers and endothelial anti-thrombogenic function. Simultaneously, mesenchymal marker expression was gained, cytoskeletal rearrangements occurred, and cells acquired a contractile phenotype. Transdifferentiated ECFCs were phenotypically stable and self-sustaining and, importantly, showed fibroblast growth factor-2 and angiopoietin-1-mediated pro-angiogenic paracrine properties. Our study is the first to demonstrate that ECFCs can give rise to smooth muscle-like progeny, with potential therapeutic benefits. These findings further illustrate that ECFCs are highly plastic, which by itself has implications for therapeutical use.
Treatment of reflux oesophagitis with ranitidine.
Authors: I C Wesdorp, W Dekker, E C Klinkenberg-Knol
Journal: Gut (1983)

The efficacy of ranitidine was evaluated using a two-staged trial in patients with endoscopically moderate or severe reflux oesophagitis. The results of a six week double blind placebo controlled trial (stage I) in 36 patients shows that ranitidine (150 mg bd) is superior to placebo in the acute treatment with significant symptomatic improvement concerning heartburn and regurgitation, and in healing or improvement of endoscopic lesions. Prolonged treatment with ranitidine for another six weeks (stage II) proved to be effective in more resistant cases. No clinical side effects or significant biochemical changes were noted during this trial.
Accelerated BEP for metastatic germ cell tumours: a multicenter phase II trial by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP)
Authors: P.S. Grimison, M.R. Stockler, M. Chatfield, D.B. Thomson, V. Gebski, M. Friedlander, A.L. Boland, B. Houghton, H. Gurney, M. Rosenthal, N. Singhal, G. Kichenadasse, S.S. Wong, C.R. Lewis, P.A. Vasey, G.C. Toner
Journal: Annals of Oncology (2013)
Hyperzincaemia and hypercalprotectinaemia: a new disorder of zinc metabolism
Authors: Barry Sampson, Magne K Fagerhol, Cord Sunderkötter, Barbara E Golden, Peter Richmond, Nigel Klein, Ilya Z Kovar, John H Beattie, Beata Wolska-Kusnierz, Yoshiaki Saito, Johannes Roth
Journal: The Lancet (2002)
Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma
Authors: M. Berry, A. Morgan, D. E Shaw, D. Parker, R. Green, C. Brightling, P. Bradding, A. J Wardlaw, I. D Pavord
Journal: Thorax (2007)

<h3>Background:</h3> Non-eosinophilic asthma is a potentially important clinicopathological phenotype since there is evidence that it responds poorly to inhaled corticosteroid therapy. However, little is known about the underlying airway immunopathology and there are no data from placebo-controlled studies examining the effect of inhaled corticosteroids. <h3>Methods:</h3> Airway immunopathology was investigated using induced sputum, bronchial biopsies, bronchial wash and bronchoalveolar lavage in 12 patients with symptomatic eosinophilic asthma, 11 patients with non-eosinophilic asthma and 10 healthy controls. The patients with non-eosinophilic asthma and 6 different patients with eosinophilic asthma entered a randomised, double-blind, placebo-controlled crossover study in which the effects of inhaled mometasone 400 μg once daily for 8 weeks on airway responsiveness and asthma quality of life were investigated. <h3>Results:</h3> Patients with non-eosinophilic asthma had absence of eosinophils in the mucosa (median 4.4 cells/mm<sup>2</sup> vs 23 cells/mm<sup>2</sup> in eosinophilic asthma and 0 cells/mm<sup>2</sup> in normal controls; p = 0.03) and normal subepithelial layer thickness (5.8 μm vs 10.3 μm in eosinophilic asthma and 5.1 μm in controls, p = 0.002). Non-eosinophilic and eosinophilic asthma groups had increased mast cell numbers in the airway smooth muscle compared with normal controls (9 vs 8 vs 0 cells/mm<sup>2</sup>, p = 0.016). Compared with placebo, 8 weeks of treatment with inhaled mometasone led to less improvement in methacholine PC<sub>20</sub> (0.5 vs 5.5 doubling concentrations, 95% CI of difference 1.1 to 9.1; p = 0.018) and asthma quality of life (0.2 vs 1.0 points, 95% CI of difference 0.27 to 1.43; p = 0.008). <h3>Conclusions:</h3> Non-eosinophilic asthma represents a pathologically distinct disease phenotype which is characterised by the absence of airway eosinophilia, normal subepithelial layer thickness and a poor short-term response to treatment with inhaled corticosteroids.
The management of the prostatic nodule
Authors: W. L. Valk
Journal: JAMA (1969)

Since carcinoma of the prostate is the third most frequent cause of cancer deaths in men,<sup>3</sup>the importance of doing routine rectal examinations in all men more than 40 years old cannot be overemphasized. Normally, the prostate is felt as a bilobar structure with a medial sulcus between the lateral lobes. The lobes are symmetrical, and have the consistency of the end of one's nose when palpated. Any irregularity, nodularity, or increased firmness must be considered as a possible neoplasm until investigations prove it otherwise. When a suspicious area in the prostate is felt, an abdominal-pelvic roentgenogram and the serum alkaline and acid phosphatase values should be obtained in addition to performing other routine studies. Prostatic infection, calculi, granulomas, and other nonneoplastic lesions may simulate a prostatic carcinoma. The ability of the physician to discern the true nature of the prostatic nodule by rectal examination alone is certainly less
Early Growth Response Gene-1 Regulates Hypoxia-Induced Expression of Tissue Factor in Glioblastoma Multiforme through Hypoxia-Inducible Factor-1–Independent Mechanisms
Authors: Yuan Rong, Fang Hu, RuoPan Huang, Nigel Mackman, Jonathan M. Horowitz, Randy L. Jensen, Donald L. Durden, Erwin G. Van Meir, Daniel J. Brat
Journal: Cancer Research (2006)

Abstract Hypoxia strongly up-regulates tissue factor and promotes plasma clotting by glioblastoma multiforme, but transcriptional mechanisms remain undefined. Here, we investigated the potential roles of early growth response gene-1 (Egr-1), Sp1, nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and hypoxia-inducible factor-1 (HIF-1) in the hypoxic regulation of tissue factor by glioblastoma multiforme cells in vitro. Hypoxia (1% O2) strongly induced Egr-1 mRNA within 1 hour and led to nuclear localization of Egr-1 protein. Using luciferase reporter plasmids in glioma cells, we found that hypoxia dramatically increased luciferase activity in cells with constructs containing Egr-1-binding sites but not in cells with constructs containing AP-1- or NF-κB-binding sites. Electrophoretic mobility shift assays revealed hypoxia-induced Egr-1, but not Sp1, binding to oligonucleotides containing the Egr-1/Sp1 motif of tissue factor gene promoter. Using an expression vector containing the minimal tissue factor promoter (−111 to +14 bp) and small interfering RNA (siRNA) directed at Egr-1 and Sp1 mRNAs, we found that Egr-1 was required for maximal hypoxic induction of promoter activity. Forced overexpression of Egr-1 but not Sp1 by cDNA transfection caused up-regulation of tissue factor in glioma cells under normoxia (21% O2), whereas siRNA directed at Egr-1 strongly attenuated hypoxia-induced tissue factor expression. To examine the effects of HIF-1α on tissue factor expression, we used glioma cells stably transfected with a HIF-1α siRNA expression vector and found that HIF-1α mRNA silencing did not affect tissue factor expression under hypoxia. We conclude that hypoxic up-regulation of tissue factor in glioblastoma multiforme cells depends largely on Egr-1 and is independent of HIF-1. (Cancer Res 2006; 66(14): 7067-74)
Pre-clinical efficacy of combined therapy with novel β-catenin antagonist BC2059 and histone deacetylase inhibitor against AML cells
Authors: W Fiskus, S Sharma, S Saha, B Shah, S G T Devaraj, B Sun, S Horrigan, C Leveque, Y Zu, S Iyer, K N Bhalla
Journal: Leukemia (2014)
Antitumor activity of a human cytotoxic T-cell line (TALL-104) in brain tumor xenografts
Authors: Birgit Geoerger, Cheng-Bi Tang, Alessandra Cesano, Sophie Visonneau, Sunil Marwaha, Kevin D. Judy, Leslie N. Sutton, Daniela Santoli, Peter C. Phillips
Journal: Neuro-Oncology (2000)

Malignant glioma in adults and primitive neuroectodermal tumors/medulloblastomas in children are the most common malignant primary brain tumors that either respond poorly to current treatment or tend to recur. Adoptive therapy with TALL-104 cells—an IL-2-dependent, major histocompatibility complex nonrestricted, cytotoxic T-cell line—has demonstrated significant antitumor activity against a broad range of implanted or spontaneously arising tumors. This study investigates distribution of systemically and locally administered TALL-104 cells and their efficacy in effecting survival of a rat model of human brain tumor. In vitro, TALL-104 cells showed significant cytotoxic activity when added to human glioblastoma cell lines U-87 MG, U-251 MG, and A1690; the medulloblastoma cell lines DAOY, D283 Med, and D341 Med; and the epidermoid cancer cell line A431. In brain tumor-bearing rats, the amount of fluorescent dye-labeled TALL-104 cells in brain increased after they were given by intracarotid injection as compared with i.v. cell administration. However, TALL-104 cells rapidly decreased to low levels within 1 h after intracarotid injection. This finding suggests that TALL-104 cells given systemically may not invade brain or tumor tissues, but rather may remain in the vascular system, making this approach less efficient for brain tumor treatment. In a model of athymic rats engrafted with human A431 carcinoma brain tumor, repetitive local administration of TALL-104 cells directly into the tumor bed resulted in a significant increase in survival time compared with control animals. Therefore, local therapy with TALL-104 cells may be a novel and highly effective treatment approach for malignant brain tumors.
Scleroderma lung study (SLS): differences in the presentation and course of patients with limited versus diffuse systemic sclerosis
Authors: P. J Clements, M. D Roth, R. Elashoff, D. P Tashkin, J. Goldin, R. M Silver, M. Sterz, J. R Seibold, D. Schraufnagel, R. W Simms, M. Bolster, R. A Wise, V. Steen, M D Mayes, K. Connelly, M. Metersky, D. E Furst
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> Pulmonary fibrosis is a leading cause of death in systemic sclerosis (SSc). This report examines the differences at baseline and over 12 months between patients with limited versus diffuse cutaneous SSc who participated in the Scleroderma Lung Study. <h3>Methods:</h3> SSc patients (64 limited; 94 diffuse) exhibiting dyspnoea on exertion, restrictive pulmonary function and evidence of alveolitis on bronchoalveolar lavage and/or high-resolution computed tomography (HRCT) were randomised to receive cyclophosphamide (CYC) or placebo and serially evaluated over 12 months. <h3>Results:</h3> Baseline measures of alveolitis, dyspnoea and pulmonary function were similar in limited and diffuse SSc. However, differences were noted with respect to HRCT-scored fibrosis (worse in limited SSc), and to functional activity, quality of life, skin and musculoskeletal manifestations (worse in diffuse SSc) (p&lt;0.05). When adjusted for the baseline level of fibrosis, both groups responded similarly to CYC with regard to lung function and dyspnoea (p&lt;0.05). Cyclophosphamide was also associated with more improvement in skin score in the diffuse disease group more than in the limited disease group (p&lt;0.05). <h3>Conclusions:</h3> After adjusting for the severity of fibrosis at baseline, CYC slowed the decline of lung volumes and improved dyspnoea equally in the limited and the diffuse SSc groups. On the other hand, diffuse SSc patients responded better than limited patients with respect to improvements in skin thickening.
p53 Inhibits Angiogenesis by Inducing the Production of Arresten
Authors: Sarah Assadian, Wissal El-Assaad, Xue Q.D. Wang, Phillipe O. Gannon, Véronique Barrès, Mathieu Latour, Anne-Marie Mes-Masson, Fred Saad, Yoshikazu Sado, Josée Dostie, Jose G. Teodoro
Journal: Cancer Research (2012)

Several types of collagen contain cryptic antiangiogenic noncollagenous domains that are released upon proteolysis of extracellular matrix (ECM). Among those is Arresten, a collagen-derived antiangiogenic factor (CDAF) that is processed from α1 collagen IV. However, the conditions under which Arresten is released from collagen IV in vivo or whether the protein functions in tumor suppressor pathways remain unknown. Here, we show that p53 induces the expression of α1 collagen IV and release of Arresten-containing fragments from the ECM. Comparison of the transcriptional activation of COL4A1 with other CDAF-containing genes revealed that COL4A1 is a major antiangiogenic gene induced by p53 in human adenocarinoma cells. p53 directly activated transcription of the COL4A1 gene by binding to an enhancer region 26 kbp downstream of its 3' end. p53 also stabilized the expression of full-length α1 collagen IV by upregulation of α(II) prolyl-hydroxylase and increased the release of Arresten in the ECM through a matrix metalloproteinase (MMP)-dependent mechanism. The resulting upregulation of α1 collagen IV and production of Arresten by the tumor cells significantly inhibited angiogenesis and limited tumor growth in vivo. Furthermore, we show that immunostaining of Arresten correlated with p53 status in human prostate cancer specimens. Our findings, therefore, link the production of Arresten to the p53 tumor suppressor pathway and show a novel mechanism through which p53 can inhibit angiogenesis.
Activation of T Cells upon Treatment with Bispecific Antibodies Correlates with the Expression of Co-Inhibitory Receptors on Tumor-Infiltrating Lymphocytes in Human Lung Cancer
Authors: D. Thommen, J. Schreiner, P. Herzig, P. Mueller, V. Karanikas, S. Savic, D. Lardinois, A. Zippelius
Journal: Annals of Oncology (2014)
miR-150 Promotes Renal Fibrosis in Lupus Nephritis by Downregulating SOCS1
Authors: Hua Zhou, Sarfaraz A. Hasni, Paola Perez, Mayank Tandon, Shyh-Ing Jang, Changyu Zheng, Jeffery B. Kopp, Howard Austin, James E. Balow, Ilias Alevizos, Gabor G. Illei
Journal: Journal of the American Society of Nephrology (2013)

MicroRNAs (miRs) seem to mediate renal fibrosis in several renal diseases, with some miRs having profibrotic effects and others having opposing effects. Although differential expression of certain miRs has been described in lupus nephritis, it is unknown whether miRs contribute to fibrosis or could serve as biomarkers of specific histologic manifestations of lupus nephritis. Here, we compared miR expression in kidney biopsies from patients with lupus nephritis and identified miR-150 as the most differentially expressed miR in kidneys with high chronicity (chronicity index [CI] ≥ 4); miR-150 positively correlated with chronicity scores and the expression of profibrotic proteins. Overexpression of miR-150 significantly reduced expression of the antifibrotic protein suppressor of cytokine signaling 1 (SOCS1) and upregulated profibrotic proteins in both proximal tubular and mesangial cells. Directly targeting SOCS1 with a small interfering RNA produced similar results. Furthermore, TGF-β1 induced miR-150 expression, decreased SOCS1, and increased profibrotic proteins in proximal tubular cells and podocytes; a miR-150 inhibitor reversed these changes, suggesting that the profibrotic effects of TGF-β1 are, at least in part, mediated by miR-150. Consistent with these in vitro observations, biopsies with high miR-150 and high CI exhibited substantial expression of TGF-β1, reduced SOCS1, and an increase in profibrotic proteins. In summary, miR-150 is a promising quantitative renal biomarker of kidney injury in lupus nephritis. Our results suggest that miR-150 promotes renal fibrosis by increasing profibrotic molecules through downregulation of SOCS1.
Original articles
Authors: C. Charfeddine, M. Mokni, R. Ben Mousli, R. Elkares, C. Bouchlaka, S. Boubaker, S. Ghedamsi, D. Baccouche, A. Ben Osman, K. Dellagi, S. Abdelhak
Journal: British Journal of Dermatology (2003)

Mal de Meleda (MDM) is a rare autosomal recessive skin disorder which belongs to the clinically and genetically heterogeneous group of palmoplantar keratodermas (PPK). Clinically, MDM is characterized by erythema and hyperkeratosis of the palms and soles with sharp demarcation that appears soon after birth and progressively extends to the dorsal surface of the hands and feet.Except for the molecular study reported in Algerian families, MDM has not yet been investigated in the Maghrebian population, characterized by its heterogeneous ethnic background and a high rate of consanguinity. In this study we report genetic and molecular investigations of eight unrelated consanguineous Tunisian families including 17 affected individuals.Eight large consanguineous MDM families who originated from cities of northern Tunisia, with a total of 17 patients and 22 unaffected family members were investigated. Families were genotyped with the following microsatellite markers: CNG003, D8S1751 and D8S1836. Mutation analyses were performed in affected patients, in both parents and in unaffected individuals. Linkage analysis was also performed.All the clinical features of MDM were constantly present. Nevertheless variable severity was noted among patients. Histological details were recorded. The haplotype analysis of markers CNG003, D8S1751 and D8S1836 revealed that all affected offspring were homozygous by descent for the three polymorphic markers. The maximum lod score value, 3.22, confirmed the evidence for linkage to the ARS gene. Three haplotypes were observed, and the findings suggest that at least three different mutations within the ARS gene segregate with these haplotypes. Three different mutations were identified, the 82delT mutation previously described and two novel missense mutations.The results suggest that the ARS gene is likely to be responsible for MDM in the eight Tunisian families. The clinical variability in the expression of PPK in MDM Tunisian patients might be accounted for by the intervention of modifier genes influencing the MDM phenotype.