tbuckley/cabot-search huggingface dataset:
Inhibition of Poly(ADP-Ribose) Polymerase-1 Enhances Temozolomide and Topotecan Activity against Childhood Neuroblastoma
Authors: Rachel A. Daniel, Agata L. Rozanska, Huw D. Thomas, Evan A. Mulligan, Yvette Drew, Deborah J. Castelbuono, Zdenek Hostomsky, E. Ruth Plummer, Alan V. Boddy, Deborah A. Tweddle, Nicola J. Curtin, Steven C. Clifford
Journal: Clinical Cancer Research (2009)

Abstract Purpose: High-risk neuroblastoma is characterized by poor survival rates, and the development of improved therapeutic approaches is a priority. Temozolomide and topotecan show promising clinical activity against neuroblastoma. Poly(ADP-ribose) polymerase-1 (PARP-1) promotes DNA repair and cell survival following genotoxic insult; we postulated that its inhibition may enhance the efficacy of these DNA-damaging drugs in pediatric cancers. Experimental Design: We evaluated the chemosensitizing properties of the PARP inhibitor AG014699 (Pfizer, Inc.) in combination with temozolomide and topotecan, against human neuroblastoma cells and xenografts, alongside associated pharmacologic and toxicologic indices. Results: Addition of PARP-inhibitory concentrations of AG014699 significantly potentiated growth inhibition by both topotecan (1.5- to 2.3-fold) and temozolomide (3- to 10-fold) in vitro, with equivalent effects confirmed in clonogenic assays. In two independent in vivo models (NB1691 and SHSY5Y xenografts), temozolomide caused a xenograft growth delay, which was enhanced by co-administration of AG014699, and resulted in complete and sustained tumor regression in the majority (6 of 10; 60%) of cases. Evidence of enhanced growth delay by topotecan/AG014699 co-administration was observed in NB1691 xenografts. AG014699 metabolites distributed rapidly into the plasma (Cmax, 1.2-1.9 nmol/L at 30 min) and accumulated in xenograft tissues (Cmax, 1-2 μmol/L at 120 min), associated with a sustained suppression of PARP-1 enzyme activity. Doses of AG014699 required for potentiation were not toxic per se. Conclusions: These data show enhancement of temozolomide and topotecan efficacy by PARP inhibition in neuroblastoma. Coupled with the acceptable pharmacokinetic, pharmacodynamic, and toxicity profiles of AG014699, our findings provide strong rationale for investigation of PARP inhibitors in pediatric early clinical studies.
Radiation-sensitizing effect of a low concentration of docetaxel on human esophageal squamous cell carcinoma cell lines
Authors: Satoshi Tabuchi, Soji Ozawa, Yuko Kitagawa, Yoshiro Saikawa, Koichi Suda, Takashi Ando, Kunihiko Hiraiwa, Naoyuki Shigematsu, Atsushi Kubo, Tetsuya Kawada, Hisao Ito, Masakazu Ueda, Masaki Kitajima
Journal: Cancer Research (2006)

4406  Background: While 5-FU/CDDP is the standard regimen used for chemoradiotherapy of esophageal cancer, there are still many unclear aspects about the combined effect of the novel anticancer agent docetaxel and radiation. Purpose: We investigated the radiation-sensitizing effect of docetaxel on human esophageal squamous cell carcinoma cell lines, in which the combined effect of the two treatment modalities has been shown to vary with the contact time. Materials and Methods: We exposed human esophageal squamous cell carcinoma cell lines TE2, TE3 and A431 to docetaxel for 3 hours each, and determined the maximum concentration of the drug at which no cytocidal effect was observed, based the on survival curves and the colony formation assay. The chemo-radiation group was exposed to docetaxel before, during, or after the irradiation, and the cytocidal effect according to the radiation dose was compared between the chemo-radiation group and the irradiation-alone group by Mann-Whitney’s U-test. In addition, nuclear DNA was measured by flow cytometry before and after exposure of each of the cell lines to low-concentration docetaxel, and the proportions of cells in each phase of the cell cycle were calculated. Results: The IC50 values (M) in the docetaxel -alone groups were as follows, in the order of the highest to the lowest sensitivity: A431 cells ; 8.4×10−10, TE3 cells ; 2.8×10−9 , TE2 cells ; 3.2×10−9 . By contrast, in the groups exposed to radiation alone, the D0 (Gy) values were: TE2 cells ; 0.7, TE3 cells ; 1.1, A431 cells ; 1.9 with a reverse order of sensitivity of the three cell lines. In the groups in which radiation and docetaxel were used in combination, a radiation-sensitizing effect of the drug was observed in all the three cell lines when irradiation was conducted after the exposure to docetaxel (p
The in vivo cytotoxic activity of CD8+ T cell clones correlates with their levels of expression of adhesion molecules.
Authors: M Rodrigues, R S Nussenzweig, P Romero, F Zavala
Journal: The Journal of Experimental Medicine (1992)

CD8+ T cell clones specific for a defined epitope present in the circumsporozoite protein of Plasmodium yoelii display striking differences in their in vivo antiplasmodial activity. The adoptive transfer of certain clones (YA23 and YA26) into naive mice inhibits by 90% or more the development of liver stages of malaria parasites and protects against malaria infection. The adoptive transfer of two other T cell clones (YB8 and YA15) results, respectively, in partial or no inhibitory activity on parasite development. We found that "protective" and "nonprotective" cytotoxic T lymphocyte (CTL) clones do not differ in their fine epitope specificity and display similar levels of lysis and DNA degradation of target cells in vitro. Their pattern of production of lymphokines and granule-associated proteins also failed to correlate with their in vivo antiplasmodial activity. Histological studies combined with autoradiography showed that, upon adoptive transfer, only T cells from the protective CTL clones are capable of "associating" with a significant percentage of parasitized hepatocytes. Fluorescence-activated cell sorter analysis of surface molecules revealed pronounced differences in the levels of CD44 and VLA-4 expression by the different clones, correlating closely with their in vivo protective activity. The correlation between in vivo antiparasite activity and the expression of CD44 was further corroborated by the results of sorting, from the partially protective YB8 clone, two sub-populations expressing high and low levels of CD44. These were protective and nonprotective, respectively. The clones also differed in their adhesive properties. Cross-linking of CD44, using specific antibodies, induced LFA-1-mediated homotypic aggregation of protective clones, while nonprotective cells failed to aggregate.
Genomic medicine in Africa: promise, problems and prospects
Authors: Ambroise Wonkam, Bongani M Mayosi
Journal: Genome Medicine (2014)

The promiseRemarkable progress has been made in using genomic information to determine how genes are regulated, and how they interact with each other and with the environment to control complex biochemical functions of living organisms in health and disease [1].This information will have major benefits for the prevention, diagnosis and management of many diseases, including communicable and genetic diseases.In Africa, where infectious diseases are highly prevalent, research on pathogen genomes has enhanced our understanding of disease transmission, virulence mechanisms and avoidance of host defenses [2].It is anticipated that this information will enable the development of new diagnostic tests, vaccines and therapeutic agents; it is also likely to lead to new approaches for vector control, and reveal why individuals and populations vary in their susceptibility to infectious diseases [1].This commentary focuses on problems and prospects for the use of new genomic knowledge in improving the health of Africans.The prospects for genomic medicine in Africa have been enhanced by major initiatives that are led by international funding agencies and academics, such as the Malaria Genomic Epidemiology Network (MalariaGEN) (www.malariagen.net/)and the Human Heredity and Health in Africa (H3Africa) program (h3africa.org/h3africa_whitepaper.pdf ).These multi-national consortia have started to build the capacity in research skills and overcome the barriers for the use of genomics to address the disease burden of Africans.The time has come for African governments to heed the call of the World Health Organization to embrace genomics for the benefit of their populations.
Interplay between adrenaline and interbeat interval on ventricular repolarisation in intact heart in vivo
Authors: P. Taggart, P. Sutton, M. Lab, J. Dean, F. Harrison
Journal: Cardiovascular Research (1990)

The aim was to examine the hypothesis that an interaction between adrenaline and change in heart rate may alter the normal time sequence of ventricular repolarisation (and hence refractoriness) in a manner that (1) may favour arrhythmia formation, (2) may partly explain conflicting reports of the effect of adrenaline, ie, there are two opposing effects on action potential duration, and (3) be relevant to T wave abnormalities that sometimes occur in normal people.As a measure of the time course of repolarisation, monophasic action potentials were recorded simultaneously from three epicardial sites in the porcine heart (left ventricular apex, left ventricular base, and mid right ventricle). During steady state pacing, test pulse intervals were interposed at progressively shorter intervals in order to construct restitution curves.Adrenaline infusion (0.4-1.5 micrograms.kg-1.min-1) resulted in earlier repolarisation in the beats after shorter interbeat intervals, and delayed repolarisation after longer interbeat intervals, tending to turn the restitution curve anticlockwise (ie, there were two opposing effects on action potential duration). The effects were not homogeneous between regions. To show this inhomogeneity, pairs of monophasic action potentials from different regions were subtracted using a differential input amplifier to produce an ECG like waveform at the amplifier output. The resulting T wave was thereby a measure of the time difference in repolarisation between the monophasic action potentials from which it was derived. The inhomogeneity of repolarisation induced by adrenaline and rate change was reflected in the morphology of this derived T wave, particularly at early (premature) beats. These T wave changes correlated closely with the true T wave changes in bipolar electrograms recorded between the same recording sites (R = 0.89; p less than 0.0001).These results show that adrenaline altered the normal relationship between interbeat interval and the timing of repolarisation. The effect was not homogeneous and when regional differences were observed they were reflected in changes in T wave morphology. These were marked at short intervals. It is possible that in addition to increased excitability observed with adrenaline, a combination of raised sympathetic activity and early beats predisposes to arrhythmias by exaggerating dispersion of repolarisation.
PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition
Authors: Yasir H. Ibrahim, Celina García-García, Violeta Serra, Lei He, Kristine Torres-Lockhart, Aleix Prat, Pilar Anton, Patricia Cozar, Marta Guzmán, Judit Grueso, Olga Rodríguez, Maria Teresa Calvo, Claudia Aura, Orland Díez, Isabel T. Rubio, José Pérez, Jordi Rodón, Javier Cortés, Leif W. Ellisen, Maurizio Scaltriti, José Baselga
Journal: Cancer Discovery (2012)

PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient-derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture.Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs.
Time courses and quantitative analysis of atrial fibrillation episode number and duration after circular plus linear left atrial lesions
Authors: Hans Kottkamp, Hildegard Tanner, Richard Kobza, Petra Schirdewahn, Anja Dorszewski, Jin-Hong Gerds-Li, Corrado Carbucicchio, Christopher Piorkowski, Gerhard Hindricks
Journal: Journal of the American College of Cardiology (2004)
Polycomb Repressor Complex-2 Is a Novel Target for Mesothelioma Therapy
Authors: Clinton D. Kemp, Mahadev Rao, Sichuan Xi, Suzanne Inchauste, Haresh Mani, Patricia Fetsch, Armando Filie, Mary Zhang, Julie A. Hong, Robert L. Walker, Yuelin J. Zhu, R. Taylor Ripley, Aarti Mathur, Fang Liu, Maocheng Yang, Paul A. Meltzer, Victor E. Marquez, Assunta De Rienzo, Raphael Bueno, David S. Schrump
Journal: Clinical Cancer Research (2011)

Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM).Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep.EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 orEED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment.Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy.
FcRγ Activation Regulates Inflammation-Associated Squamous Carcinogenesis
Authors: Pauline Andreu, Magnus Johansson, Nesrine I. Affara, Ferdinando Pucci, Tingting Tan, Simon Junankar, Lidiya Korets, Julia Lam, David Tawfik, David G. DeNardo, Luigi Naldini, Karin E. de Visser, Michele De Palma, Lisa M. Coussens
Journal: Cancer Cell (2010)
Association between sleep disordered breathing and aggressiveness markers of malignant cutaneous melanoma
Authors: Miguel-Ángel Martínez-García, Antonio Martorell-Calatayud, Eduardo Nagore, Irene Valero, Maria Jose Selma, Eusebi Chiner, Pedro Landete, Josep-Maria Montserrat, Cristina Carrera, Amalia Pérez-Gil, Francisco Campos-Rodríguez, Ramón Farré
Journal: European Respiratory Journal (2014)

Some recent studies have shown an association between sleep disordered breathing (SDB) and cancer mortality and incidence but no study has focused on a specific type of cancer. The objective of this study was to analyse the relationship between the severity of SDB and factors related to cutaneous malignant melanoma (CMM) aggressiveness. We performed a multicentre observational study in 82 consecutive patients diagnosed with CMM. 56 patients in whom melanoma measurements were available were finally included in the study. Melanoma measurements of aggressiveness included: tumour mitotic rate, Breslow index, presence of ulceration, stage of disease and growth rate of melanoma. A sleep study was performed in all the included patients. Multivariate analyses were used to examine the independent relationship between SDB severity (apnoea-hypopnea index (AHI) and nocturnal oxygen desaturation indexes (ODI3% and ODI4%)) and measures of CMM aggressiveness. 60.7% of patients had SDB (AHI ≥ 5) and 14.3% severe obstructive sleep apnoea (AHI ≥ 30). In fully adjusted multivariate analyses, AHI (OR 1.08, 95% CI 1.02-1.14), ODI3% (OR 1.08, 95% CI 1.02-1.11) and ODI4% (OR 1.1, 95% CI 1.02-1.2) were independently associated with an increased melanoma growth rate. Furthermore, AHI, ODI4% and ODI3% were significantly correlated with other aggressiveness factors of CMM, such as Breslow index, presence of ulceration and mitotic index. SDB severity markers are associated with some aggressiveness markers of CMM.
Loss of SR-BI Expression Leads to the Early Onset of Occlusive Atherosclerotic Coronary Artery Disease, Spontaneous Myocardial Infarctions, Severe Cardiac Dysfunction, and Premature Death in Apolipoprotein E–Deficient Mice
Authors: Anne Braun, Bernardo L. Trigatti, Mark J. Post, Kaori Sato, Michael Simons, Jay M. Edelberg, Robert D. Rosenberg, Mark Schrenzel, Monty Krieger
Journal: Circulation Research (2002)

Murine models of atherosclerosis, such as the apolipoprotein E (apoE) or the LDL receptor knockout mice, usually do not exhibit many of the cardinal features of human coronary heart disease (CHD), eg, spontaneous myocardial infarction, severe cardiac dysfunction, and premature death. Here we show that mice with homozygous null mutations in the genes for both the high density lipoprotein receptor SR-BI and apoE (SR-BI/apoE double knockout [dKO] mice) exhibit morphological and functional defects with similarities to those seen in human CHD. When fed a standard chow diet, these hypercholesterolemic animals developed significant atherosclerotic lesions in the aortic sinus as early as 4 to 5 weeks after birth. We now show that they also exhibited extensive lipid-rich coronary artery occlusions and spontaneously developed multiple myocardial infarctions and cardiac dysfunction (eg, enlarged hearts, reduced ejection fraction and contractility, and ECG abnormalities). Their coronary arterial lesions, which were strikingly similar to human atherosclerotic plaques, exhibited evidence of cholesterol clefts and extensive fibrin deposition, indicating hemorrhage and clotting. All of the dKO mice died by 8 weeks of age (50% mortality at 6 weeks). Thus, SR-BI/apoE dKO mice provide a new murine model for CHD and may help better define the role of lipoprotein metabolism and atherosclerosis in the pathogenesis of myocardial infarction and cardiac dysfunction. Furthermore, these animals may be useful for preclinical testing of potential genetic and/or pharmacological therapies for CHD.
The Tensin-3 Protein, Including its SH2 Domain, Is Phosphorylated by Src and Contributes to Tumorigenesis and Metastasis
Authors: Xiaolan Qian, Guorong Li, William C. Vass, Alex Papageorge, Renard C. Walker, Laura Asnaghi, Peter J. Steinbach, Giovanna Tosato, Kent Hunter, Douglas R. Lowy
Journal: Cancer Cell (2009)
Hyaluronan inhibits expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic chondrocytes
Authors: T Yatabe, S Mochizuki, M Takizawa, M Chijiiwa, A Okada, T Kimura, Y Fujita, H Matsumoto, Y Toyama, Y Okada
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Background:</h3> Intra-articular injection of hyaluronan (HA) has been suggested to have a disease-modifying effect in osteoarthritis, but little is known about the possible mechanisms. <h3>Objective:</h3> To investigate the effects of HA species of different molecular mass, including 800 kDa (HA800) and 2700 kDa (HA2700), on the expression of aggrecanases (ie, ADAMTS species), which play a key role in aggrecan degradation. <h3>Methods:</h3> The effects of HA species on the expression of ADAMTS1, 4, 5, 8, 9 and 15 in interleukin 1α (IL1α)-stimulated osteoarthritic chondrocytes were studied by reverse transcription PCR and real-time PCR. Expression of ADAMTS4 protein and aggrecanase activity and signal transduction pathways of IL1, CD44 and intracellular adhesion molecule 1 (ICAM1) were examined by immunoblotting. <h3>Results:</h3> IL1α treatment of chondrocytes induced ADAMTS4, and HA800 and HA2700 significantly decreased IL1α-induced expression of ADAMTS4 mRNA and protein. IL1α-stimulated aggrecanase activity in osteoarthritic chondrocytes was reduced by treatment with HA2700 or transfection of small interfering RNA for ADAMTS4. A similar result was obtained when HA2700 was added to explant cultures of osteoarthritic cartilage. HA2700 neither directly inhibited nor bound to ADAMTS4. Downregulation of ADAMTS4 expression by HA2700 was attenuated by treatment of IL1α-treated chondrocytes with antibodies to CD44 and/or ICAM1. The increased phosphorylation of IL1 receptor-associated kinase-1 and extracellular signal-regulated protein kinase1/2 induced by the IL1α treatment was downregulated by enhanced IRAK-M expression after HA2700 treatment. <h3>Conclusion:</h3> These data suggest that HA2700 suppresses aggrecan degradation by downregulating IL1α-induced ADAMTS4 expression through the CD44 and ICAM1 signalling pathways in osteoarthritic chondrocytes.
The bleeding grapes of wrath
Authors: A D Farmer, G J Sadler, E T Swarbrick
Journal: Gut (2009)

A 73-year-old woman presented with confusion and passing blood from her ileostomy. She had undergone panproctocolectomy for ulcerative colitis 13 years previously and had subsequently been diagnosed with primary biliary cirrhosis. On physical examination she was encephalopathic with multiple signs of chronic liver disease. She was haemodynamically unstable with fresh blood and melaena being evident in the ileostomy bag. Routine haematological and biochemical parameters revealed the following: haemoglobin 10.1 g/dl, platelets 72×109/litre, prothrombin time of 16 s with normal urea and electrolytes and liver biochemistry. Abdominal ultrasound suggested appearances consistent with liver cirrhosis with moderate ascites. An ascitic tap was negative for spontaneous bacterial peritonitis. Following intravenous fluid resuscitation, an oesophago-gastro-duodenoscopy was undertaken and showed oesophageal varices in the absence of stigmata of recent haemorrhage with no blood in the stomach. The appearances of her ileostomy are shown in …