tbuckley/cabot-search huggingface dataset:
Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy
Authors: Roberto Tonelli, Alan McIntyre, Consuelo Camerin, Zoë S. Walters, Korinne Di Leo, Joanna Selfe, Stefania Purgato, Edoardo Missiaglia, Andrea Tortori, Jane Renshaw, Annalisa Astolfi, Kathryn R. Taylor, Salvatore Serravalle, Ryan Bishop, Cristina Nanni, Linda J. Valentijn, Andrea Faccini, Ivo Leuschner, Serena Formica, Jorge S. Reis-Filho, Valentina Ambrosini, Khin Thway, Monica Franzoni, Brenda Summersgill, Rosangela Marchelli, Patrizia Hrelia, Giorgio Cantelli-Forti, Stefano Fanti, Roberto Corradini, Andrea Pession, Janet Shipley
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Rhabdomyosarcomas are a major cause of cancer death in children, described with MYCN amplification and, in the alveolar subtype, transcription driven by the PAX3-FOXO1 fusion protein. Our aim was to determine the prevalence of N-Myc protein expression and the potential therapeutic effects of reducing expression in rhabdomyosarcomas, including use of an antigene strategy that inhibits transcription. Experimental Design: Protein expression was assessed by immunohistochemistry. MYCN expression was reduced in representative cell lines by RNA interference and an antigene peptide nucleic acid (PNA) oligonucleotide conjugated to a nuclear localization signal peptide. Associated gene expression changes, cell viability, and apoptosis were analyzed in vitro. As a paradigm for antigene therapy, the effects of systemic treatment of mice with rhabdomyosarcoma cell line xenografts were determined. Results: High N-Myc levels were significantly associated with genomic amplification, presence of the PAX3/7-FOXO1 fusion genes, and proliferative capacity. Sustained reduction of N-Myc levels in all rhabdomyosarcoma cell lines that express the protein decreased cell proliferation and increased apoptosis. Positive feedback was shown to regulate PAX3-FOXO1 and N-Myc levels in the alveolar subtype that critically decrease PAX3-FOXO1 levels on reducing N-Myc. Pharmacologic systemic administration of the antigene PNA can eliminate alveolar rhabdomyosarcoma xenografts in mice, without relapse or toxicity. Conclusion: N-Myc, with its restricted expression in non-fetal tissues, is a therapeutic target to treat rhabdomyosarcomas, and blocking gene transcription using antigene oligonucleotide strategies has therapeutic potential in the treatment of cancer and other diseases that has not been previously realized in vivo. Clin Cancer Res; 18(3); 796–807. ©2011 AACR.
The Open-Artery Hypothesis
Authors: A. Solomon, B. Gersh
Journal: Annual Review of Medicine (1998)

Early reperfusion of an infarct-related coronary artery results in myocardial salvage, with subsequent improvement in left ventricular function and survival. However, late reperfusion, which occurs at a time when myocardial salvage is no longer possible, still exerts a favorable impact on left ventricular function and survival. This concept is known as the open-artery hypothesis. Possible mechanisms for this benefit include improved infarct healing, limitation of ventricular remodeling, decreased ventricular arrhythmias, and reperfusion of hibernating myocardium. Although an open infarct-related coronary artery is crucial, it has not been proven that opening an occluded coronary artery using angioplasty is beneficial. A large randomized clinical trial is clearly needed.
Modulation of tryptophan catabolism by regulatory T cells
Authors: Francesca Fallarino, Ursula Grohmann, Kwang Woo Hwang, Ciriana Orabona, Carmine Vacca, Roberta Bianchi, Maria Laura Belladonna, Maria Cristina Fioretti, Maria-Luisa Alegre, Paolo Puccetti
Journal: Nature Immunology (2003)
Cyclin A2 Induces Cardiac Regeneration After Myocardial Infarction and Prevents Heart Failure
Authors: Richard K. Cheng, Tomohiro Asai, Haiying Tang, Nurin H. Dashoush, Rina J. Kara, Kevin D. Costa, Yoshifumi Naka, Ed X. Wu, Debra J. Wolgemuth, Hina W. Chaudhry
Journal: Circulation Research (2007)

Mammalian myocardial infarction is typically followed by scar formation with eventual ventricular dilation and heart failure. Here we present a novel model system in which mice constitutively expressing cyclin A2 in the myocardium elicit a regenerative response after infarction and exhibit significantly limited ventricular dilation with sustained and remarkably enhanced cardiac function. New cardiomyocyte formation was noted in the infarcted zones as well as cell cycle reentry of periinfarct myocardium with an increase in DNA synthesis and mitotic indices. The enhanced cardiac function was serially assessed over time by MRI. Furthermore, the constitutive expression of cyclin A2 appears to augment endogenous regenerative mechanisms via induction of side population cells with enhanced proliferative capacity. The ability of cultured transgenic cardiomyocytes to undergo cytokinesis provides mechanistic support for the regenerative capacity of cyclin A2.
Contribution of the pancreas to circulating somatostatin-like immunoreactivity in the normal dog.
Authors: G J Taborsky, J W Ensinck
Journal: Journal of Clinical Investigation (1984)

These studies were performed to assess the contribution of the pancreas to the somatostatin-like immunoreactivity (SLI) circulating in arterial and portal venous plasma. Basal SLI concentrations in arterial, pancreatic venous, and portal venous plasma were 95 +/- 9, 277 +/- 32, and 130 +/- 12 pg/ml, (means +/- SEM), respectively. Measurement of pancreatic and portal venous blood flow (5 +/- 1 vs. 365 +/- 46 ml/min) and hematocrit allowed calculation of net, base-line SLI output from the right lobe of the pancreas (521 +/- 104 pg/min) and from the gastrointestinal tract (8,088 +/- 1,487 pg/min), which suggested that the contribution of the pancreas to circulating SLI was minor when the D cells were not stimulated. To stimulate the secretion of SLI from both pancreatic and nonpancreatic sources, isoproterenol, a beta-adrenergic agonist, was infused intravenously for 1 h into six anesthetized dogs. Arterial SLI increased by 52 +/- 9 pg/ml; superior pancreatico-duodenal venous SLI increased by 380 +/- 95 pg/ml; portal venous SLI increased by 134 +/- 14 pg/ml. Pancreatic venous blood flow remained unchanged at 5 +/- 1 ml/min, but portal venous blood flow increased to 522 +/- 62 ml/min. SLI output from the right lobe of the pancreas increased by 684 +/- 227 pg/min and that from the gastrointestinal tract increased by 23,911 +/- 3,197 pg/min, again suggesting that the pancreas was a minor source of circulating SLI even when the D cells were stimulated. We conclude that the measurement of arterial-venous SLI concentrations, in the absence of measurements of organ blood flow, can give a false impression of the organ's contributions of circulating SLI. To verify that the contribution of the pancreas was negligible, six dogs received an acute pancreatectomy and then an intravenous infusion of isoproterenol at the same rate. In these dogs, both the base-line level of SLI in arterial plasma (109 +/- 12 pg/ml) and the increment during isoproterenol (56 +/- 8 pg/ml) were similar to those of normal dogs. Likewise, in pancreatectomized dogs both the base-line level of SLI in portal venous plasma (129 +/- 16 pg/ml) and the increment during isoproterenol (174 +/- 34 pg/ml) were similar to those of normal dogs. We conclude that, in normal dogs, the pancreas makes a negligible contribution to the basal and stimulated level of SLI in arterial and portal venous plasma and therefore that these levels should not be used as an index of secretory activity of the pancreatic D cells.
Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma
Authors: Deepak Sampath, Mario Castro, Dwight C. Look, Michael J. Holtzman
Journal: Journal of Clinical Investigation (1999)

Cytokine effects on immunity and inflammation often depend on the transcription factors termed signal transducers and activators of transcription (STATs), so STAT signaling pathways are candidates for influencing inflammatory disease. We reasoned that selective IFN responsiveness of the first STAT family member (Stat1) and Stat1-dependent immune-response genes such as intercellular adhesion molecule-1 (ICAM-1), IFN regulatory factor-1 (IRF-1), and Stat1 itself in airway epithelial cells provides a basis for detecting cytokine signaling abnormalities in inflammatory airway disease. On the basis of nuclear localization and phosphorylation, we found that epithelial Stat1 (but not other control transcription factors) was invariably activated in asthmatic compared with normal control or chronic bronchitis subjects. Furthermore, epithelial levels of activated Stat1 correlated with levels of expression for epithelial ICAM-1, IRF-1, and Stat1, and in turn, ICAM-1 levels correlated with T-cell accumulation in tissue. However, only low levels of IFN-γ or IFN-γ–producing cells were detected in airway tissue in all subjects. The results therefore provide initial evidence linking abnormal behavior of STAT pathways for cytokine signaling to the development of an inflammatory disease. In that context, the results also change the current scheme for asthma pathogenesis to one that must include a localized gain in transcriptional signal ordinarily used for a T helper 1–type cytokine (IFN-γ) in combination with allergy-driven overproduction of T helper 2–type cytokines.
Inhibition of Nuclear Factor-κB in T Cells Suppresses Lung Fibrosis
Authors: Hajime Fujimoto, Corina N. D'Alessandro-Gabazza, Moorthy S. S. Palanki, Paul E. Erdman, Takehiro Takagi, Esteban C. Gabazza, Nelson E. Bruno, Yutaka Yano, Tatsuya Hayashi, Shigenori Tamaki, Yasuhiro Sumida, Yukihiko Adachi, Koji Suzuki, Osamu Taguchi
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Cytokines secreted by T cells play a pivotal role in the pathogenesis of lung injury and fibrosis, and the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1 are involved in the expression of cytokines from T cells during lung injury.We assessed the potential therapeutic effect of SP100030, a specific inhibitor of T-cell NF-kappaB and AP-1 in lung fibrosis.The effect of SP100030 was evaluated using a mouse model of chronic lung fibrosis.Mice treated with SP100030, as compared with untreated mice, had significantly less cachexia and less lung injury and had decreased levels of inflammatory cytokines and growth factors, decreased activation of coagulation activation, and decreased collagen deposition in the lung. The inhibitory activity of SP100030 was dose dependent and was effective in acute and chronic phases of lung fibrosis. SP100030 inhibited the activation of the protein kinase C-isoform in T-cell lines and suppressed NF-kappaB-driven cytokine expression in CD4(+) and CD8(+) T cells.These results suggest that the specific inhibition of NF-kappaB could be useful for the treatment of lung fibrosis.
The Healthy Eating Index 2005 and Risk for Pancreatic Cancer in the NIH-AARP Study
Authors: H. Arem, J. Reedy, J. Sampson, L. Jiao, A. R. Hollenbeck, H. Risch, S. T. Mayne, R. Z. Stolzenberg-Solomon
Journal: JNCI Journal of the National Cancer Institute (2013)

Dietary pattern analyses characterizing combinations of food intakes offer conceptual and statistical advantages over food- and nutrient-based analyses of disease risk. However, few studies have examined dietary patterns and pancreatic cancer risk and none focused on the 2005 Dietary Guidelines for Americans. We used the Healthy Eating Index 2005 (HEI-2005) to estimate the association between meeting those dietary guidelines and pancreatic cancer risk. We calculated the HEI-2005 score for 537 218 men and women in the National Institutes of Health–American Association of Retired Persons Diet and Health Study using responses to food frequency questionnaires returned in 1995 and 1996. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of pancreatic cancer according to HEI-2005 quintiles and explored effect modification by known risk factors. Pinteraction values were calculated using the Wald test. All statistical tests were two-sided. We identified 2383 incident, exocrine pancreatic cancer cases (median = 10.5 years follow-up). Comparing participants who met the most dietary guidelines (Q5) with those who met the fewest guidelines (Q1), we observed a reduced risk of pancreatic cancer (HR = 0.85, 95% CI = 0.74 to 0.97). Among men there was an interaction by body mass index ( Pinteraction = .03), with a hazard ratio of 0.72 (95% CI = 0.59 to 0.88) comparing Q5 vs Q1 in overweight/obese men (body mass index ≥25kg/m 2 ) but no association among normal weight men. Our findings support the hypothesis that consuming a high-quality diet, as scored by the HEI-2005, may reduce the risk of pancreatic cancer.
Radiological determination of spleen size.
Authors: L M Blendis, R Williams, L Kreel
Journal: Gut (1969)

A simple method for determining the size of the spleen would be of value in the study of both normal function and hypersplenism.In the past various radiological methods have been used.These include measurement of the long axis of the spleen (Bergstrand and Ekman, 1957), the width of the spleen 2 cm from the lower pole (Wyman, 1954;Brogdon and Crow, 1959), or the length and width (Rosch, 1965; Whitley, Maynard, and Rhyne, 1966).These are all dependent on a clear outline of the spleen but the spleen cannot always be seen even in good quality radiographs taken with measures to prevent scatter, particularly in the very thin subject.To delineate the outline further, some workers have used Siedlitz powders to distend the stomach and inflated the colon with air via a rectal tube (Zelman and Pickard, 1955; Zelman, 1958).Radioactive scanning of the spleen is also possible (Croll, Brady, Brodsky, and Stanton, 1965; Marsh, Lewis, and Szur, 1966) but this involves considerable
Low molecular weight heat shock protein HSP27 is a prognostic indicator in rectal cancer but not colon cancer
Authors: E. M. Tweedle, I. Khattak, C. W. Ang, T. Nedjadi, R. Jenkins, B. K. Park, H. Kalirai, A. Dodson, B. Azadeh, M. Terlizzo, H. Grabsch, W. Mueller, S. Myint, P. Clark, H. Wong, W. Greenhalf, J. P. Neoptolemos, P. S. Rooney, E. Costello
Journal: Gut (2010)

<h3>Objective</h3> There are currently no biomarkers in routine clinical use for determining prognosis in rectal cancer. In a preliminary proteomic study, variation in the levels of heat shock protein 27 (HSP27) in colorectal cancer samples was observed. The expression of HSP27 in a cohort of 404 patients with colorectal cancer with a predominantly poor prognosis was characterised and an investigation was undertaken of whether the differences were related to clinical outcome. HSP27 levels in diagnostic rectal biopsies were compared with matched surgical samples to determine whether changes in expression occurred in the time between biopsy and surgery and to investigate whether preoperative radiotherapy affected expression. Finally, the relationship between HSP27 expression and outcome was examined in an independent cohort of 315 patients with a predominantly good prognosis. <h3>Methods</h3> HSP27 levels were determined using combined two-dimensional gel electrophoresis and tandem mass spectrometry (12 cases) and by immunohistochemistry using tissue microarrays of colorectal cancers sampled at surgery and 80 diagnostic rectal biopsies. <h3>Results</h3> HSP27 overexpression was strongly associated with poor cancer-specific survival in rectal cancer (n=205, p=0.0063) but not colon cancer (n=199, p=0.7385) in the cohort with a poor prognosis. Multivariate Cox regression confirmed nodal metastases (p=0.0001) and HSP27 expression (p=0.0233) as independent markers of survival in rectal cancer. HSP27 levels remained unchanged in the majority of cases (65/80, 81%) between diagnostic biopsies and matched surgical samples, regardless of whether patients had undergone preoperative radiotherapy. In the cohort with a good prognosis the association between HSP27 and survival was not observed in patients with either rectal (n=115; p=0.308) or colon cancer (n=200; p=0.713). <h3>Conclusion</h3> In a large cohort of patients with a poor prognosis, HSP27 is an independent marker of poor outcome in rectal cancer; its expression is not altered by neoadjuvant radiotherapy. This finding requires validation in an independent similar cohort of patients with rectal cancer. HSP27 levels merit evaluation as a stratification factor for treatment of rectal cancer.
Generation of Potent Antitumor CTL from Patients with Multiple Myeloma Directed against HM1.24
Authors: Steven B. Rew, Karl Peggs, Irene Sanjuan, Arnold R. Pizzey, Yasuo Koishihara, Shigeto Kawai, Masaaki Kosaka, Shuji Ozaki, Benjamin Chain, Kwee L. Yong
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The purpose of this work was to test the suitability of the HM1.24 antigen as a CTL target for immunotherapy of patients with multiple myeloma. Experimental Design: Antigen-specific T cells were generated from patients with multiple myeloma using stimulation with protein-pulsed dendritic cells and tested in ELISPOT and CTL assays. Results: HM1.24-primed T cells responded selectively to HM1.24-loaded autologous peripheral blood mononuclear cells (PBMC) in an IFN-γ ELISPOT assay (median, 342; range, 198-495 IFN-γ–producing cells/105 cf. unloaded PBMC median, 98; range, 7-137; P &amp;lt; 0.05, n = 5) and also to autologous malignant plasma cells (MPC; median, 227; range, 153-335; P &amp;lt; 0.05 when compared with the response to allogeneic MPC median, 57; range, 22-158; n = 5). HM1.24-primed T cells lysed autologous MPC (at 20:1 E/T ratio: median, 48% specific killing; range, 23-88%; at 10:1 E/T ratio: median, 43%; range, 15-80%; n = 12) but not allogeneic MPC. Lysis of autologous MPC was inhibited by anti–MHC class I but not anti–MHC class II antibodies and was blocked by Concanamycin A. Lysis of autologous MPC was blocked by competition with autologous HM1.24-transfected dendritic cells (10:1 ratio with autologous MPC). Unmanipulated, or control plasmid–transfected dendritic cells had no effect on lysis of autologous MPC. Conclusion: Our results indicate that HM1.24 is a promising target for immunotherapy of multiple myeloma.
p53-Independent Abrogation of a Postmitotic Checkpoint Contributes to Human Papillomavirus <i>E6</i>-Induced Polyploidy
Authors: Yingwang Liu, Susan A. Heilman, Diego Illanes, Greenfield Sluder, Jason J. Chen
Journal: Cancer Research (2007)

Abstract Polyploidy is often an early event during cervical carcinogenesis, and it predisposes cells to aneuploidy, which is thought to play a causal role in tumorigenesis. Cervical and anogenital cancers are induced by the high-risk types of human papillomavirus (HPV). The HPV E6 oncoprotein induces polyploidy in human keratinocytes, yet the mechanism is not known. It was believed that E6 induces polyploidy by abrogating the spindle checkpoint after mitotic stress. We have tested this hypothesis using human keratinocytes in which E6 expression induces a significant amount of polyploidy. We found that E6 expression does not affect the spindle checkpoint. Instead, we provide direct evidence that E6 is capable of abrogating the subsequent G1 arrest after adaptation of the mitotic stress. E6 targets p53 for degradation, and previous studies have shown an important role for p53 in modulation of the G1 arrest after mitotic stress. Importantly, we have discovered that E6 mutants defective in p53 degradation also induce polyploidy, although with lower efficiency. These results suggest that E6 is able to induce polyploidy via both p53-dependent and p53-independent mechanisms. Therefore, our studies highlight a novel function of HPV E6 that may contribute to HPV-induced carcinogenesis and improve our understanding of the onset of the disease. [Cancer Res 2007;67(6):2603–10]
Multidisciplinary team-led management of acute Type B aortic dissection in the United Kingdom?
Authors: Mark L Field, Manoj Kuduvalli, Aung Oo
Journal: Journal of the Royal Society of Medicine (2011)

Acute aortic dissection is associated with poor outcomes.1 Aortic dissection is classified as Stanford Type A when involving the ascending aorta and Type B when involving the descending aorta or arch.2

Stanford Type A has a well-accepted management algorithm with aggressive control of blood pressure and immediate transfer to a cardiac surgery unit for surgical intervention (American Heart Association Guidelines [AHA] and European Society of Cardiology3,4). Stanford Type B, however, has been shown to have significantly better outcomes when treated medically (International Registry Aortic Dissection [IRAD]1). As such simple uncomplicated acute Type B aortic dissection within the UK has for decades largely been treated in non-specialized departments with attempts to refer to cardiac services rebuffed. The incidence and prevalence of Type B aortic dissection in the UK is unknown and there has been no systematic collection of data on diagnosis, management or outcomes. These patients are commonly young and they are not served well by the current often indifferent attitude of concerned specialties.

Type B aortic dissection is a complex dynamic disease with true and false lumens, rentry sites and malperfusion syndromes affecting multiple organs. Selected complicated cases with malperfusion syndromes are accepted into specialized units for intervention, either open, endovascular or hybrid approaches, however, the majority are managed medically. Managing blood pressure is complex in this setting and on occasions requires high-level care with invasive monitoring including arterial lines and spinal drainage. As thoracic aortic intervention in the UK enters a new era, it is incumbent on us to set standards for best care. Our suggestion is that it is no longer an acceptable standard of care to leave management of patients with acute Type B aortic dissections to non-specialized units.

We review current relevant guidelines and develop a case for registration and or transfer of all Type B aortic dissections to centres which offer a subspecialized aortic service which is multidisciplinary team (MDT)-led and capable of offering a full range of interventional services whether open surgery, endovascular or a hybrid procedure.
Passive smoking and respiratory symptoms in the FinEsS Study
Authors: M.L. Larsson, H-M. Loit, M. Meren, J. Põlluste, A. Magnusson, K. Larsson, B. Lundbäck
Journal: European Respiratory Journal (2003)

The aim of the present study was to examine the relationship between reported environmental tobacco smoke (ETS) exposure and respiratory symptoms. In 1996, a postal questionnaire was randomly distributed in three areas of Estonia to a population-based sample, of which 4,995 females and 1,822 males had never smoked. The main outcome measures were current respiratory symptoms and the amount of reported ETS exposure outside the home. ETS exposure at home was more common in females (31% versus 19%), while exposure outside of the home was more common in males (53% versus 7%). Females reported more symptoms from tobacco smoke than males (37.7% versus 21.6%). If ETS exposure outside of the home exceeded 5 h daily, the risk for wheeze (odds ratio (OR) 2.67, 95% confidence interval (CI) 1.98–3.61) and physician-diagnosed asthma (OR 1.79, 1.02–3.16) were increased. ETS exposure outside of the home was shown to be strongly related to almost all respiratory symptoms in a dose/response manner. ETS exposure at home did not show significantly elevated ORs for any respiratory symptoms. This study shows that females seem to be more troubled by environmental smoke exposure than males and provides further evidence of the serious health hazards associated with environmental smoke exposure. Indeed, the findings of this study support a ban on smoking in the workplace and public areas.