tbuckley/cabot-search huggingface dataset:
Herpes simplex virus type 1 thymidine kinase–armed bovine herpesvirus type 4–based vector displays enhanced oncolytic properties in immunocompetent orthotopic syngenic mouse and rat glioma models
Authors: Marco Redaelli, Valentina Franceschi, Antonio Capocefalo, Domenico D'Avella, Luca Denaro, Sandro Cavirani, Carla Mucignat-Caretta, Gaetano Donofrio
Journal: Neuro-Oncology (2012)

Gliomas are devastating tumors of the brain resistant to therapies. Although some therapies can prolong the survival time among the affected persons, gliomas are not curable and new therapeutic approaches need to be investigated. Oncolytic viruses seem to represent an interesting alternative, because anticancer agents and new viral agents have to be explored to identify the one with the best characteristics. Bovine herpesvirus type 4 (BoHV-4) is a gammaherpesvirus with a striking tropism and permissive replication toward cancer cells and rat, mouse, and human glioma cells. However, BoHV-4 does not replicate into the normal brain parenchyma. The BoHV-4 genome was cloned as a bacterial artificial chromosome to easily manipulate this large genome and be used as a viral vector platform. In the present study, a herpes simplex virus type 1 thymidine kinase suicide gene–armed BoHV-4 was constructed, characterized, and proven to be highly efficient in killing by apoptosis glioma cells in vitro when co-administered with the pro-drug ganciclovir (GCV). When the armed BoHV-4/GCV therapeutic approach was tested in immunocompetent orthotopic syngenic mouse and rat glioma models in vivo, a significant increase in survival among the treated animals was achieved, and some animals were completely cured. The BoHV-4–based vector represents a promising alternative oncolytic virus for glioma and, perhaps, other types of cancer treatment that merit further investigation. This article represents the result of a mutual interaction between human medical science and veterinary science, a combination of scientific knowledge often neglected.
A Phase II, Pharmacokinetic, and Biological Correlative Study of Oblimersen Sodium and Docetaxel in Patients with Hormone-Refractory Prostate Cancer
Authors: Anthony W. Tolcher, Kim Chi, John Kuhn, Martin Gleave, Amita Patnaik, Chris Takimoto, Garry Schwartz, Ian Thompson, Kristin Berg, Susan D'Aloisio, Nevin Murray, Stanley R. Frankel, Elzbieta Izbicka, Eric Rowinsky
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To determine the antitumor activity and safety of oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the bcl-2 mRNA, with docetaxel in patients with hormone-refractory prostate cancer (HRPC) and to determine if relevant pharmacokinetic and pharmacodynamic variables of oblimersen or docetaxel influence response to this therapy. Experimental Design: Patients with HRPC were treated with oblimersen sodium by continuous i.v. infusion on days 1 to 8 with docetaxel given i.v. over 1 hour on day 6 every 3 weeks. Plasma samples were analyzed to characterize the pharmacokinetic variables of both oblimersen and docetaxel, and paired collections of peripheral blood mononuclear cells were collected to determine Bcl-2 protein expression pretreatment and post-treatment. Results: Twenty-eight patients received 173 courses of oblimersen (7 mg/kg/d continuous i.v. infusion on days 1-8) and docetaxel (75 mg/m2 i.v. on day 6). Prostate-specific antigen responses were observed in 14 of 27 (52%) patients, whereas 4 of 12 (33%) patients with bidimensionally measurable disease had objective responses. The mean oblimersen steady-state concentration (Css) was a significant determinant of antitumor activity; mean Css values were higher in responders compared with nonresponders (6.24 ± 1.68 versus 4.27 ± 1.22; P = 0.008). The median survival of all patients was 19.8 months. Bcl-2 protein expression decreased a median of 49.9% in peripheral blood mononuclear cells post-treatment, but the individual incremental change did not correlate with either oblimersen Css or response. Conclusions: Oblimersen combined with docetaxel is an active combination in HRPC patients demonstrating both an encouraging response rate and an overall median survival. The absence of severe toxicities at this recommended dose, evidence of Bcl-2 protein inhibition, and encouraging antitumor activity in HPRC patients warrant further clinical evaluation of this combination, including studies to optimize oblimersen Css.
1096 ASUNAPREVIR (ASV; BMS-650032), AN NS3 PROTEASE INHIBITOR, IN COMBINATION WITH PEGINTERFERON AND RIBAVIRIN IN TREATMENT-NAIVE PATIENTS WITH GENOTYPE 1 CHRONIC HEPATITIS C INFECTION
Authors: J.-P. Bronowicki, S. Pol, P. Thuluvath, D. Larrey, C.T. Martorell, V.K. Rustgi, D.W. Morris, Z. Younes, M.W. Fried, M. Bourliere, C. Hezode, R. Reddy, O. Massoud, G.A. Abrams, V. Ratziu, B. He, T. Eley, A. Ahmad, A. Thiry, C. Llamoso, P. Mendez, E. Hughes
Journal: Journal of Hepatology (2012)
Clinical presentation of chronic obstructive pulmonary disease (COPD): Study on-sint
Authors: Lucía Marín Barrera, Cecilia López Ramírez, José Luis López-Campos, Carmen Calero Acuña, Alberto Fernández-Villar, Cristina Represas Represas, Ana Priegue Carrera, Ricard Casamor
Journal: European Respiratory Journal (2014)

OBJECTIVE:Identify clinical signs and symptoms,previous exacerbations,comorbidities and clinical situation at the time of diagnosis COPD in Primary Care and Respiratory Units.

METHODS:Retrospective,multicenter observational study where patient data were collected from single medical visit and by medicals records.On-Sint cohort was formed by adult COPD patients,smokers or ex-smokers(≥10packs-years),who were regularly followed-up by 329 primary care physicians(PC) or Pulmonologists(P).Clinical signs and symptoms at the moment of diagnosis COPD,frequency and severity of exacerbations,comorbidities,pulmonary function,sociodemographic and anthropometric data were collected and quantitative data expressed as mean(standard deviation).

RESULTS:1214 patients met inclusion criteria (age of 66.4(9.7)years,78.7% male,857(70.6%)by PC).The average followed-up time from diagnosis was 8(7.2)years. BMI 27.7(4.1),77% with a BMI>25.54.8% were active smokers.At least 90.9% had one comorbidity with a mean of 2.8(SD 1.8).Most of the patients suffered more than one symptom at the same time.The most prevalent symptom was dyspnea in 92.2%(52.7% grade 0-1,47.3% grade 2-4 in mMRC),followed by chronic cough(83.2%)and chronic sputum(72.2%) and 13.3% had other symptoms.Only 7.2% were asymptomatic.52.8% had chronic respiratory failure,53.5% had suffered an exacerbation in the last year(mean 2.3,SD 1.9)and 18% were hospitalized.Patients included by PC had higher frequency of cough,expectoration,exacerbations and comorbidities than patients included by P.

CONCLUSIONS:At diagnosis COPD patients present with intense symptoms,exacerbations and comorbidities already.This suggests the need to intensify an earlier detection of COPD.
Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation
Authors: Alexandre Calon, Elisa Espinet, Sergio Palomo-Ponce, Daniele V.F. Tauriello, Mar Iglesias, María Virtudes Céspedes, Marta Sevillano, Cristina Nadal, Peter Jung, Xiang H.-F. Zhang, Daniel Byrom, Antoni Riera, David Rossell, Ramón Mangues, Joan Massagué, Elena Sancho, Eduard Batlle
Journal: Cancer Cell (2012)
Curcumin inhibits VEGF-mediated angiogenesis in human intestinal microvascular endothelial cells through COX-2 and MAPK inhibition
Authors: D G Binion, M F Otterson, P Rafiee
Journal: Gut (2008)

<h3>Background:</h3> Angiogenesis, the growth of new blood vessels, is a critical homeostatic mechanism which regulates vascular populations in response to physiological requirements and pathophysiological demand, including chronic inflammation and cancer. The importance of angiogenesis in gastrointestinal chronic inflammation and cancer has been defined, as antiangiogenic therapy has demonstrated benefit in models of inflammatory bowel disease and colon cancer treatment. Curcumin is a natural product undergoing evaluation for the treatment of chronic inflammation, including inflammatory bowel disease (IBD). The effect of curcumin on human intestinal angiogenesis is not defined. <h3>Methods:</h3> The antiangiogenic effect of curcumin on in vitro angiogenesis was examined using primary cultures of human intestinal microvascular endothelial cells (HIMECs), stimulated with vascular endothelial growth factor (VEGF). <h3>Results:</h3> Curcumin inhibited proliferation, cell migration and tube formation in HIMECs induced by VEGF. Activation of HIMECs by VEGF resulted in enhanced expression of cyclo-oxygenase-2 (COX-2) mRNA, protein and prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) production. Pretreatment of HIMECs with 10 μM curcumin as well as 1 μM NS398, a selective inhibitor of COX-2, resulted in inhibition of COX-2 at the mRNA and protein level and PGE<sub>2</sub> production. Similarly COX-2 expression in HIMECs was significantly inhibited by Jun N-terminal kinase (JNK; SP600125) and p38 mitogen-activated protein kinase (MAPK; SB203580) inhibitors and was reduced by p44/42 MAPK inhibitor (PD098059). <h3>Conclusions:</h3> Taken together, these data demonstrate an important role for COX-2 in the regulation of angiogenesis in HIMECs via MAPKs. Moreover, curcumin inhibits microvascular endothelial cell angiogenesis through inhibition of COX-2 expression and PGE<sub>2</sub> production, suggesting that this natural product possesses antiangiogenic properties, which warrants further investigation as adjuvant treatment of IBD and cancer.
Low incidence of pulmonary complications following nonmyeloablative stem cell transplantation
Authors: S. Nusair, R. Breuer, M.Y. Shapira, N. Berkman, R. Or
Journal: European Respiratory Journal (2004)

Bone marrow transplantation is associated with pulmonary opportunistic infections and immune-mediated pulmonary processes such as idiopathic pneumonia syndrome and bronchiolitis obliterans. The aim of the present study was to test the hypothesis that nonmyeloablative stem cell transplantation (NST) has less adverse effects on the lungs. A review was undertaken of the pulmonary complications occurring in 53 patients with various haematological malignancies, some of whom were considered high-risk patients with chemoresistant disease, who underwent fludarabine-based irradiation-free conditioning for NST performed between March 1996 and October 1998. All data related to transplant procedure, disease outcome, graft- versus -host disease (GVHD), chest imaging, microbial cultures and lung biopsies, were retrieved from information collected prospectively at the time of transplantation. The median follow-up period after transplantation was 45 months, with 35 patients surviving &gt;100 days. Approximately half of the patients displayed some form of GVHD, with 11% developing severe chronic GVHD. In 17 (32%) patients, the lungs were somehow adversely affected. Only two (3.8%) patients developed a clinical picture consistent with idiopathic pneumonia syndrome and none developed diffuse alveolar haemorrhage or bronchiolitis obliterans. Dose-reduced conditioning is associated with a low rate of pulmonary toxicity and side-effects. These findings may extend understanding of significant immune-mediated complications occurring after bone marrow transplantation.
Free radicals and inflammation
Authors: F BERENBAUM
Journal: Annals of the Rheumatic Diseases (2001)

Free radicals and inflammation . P G Winyard, D R Blake, C H Evans. (Pp 272; DM238.) Basle: Birkhauser Verlag AG, 2000. ISBN 3-7643-5851-3.

Understanding the genesis, propagation, and persistence of the inflammatory process in arthritis is one of the most challenging problems facing biologists and clinical investigators. Our understanding of the role of free radicals in inflammation has increased dramatically over the past decade. Searches for key words such as “reactive oxygen species and inflammation” in the PubMed database turn up 1000 papers—900 of which will have been written within the past 10 years! It …
Obesity Is an Independent Risk Factor for Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients
Authors: Takamasa Ohki, Ryosuke Tateishi, Takahisa Sato, Ryota Masuzaki, Jun Imamura, Tadashi Goto, Noriyo Yamashiki, Hideo Yoshida, Fumihiko Kanai, Naoya Kato, Shuichiro Shiina, Haruhiko Yoshida, Takao Kawabe, Masao Omata
Journal: Clinical Gastroenterology and Hepatology (2008)
Innovations in Treatment for Drug Abuse: Solutions to a Public Health Problem
Authors: Jody L Sindelar, David A Fiellin
Journal: Annual Review of Public Health (2001)

▪ Abstract Illicit drug use is an important public health problem with broad social costs. The low effectiveness of prevention efforts leaves treatment of drug dependence as one of the most powerful means of fighting illicit drug use. Treatment reduces drug use and crime and increases individuals' functioning. However, programs that treat drug dependence have high dropout rates and low completion rates. In addition, some individuals continue to use drugs while in treatment, and relapse is common. Furthermore, only a fraction of those who need treatment receive it. Recently, there have been important innovations that reduce barriers and increase effectiveness of treatment. These innovations include new pharmacological agents, novel counseling strategies, promising ways to motivate, and treatment in new settings. This paper describes standard treatments and recent innovations designed to increase (a) effectiveness of treatment, (b) motivation to seek care, (c) access, (d) retention, and (e) cost-effectiveness. We provide criteria on how these innovations should be evaluated in order to determine which should be adopted, funded, and transferred to existing and future treatment programs.
Hypoxia-Inducible Factor-1 Mediates Activation of Cultured Vascular Endothelial Cells by Inducing Multiple Angiogenic Factors
Authors: Midori Yamakawa, Louis X. Liu, Taro Date, Adam J. Belanger, Karen A. Vincent, Geoffrey Y. Akita, Takayuki Kuriyama, Seng H. Cheng, Richard J. Gregory, Canwen Jiang
Journal: Circulation Research (2003)

Hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of vascular endothelial growth factor (VEGF) and other hypoxia-responsive genes. Transgenic expression of a constitutively stable HIF-1alpha mutant increases the number of vascular vessels without vascular leakage, tissue edema, or inflammation. This study aimed to investigate the molecular basis by which HIF-1 mediates the angiogenic response to hypoxia. In primary human endothelial cells, hypoxia, desferrioxamine, or infection with Ad2/HIF-1alpha/VP16, an adenoviral vector encoding a constitutively stable hybrid form of HIF-1alpha, increased the mRNA and protein levels of VEGF, angiopoietin-2 (Ang-2), and angiopoietin-4 (Ang-4). Infection with Ad2/CMVEV (a control vector expressing no transgene) had no effect. Angiopoietin-1 (Ang-1) expression was not detected in human endothelial cells. Ang-4 was also induced by hypoxia or Ad2/HIF-1alpha/VP16 in human cardiac cells, whereas Ang-1 expression remained unchanged. Recombinant Ang-4 protein protected endothelial cells against serum starvation-induced apoptosis and increased cultured endothelial cell migration and tube formation. Ad2/HIF-1alpha/VP16 stimulated endothelial cell proliferation and tube formation. Hypoxia- or Ad2/HIF-1alpha/VP16-induced tube formation was significantly reduced by a Tie-2 inhibitor. These results suggest that HIF-1 mediates the angiogenic response to hypoxia by upregulating the expression of multiple angiogenic factors. Ang-4 can function similarly as Ang-1 and substitute for Ang-1 to participate in hypoxia-induced angiogenesis. Activation of the angiopoietin/Tie-2 system may play a role in the ability of HIF-1 to induce hypervascularity without excessive permeability.
Proteasome Inhibition Blocks Ligand-Induced Dynamic Processing and Internalization of Epidermal Growth Factor Receptor via Altered Receptor Ubiquitination and Phosphorylation
Authors: Aparna H. Kesarwala, Mustapha M. Samrakandi, David Piwnica-Worms
Journal: Cancer Research (2009)

Epidermal growth factor (EGF) receptor (EGFR), a member of the EGF superfamily of receptor tyrosine kinases, is a critical regulator of cell growth and an important target for single agent and combination anticancer therapeutics. To further investigate the dynamics of ligand-induced EGFR processing and regulation noninvasively, we developed a chimeric EGFR-firefly luciferase (FLuc) fusion reporter to directly monitor processing of EGFR in real-time. In a stable HeLa cell line expressing the reporter at physiologically relevant levels, bioluminescence imaging continuously monitored reporter dynamics, correlating with the ligand-induced response of endogenous EGFR as determined by Western blot, subcellular localization of an EGFR-green fluorescent protein (GFP) fusion protein, and validated pharmacologic responses. The signaling competency of the reporter was confirmed by gene rescue experiments in EGFR-null cells. Bioluminescence analysis further showed that proteasome inhibition with bortezomib or MG132 attenuated overall ligand-induced degradation of EGFR. In cells expressing EGFR-GFP, pretreatment with proteasome inhibitors trapped essentially all of the receptor at the cell membrane both before and after ligand-induced activation with EGF. Furthermore, proteasome inhibition enhanced receptor ubiquitination in both the basal and ligand-activated states as well as delayed the processing of ligand-activated phosphorylation of the receptor, kinetically correlating with attenuated receptor degradation. These observations point to a potential mechanism for the synergistic therapeutic effects of combination EGFR- and proteasome-targeted therapies.
Vertebral sclerosis in adults.
Authors: A S Russell, J S Percy, B C Lentle
Journal: Annals of the Rheumatic Diseases (1979)

Narrowing of the intervertebral disc space with sclerosis of the adjacent vertebral bodies may occur as a consequence of infection, neoplasia, trauma, or rheumatic disease. Some patients have been described with backache and these radiological appearances without any primary cause being apparent. The lesions were almost always of 1 or, at most, 2 vertebrae and most frequently involved the inferior margin of L4. We describe 3 patients with far more extensive vertebral involvement and present the clinical, radiological, scintiscan, and histological findings. The only patient we have seen with the better known, isolated L4/5 lesion was shown on biopsy to have staphylococcal osteomyelitis. For this reason we would still recommend a biopsy of all such sclerotic vertebral lesions if they occur in the absence of other rheumatic disease.
Imaging at London 2012 summer Olympic Games: analysis of demand and distribution of workload
Authors: Sarath Bethapudi, Richard Budgett, Lars Engebretsen, Philip O'Connor
Journal: British Journal of Sports Medicine (2013)

Background Very little data on the provision of imaging services at the summer Olympic Games have been published before. With 7.9 million Euros (£6.6 million, US$11 million) invested into setting up the imaging equipment at the purpose-built polyclinics for London 2012 summer Olympics, an ideal opportunity was presented to study the demand and distribution of workload on imaging services at the games. Setting Imaging services within polyclinics, London 2012 summer Olympic Games. Aims To analyse the demand and distribution of workload on radiology services at the London 2012 summer Olympic Games. Methods Data on radiological investigations performed at London 2012 summer Olympic Games were retrieved from Radiology Information System-picture archiving communication system, ATOS medical encounter database and analysed. Results 1711 diagnostic and interventional procedures were performed at the Stratford Polyclinic within the main games village. Of these 48.8% were MRI scans, 20.2% were diagnostic ultrasound examinations, 23.6% were plain radiographs, 2.9% were CT scans and interventional procedures accounted for 4.3%. Nearly 75% of imaging was performed on athletes while less than 5% of the services were utilised by the workforce. Demand on radiology services peaked during week 2 of the games. Conclusions Imaging played a substantial role in providing medical services at the London 2012 summer Olympics.
The Certainties and the Uncertainties of Ductal Carcinoma In Situ
Authors: M. Morrow
Journal: JNCI Journal of the National Cancer Institute (2004)

Ductal carcinoma in situ (DCIS) was an uncommon problem before the use of screening mammography, but it is estimated that 55 700 new cases of DCIS were diagnosed in the United States in 2003 (1). Our lack of understanding of the natural history of DCIS, coupled with treatment options ranging from excision alone to mastectomy plus tamoxifen therapy, has resulted in confusion among both women and their physicians regarding the selection of an appropriate management strategy. This is refl ected in the study by Baxter et al. (2), in this issue of the Journal, who documented that between 1992 and 1999 the use of both mastectomy and axillary surgery for women with DCIS decreased, while treatment with excision alone remained common throughout the study period. The authors concluded that their study documents both overtreatment (mastectomy) and undertreatment (failure to use radiation) and that care could be improved with the use of standards. What information exists to develop standards for treating DCIS? First, we know that, even with the availability of largecore biopsy needles and vacuum-assisted biopsy devices, 11%– 20% of mammographic lesions diagnosed as DCIS will be found to contain invasive cancer when completely excised (3,4). Complete excision is clearly a management requirement to be certain that only DCIS is present, but it may necessitate mastectomy. Although DCIS is thought of as early-stage cancer, DCIS lesions are often quite large. In a study of mastectomy specimens containing DCIS (5), 46% of the lesions were larger than 3 cm in size, even though 86% were mammographically detected. At present, no data are available from population-based studies to indicate how often mastectomy is medically necessary in DCIS, but a report from a single institution (6) suggests that mastectomy is medically indicated statistically signi fi cantly more frequently in DCIS than in stage I invasive breast cancer, primarily because of the large size of many of the lesions. Information from a large population-based dataset on the medical necessity of mastectomy would provide valuable insight into the issue of overtreatment. Another certainty is that pure DCIS does not metastasize to the axillary lymph nodes, or elsewhere, so that axillary dissection should not be a part of surgical therapy. This fact appears to be widely recognized, as shown by the 8.5% incidence of