tbuckley/cabot-search huggingface dataset:
Altered Nrf2/Keap1-Bach1 equilibrium in pulmonary emphysema
Authors: D Goven, A Boutten, V Lecon-Malas, J Marchal-Somme, N Amara, B Crestani, M Fournier, G Leseche, P Soler, J Boczkowski, M Bonay
Journal: Thorax (2008)

<h3>Background:</h3> Oxidative stress, resulting from the increased oxidative burden and decreased level of antioxidant proteins, plays a role in the pathophysiology of smoking-related pulmonary emphysema. Expression of several antioxidant proteins, such as heme oxygenase-1 (HO-1), glutathione peroxidase 2 (GPX2) and NAD(P)H:quinone oxidoreductase 1 (NQO1), results from an equilibrium created by positive or negative regulation by the transcription factors Nrf2, Keap1 and Bach1, respectively. However, whether the expression of these transcription factors is altered in emphysema and could account for decreased expression of antioxidant proteins is not known. A study was undertaken to investigate the expression and subcellular localisation of Nrf2, Keap1 and Bach1 as potential regulators of HO-1, GPX2 and NQO1 in alveolar macrophages, a key cell in oxidative stress, in lung surgical specimens from non-smokers without emphysema and smokers with and without emphysema. <h3>Methods and results:</h3> Western blot, immunohistochemical and laser scanning confocal analysis revealed that the Nrf2 protein level decreased significantly in whole lung tissue and alveolar macrophages (cytosol and nucleus) in patients with emphysema compared with those without emphysema. Conversely, Bach1 and Keap1 levels were increased in patients with emphysema. These modifications were associated with a parallel decrease in the expression of HO-1, GPX2 and NQO1 at the cellular level, which was inversely correlated with airway obstruction and distension indexes, and increased macrophage expression of the lipid peroxidation product 4-hydroxy-2-nonenal. Silencing RNA experiments in vitro in THP-1 cells were performed to confirm the cause-effect relation between the loss of Nrf2 and the decrease in HO-1, NQO1 and GPX2 expression. Nrf2/Keap1-Bach1 equilibrium was altered in alveolar macrophages in pulmonary emphysema, which points to a decreased stress response phenotype. <h3>Conclusions:</h3> This finding opens a new view of the pathophysiology of emphysema and could provide the basis for new therapeutic approaches based on preservation and/or restoration of such equilibrium.
Comparison of initial characteristics and long-term outcome of patients with lymphocyte-predominant Hodgkin lymphoma and classical Hodgkin lymphoma at clinical stages IA and IIA prospectively treated by brief anthracycline-based chemotherapies plus extended high-dose irradiation
Authors: P. Feugier
Journal: Blood (2004)

Lymphocyte-predominant Hodgkin lymphoma (LPHL), according to the Revised European-American Lymphoma classification, was considered on a retrospective basis as a specific clinical entity with a large majority of patients at clinical stage (CS) IA or IIA. Of the 500 patients with CS IA/IIA Hodgkin lymphoma (HL) prospectively treated between 1981 and 1996 by one or 3 courses of anthracycline-based chemotherapies combined with high-dose extended irradiation, disease in 42 patients was reclassified as LPHL. These 42 patients, none of whom had mediastinal involvement (MI), were compared with the 458 patients with classical HL (cHL), 144 without MI and 314 with MI. Surprisingly, the male-female ratio, age, first site involved, hemoglobin level, lymphocyte count, and sedimentation rate of patients with LPHL and cHL without MI were identical and significantly different from those of patients with cHL with MI. Moreover, 15-year HL mortality rates were similarly low in patients with LPHL (2.4%) and cHL without MI (0.7%). Overall survival rates were also similar (86% and 82%) and as high as 100% and 95% in patients treated before the age of 40 years. This study demonstrated that LPHL and cHL without MI shared the same presenting characteristics and the same excellent long-term prognosis after a brief anthracycline-based chemotherapy plus high-dose extended irradiation.
Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice
Authors: Almut Grenz, Jessica D. Bauerle, Julee H. Dalton, Douglas Ridyard, Alexander Badulak, Eunyoung Tak, Eóin N. McNamee, Eric Clambey, Radu Moldovan, German Reyes, Jost Klawitter, Kelly Ambler, Kristann Magee, Uwe Christians, Kelley S. Brodsky, Katya Ravid, Doo-Sup Choi, Jiaming Wen, Dmitriy Lukashev, Michael R. Blackburn, Hartmut Osswald, Imogen R. Coe, Bernd Nürnberg, Volker H. Haase, Yang Xia, Michail Sitkovsky, Holger K. Eltzschig
Journal: Journal of Clinical Investigation (2012)

A complex biologic network regulates kidney perfusion under physiologic conditions. This system is profoundly perturbed following renal ischemia, a leading cause of acute kidney injury (AKI) — a life-threatening condition that frequently complicates the care of hospitalized patients. Therapeutic approaches to prevent and treat AKI are extremely limited. Better understanding of the molecular pathways promoting postischemic reflow could provide new candidate targets for AKI therapeutics. Due to its role in adapting tissues to hypoxia, we hypothesized that extracellular adenosine has a regulatory function in the postischemic control of renal perfusion. Consistent with the notion that equilibrative nucleoside transporters (ENTs) terminate adenosine signaling, we observed that pharmacologic ENT inhibition in mice elevated renal adenosine levels and dampened AKI. Deletion of the ENTs resulted in selective protection in Ent1–/– mice. Comprehensive examination of adenosine receptor–knockout mice exposed to AKI demonstrated that renal protection by ENT inhibitors involves the A2B adenosine receptor. Indeed, crosstalk between renal Ent1 and Adora2b expressed on vascular endothelia effectively prevented a postischemic no-reflow phenomenon. These studies identify ENT1 and adenosine receptors as key to the process of reestablishing renal perfusion following ischemic AKI. If translatable from mice to humans, these data have important therapeutic implications.
Eosinophilic bronchitis: clinical manifestations and implications for treatment
Authors: P G Gibson
Journal: Thorax (2002)

Airway inflammation with eosinophils is now reported to occur not only in asthma but in other airway diseases such as cough variant asthma, chronic cough, atopic cough, episodic symptoms without asthma, allergic rhinitis, and COPD. Although the prevalence of eosinophilic bronchitis (EB) is less than in asthma, the causes, mechanisms and treatment of EB in these conditions appears to be similar to asthma where allergen induced IL-5 secretion and symptoms are readily responsive to inhaled corticosteroids. The prognosis of EB without asthma is not known but it may be a precursor for asthma and, if so, recognition of this syndrome may permit effective treatment and reduction in the rising prevalence of asthma. Induced sputum analysis allows recognition of EB in clinical practice. The place of the asthma treatment paradigm with early and sustained corticosteroid treatment needs to be defined in EB without asthma. Airway wall remodelling can occur in rhinitis, COPD, and cough variant asthma with EB. The mechanisms and long term implications of this complication in EB without asthma need to be clarified.
MORTALITY AND MORBIDITY RESULTS FROM THE EUROPEAN WORKING PARTY ON HIGH BLOOD PRESSURE IN THE ELDERLY TRIAL*1, *2
Authors: A. Amery, P. Brixko, D. Clement, A. De Schaepdryver, R. Fagard, J. Forte, J.F. Henry, G. Leonetti, K. O'Malley, T. Strasser, W. Birkenhäger, C. Bulpitt, M. Deruyttere, C. Dollery, F. Forette, R. Hamdy, J.V. Joossens, P. Lund-Johansen, J. Petrie, J. Tuomilehto, B. Williams
Journal: The Lancet (1985)
Progress in Chemoprevention Drug Development: The Promise of Molecular Biomarkers for Prevention of Intraepithelial Neoplasia and Cancer—A Plan to Move Forward
Authors: Gary J. Kelloff, Scott M. Lippman, Andrew J. Dannenberg, Caroline C. Sigman, Homer L. Pearce, Brian J. Reid, Eva Szabo, V. Craig Jordan, Margaret R. Spitz, Gordon B. Mills, Vali A. Papadimitrakopoulou, Reuben Lotan, Bharat B. Aggarwal, Robert S. Bresalier, Jeri Kim, Banu Arun, Karen H. Lu, Melanie E. Thomas, Helen E. Rhodes, Molly A. Brewer, Michele Follen, Dong M. Shin, Howard L. Parnes, Jill M. Siegfried, Alison A. Evans, William J. Blot, Wong-Ho Chow, Patricia L. Blount, Carlo C. Maley, Kenneth K. Wang, Stephen Lam, J. Jack Lee, Steven M. Dubinett, Paul F. Engstrom, Frank L. Meyskens, Joyce O'Shaughnessy, Ernest T. Hawk, Bernard Levin, William G. Nelson, Waun Ki Hong
Journal: Clinical Cancer Research (2006)

This article reviews progress in chemopreventive drug development, especially data and concepts that are new since the 2002 AACR report on treatment and prevention of intraepithelial neoplasia. Molecular biomarker expressions involved in mechanisms of carcinogenesis and genetic progression models of intraepithelial neoplasia are discussed and analyzed for how they can inform mechanism-based, molecularly targeted drug development as well as risk stratification, cohort selection, and end-point selection for clinical trials. We outline the concept of augmenting the risk, mechanistic, and disease data from histopathologic intraepithelial neoplasia assessments with molecular biomarker data. Updates of work in 10 clinical target organ sites include new data on molecular progression, significant completed trials, new agents of interest, and promising directions for future clinical studies. This overview concludes with strategies for accelerating chemopreventive drug development, such as integrating the best science into chemopreventive strategies and regulatory policy, providing incentives for industry to accelerate preventive drugs, fostering multisector cooperation in sharing clinical samples and data, and creating public-private partnerships to foster new regulatory policies and public education.
Guidelines for Preventing Opportunistic Infections among HIV-Infected Persons—2002: Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America*
Authors: Prepared by Henry Masur
Journal: Annals of Internal Medicine (2002)

Summary In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections (OIs) among persons infected with human immunodeficiency virus (HIV); these guidelines were updated in 1997 and 1999. This fourth edition of the guidelines, made available on the Internet in 2001, is intended for clinicians and other health-care providers who care for HIV-infected persons. The goal of these guidelines is to provide evidence-based guidelines for preventing OIs among HIV-infected adults and adolescents, including pregnant women, and HIV-exposed or infected children. Nineteen OIs, or groups of OIs, are addressed, and recommendations are included for preventing exposure to opportunistic pathogens, preventing first episodes of disease by chemoprophylaxis or vaccination (primary prophylaxis), and preventing disease recurrence [secondary prophylaxis]. Major changes since the last edition of the guidelines include 1) updated recommendations for discontinuing primary and secondary OI prophylaxis among persons whose CD4+ T lymphocyte counts have increased in response to antiretroviral therapy; 2) emphasis on screening all HIV-infected persons for infection with hepatitis C virus; 3) new information regarding transmission of human herpesvirus 8 infection; 4) new information regarding drug interactions, chiefly related to rifamycins and antiretroviral drugs; and 5) revised recommendations for immunizing HIV-infected adults and adolescents and HIV-exposed or infected children.
Detailed Distribution of NK012, an SN-38–Incorporating Micelle, in the Liver and Its Potent Antitumor Effects in Mice Bearing Liver Metastases
Authors: Amane Takahashi, Nobuhiro Ohkohchi, Masahiro Yasunaga, Jun-ichiro Kuroda, Yoshikatsu Koga, Hirotsugu Kenmotsu, Taira Kinoshita, Yasuhiro Matsumura
Journal: Clinical Cancer Research (2010)

To clarify and compare the antitumor effects and specific biodistribution of NK012, an SN-38-incorporating polymeric micelle, in mice bearing multiple liver metastases of human colon cancer HT-29 cells with irinotecan hydrochloride (CPT-11).The maximum tolerable dose of NK012 (30 mg/kg) or CPT-11 (66.7 mg/kg) was i.v. administered three times every 4 days to mice bearing metastases to the liver colonized 7 days after the portal administration of HT-29 cells (n = 6). In vivo antitumor effects were evaluated by bioluminescence imaging and histopathologic examination. Drug biodistribution was analyzed by high-performance liquid chromatography and fluorescence microscopy (n = 3).NK012 eradicated the liver metastases and produced a significant longer survival rate than CPT-11 (P = 0.0006). High-performance liquid chromatography showed the prolonged distribution of NK012 and free SN-38 released from NK012 in the tumors, liver, and spleen for weeks after NK012 administration. On the other hand, the accumulation levels of CPT-11 and free SN-38 converted from CPT-11 rapidly decreased within 1 day after CPT-11 administration. In the liver metastases, fluorescence microscopy and immunohistochemistry showed that administered NK012 was distributed mainly adjacent to tumor vessels after 1 day. As for the normal liver, NK012 was distributed in Kupffer cells instead of hepatocytes for at least 7 days after administration.This study suggests that NK012 is strongly effective against liver metastases and does not damage the liver despite the long retention time of NK012 in Kupffer cells.
Animal models for the study of tendinopathy
Authors: S J Warden
Journal: British Journal of Sports Medicine (2006)

Tendinopathy is a common and significant clinical problem characterised by activity-related pain, focal tendon tenderness and intratendinous imaging changes. Recent histopathological studies have indicated the underlying pathology to be one of tendinosis (degeneration) as opposed to tendinitis (inflammation). Relatively little is known about tendinosis and its pathogenesis. Contributing to this is an absence of validated animal models of the pathology. Animal models of tendinosis represent potential efficient and effective means of furthering our understanding of human tendinopathy and its underlying pathology. By selecting an appropriate species and introducing known risk factors for tendinopathy in humans, it is possible to develop tendon changes in animal models that are consistent with the human condition. This paper overviews the role of animal models in tendinopathy research by discussing the benefits and development of animal models of tendinosis, highlighting potential outcome measures that may be used in animal tendon research, and reviewing current animal models of tendinosis. It is hoped that with further development of animal models of tendinosis, new strategies for the prevention and treatment of tendinopathy in humans will be generated.
Hepatic toxicity associated with fluorouracil plus levamisole adjuvant therapy.
Authors: C G Moertel, T R Fleming, J S Macdonald, D G Haller, J A Laurie
Journal: Journal of Clinical Oncology (1993)

PURPOSE To determine the frequency and nature of hepatic toxicity associated with fluorouracil (5-FU) plus levamisole adjuvant therapy. PATIENTS AND METHODS All patients had resection of stage II or stage III colon cancer and were randomized to receive observation only, levamisole alone, or 5-FU plus levamisole. Serial liver function studies were documented in 1,025 patients who did not develop recurrence during the year of therapy. RESULTS One hundred forty-nine (39.6%) of 376 patients treated with 5-FU plus levamisole showed laboratory abnormalities consistent with hepatic toxicity, compared with 16.3% of 251 patients treated with levamisole alone and 16.1% of 398 untreated controls. Most common was elevation of alkaline phosphatase, frequently accompanied by elevations of transaminase or serum bilirubin. Characteristically, these changes were mild, not associated with symptoms, and resolved when therapy was stopped. In some instances, they were associated with elevated carcinoembryonic antigen (CEA) tests or with fatty liver seen on computed tomographic (CT) scan or liver biopsy. CONCLUSION Mild and reversible hepatotoxicity is a common consequence of 5-FU plus levamisole adjuvant therapy, but this is only rarely symptomatic. However, the oncologist should be alert to this phenomenon, since the associated laboratory and imaging findings may simulate those associated with hepatic metastasis.
Can Diaphragmatic Contractility be Assessed by Twitch Airway Pressures in Patients with Chronic Obstructive Pulmonary Disease?
Authors: ARZU TOPELI, FRANCO LAGHI, MARTIN J. TOBIN
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

In healthy subjects and in patients without lung diseases, twitch airway pressure (Paw(tw)) responses to phrenic nerve stimulation can be used to predict twitch esophageal pressure (Pes(tw)) and twitch transdiaphragmatic pressure (Pdi(tw)), thus overcoming the need for placement of esophageal and gastric balloons. The aim of this study was to determine whether measurements of Paw(tw) combined with simple maneuvers could be used to predict Pes(tw), and possibly Pdi(tw), in patients with severe chronic obstructive pulmonary disease (COPD) (n = 12). Stimulations delivered at relaxed FRC produced a correlation coefficient (r) between Paw(tw) and Pes(tw) of 0.44 (p < 0.001) and of 0.62 (p < 0.001) during stimulations while patients performed a gentle exhalation from FRC. Stimulations performed during a gentle inhalation produced a good correlation between Paw(tw) and Pes(tw) (r = 0.92, p < 0.001); however, the limits of agreement between Paw(tw) and Pes(tw) were wide. Correlations between Paw(tw) and Pdi(tw) during the three experimental conditions were weak. In conclusion, during a gentle inspiratory effort in patients with severe COPD the correlation between Paw(tw) and Pdi(tw) was weak, whereas the correlation between Paw(tw) and Pes(tw) was good, but it was not sufficient to allow the prediction of Pes(tw) from Paw(tw) in all patients.
Longer-Term Outcomes of Letrozole Versus Placebo After 5 Years of Tamoxifen in the NCIC CTG MA.17 Trial: Analyses Adjusting for Treatment Crossover
Authors: Huan Jin, Dongsheng Tu, Naiqing Zhao, Lois E. Shepherd, Paul E. Goss
Journal: Journal of Clinical Oncology (2011)

The interim analysis of the National Cancer Institute of Canada Clinical Trials Group MA.17 trial showed that letrozole was significantly better than placebo in disease-free survival (DFS) for postmenopausal women with hormone receptor-positive breast cancer following about 5 years of tamoxifen therapy. When patients were unblinded, those on placebo were offered letrozole. Longer-term efficacy of letrozole, especially survival, was of particular interest because the median follow-up of the first interim analysis was only 2.5 years. Efficacy was difficult to assess because more than 60% of placebo patients crossed over to letrozole after being unblinded.Two statistical approaches were used to adjust for the potential effects of treatment crossover: one was based on the inverse probability of censoring weighted (IPCW) Cox model and the other on a Cox model with time-dependent covariates.With a median follow-up of 64 months, the hazard ratios (HRs) of letrozole and placebo from the IPCW analyses were HR of 0.52 (95% CI, 0.45 to 0.61; P < .001) for DFS, HR of 0.51 (95% CI, 0.42 to 0.61; P < .001) for distant disease-free survival (DDFS), and HR of 0.61 (95% CI, 0.52 to 0.71; P < .001) for overall survival (OS). The results from the analyses based on the Cox model with time-dependent covariates were similar for letrozole and placebo: HR of 0.58 (95% CI, 0.47 to 0.72; P < .001) for DFS, HR of 0.68 (95% CI, 0.52 to 0.88; P = .004) for DDFS, and HR of 0.76 (95% CI, 0.60 to 0.96; P = .02) for OS.Exploratory analyses based on longer follow-up and adjusting for treatment crossover suggest that extended adjuvant letrozole was superior to placebo in DFS, DDFS, and OS.
Functional Mapping of Receptor Tyrosine Kinases in Myxoid Liposarcoma
Authors: Tiziana Negri, Emanuela Virdis, Silvia Brich, Fabio Bozzi, Elena Tamborini, Eva Tarantino, Genny Jocollè, Giuliana Cassinelli, Federica Grosso, Roberta Sanfilippo, Patrizia Casalini, Angela Greco, Marco A. Pierotti, Silvana Pilotti
Journal: Clinical Cancer Research (2010)

Abstract Purpose: The aim of this study was to analyze receptor tyrosine kinases (RTK) and their downstream signaling activation profile in myxoid liposarcomas (MLS) by investigating 14 molecularly profiled tumors: 7 naive and 7 treated with conventional chemotherapy/radiotherapy or the new drug trabectedin. Experimental Design: Frozen and matched formalin-fixed, paraffin-embedded material from surgical specimens were analyzed using biochemical, molecular, and molecular/cytogenetic approaches, complemented by immunohistochemistry and confocal microscopy. Results: In the absence of any RTK and downstream effector deregulation, the naive cases revealed epidermal growth factor receptor, platelet-derived growth factor receptor B, RET, and MET activation sustained by autocrine/paracrine loops, and RTK cross-talk as a result of heterodimerization. Interestingly, RET and MET activation seems to play a major role in the pathogenesis of MLS by involving different targets through different mechanisms. RET activation (which may activate MET) involves the tumoral vascular component by means of RET/MET cross-talk and VEGFA (vascular endothelial growth factor A)/GFRα3 (glial cell–derived neurotrophic factor family receptor α3)/artemin–mediated signaling as revealed by VEGF receptor 2/RET coimmunoprecipitation. MET activation involves the cellular tumor component by means of a direct ligand-dependent loop and indirect GFRα3 (RET coreceptor)/artemin–mediated signaling. About downstream signaling, the association of AKT activation with the round cell variant is interesting. No relevant changes in the original RTK activation profiles were observed in the posttreatment cases, a finding that is in keeping with the nontargeted treatments used. Conclusions: These findings highlight the particular cell-specific activation profile of RET/GFRα3 and MET in MLS, and the close correlation between AKT activation and the round cell variant, thus opening up new therapeutic perspectives for MET/AKT inhibitors and antagonistic small molecules binding GFRα3. Clin Cancer Res; 16(14); 3581–93. ©2010 AACR.
Snoring in preschool children: prevalence, severity and risk factors
Authors: C. E. Kuehni, M-P. F. Strippoli, E. S. Chauliac, M. Silverman
Journal: European Respiratory Journal (2007)

Epidemiological data on snoring from preschool children are scarce, although habitual snoring (snoring on almost all nights) has been associated with poor long-term outcomes. In a population survey of 6,811 children aged 1-4 yrs (from Leicestershire, UK) the present authors determined prevalence, severity and risk factors for snoring, especially habitual snoring. In 59.7% of the children, parents reported snoring in the previous 12 months, including 7.9% with habitual snoring and 0.9% with habitual snoring and sleep disturbance. Prevalence of habitual snoring increased with age from 6.6% in 1-yr-olds to 13.0% in 4-yr-olds. Habitual snoring was associated with: one and both parents smoking (adjusted odds ratio (OR) 1.46 and 2.09, respectively); road traffic (OR 1.23); single parent (OR 1.60); and in White but not South Asian children, socioeconomic deprivation (OR 1.25 and 2.03 for middle and upper thirds of Townsend score, respectively). Respiratory tract symptoms related to atopic disorders and to respiratory infections were strongly associated with snoring; however, body mass index was not. In conclusion, habitual snoring is common in preschool children with one-third of cases attributable to avoidable risk factors. The strong association with atopic disorders, viral infections and environmental exposures suggests a complex aetiology, based on a general vulnerability of the respiratory tract.