tbuckley/cabot-search huggingface dataset:
An ErbB3 Antibody, MM-121, Is Active in Cancers with Ligand-Dependent Activation
Authors: Birgit Schoeberl, Anthony C. Faber, Danan Li, Mei-Chih Liang, Katherine Crosby, Matthew Onsum, Olga Burenkova, Emily Pace, Zandra Walton, Lin Nie, Aaron Fulgham, Youngchul Song, Ulrik B. Nielsen, Jeffrey A. Engelman, Kwok-Kin Wong
Journal: Cancer Research (2010)

ErbB3 is a critical activator of phosphoinositide 3-kinase (PI3K) signaling in epidermal growth factor receptor (EGFR; ErbB1), ErbB2 [human epidermal growth factor receptor 2 (HER2)], and [hepatocyte growth factor receptor (MET)] addicted cancers, and reactivation of ErbB3 is a prominent method for cancers to become resistant to ErbB inhibitors. In this study, we evaluated the in vivo efficacy of a therapeutic anti-ErbB3 antibody, MM-121. We found that MM-121 effectively blocked ligand-dependent activation of ErbB3 induced by either EGFR, HER2, or MET. Assessment of several cancer cell lines revealed that MM-121 reduced basal ErbB3 phosphorylation most effectively in cancers possessing ligand-dependent activation of ErbB3. In those cancers, MM-121 treatment led to decreased ErbB3 phosphorylation and, in some instances, decreased ErbB3 expression. The efficacy of single-agent MM-121 was also examined in xenograft models. A machine learning algorithm found that MM-121 was most effective against xenografts with evidence of ligand-dependent activation of ErbB3. We subsequently investigated whether MM-121 treatment could abrogate resistance to anti-EGFR therapies by preventing reactivation of ErbB3. We observed that an EGFR mutant lung cancer cell line (HCC827), made resistant to gefitinib by exogenous heregulin, was resensitized by MM-121. In addition, we found that a de novo lung cancer mouse model induced by EGFR T790M-L858R rapidly became resistant to cetuximab. Resistance was associated with an increase in heregulin expression and ErbB3 activation. However, concomitant cetuximab treatment with MM-121 blocked reactivation of ErbB3 and resulted in a sustained and durable response. Thus, these results suggest that targeting ErbB3 with MM-121 can be an effective therapeutic strategy for cancers with ligand-dependent activation of ErbB3.
Vascular Endothelial Growth Factor Gene Therapy Increases Survival, Promotes Lung Angiogenesis, and Prevents Alveolar Damage in Hyperoxia-Induced Lung Injury
Authors: Bernard Thébaud, Faruqa Ladha, Evangelos D. Michelakis, Monika Sawicka, Gavin Thurston, Farah Eaton, Kyoko Hashimoto, Gwyneth Harry, Alois Haromy, Greg Korbutt, Stephen L. Archer
Journal: Circulation (2005)

Background— Bronchopulmonary dysplasia (BPD) and pulmonary emphysema, both significant global health problems, are characterized by a loss of alveoli. Vascular endothelial growth factor ( VEGF) is a trophic factor required for endothelial cell survival and is abundantly expressed in the lung. Methods and Results— We report that VEGF blockade decreases lung VEGF and VEGF receptor 2 (VEGFR-2) expression in newborn rats and impairs alveolar development, leading to alveolar simplification and loss of lung capillaries, mimicking BPD. In hyperoxia-induced BPD in newborn rats, air space enlargement and loss of lung capillaries are associated with decreased lung VEGF and VEGFR-2 expression. Postnatal intratracheal adenovirus-mediated VEGF gene therapy improves survival, promotes lung capillary formation, and preserves alveolar development in this model of irreversible lung injury. Combined VEGF and angiopoietin-1 gene transfer matures the new vasculature, reducing the vascular leakage seen in VEGF-induced capillaries. Conclusions— These findings underscore the importance of the vasculature in what is traditionally thought of as an airway disease and open new therapeutic avenues for lung diseases characterized by irreversible loss of alveoli through the modulation of angiogenic growth factors.
Evaluation by double‐blind placebo‐controlled oral challenge of the clinical relevance of IgE antibodies against plant glycans
Authors: A. Mari, P. Ooievaar‐de Heer, E. Scala, M. Giani, L. Pirrotta, L. Zuidmeer, D. Bethell, R. Van Ree
Journal: Allergy (2008)

The clinical relevance of immunoglobulin E (IgE) to plant glycans is a longstanding debate. We sought to evaluate their clinical reactivity using the human glycoprotein lactoferrin expressed in rice.Allergic patients with IgE antibodies against plant glycans were analyzed for the presence of IgE against rice-produced lactoferrin. The potency of IgE to induce mediator release was assessed by basophil histamine release and skin prick tests (SPTs). Clinical relevance was evaluated by double-blind placebo-controlled oral challenge (DBPCOC).Twenty-four of 29 sera (82.7%) with IgE antibodies against plant glycans demonstrated IgE binding to transgenic lactoferrin. In three of five cases transgenic lactoferrin induced histamine release. Compared to a control major grass pollen allergen lactoferrin concentrations needed for biological activity of IgE were 5-6 orders of magnitude higher. Skin prick test and DBPCOC were negative in five patients with potential clinical reactivity that volunteered to undergo these in vivo challenges.Poor or no biological activity and lack of clinical relevance of IgE-binding plant glycans (five out of five) was demonstrated using human lactoferrin expressed in rice as a model.
Primary biliary cirrhosis and cancer risk: A systematic review and meta-analysis
Authors: Yan Liang, Zaixing Yang, Renqian Zhong
Journal: Hepatology (2012)

Several studies have indicated that primary biliary cirrhosis (PBC) may be associated with increased risk of some cancers, but the results are controversial. We conducted a systematic review of studies to examine the association of PBC with cancer risk by meta-analysis. We searched the PubMed and EMBASE databases for English-language studies published before November 2011. Studies were included if they reported relative risk estimates with 95% confidence intervals (CIs) or related data for the association between PBC and cancer risk. Approximately 16,300 PBC patients from several countries were included in this analysis. Of the 3510 titles identified, 16 publications involving 17 studies meeting the inclusion criteria were included in the meta-analysis. Compared with the general population, PBC patients had a significantly higher risk of overall cancer (pooled rate ratio [RR], 1.55; 95% CI, 1.28-1.83) and hepatocellular carcinoma (HCC) (pooled RR, 18.80; 95% CI, 10.81-26.79). For stomach and pancreas cancers, the results of one study that only examined male patients with PBC indicated that PBC patients had increased risk of stomach cancer and pancreatic cancer, whereas the results of other studies of mixed-sex patients showed no significant association. Therefore, despite inconsistent results, the meta-analysis could not be conducted for assessing the association. PBC was not significantly associated with increased risk of other cancers.The present systematic review and meta-analysis demonstrate that PBC is closely associated with a greater risk of overall cancer and HCC, but not with other cancers. The data regarding the association between PBC and risks of several cancers need to be further confirmed in future studies.
Genomic and Proteomic Profiling of Lung Cancers: Lung Cancer Classification in the Age of Targeted Therapy
Authors: Matthew Meyerson, David Carbone
Journal: Journal of Clinical Oncology (2005)

Both proteomic and genomic methods offer promise for the classification of human lung carcinomas. This review summarizes the range of proteomic methods in development for lung cancer classification, and describes a number of recent analyses of messenger RNA expression in lung cancer. Multiple independent studies of mRNA expression profiles in lung adenocarcinoma have proven highly reproducible. Analyses of the relationship between expression profiles and tumor development and differentiation, the presence or absence of specific pathogenic mutations, patient prognosis and survival after surgical treatment, and specific histopathology all appear to be promising.
Efficacy of levodropropizine: A meta-analysis in adults and children
Authors: Alessandro Zanasi, Luigi Lanata, Giovanni Fontana, Federico Saibene, Peter Dicpinigaitis, Rossella Balsamo, Francesco De Blasio
Journal: European Respiratory Journal (2013)

Introduction: Cough is a very common symptom with deep impact on day life, often requiring an empiric treatment with antitussive agents, among which Levodropropizine is a very well tolerated peripheral drug.  Objective: Our study is a meta-analysis of published studies both in adults and children, with the aim to evaluate the overall comparative efficacy of Levodropropizine.  Methods: After systematic literature search, we performed a standardized meta-analysis of 7 controlled clinical studies of Levodropropizine (5 vs. central antitussives and 2 vs. placebo) assessing efficacy cough outcomes, including a total of 2633 patients. Main efficacy parameters were cough frequency, severity, and night awakenings.  Results: Meta-analysis of all standardized efficacy parameters showed a highly statistically significant difference in the overall antitussive efficacy in favor of Levodropropizine vs. control treatments (p = 0.001). The heterogeneity test for the efficacy outcome was not statistically significant (p=0.0619).  Conclusions: Our meta-analysis indicates that Levodropropizine is an effective antitussive drug both in adults and children, with statistically significant better overall efficacy outcomes vs. central antitussives, in terms of reducing cough intensity, frequency and nocturnal awakenings. These results further reinforce the favorable benefit/risk profile of Levodropropizine in the management of cough.
Subsets of Very Low Risk Wilms Tumor Show Distinctive Gene Expression, Histologic, and Clinical Features
Authors: Simone T. Sredni, Samantha Gadd, Chiang-Ching Huang, Norman Breslow, Paul Grundy, Daniel M. Green, Jeffrey S. Dome, Robert C. Shamberger, J. Bruce Beckwith, Elizabeth J. Perlman
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Recent studies suggest that children &amp;lt;24 months with stage I favorable histology Wilms tumors &amp;lt;550 g [very low risk Wilms tumors (VLRWT)] have an excellent prognosis when treated with nephrectomy only, without adjuvant chemotherapy. The identification of risk categories within VLRWT may enable refinement of their definition and optimization of their therapy. Experimental Design: To define biologically distinct subsets, global gene expression analysis was done on 39 VLRWT that passed all quality-control parameters and the clusters identified were validated in an independent set of 11 VLRWT. Validation of select differentially expressed genes was done with immunohistochemistry on a tissue microarray from 20 of 39 tumors. Loss of heterozygosity (LOH) for 11p15, 1p, and 16q was analyzed in 52 tumors using PCR. Results: Two distinctive clusters were identified. One cluster included 9 tumors with epithelial differentiated tubular histology, paucity of nephrogenic rests, lack of LOH for 1p, 16q, and 11p, absence of relapse, and a unique gene expression profile consistent with arrest following mesenchymal-to-epithelial transition. The second cluster included 13 tumors with mixed histology, intralobar nephrogenic rests, and decreased expression of WT1. Three of 6 relapses occurred in this cluster. Of 43 informative tumors, 11p LOH was present in 5 of 5 relapses and 11 of 38 nonrelapses. Conclusions: Two subsets comprising a total of 56 of VLRWT are identified that have pathogenetic and molecular differences and apparent differences in risk for relapse. If these predictors can be prospectively validated, this would enable the refinement of clinical stratification and less arbitrary definition of VLRWT. (Clin Cancer Res 2009;15(22):68009)
CD47-blocking therapies stimulate macrophage cytokine secretion and are effective in a model of peritoneal carcinomatosis
Authors: Kipp Weiskopf, Aaron Ring, K Christopher Garcia, Irving Weissman
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Peritoneal carcinomatosis is an advanced state of malignancy often arising from gastrointestinal or ovarian cancers. It is characterized by dissemination of tumors throughout the peritoneal cavity and is associated with 5-year survival rates less than 25%. Since the peritoneal
Immunogenetic heterogeneity of rheumatoid arthritis.
Authors: M L Westedt, F C Breedveld, G M Schreuder, J D'Amaro, A Cats, R R de Vries
Journal: Annals of the Rheumatic Diseases (1986)

Association of HLA-DR4/Dw4 with rheumatoid arthritis (RA) is well established, but conflicting data exist on a possible association with the severity of the disease, including its extra-articular manifestations. In order to investigate whether a subgroup of RA is preferentially associated with DR4, HLA typing was performed in two groups of patients with severe extra-articular manifestations (Felty9s syndrome and histologically proved leucocytoclastic vasculitis), patients with severe joint destruction (seropositive and seronegative), a group with only mild joint destruction, and in healthy controls. The frequency of HLA-DR4 was significantly raised in all patient groups compared with that in healthy controls. The two groups with severe extra-articular manifestations, however, both had a DR4 frequency of 92%, which was significantly (p = 0.002) higher than the 62.7% found in the remaining patients. No significant differences were observed between severe or mild joint destruction and seropositivity or seronegativity in the groups without the above-mentioned extra-articular manifestations. From these data we concluded that DR4 is preferentially associated with severe extra-articular disease manifestations of RA. This observation provides an immunogenetic basis for the disease heterogeneity and for the immunological analogy between RA and leprosy.
Pulmonary Glutathione Levels in Acute Episodes of Farmer's Lung
Authors: JÜRGEN BEHR, BARBARA DEGENKOLB, THOMAS BEINERT, FRITZ KROMBACH, CLAUS VOGELMEIER
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Acute episodes of farmer's lung (FL) are associated with activation and migration of neutrophils into the lungs, causing oxidative stress. We conducted a study to evaluate the effect of episodes of FL on antioxidant defense of the lung by glutathione (GSH). A total of 15 patients with symptomatic FL (one female and 14 males, age 42 ± 1 yr [mean ± SEM]) underwent a standardized hay exposure test for 1 h and were then monitored through lung function measurements for 6 h, after which bronchoalveolar lavage (BAL) was performed. As a control, 10 asymptomatic farmers (AF) (two males and eight females, age 43 ± 1 yr) underwent the same diagnostic procedures. At 3 to 6 h after antigen exposure, the lung function of FL patients was significantly impaired (VC: − 31 ± 4%; single-breath diffusing capacity of carbon monoxide [Dl CO]: − 17 ± 3%; and PaO2 : − 14 ± 2%, all versus baseline, whereas in AF, only minor changes occurred VC: − 4 ± 5%; Dl CO: − 9 ± 3%, and PaO2 : − 5 ± 2%, all versus baseline). The number of neutrophils in bronchoalveolar lavage fluid was increased in FL patients as compared with AF (29 ± 7 × 104/ml versus 10 ± 7 × 104/ml, p < 0.05). The concentrations of total and reduced glutathione (GSHT and GSH, respectively) in epithelial lining fluid were decreased in FL patients and increased in AF (GSHT: 292.5 ± 27.5 μ M versus 1,185.0 ± 189.9 μ M, respectively, p < 0.001; GSH: 256.8 ± 22.1 μ M versus 1,054.5 ± 172.9 μ M, respectively, p < 0.001). These findings suggest that the individual ability to upregulate GSH in the alveolar space in response to an inflammatory stimulus may have implications for the development of symptomatic FL. We conclude that intrapulmonary GSH levels are distinctly different in patients with FL and AF, and that the regulation of GSH may play an important role in the pathogenesis of FL.
Clinical and Outcome Characteristics of Children With Adrenocortical Tumors: A Report From the International Pediatric Adrenocortical Tumor Registry
Authors: E. Michalkiewicz, R. Sandrini, B. Figueiredo, E.C.M. Miranda, E. Caran, A.G. Oliveira-Filho, R. Marques, M.A.D. Pianovski, L. Lacerda, L.M. Cristofani, J. Jenkins, C. Rodriguez-Galindo, R.C. Ribeiro
Journal: Journal of Clinical Oncology (2004)

We created a registry for pediatric adrenocortical tumors (ACTs), which are rare and are not well characterized. We provide a descriptive analysis of 254 patients registered on the International Pediatric Adrenocortical Tumor Registry.Between January 1990 and December 2001, 254 patients younger than 20 years of age with newly diagnosed or previously treated ACTs were registered. A histologic diagnosis of ACT was required, although central review was not mandatory. Follow-up information was periodically requested from the referring physician. Treatment was chosen by the primary physician.The overall female-male ratio was 1.6:1, but it varied widely among age groups. The most common presenting sign (84.2%) was virilization. Cushing's syndrome without virilization was uncommon (5.5%). Tumors were completely resected in 83% of patients. Patients with disseminated or residual disease received mitotane, cisplatin, etoposide, and/or doxorubicin, and rarely, radiation therapy. At a median follow-up of 2 years and 5 months, 157 patients (61.8%) survived without evidence of disease and 97 patients (38.2%) had died. The 5-year event-free survival estimate was 54.2% (95% CI, 48.2% to 60.2%). In a multivariate analysis, disease stage, presenting signs of endocrine dysfunction, and age were independently associated with prognosis.Childhood ACTs occur predominantly in females and almost always causes clinical signs. Complete resection is required for cure. Residual or metastatic disease carries a poor prognosis. Our results demonstrate the feasibility of a disease-specific database for obtaining meaningful clinical and outcome information.
Comparative Effects of d-and L-3,5,3'-Triiodothyronine in Chronic Treatment of Hypercholesteremic Dogs
Authors: THEODORE ELLISON, SAMUEL M. GREENBERG, TIEN-HUI LIN
Journal: Circulation Research (1961)

Twenty intact, naturally hypercholestere-mic dogs were divided into five groups and chronically administered D-3,5,3'-triiodothy-ronine (d-T3) and L-3,5,3'-triiodothyronine (l-T3) at two levels, respectively, for 31 weeks. The administration of the drugs was divided into two periods, the first for 21 weeks, after which the dosage level for each of the four test groups was doubled for an additional 10 weeks. Plasma total cholesterol, total lipids, and phospholipids were significantly lowered by the administration at both levels of d-T3 and the higher level of l-T3. At the end of 21 and 29 weeks of thyromimetic administration, no differences in percentage of free or esterified cholesterol were observed for any of the treated groups when compared with the control groups. A battery of physiological and functional tests was performed at suitable intervals throughout the experimental period with no evidence of abnormalities due to the administration of the thyromimetic agents. The only significant functional change measured was a reduction in protein-bound-iodine levels in the clogs receiving the higher level of l-T3. Throughout the entire experiment, all dogs remained in good health as judged by gross appearances and actions. The dogs receiving d-T3 gained less weight than did either the controls or the L-T3-treated groups, even though all animals ate isocaloric balanced diets. At post mortem, after 31 weeks of chronic thyromimetic administration, gross pathology was negative; chemical analyses of cholesterol content of aortas, adrenals, and livers indicated no significant differences. Analyses of livers for total lipids showed no significant differences, and no evidence of aortic sudanophilia was apparent in any of the experimental dogs.
Dynamic and not static change in ventricular repolarization is a substrate of ventricular arrhythmia on chronic ischemic myocardium
Authors: K YUUKI
Journal: Cardiovascular Research (2004)

The restitution mechanism has been the focus of attention as the possible mechanism behind ventricular fibrillation (VF). However, its contribution in chronic ischemic heart has not been established.We investigated chronic ischemic dogs with occlusion of left anterior descending artery. Sixty unipolar electrograms were simultaneously recorded from an entire cardiac surface. Activation-recovery intervals (ARIs) and QRST deflection area (AQRST) were measured during constant atrial pacing. The ischemic dogs were divided into two groups, five dogs in VF(+) group or seven dogs in VF(-) group, according to VF occurrence by programmed electrical stimulation.When investigating ARI dispersions on an epicardium, there was no difference between VF(+) and VF(-) groups. The relationship between ARIs and diastolic intervals was quantified as an electrical restitution curve. The slopes of the ARI restitution curve for the anterior left ventricle in VF(+) dogs were significantly steeper than those of VF(-) dogs. The amplitude of AQRST alternans were significantly greater in VF(+) dogs than VF(-) dogs.Combined observation of steep restitution slopes and increased electrical alternans supported the restitution mechanism as being involved in the arrhythmia. Dynamic restitution properties and not static single-beat ARI dispersion may play an important role in the VF arrhythmia in the chronic ischemic heart.
Brain-Derived Neurotrophic Factor Activation of TrkB Induces Vascular Endothelial Growth Factor Expression via Hypoxia-Inducible Factor-1α in Neuroblastoma Cells
Authors: Katsuya Nakamura, Kelly C. Martin, Jennifer K. Jackson, Kiichiro Beppu, Chan-Wook Woo, Carol J. Thiele
Journal: Cancer Research (2006)

Abstract The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Recently, we have shown that insulin-like growth factor-I and serum-derived growth factors stimulate VEGF expression in neuroblastoma cells via induction of hypoxia-inducible factor-1α (HIF-1α). Because another marker of poor prognosis in neuroblastoma tumors is high expression of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor, TrkB, we sought to evaluate the involvement of BDNF and TrkB in the regulation of VEGF expression. VEGF mRNA levels in neuroblastoma cells cultured in serum-free media increased after 8 to 16 hours in BDNF. BDNF induced increases in VEGF and HIF-1α protein, whereas HIF-1β levels were unaffected. BDNF induced a 2- to 4-fold increase in VEGF promoter activity, which could be abrogated if the hypoxia response element in the VEGF promoter was mutated. Transfection of HIF-1α small interfering RNA blocked BDNF-stimulated increases in VEGF promoter activity and VEGF protein expression. The BDNF-stimulated increases in HIF-1α and VEGF expression required TrkB tyrosine kinase activity and were completely blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. These data indicate that BDNF plays a role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to BDNF/TrkB, PI3K, mTOR signal transduction pathways, and/or HIF-1α have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth. (Cancer Res 2006; 66(8): 4249-55)