tbuckley/cabot-search huggingface dataset:
Controlled Activation of ErbB1/ErbB2 Heterodimers Promote Invasion of Three-Dimensional Organized Epithelia in an ErbB1-Dependent Manner: Implications for Progression of ErbB2-Overexpressing Tumors
Authors: Lixing Zhan, Bin Xiang, Senthil K. Muthuswamy
Journal: Cancer Research (2006)

Abstract Receptor tyrosine kinases of the ErbB family are implicated in a number of cancers, including that of the breast. ErbB receptors are activated by ligand-induced formation of homodimers and heterodimers. Receptor heterodimerization is thought to play a critical role in breast cancers overexpressing multiple members of the ErbB family. Although coexpression of ErbB receptors is associated with poor patient prognosis, the mechanisms by which receptor heterodimerization regulates tumor progression are not clear, due in part to a lack of methods that allow controlled activation of specific receptor heterodimers in mammary epithelial cells. Here, we report an approach to activate ErbB1-ErbB2 heterodimers in a nontumorigenic breast epithelial cell line, MCF-10A, without interference from endogenous ErbB receptors. Using such a method, we show that whereas both ErbB2 homodimers and ErbB1-ErbB2 heterodimers were equally potent in activating the Ras/mitogen-activated protein kinase pathway, the heterodimers were more potent in activating the phosphoinositide 3′-kinase (PI3K) and phospholipase Cγ1 pathways than ErbB2 homodimers. We combined the dimerization system with a three-dimensional cell culture approach to show that whereas both ErbB2 homodimers and ErbB1-ErbB2 heterodimers induced disruption of three-dimensional acini-like structures, only heterodimers promoted invasion of cells through extracellular matrix. The ability of heterodimers to induce invasion required the ErbB1 kinase activity and required activation of PI3K, Ras/mitogen-activated protein kinase, and phospholipase Cγ1 signaling pathways. Thus, we have identified cell invasion as a heterodimer-specific biological outcome and suggest that coexpression of ErbB1 may critically regulate invasive progression of ErbB2-positive breast cancers. (Cancer Res 2006; 66(10): 5201-8)
Sublingual immunotherapy with a standardized cat dander extract: evaluation of efficacy in a double blind placebo controlled study
Authors: E. Álvarez‐Cuesta, P. Berges‐Gimeno, E. G. Mancebo, E. Fernández‐Caldas, J. Cuesta‐Herranz, M. Casanovas
Journal: Allergy (2007)

Background: Little information is available on the clinical efficacy of sublingual immunotherapy (SLIT) using extracts derived from mammalian epithelia. Objectives: To assess clinical efficacy of cat SLIT based on natural exposure challenge test (NCT). Material and methods: Fifty cat allergic patients with rhinoconjunctivitis with or without asthma were included in a randomized double blind placebo controlled clinical trial of cat SLIT during 1 year. Twenty‐five patients received active treatment and 25 placebo. Sublingual immunotherapy efficacy was assessed by natural exposure challenge to a cat in a cat‐room and by skin tests. Airborne Fel d 1 levels, symptom scores and peak expiratory flow (PEF) values were monitored. Results: Thirty‐three (66%) out of 50 patients completed the treatment. Fel d 1 content of the maximum concentration was 0.51 μ g per ml. During the build up phase, the accumulated dose was 1.7 μ g of Fel d 1 and during the entire length of the study was 17.1. No adverse reports were reported. The active group showed a marked reduction (62%) in symptoms during the NCT ( P &lt; 0.001) with no changes in placebo group. Active group also showed a reduced PEF response to cat exposure ( P &lt; 0.05), and an improvement in skin test reactivity to a standardized cat extract ( P &lt; 0.05), without significant changes in placebo group. Mean Fel d 1 exposure during the NCT was 6.2 ± 2.21 ng/m 3 . Conclusions: The results suggest that the cat SLIT used in this study was able to improve cat allergy based on natural exposure challenge.
Phase I Study of SS1P, a Recombinant Anti-Mesothelin Immunotoxin Given as a Bolus I.V. Infusion to Patients with Mesothelin-Expressing Mesothelioma, Ovarian, and Pancreatic Cancers
Authors: Raffit Hassan, Susie Bullock, Ahalya Premkumar, Robert J. Kreitman, Hedy Kindler, Mark C. Willingham, Ira Pastan
Journal: Clinical Cancer Research (2007)

To determine the toxicities, maximum tolerated dose (MTD) and pharmacokinetics of the recombinant immunotoxin SS1P (anti-mesothelin dsFv-PE38) in patients with mesothelin-expressing cancers.SS1P given as a 30-min i.v. infusion every other day (QOD) for six or three doses was administered to 34 patients with advanced mesothelioma (n = 20), ovarian (n = 12), and pancreatic (n = 2) cancer.The initial cohort of 17 patients received SS1P QOD x 6 doses and the MTD was 18 microg/kg/dose. Dose-limiting toxicities (DLT) included grade 3 uticaria (one patient) and grade 3 vascular leak syndrome (two patients). To allow further SS1P dose escalation, 17 patients were treated on the QOD x 3 schedule and the MTD was 45 microg/kg/dose. The DLT was grade 3 pleuritis and was seen in two of two patients treated at a dose of 60 microg/kg and in one of nine patients treated at a dose of 45 microg/kg. At the MTD of 45 microg/kg, the mean C(max) of SS1P was 483 ng/mL and half-life was 466 min. Of the 33 evaluable patients treated, 4 had minor responses, 19 had stable disease (including 2 with resolution of ascites), and 10 had progressive disease.SS1P is well tolerated with pleuritis as the DLT at the highest dose level. Evidence of clinical activity was noted in a group of heavily pretreated patients. Phase II clinical trials of SS1P are being planned for malignant mesothelioma and other mesothelin-expressing malignancies.
High-Dose Recombinant Interleukin-2 Alone: A Regimen With Limited Activity in the Treatment of Advanced Renal Cell Carcinoma
Authors: J. S. Abrams, A. A. Rayner, P. H. Wiernik, D. R. Parkinson, M. Eisenberger, F. R. Aronson, R. Gucalp, M. B. Atkins, M. J. Hawkins
Journal: JNCI Journal of the National Cancer Institute (1990)

Journal Article High-Dose Recombinant Interleukin-2 Alone: A Regimen With Limited Activity in the Treatment of Advanced Renal Cell Carcinoma Get access Jeffrey S. Abrams, Jeffrey S. Abrams * Division of Medical Oncology, University of Maryland Cancer CenterBaltimore, Md *Correspondence to : Jeffrey S. Abrams, M.D., Division of Medical Oncology, University of Maryland Cancer Center, 22 S. Greene St., Baltimore, MD 21201. Search for other works by this author on: Oxford Academic PubMed Google Scholar Anthony A. Rayner, Anthony A. Rayner University of California at San FranciscoSan Francisco, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar Peter H. Wiernik, Peter H. Wiernik Albert Einstein Cancer CenterNew York, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar David R. Parkinson, David R. Parkinson Tufts-New England Medical CenterBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Mario Eisenberger, Mario Eisenberger Division of Medical Oncology, University of Maryland Cancer CenterBaltimore, Md Search for other works by this author on: Oxford Academic PubMed Google Scholar Frederick R. Aronson, Frederick R. Aronson University of California at San FranciscoSan Francisco, Calif Search for other works by this author on: Oxford Academic PubMed Google Scholar Rasim Gucalp, Rasim Gucalp Albert Einstein Cancer CenterNew York, NY Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael B. Atkins, Michael B. Atkins Tufts-New England Medical CenterBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael J. Hawkins Michael J. Hawkins Cancer Therapy Evaluation Program, National Cancer InstituteBethesda, Md Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 82, Issue 14, 18 July 1990, Pages 1202–1206, https://doi.org/10.1093/jnci/82.14.1202 Published: 18 July 1990 Article history Received: 26 January 1990 Revision received: 18 April 1990 Accepted: 26 April 1990 Published: 18 July 1990
The Anticancer Drug Ellipticine Forms Covalent DNA Adducts, Mediated by Human Cytochromes P450, through Metabolism to 13-Hydroxyellipticine and Ellipticine<b><i>N</i></b>2-Oxide
Authors: Marie Stiborová, Jan Sejbal, Lucie Bořek-Dohalská, Dagmar Aimová, Jitka Poljaková, Kristina Forsterová, Martina Rupertová, Jiří Wiesner, Jiří Hudeček, Manfred Wiessler, Eva Frei
Journal: Cancer Research (2004)

Abstract Ellipticine is an antineoplastic agent, the mode of action of which is considered to be based on DNA intercalation and inhibition of topoisomerase II. We found that ellipticine also forms the cytochrome P450 (CYP)-mediated covalent DNA adducts. We now identified the ellipticine metabolites formed by human CYPs and elucidated the metabolites responsible for DNA binding. The 7-hydroxyellipticine, 9-hydroxyellipticine, 12-hydroxyellipticine, 13-hydroxyellipticine, and ellipticine N2-oxide are generated by hepatic microsomes from eight human donors. The role of specific CYPs in the oxidation of ellipticine and the role of the ellipticine metabolites in the formation of DNA adducts were investigated by correlating the levels of metabolites formed in each microsomal sample with CYP activities and with the levels of the ellipticine-derived deoxyguanosine adducts in DNA. On the basis of this analysis, formation of 9-hydroxyellipticine and 7-hydroxyellipticine was attributable to CYP1A1/2, whereas production of 13-hydroxyellipticine and ellipticine N2-oxide, the metabolites responsible for formation of two major DNA adducts, was attributable to CYP3A4. Using recombinant human enzymes, oxidation of ellipticine to 9-hydroxyellipticine and 7-hydroxyellipticine by CYP1A1/2 and to 13-hydroxyellipticine and N2-oxide by CYP3A4 was corroborated. Homologue modeling and docking of ellipticine to the CYP3A4 active center was used to explain the predominance of ellipticine oxidation by CYP3A4 to 13-hydroxyellipticine and N2-oxide.
Systematic Review: Comparative Effectiveness of Core-Needle and Open Surgical Biopsy to Diagnose Breast Lesions
Authors: Wendy Bruening
Journal: Annals of Internal Medicine (2010)

Background: Most women undergoing breast biopsy are found not to have cancer. Purpose: To compare the accuracy and harms of different breast biopsy methods in average-risk women suspected of having breast cancer. Data Sources: Databases, including MEDLINE and EMBASE, searched from 1990 to September 2009. Study Selection: Studies that compared core-needle biopsy diagnoses with open surgical diagnoses or clinical follow-up. Data Extraction: Data were abstracted by 1 of 3 researchers and verified by the primary investigator. Data Synthesis: 33 studies of stereotactic automated gun biopsy; 22 studies of stereotactic-guided, vacuum-assisted biopsy; 16 studies of ultrasonography-guided, automated gun biopsy; 7 studies of ultrasonography-guided, vacuum-assisted biopsy; and 5 studies of freehand automated gun biopsy met the inclusion criteria. Low-strength evidence showed that core-needle biopsies conducted under stereotactic guidance with vacuum assistance distinguished between malignant and benign lesions with an accuracy similar to that of open surgical biopsy. Ultrasonography-guided biopsies were also very accurate. The risk for severe complications is lower with core-needle biopsy than with open surgical procedures (<1% vs. 2% to 10%). Moderate-strength evidence showed that women in whom breast cancer was initially diagnosed by core-needle biopsy were more likely than women with cancer initially diagnosed by open surgical biopsy to be treated with a single surgical procedure (random-effects odds ratio, 13.7 [95% CI, 5.5 to 34.6]). Limitation: The strength of evidence was rated low for accuracy outcomes because the studies did not report important details required to assess the risk for bias. Conclusion: Stereotactic- and ultrasonography-guided core-needle biopsy procedures seem to be almost as accurate as open surgical biopsy, with lower complication rates. Primary Funding Source: Agency for Healthcare Research and Quality.
P02.02 * PRELIMINARY CHARACTERIZATION OF THE IMMUNE RESPONSE IN GLIOBLASTOMA BEFORE AND AFTER FIRST-LINE THERAPY
Authors: B. Kiesel, M. Millesi, A. S. Berghoff, J. A. Hainfellner, G. Widhalm, C. Marosi, R. Hoftberger, C. Haberler, A. Woehrer
Journal: Neuro-Oncology (2014)

BACKGROUND: Glioblastoma constitutes the most common primary malignant brain tumor in adults. Its aggressive disease course is mediated by a hitherto poorly understood interplay of rapid tumor progression and therapy-related effects. Crucial factors include - amongst hypoxia, angiogenesis, and others - an immune response upfront and/or as a consequence to combined chemo-radiotherapy. Herein, we aim at a systematic morphological characterization of this immune response based on a homogenous series of paired pre- and posttherapeutic glioblastoma samples. PATIENTS AND METHODS: A total of 15 glioblastoma patients newly diagnosed from 2005-2010 at the Medical University of Vienna were included in the analysis. All patients underwent neursurgical resection followed by standard radio- and TMZ-chemotherapy. At time of tumor recurrence second surgery was performed in all cases. Information on clinical characteristics and last follow-up were available. The tumor-associated immune response was semiquantitatively assessed using immunohistochemistry for anti-HLA-DR, CD3, and CD8. In addition, tumor-associated eosinophilia was assessed on conventional HE stains. RESULTS: Median age at diagnosis was 54 ys (range 21-69 ys). Median time from first to second surgery was 12.0 mths (range 1-26 mths) and median overall survival was 46.0 mths of the total cohort. While tumor-infiltrating CD3+ and CD8+ T-lymphocytes did not show a significant difference between first and second surgery (p = 0.07 and p = 0.3, respectively), a significant increase of HLA-DR+ microglia/macrophages (p = 0.01) was observed at time of tumor recurrence in the majority of cases (10/15; 66.7%). No unequivocal differences in overall survival were observed for those patients with enhanced microglial/macrophage response at time of tumor recurrence (log rank test; p = 0.34). A single case showed massive infiltration of eosinophils at second surgery only. This case differed from others by young age at diagnosis (26 ys), positive IDH-1 mutational and MGMT methylation status, short time to second surgery (1 mth) and exceptional favorable overall survival with stable disease at 84 mths. No peripheral eosinophilia or prior history of atopic disease was noted. Further screening for anti-neuronal/glial antibodies on a tissue-based assay did not yield a positive result. CONCLUSION: Although the small sample size implies cautious interpretation, we observed a significant increase of tumor-infiltrating microglia/macrophages in glioblastoma samples obtained after first-line therapy, while no significant differences were observed for tumor-infiltrating CD3+ and CD8+ T-lymphocytes. Of note, a single patient showed prominent tumor-associated eosinophilia upon second surgery which was associated with long-term survival.
Hemodynamic Correlates of the Various Components of the First Heart Sound
Authors: P. M. SHAH, M. MORI, D. M. MACCANON, A. A. LUISADA
Journal: Circulation Research (1963)

Previous studies in this laboratory having demonstrated that AV valve closure is not directly responsible for the rapid vibrations of the first heart sound, the mechanism of production of this "sound" was studied further in 30 experiments in dogs. The experiments were performed with multiple pressure catheterization, and intracardiac phonocatheterization, and were compared with external phonocardiograms and electrocardiograms. In 10 experiments, the first derivatives of the left and right ventricular pressures were also recorded. In four experiments, direct epicardial and arterial sound tracings were obtained. These experiments revealed that three groups of vibrations, or components, were often visible in the external phonocardiogram, and in intracardiac and epicardial tracings. The first component follows the onset of left ventricular pressure rise and closure of the mitral valve but coincides with the rapid rise of the first derivative of LV pressure. The second component has no relationship with right heart events, occurs before aortic valve opening, and coincides with the sudden change of course of the first derivative of LV pressure. The third component occurs slightly after aortic valve opening, and seems related to sudden increase of aortic wall tension. It is probably the physiological equivalent of the aortic "ejection sound." Thus, the first two components are both left ventricular in origin while the third is of aortic origin.
Experimental Colon Neoplasia Enhanced by Extract of Sperm (Protamine)
Authors: R K S Phillips, D S Quill, H A F Dudley
Journal: Journal of the Royal Society of Medicine (1984)

An experimental study of colorectal tumorigenesis in inbred rats given the potent carcinogen dimethylhydrazine has shown that protamine, given before any tumours had developed, significantly enhanced the development of large bowel tumours (100% incidence). Those animals having no adjuvant therapy or who received either heparin or 5-fluorouracil (alone or in combination) had an approximate 50% incidence of such tumours.
Empagliflozin as Add-On to Metformin in Patients With Type 2 Diabetes: A 24-Week, Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Hans-Ulrich Häring, Ludwig Merker, Elke Seewaldt-Becker, Marc Weimer, Thomas Meinicke, Uli C. Broedl, Hans J. Woerle
Journal: Diabetes Care (2014)

OBJECTIVE To investigate the efficacy and tolerability of empagliflozin as an add-on to metformin therapy in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Patients with HbA1c levels of ≥7% to ≤ 10% (≥53 to ≤86 mmol/mol) while receiving metformin (≥1,500 mg/day) were randomized and treated with once-daily treatment with empagliflozin 10 mg (n = 217), empagliflozin 25 mg (n = 213), or placebo (n = 207) for 24 weeks. The primary end point was the change in HbA1c level from baseline at week 24. Key secondary end points were changes from baseline in weight and mean daily glucose (MDG) at week 24. RESULTS At week 24, adjusted mean (SE) changes from baseline in HbA1c were −0.13% (0.05)% (−1.4 [0.5] mmol/mol) with placebo, −0.70% (0.05)% (−7.7 [0.5] mmol/mol) with empagliflozin 10 mg, and −0.77% (0.05)% (−8.4 [0.5] mmol/mol) with empagliflozin 25 mg (both P &amp;lt; 0.001). Empagliflozin significantly reduced MDG level and systolic and diastolic blood pressure (BP) versus placebo. Adjusted mean (SE) changes from baseline in weight were −0.45 kg (0.17 kg) with placebo, −2.08 kg (0.17 kg) with empagliflozin 10 mg, and −2.46 kg (0.17 kg) with empagliflozin 25 mg (both P &amp;lt; 0.001). Adverse events (AEs) were similar across groups (placebo 58.7%; empagliflozin 49.5–57.1%). Confirmed hypoglycemic AEs were reported in 0.5%, 1.8%, and 1.4% of patients receiving placebo, empagliflozin 10 mg, and empagliflozin 25 mg, respectively. Events consistent with urinary tract infections were reported in 4.9%, 5.1%, and 5.6% of patients, and events consistent with genital infections were reported in 0%, 3.7%, and 4.7% of patients, respectively. CONCLUSIONS Empagliflozin 10 and 25 mg for 24 weeks as add-on to metformin therapy significantly improved glycemic control, weight, and BP, and were well-tolerated.
U.S. Disparities in Health: Descriptions, Causes, and Mechanisms
Authors: Nancy E. Adler, David H. Rehkopf
Journal: Annual Review of Public Health (2007)

Eliminating health disparities is a fundamental, though not always explicit, goal of public health research and practice. There is a burgeoning literature in this area, but a number of unresolved issues remain. These include the definition of what constitutes a disparity, the relationship of different bases of disadvantage, the ability to attribute cause from association, and the establishment of the mechanisms by which social disadvantage affects biological processes that get into the body, resulting in disease. We examine current definitions and empirical research on health disparities, particularly disparities associated with race/ethnicity and socioeconomic status, and discuss data structures and analytic strategies that allow causal inference about the health impacts of these and associated factors. We show that although health is consistently worse for individuals with few resources and for blacks as compared with whites, the extent of health disparities varies by outcome, time, and geographic location within the United States. Empirical work also demonstrates the importance of a joint consideration of race/ethnicity and social class. Finally, we discuss potential pathways, including exposure to chronic stress and resulting psychosocial and physiological responses to stress, that serve as mechanisms by which social disadvantage results in health disparities.
Presence of osteoclast-like multinucleated giant cells in the bone and nonostotic lesions of Langerhans cell histiocytosis
Authors: Cristiana E.T. da Costa, Nicola E. Annels, Claudia M.J.M. Faaij, Ramses G. Forsyth, Pancras C.W. Hogendoorn, R. Maarten Egeler
Journal: The Journal of Experimental Medicine (2005)

Langerhans cell histiocytosis (LCH) is a disease that can involve one or multiple organ systems characterized by an accumulation of CD1a+ Langerhans-like cells as well as several other myeloid cell types. The precise origin and role of one of these populations, the multinucleated giant cell (MGC), in this disease remains unknown. This work shows that in three different lesional tissues, bone, skin, and lymph node, the MGCs expressed the characteristic osteoclast markers, tartrate-resistant acid phosphatase and vitronectin receptor, as well as the enzymes cathepsin K and matrix metalloproteinase-9. Although, in bone lesions, the osteoclast-like MGCs were only CD68+, in the nonostotic sites, they coexpressed CD1a. The presence of osteoclast-like MGCs may be explained by the production of osteoclast-inducing cytokines such as receptor activator of nuclear factor κB ligand and macrophage colony-stimulating factor by both the CD1a+ LCH cells and T cells in these lesions. As osteoclast-derived enzymes play a major role in tissue destruction, the osteoclast-like nature of MGCs in all LCH lesions makes them a potential target for the treatment of this disease.