tbuckley/cabot-search huggingface dataset:
Phase II study of cixutumumab (IMC-A12) plus depot octreotide for patients with metastatic carcinoid or islet cell carcinoma.
Authors: L. B. Anthony, P. J. Loehrer, S. Leong, M. H. Shah, H. Safran, N. N. Senzer, N. J. Zojwalla, H. Youssoufian
Journal: Journal of Clinical Oncology (2010)

TPS220 Background: The somatostatin analogue octreotide is an established therapy offering symptom relief in patients with neuroendocrine tumors; however, their prognosis remains limited. Cixutumumab, a fully human IgG1 monoclonal antibody, specifically targets insulin-like growth factor receptor I (IGF-IR) with high affinity and antagonizes IGF-I and IGF-II ligand binding and signaling. It inhibits the IGF-IR pathway by effecting internalization and degradation of IGF-IR, leading to a reduction in surface receptors. In vitro and in vivo, cixutumumab inhibits proliferation of a variety of human tumor cell lines (Cancer Res. 2003;63:8912; Clin Cancer Res. 2005;11:3065). A significant proportion of neuroendocrine tumors express IGF and/or the IGF-IR and the binding of IGF-I to its receptor appears to promote cell growth. High levels of IGF-IR expression have been associated with faster tumor growth, increased aggressiveness, and lower likelihood of cure in one NET subtype (gastrinoma). (Clin Cancer Res. 2005;11;9:3233). IGF-IR inhibition effects a reduction in IGF-stimulated IGF-IR phosphorylation, promoted apoptosis, and inhibits the growth of tumor cells in vitro and in vivo. Methods: Adult subjects currently receiving depot octreotide therapy for metastatic neuroendocrine carcinomas of carcinoid (30 patients) or islet cell (30 patients) histology that have progressed on prior therapy will be enrolled. Tumors must have Ki-67 expression ≤ 20%. Safety and efficacy will be evaluated with 6-month progression-free survival as the primary variable. Possible reduction in tumor-specific markers and the effect of combination therapy on selected pharmodynamic markers will be assessed. Patients will receive cixutumumab (10 mg/kg i.v.) every 2 weeks and will continue to receive the same dose and schedule of their last regimen of depot octreotide until disease progression or other reasons for study termination. Results: As of January 12, 2010, 27 patients have been enrolled at 7 study sites in the United States. Conclusions: This Phase II study is currently accruing at the expected rate. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ImClone Systems ImClone Systems
Disease‐Associated Single‐Nucleotide Polymorphisms From Noncoding Regions in Juvenile Idiopathic Arthritis Are Located Within or Adjacent to Functional Genomic Elements of Human Neutrophils and CD4+ T Cells
Authors: Kaiyu Jiang, Lisha Zhu, Michael J. Buck, Yanmin Chen, Bradley Carrier, Tao Liu, James N. Jarvis
Journal: Arthritis & Rheumatology (2015)

Juvenile idiopathic arthritis (JIA) is considered a complex disease in which the environment interacts with inherited genes to produce a phenotype that shows broad interindividual variability. Twenty-four regions of genetic risk for JIA were identified in a recent genome-wide association study (GWAS); however, as is typical of the results of GWAS, most of the regions of genetic risk (22 of 24) were in noncoding regions of the genome. This study was undertaken to identify functional elements (other than genes) that might be located within the regions of genetic risk.We used paired-end RNA sequencing to identify noncoding RNAs (ncRNAs) located within 5 kb of disease-associated single-nucleotide polymorphisms (SNPs). In addition, we used chromatin immunoprecipitation (ChIP) followed by sequencing to identify epigenetic marks associated with enhancer function (H3K4me1 and H3K27ac) in human neutrophils to determine whether enhancer-associated histone marks were enriched in the linkage disequilibrium blocks that encompassed the 22 SNPs identified in the GWAS.In human neutrophils, we identified H3K4me1 and/or H3K27ac marks in 15 of the 22 regions previously identified as risk loci for JIA. In CD4+ T cells, 18 regions had H3K4me1 and/or H3K27ac marks. In addition, we identified ncRNA transcripts at the rs4705862 and rs6894249 loci in human neutrophils.Much of the genetic risk for JIA lies within or adjacent to regions of neutrophil and CD4+ T cell genomes that carry epigenetic marks associated with enhancer function and/or ncRNA transcripts. These findings are consistent with the hypothesis that JIA is fundamentally a disorder of gene regulation that includes both the innate and the adaptive immune system. Elucidating the specific roles of these noncoding elements within leukocyte genomes will be critical to our understanding of JIA pathogenesis.
Value of HRCT in assessment of airway wall thickness in uncontrolled asthmatic: Five years follow-up study
Authors: Aliae Mohamed-Hussein, Samy Ahmed
Journal: European Respiratory Journal (2013)

Recently, high resolution CT (HRCT) has been used to indirectly assess airway remodeling in vivo, on the basis of findings such as airway wall thickening.  Objectives:1) To assess airway wall thickness by HRCT in uncontrolled asthmatics, 2) to investigate the association between patients characteristics, disease severity and prognosis with airway wall thickness parameters before and after 5 years of follow-up.  Subjects and methods:Fifty -two patients with asthma and 23 healthy controls were recruited in the study. We measured airway luminal area (Ai) corrected by body surface area (Ai/BSA), airway wall area (WA) corrected by body surface area (WA/BSA), the percentage of wall area (WA %), absolute wall thickness (T)/ BSA, and thickness to diameter ratio (TDR) by HRCT in 2007 and 2012. Spirometric tests were also performed.  Results:In uncontrolled asthmatics, Ai/ BSA, WA/BSA, WA%, and T/BSA were all significantly greater than those in controlled and healthy control subjects. No significant difference in airway wall thickness parameters were found between controlled asthmatics and healthy controls. The degree of airway wall thickness increased after 5 years in: older patients, male gender, persistent smokers, irregular users of ICS, and anti- leukotreines and those with lower post- bronchodilator reversibility.  Conclusions:Airway wall thickness can be reliably followed by HRCT in uncontrolled asthmatics to assess airway remodeling. Smoking, age, male gender, lack of adherence to anti inflammatory drugs and irreversibility of airflow obstruction may be important factors in determining the airway wall thickness and hence the prognosis in this group of patients.
Chagas disease in Latin American migrants: a Spanish challenge
Authors: A. Pérez-Ayala, J.A. Pérez-Molina, F. Norman, M. Navarro, B. Monge-Maillo, M. Díaz-Menéndez, J. Peris-García, M. Flores, C. Cañavate, R. López-Vélez
Journal: Clinical Microbiology and Infection (2010)
Flat Dysplastic Aberrant Crypt Foci Are Related to Tumorigenesis in the Colon of Azoxymethane-Treated Rat
Authors: Jan Erik Paulsen, Else Marit Løberg, Hege Benedikte Ølstørn, Helle Knutsen, Inger-Lise Steffensen, Jan Alexander
Journal: Cancer Research (2005)

Abstract We evaluated the role of aberrant crypt foci (ACF) as biomarkers of colon cancer by studying the sequential development (6-28 weeks) from early lesion to tumor in the colon of azoxymethane-exposed F344 rats (15 mg/kg bw × 2). Surface examination of unsectioned methylene blue–stained colon preparations, transilluminated in the inverse light microscope, revealed two types of early lesions: classic elevated ACF and small flat lesions, which we denoted flat ACF and which were characterized by bright blue staining, compressed crypt openings, and crypts not elevated above the surrounding mucosa. At a later stage, the crypts surrounding large flat ACF became enlarged, a change that slightly raised the structure; principally, large flat ACF and nascent tumors displayed the same surface morphology. Furthermore, flat ACF with 18.6 ± 10.6 crypt/focus and tumors showed a uniform picture of severe dysplasia with frequent presence of Paneth cells, compressed crypts, cytoplasmic/nuclear overexpression of β-catenin, and nuclear overexpression of cyclin D1. In contrast, classic elevated ACF with 5.3 ± 2.5 crypts/focus did not display such changes: they showed mainly hyperplasia, mild or moderate dysplasia but never severe dysplasia. Along the time course, the number of flat ACF + tumors, including microscopic and macroscopic, was virtually constant, ∼2.5 lesions/rat. The number of classic elevated ACF was initially ∼180 lesions/rat and terminally ∼80 lesions/rat. Flat ACF grew significantly faster than classic elevated ACF. In conclusion, our data indicate a continuous developmental growth from small flat dysplastic ACF to the stage of a tumor. In contrast, classic elevated ACF do not seem to be as closely related to tumorigenesis.
e.SCCAN self-audit assessment in 15 Portuguese hospital-based smoking cessation services
Authors: Sofia Belo Ravara, José Manuel Calheiros
Journal: European Respiratory Journal (2012)

Introduction and Aim : Smoking cessation (SC) should be systematically integrated in healthcare. In 2009, the Project leader Professor B. Dautzenberg created the European smoking cessation clinics assessment and network group (e.SCCAN), joining tobacco control experts from 27 EU countries. The aim is to create a network of smoking cessation clinics for identification, definition and dissemination of good practices. Methods: The e.SCCAN developed a questionnaire-tool to evaluate smoking cessations services (SCS): e.SCCAN self-audit. In 2011, the self-audit was applied to 15 Portuguese hospital-based SCS (online survey, 100% collaboration, 30% of total hospitals). Results: Most HCPs working at SCS have been trained in SC. Most SCS participate in SC education activities, but few healthcare providers (HCPs), besides physicians, are involved in SC training. Data analysis showed that there is a need to:

• Announce proactively the SCS to the general public and HCPs (healthcare, media, internet)

• Educate and Certificate HCPs as cessation experts

• Develop team-based SC programmes

• Integrate multimodal and complementary SC programmes

• Allocate sufficient resources to cessation (time to organization and evaluation-this is part of our job)

• Develop tailored programes to specific populations

• Interact and work with the community –Health Promotion

• Integrate systematic evaluation and research- mandatory cessation indicators

Conclusions : In Portugal, there is room for improvement regarding smoking cessation healthcare services. Smoking cessation should become a priority of the National Healthcare System.
Optimizing Systemic Therapy Selection in Metastatic Colorectal Cancer
Authors: Axel Grothey
Journal: Journal of the National Comprehensive Cancer Network (2015)

For metastatic colorectal cancer, many effective agents can be incorporated into multiple lines of therapy across the nearly 3-year continuum of treatment. Emphasis should be on using all the recommended agents, with extended duration of anti-vascular endothelial growth factor treatment, and on identifying patients with any mutation in the RAS pathway. Chemotherapy plus bevacizumab or an epidermal growth factor receptor antibody are both viable options as first-line therapy in patients with RAS wild-type disease.
Heart rate variability and its relation to long-term smoking
Authors: Christoph Häcki, Martin Adam, Nicole Probst-Hensch, Nino Künzli, Urs Frey, Edgar Delgado-Eckert
Journal: European Respiratory Journal (2013)

Introduction. Heart rate variability (HRV) has been used in clinical studies to determine alterations in heart function. The deleterious effects of smoking on the cardiovascular system have also been reported extensively. We tested the hypothesis that long term active exposure to tobacco smoke triggers an irreversible change in the adaptability of the cardiovascular system, and that this effect may be reflected in alterations of HRV.

Methods. We analyzed series of inter beat intervals using a nonlinear method, leading to a parameter known as the maximal Lyapunov exponent (coefficient λ), which can be interpreted as a measure of unpredictability of the heart beat. By using multivariable regression models, we were able to explore the association between HRV and tobacco smoke exposure. The datasets were part of the SAPALDIA (Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults) cohort study, which contains 24h ECG data for 1586 participants and information about tobacco smoke exposure and further covariates such as biometric and disease related variables.

Results. The covariate pack-years was significantly associated with lower λ coefficients in men and women, indicating higher predictability of heart rate among smokers. The effect remained the same when we analyzed ex-smokers and current smokers separately. The number of years of having quit smoking does not correlate with an increase of λ among ex-smokers.

Conclusion. Smoking is associated with a significant increase in heart rate predictability, irrespectively of the current smoking status and the years of having quit smoking. Therefore, direct long term exposure to tobacco smoke may irreversibly affect the adaptability of the cardiovascular system.
Abstract 16395: Comparative Long-Term Risk of Death and Graft Failure in Renal Transplant Recipients Undergoing Coronary Revascularization With Coronary Artery Bypass Surgery versus Percutaneous Coronary Intervention
Authors: Charles A Herzog, David Charytan, Yang Qiu, Shuling Li
Journal: Circulation (2011)

Introduction/Methods: There are few published data on the comparative long-term risk of graft failure after coronary artery bypass surgery (CAB) vs percutaneous coronary intervention (PCI) in pts w...
Abstract 1423: Pitavastatin Ameliorates Angiotensin II-induced Cardiorenal Insufficiency In eNOS Knockout Mice Through Attenuating Rac-1-mediated Oxidative Stress
Authors: Shusuke Yagi, Kenichi Aihara, Yasumasa Ikeda, Takayuki Ise, Yuka Sumitomo, Takashi Iwase, Masashi Akaike, Toshio Matsumoto
Journal: Circulation (2007)

Background: It is well known that angiotensin II (Ang II) generates reactive oxygen species through NADPH oxidase activation, leading to promotion of cardiorenal diseases, especially in a condition with decreased nitric oxide (NO) bioavailability. In previous scientific sessions, we have shown that pitavastatin, an HMGCoA reductase inhibitor, ameliorates Ang II-induced cardiorenal damage in eNOS knockout (KO) mice through inhibition of the TGF-β-Smad2/3 pathway. However, the mechanism underlying eNOS-independent protective actions by pitavastatin has not been fully elucidated. Methods and Results: eNOS KO mice at 10 weeks of age were infused with Ang II (2.0 mg/kg/day) by an osmotic mini-pump for 2 weeks and they were divided into 3 treatment groups: pitavastatin (0.2 mg/kg/day), tempol, a free radical scavenger, (1.5 mg/kg/day), or a vehicle. Pitavastatin as well as tempol ameliorated Ang II-induced left ventricular hypertrophy with interstitial and pericoronary artery fibrosis and ameliorated diastolic dysfunction and they attenuated Ang II-induced glomerular damage, such as low glomerular filtration rate, increased albuminuria and PAS-positive glomerular depositions compared to those in vehicle-treated mice. Ang II-induced high mortality rate in eNOS KO mice was restored by pitavastatin as well as tempol treatment. Moreover, in eNOSKO mice, Ang II-induced cardiorenal superoxide production, detected with dihydroethidium staining, and Ang II-induced activity of rac-1-GTPase, a small G-protein involved in the activation of NADPH oxidase, were attenuated by pitavastatin treatment. Conclusions: Pitavastatin exerts an eNOS-independent protective action against Ang II-induced cardiorenal insufficiency through attenuating rac-1-GTPase-mediated oxidative stress. Our findings suggest that pitavastatin treatment is useful for caridorenal protection in patients with impaired NO bioavailability.
Safety and usefulness of bronchoscopy in patients with hematological disorders
Authors: Sato Toshitaka, Uruga Hironori, Takahashi Yui, Ogawa Kazuma, Hanada Shigeo, Mochizuki Sayaka, Suzuki Shinko, Takaya Hisashi, Miyamoto Atsushi, Morokawa Nasa, Tsuji Masanori, Uchida Naoyuki, Taniguchi Shuichi, Kishi Kazuma
Journal: European Respiratory Journal (2013)

[Purpose]To evaluate the safety and usefulness of bronchoscopy for post-transplantation pulmonary lesions and/or opportunistic infections in patients with hematological disorders.  [Subjects and methods]Between January 2009 and June 2012, 113 patients having hematological disorders with pulmonary lesions underwent bronchoscopy, with 7 patients undergoing it twice and 3 undergoing in thrice. Bronchoscopic procedure and its complications were evaluated.  [Results]Eighty-two males and 31 females with a median age of 60 years were included in this study. The underlying disease was acute myelogenous leukemia in 64 patients, malignant lymphoma in 18, acute lymphocytic leukemia in 9, myelodysplastic syndrome in 13, and others in 6. The median blood platelet count was 82,000/μl and 59 patients (52.2%) underwent platelet transfusion a day before or on the day of bronchoscopy. Moreover, before bronchoscopy, 31 patients (27.4%) were administered supplemental oxygen. The bronchoscopic procedures included bronchial washing in 68 patients, bronchoalveolar lavage in 41, and transbronchial lung biopsy in 41. With regard to complications, the respiratory condition deteriorated for more than two days after bronchoscopy in 9 patients (8.0%), and in 4 (3.5%) there was no improvement and the patients died within a month. In addition, 60 patients (53.1%) had post-bronchoscopy treatment changes.  [Conclusions]Our result suggest that bronchoscopy is useful in making treatment decisions regarding pulmonary lesions in patients with hematological disorders. However, we recommend that special attention should also be paid toward the patients’ respiratory condition.
Inflammasome activity in acute exacerbations of chronic obstructive pulmonary disease
Authors: Matina Kardara, Efrossini Dima, Harilena Giannakopoulou, Sofia Vakali, Charis Roussos, Nikolaos Koulouris, Nikoletta Rovina
Journal: European Respiratory Journal (2012)

Inflammasome is a multi-protein complex that mediates activation of caspase-1 which promotes the secretion of the proinflammatory cytokines IL-1β and IL-18 via Toll-like receptors (TLRs), which detect the presence of pathogens through pathogen associated molecular patterns (PAMPs). Aim of the study was to examine the changes occuring in inflammasome linked components during bacterial acute COPD exacerbations (AECOPD).  We examined 26 patients with COPD hospitalized for infectious AECOPD according to Anthonisen9s criteria and 20 patients with stable COPD. Bacterial infection was documented by PCR. IL-18, IL-1β, caspase-1, and TLR-2 levels were measured in induced sputum and serum at baseline and after the AECOPD treatment using ELISA, as well as in control subjects.  IL-1β, TLR-2 and caspase-1 (p=0.013) levels were increased in AECOPD. In contrast, IL-18 levels were found significantly lower in sputum of AECOPD compared to stable state (p=0.05), while right after treatment increased to the stable state levels. An inverse correlation was found between IL-18 levels and sputum macrophages in AECOPD (r=-630, p=0.028). Positive staining of IL-18 was observed in macrophages in immunocytochemistry. Serum IL-18 levels were elevated in exacerbations (p>0.05) compared to stable state, and decreased after treatment to stable disease levels (p>0.05).  Our data indicate that there is a dysregulated inflammasome activity in bacterial AECOPD that might contribute to the susceptibility of COPD patients in repeated bacterial exacerbations. Understanding the inflammasome pathways may provide insights into disease pathogenesis that might serve as potential targets for therapeutic intervention.
Estrogen Replacement Therapy and Benign Breast Disease&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: E J Trapido, L A Brinton, C Schairer, R Hoover
Journal: JNCI Journal of the National Cancer Institute (1984)

The relationship between estrogen replacement therapy (ERT) and the risk of benign breast disease (BBD) was examined among 929 postmenopausal cases and 846 postmenopausal controls identified through a large breast cancer screening program. Prior use of ERT among postmenopausal women was associated with an increased risk of both fibrocystic breast disease [odds ratio (OR) = 1.4; 95% confidence interval (Cl) = 1.1-1.8] and fibroadenoma (OR = 1.6; Cl = 0.8-3.5). The risk of all BBD rose with increasing years of use (OR = 1.9 for greater than or equal to 15 yr of total use) and with years since initial use (OR = 1.6 for greater than or equal to 15 yr since first use). Among users of the conjugated estrogen Premarin, increased risks were found at all but the lowest dose. Finally, risks associated with ERT were higher in women with a bilateral oophorectomy than in other postmenopausal women. These results suggested, overall, an increased risk of BBD associated with ERT.
A Reliable, Efficient, Microinjection Apparatus and Methodology for the In Vivo Exposure of Rainbow Trout and Salmon Embryos to Chemical Carcinogens&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: J J Black, A E Maccubbin, M Schiffert
Journal: JNCI Journal of the National Cancer Institute (1985)

A modular apparatus and technique for the injection of salmonid fish embryos with chemical carcinogens are described. A key feature of the methodology is the relative ease of routine through-the-eggshell injection, into the yolk sac of living salmonid fish embryos, inside the "eyed-stage" egg. The procedure is sufficiently rapid that 2 persons working as a team can give injections to 200 embryos per hour. The injection per se induces low mortality, i.e., optimal net survival rates (controls given an injection of dimethyl sulfoxide vs. those not given an injection) in the range of 70-90%. Because only small amounts of chemical are handled in relatively dilute form, the exposure method poses low risks to both the experimentalist and the environment. Preliminary results in a test of 4 carcinogens that differed widely in their structures and requirements for metabolic activation indicated that hepatocellular neoplasms were induced in rainbow trout (Salmo gairdneri) in response to 100 ng aflatoxin B1 (CAS: 1162-65-8)/egg, 1 microgram N-methyl-N'-nitro-N-nitrosoguanidine (CAS: 70-25-7)/egg, and 10 micrograms benzo[a]pyrene (CAS: 50-32-8)/egg. Nine months after exposure, liver neoplasms were observed in 25, 21, and 9%, respectively, of the rainbow trout, but no neoplasms were observed in rainbow trout exposed to 100 micrograms dimethylnitrosamine (CAS: 62-75-9)/egg. Liver neoplasms were also induced in 17% of coho salmon (Oncorhynchus kisutch) given an injection as embryos of 90 ng aflatoxin B1/egg or 5 micrograms N-methyl-N'-nitro-N-nitrosoguanidine/egg.