tbuckley/cabot-search huggingface dataset:
Treatment of Metastatic Ewing's Sarcoma or Primitive Neuroectodermal Tumor of Bone: Evaluation of Combination Ifosfamide and Etoposide—A Children's Cancer Group and Pediatric Oncology Group Study
Authors: James S. Miser, Mark D. Krailo, Nancy J. Tarbell, Michael P. Link, Christopher J.H. Fryer, Douglas J. Pritchard, Mark C. Gebhardt, Paul S. Dickman, Elizabeth J. Perlman, Paul A. Meyers, Sarah S. Donaldson, Sheila Moore, Aaron R. Rausen, Teresa J. Vietti, Holcolmbe E. Grier
Journal: Journal of Clinical Oncology (2004)

Purpose One hundred twenty patients with metastatic Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone were entered onto a randomized trial evaluating whether the addition of ifosfamide and etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin improved outcomes. Methods Thirty-two patients had metastases to lungs only, 12 patients had metastases to bone marrow or bones only, 64 patients had metastases in multiple sites, and five patients had metastases in other sites; seven patients could not be assessed precisely. Treatment comprised 9 weeks of chemotherapy before local control and 42 weeks of chemotherapy; thereafter, regimen A consisted of vincristine 2 mg/m 2 , cyclophosphamide 1,200 mg/m 2 , and either doxorubicin 75 mg/m 2 or dactinomycin 1.25 mg/m 2 . Regimen B consisted of regimen A alternating every 3 weeks with ifosfamide 1,800 mg/m 2 /d for 5 days and etoposide 100 mg/m 2 /d for 5 days. Results Patients treated on regimen B did not have significantly better survival than those treated on regimen A. The event-free survival (EFS) and survival (S) at 8 years were 20% (SE, 5%) and 32% (SE, 6%), respectively, for those treated on regimen A and 20% (SE, 6%) and 29% (SE, 6%), respectively, for those treated on regimen B. Patients who had only lung metastases had EFS and S of 32% (SE, 8%) and 41% (SE, 9%), respectively, at 8 years. There were six toxic deaths (5%), four from cardiac toxicity and two from sepsis (four treated on regimen B and two treated on regimen A). Two had second malignant neoplasms. Conclusion Adding ifosfamide and etoposide to standard therapy does not improve outcomes of patients with Ewing's sarcoma or PNET of bone with metastases at diagnosis.
Randomized controlled trial of interferon therapy as chemoprevention of HCC in HCV related cirrhosis
Authors: L. Benvegnu, M. Gios, G. Carrara, F. Belussi, C. Antona, M. Felder, R. Marin, G. Dona, D. Pancotti, F. Cavinato, A. Alberti
Journal: Journal of Hepatology (2001)
Targeted In Vivo Labeling of Receptors for Vascular Endothelial Growth Factor
Authors: Erxiong Lu, William R. Wagner, Ute Schellenberger, Judith A. Abraham, Alexander L. Klibanov, Steven R. Woulfe, Melissa M. Csikari, David Fischer, George F. Schreiner, Gary H. Brandenburger, Flordeliza S. Villanueva
Journal: Circulation (2003)

A method for identifying tissue experiencing hypoxic stress due to atherosclerotic vascular disease would be clinically useful. Vascular endothelial growth factor-121 (VEGF121) is an angiogenic protein secreted in response to hypoxia that binds to VEGF receptors overexpressed by ischemic microvasculature. We tested the hypothesis that VEGF receptors could serve as markers for ischemic tissue and hence provide a target for imaging such tissue with radiolabeled human VEGF121.A rabbit model of unilateral hindlimb ischemia was created by femoral artery excision (n=14). Control rabbits (n=5) underwent identical surgery without femoral excision. On postoperative day 10, rabbits were intravenously administered 100 microCi of 111In-labeled recombinant human VEGF121, and biodistribution studies and planar imaging were conducted at 3, 24, and 48 hours. On postmortem gamma counting, there was greater accumulation of 111In-labeled VEGF121 in ischemic than in control tissue (P<0.02). Differential uptake of isotope by ischemic muscle was not seen in rabbits injected with 125I-labeled human serum albumin (n=6). Radioactivity imaged in hindlimb regions of interest was significantly higher in ischemic muscle than in sham-operated and contralateral nonoperated hindlimb at 3 hours (P<0.02). Immunohistochemical staining confirmed upregulation of VEGF receptors in ischemic skeletal muscle.Identification of the ischemic state via targeted radiolabeling of hypoxia-induced angiogenic receptors is possible. This approach could be useful for monitoring the efficacy of revascularization strategies such as therapeutic angiogenesis.
S19 Increased CRTH2 expression in asthmatic bronchial epithelium: Abstract S19 Table 1.
Authors: K Johal, T Southworth, J Plumb, D Singh
Journal: Thorax (2013)

<h3>Introduction and Objectives</h3> Prostaglandin-D2 (PGD2) mediates chemotaxis of Th2 cells, basophils and eosinophils through the chemoattractant receptor homologous-molecule expressed on T-helper-type-2 cells (CRTh2). Pulmonary PGD2 levels are increased in patients with more severe asthma and higher levels of Th2 inflammation. CRTh2 antagonists, designed to block PDG2 signalling, are in clinical development for the treatment of asthma. We investigated whether pulmonary CRTh2 expression is upregulated in patients with asthma compared to controls; we focused on the bronchial epithelium and cells within the submucosa. <h3>Methods</h3> Bronchial biopsies were obtained from asthmatic patients (n = 20) and healthy subjects (n = 10). Sections were probed with an anti-human CRTh2 antibody, a secondary biotinylated goat anti-rabbit antibody and the position of the CRTh2 receptors were visualised with 3,39-Diaminobenzidine (DAB) and counter-staining with haemotoxylin. Digital micrographs were taken and analysed using the ImageProPlus 6.0 software. The percentage positive area of epithelium was calculated along with the intensity of staining. These values were multiplied together to give an overall immunohistochemical (IHC) score for each subject. The number of positive cells/mm<sup>2</sup> within the submucosa was also counted. <h3>Results</h3> CRTh2 expression was predominantly within the epithelium rather than the submucosa. There was a statistically significant (p = 0.04) increase the immunohistochemical score in the epithelium of asthmatics (74.7) compared to healthy non-smokers (38.8). There was no significant difference (p = 0.64) in the number of positive cells expressing CRTh2 within the submucosa between asthma patients (473/mm<sup>2</sup>) and healthy controls (353/mm<sup>2</sup>). <h3>Conclusion</h3> CRTh2 expression is upregulated in the epithelium of asthmatic patients compared to healthy controls. This is a novel finding, suggesting that CRTh2 antagonists may exert therapeutic effects on the bronchial epithelium as well as blocking inflammatory cell chemotaxis in asthma.
Reply to W.F. Pirl et al
Authors: Jeffrey A. Morgan, Richard Quek, Suzanne George, Susan D. Block, George D. Demetri
Journal: Journal of Clinical Oncology (2009)

We welcome the insightful contribution of Pirl et al 1 to the growing literature on the potential neuropsychiatric effects of molecular-targeted cancer therapies.As Pirl et al appropriately point out, the term tyrosine kinase inhibitors (TKIs) was used in our initial paper to refer to a variety of small molecule drugs with activity against a number of different receptor and nonreceptor tyrosine kinases, including imatinib (inhibitory against ABL, BCR-ABL, KIT, and platelet-derived growth factor receptors [PDGFRs]), sunitinib (inhibitory against KIT, PDGFRs, and vascular endothelial growth factor receptors), and dasatinib (inhibitory against ABL, BCR-ABL, SRC, KIT and PDGFRs).Our observations may indeed be quite different from what one might expect to see with the exquisitely specific drugs, such as gefitinib or erlotinib, which inhibit the epidermal growth factor receptor (EGFR).Interestingly, small-molecule TKIs targeting EGFR tend to be far more specific for this receptor tyrosine kinase than for other kinase targets, probably reflecting a unique structural biology for the adenosine triphosphate-binding pocket in the EGFR.Moreover, our observations were derived solely from our team's extensive experience managing GI stromal tumor, one of the three major diseases managed with drugs in this class (the others being chronic myelogenous leukemia and renal cell carcinoma).Of note, links between depression and specific drug exposure may be missed in large database analyses, for multiple reasons.Most importantly, the linkage may be idiosyncratic and/or uncommon.Our observations suggest the incidence of imatinib-associated depression in the GI stromal tumor population to be no more than 2%; many toxicity analyses are reported only if the toxicity is severe or if it occurs in at least 5% to 10% of exposed patients.Second, if the possibility of causality from drug is not considered, depression in a patient suffering from advanced cancer may not be scored as a drug-associated toxicity.Only after recognition of the syndrome in patient 1 were we able to consider and subsequently clinically confirm the diagnosis in other patients in the series.Until further studies are conducted, because of the high morbidity and mortality associated with underdiagnosed and undertreated depression, we believe that the possibility of drug induc-tion of depression or other mood changes should be considered in the differential diagnosis of psychological distress in patients treated with these agents.
Selection of Tumor-binding Ligands in Cancer Patients with Phage Display Libraries
Authors: David N. Krag, Girja S. Shukla, Guang-Ping Shen, Stephanie Pero, Taka Ashikaga, Susan Fuller, Donald L. Weaver, Susan Burdette-Radoux, Christian Thomas
Journal: Cancer Research (2006)

Phage display has been used extensively in vitro and in animal models to generate ligands and to identify cancer-relevant targets. We report here the use of phage-display libraries in cancer patients to identify tumor-targeting ligands. Eight patients with stage IV cancer, including breast, melanoma, and pancreas, had phage-displayed random peptide or scFv library (1.6 x 10(8)-1 x 10(11) transducing units/kg) administered i.v.; tumors were excised after 30 minutes; and tumor-homing phage were recovered. In three patients, repeat panning was possible using phage recovered and amplified from that same patient's tumor. No serious side effects, including allergic reactions, were observed with up to three infusions. Patients developed antiphage antibodies that reached a submaximal level within the 10-day protocol window for serial phage administration. Tumor phage were recoverable from all the patients. Using a filter-based ELISA, several clones from a subset of the patients were identified that bound to a tumor from the same patient in which clones were recovered. The clone-binding to tumor was confirmed by immunostaining, bioassay, and real-time PCR-based methods. Binding studies with noncancer and cancer cell lines of the same histology showed specificity of the tumor-binding clones. Analysis of insert sequences of tumor-homing peptide clones showed several motifs, indicating nonrandom accumulation of clones in human tumors. This is the first reported series of cancer patients to receive phage library for serial panning of tumor targeting ligands. The lack of toxicity and the ability to recover clones with favorable characteristics are a first step for further research with this technology in cancer patients.
Isolation and expansion of cytomegalovirus-specific cytotoxic T lymphocytes to clinical scale from a single blood draw using dendritic cells and HLA-tetramers
Authors: Susann Szmania, Amanda Galloway, Mary Bruorton, Philip Musk, Geraldine Aubert, Andrew Arthur, Haywood Pyle, Nancy Hensel, Nga Ta, Lawrence Lamb, Toni Dodi, Alejandro Madrigal, John Barrett, Jean Henslee-Downey, Frits van Rhee
Journal: Blood (2001)
ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function
Authors: Tetsuro Murakami, Seema Qamar, Julie Qiaojin Lin, Gabriele S. Kaminski Schierle, Eric Rees, Akinori Miyashita, Ana R. Costa, Roger B. Dodd, Fiona T.S. Chan, Claire H. Michel, Deborah Kronenberg-Versteeg, Yi Li, Seung-Pil Yang, Yosuke Wakutani, William Meadows, Rodylyn Rose Ferry, Liang Dong, Gian Gaetano Tartaglia, Giorgio Favrin, Wen-Lang Lin, Dennis W. Dickson, Mei Zhen, David Ron, Gerold Schmitt-Ulms, Paul E. Fraser, Neil A. Shneider, Christine Holt, Michele Vendruscolo, Clemens F. Kaminski, Peter St George-Hyslop
Journal: Neuron (2015)

The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.
Effect of a multifaceted intervention on number of antimicrobial prescriptions for suspected urinary tract infections in residents of nursing homes: cluster randomised controlled trial
Authors: Mark Loeb, Kevin Brazil, Lynne Lohfeld, Allison McGeer, Andrew Simor, Kurt Stevenson, Dick Zoutman, Stephanie Smith, Xiwu Liu, Stephen D Walter
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To assess whether a multifaceted intervention can reduce the number of prescriptions for antimicrobials for suspected urinary tract infections in residents of nursing homes. <b>Design</b> Cluster randomised controlled trial. <b>Setting</b> 24 nursing homes in Ontario, Canada, and Idaho, United States. <b>Participants</b> 12 nursing homes allocated to a multifaceted intervention and 12 allocated to usual care. Outcomes were measured in 4217 residents. <b>Interventions</b> Diagnostic and treatment algorithm for urinary tract infections implemented at the nursing home level using a multifaceted approach—small group interactive sessions for nurses, videotapes, written material, outreach visits, and one on one interviews with physicians. <b>Main outcome measures</b> Number of antimicrobials prescribed for suspected urinary tract infections, total use of antimicrobials, admissions to hospital, and deaths. <b>Results</b> Fewer courses of antimicrobials for suspected urinary tract infections per 1000 resident days were prescribed in the intervention nursing homes than in the usual care homes (1.17 <i>v</i> 1.59 courses; weighted mean difference −0.49, 95% confidence intervals −0.93 to −0.06). Antimicrobials for suspected urinary tract infection represented 28.4% of all courses of drugs prescribed in the intervention nursing homes compared with 38.6% prescribed in the usual care homes (weighted mean difference −9.6%, −16.9% to −2.4%). The difference in total antimicrobial use per 1000 resident days between intervention and usual care groups was not significantly different (3.52 <i>v</i> 3.93; weighted mean difference −0.37, −1.17 to 0.44). No significant difference was found in admissions to hospital or mortality between the study arms. <b>Conclusion</b> A multifaceted intervention using algorithms can reduce the number of antimicrobial prescriptions for suspected urinary tract infections in residents of nursing homes.
Reduced Hypoglycemia Risk With Insulin Glargine
Authors: Julio Rosenstock, George Dailey, Massimo Massi-Benedetti, Andreas Fritsche, Zhengning Lin, Alan Salzman
Journal: Diabetes Care (2005)

OBJECTIVE—Insulin glargine (LANTUS) is a once-daily basal insulin analog with a smooth 24-h time-action profile that provides effective glycemic control with reduced hypoglycemia risk (particularly nocturnal) compared with NPH insulin in patients with type 2 diabetes. A recent “treat-to-target” study has shown that more patients on insulin glargine reached HbA1c levels ≤7.0% without confirmed nocturnal hypoglycemia compared with NPH insulin. We further assessed the risk for hypoglycemia in a meta-analysis of controlled trials of a similar design for insulin glargine versus once- or twice-daily NPH insulin in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS—All studies were 24–28 weeks long, except one 52-week study, for which interim 20-week data were used. RESULTS—Patient demographics were similar between the insulin glargine (n = 1,142) and NPH insulin (n = 1,162) groups. The proportion of patients achieving target HbA1c (≤7.0%) was similar between insulin glargine–and NPH insulin–treated patients (30.8 and 32.1%, respectively). There was a consistent significant reduction of hypoglycemia risk associated with insulin glargine, compared with NPH insulin, in terms of overall symptomatic (11%; P = 0.0006) and nocturnal (26%; P &amp;lt; 0.0001) hypoglycemia. Most notably, the risk of severe hypoglycemia and severe nocturnal hypoglycemia were reduced with insulin glargine by 46% (P = 0.0442) and 59% (P = 0.0231), respectively. CONCLUSIONS—These results confirmed that insulin glargine given once daily reduces the risk of hypoglycemia compared with NPH insulin, which can facilitate more aggressive insulin treatment to a HbA1c target of ≤7.0% in patients with type 2 diabetes.
Novel ALK inhibitors in clinical use and development
Authors: Chaitanya Iragavarapu, Milaim Mustafa, Akintunde Akinleye, Muhammad Furqan, Varun Mittal, Shundong Cang, Delong Liu
Journal: Journal of Hematology & Oncology (2015)

Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. ALK-1 was initially found in anaplastic large cell lymphoma (ALCL). ALK mutations have also been implicated in the pathogenesis of non-small cell lung cancer (NSCLC) and other solid tumors. Multiple small molecule inhibitors with activity against ALK and related oncoproteins are under clinical development. Two of them, crizotinib and ceritinib, have been approved by FDA for treatment of locally advanced and metastatic NSCLC. More agents (alectinib, ASP3026, X396) with improved safety, selectivity, and potency are in the pipeline. Dual inhibitors targeting ALK and EGFRm (AP26113), TRK (TSR011), FAK (CEP-37440), or ROS1 (RXDX-101, PF-06463922) are under active clinical development.
Randomised vitamin E supplementation and risk of chronic lung disease in the Women's Health Study
Authors: A. H. Agler, T. Kurth, J. M. Gaziano, J. E. Buring, P. A. Cassano
Journal: Thorax (2011)

The oxidant/antioxidant balance in lung tissue is hypothesised to contribute to the risk of chronic obstructive pulmonary disease (COPD). Observational studies consistently report higher antioxidant status associated with lower COPD risk, but few randomised studies have been reported.A post hoc analysis of 38,597 women without chronic lung disease at baseline was conducted in the Women's Health Study (WHS) to test the effect of vitamin E on the risk of incident chronic lung disease. The WHS is a randomised double-blind placebo-controlled factorial trial of vitamin E (600 IU every other day) and aspirin (100 mg every other day) in female health professionals aged≥45 years. Using Cox proportional hazards models, the effect of randomised vitamin E assignment on self-reported physician-diagnosed chronic lung disease was evaluated.During 10 years of follow-up (376,710 person-years), 760 first occurrences of chronic lung disease were reported in the vitamin E arm compared with 846 in the placebo arm (HR 0.90; 95% CI 0.81 to 0.99; p=0.029). This 10% reduction in the risk of incident chronic lung disease was not modified by cigarette smoking, age, randomised aspirin assignment, multivitamin use or dietary vitamin E intake (minimum p for interaction=0.19). Current cigarette smoking was a strong predictor of chronic lung disease risk (HR 4.17; 95% CI 3.70 to 4.70; vs. never smokers).In this large randomised trial, assignment to 600 IU vitamin E led to a 10% reduction in the risk of chronic lung disease in women.
Crucial Role of Phospholipase Cε in Skin Inflammation Induced by Tumor-Promoting Phorbol Ester
Authors: Shuzo Ikuta, Hironori Edamatsu, Mingzhen Li, Lizhi Hu, Tohru Kataoka
Journal: Cancer Research (2008)

Abstract In two-stage skin chemical carcinogenesis, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) acts as a promoter essential for clonal expansion of the initiated cells carrying the activated ras oncogenes. Although protein kinase C (PKC) isozymes are the main targets of TPA, their role in tumor promotion remains controversial. We previously reported that mice lacking a Ras/Rap effector phospholipase Cε (PLCε−/− mice) exhibited marked resistance to tumor formation in the two-stage skin carcinogenesis. PLCε−/− mice also failed to exhibit basal layer cell proliferation and epidermal hyperplasia induced by TPA, suggesting a role of PLCε in tumor promotion. Here, we show that PLCε−/− mice exhibit resistance to TPA-induced skin inflammation as assessed by reduction in edema, granulocyte infiltration, and expression of a proinflammatory cytokine, interleukin-1α (IL-1α). On the other hand, the proliferative potentials of keratinocytes or dermal fibroblasts in culture remain unaffected by the PLCε background, suggesting that the PLCε's role in tumor promotion may be ascribed to augmentation of inflammatory responses. In dermal fibroblast primary culture, TPA can induce activation of the PLCε lipase activity, which leads to the induction of IL-1α expression. Experiments using small interfering RNA–mediated knockdown indicate that this activation is mediated by Rap1, which is activated by a TPA-responsive guanine nucleotide exchange factor RasGRP3. Moreover, TPA-induced activation of Rap1 and PLCε is inhibited by a PKC inhibitor GF109203X, indicating a crucial role of PKC in signaling from TPA to PLCε. These results imply that two TPA targets, RasGRP3 and PKC, are involved in TPA-induced inflammation through PLCε activation, leading to tumor promotion. [Cancer Res 2008;68(1):64–72]
Inhibition of coronary atherosclerosis by propranolol in behaviorally predisposed monkeys fed an atherogenic diet.
Authors: J R Kaplan, S B Manuck, M R Adams, K W Weingand, T B Clarkson
Journal: Circulation (1987)

We studied the effect of propranolol on the diet-induced coronary artery atherosclerosis (CAA) in 30 adult male cynomolgus monkeys living in social groupings of five animals each. Animals in the "treated" segment (n = 15) consumed propranolol, which was mixed into an atherogenic diet. Animals in the "untreated" group (n = 15) consumed only the atherogenic diet. Finally, the social groupings were subjected to disruption through monthly redistribution of monkeys among the groups within each treatment segment. The experiment lasted 26 months, following which all animals underwent autopsy during which the coronary arteries were evaluated for atherosclerosis. Regarding atherosclerosis, we observed a significant interaction between social status and experimental condition (p less than .03). Socially dominant animals had (as in previous studies) significantly exacerbated CAA, but only in the untreated segment; the effect of social dominance on CAA was abolished by long-term administration of propranolol. The antiatherogenic effect of propranolol on dominant animals was independent of the influences of serum lipid concentrations, blood pressure, and resting heart rate. We conclude that treatment with beta-adrenergic-blocking agents may confer a degree of protection against CAA among individuals behaviorally predisposed to coronary heart disease.