tbuckley/cabot-search huggingface dataset:
ZD1839, a Selective Oral Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor, Is Well Tolerated and Active in Patients With Solid, Malignant Tumors: Results of a Phase I Trial
Authors: Malcolm Ranson, Lisa A. Hammond, David Ferry, Mark Kris, Andrew Tullo, Philip I. Murray, Vince Miller, Steve Averbuch, Judy Ochs, Charles Morris, Andrea Feyereislova, Helen Swaisland, Eric K. Rowinsky
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors. PATIENTS AND METHODS: This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non–small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for ≥ 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for ≥ 6 months. CONCLUSION: ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.
Chemotherapeutic Effects on Mammalian Tumor Cells. III. Modification of Leukemia L1210 Growth Kinetics With an Antimetabolite
Authors: Ralph E. Johnson, Walter G. Hardy, Marvin Zelen
Journal: JNCI Journal of the National Cancer Institute (1966)

A biologically stable ascites line of Leukemia L1210 was treated with amethopterin under conditions designed to reduce the surviving cells to a minimum number. A mathematical model suggested an alteration of the growth kinetics of these sublethally damaged surviving cells. Bioassay studies on sublines developed from recurrent tumors confirmed a transient decrease in virulence associated with a prolonged tumor doubling time. Cytogenetic studies demonstrated a high frequency of chromatid breaks in sublines derived from amethopterin-treated cells.
Akt/Protein Kinase B Signaling Inhibitor-2, a Selective Small Molecule Inhibitor of Akt Signaling with Antitumor Activity in Cancer Cells Overexpressing Akt
Authors: Lin Yang, Han C. Dan, Mei Sun, Qiyuan Liu, Xia-meng Sun, Richard I. Feldman, Andrew D. Hamilton, Mark Polokoff, Santo V. Nicosia, Meenhard Herlyn, Said M. Sebti, Jin Q. Cheng
Journal: Cancer Research (2004)

Accumulated studies have shown that activation of the Akt pathway plays a pivotal role in malignant transformation and chemoresistance by inducing cell survival, growth, migration, and angiogenesis. Therefore, Akt is believed to be a critical target for cancer intervention. Here, we report the discovery of a small molecule Akt pathway inhibitor, Akt/protein kinase B signaling inhibitor-2 (API-2), by screening the National Cancer Institute Diversity Set. API-2 suppressed the kinase activity and phosphorylation level of Akt. The inhibition of Akt kinase resulted in suppression of cell growth and induction of apoptosis in human cancer cells that harbor constitutively activated Akt due to overexpression of Akt or other genetic alterations such as PTEN mutation. API-2 is highly selective for Akt and does not inhibit the activation of phosphatidylinositol 3'-kinase, phosphoinositide-dependent kinase-1, protein kinase C, serum- and glucocorticoid-inducible kinase, protein kinase A, signal transducer and activators of transcription 3, extracellular signal-regulated kinase-1/2, or c-Jun NH(2)-terminal kinase. Furthermore, API-2 potently inhibited tumor growth in nude mice of human cancer cells in which Akt is aberrantly expressed/activated but not of those cancer cells in which it is not. These findings provide strong evidence for pharmacologically targeting Akt for anticancer drug discovery.
Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis
Authors: Renate Kain, Markus Exner, Ricarda Brandes, Reinhard Ziebermayr, Dawn Cunningham, Carol A Alderson, Agnes Davidovits, Ingrid Raab, Renate Jahn, Oliver Ashour, Susanne Spitzauer, Gere Sunder-Plassmann, Minoru Fukuda, Per Klemm, Andrew J Rees, Dontscho Kerjaschki
Journal: Nature Medicine (2008)
Comparative structural analysis of the transcriptionally active proopiomelanocortin genes A and B of Xenopus laevis.
Authors: P M Deen, M J Bussemakers, D Terwel, E W Roubos, G J Martens
Journal: Molecular Biology and Evolution (1992)

In the intermediate lobe of the pituitary gland, the prohormone proopiomelanocortin (POMC) is processed to, among other peptides, melanocyte-stimulating hormone (alpha-MSH). In the toad Xenopus laevis alpha-MSH controls skin darkening during background adaptation, and the level of POMC gene transcription in the intermediate lobe depends on the color of the background. In the lobe, two structurally different POMC proteins are produced from two mRNAs that are transcribed to approximately the same level from two POMC genes (A and B). We previously reported the entire nucleotide sequence of Xenopus POMC gene B. To identify conserved-- and thus potential regulatory--DNA elements in the Xenopus POMC gene, we here report the determination and analysis of the complete nucleotide sequence of Xenopus POMC gene A and its 5'- and 3'-flanking regions. Comparison of the two Xenopus POMC genes revealed, in addition to the exons, three highly conserved regions. First, the promoter regions are greater than 90% identical. The second region concerns JH12 repetitive elements situated at approximately the same position in both genes. These elements are greater than 86% identical. The third region is a 500-bp sequence just upstream of exon three (63% identity). Besides these three large regions, several small regions with significant identity were found at similar positions in the two POMC genes. The fact that, except for the JH12 element, the repetitive elements are not conserved between the two POMC genes indicates that these repeats are not functionally important.
Refining the Amsterdam Criteria and Bethesda Guidelines: Testing Algorithms for the Prediction of Mismatch Repair Mutation Status in the Familial Cancer Clinic
Authors: L.R. Lipton, V. Johnson, C. Cummings, S. Fisher, P. Risby, A.T. Eftekhar Sadat, T. Cranston, L. Izatt, P. Sasieni, S.V. Hodgson, H.J.W. Thomas, I.P.M. Tomlinson
Journal: Journal of Clinical Oncology (2004)

Purpose Hereditary nonpolyposis colon cancer (HNPCC) is a Mendelian dominant syndrome of bowel, endometrial, and other cancers and results from germline mutations in mismatch repair (MMR) genes. HNPCC is now best diagnosed on molecular grounds using MMR mutation screening, aided by microsatellite instability (MSI) and immunohistochemistry in tumors. Selection of families for molecular investigation of HNPCC is usually based on suboptimal methods (Amsterdam Criteria or Bethesda Guidelines), but these can be improved using additional clinical data (mean ages of affected persons and presence of endometrial cancer) in a quantitative model. Methods We have verified the performance of the Wijnen model and have shown that it remains valid when HNPCC is diagnosed using mutation screening, MSI, and immunohistochemistry. We have also set up and verified our own models (Amsterdam-plus and Alternative), which perform at least as well as the Wijnen model. Results The Amsterdam-plus model improves on the Amsterdam Criteria by using five extra variables (numbers of colorectal and endometrial cancers in the family, number of patients with five or more adenomas, number with more than one primary cancer of the colorectum or endometrium, and mean age of presentation) and performs better than the Wijnen model. The Alternative model avoids the need to evaluate the Amsterdam Criteria and performs nearly as well as the other models. Conclusion We believe that a quantitative model, such as the Amsterdam-plus model, should be the first choice for selecting families or patients for evaluation of HNPCC using molecular tests. We present an algorithm for this process.
Effects of atorvastatin added to inhaled corticosteroids on lung function and sputum cell counts in atopic asthma
Authors: E J Hothersall, R Chaudhuri, C McSharry, I Donnelly, J Lafferty, A D McMahon, C J Weir, J Meiklejohn, N Sattar, I McInnes, S Wood, N C Thomson
Journal: Thorax (2008)

Statins have anti-inflammatory properties that may be beneficial in the treatment of asthma. A study was undertaken to test the hypothesis that atorvastatin added to inhaled corticosteroids improves lung function and airway inflammation in atopic adults with asthma.54 adults with atopic asthma were recruited to a double-blind randomised controlled crossover trial comparing the effect of oral atorvastatin 40 mg daily with that of a matched placebo on asthma control and airway inflammation. Each treatment was administered for 8 weeks separated by a 6-week washout period. The primary outcome was morning peak expiratory flow (PEF). Secondary outcomes included forced expiratory volume in 1 s, asthma control questionnaire score, airway hyper-responsiveness to methacholine, induced sputum cytology and inflammatory biomarkers.At 8 weeks the change in mean morning PEF compared with baseline did not differ substantially between the atorvastatin and placebo treatment periods (mean difference -0.5 l/min, 95% CI -10.6 to 9.6, p = 0.921). Values for other clinical outcomes were similar between the atorvastatin and placebo treatment periods. The absolute sputum macrophage count was reduced after atorvastatin compared with placebo (mean difference -45.0 x 10(4) cells, 95% CI -80.1 to -9.7, p = 0.029), as was the sputum fluid leucotriene B4 (mean difference -88.1 pg/ml, 95% CI -156.4 to -19.9, p = 0.014).The addition of atorvastatin to inhaled corticosteroids results in no short-term improvement in asthma control but reduces sputum macrophage counts in mild to moderate atopic asthma. The change in sputum macrophage count suggests potential areas for investigation of statins in other chronic lung diseases.
Optimization of Optical Excitation of Upconversion Nanoparticles for Rapid Microscopy and Deeper Tissue Imaging with Higher Quantum Yield
Authors: Qiuqiang Zhan, Sailing He, Jun Qian, Hao Cheng, Fuhong Cai
Journal: Theranostics (2013)

Relatively low quantum yield (QY), time-consuming scanning and strong absorption of light in tissue are some of the issues present in the development of upconversion nanoparticles (UCNPs) for biomedical applications.In this paper we systematically optimize several aspects of optical excitation of UCNPs to improve their applicability in bioimaging and biotherapy.A novel multi-photon evanescent wave (EW) excitation modality is proposed for UCNP-based microscopy.The scanning-free, ultrahigh contrast and high spatiotemporal resolution method could simultaneously track a few particles in a large area with a speed of up to 350 frames per second.The HeLa cancer cell membrane imaging was successfully performed using NaYF 4 : 20% Yb 3+ /2% Er 3+ targeting nanoparticles.Studies with different tissues were made to illustrate the impact of optical property parameters on the deep imaging ability of 920-nm band excitation.In the experiments a semiconductor laser with a 920 nm wavelength was used to excite UCNPs in tissue phantom at five depths.Our experimental and computational results have shown that in UCNP-based diffusion optical imaging with 920-nm laser excitation could lead to larger imaging depth range compared to traditional 974-nm excitation in a wide dynamic range of tissue species.As the QY is power density dependent, a pulsed laser is proposed to improve the QY of UCNPs.This proposal is promising in drastically increasing the imaging depth and efficiency of photodynamic therapy.
Meat, Fish, and Colorectal Cancer Risk: The European Prospective Investigation into Cancer and Nutrition
Authors: Teresa Norat, Sheila Bingham, Pietro Ferrari, Nadia Slimani, Mazda Jenab, Mathieu Mazuir, Kim Overvad, Anja Olsen, Anne Tjønneland, Francoise Clavel, Marie-Christine Boutron-Ruault, Emmanuelle Kesse, Heiner Boeing, Manuela M. Bergmann, Alexandra Nieters, Jakob Linseisen, Antonia Trichopoulou, Dimitrios Trichopoulos, Yannis Tountas, Franco Berrino, Domenico Palli, Salvatore Panico, Rosario Tumino, Paolo Vineis, H. Bas Bueno-de-Mesquita, Petra H. M. Peeters, Dagrun Engeset, Eiliv Lund, Guri Skeie, Eva Ardanaz, Carlos González, Carmen Navarro, J. Ramón Quirós, María-José Sanchez, Göran Berglund, Irene Mattisson, Göran Hallmans, Richard Palmqvist, Nicholas E. Day, Kay-Tee Khaw, Timothy J. Key, Miguel San Joaquin, Bertrand Hémon, Rodolfo Saracci, Rudolf Kaaks, Elio Riboli
Journal: JNCI Journal of the National Cancer Institute (2005)

Current evidence suggests that high red meat intake is associated with increased colorectal cancer risk. High fish intake may be associated with a decreased risk, but the existing evidence is less convincing.
Osteosarcoma of the mobile spine
Authors: K. Zils, S. Bielack, M. Wilhelm, M. Werner, R. Schwarz, R. Windhager, G. Hofmann-Wackersreuther, T. Andus, L. Kager, T. Kuehne, P. Reichardt, T. von Kalle
Journal: Annals of Oncology (2013)
Genomic Index of Sensitivity to Endocrine Therapy for Breast Cancer
Authors: W. Fraser Symmans, Christos Hatzis, Christos Sotiriou, Fabrice Andre, Florentia Peintinger, Peter Regitnig, Guenter Daxenbichler, Christine Desmedt, Julien Domont, Christian Marth, Suzette Delaloge, Thomas Bauernhofer, Vicente Valero, Daniel J. Booser, Gabriel N. Hortobagyi, Lajos Pusztai
Journal: Journal of Clinical Oncology (2010)

We hypothesize that measurement of gene expression related to estrogen receptor α (ER; gene name ESR1) within a breast cancer sample represents intrinsic tumoral sensitivity to adjuvant endocrine therapy.A genomic index for sensitivity to endocrine therapy (SET) index was defined from genes coexpressed with ESR1 in 437 microarray profiles from newly diagnosed breast cancer, unrelated to treatment or outcome. The association of SET index and ESR1 levels with distant relapse risk was evaluated from microarrays of ER-positive breast cancer in two cohorts who received 5 years of tamoxifen alone as adjuvant endocrine therapy (n = 225 and 298, respectively), a cohort who received neoadjuvant chemotherapy followed by tamoxifen and/or aromatase inhibition (n = 122), and two cohorts who received no adjuvant systemic therapy (n = 208 and 133, respectively).The SET index (165 genes) was significantly associated with distant relapse or death risk in both tamoxifen-treated cohorts (hazard ratio [HR] = 0.70, 95% CI, 0.56 to 0.88, P = .002; and HR = 0.76, 95% CI, 0.63 to 0.93, P = .007) and in the chemo-endocrine-treated cohort (HR = 0.19; 95% CI, 0.05 to 0.69, P = .011) independently from pathologic response to chemotherapy, but was not prognostic in two untreated cohorts. No distant relapse or death was observed after tamoxifen alone if node-negative and high SET or after chemo-endocrine therapy if intermediate or high SET.The SET index of ER-related transcription predicted survival benefit from adjuvant endocrine therapy, not inherent prognosis. Prior chemotherapy seemed to enhance the efficacy of adjuvant endocrine therapy related to SET index.
Risk Factors for Acute Graft-Versus-Host Disease After Human Leukocyte Antigen–Identical Sibling Transplants for Adults With Leukemia
Authors: Theresa Hahn, Philip L. McCarthy, Mei-Jie Zhang, Dan Wang, Mukta Arora, Haydar Frangoul, Robert Peter Gale, Gregory A. Hale, John Horan, Luis Isola, Richard T. Maziarz, Jon J. van Rood, Vikas Gupta, Joerg Halter, Vijay Reddy, Pierre Tiberghien, Mark Litzow, Claudio Anasetti, Stephen Pavletic, Olle Ringdén
Journal: Journal of Clinical Oncology (2008)

Acute graft-versus-host disease (GVHD) causes substantial morbidity and mortality after human leukocyte antigen (HLA)-identical sibling transplants. No large registry studies of acute GVHD risk factors have been reported in two decades. Risk factors may have changed in this interval as transplant-related techniques have evolved.
Nuclear Receptors in Lipid Metabolism: Targeting the Heart of Dyslipidemia
Authors: Simon W. Beaven, Peter Tontonoz
Journal: Annual Review of Medicine (2006)

Dyslipidemia is the sine qua non of atherosclerosis, but it is also strongly associated with the metabolic syndrome, obesity, diabetes, and fatty liver disease. The molecular basis for future therapies requires understanding the pivotal role of nuclear hormone receptors in lipid and inflammatory homeostasis. This review summarizes evidence that the liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR) are key transcriptional regulators in lipid metabolism. Additionally, their effects on glucose homeostasis and inflammation make LXR and PPAR signaling networks attractive molecular targets for managing lipid-related diseases.
Randomised controlled trial of primary school based intervention to reduce risk factors for obesity
Authors: P. Sahota, M. C J Rudolf, R. Dixey, A. J Hill, J. H Barth, J. Cade
Journal: BMJ (2001)

<h3>Abstract</h3> <b>Objective:</b> To assess if a school based intervention was effective in reducing risk factors for obesity. <b>Design:</b> Group randomised controlled trial. <b>Setting:</b> 10 primary schools in Leeds. <b>Participants:</b> 634 children aged 7-11 years. <b>Intervention:</b> Teacher training, modification of school meals, and the development of school action plans targeting the curriculum, physical education, tuck shops, and playground activities. <b>Main outcome measures:</b> Body mass index, diet, physical activity, and psychological state. <b>Results:</b> Vegetable consumption by 24 hour recall was higher in children in the intervention group than the control group (weighted mean difference 0.3 portions/day, 95% confidence interval 0.2 to 0.4), representing a difference equivalent to 50% of baseline consumption. Fruit consumption was lower in obese children in the intervention group (−1.0, −1.8 to −0.2) than those in the control group. The three day diary showed higher consumption of high sugar foods (0.8, 0.1 to 1.6)) among overweight children in the intervention group than the control group. Sedentary behaviour was higher in overweight children in the intervention group (0.3, 0.0 to 0.7). Global self worth was higher in obese children in the intervention group (0.3, 0.3 to 0.6). There was no difference in body mass index, other psychological measures, or dieting behaviour between the groups. Focus groups indicated higher levels of self reported behaviour change, understanding, and knowledge among children who had received the intervention. <b>Conclusion:</b> Although it was successful in producing changes at school level, the programme had little effect on children9s behaviour other than a modest increase in consumption of vegetables. <h3>What is already known on this topic</h3> Obesity is increasing among school children and demands preventive strategies Randomised controlled trials of school based primary prevention programmes have all used a prescriptive approach <h3>What this study adds</h3> Behavioural changes were disappointing with this programme based on the health promoting schools philosophy, despite changes at school level The only positive outcome was a modest increase in vegetable consumption The discrepancy between changes achieved at the individual and school level raises issues regarding the problems inherent in such trials
Competing Causes of Death and Second Primary Tumors in Patients with Locoregionally Advanced Head and Neck Cancer Treated with Chemoradiotherapy
Authors: Athanassios Argiris, Bruce E. Brockstein, Daniel J. Haraf, Kerstin M. Stenson, Bharat B. Mittal, Merrill S. Kies, Fred R. Rosen, Borko Jovanovic, Everett E. Vokes
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this retrospective analysis was to evaluate the emergence of second primary malignancies and the contribution of different causes of death to the outcome of patients with locoregionally advanced head and cancer receiving primary chemoradiotherapy. Experimental Design: We studied 324 patients with stage IV squamous cell head and neck cancer who were enrolled on five consecutive multicenter Phase II studies of concurrent chemoradiotherapy. All of the regimens included concurrent 5-fluorouracil and hydroxyurea on an alternate week schedule with radiotherapy, either alone (FHX) or with cisplatin (C-FHX) or paclitaxel (T-FHX). The cumulative incidence of second primary tumors or death from any cause was estimated using methods of competing risk analysis. Results: Median follow-up of surviving patients was 5.2 years (2–10.6 years). The 5-year overall survival and progression-free survival of the cohort were 46% and 65%, respectively. Causes of death and median time of occurrence were as follows: disease (n = 88; 1.5 years), treatment-associated acute or late complications (n = 30; 4 months), second primary tumors (n = 18; 3.5 years), comorbidities (n = 41; 1.9 years), and unknown (n = 20; 5.1 years). Predominant causes of death from comorbidities were cardiac and respiratory illnesses. Twenty-six patients (8%) developed a second primary tumor at a median time of 2.8 years (4 months to 10 years). The cumulative incidence of second primary tumors was 5%, 7%, and 13% at 3, 5, and 10 years, respectively. The most frequent site of second primaries was the lung (n = 13), followed by the esophagus (n = 3) and head and neck (n = 2) Conclusions: Patients with locoregionally advanced head and neck cancer treated with concurrent chemoradiotherapy are potentially curable but face significant risks of mortality from causes other than disease progression. Ameliorating toxicity, and implementing secondary screening and chemoprevention strategies are major goals in the management of head and neck cancer.