tbuckley/cabot-search huggingface dataset:
Survival Improvement in Patients With Medullary Thyroid Carcinoma Who Undergo Pretargeted Anti–Carcinoembryonic-Antigen Radioimmunotherapy: A Collaborative Study With the French Endocrine Tumor Group
Authors: Jean-François Chatal, Loïc Campion, Françoise Kraeber-Bodéré, Stephane Bardet, Jean-Philippe Vuillez, Bernard Charbonnel, Vincent Rohmer, Chien-Hsing Chang, Robert M. Sharkey, David M. Goldenberg, Jacques Barbet
Journal: Journal of Clinical Oncology (2006)

No effective therapy is currently available for the management of patients with metastatic medullary thyroid carcinoma (MTC). The efficacy of pretargeted radioimmunotherapy (pRAIT) with bispecific monoclonal antibody (BsMAb) and a iodine-131 (131I) -labeled bivalent hapten is evaluated.Twenty-nine patients with advanced, progressive MTC, as documented by short serum calcitonin doubling times (Ct DTs), received an anti-carcinoembryonic antigen (CEA)/anti-diethylenetriamine pentaacetic acid (DTPA) -indium BsMAb, followed 4 days later by a 131I-labeled bivalent hapten. Overall survival (OS) was compared with 39 contemporaneous untreated MTC patients with comparable prognostic indicators.OS was significantly longer in high-risk, treated patients (Ct DT < 2 years) than in high-risk, untreated patients (median OS, 110 v 61 months; P < .030). Forty-seven percent of patients, defined as biologic responders by a more than 100% increase in CtDT, experienced significantly longer survival than nonresponders (median OS, 159 v 109 months; P < .035) and untreated patients (median OS, 159 v 61 months; P < .010). Treated patients with bone/bone-marrow disease had a longer survival than patients without such involvement (10-year OS, 83% v 14%; P < .023). Toxicity was mainly hematologic and related to bone/bone-marrow tumor spread.pRAIT against CEA induced long-term disease stabilization and a significantly longer survival in high-risk patients with Ct DTs less than 2 years, compared with similarly high-risk, untreated patients. Ct DT and bone-marrow involvement appear to be prognostic indicators in MTC patients who undergo pRAIT.
ASSOCIATION OF CORONARY ARTERY DIAMETER ON NON CONTRAST CARDIAC COMPUTED TOMOGRAPHY WITH CORONARY ARTERY CALCIUM SCORES AND TRADITIONAL RISK FACTORS.
Authors: Yasmin S. Hamirani, Emil Avanes, Jigar Kadakia, Khurram Nasir, Amish Patel, Matthew J. Budoff
Journal: Journal of the American College of Cardiology (2010)
Changes in the small airways in idiopathic pulmonary fibrosis
Authors: Stijn Willems, Stijn Verleden, John McDonough, Bart Vanaudenaerde, Geert Verleden, Marc Decramer, Johny Verschakelen, James Hogg, Wim Wuyts
Journal: European Respiratory Journal (2013)

Introduction and Aims:  Idiopathic Pulmonary Fibrosis (IPF) is an interstitial lung disease characterized by architectural deformation of the parenchyma due to fibrosis. The structural changes of the small airways in IPF are unclear. Micro-CT can be used to examine alterations of the terminal bronchioles (TB) in IPF.  Methods:  Explant lungs from patients with IPF (n=7) undergoing lung transplantation and from unused donor lungs -control- (n=5) were collected. Lungs were inflated to TLC with air and frozen solid in liquid nitrogen vapor. Each explant lung underwent ex vivo CT scan to calculate lung volume and mass. Lungs were cut from apex to base into 2 cm-thick slices and a random core (1.4 cm diameter and 2 cm length) taken from each slice was processed for micro-CT examination. Using micro-CT scans of each core, the number of TB per ml of lung volume and per total lung volume, minimal lumen diameter and area of TB were assessed.  Results:  Explanted IPF lungs were decreased in volume and increased in mass compared to control (p=0.0025; p=0.010). The number of TB/ml of lung volume (p  Conclusion:  These data confirm that the TB are reduced in number and total area in IPF and that the surviving airways tend to have slighlty dilated lumens.
Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide–MHC
Authors: John A.H. Hoerter, Joanna Brzostek, Maxim N. Artyomov, Steven M. Abel, Javier Casas, Vasily Rybakin, Jeanette Ampudia, Carina Lotz, Janet M. Connolly, Arup K. Chakraborty, Keith G. Gould, Nicholas R.J. Gascoigne
Journal: The Journal of Experimental Medicine (2013)

Recent work has demonstrated that nonstimulatory endogenous peptides can enhance T cell recognition of antigen, but MHCI- and MHCII-restricted systems have generated very different results. MHCII-restricted TCRs need to interact with the nonstimulatory peptide–MHC (pMHC), showing peptide specificity for activation enhancers or coagonists. In contrast, the MHCI-restricted cells studied to date show no such peptide specificity for coagonists, suggesting that CD8 binding to noncognate MHCI is more important. Here we show how this dichotomy can be resolved by varying CD8 and TCR binding to agonist and coagonists coupled with computer simulations, and we identify two distinct mechanisms by which CD8 influences the peptide specificity of coagonism. Mechanism 1 identifies the requirement of CD8 binding to noncognate ligand and suggests a direct relationship between the magnitude of coagonism and CD8 affinity for coagonist pMHCI. Mechanism 2 describes how the affinity of CD8 for agonist pMHCI changes the requirement for specific coagonist peptides. MHCs that bind CD8 strongly were tolerant of all or most peptides as coagonists, but weaker CD8-binding MHCs required stronger TCR binding to coagonist, limiting the potential coagonist peptides. These findings in MHCI systems also explain peptide-specific coagonism in MHCII-restricted cells, as CD4–MHCII interaction is generally weaker than CD8–MHCI.
FRA(X)(p22) NOT ASSOCIATED WITH INFANTILE AUTISM
Authors: M. Fitchett, EdmundC. Jenkins, W.Ted Brown, MichaelS. Krawczun, CharlotteJ. Duncan, Judith Brooks, Ann Gross, KusumP. Lele, Annette Masia, SarahL. Nolin, MaureenM. Sanz, Ira Cohen
Journal: The Lancet (1984)
Genetic Screening for OPA1 and OPA3 Mutations in Patients with Suspected Inherited Optic Neuropathies
Authors: Patrick Yu-Wai-Man, Suma P. Shankar, Valérie Biousse, Neil R. Miller, Lora J.H. Bean, Bradford Coffee, Madhuri Hegde, Nancy J. Newman
Journal: Ophthalmology (2010)
A Novel Class of Anticancer Compounds Targets the Actin Cytoskeleton in Tumor Cells
Authors: Justine R. Stehn, Nikolas K. Haass, Teresa Bonello, Melissa Desouza, Gregg Kottyan, Herbert Treutlein, Jun Zeng, Paula R.B.B. Nascimento, Vanessa B. Sequeira, Tanya L. Butler, Munif Allanson, Thomas Fath, Timothy A. Hill, Adam McCluskey, Galina Schevzov, Stephen J. Palmer, Edna C. Hardeman, David Winlaw, Vivienne E. Reeve, Ian Dixon, Wolfgang Weninger, Timothy P. Cripe, Peter W. Gunning
Journal: Cancer Research (2013)

Abstract The actin cytoskeleton is a potentially vulnerable property of cancer cells, yet chemotherapeutic targeting attempts have been hampered by unacceptable toxicity. In this study, we have shown that it is possible to disrupt specific actin filament populations by targeting isoforms of tropomyosin, a core component of actin filaments, that are selectively upregulated in cancers. A novel class of anti-tropomyosin compounds has been developed that preferentially disrupts the actin cytoskeleton of tumor cells, impairing both tumor cell motility and viability. Our lead compound, TR100, is effective in vitro and in vivo in reducing tumor cell growth in neuroblastoma and melanoma models. Importantly, TR100 shows no adverse impact on cardiac structure and function, which is the major side effect of current anti-actin drugs. This proof-of-principle study shows that it is possible to target specific actin filament populations fundamental to tumor cell viability based on their tropomyosin isoform composition. This improvement in specificity provides a pathway to the development of a novel class of anti-actin compounds for the potential treatment of a wide variety of cancers. Cancer Res; 73(16); 5169–82. ©2013 AACR.
Should C-Reactive Protein Be a Target of Therapy?
Authors: Jisun Oh, Hwee Teoh, Lawrence A. Leiter
Journal: Diabetes Care (2011)

Multiple studies have demonstrated that elevated levels of high-sensitivity C-reactive protein (hs-CRP) are associated with increased cardiovascular (CV) risk. Newer CV risk stratification strategies incorporating hs-CRP (e.g., Reynolds Risk Score) have also been shown to improve risk stratification better than algorithms incorporating only traditional risk factors. There is also evidence from several landmark statin trials that on-treatment hs-CRP levels predict the likelihood of CV events. Although there is increasing evidence that CRP may be directly involved in the pathogenesis of atherosclerosis, the question of whether reduction in CRP levels and/or its associated downstream effects will provide novel therapeutic avenues to reduce CV risk requires further investigation.

CV diseases are the number one cause of mortality worldwide (1). Recent efforts directed at primary prevention of atherosclerosis have significantly reduced the incidence of initial clinical presentation of atherosclerosis. It is well established that patients with known diabetes or other traditional CV risk factors have an increased risk of atherosclerosis. Nonetheless, 15–20% of major CV events occur in patients with no major traditional CV risk factors (2). As a result, recent preventive efforts have been directed at finding newer, nontraditional, biomarkers to improve risk stratification, particularly in otherwise apparently low-risk individuals.

hs-CRP, previously considered to be an indicator of systemic inflammation, has recently received much attention in the scientific literature, not only as a potential marker of increased atherosclerotic risk, but also as a potential target of therapy for the prevention of atherosclerotic CV disease. In this review, we discuss whether hs-CRP should indeed be a target for therapy in the prevention of CV disease as well as other potential clinical implications related to hs-CRP.

Multiple studies have demonstrated that elevated levels of hs-CRP are clearly associated with increased CV risk (3,4). However, considerable controversy exists on whether CRP itself is …
Impact of acute exposure to tobacco smoke on gelatinases in the bronchoalveolar space
Authors: P. Glader, B. Eldh, S. Bozinovski, K. Andelid, M. Sjöstrand, C. Malmhäll, G. P. Anderson, G. C. Riise, I. Qvarfordt, A. Lindén
Journal: European Respiratory Journal (2008)

Clinical studies have indicated increased gelatinase activity in the airways of patients suffering from chronic obstructive pulmonary disease caused by tobacco smoke. The present study aimed to determine whether acute exposure to tobacco smoke per se causes a substantial and lasting impact on gelatinases and their inhibitors in the peripheral airways of atopic and nonatopic human subjects. Bronchoscopy with bronchoalveolar lavage (BAL) was performed on occasional smokers with and without atopy before and after smoking 10 cigarettes over a 48-h period. Samples from a group of never-smokers not exposed to tobacco smoke served as controls. Gelatinase identity and activity were measured using zymography, and gelatinase activity assay and concentrations of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 were measured using ELISA. The results revealed no pronounced changes in identity, net activity or concentration of the gelatinases or changes in concentrations of TIMP-1 and TIMP-2 in BAL fluid before and after acute exposure to tobacco smoke. In conclusion, the present experimental study indicates that acute exposure to tobacco smoke does not cause any substantial impact on gelatinases or their inhibitors in the peripheral airways, irrespective of atopy status, a finding that is compatible with the fact that it takes many years of tobacco smoking to establish chronic obstructive pulmonary disease.
Intraindividual variability of the bioavailability of low dose methotrexate after oral administration in rheumatoid arthritis.
Authors: C Lebbe, C Beyeler, N J Gerber, J Reichen
Journal: Annals of the Rheumatic Diseases (1994)

OBJECTIVES--To analyse whether the intraindividual variability of the bioavailability of oral methotrexate in rheumatoid arthritis (RA) is as high as the interindividual variability and whether the bioavailability testing can be simplified. METHODS--Fifteen mg methotrexate was given orally after an overnight fast to 10 patients with RA on two occasions, one week (n = 4) or two years (n = 6) apart, respectively. Plasma samples were taken at specific time intervals and analysed by fluorescence polarisation immunoassay. The areas under the plasma concentration versus time curves from 0 to infinity (AUC) were calculated after fitting to a two-compartment extravascular model with lag time. RESULTS--The interindividual variability of the AUCs showed a more than five fold range from 77 to 471 min x mumol/l. In contrast, the intraindividual differences of AUCs between the two visits ranged from 3 to 100 min x mumol/l, reflecting a 3-30% change in nine of 10 patients. Close correlations were found between the AUCs and the plasma concentrations with a most pronounced correlation eight hours after methotrexate intake (r = 0.975; p &lt; 0.001). CONCLUSIONS--The high interindividual variability of the AUCs was confirmed. Conversely, only a modest intraindividual variability was disclosed. Plasma sample analysis at a single time point four to eight hours after methotrexate application could simplify estimation of the bioavailability.
Angiogenic gene therapy for heart disease: a review of animal studies and clinical trials
Authors: H Hammond
Journal: Cardiovascular Research (2001)

The current published clinical literature on angiogenic gene therapy for the treatment of myocardial ischemia does not include a single randomized, placebo-controlled trial. Based on current clinical literature, it is an unproven therapy. Successful animal studies combined with published reports of good outcomes in patients enrolled in uncontrolled trials has led to the expectation that angiogenic gene therapy will ultimately become a clinical reality. The next important landmark in the field will be the publication of data showing a favorable effect of angiogenic gene transfer in placebo-controlled, blinded clinical trials.
Second Primary Cancers Related to Smoking and Treatment of Small-Cell Lung Cancer
Authors: M. A. Tucker, N. Murray, E. G. Shaw, D. S. Ettinger, M. Mabry, M. H. Huber, R. Feld, F. A. Shepherd, D. H. Johnson, S. C. Grant, J. Aisner, B. E. Johnson
Journal: JNCI Journal of the National Cancer Institute (1997)

An increased risk of second primary cancers has been reported in patients who survive small-cell carcinoma of the lung. The treatment's contribution to the development of second cancers is difficult to assess, in part because the number of long-term survivors seen at any one institution is small. We designed a multi-institution study to investigate the risk among survivors of developing second primary cancers other than small-cell lung carcinoma.Demographic, smoking, and treatment information were obtained from the medical records of 611 patients who had been cancer free for more than 2 years after therapy for histologically proven small-cell lung cancer, and person-years of follow-up were cumulated. Population-based rates of cancer incidence and mortality were used to estimate the expected number of cancers or deaths. The actuarial risk of second cancers was estimated by the Kaplan-Meier method.Relative to the general population, the risk of all second cancers among these patients (mostly non-small-cell cancers of the lung) was increased 3.5-fold. Second lung cancer risk was increased 13-fold among those who received chest irradiation in comparison to a sevenfold increase among nonirradiated patients. It was higher in those who continued smoking, with evidence of an interaction between chest irradiation and continued smoking (relative risk = 21). Patients treated with various forms of combination chemotherapy had comparable increases in risk (9.4- to 13-fold, overall), except for a 19-fold risk increase among those treated with alkylating agents who continued smoking.Because of their substantially increased risk, survivors should stop smoking and may consider entering trials of secondary chemoprevention.
Quality of Reporting of Modern Randomized Controlled Trials in Medical Oncology: A Systematic Review
Authors: J. Peron, G. R. Pond, H. K. Gan, E. X. Chen, R. Almufti, D. Maillet, B. You
Journal: JNCI Journal of the National Cancer Institute (2012)

The Consolidated Standards of Reporting Trials (CONSORT) guidelines were developed in the mid-1990s for the explicit purpose of improving clinical trial reporting. However, there is little information regarding the adherence to CONSORT guidelines of recent publications of randomized controlled trials (RCTs) in oncology. All phase III RCTs published between 2005 and 2009 were reviewed using an 18-point overall quality score for reporting based on the 2001 CONSORT statement. Multivariable linear regression was used to identify features associated with improved reporting quality. To provide baseline data for future evaluations of reporting quality, RCTs were also assessed according to the 2010 revised CONSORT statement. All statistical tests were two-sided. A total of 357 RCTs were reviewed. The mean 2001 overall quality score was 13.4 on a scale of 0–18, whereas the mean 2010 overall quality score was 19.3 on a scale of 0–27. The overall RCT reporting quality score improved by 0.21 points per year from 2005 to 2009. Poorly reported items included method used to generate the random allocation (adequately reported in 29% of trials), whether and how blinding was applied (41%), method of allocation concealment (51%), and participant flow (59%). High impact factor (IF, P = .003), recent publication date (P = .008), and geographic origin of RCTs (P = .003) were independent factors statistically significantly associated with higher reporting quality in a multivariable regression model. Sample size, tumor type, and positivity of trial results were not associated with higher reporting quality, whereas funding source and treatment type had a borderline statistically significant impact. The results show that numerous items remained unreported for many trials. Thus, given the potential impact of poorly reported trials, oncology journals should require even stricter adherence to the CONSORT guidelines.
Establishment and Characterization of a Model of Acquired Resistance to Epidermal Growth Factor Receptor Targeting Agents in Human Cancer Cells
Authors: Sergio Benavente, Shyhmin Huang, Eric A. Armstrong, Alexander Chi, Kun-Tai Hsu, Deric L. Wheeler, Paul M. Harari
Journal: Clinical Cancer Research (2009)

The epidermal growth factor receptor (EGFR) is recognized as a key mediator of proliferation and progression in many human tumors. A series of EGFR-specific inhibitors have recently gained Food and Drug Administration approval in oncology. These strategies of EGFR inhibition have shown major tumor regressions in approximately 10% to 20% of advanced cancer patients. Many tumors, however, eventually manifest resistance to treatment. Efforts to better understand the underlying mechanisms of acquired resistance to EGFR inhibitors, and potential strategies to overcome resistance, are greatly needed.To develop cell lines with acquired resistance to EGFR inhibitors we utilized the human head and neck squamous cell carcinoma tumor cell line SCC-1. Cells were treated with increasing concentrations of cetuximab, gefitinib, or erlotinib, and characterized for the molecular changes in the EGFR inhibitor-resistant lines relative to the EGFR inhibitor-sensitive lines.EGFR inhibitor-resistant lines were able to maintain their resistant phenotype in both drug-free medium and in athymic nude mouse xenografts. In addition, EGFR inhibitor-resistant lines showed a markedly increased proliferation rate. EGFR inhibitor-resistant lines had elevated levels of phosphorylated EGFR, mitogen-activated protein kinase, AKT, and signal transducer and activator of transcription 3, which were associated with reduced apoptotic capacity. Subsequent in vivo experiments indicated enhanced angiogenic potential in EGFR inhibitor-resistant lines. Finally, EGFR inhibitor-resistant lines showed cross-resistance to ionizing radiation.We have developed EGFR inhibitor-resistant human head and neck squamous cell carcinoma cell lines. This model provides a valuable preclinical tool to investigate molecular mechanisms of acquired resistance to EGFR blockade.
Metabolic Stress Modulates Alzheimer’s β-Secretase Gene Transcription via SIRT1-PPARγ-PGC-1 in Neurons
Authors: Ruishan Wang, Jing Jing Li, Shiyong Diao, Young-Don Kwak, Li Liu, Lianteng Zhi, Hansruedi Büeler, Narayan R. Bhat, Robert W. Williams, Edwards A. Park, Francesca-Fang Liao
Journal: Cell Metabolism (2013)
State-wide surveillance of antibiotic resistance patterns and spa types of methicillin-resistant Staphylococcus aureus from blood cultures in North Rhine-Westphalia, 2011–2013
Authors: C. Cuny, F. Layer, G. Werner, D. Harmsen, I. Daniels-Haardt, A. Jurke, A. Mellmann, W. Witte, R. Köck
Journal: Clinical Microbiology and Infection (2015)
A Synthetic Lethality–Based Strategy to Treat Cancers Harboring a Genetic Deficiency in the Chromatin Remodeling Factor BRG1
Authors: Takahiro Oike, Hideaki Ogiwara, Yuichi Tominaga, Kentaro Ito, Osamu Ando, Koji Tsuta, Tatsuji Mizukami, Yoko Shimada, Hisanori Isomura, Mayumi Komachi, Koh Furuta, Shun-Ichi Watanabe, Takashi Nakano, Jun Yokota, Takashi Kohno
Journal: Cancer Research (2013)

The occurrence of inactivating mutations in SWI/SNF chromatin-remodeling genes in common cancers has attracted a great deal of interest. However, mechanistic strategies to target tumor cells carrying such mutations are yet to be developed. This study proposes a synthetic-lethality therapy for treating cancers deficient in the SWI/SNF catalytic (ATPase) subunit, BRG1/SMARCA4. The strategy relies upon inhibition of BRM/SMARCA2, another catalytic SWI/SNF subunit with a BRG1-related activity. Immunohistochemical analysis of a cohort of non-small-cell lung carcinomas (NSCLC) indicated that 15.5% (16 of 103) of the cohort, corresponding to preferentially undifferentiated tumors, was deficient in BRG1 expression. All BRG1-deficient cases were negative for alterations in known therapeutic target genes, for example, EGFR and DDR2 gene mutations, ALK gene fusions, or FGFR1 gene amplifications. RNA interference (RNAi)-mediated silencing of BRM suppressed the growth of BRG1-deficient cancer cells relative to BRG1-proficient cancer cells, inducing senescence via activation of p21/CDKN1A. This growth suppression was reversed by transduction of wild-type but not ATPase-deficient BRG1. In support of these in vitro results, a conditional RNAi study conducted in vivo revealed that BRM depletion suppressed the growth of BRG1-deficient tumor xenografts. Our results offer a rationale to develop BRM-ATPase inhibitors as a strategy to treat BRG1/SMARCA4-deficient cancers, including NSCLCs that lack mutations in presently known therapeutic target genes.