tbuckley/cabot-search huggingface dataset:
Prospective Study of Family History and Colorectal Cancer Risk by Tumor LINE-1 Methylation Level
Authors: Shuji Ogino, Reiko Nishihara, Paul Lochhead, Yu Imamura, Aya Kuchiba, Teppei Morikawa, Mai Yamauchi, Xiaoyun Liao, Zhi Rong Qian, Ruifang Sun, Kaori Sato, Gregory J. Kirkner, Molin Wang, Donna Spiegelman, Jeffrey A. Meyerhardt, Eva S. Schernhammer, Andrew T. Chan, Edward Giovannucci, Charles S. Fuchs
Journal: JNCI Journal of the National Cancer Institute (2012)

Beyond known familial colorectal cancer (CRC) syndromes, the mechanisms underlying the elevated CRC risk associated with CRC family history remain largely unknown. A recent retrospective study suggests familial clustering of CRC with hypomethylation in long interspersed nucleotide element 1 (LINE-1). We tested the hypothesis that CRC family history might confer a higher risk of LINE-1 methylation-low CRC.Using the Nurses' Health Study and the Health Professionals Follow-up Study, we prospectively examined the association between CRC family history and the risk of rectal and colon cancer (N = 1224) according to tumor LINE-1 methylation level by duplication method Cox proportional hazards regression. We examined microsatellite instability (MSI) status to exclude the influence of Lynch syndrome. All statistical tests were two-sided.The association between CRC family history and non-MSI CRC risk differed statistically significantly by LINE-1 methylation level (P (heterogeneity) = .02). CRC family history was associated with a statistically significantly higher risk of LINE-1 methylation-low non-MSI cancer (multivariable hazard ratio [HR] = 1.68, 95% confidence interval [CI] = 1.19 to 2.38 for 1 vs 0 first-degree relatives with CRC; multivariable HR = 3.48, 95% CI = 1.59 to 7.6 for ≥2 vs 0 first-degree relatives with CRC; P (trend) < .001). In contrast, CRC family history was not statistically significantly associated with LINE-1 methylation-high non-MSI cancer (P (trend) = .35).This molecular pathological epidemiology study shows that CRC family history is associated with a higher risk of LINE-1 methylation-low CRC, suggesting previously unrecognized heritable predisposition to epigenetic alterations. Additional studies are needed to evaluate tumor LINE-1 methylation as a molecular biomarker for familial cancer risk assessment.
Hypothalamic-pituitary-adrenal axis stress test in patients with early RA: role of corticotropin-releasing hormone promoter polymorphisms
Authors: O. Malysheva, U. Wagner, M. Wahle, M. Pierer, U. Wagner, G. K. Stalla, C. G. O. Baerwald
Journal: Annals of the Rheumatic Diseases (2011)

This review article summarizes the recent progress of ultraviolet rays (UV) protective substances, including our original reports. We have established a simple assay method for the determination of anti-UV activity that can be applicable to any kind of adherent cells. This method provides information of both anti-UV activity and cytotoxicity of any kind of samples even though those samples contain unknown amounts of test compounds. We found that lignin-carbohydrate complex (LCC) showed one- or two-order higher anti-UV activity compared to well-known lower molecular weight polyphenols and hot-water extracts of Kampo medicines and tea leaves. Among synthetic compounds, water-soluble azulenes showed the highest anti-UV activity. LCC showed additive or synergistic anti-UV activity with vitamin C. Alkaline extract of Sasa senanensis Rehder leaves (SE), an LCC-rich over-the-counter (OTC) drug, also showed potent antiviral and vitamin C-synergized radical scavenging activity. SE has been utilized to manufacture tooth paste, soap and gel cosmetic to increase the level of quality of life (QOL).
Changes in bronchial responsiveness to histamine at intervals after allergen challenge.
Authors: D W Cockcroft, K Y Murdock
Journal: Thorax (1987)

Bronchial responsiveness to inhaled histamine was measured two, seven, and 30 hours after allergen inhalation challenge in 19 atopic subjects. The provocative histamine concentrations causing a 20% fall in FEV1 (PC20) at these three times were compared with the baseline value, with values obtained two and seven hours after diluent inhalation, and with those obtained five to seven days after allergen challenge in the 12 late responders. Seven subjects had allergen induced isolated early asthmatic responses (delta FEV1 22.6% (SD 6.6%)) with less than a 5% late fall in FEV1. There was no change in the six histamine PC20 values measured in these seven subjects; the geometric mean PC20 was 1.0-1.3 mg/ml on all six occasions. Twelve subjects had an allergen induced early asthmatic response (delta FEV1 26.3% (9.8%)) followed by a definite (greater than 15% delta FEV1, n = 7) or equivocal (5-15% delta FEV1, n = 5) late asthmatic response. The geometric mean histamine PC20 was not significantly different two hours after allergen inhalation either from baseline (0.67 v 0.78 mg/ml) or from that seen two hours after diluent (0.67 v 0.95). It was significantly reduced at seven (0.24 mg/ml) and at 30 hours (0.44 mg/ml) but had returned to baseline when repeated five to seven days later (0.74 mg/ml). In 10 subjects with a dual response who had a repeat antigen challenge the mean early and late response and delta PC20 at seven and 30 hours were similar. These data show that bronchial responsiveness to a non-allergic stimulus has not increased two hours after allergen inhalation following spontaneous recovery of the early asthmatic response but before the start of the late asthmatic response.
Prostate-Specific Antigen Testing in Men Aged 40-64 Years: Impact of Publication of Clinical Trials
Authors: J. S. Goodwin, A. Tan, E. Jaramillo, Y.-F. Kuo
Journal: JNCI Journal of the National Cancer Institute (2013)

We assessed the impact of the publication of trials and changes in recommendations on the rates of prostate-specific antigen (PSA) screening in men aged 40 to 64 years by analyzing monthly medical claims for PSA testing in a commercial insurance database from 2001 to 2011, covering more than 1.5 million men in each year. The testing rates for men aged 40 to 49 years, 50 to 59 years, and 60 to 64 years were 12.1%, 32.7%, and 42.7%, respectively, in 2001 vs 15.7%, 34.2%, and 42.0%, respectively, in 2011. Men aged 40 to 49 years experienced a gradual increase in testing rate from 2001 through 2008 (annual change in PSA testing per 10 000 men [AC] = 4.37; P < .001), which became flat from mid-2009 through 2011(AC = −0.06; P =.98). The slope of PSA testing rates did not change in men aged 50 to 59 years or 60 to 64 years with the publication of the results of the large trials in 2009 or with the subsequent changes in recommendations on PSA testing.
Occupational asthma: validity of monitoring of peak expiratory flow rates and non-allergic bronchial responsiveness as compared to specific inhalation challenge
Authors: B Perrin, F Lagier, J L'Archeveque, A Cartier, LP Boulet, J Cote, JL Malo
Journal: European Respiratory Journal (1992)

The sensitivity and specificity of monitoring peak expiratory flow rates (PEFR) and bronchial responsiveness to the provocative concentration of histamine or methacholine (PC20) has been determined as compared to specific inhalation challenges in the diagnosis of occupational asthma. A prospective study of 61 subjects referred for occupational asthma to various agents was performed. PEFR was assessed every 2 h during a period away from work for at least 2 weeks. The period at work was 2 weeks, or less if there was increased symptomatology or marked changes in PEFR. At least one PC20 assessment was obtained at work and away from work. Graphs of PEFR and PC20 values were interpreted in blind fashion by three experienced readers. There was complete agreement among the three in 54 out of 61 instances (78%). Twenty five out of 61 subjects (41%) had positive specific inhalation challenges. The best index for comparing results of PEFR with specific inhalation challenges was the visual analysis of PEFR with sensitivity and specificity of 81% and 74%. All of the numerical indices were significantly less satisfactory. We conclude that visual analysis of PEFR is an interesting tool for investigating occupational asthma, although sensitivity and specificity values do not seem satisfactory enough to warrant using it alone.
HAZARDS OF DRUG EVALUATION : TRIALS OF 84 NON-APPROVED DRUGS
Authors: JACKSON A. SMITH, CECIL L. WITTSON
Journal: American Journal of Psychiatry (1960)

1. If sufficient medical care is provided, compounds on which adequate animal toxicity studies have been done, do not appear to involve hazards in clinical trials. This conclusion is based on 93 drugs evaluated over a 4-year period in 1,704 patients; 84 of these drugs had not been approved by the Food and Drug Administration. 2. Other factors which tend to delay drug evaluation efforts include: the isolation of the chronically mentally ill from medical research centers, the lack of status associated with this type of research, the peculiarities of psychiatric practice and the source of the new compounds available for evaluation.
BAY 43-9006 Inhibition of Oncogenic RET Mutants
Authors: Francesca Carlomagno, Suresh Anaganti, Teresa Guida, Giuliana Salvatore, Giancarlo Troncone, Scott M. Wilhelm, Massimo Santoro
Journal: JNCI Journal of the National Cancer Institute (2006)

Background : Medullary and papillary thyroid carcinomas are often associated with oncogenic activation of the RET tyrosine kinase. We evaluated whether the biaryl urea BAY 43-9006, which is known to inhibit several other tyrosine kinases, blocks RET kinase function and oncogenic activity. Methods : We examined BAY 43-9006 activity against oncogenic RET in vitro and in cellular RET signaling in oncogenic RET-transfected NIH3T3 fibroblasts by using immunocomplex kinase assays and immunoblotting with phospho-specific antibodies. The effects of BAY 43-9006 on proliferation of human TPC1 and TT thyroid carcinoma cells, which harbor spontaneous oncogenic RET alleles, and on RAT1 fibroblasts transformed with oncogenic RET mutants, including mutants that are resistant to other chemotherapeutic agents, were determined using growth curves and flow cytometry. Growth of TT cell–derived xenograft tumors in athymic mice treated orally with BAY 43-9006 or with vehicle was measured. All statistical tests were two-sided. Results : BAY 43-9006 inhibited oncogenic RET kinase activity at half-maximal inhibitory concentrations (IC 50 s) of 50 nM or less in NIH3T3 cells. It also arrested the growth of NIH3T3 and RAT1 fibroblasts transformed by oncogenic RET and of thyroid carcinoma cells that harbor spontaneous oncogenic RET alleles. Moreover, BAY 43-9006 inhibited the growth of cells carrying RET V804L (IC 50 = 110 nM, 95% confidence interval [CI] = 88 to 133 nM) or RET V804M (IC 50 = 147 nM, 95% CI = 123 nM to 170 nM), both mutants that are resistant to anilinoquinazolines and pyrazolopyrimidines. After 3 weeks of oral treatment with BAY 43-9006 (60 mg/kg/day), the volume of TT cell xenografts ( n = 7) was reduced from 72.5 to 44 mm 3 (difference = 28.5 mm 3 , 95% CI = 7 mm 3 to 50 mm 3 ), whereas in vehicle-treated mice ( n = 7), mean tumor volume increased to 408 mm 3 (difference = 320 mm 3 , 95% CI = 180 mm 3 to 460 mm 3 ; untreated versus treated, P =.02). This inhibition paralleled a decrease in RET phosphorylation. Conclusions : BAY 43-9006 is a powerful inhibitor of the RET kinase. Its potential as a therapeutic tool for RET-positive thyroid tumors, including those expressing V804 mutations merits study.
Endometrial Profile of Tamoxifen and Low-Dose Estradiol Combination Therapy
Authors: Charles E. Wood, Jay R. Kaplan, M. Babette Fontenot, J. Koudy Williams, J. Mark Cline
Journal: Clinical Cancer Research (2010)

Combination estrogen + progestin therapy has been associated with increased breast cancer risk in postmenopausal women. Selective estrogen receptor modulators (SERM) are potential alternatives to progestins, although the endometrial safety of estrogen + SERM co-therapies is not known. The goal of this study was to evaluate the endometrial profile of low-dose estradiol and the SERM tamoxifen alone and in combination.Twenty-four postmenopausal female cynomolgus macaques were randomized by social group to receive placebo, low-dose micronized estradiol (E(2); 0.25 mg/1,800 kcal), the SERM tamoxifen (Tam; 20 mg/1,800 kcal), or E(2) + Tam for 4 months in a parallel-arm design.Tamoxifen alone resulted in overlapping but distinct effects compared with E(2). Both E(2) and Tam increased uterine weight and endometrial thickness, whereas only E(2) increased endometrial proliferation. Morphologic effects were similar for Tam and E(2) + Tam, which both induced stromal fibrosis and cystic change. Tamoxifen inhibited E(2)-induced proliferation and expression of genes related to cell cycle progression while exhibiting mixed agonist and antagonist effects on gene markers of estrogen receptor activity. The gene expression profile for E(2) + Tam was distinct from either E(2) or Tam alone but dominated by the Tam effect for estrogen-regulated genes. Tam also attenuated E(2) effects on both vaginal maturation and cervical epithelial height.These findings characterize a novel phenotype resulting from estrogen + SERM co-therapy. The predominance of Tam effects on endometrial proliferation, morphology, and transcriptional profiles suggests that endometrial risks for E(2) + Tam may be similar to Tam alone.
Induced sputum for diagnosing<i>Pneumocystis carinii</i>pneumonia in HIV patients: new data, new issues
Authors: D. Turner, Y. Schwarz, I. Yust
Journal: European Respiratory Journal (2003)

The complexity of bronchoalveolar lavage (BAL) has motivated the search for noninvasive methodology to retrieve specimens for detecting the presence of various pulmonary diseases. Induced sputum (IS) has been shown to be a reliable tool in terms of sensitivity and specificity comparable to BAL. Investigators from institutions worldwide have published several reports providing evidence in support of one or the other or a combination of both approaches. Among them are studies demonstrating the sensitivity and specificity of IS in diagnosing Pneumocystis carinii pneumonia (PCP) in patients with acquired immunodeficiency syndrome (AIDS). In 1996, highly active antiretroviral therapy was introduced for routine use and the morbidity from opportunistic infections decreased sharply. An earlier study showed that cost-effectiveness depends on the prevalence of a given condition in the population. More recent studies have confirmed that prophylaxis against PCP can be stopped after increasing the CD4 cell count, thus reducing the attractiveness of IS as a preferred method for monitoring the course of disease. This review presents a brief description of the evolution of the bronchoalveolar lavage versus induced sputum controversy and reconsiders the strengths and weaknesses of the earlier arguments in light of newer data that have emerged with regard to Pneumocystis carinii pneumonia in acquired immunodeficiency syndrome.
<i>Pseudomonas aeruginosa</i> Microevolution during Cystic Fibrosis Lung Infection Establishes Clones with Adapted Virulence
Authors: Alessandra Bragonzi, Moira Paroni, Alessandro Nonis, Nina Cramer, Sara Montanari, Joanna Rejman, Clelia Di Serio, Gerd Döring, Burkhard Tümmler
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

During long-term lung infection in patients with cystic fibrosis (CF), Pseudomonas aeruginosa strains develop mutations leading to clonal expansion. This microevolution is believed to be correlated with a reduced virulence.We tested this hypothesis in models of lung infection, using mice with different genetic backgrounds.From infected airways of six patients with CF, 25 P. aeruginosa clones were isolated during a period of up to 16.3 years and genotypically and phenotypically characterized. Virulence of the 8 early, 6 intermediate, and 11 late CF isolates and 5 environmental strains was assessed by monitoring acute mortality versus survival and P. aeruginosa chronic persistence versus lung clearance in mice of different genetic backgrounds, including CF mice.Different patients harbored clonally unrelated strains, but early, intermediate, and late P. aeruginosa isolates from single patients were clonally related, allowing comparative in vivo analysis. Although late isolates were attenuated in causing acute mortality in the mouse models, compared with early and intermediate clonal isolates and environmental strains, they did not differ from early and intermediate clonal isolates in their capacity to establish chronic infection and cause extensive inflammation in the murine respiratory tract.Our findings indicate that clonal expansion of P. aeruginosa strains during microevolution within CF lungs leads to populations with altered but not reduced virulence. These P. aeruginosa clones with adapted virulence play a critical role in the pathogenesis of chronic infections and may serve to define virulence determinants as targets for novel therapies.
Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with mitoxantrone, chlorambucil and prednisone (MCP)
Authors: S. Wöhrer, J. Drach, M. Hejna, W. Scheithauer, A. Dirisamer, A. Püspök, A. Chott, M. Raderer
Journal: Annals of Oncology (2003)
Phase I Study of BIIB028, a Selective Heat Shock Protein 90 Inhibitor, in Patients with Refractory Metastatic or Locally Advanced Solid Tumors
Authors: David Hong, Rabih Said, Gerald Falchook, Aung Naing, Stacy Moulder, Apostolia-Maria Tsimberidou, Gerald Galluppi, Naveen Dakappagari, Chris Storgard, Razelle Kurzrock, Lee S. Rosen
Journal: Clinical Cancer Research (2013)

Heat shot protein 90 (Hsp90) is a ubiquitous molecular chaperone involved in protein folding, activation, and assembly, including key mediators of signal transduction, cell-cycle control, and transcriptional regulation. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of BIIB028, a prodrug designed to inhibit Hsp90 activity.
Phase II trial of pentostatin in refractory lymphomas and cutaneous T-cell disease.
Authors: F J Cummings, K Kim, R S Neiman, R L Comis, M M Oken, S A Weitzman, R B Mann, M J O'Connell
Journal: Journal of Clinical Oncology (1991)

Thirty-seven patients with refractory lymphoma or cutaneous T-cell lymphoma were treated with 2'-deoxycoformycin (pentostatin; dCF), 5 mg/m2 intravenous (IV) bolus for 3 consecutive days of every 3-week cycle in this Eastern Cooperative Oncology Group (ECOG) trial. Included were 25 with the diagnosis of non-Hodgkin's lymphoma, three with Hodgkin's disease, eight with cutaneous T-cell lymphoma (CTCL), and one with unknown subtype, of whom 31 were considered eligible. The majority had failed at least two, but no more, conventional chemotherapy regimens. Ten (32%) of the eligible patients had a partial response (PR), including patients with nodular poorly differentiated lymphocytic (NPDL), nodular mixed (NM), diffuse poorly differentiated lymphocytic (DPDL), or diffuse histiocytic (DH), lymphoma mixed-cellularity (MC), Hodgkin's disease, and unknown subtype, and in four patients with CTCL. The overall median time to treatment failure (TTF) was only 1.3 months, but the range extended to 57.3 months. The overall response duration was 16.0 months, and the range extended to 53.4 months. Overall median survival was 2.7 months, with the range extending to 63.2 months. The majority of patients had no toxicity, but there were some instances of severe or life-threatening events. Four fatal toxicities occurred, in two patients with underlying pulmonary conditions and two with prior cardiac histories. From this study, we conclude that dCF is active in refractory lymphomas and CTCLs, should be avoided in patients with a history of serious pulmonary or cardiac diseases, and warrants consideration for incorporation of a low-dosage schedule into conventional combination chemotherapy regimens, including its use with biologic response modifiers.
Activation of fractalkine/CX3CR1 by vascular endothelial cells induces angiogenesis through VEGF-A/KDR and reverses hindlimb ischaemia
Authors: J. Ryu, C.-W. Lee, K.-H. Hong, J.-A. Shin, S.-H. Lim, C.-S. Park, J. Shim, K. B. Nam, K.-J. Choi, Y.-H. Kim, K. H. Han
Journal: Cardiovascular Research (2007)

AimsThe present study investigated the detailed mechanism by which fractalkine (Fkn), a CX3C chemokine, induces angiogenesis and its functional implication in alleviating ischaemia in vivo.
Genome sequence of Vibrio parahaemolyticus: a pathogenic mechanism distinct from that of V cholerae
Authors: Kozo Makino, Kenshiro Oshima, Ken Kurokawa, Katsushi Yokoyama, Takayuki Uda, Kenichi Tagomori, Yoshio Iijima, Masatomo Najima, Masayuki Nakano, Atsushi Yamashita, Yoshino Kubota, Shigenobu Kimura, Teruo Yasunaga, Takeshi Honda, Hideo Shinagawa, Masahira Hattori, Tetsuya Iida
Journal: The Lancet (2003)
Pancoast's syndrome as a result of metastatic renal cell carcinoma
Authors: T W Marjanski
Journal: Thorax (2003)

Infections, lymphomas, and metastases1–3 are unique causes of Pancoast’s syndrome. The most common aetiological factor is non-small cell lung cancer (NSCLC). Pancoast’s syndrome resulting from metastatic renal cell carcinoma (RCC) has not previously been reported. We present the case of a metastatic Pancoast tumour in the left lung in a patient who had previously undergone resection for RCC.

A 49 year …
Histamine H <sub>3</sub> -Receptor–Mediated Inhibition of Calcitonin Gene-Related Peptide Release From Cardiac C Fibers
Authors: Michiaki Imamura, Neil C.E. Smith, Monique Garbarg, Roberto Levi
Journal: Circulation Research (1996)

Antidromic stimulation of cardiac sensory C fibers releases calcitonin gene-related peptide (CGRP), which increases heart rate, contractility, and coronary flow. C-fiber endings are closely associated with mast cells, and CGRP may release mast-cell histamine. Because prejunctional histamine H3-receptors inhibit transmitter release from autonomic nerves, we tested the hypothesis that H3-receptors modulate CGRP release in the heart. CGRP released by bradykinin in the electrically paced guinea pig left atrium and by capsaicin in the spontaneously beating isolated heart caused marked positive inotropic and chronotropic effects, respectively. Capsaicin significantly enhanced the overflow of CGRP (fivefold) and histamine (twofold) into the coronary effluent. All of these effects were prevented by prior chemical destruction of C fibers in vivo. The H3-receptor agonist imetit attenuated the inotropic response to bradykinin by 50%. Imetit also decreased the capsaicin-induced tachycardia and the increase in CGRP overflow by 50%. Imetit, however, did not modify the response to exogenous CGRP. The effects of imetit were blocked by the H3-receptor antagonist thioperamide. Notably, thioperamide by itself potentiated the capsaicin-evoked increases in heart rate and CGRP overflow (by 25% and 50%, respectively). Thus, our findings identify a negative-feedback loop, whereby CGRP releases histamine from cardiac mast cells and histamine in turn inhibits CGRP releases by activating H3-receptors on C-fiber terminals. Because CGRP release is augmented in pathophysiological conditions, such as septic shock, heart failure, and acute myocardial infarction, modulation of CGRP release may be clinically relevant.