tbuckley/cabot-search huggingface dataset:
FHIT Is Up-Regulated by Inflammatory Stimuli and Inhibits Prostaglandin E2–Mediated Cancer Progression
Authors: Koshi Mimori, Hideshi Ishii, Hisashi Nagahara, Tomoya Sudo, Keishi Yamashita, Hiroshi Inoue, Graham F. Barnard, Masaki Mori
Journal: Cancer Research (2006)

Abstract The FHIT gene is known to be susceptible to environmental carcinogens. Formation of prostaglandin E2 (PGE2) is catalyzed by cyclooxygenase-2 (COX-2) and may influence malignant phenotype in colorectal cancer. We explored whether FHIT might play a role in progression of colorectal cancer through inflammation-associated PGE2 activity. Immunohistochemical study of COX-2 and FHIT expression was done in 92 colorectal cancer tumors. We also used a FHIT-expressing cancer cell line (H460) induced by ponasterone A and two FHIT small interfering RNA–treated colorectal cancer cell lines (CCK81 and DLD1). After PGE2 stimulation, we compared synthesis of PGE2 (ELISA assay) and cell proliferation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay]. Immunohistochemistry showed a significant association between COX-2 and FHIT expression in colorectal cancers (P &amp;lt; 0.01). In a subset of 41 COX-2–expressing tumors, 12 FHIT− tumors showed deeper cancer invasion than 29 FHIT+ tumors (P &amp;lt; 0.01). Experimental study, however, showed there was no direct interaction between FHIT and COX-2. Considered with results from another experiment with epidermal growth factor receptor (EGFR), we hypothesize that FHIT and COX-2 might be regulated by a common molecule, such as EGFR. Additionally, there was an inverse and direct correlation between PGE2 synthesis and FHIT in vitro, suggesting that FHIT's postulated antiaggressive effect on tumor goes through PGE2 but not COX-2. Loss of FHIT expression in colorectal cancer suggests higher malignant potential. We conclude that FHIT suppressed cancer cell proliferation in this malignancy by directly inhibiting synthesis of PGE2 but not affecting that of COX-2. (Cancer Res 2006; 66(5): 2683-90)
Airway hyperresponsiveness in workers exposed to low levels of irritants
Authors: AM Kremer, TM Pal, JP Schouten, B Rijcken
Journal: European Respiratory Journal (1995)

The purpose of this study was to assess the association between occupational exposure to low levels of airway irritants, and airway responsiveness to histamine. In 688 male workers, symptom prevalence was assessed according to the British Medical Research Council (BMRC) questionnaire. All subjects performed a 30 s tidal breathing challenge test. Airway hyperresponsiveness (AHR) was defined as a 20% fall in forced expiratory volume in one second (FEV1) at &lt; or = 32 mg.ml-1 histamine. On the basis of job titles and working department, the exposure status of all workers was characterized into seven groups: 1) reference group; 2) white collars; 3) SO2, HCl, SO4(2-); 4) polyester vapour; 5) oil mist and oil vapour; 6) polyamide and polyester vapour; and 7) multiple exposures. Using multiple logistic regression, no association was found between the exposure groups and a higher prevalence of AHR. A higher prevalence was significantly associated with a low FEV1, a history of allergy, and the presence of chronic respiratory symptoms. Subjects in the SO2 group and the oil mist group with &lt; or = 5 exposure years had a lower prevalence of AHR, probably due to pre-employment selection procedures. There was some trend for subjects with more than 5 yrs exposure to polyester vapour and to oil mist and to oil vapour to have a higher prevalence of AHR. Analyses using the dose-response slope according to O'Connor, revealed similar results and provides no additional information. We conclude that no association could be demonstrated between low grade exposure to airway irritants and airway hyperresponsiveness, and that further research is needed to elucidate this relationship.
Allergic responses reduce the relaxant effect of beta-agonists but not potassium channel openers in guinea-pig isolated trachea
Authors: S Houjou, K Iizuka, K Dobashi, T Nakazawa
Journal: European Respiratory Journal (1996)

This study was conducted to determine whether the relaxant effect of adenosine triphosphate (ATP)-sensitive potassium channel (KATP) openers on airway smooth muscle are reduced during the hyporesponsiveness of beta-adrenergic receptors. Isometric tension was measured and dose-response curves were constructed for levcromakalim (a KATP opener), Y-26763 (another KATP opener), isoprenaline and theophylline in guinea-pig isolated trachea that was challenged with ovalbumin or pretreated in vitro with either isoprenaline or the KATP openers. Antigen challenge in vitro significantly reduced the potency but not the efficacy of isoprenaline in tracheal strips from actively sensitized guinea-pigs. The concentration of drug that produced a half-maximum inhibition (IC50) was 0.014 +/- 0.004 microM in the challenge group versus 0.006 +/- 0.001 microM in the control group (p &lt; 0.05; n = 9). The IC50 of levcromakalim (1.73 +/- 0.17 microM; n = 6) and of theophylline (110 +/- 3.1 microM; n = 6) were unaffected. Exposure to 4 microM isoprenaline for 30 min evoked beta-adrenergic hyporesponsiveness: the IC50 of isoprenaline rose significantly from 0.010 +/- 0.001 to 0.017 +/- 0.002 microM (p &lt; 0.01; n = 6). No effect was observed on the relaxant actions of levcromakalim and theophylline. In contrast, prior incubation with either levcromakalim or Y-26763 (300 microM for 30 min) significantly reduced the subsequent potency and efficacy of levcromakalim, but did not alter the effects of isoprenaline and theophylline. We conclude that the relaxant effect of the adenosine triphosphate-sensitive potassium channel openers was independent of beta-adrenergic hyporesponsiveness in airway smooth muscle of guinea-pigs.
Cellular immunity to Bacteroides fragilis capsular polysaccharide.
Authors: M E Shapiro, A B Onderdonk, D L Kasper, R W Finberg
Journal: The Journal of Experimental Medicine (1982)

The polysaccharide capsule of Bacteroides fragilis has been shown to be important in the virulence of the organism. The capsular polysaccharide (CP) of B. fragilis has been extensively purified. Using a murine model of intraabdominal abscess formation, we have been able to demonstrate cellular immunity to the capsular polysaccharide of B. fragilis. Immunization of C57BL/10J mice with the CP over 5 wk prevents abscess formation when the mice are challenged with B. fragilis intraperitoneally. This immunity can be transferred to naive mice with spleen cells from immune animals. The immune cells bear Thy-1.2 and Ly-2.2 antigens. The immune response has been shown to be antigen specific, but not H-2 restricted. The possibility that these immune cells are suppressor T cells is discussed. The experimental system presented provides a model for the examination of the cellular interactions responsible for abscess formation and the cellular response to bacterial pathogens.
A role for thrombin in liver fibrosis
Authors: J G. Duplantier
Journal: Gut (2004)

Several lines of evidence incriminate the serine proteinase thrombin in liver fibrogenesis either through its procoagulant function or its signaling via cell-surface receptors. The aim of this study was therefore to evaluate the effect of thrombin inhibition on experimental liver fibrosis.Fibrosis was induced in rats by administration of CCl4 for either three or seven weeks. Oral administration of the thrombin antagonist SSR182289 started one week after the start of CCl4 intoxication. Fibrosis and the area occupied by alpha smooth muscle actin (ASMA) positive cells were quantified with histomorphometry. Expression of fibrosis related genes was measured by real time RT-PCR.After three weeks of CCl4, treatment with SSR182289 did not significantly decrease the area of fibrosis but significantly decreased the area of ASMA positive cells by 22% (p = 0.03) and the expression of TIMP-1 mRNA by 52% (p = 0.02). There was no effect on gene expression of collagen I, MMP-2, or TIMP-2. After seven weeks of CCl4, treatment with SSR182289 resulted in a significant decrease in fibrosis (-30%, p = 0.04) and ASMA positive areas (-35%, p = 0.05). SSR182289 alone had no effect on the measured parameters. Additionally, it did not alleviate the acute toxicity of CCl4 as shown by measuring levels of serum aminotransferases and the area of necrosis.These data provide evidence that thrombin antagonism can reduce liver fibrogenesis. The early effect of SSR182289 on ASMA and TIMP-1 expression suggests that it is beneficial in reducing fibrogenic cell activation.
Lansley denies primary care trusts are in "meltdown" as 2000 managers agree to go
Authors: A. O'Dowd
Journal: BMJ (2010)

Primary care trusts are not in “meltdown,” the health secretary Andrew Lansley has said, despite figures that show more than 2000 managers have agreed to a voluntary resignation scheme.

Mr Lansley told MPs on the parliamentary health select committee on 23 November that primary care trusts were not, as had been suggested to him, “in meltdown” over the government’s plans to abolish them along with strategic health authorities as GP-led consortiums take control of much of the NHS budget by 2013.

As part of the committee’s inquiry into public expenditure, Nadine Dorries, Conservative MP for mid-Bedfordshire, asked about the impact of the government’s Equity and Excellence white paper published in July ( BMJ 2010;341:c3796, doi:10.1136/bmj.c3796) on primary care …
Prevalence of Hepatitis B and C Viral Markers in Black and White Patients With Hepatocellular Carcinoma in the United States
Authors: Mimi C. Yu, Myron J. Tong, Pierre Coursaget, Ronald K. Ross, Sugantha Govindarajan, Brian E. Henderson
Journal: JNCI Journal of the National Cancer Institute (1990)

The recent cloning of the genome of a non-A, non-B hepatitis agent, designated the hepatitis C virus (HCV), has led to the development of an immunoassay for circulating HCV antibodies (anti-HCV). We used this immunoassay to investigate the possible association between HCV infection and hepatocellular carcinoma in black and white residents of Los Angeles County, California. Serum samples from 51 patients (12 black and 39 white) in Los Angeles County with hepatocellular carcinoma and 128 control subjects (1 black and 127 white) were tested for the presence of anti-HCV. In addition, samples were tested for hepatitis B surface antigen (HBsAg), antibodies to the hepatitis B core antigen (anti-HBc), and antibodies to HBsAg (anti-HBs). Our results indicate that the presence of anti-HCV was a significant risk factor for hepatocellular carcinoma; the relative risk was 10.5 (95% confidence limits = 3.5, 31.3). Hepatocellular carcinoma risk was also significantly related to the presence of one or more of the hepatitis B virus (HBV) markers, primarily HBsAg and anti-HBc, and the relative risk was 7.0 (95% confidence limits = 3.1, 16.1). HCV and HBV independently contributed to hepatocellular carcinoma development. Significantly increased risk of hepatocellular carcinoma was demonstrated in individuals with HCV (relative risk = 4.8) or HBV (relative risk = 4.4) serologic markers alone. A synergistic effect on risk was observed when both hepatitis B and C viral markers were present in peripheral blood (10 cases vs. no controls). We estimate that approximately 47% of hepatocellular carcinoma occurring in black and white residents of Los Angeles County could be attributed to prior HCV and/or HBV infections: 9% were related to HCV alone, 20% to HBV alone, and 18% to occurrence of both HCV and HBV infections.
Phase I and Pharmacokinetic Study of Pemetrexed with High-Dose Folic Acid Supplementation or Multivitamin Supplementation in Patients with Locally Advanced or Metastatic Cancer
Authors: Chris H. Takimoto, Lisa A. Hammond-Thelin, Jane E. Latz, Leonardo Forero, Muralidhar Beeram, Bahram Forouzesh, Johann de Bono, Anthony W. Tolcher, Amita Patnaik, Pamela Monroe, Leslie Wood, Karen B. Schneck, Romnee Clark, Eric K. Rowinsky
Journal: Clinical Cancer Research (2007)

Abstract Purpose: This phase I study evaluated the effect of folate supplementation on the toxicity, tolerability, and pharmacokinetics of pemetrexed in patients with locally advanced or metastatic cancer. It also examined two different types of vitamin supplementation and whether the extent of prior myelosuppressive therapy affected pemetrexed tolerability. Patients and Methods: Patients received a 10-min infusion of 600 to 14,00 mg/m2 pemetrexed every 3 weeks. Patients were stratified into cohorts by pretreatment status [lightly pretreated (LPT) or heavily pretreated (HPT)] and were supplemented with intermittent high-dose folic acid (HDFA) or with continuous daily multivitamins (MVI) containing nutritional doses of folic acid. Pemetrexed plasma pharmacokinetics were evaluated for cycle 1. Results: Sixty-two HDFA patients (28 HPT and 34 LPT) were treated with 204 cycles of pemetrexed, and 43 MVI patients (20 HPT and 23 LPT) were treated with 182 cycles. Hematologic dose-limiting toxicities included grade 4 neutropenia (5 of 105 patients), grade 4 thrombocytopenia (4 of 105 patients), and febrile neutropenia (3 of 105 patients). Nonhematologic toxicities included fatigue, vomiting, diarrhea, and nausea. Pemetrexed doses of 800 and 1,050 mg/m2 were well tolerated when administered with vitamin supplementation to HPT and LPT patients, respectively. There were no clinically relevant differences in toxicities or pemetrexed pharmacokinetics for LPT versus HPT patients or for patients receiving HDFA versus daily MVI supplementation. Conclusions: The pemetrexed doses tolerated in this study with vitamin supplementation were significantly higher than those tolerated in earlier studies without supplementation, and toxicities were independent of the type of vitamin supplementation or prior myelosuppressive treatment. The recommended dose of pemetrexed is 1,050 mg/m2 in LPT patients and 800 mg/m2 in HPT patients, irrespective of the type of vitamin supplementation.
Abstract 5335: The antigen target of IMGN901, CD56, is expressed at significant levels in merkel cell carcinoma (MCC)
Authors: Christina N. Carrigan, Shanqin Xu, Yiwei Zhao, Jessica O'Keefe, Albert Qin, James O'Leary, Gillian Payne, Robert Lutz
Journal: Cancer Research (2010)

Abstract Background: IMGN901 consists of a CD56-binding monoclonal antibody, huN901, with a maytansinoid agent, DM1, attached via a stable disulfide linker, SPP. The CD56 antigen, also known as neural cell adhesion molecule (NCAM), is present in a number of malignancies including Merkel cell carcinoma (MCC), small cell lung carcinoma and other neuroendocrine tumors, ovarian cancers and multiple myeloma. Once bound to CD56, IMGN901 is internalized into a cancer cell and its DM1 is released to cause cell death via inhibition of tubulin polymerization. IMGN901 is currently in Phase I testing for the treatment of CD56-positive multiple myeloma and CD56-positive solid tumors. Six patients with MCC have received IMGN901, used as a single agent, in one of the Phase I trials underway. Clinical benefit was observed in 3 of these 6 patients: one complete response (CR), one partial response (PR) and one stable disease (SD). Objective: The goal of this study was to assess the potential utility of IMGN901 as a treatment for MCC by identifying the range of CD56 antigen expression levels in MCC. Methods: A calibrated immunohistochemical (IHC) staining method for CD56 was developed. CD56 staining conditions were established where 4 formalin fixed paraffin embedded (FFPE) MCC samples showed differential staining. FFPE cell pellet controls prepared from human tumor cell lines were next identified which showed CD56 staining in the same range as the MCC samples. The CD56 antigen level for each tumor cell line was subsequently quantified by flow cytometry. The calibrated IHC staining method was then applied to positive cell pellet controls and an extended panel of MCC tissues. For each resulting tissue section, the extent and intensity of immunostaining was evaluated and the CD56 expression level was estimated by comparing to the cell pellet controls. Results: The majority of samples from the MCC panel exhibited heterogeneous or homogeneous staining with significant levels of CD56 expression. Tissues from primary biopsy sites and from metastases showed comparable levels of CD56 expression. To date, biopsy samples have been acquired from 3 of the 6 MCC patients who have received IMGN901 (two IMGN901 non-responders and one responder) and these all showed high and homogeneous levels of CD56 expression. Conclusion: This IHC study indicates that the majority of MCC patient tissues express significant levels of CD56, supporting the development of the CD56-targeting compound, IMGN901, for this indication. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5335.
Regulatory Polymorphisms in β-Tubulin IIa Are Associated with Paclitaxel-Induced Peripheral Neuropathy
Authors: Luis J. Leandro-García, Susanna Leskelä, Carlos Jara, Henrik Gréen, Elisabeth Åvall-Lundqvist, Heather E. Wheeler, M. Eileen Dolan, Lucia Inglada-Perez, Agnieszka Maliszewska, Aguirre A. de Cubas, Iñaki Comino-Méndez, Veronika Mancikova, Alberto Cascón, Mercedes Robledo, Cristina Rodríguez-Antona
Journal: Clinical Cancer Research (2012)

Peripheral neuropathy is the dose-limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat several solid tumors such as breast, lung, and ovary. The cytotoxic effect of paclitaxel is mediated through β-tubulin binding in the cellular microtubules. In this study, we investigated the association between paclitaxel neurotoxicity risk and regulatory genetic variants in β-tubulin genes.We measured variation in gene expression of three β-tubulin isotypes (I, IVb, and IIa) in lymphocytes from 100 healthy volunteers, sequenced the promoter region to identify polymorphisms putatively influencing gene expression and assessed the transcription rate of the identified variants using luciferase assays. To determine whether the identified regulatory polymorphisms were associated with paclitaxel neurotoxicity, we genotyped them in 214 patients treated with paclitaxel. In addition, paclitaxel-induced cytotoxicity in lymphoblastoid cell lines was compared with β-tubulin expression as measured by Affymetrix exon array.We found a 63-fold variation in β-tubulin IIa gene (TUBB2A) mRNA content and three polymorphisms located at -101, -112, and -157 in TUBB2A promoter correlated with increased mRNA levels. The -101 and -112 variants, in total linkage disequilibrium, conferred TUBB2A increased transcription rate. Furthermore, these variants protected from paclitaxel-induced peripheral neuropathy [HR, 0.62; 95% confidence interval (CI), 0.42-0.93; P = 0.021, multivariable analysis]. In addition, an inverse correlation between TUBB2A and paclitaxel-induced apoptosis (P = 0.001) in lymphoblastoid cell lines further supported that higher TUBB2A gene expression conferred lower paclitaxel sensitivity.This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of a β-tubulin gene.
Ultrasound Examination of the Gallbladder
Authors: M. L. Janower
Journal: JAMA (1977)

<h3>To the Editor.—</h3> The article by Bartrum et al (236:1147, 1976) entitled "Ultrasound Examination of the Gallbladder" brought both good news and bad news. The good news is that ultrasound is a useful method of studying gallbladders that cannot be visualized through the use of contrast material, such as in jaundiced patients. The bad news, however, is the confusion in the authors' minds about the meaning of nonvisualization of the gallbladder following two doses of oral contrast material in which no extrinsic factors (ie, jaundice, vomiting, diarrhea) are present. The authors state that patients who met their third criteria (ie, had gallbladders which were not visualized after two doses of oral contrast material but were visualized on intravenous cholangiograms and did not show stones) were called normal. Mujahed et al<sup>1</sup>have clearly documented that this is false; in their series, there were 14 patients with gallbladders that appeared normal
Predictive factors of work disability in rheumatoid arthritis: a systematic literature review
Authors: E M de Croon, J K Sluiter, T F Nijssen, B A C Dijkmans, G J Lankhorst, M H W Frings-Dresen
Journal: Annals of the Rheumatic Diseases (2004)

Work disability-a common outcome of rheumatoid arthritis (RA)-is a societal (for example, financial costs) and individual problem (for example, loss of status, income, social support, and distraction from pain and distress). Until now, factors that predict work disability in RA have not been systematically reviewed.To determine predictive factors of work disability in RA as reported in the literature.A systematic literature search in Cinahl (1988-2004), Embase (1988-2004), and Medline (1989-2004) was followed by the application of two sets of criteria related to: (a) methodological quality, and (b) measurement of the predictive factor. Based on the quality and the consistency of the findings, a rating system was used to assess the level of evidence for each predictive factor.Nineteen publications (17 cohorts) were identified, of which 13 met the general methodological quality criteria. Results provided strong evidence that physical job demands, low functional capacity, old age, and low education predict work disability in RA. Remarkably, biomedical variables did not consistently predict work disability. Moreover, owing to the lack of high quality studies no evidence was found for personal factors such as coping style, and work environmental factors such as work autonomy, support, work adjustments that are presumed crucial in the work disablement process.The results indicate that work disability in RA is a biopsychosocially determined misfit between individual capability and work demands.
Robotic Partial Nephrectomy Versus Laparoscopic Cryoablation for the Small Renal Mass
Authors: Julien Guillotreau, Georges-Pascal Haber, Riccardo Autorino, Ranko Miocinovic, Shahab Hillyer, Adrian Hernandez, Humberto Laydner, Rachid Yakoubi, Wahib Isac, Jean-Alexandre Long, Robert J. Stein, Jihad H. Kaouk
Journal: European Urology (2012)