tbuckley/cabot-search huggingface dataset:
Development of an interleukin (IL) 6 receptor antagonist that inhibits IL-6-dependent growth of human myeloma cells.
Authors: F D de Hon, M Ehlers, S Rose-John, S B Ebeling, H K Bos, L A Aarden, J P Brakenhoff
Journal: The Journal of Experimental Medicine (1994)

The pleiotropic cytokine interleukin 6 (IL-6) plays a role in the pathogenesis of various diseases, such as multiple myeloma, autoimmune and inflammatory diseases and osteoporosis. Therefore, specific inhibitors of IL-6 may have clinical applications. We previously succeeded in developing receptor antagonists of IL-6 that antagonized wild-type IL-6 activity on the human Epstein-Barr virus (EBV)-transformed B cell line CESS and the human hepatoma cell line HepG2. However, these proteins still had agonistic activity on the human myeloma cell line XG-1. We here report the construction of a novel mutant protein of IL-6 in which two different mutations are combined that individually disrupt the association of the IL-6/IL-6 receptor (R) alpha complex with the signaltransducing "beta" chain, gp130, but leave the binding of IL-6 to IL-6R alpha intact. The resulting mutant protein (with substitutions of residues Gln160 to Glu, Thr163 to Pro, and replacement of human residues Lys42-Ala57 with the corresponding residues of mouse IL-6) was inactive on XG-1 cells and weakly antagonized wild-type IL-6 activity on these cells. By introducing two additional substitutions (Phe171Leu, Ser177Arg), the affinity of the mutant protein for IL-6R alpha was increased fivefold, rendering it capable of completely inhibiting wild-type IL-6 activity on XG-1 cells. Moreover, this mutant also antagonized the activity of IL-6, but not that of leukemia inhibitory factor, oncostatin M, or GM-CSF on the human erythroleukemia cell line TF-1, demonstrating its specificity for IL-6. These data demonstrate the feasibility of developing specific IL-6R antagonists. The availability of such antagonists may offer an approach to specifically inhibit IL-6 activity in vivo.
<i>BRCA1</i> Loss Preexisting in Small Subpopulations of Prostate Cancer Is Associated with Advanced Disease and Metastatic Spread to Lymph Nodes and Peripheral Blood
Authors: Natalia Bednarz, Elke Eltze, Axel Semjonow, Michael Rink, Antje Andreas, Lennart Mulder, Juliane Hannemann, Margit Fisch, Klaus Pantel, Heinz-Ulrich G. Weier, Krzysztof P. Bielawski, Burkhard Brandt
Journal: Clinical Cancer Research (2010)

Abstract Purpose: A preliminary study performed on a small cohort of multifocal prostate cancer (PCa) detected BRCA1 allelic imbalances among circulating tumor cells (CTC). The present analysis was aimed to elucidate the biological and clinical roles of BRCA1 losses in metastatic spread and tumor progression in PCa patients. Experimental Design: To map molecular progression in PCa outgrowth, we used fluorescence in situ hybridization analysis of primary tumors and lymph node sections, and CTCs from peripheral blood. Results: We found that 14% of 133 tested patients carried monoallelic BRCA1 loss in at least one tumor focus. Extended molecular analysis of chr17q revealed that this aberration was often a part of larger cytogenetic rearrangement involving chr17q21 accompanied by allelic imbalance of the tumor suppressor gene PTEN and lack of BRCA1 promoter methylation. The BRCA1 losses correlated with advanced T stage (P &amp;lt; 0.05), invasion to pelvic lymph nodes (P &amp;lt; 0.05), as well as biochemical recurrence (P &amp;lt; 0.01). Their prevalence was twice as high within 62 lymph node metastases (LNM) as in primary tumors (27%, P &amp;lt; 0.01). The analysis of 11 matched primary PCa-LNM pairs confirmed the suspected transmission of genetic abnormalities between these two sites. In four of seven patients with metastatic disease, BRCA1 losses appeared in a minute fraction of cytokeratin- and vimentin-positive CTCs. Conclusions: Small subpopulations of PCa cells bearing BRCA1 losses might be one confounding factor initiating tumor dissemination and might provide an early indicator of shortened disease-free survival. Clin Cancer Res; 16(13); 3340–8. ©2010 AACR.
Single port versus standard laparoscopic right colectomies: results of a case–control retrospective study on one hundred patients
Authors: Carlo Maria Rosati, Luigi Boni, Gianlorenzo Dionigi, Elisa Cassinotti, Luisa Giavarini, Giulia David, Stefano Rausei, Francesca Rovera, Renzo Dionigi
Journal: International Journal of Surgery (2013)
Repeated head trauma is associated with smaller thalamic volumes and slower processing speed: the Professional Fighters’ Brain Health Study
Authors: Charles Bernick, Sarah J Banks, Wanyong Shin, Nancy Obuchowski, Sam Butler, Michael Noback, Michael Phillips, Mark Lowe, Stephen Jones, Michael Modic
Journal: British Journal of Sports Medicine (2015)

Cumulative head trauma may alter brain structure and function. We explored the relationship between exposure variables, cognition and MRI brain structural measures in a cohort of professional combatants.224 fighters (131 mixed martial arts fighters and 93 boxers) participating in the Professional Fighters Brain Health Study, a longitudinal cohort study of licensed professional combatants, were recruited, as were 22 controls. Each participant underwent computerised cognitive testing and volumetric brain MRI. Fighting history including years of fighting and fights per year was obtained from self-report and published records. Statistical analyses of the baseline evaluations were applied cross-sectionally to determine the relationship between fight exposure variables and volumes of the hippocampus, amygdala, thalamus, caudate, putamen. Moreover, the relationship between exposure and brain volumes with cognitive function was assessed.Increasing exposure to repetitive head trauma measured by number of professional fights, years of fighting, or a Fight Exposure Score (FES) was associated with lower brain volumes, particularly the thalamus and caudate. In addition, speed of processing decreased with decreased thalamic volumes and with increasing fight exposure. Higher scores on a FES used to reflect exposure to repetitive head trauma were associated with greater likelihood of having cognitive impairment.Greater exposure to repetitive head trauma is associated with lower brain volumes and lower processing speed in active professional fighters.
Fatigue in primary Sjogren's syndrome: Is there a link with the fibromyalgia syndrome?
Authors: I Giles
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVE</h3> To determine whether fibromyalgia (FM) is more common in patients with primary Sjögren9s syndrome (pSS) who complain of fatigue. The association and prevalence of fatigue and FM was recorded in a group of patients with pSS and a control group of lupus patients, a subset of whom had secondary Sjögren9s syndrome (sSS). <h3>METHODS</h3> 74 patients with pSS and 216 patients with lupus were assessed with a questionnaire to identify the presence of fatigue and generalised pain. From the lupus group, in a subset of 117 lupus patients (from the Bloomsbury unit) those with sSS were identified. All patients were studied for the presence of FM. <h3>RESULTS</h3> 50 of 74 patients with pSS (68%) reported fatigue—a prevalence significantly higher than in the lupus group (108/216 (50%); p&lt;0.0087). Fatigue was present in 7/13 (54%) patients with SLE/sSS. FM was present in 9/74 patients with pSS (12%), compared with 11/216 lupus patients (5%), and in none of the patients with SLE/sSS. None of these values corresponds with previously reported figures of the incidence of FM in pSS. <h3>CONCLUSION</h3> The results show that fatigue in patients with pSS and sSS is not due to the coexistence of FM in most cases. A lower incidence in the United Kingdom of FM in patients with pSS was found than has been previously reported.
Boys in the UK should be offered vaccination against human papillomavirus (HPV)
Authors: D. Mitchell, R. Audisio, G. Cruickshank, S. Cannon, T. Gill, A. Hayes, S. Kehoe, J. McGuigan, B. Powell, N. Price, N. Roland, L. Wyld
Journal: BMJ (2014)

Wise reported that of 74% of the girls and young women who were offered vaccination against human papillomavirus (HPV) only half the women not in education, employment, or training were included in the offer.1

Much more concerning is the fact that oropharyngeal cancer driven by HPV has the fastest rising incidence of any cancer, yet no boys in the United Kingdom are offered vaccination.

We …
Heterozygous FZ alpha 1 antitrypsin deficiency associated with severe emphysema and hepatic disease: case report and family study.
Authors: C P Kelly, D N Tyrrell, G S McDonald, D B Whitehouse, J S Prichard
Journal: Thorax (1989)

A patient with advanced emphysema and cor pulmonale had the changes of alpha 1 antitrypsin deficiency in a liver biopsy specimen and was shown to have the phenotype PiFZ. This case supports the contention that the F allele of alpha 1 antitrypsin predisposes to the development of emphysema, particularly when it occurs in conjunction with the Z allele.
Pregnane × Receptor (PXR) expression in colorectal cancer cells restricts irinotecan chemosensitivity through enhanced SN-38 glucuronidation
Authors: Caroline Raynal, Jean-Marc Pascussi, Géraldine Leguelinel, Cyril Breuker, Jovana Kantar, Benjamin Lallemant, Sylvain Poujol, Caroline Bonnans, Dominique Joubert, Frédéric Hollande, Serge Lumbroso, Jean-Paul Brouillet, Alexandre Evrard
Journal: Molecular Cancer (2010)

Abstract Background Clinical efficacy of chemotherapy in colorectal cancer is subjected to broad inter-individual variations leading to the inability to predict outcome and toxicity. The topoisomerase I inhibitor irinotecan (CPT-11) is worldwide approved for the treatment of metastatic colorectal cancer and undergoes extensive peripheral and tumoral metabolism. PXR is a xenoreceptor activated by many drugs and environmental compounds regulating the expression of drug metabolism and transport genes in detoxification organs such as liver and gastrointestinal tract. Considering the metabolic pathway of irinotecan and the tissue distribution of Pregnane × Receptor (PXR), we hypothesized that PXR could play a key role in colon cancer cell response to irinotecan. Results PXR mRNA expression was quantified by RT-quantitative PCR in a panel of 14 colon tumor samples and their matched normal tissues. PXR expression was modulated in human colorectal cancer cells LS174T, SW480 and SW620 by transfection and siRNA strategies. Cellular response to irinotecan and its active metabolic SN38 was assessed by cell viability assays, HPLC metabolic profiles and mRNA quantification of PXR target genes. We showed that PXR was strongly expressed in colon tumor samples and displayed a great variability of expression. Expression of hPXR in human colorectal cancer cells led to a marked chemoresistance to the active metabolite SN38 correlated with PXR expression level. Metabolic profiles of SN38 showed a strong enhancement of SN38 glucuronidation to the inactive SN38G metabolite in PXR-expressing cells, correlated with an increase of UDPglucuronosyl transferases UGT1A1, UGT1A9 and UGT1A10 mRNAs. Inhibition of PXR expression by lentivirus-mediated shRNA, led to SN38 chemoresistance reversion concomitantly to a decrease of UGT1A1 expression and SN38 glucuronidation. Similarly, PXR mRNA expression levels correlated to UGT1A subfamily expression in human colon tumor biopsies. Conclusion Our results demonstrate that tumoral metabolism of SN38 is affected by PXR and point to potential therapeutic significance of PXR quantification in the prediction of irinotecan response. Furthermore, our observations are pharmacologically relevant since many patients suffering from cancer diseases are often exposed to co-medications, food additives or herbal supplements able to activate PXR. A substantial part of the variability observed among patients might be caused by such interactions
Tumour regression predicts higher risk of sentinel node involvement in thin cutaneous melanomas
Authors: J. Olah, R. Gyulai, I. Korom, E. Varga, A. Dobozy
Journal: British Journal of Dermatology (2003)

Journal Article Tumour regression predicts higher risk of sentinel node involvement in thin cutaneous melanomas Get access J. Oláh, J. Oláh Department of Dermatology and Allergology, University of Szeged, Faculty of Medicine, Albert Szent‐Györgyi Medical and Pharmaceutical Center, Korányi fasor 6, 6720 Szeged, Hungary E‐mail: oj@derma.szote.u‐szeged.hu Search for other works by this author on: Oxford Academic Google Scholar R. Gyulai, R. Gyulai Department of Dermatology and Allergology, University of Szeged, Faculty of Medicine, Albert Szent‐Györgyi Medical and Pharmaceutical Center, Korányi fasor 6, 6720 Szeged, Hungary E‐mail: oj@derma.szote.u‐szeged.hu Search for other works by this author on: Oxford Academic Google Scholar I. Korom, I. Korom Department of Dermatology and Allergology, University of Szeged, Faculty of Medicine, Albert Szent‐Györgyi Medical and Pharmaceutical Center, Korányi fasor 6, 6720 Szeged, Hungary E‐mail: oj@derma.szote.u‐szeged.hu Search for other works by this author on: Oxford Academic Google Scholar E. Varga, E. Varga Department of Dermatology and Allergology, University of Szeged, Faculty of Medicine, Albert Szent‐Györgyi Medical and Pharmaceutical Center, Korányi fasor 6, 6720 Szeged, Hungary E‐mail: oj@derma.szote.u‐szeged.hu Search for other works by this author on: Oxford Academic Google Scholar A. Dobozy A. Dobozy Department of Dermatology and Allergology, University of Szeged, Faculty of Medicine, Albert Szent‐Györgyi Medical and Pharmaceutical Center, Korányi fasor 6, 6720 Szeged, Hungary E‐mail: oj@derma.szote.u‐szeged.hu Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 149, Issue 3, 1 September 2003, Pages 662–663, https://doi.org/10.1046/j.1365-2133.2003.05502.x Published: 01 September 2003
Use of non-invasive haemodynamic measurements to detect treatment response in precapillary pulmonary hypertension
Authors: W.-T. N. Lee, A. Brown, A. J. Peacock, M. K. Johnson
Journal: Thorax (2011)

Haemodynamic measurements may be superior to the 6-min walk distance (6MWD) as outcome measures in pulmonary hypertension (PH) as they are directly linked to the mechanisms of disease and are not subject to a ceiling effect. The aim of this study was to determine if treatment response in precapillary PH could be detected by pulmonary blood flow (PBF) and stroke volume (SV) measured non-invasively by the inert gas rebreathing (IGR) method at rest and during submaximal constant-load cycle exercise.Twenty-four patients with precapillary PH receiving de novo or modified disease-targeted therapy were studied. Isotime metabolic variables, PBF and SV were measured at rest and during constant-load cycle exercise at 40% maximal work rate alongside conventional outcome variables, at baseline and after 3 months of new therapy.At follow-up there was a significant increase in PBF (supine rest: mean 0.7±SD 0.9 l/min, erect rest: 0.7±0.8 l/min, exercise: 0.8±1.0 l/min, p<0.005) and SV (supine rest: 7±10 ml, erect rest: 10±11 ml, exercise: median 6 (IQR 3-11) ml, p<0.005). There was a trend for 6MWD to increase by 17±42 or 29 (13-47) m (p=0.061), whereas WHO functional class, N-terminal pro-brain natriuretic peptide or Cambridge Pulmonary Hypertension Outcome Review score were unchanged. In patients with higher baseline 6MWD, IGR measurements were more sensitive than 6MWD in detecting treatment response.Non-invasive IGR haemodynamic measurements could be used to detect treatment response in patients with precapillary PH and may be more responsive to change than 6MWD in fitter patients.
Arginine stimulates intestinal cell migration through a focal adhesion kinase dependent mechanism
Authors: J M Rhoads, W Chen, J Gookin, G Y Wu, Q Fu, A T Blikslager, R A Rippe, R A Argenzio, W G Cance, E M Weaver, L H Romer
Journal: Gut (2004)

<b>Background:</b>l-Arginine is a nutritional supplement that may be useful for promoting intestinal repair. Arginine is metabolised by the oxidative deiminase pathway to form nitric oxide (NO) and by the arginase pathway to yield ornithine and polyamines. <b>Aims:</b> To determine if arginine stimulates restitution via activation of NO synthesis and/or polyamine synthesis. <b>Methods:</b> We determined the effects of arginine on cultured intestinal cell migration, NO production, polyamine levels, and activation of focal adhesion kinase, a key mediator of cell migration. <b>Results:</b> Arginine increased the rate of cell migration in a dose dependent biphasic manner, and was additive with bovine serum concentrate (BSC). Arginine and an NO donor activated focal adhesion kinase (a tyrosine kinase which localises to cell matrix contacts and mediates β1 integrin signalling) after wounding. Arginine stimulated cell migration was dependent on focal adhesion kinase (FAK) signalling, as demonstrated using adenovirus mediated transfection with a kinase negative mutant of FAK. Arginine stimulated migration was dependent on NO production and was blocked by NO synthase inhibitors. Arginine dependent migration required synthesis of polyamines but elevating extracellular arginine concentration above 0.4 mM did not enhance cellular polyamine levels. <b>Conclusions:</b> These results showed that l-arginine stimulates cell migration through NO and FAK dependent pathways and that combination therapy with arginine and BSC may enhance intestinal restitution via separate and convergent pathways.
New strategies in mechanical ventilation for acute lung injury
Authors: H Burchardi
Journal: European Respiratory Journal (1996)

In the fluid-filled lungs of early adult respiratory distress syndrome (ARDS) the dependent parts are compressed and atelectatic; whereas, the nondependent areas remain aerated and functional. Ventilating these considerably restricted lungs carries the risk of overinflation and ventilatory-induced lung injury (baro-volutrauma). The consequences for adjusting mechanical ventilation are: 1) reducing tidal volumes in order to avoid alveolar hyperinflation and excessive alveolar pressures; 2) considering permissive hypercapnia if adequate CO2 elimination cannot be maintained; 3) keeping open the unstable alveoli by positive end-expiratory pressure (PEEP) (external or intrinsic). However, the large variations in regional lung compliance make it improbable that an optimal external PEEP level beneficial for the whole lung will be found; 4) using intrinsic PEEP in the inverse ratio ventilation (IRV) mode which varies with differences in regional ventilatory kinetics. No clinical study has yet convincingly demonstrated the benefit of IRV compared to conventional ventilation, controlled clinical long-term trials are not yet available; and 5) using superimposed spontaneous breathing which may be considerably more effective in opening up collapsed alveoli, combined with intentional intrinsic PEEP this is achieved in airway pressure release ventilation (APRV). Other new principles of mechanical ventilation, such as "proportional assist ventilation" or "tracheal gas insufflation" must still be considered as experimental.
Genotype, slow decrease in virus titer during interferon treatment and high degree of sequence variability of hypervariable region are indicative of poor response to interferon treatment in patients with chronic hepatitis type C
Authors: Kazuaki Chayama, Akihito Tsubota, Yasuji Arase, Satoshi Saitoh, Kenji Ikeda, Toyomi Matsumoto, Michie Hashimoto, Mariko Kobayashi, Masumi Kanda, Tsuto Morinaga, Hiromitsu Kumada
Journal: Journal of Hepatology (1995)
Hypocellular bone marrow with increased blasts
Authors: Candece L. Gladson, Faramarz Naeim
Journal: American Journal of Hematology (1986)

Twenty patients with hypocellular bone marrow and increased blasts (HBMIB) were reviewed. The median age was 60 years with a male:female ratio of 17:3. History of alcohol abuse was noted in 30%, potential exposure to toxic chemicals in 20%, second malignancies in 20%, and aplastic anemia in 25%. Pancytopenia with marrow hypocellularity and increased marrow blast cells were characteristic hematopathologic features. Marrow hypocellularity was moderate to severe (less than or equal to 25%) in over half of the cases and mild to moderate (greater than 25, less than or equal to 35%) in the remainder. Blast cells were the predominant cellular elements in the marrow displaying scanty to moderate amounts of cytoplasm, round to oval nuclei, and one or more nucleoli. Special stains were performed in 19 cases. Blast cells morphologically displayed myeloid features, but Sudan black B and/or peroxidase positivity was noted in only ten patients. The overall mortality was high, especially in patients undergoing chemotherapy. At 1 year follow-up, 11 patients had received chemotherapy and eight of these eleven were dead compared to three of nine patients dead in those not receiving chemotherapy. Only two patients developed "overt" leukemia evidenced by hypercellular marrow and over 30% blast cells in the peripheral blood. HBMIB is a distinct clinicopathologic entity characterized by severe marrow failure and a low response rate to chemotherapy.
Carcinogenic Effects of Diethylnitrosamine in RF Mice&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Neal K. Clapp, A. W. Craig
Journal: JNCI Journal of the National Cancer Institute (1967)

Noninbred 10-week-old male mice of the RF/Un strain were given 4 mg of diethylnitrosamine (DEN)/100 ml drinking water daily for 22 weeks. Tumors were first observed in high incidences after 22 weeks of treatment (mice 32 weeks old) and consisted of pulmonary adenomas, liver hepatomas, and squamous cell carcinomas of the stomach. In histologically examined animals, the incidences were 74% for lung tumors, 90% for liver fumors, and 100% for stomach tumors in animals that survived the 22-week treatment period. In addition, 4 mice (18%) had esophageal tumors (squamous cell carcinomas). In contrast to previous reports on mice in which the principal tumors were hemangioendotheliomas and adenomas of the liver, hepatomas were the principal liver tumors produced. This fact and the observation of a high incidence of squamous cell carcinomas of the forestomach point to the influence of drug metabolism, excretion, and perhaps certain other physiologic factors on the site of tumor production by DEN. No significant effect of DEN on leukemia incidence was observed.