tbuckley/cabot-search huggingface dataset:
P2 Characterisation Of A - And C-fibres Innervating Guinea-pig Airways
Authors: J. Adcock, M. Birrell, S. Maher, S. Bonvini, E. Dubuis, M. Wortley, K. Baker, M. Belvisi
Journal: Thorax (2014)

<h3>Introduction and objectives</h3> Activation of afferent fibres from the lungs are involved in the cough reflex. <i>In vitro</i> studies in guinea-pig have demonstrated that there are various sub-types of Aδ-fibres (RAR’s, nociceptive and cough)<sup>1</sup> and C-fibres (either nodose or jugular ganglia derived),<sup>1,2</sup> however, little is known about their equivalent characteristics <i>in vivo</i>. This study aims to characterise the responsiveness of airway sensory nerves, <i>in vivo,</i> ultimately providing a better insight into understanding the role/contribution of the various types/subtypes of Aδ and C-fibres in airway reflexes such as cough. <h3>Methods</h3> Male guinea-pigs were anaesthetized with urethane (i.p. 1.5 g kg<sup>-1</sup>), paralysed and artificially ventilated via a tracheal cannula. A vagus nerve was isolated: single fibres were identified as originating from Aδ- and C-fibres using several criteria. Action potentials were recorded<sup>3</sup> and agents were administered to the airways by aerosol. <h3>Results</h3> Fibre-types were classified according to their conduction velocities (Table 1). All C-fibres examined were activated by capsaicin, whereas in the Aδ-fibres studies there were both capsaicin responsive and non-responsive fibres, irrespective of their CV range. All fibres exposed to CA responded strongly. There were marked differences in the responsiveness to the TRPV4 agonist, GSK1016790A: Aδ-fibres from all subgroups responded vigorously, but the C-fibres examined were not activated. Interestingly, administration of hypotonic solutions activated all of the Aδ-fibres, but had no effect on C-fibres. In contrast, all C-fibres responded to the TRPA1 agonist, acrolein, with no effect on Aδ-fibres. <h3>Conclusion</h3> Several vagalafferent nerve subtypes have been identified in guinea-pig airways <i>in vivo</i>, although the classification does not appear as obvious to that observed <i>in vitro</i>. It is clear that there is a marked variation in their sensitivity to TRP channel agonists, TRPV1, TRPA1 and TRPV4, which have all been shown to evoke cough in a preclinical model in conscious guinea-pigs. It seems probable, therefore, that the different afferent pathways all regulate cough to a greater or lesser degree depending on the nature of the stimulus and underlying cause of the cough. <h3>References</h3> Canning 2004: <i>J Physiol-</i>557 (2):543–558 Weigand 2012: <i>J Physiol-</i>590, (16):4109–4120 Adcock 2003: <i>Brit J Pharmacol-</i>138:407–416
Steady increase of lymphogranuloma venereum cases, Czech Republic, 2010 to 2015
Authors: Filip Rob, Kateřina Jůzlová, Helena Krutáková, Hana Zákoucká, Daniela Vaňousová, Zuzana Kružicová, Ladislav Machala, Dan Veselý, David Jilich, Jana Hercogová
Journal: Eurosurveillance (2016)

Since the notification of the first case of lymphogranuloma venereum (LGV) in the Czech Republic in 2010, the numbers of LGV cases have steadily increased in the country. In 2015, 40 LGV cases were diagnosed, bringing the total for 2010-2015, to 88 cases. The profile of the most affected group, HIV-positive men who have sex with men with a previous sexually transmitted infection, matches that of those described in LGV outbreaks in western Europe.
The Risk of Zoster after Varicella Vaccination in Children with Leukemia
Authors: R Lawrence, A A Gershon, R Holzman, S P Steinberg
Journal: New England Journal of Medicine (1988)

We examined the incidence of zoster in 346 children with underlying acute lymphoblastic leukemia who were immunized with live attenuated varicella vaccine while in remission. We also compared a subset of 84 of these children with a matched group of 84 children with leukemia who had had natural infection with varicella. Of the 346 vaccinated children, 5 (1.45 percent) became infected with zoster after 10,878 months of observation, for an incidence of 0.552 case per 100 person-years. Among the matched pairs of subjects, zoster occurred in 3 (3.6 percent) of the 84 vaccinated subjects during 2936 months of observation--an incidence of 1.23 cases per 100 person-years--and in 11 (13.1 percent) of the subjects with natural infection during 4245 months--an incidence of 3.11 cases of zoster per 100 person-years. Although the incidence of zoster was more than twice as high in the control children as in the vaccinated children (3.11 vs. 1.23 cases per 100 person-years), a Kaplan-Meier product-limit analysis revealed no significant differences in incidence between the two groups. Children from both groups in whom leukemia recurred were more likely to contract zoster than those who did not have a recurrence (7 of 35 vs. 7 of 133, P less than 0.025). Zoster was not a marker for impending relapse. No case of zoster was severe or disseminated. We conclude that the incidence of zoster following immunization with live attenuated varicella vaccine is no greater than that following natural varicella infection.
Abstract A40: Investigating the functional response of the ARF tumor suppressor to acute p53 loss
Authors: Jason T. Forys, Raleigh D. Kladney, Jason D. Weber
Journal: Cancer Research (2011)

Abstract The tumor suppressor, p19ARF, is classically considered to function in response to hyerproliferative signals by binding and sequestering MDM2 in the nucleolus, thereby activating p53. Steady-state levels of ARF are kept low to prevent activation of p53 and are thought to monitor nucleolar function. Interestingly, p53 itself inhibits the Arf locus by recruiting proteins involved in heterochromatin formation. Cell lines that lack functional p53, therefore, accumulate enormous amounts of ARF protein but proliferate relatively well. Given that ARF is known to have functions independent of p53 both in vitro and in vivo, we wanted to investigate the function of ARF in the setting of acute p53 loss using conditional deletion of p53 from p53Flox/Flox mouse embryonic fibroblasts (MEFs). Cre-mediated excision of p53 leads to an induction of ARF by 4 days post infection, but levels do not peak until 10 days. Adeno-Cre infected MEFs have a higher proliferation rate than Adeno-LacZ controls, and do not undergo replicative senescence. However, knockdown of Arf in p53Δ/Δ MEFs using lentiviral shRNAs results in an increase in proliferation and enhanced growth in semisolid medium following RasI/12 transformation. These findings suggest that the induced ARF levels are acting to inhibit p53-null cells in some capacity. Loss of p53 also leads to a dramatic downregulation of MDM2 protein levels. Immunoprecipitation experiments indicate that ARF predominantly interacts with MDM2 in LacZ-infected cells, but binds the ribosomal chaperone nucleophosmin (NPM) more readily in p53Δ/Δ MEFs. Since inhibition of NPM by ARF has been shown to negatively affect overall protein synthesis, we hypothesize that in the absence of p53, ARF functions to negatively regulate overall protein synthesis through NPM in an effort to slow proliferation. Indeed, p53Δ/Δ MEFs contain less total protein per cell, copies of 47S rRNA, and have reduced active translation compared to their LacZ counterparts. We are currently testing whether knockdown Arf in p53Δ/Δ MEFs can rescue protein synthesis, thus allowing these cells to proliferate at an even faster rate. These findings could explain why certain cancers (i.e., pancreatic cancer) preferentially inactivate both ARF and p53. We are also attempting to understand why the high levels of endogenous ARF seen in the absence of p53 are not able to induce a cell cycle arrest when ARF is clearly capable of eliciting such a response independently of p53. As p53 mutation occurs in over 50% of all cancers it would be of interest to know how we could activate this function of ARF in those patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A40.
A6.18 Analysis of<i>ABCG2</i>gene in primary hyperuricemia and gout
Authors: B Stiburkova, P Simek, P Cepek, J Zavada, L Petru, K Pavelka
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> In the present study, we describe the identification and functional analysis of allelic variants in the <i>ABCG2</i> gene, a physiologically important urate transporter whose dysfunction plays a major role in pathogenesis of gout, in a cohort with primary hyperuricemia and gout. <h3>Materials and methods</h3> The cohort consisted of 128 individuals: 29/99 primary hyperuricemics/gout. The definition of hyperuricemia was as follows: &gt;420/360 µmol/l at two repeated measurements at intervals of at least 4 weeks in men/women. Gouty arthritis was diagnosed according to the 1977 preliminary criteria of the American College of Rheumatology for acute arthritis of gout. Patients suffering from secondary gout were excluded. We analysed 15 exons of <i>ABCG2</i> by PCR amplification and sequenced directly. The functional analysis of identified allelic variants is in process (<i>Xenopus</i> oocyte, HEK cells). <h3>Results</h3> In the <i>ABCG2</i> gene, 16 intronic sequence variants and seven exon variants were detected. In the case of c.689+1G &gt;A, related to an individual with severe gouty phenotype, two abnormal splicing variants were identified: a) r.[532_689del]; b) r.[532_689del], r.[944_949del]. Identified deletions lead to frameshift and premature stop codon introduction. From the 7 exon variants detected, there were five non-synonymous: p.V12M (<i>rs2231137</i>), p.Q141K (<i>rs2231142</i>), p.T153M (<i>rs753759474</i>), p.F373C (<i>rs752626614</i>) and p.D620N (<i>rs34783571</i>). Heterozygous p.V12M variant was detected in seven individuals. Variant p.T153M, p.F373C and p.D620N was detected once in heterozygous state. Variants p.T153M and p.F373C were <i>in silico</i> predicted using Polyphen and Sift program as a probably damaging. The p.Q141K, previously functionally characterised allelic variant with an strong effect on uric acid secretion impairment, was in cohort of hyperuricemic/gout patients presented with higher frequency: 40 heterozygotes/5 homozygotes, allele frequency 0.195 than in population of European origin (MAF&nbsp;=&nbsp;0.09) and world-wide population (MAF&nbsp;=&nbsp;0.12). <h3>Conclusions</h3> Our results show that genetic factor <i>ABCG2</i> should be considered to be one of the common risks for hyperuricemia/gout. In clinical practice, <i>ABCG2</i> dysfunction can be estimated easily by genotyping and these findings will help to recognise a trait of hyperuricemia at a very early stage. &nbsp;This study was supported by the grants from the Czech Republic Ministry of Health AZV 15–26693A and the IMI-funded project BeTheCure 115142–2f.
Abstract 113: Gamma-H2AX level in peripheral blood lymphocytes as a risk predictor for bladder cancer.
Authors: Mario I. Fernandez, Yilei Gong, Yuanqing Ye, Jie Lin, David Chang, Xifeng Wu
Journal: Cancer Research (2013)

Abstract Introduction: Identification of susceptibility to double-strand breaks (DSB) may provide valuable information about genomic instability and cancer risk. The formation of gamma-H2AX foci is a highly sensitive marker for DNA DSBs induction. We assessed whether levels of gamma-H2AX in peripheral blood lymphocytes (PBL) obtained after stimulation by ionizing radiation (IR) are associated with bladder cancer risk in a bladder cancer case-control study. Material and Methods: Patients and controls were enrolled from an ongoing bladder cancer case-control study. Epidemiologic data were collected during an in-person interview using a structured questionnaire. Baseline and IR induced H2AX-phosphorylation was assessed in PBL from 174 newly diagnosed, previously untreated bladder cancer patients and from 174 age, sex and ethnicity matched, healthy control subjects by a novel, image-based, high-throughput phenotypic assay. The ratio of gamma-H2AX level of IR-treated cells to that of non-treated cells (baseline) derived from the same blood sample was used as the parameter to assess the sensitivity to the mutagen. Logistic regression analysis was used to estimate odds ratios associated with gamma-H2AX. We also compared the discriminatory ability of a model with only demographic variables and a model including gamma-H2AX ratio. Results: The mean gamma-H2AX ratios were significantly higher for cases than for controls (1.43±0.14 vs. 1.35±0.12; p=1.44E-08). This trend was irrespective of age, sex or smoking status. The risk estimates of bladder cancer for induced DNA DSBs showed a significant trend for increased risk at the highest tertiles for the whole cohort (OR=3.09; 95%CI 1.76-5.40; p=8.15E-05 for the second tertile and OR=3.78; 95%CI 2.26-6.33; p=4.18E-07 for the third tertile) as well as for each category. Discrimination ability of the epidemiological model was moderate, with an area under curve (AUC) of 0.64. However, the AUC increased significantly to 0.74 when gamma-H2AX ratio was incorporated. Conclusions: Our findings suggest that a higher susceptibility to induction of DSBs as measured by the gamma-H2AX assay is significantly associated with an increased risk for bladder cancer. This might help to identify individuals at high risk for this cancer, adding new perspectives to established epidemiological and genetic risk factors. Further research of the role of gamma-H2AX in biological processes of bladder cancer is warranted. Citation Format: Mario I. Fernandez, Yilei Gong, Yuanqing Ye, Jie Lin, David Chang, Xifeng Wu. Gamma-H2AX level in peripheral blood lymphocytes as a risk predictor for bladder cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 113. doi:10.1158/1538-7445.AM2013-113
Bayesian Methods and Ethics in a Clinical Trial Design, by Ed Joseph B Kadane
Authors: R. A Crouch
Journal: BMJ (1997)

Ed Joseph B Kadane / John Wiley, £65, pp 318 ISBN 0 471 84680 5

When confronted with the ubiquitous P value, the statistical novice usually concludes (wrongly) that it represents the answer to the clinically important question “What is the probability that treatment A is superior to treatment B?” Yet classical (frequentist) statistical methods–the standard used in clinical research–do not address this question; Bayesian methods do. Bayesian researchers can formally quantify prior beliefs about relative efficacies of treatments (from previously published literature and from “informal” clinical experience), and they can then update these “priors” …
Abstract 2350: MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1
Authors: Mohit Sachdeva, Yin Yuan Mo
Journal: Cancer Research (2010)

Abstract MicroRNAs (miRNAs) are important gene regulators that could play a profound role in tumorigenesis. Our previous studies indicate that miR-145 is a tumor suppressor capable of inhibiting tumor cell growth both in vitro and in vivo. In this study, we show that miR-145 exerts its function in a cell-specific manner. Although miR-145 inhibits cell growth in MCF-7 and HCT-116 cells, it has no significant effect on cell growth in metastatic breast cancer cell lines. However, miR-145 significantly suppresses cell invasion in these cells, as shown by matrigel chamber assays; in contrast, the antisense oligo against miR-145 increases cell invasion. MiR-145 is also able to suppress lung metastasis in an experimental metastasis animal model. This miR-145-mediated suppression of cell invasion is in part due to the silencing of the metastasis gene mucin 1 (MUC1). Using luciferase reporters carrying the 3′-untranslated region of MUC1 combined with western blot and immunofluorescence staining, we identify MUC1 as a direct target of miR-145. Moreover, ectopic expression of MUC1 enhances cell invasion, which can be blocked by miR-145. Of interest, suppression of MUC1 by miR-145 causes a reduction of β-catenin as well as the oncogenic cadherin 11. Finally, suppression of MUC1 by RNAi mimics the miR-145 action in suppression of invasion, which is associated with downregulation of β-catenin and cadherin 11. Taken together, these results suggest that as a tumor suppressor, miR-145 inhibits not only tumor growth, but also cell invasion and metastasis. 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 2350.
Abstract 1417: Tumour stroma interaction and radiation resistance in pancreatic cancer
Authors: Tine S. Mantoni, Serena Lunardi, Thomas B. Brunner
Journal: Cancer Research (2010)

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is characterised by a strong desmoplasmic reaction where the stromal compartment encounts for up to half the tumour volume. The enriched stroma is believed to be a contributing factor to the poor therapeutic response of PDAC, which is reflected in only 13% surviving the first year after diagnosis. A central mediator of the desmoplastic reaction is the pancreatic stellate cells (PSC). Signalling between PSC and tumour cells stimulates proliferation and migration of both cell types as well as secretion of extracellular matrix (ECM) proteins by the PSC. We aim to gain a better understanding of the crosstalk between PSC and tumour cells and how this affects tumour cell response to ionising radiation. Methods We have set up a co-culture system, which allow studies of tumour cells directly and indirectly co-cultured with PSC. Clonogenic survival assays were used to assess the radiosensitivity of mono- and co-cultured tumour cells. We also use in vivo mouse models to study the effects of PSC on tumour proliferation and tumour regrowth in response to radiation. Results and conclusion We demonstrate that PSC promote radioprotection and stimulate proliferation in pancreatic tumour cells in both direct and indirect co-culture. This is a PSC specific response as fibroblasts do not have a radioprotective effect on the tumour cells. Our in vivo studies of xenograft tumours in mice likewise demonstrate PSC dependent radioprotection and increased tumour proliferation. The kinetics of DNA repair in tumour cells were investigated but showed no changes in the presence of PSC and was therefore concluded not to form part of this radioprotective response. Previous studies have shown that cell adhesion to ECM proteins by integrin molecules mediates resistance to genotoxic stress. We here show that abrogating β1-integrin signalling by means of a blocking antibody results in a significant decrease in the PSC mediated radioresistance in tumour cells. Taken together we here demonstrate for the first time that PSC promote radioprotection of pancreatic tumour cells in vitro and in vivo. Our data points towards a role of β1-integrin signalling in this radioprotective response. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 1417.
AB0852-HPR Pedobagraphic measurements of rheumatoid feet and comparison with clinical parameters
Authors: Y. Yumusakhuylu, A. Icagasioglu, S. T. Turgut, E. Selimoglu, S. Murat, E. K. Gunal, B. Turgut
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Foot involvement in rheumatoid arthritis (RA) have been reported to be 56-100% in different studies. Pedobarography is used for dynamic plantar pressure measurement and to point out deformities of rheumatoid feet. <h3>Objectives</h3> The aim of this study was to assess the use of pedobarographic measurements for the investigation of the relationship between plantar pressure alterations and disease activity, radiological changes and foot indexes in patients with RA. <h3>Methods</h3> Patients over 18 years of age with rheumatoid arthritis experiencing foot pain were included. Data on patients sociodemographics, foot symptoms, anatomical distribution, intensity and duration of pain and access to podiatry services were collected using questionnaires completed during outpatient visit. For the functional status the scores of disease activity scale of 28 joints (DAS 28) and Health Assessment Questionnaire (HAQ) was used. Foot function index (FFI) and Manchester Foot Pain and Disability Index (MFPDI) were also administered to all RA patients. Modified Larsen scoring was used to asess radiological changes. Pedobarographic measurements was used to analyze foot loading characteristics. <h3>Results</h3> A total of 104 feet of 52 RA patients (48 female, 4 male) with a mean age of 53,88±11,36 years was evaluated. DAS 28 scores did not correlate with the plantar pressure changes (p&gt;0,05). We found a significant correlation between HAQ scores and right medial midfoot loading pressure (r=0,355; p&lt;0,01). FFI scores were pozitively correlated with right lateral midfoot loading pressure (r=0,302; p&lt;0,05). We did not found a relationship between MFPDI and plantar loading characteristics. The radiological scores were correlated with the left lateral hindfoot plantar pressure (r=0,286; p&lt;0,05). <h3>Conclusions</h3> Pedobarographic investigation of rheumatoid feet may provide a concept for treatment planning and rehabilitative care. <h3>References</h3> Tuna H, Birtane M, Taştekin N, Kokino S.Pedobarography and its relation to radiologic erosion scores in rheumatoid arthritis. Rheumatol Int. 2005 Nov;26(1):42-7. Borman P, Ayhan F, Tuncay F, Sahin M. Foot problems in a group of patients with rheumatoid arthritis: an unmet need for foot care. Open Rheumatol J. 2012;6:290-5. <h3>Disclosure of Interest</h3> None Declared
P296 Effectiveness Of Adaptive Servo Ventilation In The Treatment Of Central Sleep Apnea
Authors: A. Al-Ameri, M. Latham, J. Pateraki, M. Elliott
Journal: Thorax (2014)

<h3>Background</h3> Adaptive Servo Ventilation (ASV) was developed to treat Central Sleep Apnea in patients with heart failure, which is usually associated with a low or normal PaCO2. The aim of ASV is to stabilise rather than increase overall ventilation. Evidence is limited regarding the use of ASV not only in heart failure patients but central sleep apnea of other aetiologies. The current study therefore explored this therapy in a regional sleep centre in the UK. <h3>Method</h3> A retrospective review of the outcomes of 42 patients who were treated with ASV between January 2012 and December 2013, either following conventional positive airway pressure (PAP) or as an initial therapy. Measurements included the Apnea Hypopnea Index (AHI), compliance (measured by hours of machine use/night) and subjective sleep quality, pre and post ASV. <h3>Results</h3> All patients demonstrated evidence of central sleep apnea with a reduced or normal transcutaneous CO2 during daytime spontaneous ventilation. Seven patients (16%) met the criteria for complex sleep apnea. 16 (38%) had evidence of heart failure whilst opioids were in use in six patients (14%). The majority of patients, (n = 36, 86%), were on PAP prior to ASV (mean duration 2.4 years), 22 patients (53%) were on Bi-level and 14 (33%) were on CPAP. Six patients (14%) had ASV as an initial therapy. The mean AHI improved from 31.7/h (range 2–84/h) to 5.1/h (Range 0–50/h) with ASV [Figure 1]. Compliance improved from 5.2 h/night to 6.4 h/night with ASV. 22 patients (52%) reported a subjective improvement in their sleep quality using ASV. <h3>Conclusion</h3> ASV appeared superior to traditional PAP in improving AHI, compliance and sleep quality for patients with central sleep apnea of various aetiologies.