tbuckley/cabot-search huggingface dataset:
A single domain antibody fragment that recognizes the adaptor ASC defines the role of ASC domains in inflammasome assembly
Authors: Florian I. Schmidt, Alvin Lu, Jeff W. Chen, Jianbin Ruan, Catherine Tang, Hao Wu, Hidde L. Ploegh
Journal: The Journal of Experimental Medicine (2016)

Myeloid cells assemble inflammasomes in response to infection or cell damage; cytosolic sensors activate pro–caspase-1, indirectly for the most part, via the adaptors ASC and NLRC4. This leads to secretion of proinflammatory cytokines and pyroptosis. To explore complex formation under physiological conditions, we generated an alpaca single domain antibody, VHHASC, which specifically recognizes the CARD of human ASC via its type II interface. VHHASC not only impairs ASCCARD interactions in vitro, but also inhibits inflammasome activation in response to NLRP3, AIM2, and NAIP triggers when expressed in living cells, highlighting a role of ASC in all three types of inflammasomes. VHHASC leaves the Pyrin domain of ASC functional and stabilizes a filamentous intermediate of inflammasome activation. Incorporation of VHHASC-EGFP into these structures allowed the visualization of endogenous ASCPYD filaments for the first time. These data revealed that cross-linking of ASCPYD filaments via ASCCARD mediates the assembly of ASC foci.
PTH-174 Development of a Network Multidisciplinary Team and National Referral Centre for Treatment of Complex benign Colorectal Polyps
Authors: S Dolwani, H Heard M Davies, N Williams, G Tudor, M Morgan, R Davies, A Maw, C Lewis
Journal: Gut (2013)

<h3>Introduction</h3> Large flat or sessile lesions are not uncommon on a screening colonoscopy list and endoscopic removal is often technically challenging. The assessment process for screening colonoscopists in Wales does not assess therapeutic skill and variation in rates of referral to surgery suggest that clinician skill level may influence management decisions. A Network Multi Disciplinary Team (NMDT) and National Referral Centre (NRC) pilot was established to offer the opportunity for expert opinion and discussion of therapeutic options for participants of the welsh bowel screening programme. <h3>Methods</h3> The six month pilot began in October 2011 by taking referrals from Screening Colonoscopists and local MDT’s. The aim was to provide a service that would reduce variation of practise with potential value for education on lesion recognition, EMR technique and decision making. Expressions of interest were invited and expert advisors appointed for Colonoscopy, Pathology, Radiology and Surgery. Specialist Screening Practitioners and management staff were appointed and the NMDT established as a virtual group to meet biweekly. Referral criteria were agreed based on a composite of size, morphology and accessibility of lesion. Participants with lesions satisfying the criteria were referred to the NMDT electronically. Local Assessment Centres were provided with image capture devices and staff trained to record and edit video clips which were subsequently saved on a share drive, reviewed by expert advisors and discussed at NMDT meetings. Expertise in complex polypectomy is often limited to few centres and the NRC was designated in a unit accessible to colonoscopists with appropriate skills. It was established in Cardiff at University Hospital Llandough via an agreement with Public Health Wales. Depending on outcomes of NMDT discussions participants were given the option of accessing local surgery or travelling to the NRC for therapeutic endoscopy where appropriate. <h3>Results</h3> During the initial pilot phase 13 meetings were held. No meeting was cancelled due to availability of advisors, 1 was cancelled on a bank holiday and 1 because of technical difficulties. Thirty eight cases were referred for discussion and 15 of them referred to the NRC for therapeutic procedures. Challenges including image quality, video transmission and interface with local MDT’s were discussed at a multidisciplinary workshop and solutions identified for future development. Evaluation of the pilot indicates that the service has been well received by participants, NMDT members and local teams. <h3>Conclusion</h3> This development has been logistically feasible, safe and successful in providing an equitable service for participants of the bowel screening programme in Wales and has contributed to a reduction in referrals for surgery for benign lesions. <h3>Disclosure of Interest</h3> None Declared.
Abstract P4-17-06: The use of specialist nurse-led clinics in preparation for reconstructive breast surgery.
Authors: AM Affan, RA Ali, JA Morton-Gittens, A Perry, A Harry, JM O'Donoghue, R Rampaul
Journal: Cancer Research (2012)

Abstract Objective: To assess the effectiveness of a specialist nurse in a breast oncoplastic clinic. This was done by comparing patient reported outcome measures (PROMS) following information given about breast reconstructive surgery by either a specialist nurse or consultant surgeon. Design &amp; Methods: From June 2011 to December 2011 a study specific questionnaire was administered to patients who were considering breast reconstruction at the St. James Breast Service in Trinidad. A modified questionnaire was used which employed a Likert scale in order to provide a measure of patient satisfaction with the preoperative information and preparation provided by either a specialist breast cancer nurse (Group 1) as compared to the consultant breast surgeon (Group 2). The scale graded satisfaction levels from one to five where one represented patient dissatisfaction while five indicated complete satisfaction. Data was collated and analyzed using SPSS 17 with the significance level set at p = 0.05. Results: Seventy-five (75) patients were obtained for the study. Sixty-three (63) of these patients responded adequately to the questionnaire resulting in an eighty-five percent (85%) response rate. There was a 97% overall satisfaction (n = 61) with the preoperative information given whether administered by the specialist nurse or the consultant surgeon. Ninety-five percent (95%) (n = 60) of patients indicated that verbal information from the consultant was extremely useful while eighty-seven percent (87%) (n = 55) of patients responded favorably to the information departed by the specialist nurse (X21.21; p = 0.271). Additonally, ninety-five percent (95%) (n = 60) were completely satisfied with the response from the consultant while ninety percent (90%) (n = 56) with that of the specialist nurse (X22.072; p = 0.150). Overall conversion rate to breast reconstruction has been 89%. Conclusions: This data demonstrates that there appears to be no difference between the patient reported outcomes when receiving information from either the specialist nurse or the surgeon. Therefore, a pre-operative nurse led clinic for breast reconstruction can be an effective and acceptable approach for patients seeking this service. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-17-06.
AB0237 Endothelin-1 induces alpha-smooth muscle actin (alpha-SMA) expression in cultured human endothelial cells
Authors: S. Soldano, P. Montagna, R. Brizzolara, A. Sulli, B. Villaggio, M. Cutolo
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Myofibroblasts are activated fibroblasts mainly characterized by the expression of α-smooth muscle actin (α-SMA) playing a prominent role in the fibrotic process that characterizes some connective tissue diseases, in particular systemic sclerosis (SSc) (1). Recently, it was shown that myofibroblasts may arise by the transition from epithelial or endothelial cells, thus expressing α-SMA, vimentin and type I collagen. This mechanism mightbe induced by transforming growth factor β (TGF-β) and/or endothelin-1 (ET-1) (2-4). <h3>Objectives</h3> To investigate the involvement of ET-1 in cell proliferation and entothelial-to-myofibroblast transition by evaluating α-SMA expression in cultures of human endothelial cells. <h3>Methods</h3> Human umbilical vein endothelial cells (HUVEC) were cultured in collagen-coated dishes with completed endothelial cell basal medium (EGM-2) at 2% of fetal bovine serum and used between the third and fifth passages for the experiments. The cells were treated with ET-1 (100nM) for 24 hrs, 3 days and 6 days, whereas untreated cells were used as controls (cnt). Cell proliferation was evaluated by methyl-tetrazolium salt test (MTT) at 24 hrs whereas the α-SMA expression was evaluated at 3 and 6 days by immunocytochemistry (ICC), immunofluorescence (IF) and western blotting analysis (WB) according to a recent study (5). The data were obtained from four different experiments and statistical analysis was carried out by a non-parametric Friedman test. <h3>Results</h3> ET-1 significantly increased the endothelial cell proliferation (p&lt;0.01 vs. cnt) at 24 hrs from treatment, as detected by MTT test in cell cultures. In addition, ET-1 stimulated endothelial cells to express the myofibroblasts marker α-SMA after 6 days from treatment. The data were obtained by IF, ICC and confirmed by WB. <h3>Conclusions</h3> Results showed that ET-1 may stimulate human endothelial cell growth supporting its mitogenic effects as already shown for other cell types involved in the fibrotic process (6). Interestingly, ET-1 induced the α-SMA expression in human endothelial cells, supporting a possible transition from endothelial to the myofibroblast phenotype (2, 5). The implications in the fibrotic process that characterize SSc are matter of further evaluations. <h3>References</h3> Wynn TA.J Pathol 2008;214:199-210. Piera-Velazquez S et al. Am J Pathol 2011;179:1074-80. Lagares D et al. Arthrit Rheum 2010;62:878-89. Leask A. Pharmacol Res 2011;63:502-3. Widyantoro B et al. Circulation 2010;8:2407-18. Adraham D et al. Arthrit Res Ther 2007;9:doi:10.1186/ar2186. <h3>Disclosure of Interest</h3> None Declared
Abstract 3707: Early stage inhibition of murine mammary carcinogenesis by ultraviolet radiation.
Authors: Anastasia M. Makarova, Grace Wang, Lynn Wang, Joy Wang, Yefim Khaimskiy, Ervin H. Epstein
Journal: Cancer Research (2013)

Abstract Epidemiological studies of geographical variations in breast cancer mortality rates have found increased death rates at higher latitudes in USA and other countries 1. This breast cancer latitudinal gradient is hypothesized to be mediated by ultraviolet radiation (UVR) - produced vitamin D3. We first have tested this latitudinal hypotheses using the well-described C3(1)/Tag transgenic murine mammary carcinogenesis model2. We have found that UVR significantly prolongs palpable tumor - free survival (135±23 vs.118±18 days) and reduces the tumor burden and multiplicity (2.9±1.6 vs. 7.2±2.3 tumors), but does not alter the time between the appearance of the first palpable tumor and death in Tag female mice. Therefore we have focused on the effects of UVR on earlier stage carcinogenesis. Tag transgenic female mice have a time-dependent increase in the incidence of ductal carcinoma in situ (DCIS) - like incidence. Thus, Tag mice develop ductal epithelial atypia in 50% of mice at age 8 wks, with progression to intraepithelial neoplasia (resembling human DCIS) in 70-90% of mice (in at least one gland) at 10-13 wks, and DCIS-like changes and early invasion in 100% of mice at age 14-15 wks. We compared weekly the similarity of histological changes between the pairs of mammary glands and found no significant gland site-to-gland site variations. UVR treatment, 350mJ/cm2 thrice weekly from age 6 wks to 15 wks, reduced both the percentage of DCIS-bearing mice (65, 60, 51, 32 and 20% reduction at week 8, 9, 11, 13 and 14) and the percentage of DCIS-bearing glands in each animal (82, 55, 66, 20 and 19% reduction at week 9, 11, 13, 14 and 15). The mechanism of the UVR-mediated prevention of the murine mammary carcinogenesis is unclear but there is evidence favoring a Hedgehog (HH) signaling-dependent mechanism, since D3 is a potent inhibitor of the HH signaling pathway, which is upregulated in many cancers including breast cancer3-5. Consistent with this idea we found that UVR reduces DCIS-like changes in Ptch+/- mice. Taken together our results support our hypothesis that inhibition of early stage mammary carcinogenesis by UVR-produced vitamin D3 underlies the latitudinal gradient. 1. Garland, F. C. et all. Prev Med 1990, 19, 614-22. 2. Green, J. E. et all. Oncogene 2000, 19, 1020-7. 3. Bijlsma, M. F. et all. PLoS Biol 2006, 4, e232. 4. Moraes, R. C. et all. Development 2009, 136, 1423-32. 5. Lewis, M. T. et all. Development 1999, 126, 5181-93. Citation Format: Anastasia M. Makarova, Grace Wang, Lynn Wang, Joy Wang, Yefim Khaimskiy, Ervin H. Epstein. Early stage inhibition of murine mammary carcinogenesis by ultraviolet radiation. [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 3707. doi:10.1158/1538-7445.AM2013-3707
Abstract 4095: Aberrant expression of epigenetically regulated microRNAs in liver cancer
Authors: Chun-Ming Wong, Carmen Chak-Lui Wong, Aegean Hoy Kam Tam, Irene Oi-Lin Ng
Journal: Cancer Research (2010)

Abstract Liver cancer (hepatocellular carcinoma, HCC) is a major malignancy worldwide. Despite definite improvements in the outcome of patients with HCC, the overall prognosis of this cancer is still unsatisfactory because of late presentation and frequent tumor recurrence after surgical resection. New diagnostic and adjuvant treatment modalities are much awaited. MicroRNAs (miRNAs) are a class of small (∼22 nt) single-stranded noncoding RNAs widely expressed in eukaryotic cells. miRNAs play an important role in modulating gene expression by promoting mRNA degradation or translational repression. There is mounting evidence that miRNAs are implicated in almost all major physiological processes, including cell proliferation, differentiation, apoptosis, and human carcinogenesis. Epigenetic alterations including aberrant DNA methylation and histone modification are important in regulating chromatin structure and gene expression. In this study, we investigated the role of epigenetic alterations in miRNA deregulation in human HCC. miRNA expression changes of HCC cell lines upon treatment with DNA demethylating agent (5-Aza-dC) and histone deacetylase inhibitor (Trichostatin A, TSA) were compared with stem-loop RT-qPCR based TaqMan low density array. In total, 98 miRNAs were remarkably up-regulated upon 5-Aza-dC/TSA treatment. Among these, 35 miRNA were commonly upregulated by treatment with the epigenetic inhibitors in both cell lines. The majority of these miRNAs was either associated with promoter CpG islands or located on imprinted regions. Expression analysis revealed that these epigenetically regulated miRNAs were frequently deregulated in human HCCs, and their expression pattern was able to distinguish primary HCCs from their corresponding non-tumorous livers. Interestingly, CpG island-associated miRNAs tended to be down-regulated in human HCCs, whereas, miRNAs located on imprinted regions were frequently overexpressed in human HCC samples. Our findings suggest that aberrant epigenetic silencing and loss of imprinting may contribute to miRNA deregulation in human HCC. 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 4095.
Effect of Neoadjuvant Chemotherapy on the Surgical Treatment of Patients with Locally Advanced Breast Cancer Requiring Initial Mastectomy
Authors: J. Antomarchi, C. Cavrot, E. Chamorey, T. Ihrai, B. Flipo, I. Peyrottes, P. Follana, C. Chapellier, J. Ferrero, E. Barranger
Journal: Annals of Oncology (2014)
Immunologic Factors Determining Survival of Cadaver-Kidney Transplants
Authors: Flavio Vincenti, Robert M. Duca, William Amend, Herbert A. Perkins, Kent C. Cochrum, Nicholas J. Feduska, Oscar Salvatierra
Journal: New England Journal of Medicine (1978)

We assessed immunologic factors determining graft survival in 510 recipients of primary cadaver allografts at one center. The degree of HLA match grade did not directly affect graft survival (54 per cent in no-antigen match, and 42 per cent in three-antigen match, at two years). There was no correlation between the HLA match grade and the degree of stimulation of the mixed lymphocyte culture. Patients receiving more than five blood transfusions had a significantly better graft survival than nontransfused recipients (52 versus 23 per cent, respectively, at two years, P<0.001). The beneficial effect of transfusions was noted whether or not lymphocytotoxic antibodies were produced, provided adequate screening was performed before transplantation. Transfusions did not alter the degree of stimulation in the mixed lymphocyte culture. More liberal use of transfusions and frequent screening for cytotoxic antibodies would probably result in more effective cadaver-kidney transplantation. (N Engl J Med 299:793–798, 1978)
SP0131 Confounding or REAL Effect: How to Assess?
Authors: A. Zink
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> In the context of observational cohort studies, it is often difficult to distinguish potential adverse effects of GCs from the effects directly related to the activity of the underlying disease, prompting prescription of GCs. This channelling bias which means that more severely ill patients are treated with more effective, but also potentially harmful agents is present in all real-world studies of drug exposure. In rheumatoid arthritis, as an example, adverse outcomes that are linked to highly active disease can be prevented by drugs that efficiently reduce disease activity, such as GCs. However, the same adverse outcome can also be a direct result of the immunosuppressive effect of GCs. Therefore, the challenge is to disentangle treatment and disease-associated effects. Due to some practice variation among physicians, large observational cohorts can be used to analyse the effects of GCs (e.g. on the risk for infection or mortality) separately from the effects of high disease activity. Multivariate statistical models are applied to estimate the individual effects of disease and treatment. Since GCs are not given at fixed dosages, statistical modelling has further to consider time-varying risks resulting from changing dosages of GCs. With examples from the German biologics register RABBIT on serious infections and on mortality I will demonstrate how confounding by indication and real effect can be analysed separately and what this means for the assessment of the adverse potential of GCs. The data show that, after control for baseline confounding and time-varying risks, there is a considerable remaining risk for higher dosages of GCs if given over longer periods of time. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6274
La dissection endoscopique sous-muqueuse en France: analyse du registre de la Sfed 2011 – 2013 et comparaison avec la période 2008 – 2010
Authors: F Prat, S Leblanc, A Esch, M Pioche, V Lépilliez, S Chaussade, D Coumaros, G Rahmi, E Chabrun, E Coron, P Bauret, A Charachon, S Bellon, P Bulois, P Bichard, S Koch, E Vaillant, S Farhat, T Ponchon, N Kaddour, F Robin
Journal: Endoscopy (2014)

La dissection endoscopique sous-muqueuse (ESD) est une technique émergente en France. Un registre destiné à apprécier l'état et l'évolution de la pratique de l'ESD a été initié en 2008 sous l'égide de la Sfed; la période 2008 – 2010 a été analysée précédemment (S Farhat et al, Endoscopy 2011; 43: 664 – 70). Ce recueil de données a été poursuivi pour la période 2011 – 2013.
A National Survey of Physician-Assisted Suicide and Euthanasia in the United States
Authors: Diane E. Meier, Carol-Ann Emmons, Sylvan Wallenstein, Timothy Quill, R. Sean Morrison, Christine K. Cassel
Journal: New England Journal of Medicine (1998)

Although there have been many studies of physician-assisted suicide and euthanasia in the United States, national data are lacking.In 1996, we mailed questionnaires to a stratified probability sample of 3102 physicians in the 10 specialties in which doctors are most likely to receive requests from patients for assistance with suicide or euthanasia. We weighted the results to obtain nationally representative data.We received 1902 completed questionnaires (response rate, 61 percent). Eleven percent of the physicians said that under current legal constraints, there were circumstances in which they would be willing to hasten a patient's death by prescribing medication, and 7 percent said that they would provide a lethal injection; 36 percent and 24 percent, respectively, said that they would do so if it were legal. Since entering practice, 18.3 percent of the physicians (unweighted number, 320) reported having received a request from a patient for assistance with suicide and 11.1 percent (unweighted number, 196) had received a request for a lethal injection. Sixteen percent of the physicians receiving such requests (unweighted number, 42), or 3.3 percent of the entire sample, reported that they had written at least one prescription to be used to hasten death, and 4.7 percent (unweighted number, 59), said that they had administered at least one lethal injection.A substantial proportion of physicians in the United States report that they receive requests for physician-assisted suicide and euthanasia, and about 7 percent of those who responded to our survey have complied with such requests at least once.