tbuckley/cabot-search huggingface dataset:
Abstract 2553: Characterization of rare germline variants in somatically mutated melanoma genes in melanoma-prone families.
Authors: Xiaohong (Rose) Yang, Laura Burke, Kevin Jacobs, Michael Cullen, Joseph Boland, Laurie Burdett, Michael Malasky, Melissa Rotunno, Meredith Yeager, Stephen Chanock, Margaret Tucker, Alisa Goldstein
Journal: Cancer Research (2013)

Abstract CDKN2A and CDK4 are the two major susceptibility genes for melanoma identified so far. However, these two genes only account for melanoma susceptibility in a small proportion of melanoma-prone families, suggesting the existence of other susceptibility genes. In addition, melanoma is among the tumors with the highest mutation rate and a large number of mutated genes have been identified that affect multiple key biological pathways. The goal of this study is to examine whether rare germline sequence variants and/or copy number variations (CNVs) in these genes may influence melanoma risk in melanoma-prone families without known CDKN2A/CDK4 mutations. Methods: We conducted exome sequencing in blood-derived DNA in 75 melanoma cases from 23 American melanoma families with ≥3 affected members. We evaluated rare non-synonymous variants, defined as allele frequency less than 0.1% reported in public databases (dbSNP, 1000 Genomes, or NHLBI's Exome Variant Server), in 37 genes (including BRAF, NRAS, KIT,PTEN, CDKN2A, GRIN2A, etc.) that are frequently mutated in melanoma. We also screened CNVs in these genes using data from the Nimblegen 3x720k exon-focused CGH tiling arrays, in which blood-derived DNA from 79 melanoma cases and 25 spouses were analyzed in the same mutation-negative families. We used the Nexus Copy Number™ built-in FASST2 algorithm to identify significant CNVs (significant threshold=0.000001; minimal number of probes per segment=5; log2 ratio&amp;gt;0.3 for gains and -0.3 for losses). Results: We identified 10 rare variants in 10 genes that showed partial/complete co-segregation with disease and were absent in our internal controls (N∼400). Four of these variants occurred in all cases within their respective families and 3 of them were novel. We did not identify any disease-related CNVs in these genes except for a deletion in exon 1β of CDKN2A/ p14ARF in 6 out of 7 melanoma cases in one big family. Our findings suggest that rare variants in somatically mutated genes may confer susceptibility to melanoma risk in a subset of families. However, these variants need to be validated, checked for functional relevance, and evaluated in a large number of cases and controls to determine their role in disease susceptibility. Citation Format: Xiaohong (Rose) Yang, Laura Burke, Kevin Jacobs, Michael Cullen, Joseph Boland, Laurie Burdett, Michael Malasky, Melissa Rotunno, Meredith Yeager, Stephen Chanock, Margaret Tucker, Alisa Goldstein. Characterization of rare germline variants in somatically mutated melanoma genes in melanoma-prone families. [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 2553. doi:10.1158/1538-7445.AM2013-2553
Paediatric cancer stage in population-based cancer registries: the Toronto consensus principles and guidelines
Authors: Sumit Gupta, Joanne F Aitken, Ute Bartels, James Brierley, Mae Dolendo, Paola Friedrich, Soad Fuentes-Alabi, Claudia P Garrido, Gemma Gatta, Mary Gospodarowicz, Thomas Gross, Scott C Howard, Elizabeth Molyneux, Florencia Moreno, Jason D Pole, Kathy Pritchard-Jones, Oscar Ramirez, Lynn A G Ries, Carlos Rodriguez-Galindo, Hee Young Shin, Eva Steliarova-Foucher, Lillian Sung, Eddy Supriyadi, Rajaraman Swaminathan, Julie Torode, Tushar Vora, Tezer Kutluk, A Lindsay Frazier
Journal: The Lancet Oncology (2016)
Case of vaccine-associated measles five weeks post-immunisation, British Columbia, Canada, October 2013
Authors: M Murti, M Krajden, M Petric, J Hiebert, F Hemming, B Hefford, M Bigham, P Van Buynder
Journal: Eurosurveillance (2013)

We describe a case of vaccine-associated measles in a two-year-old patient from British Columbia, Canada, in October 2013, who received her first dose of measles-containing vaccine 37 days prior to onset of prodromal symptoms. Identification of this delayed vaccine-associated case occurred in the context of an outbreak investigation of a measles cluster.
THU0043 AAA-ATPASE P97 Regulates Apoptotic and Autophagy-Associated Cell Death in Arthritis
Authors: M. Kato, K. Klein, C. Ospelt, C. Kolling, M. Kono, S. Yasuda, R.E. Gay, S. Gay, T. Atsumi
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Valosin containing protein (p97/VCP) is an ATPase implicated in the degradation of ubiquitin-labelled proteins through the proteasome. We recently described a resistance to apoptotic cell death induced by proteasome inhibition and a hypersensitivity to autophagy-associated cell death under conditions of severe endoplasmic reticulum (ER) stress in rheumatoid arthritis synovial fibroblasts (RASF) compared to osteoarthritis synovial fibroblasts. <h3>Objectives</h3> To investigate the role of p97 in apoptotic and autophagy-associated cell death in RASF and in in vivo arthritis model. <h3>Methods</h3> RASF were transfected with siRNA targeting p97 or treated with the selective p97 inhibitor DBeQ (5 μM). To induce cell death, RASF were treated with TRAIL (100 ng/ml) for 24 hours or the ER stress inducer thapsigargin (TG, 5 nM-5 μM) for 72 hours. 3-methyladenine (5 mM) was used as an autophagy inhibitor. The distribution and amount of poly-ubiquitinated proteins were evaluated by immunofluorescence and immunoblotting. Cell death was evaluated by flow cytometry using annexin V/ propidium iodide staining and a caspase-3 activity assay (NucView 488, Biotium). Collagen-induced arthritis (CIA) was induced in Lewis rats. Scrambled or p97 siRNA-atelocollagen complexes were injected into ankle joints of rats. CIA was scored according to paw thickness and ankle diameter. Bone erosion was assessed by micro-CT. Proliferation of fibroblasts in rat synovial tissue was quantified by immunolabeling for Hsp47. <h3>Results</h3> siRNA-mediated knockdown of p97 in RASF increased cell death induced by TRAIL (p=0.009, n=6), accompanied by caspase-3 activation. Both siRNA-mediated knockdown and inhibition of p97 in RASF boosted cell death induced by 5 μM TG, accompanied by a massive cytoplasmic vacuolization, the formation of poly-ubiquitinated protein aggregates and the accumulation of poly-ubiquitinated proteins, and cell death was inhibited by 3-methyladenine. Smaller amounts of TG (50 or 500 nM) induced a cytoplasmic vacuolization and the formation of poly-ubiquitinated protein aggregates in p97-inhibited RASF but not in control RASF. Intra-articular injection of p97 siRNA significantly suppressed CIA (p=0.002, n=6), bone erosion (p=0.02, n=6) and proliferation of synovial fibroblasts (p=0.004, n=6) in rats. <h3>Conclusions</h3> Our data indicate that the inhibition of p97 promotes both apoptotic and autophagy-associated cell death in RASF and suppresses CIA, bone erosion and proliferation of synovial fibroblasts in vivo. p97 may be a new potential target in the treatment of arthritis. <h3>References</h3> Kato M, et al. Arthritis Rheum 2014 Jan;66(1):40-8. <h3>Acknowledgements</h3> This work was supported by MHLW, MEXT, IMI-BT Cure, IAR Epalinges, euroTEAM. <h3>Disclosure of Interest</h3> None declared
FRI0219 Optimisation of Interface Management between General Practitioners and Rheumatologists - Results of A Survey
Authors: R. Puchner, E. Mur, M. Edlinger, G. Eberl, K. Machold
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> We aimed to assess the views of general practitioners (GPs) and rheumatologists in Austria on how to optimize their cooperation in handling rheumatic patients. <h3>Methods</h3> A questionnaire covering aspects of collaboration between GPs and rheumatologists, was sent to all 4016 GPs and 180 internal rheumatologists in Austria. Topics covered were (i) examinations and interventions to be performed by GPs before referral, (ii) the spectrum of diseases to be referred, and (iii) the role of GPs in prescribing drugs and follow-up of patients. <h3>Results</h3> 1229 GPs and 110 rheumatologists responded to the questionnaire. In cases of suspected arthritis, 99% of the GPs and 92% of the rheumatologists recommended laboratory tests and 92% and 70%, respectively required X-rays of affected joints before referral. Beyond rheumatoid arthritis and spondyloarthritis, psoriatic arthritis and connective tissue disease were seen unanimously as indications for presentation to a rheumatologist in any case. Only 22% of rheumatologists felt responsible for treatment of hand osteoarthritis and fibromyalgia. Some 80% of GPs and 85% of rheumatologists agreed that treatment with synthetic or biological disease modifying drugs should be initiated by a specialist. Subsequent drug prescription and administration by GPs was supported by a majority of GPs and rheumatologists, with concomitant rheumatologist follow-up every three to six months. In case of disease flare 87% of the GPs and 50% of the rheumatologists recommended the GP to be seen first, in case of drug toxicity, 77% and 48% respectively. <h3>Conclusions</h3> The results of the survey show a substantial need to clearly define shared roles between rheumatologists and GPs in care of patients with rheumatic diseases. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4704
158 RESPONSE PREDICTION IN CHRONIC HEPATITIS C AFTER LIVER TRANSPLANT BY ASSESSMENT ENT-1-RELATED SINGLE NUCLEOTIDE POLYMORPHISMS
Authors: V. Giannelli, U. Visco Comandini, M. Simmaco, M. Giusto, G. Gentile, L. Lionetto, S. Ginanni Corradini, A. Molinaro, E. Biliotti, A.F. Attili, G. Taliani, M. Merli
Journal: Journal of Hepatology (2013)
In Vivo and In Vitro Evidence of Somatostatin Receptors Expression in a Dedifferentiated Retroperitoneal Liposarcoma
Authors: Alessio Imperiale, Marie-Pierre Chenard, Serge Rohr, Anne Barlier, Bernard Goichot
Journal: Clinical Nuclear Medicine (2014)

A 62-year-old patient presented with mildly elevated catecholamines and an abdominal painless mass. Abdominal CT revealed an 18 × 12 cm tumor in the right retroperitoneum with intense contrast enhancement. Somatostatin receptor scintigraphy (SRS) showed pathologic uptake by the lesion. Given the suspicion of paraganglioma, the patient was referred to surgery for tumor removal. Surprisingly, the histopathological examination revealed a dedifferentiated liposarcoma. Somatostatin receptors of type 2 were identified and quantified by reverse transcription polymerase chain reaction. The unexpected presentation of our patient draws clinicians' attention when performing diagnostic procedure for retroperitoneal lesions, even though hormone secretion and positive SRS strongly suggest paraganglioma.
P3-14-07: Relative Risk of Recurrence (RR) over Time in ER Positive and Negative T4 Breast Cancer Patients Achieving Less Than pCR (&amp;lt;pCR) after Primary Chemotherapy: A Reversal Trend of Recurrence beyond 60 Months after Diagnosis.
Authors: MT Ionta, F Atzori, V Pusceddu, F Notari, E Valle, D Guerzoni, A Chiappe, M Marongiu, L Minerba, B Massidda
Journal: Cancer Research (2011)

Abstract Background It is widely assumed that patients (pts) who achieve a pCR have a good prognosis and better outcomes compared with pts with &amp;lt;pCR, regardless of hormone receptor status. Emerging data suggest that achieving &amp;lt;pCR identifies a heterogeneous group with different risks of recurrence and death, being ER negative the subgroup with the worst prognosis. Aim of our study was to evaluate the relative risk of recurrence (RR) over time in ER-positive (ER+) and ER-negative (ER-) &amp;lt;pCR patients. Material and Methods: We analyzed 139 consecutive &amp;lt;pCR T4 pts, of whom 85 were ER+ (cut-off 10%) and 54 were ER-. Median age was 53 y ( range 29–73). Median follow up was 137 months (range 8–233). All pts received primary anthra-based chemotherapy with or without taxanes followed by endocrine therapy for 5 years, if hormone receptor positive. We examined the RR of recurrence at 0–24, 25–60, 61–120 and beyond 120 months (m) interval after diagnosis. Results: For all 139 pts, the total number of pts with recurrence was 95 (68%), 54 (63%) in ER+ and 41 (76%) in ER-.tumors. For the entire group and both in ER+ and in ER-, the RR of recurrence was greatest for the interval between 0–24 months, then decreased rapidly in ER- and slowly in ER+ through the 25–120 m interval. For the 0–24 m and 25–60 m intervals the RR of recurrence was higher for ER-pts and after 60 m it crossed and beyond 60 m the RR of recurrence was higher in ER+ than in ER- pts. Notably, beyond 120 months we observed a little second peak of recurrence, higher in ER+ (7) than in ER- (3) pts. Nine of these 10 relapses occurred between 120 to 180 m interval, 7 in ER+ (13%) and 2 in ER- (5%) subgroup. In the first 24 m ER- pts were 86% more likely to relapse compared with ER+, vice versa between 61–120 and beyond 120 m intervals, ER- pts were 19% and 18% less likely to relapse, respectively, compared with ER+ pts. Conclusions: The present study confirmed the previous reports which showed unfavorable prognosis of the &amp;lt;pCR patients with negative ER status, due to their significantly higher relative risk of recurrence between 0 to 60 months interval. The ER+ recurrences occurred more frequently in late follow-up. A reversal of recurrence between ER positive and negative patients beyond 60 months after diagnosis was detected. The fact might indicate the importance of long term adjuvant hormone therapy for T4 ER positive breast cancer patients with &amp;lt;pCR after primary chemotherapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-07.
IMPACT OF TYPE OF EPICARDIAL CORONARY SPASM DURING INTRACORONARY ACETYLCHOLINE PROVOCATION TEST
Authors: Yuichi Saito, Hideki Kitahara, Toshihiro Shoji, Satoshi Tokimasa, Takashi Nakayama, Yoshihide Fujimoto, Yoshio Kobayashi
Journal: Journal of the American College of Cardiology (2016)
A rare presentation of esophageal actinomycosis in an immunocompetent patient
Authors: H. Korkmaz, U. Kutluana, M. Bugdaci, I. Kucukosmanoglu
Journal: Endoscopy (2013)

A 56-year-old man was referred to our hospital with a 2-month history of odynophagia, heartburn, and dysphagia. His physical examination was normal. Laboratory investigations showed a normal complete blood count, normal biochemistry panel, and negative serology for human immunodeficiency virus (HIV).
The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure
Authors: Milton Packer, Michael R. Bristow, Jay N. Cohn, Wilson S. Colucci, Michael B. Fowler, Edward M. Gilbert, Neil H. Shusterman
Journal: New England Journal of Medicine (1996)

Controlled clinical trials have shown that beta-blockers can produce hemodynamic and symptomatic improvement in chronic heart failure, but the effect of these drugs on survival has not been determined.
Preventing Weight Gain in Women in Rural Communities: A Cluster Randomised Controlled Trial
Authors: Catherine Lombard, Cheryce Harrison, Samantha Kozica, Sophia Zoungas, Sanjeeva Ranasinha, Helena Teede
Journal: PLoS Medicine (2016)

Background Obesity is reaching epidemic proportions in both developed and developing countries. Even modest weight gain increases the risk for chronic illness, yet evidence-based interventions to prevent weight gain are rare. This trial will determine if a simple low-intensity intervention can prevent weight gain in women compared to general health information. Methods and Findings We conducted a 1-yr pragmatic, cluster randomised controlled trial in 41 Australian towns (clusters) randomised using a computer-generated randomisation list for intervention (n = 21) or control (n = 20). Women aged 18 to 50 yr were recruited from the general population to receive a 1-yr self-management lifestyle intervention (HeLP-her) consisting of one group session, monthly SMS text messages, one phone coaching session, and a program manual, or to a control group receiving one general women's health education session. From October 2012 to April 2014 we studied 649 women, mean age 39.6 yr (+/− SD 6.7) and BMI of 28.8 kg/m2 (+/− SD 6.9) with the primary outcome weight change between groups at 1 yr. The mean change in the control was +0.44 kg (95% CI −0.09 to 0.97) and in the intervention group −0.48kg (95% CI −0.99 to 0.03) with an unadjusted between group difference of −0.92 kg (95% CI −1.67 to −0.16) or −0.87 kg (95% CI −1.62 to −0.13) adjusted for baseline values and clustering. Secondary outcomes included improved diet quality and greater self-management behaviours. The intervention appeared to be equally efficacious across all age, BMI, income, and education subgroups. Loss to follow-up included 23.8% in the intervention group and 21.8% in the control group and was within the anticipated range. Limitations include lack of sensitive tools to measure the small changes to energy intake and physical activity. Those who gained weight may have been less inclined to return for 1 yr weight measures. Conclusions A low intensity lifestyle program can prevent the persistent weight gain observed in women. Key features included community integration, nonprescriptive simple health messages, small changes to behaviour, low participant burden, self-weighing, and delivery including a mix of group, phone, and SMS text reminders. The findings support population strategies to halt the rise in obesity prevalence.
618 GLOMERULAR FILTRATION RATE PERFORMS BETTER COMPARED TO MELD SCORE IN PATIENTS WITH DECOMPENSATED CIRRHOSIS
Authors: E. Cholongitas, G. Arsos, J. Goulis, T. Nakouti, J. Kouvelis, J. Tsechelidis, C. Birtsou, K. Karakatsanis, E. Akriviadis
Journal: Journal of Hepatology (2012)
381 DLL4 AND JAGGED-1 PROVIDE OPPOSING EFFECTS IN LIVER FIBROSIS
Authors: Y. Liu, Z. Shen, M.-Y. Xu, C. Meyer, A. Müller, S. Munker, Q. Li, I. Ilkavets, C. Stump, R. Müllenbach, V. Zimmer, F. Lammert, P.R. Mertens, J. Li, Y.-M. Li, L.-G. Lu, S. Dooley, H.-L. Weng
Journal: Journal of Hepatology (2012)
Mevalonic Aciduria — An Inborn Error of Cholesterol and Nonsterol Isoprene Biosynthesis
Authors: Georg Hoffmann, Kenneth M. Gibson, Ira K. Brandt, Patricia I. Bader, Rebecca S. Wappner, Lawrence Sweetman
Journal: New England Journal of Medicine (1986)

A two-year-old boy presented with severe failure to thrive, developmental delay, anemia, hepatosplenomegaly, central cataracts, and dysmorphic features. Quantitative analyses of urinary organic acids revealed massive excretion of mevalonic acid, a metabolic precursor of cholesterol and nonsterol isoprenes: 46,000 to 56,200 mmol per mole of creatinine, as compared with 0.2 to 0.3 mmol per mole in normal children. The mevalonic acid concentration in plasma was also greatly increased at 440 μmol per liter (normal, <0.05). The activity of mevalonate kinase, the enzyme that catalyzes the first step in mevalonate metabolism, was severely deficient in the patient's fibroblasts, lymphocytes, and lymphoblasts. In the subsequent pregnancy of the patient's mother, gas chromatography–mass spectrometry demonstrated a marked elevation of mevalonic acid in the mother's urine and a 3000-fold elevation, as compared with control levels in the amniotic fluid, suggesting that the fetus was affected. The diagnosis was confirmed by demonstration of the deficiency of mevalonate kinase in amniocytes and ultimately in liver from the abortus. Intermediate activities of the enzyme in both parents indicated an autosomal recessive mode of inheritance. These observations identify an inherited disorder of cholesterol and nonsterol isoprene biosynthesis in humans. (N Engl J Med 1986; 314: 1610–4.)
PTU-079 The Tpmt And Abcb1 Polymorphisms In Ibd Patients In Crete: Impact On Disease And Response To Treatment
Authors: C Coucoutsi, O Sfakianaki, G Emmanuel, E Marinidou, A Voumvouraki, I Koutroubakis, E Kouroumalis
Journal: Gut (2014)

<h3>Introduction</h3> It is well known that polymorphisms of the TPMT gene (coding for thiopourine methyl-transferase), influence response to treatment with azathioprine. Polymorphisms of the ABCB1 gene (coding for p-glycoprotein 170) has been associated with IBD and resistance to treatment but results are conflicting. The aim of this study was to determine the frequencies of TPMT and ABCB1 gene polymorphisms in IBD patients from Crete, a population genetically homogeneous, and how these polymorphisms might influence response to treatment and disease behaviour. <h3>Methods</h3> A total of 222 IBD patients records were reviewed for intake of azathioprine, possible adverse reactions, response to treatment and need for colectomy. All patients were genotyped for TPMT gene polymorphisms, that have been related to intolerance to azathioprine (G238C, G460A and A719C) as well as ABCB1 gene polymorphisms (G2677T/A and C3435T), using a PCR-RFLP method. The same polymorphisms were also determined in 119 age and sex healthy controls. <h3>Results</h3> Allele frequencies of TPMT gene in our study population were found to be in concordance with those reported in other Caucasian populations. 76 IBD patients were identified receiving azathioprine, of whom 16 were discontinued (10 CD, 6 UC) due to adverse reaction. 2 of them were found to carry the G460A and A719G alleles (TPMT 3A genotype) (12.5%). For the ABCB1 gene, G2677T/A allele frequencies were found to be similar to those reported in the literature. There was no association of G2677T/A or C3435T with clinical phenotype, or resistance to treatment. However, 77.3% of 22/222 patients who did not respond to therapy and required surgery, where found to carry both the C3434T and the G2677T mutation. <h3>Conclusion</h3> Our study was conducted in a genetically homogenous population in the island of Crete. No correlation of any single SNP was found with either clinical activity or response to treatment. However, most patients who carried both the G2677T and C3435T mutations were refractory to treatment, a finding which implies that resistance to treatment in IBD patients is a more complex issue, which requires the presence of a genetic locus rather than a single SNP. <h3>Disclosure of Interest</h3> None Declared.