tbuckley/cabot-search huggingface dataset:
A FANCD2/FANCI-Associated Nuclease 1-Knockout Model Develops Karyomegalic Interstitial Nephritis
Authors: Rannar Airik, Markus Schueler, Merlin Airik, Jang Cho, Jonathan D. Porath, Elina Mukherjee, Sunder Sims-Lucas, Friedhelm Hildebrandt
Journal: Journal of the American Society of Nephrology (2016)

Karyomegalic interstitial nephritis (KIN) is a chronic interstitial nephropathy characterized by tubulointerstitial nephritis and formation of enlarged nuclei in the kidneys and other tissues. We recently reported that recessive mutations in the gene encoding FANCD2/FANCI-associated nuclease 1 (FAN1) cause KIN in humans. FAN1 is a major component of the Fanconi anemia–related pathway of DNA damage response (DDR) signaling. To study the pathogenesis of KIN, we generated a Fan1 knockout mouse model, with abrogation of Fan1 expression confirmed by quantitative RT-PCR. Challenging Fan1−/− and wild-type mice with 20 mg/kg cisplatin caused AKI in both genotypes. In contrast, chronic injection of cisplatin at 2 mg/kg induced KIN that led to renal failure within 5 weeks in Fan1−/− mice but not in wild-type mice. Cell culture studies showed decreased survival and reduced colony formation of Fan1−/− mouse embryonic fibroblasts and bone marrow mesenchymal stem cells compared with wild-type counterparts in response to treatment with genotoxic agents, suggesting that FAN1 mutations cause chemosensitivity and bone marrow failure. Our data show that Fan1 is involved in the physiologic response of kidney tubular cells to DNA damage, which contributes to the pathogenesis of CKD. Moreover, Fan1−/− mice provide a new model with which to study the pathomechanisms of CKD.
Vaccination against Lyme Disease with Recombinant<i>Borrelia burgdorferi</i>Outer-Surface Lipoprotein A with Adjuvant
Authors: Allen C. Steere, Vijay K. Sikand, François Meurice, Dennis L. Parenti, Erol Fikrig, Robert T. Schoen, John Nowakowski, Christopher H. Schmid, Sabine Laukamp, Charles Buscarino, David S. Krause
Journal: New England Journal of Medicine (1998)

The risk of acquiring Lyme disease is high in areas in which the disease is endemic, and the development of a safe and effective vaccine is therefore important.
An 11 Gene Q-PCR Assay to Sub-Stratify Breast Tumors Into Categories Useful in Deciding Anti-HER-2 Therapies
Authors: K. Aruna, J.S. Prabhu, K. Desai, S. Manjunath, M. Correa, K.S. Gopinath, B.S. Srinath, A. Mehta, D.C. Doval, T.S. Sridhar
Journal: Annals of Oncology (2013)
Abstract 2123: Novel integration sites for Friend murine leukemia virus
Authors: Mehran Haeri, Yaacov Ben-David
Journal: Cancer Research (2010)

Abstract Background: Friend murine leukemia virus (F-MuLV), a type C retrovirus, induces erythroleukemia when injected into certain strains of mice. The Induction of erythroleukemia is associated with viral integration into Friend leukemia integration site-1 (Fli-1). In some F-MuLV-infected mice we did not observe viral integration into Fli-1 region by Southern blot analysis. We hypothesize that induction of leukemia in these mice is due to insertion of F-MuLV into a novel integration site distinct from Fli-1. Methods: The genomic DNA of F-MuLV-induced leukemic cells is digested by StuI restriction enzyme. DNA sequences of about 50 base pairs in length, termed adaptors, are then ligated to both ends of the digested fragments. Using primers for the adaptors and F-MuLV sequences, we performed PCR, followed by nested PCR to amplify those fragments that contain F-MuLV sequence. The PCR product is gel purified, cloned into a TA vector and sequenced. The sequences are compared to mouse genome databank to determine the F-MuLV flanking sequences. Results: We identified seven novel integration sites for F-MuLV. Three of these sites are located inside genes and the remaining four do not interrupt any genes. We performed PCR to check if any of these integration sites were also targets of F-MuLV in twenty other tumors of the same type. We found that one of these integration sites which is close to Myb gene occurred in twenty five percent of the tested tumors in an area 1 kb in length. Conclusion: We identified seven novel F-MuLV integration sites for F-MuLV. We showed that the integration site on chromosome 10 close to the Myb gene occurs in 25% of F-MuLV- induced tumors and is therefore a common integration site. 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 2123.
Diagnostic ileoscopy assisting in the diagnosis of Whipple's disease
Authors: J. Dinis Silva, V. Fernandes, M. Alves, J. Freitas
Journal: Endoscopy (2013)

A 70-year-old white man had been aware of mild memory loss, arthralgia, and altered bowel habits for 3 years prior to his referral. His gastrointestinal symptoms had worsened during the 2-month period preceding his referral, with diarrhea (five to six bowel movements of fatty stools per day) and a 4-kg weight loss. His laboratory workup, including thyroid function and human immunodeficiency virus (HIV) screening, was unremarkable. Colonoscopy showed normal colonic mucosa but ileoscopy revealed a diffuse brown appearance of the mucosa with scattered white plaques ([Fig. 1]).
Radioiodine Uptake in Rheumatoid Arthritis-Associated Lung Disease Mimicking Thyroid Cancer Metastases
Authors: SIEMA M.B. BAKHEET, MUHAMMAD M. HAMMAMI, JOHN POWE
Journal: Clinical Nuclear Medicine (1998)

We report an 8-year-old girl in remission from thyroid cancer who, on follow-up whole body scan, showed focal radioiodine uptake in the lungs due to rheumatoid lung disease. In a patient with differentiated thyroid cancer, radioiodine chest uptake does not always represent pulmonary metastases. It could be due to unrelated lung pathology, such as rheumatoid arthritis-associated lung disease.
PWE-106 Association Study Of Il23R And Atg16L1 Variants In Ibd Moroccan Patients
Authors: N Serbati, N Senhaji, B Diakite, W Badre, S Nadifi
Journal: Gut (2013)

<h3>Introduction</h3> IBD (Crohn’s disease and Ulcerative Colitis) is chronic and multifactorial disease of the gastrointestinal tract. Although several studies have tried to explore these diseases, their pathogenesis is still unclear. Recently, CD has been associated with the variants in interleukin 23 receptor (<i>IL23R</i>) and autophagy-related 16-like 1 (<i>ATG16L1</i>) genes. The aim of our study was to assess the frequency of ATG16L1 (T300A) and IL23R (L310P) variants in Moroccan IBD patients and to determine a possible effect of these variants on Disease’s phenotype and clinical course. <h3>Methods</h3> we genotyped a group of 96 Moroccan IBD patients and 114 unrelated volunteers for <i>ATG16L1</i>(T300A) and <i>IL23R</i> (L310P) variants. <h3>Results</h3> Our results showed no significantly increased risk of Crohn’s disease among individuals carrying the GG genotype or the G allele for the (Thr300Ala) polymorphism, in contrast to the (L310P) polymorphism which confers a protective effect. We also noticed the presence of a positive correlation between Crohn’s disease Type and ATG16L1 polymorphism. For UC, the carriage of the mutated allele in the ATG16L1 gene confers a protective effect. <h3>Conclusion</h3> Our results showed a limited role of <i>ATG16L1</i> and <i>IL23R</i> variants in the Moroccan population <h3>Disclosure of Interest</h3> None Declared.
Development and initial validation of an endoscopic part-task training box
Authors: Christopher Thompson, Pichamol Jirapinyo, Nitin Kumar, Amy Ou, Andrew Camacho, Balazs Lengyel, Michele Ryan
Journal: Endoscopy (2014)

<b>Background and study aims:</b> There is currently no objective and validated methodology available to assess the progress of endoscopy trainees or to determine when technical competence has been achieved. The aims of the current study were to develop an endoscopic part-task simulator and to assess scoring system validity. <b>Methods:</b> Fundamental endoscopic skills were determined via kinematic analysis, literature review, and expert interviews. Simulator prototypes and scoring systems were developed to reflect these skills. Validity evidence for content, internal structure, and response process was evaluated. <b>Results:</b> The final training box consisted of five modules (knob control, torque, retroflexion, polypectomy, and navigation and loop reduction). A total of 5 minutes were permitted per module with extra points for early completion. Content validity index (CVI)-realism was 0.88, CVI-relevance was 1.00, and CVI-representativeness was 0.88, giving a composite CVI of 0.92. Overall, 82 % of participants considered the simulator to be capable of differentiating between ability levels, and 93 % thought the simulator should be used to assess ability prior to performing procedures in patients. Inter-item assessment revealed correlations from 0.67 to 0.93, suggesting that tasks were sufficiently correlated to assess the same underlying construct, with each task remaining independent. Each module represented 16.0 % – 26.1 % of the total score, suggesting that no module contributed disproportionately to the composite score. Average box scores were 272.6 and 284.4 (<i>P</i> = 0.94) when performed sequentially, and average score for all participants with proctor 1 was 297.6 and 308.1 with proctor 2 (<i>P</i> = 0.94), suggesting reproducibility and minimal error associated with test administration. <b>Conclusion:</b> A part-task training box and scoring system were developed to assess fundamental endoscopic skills, and validity evidence regarding content, internal structure, and response process was demonstrated.
Abstract 3900: Discovery of FQIT: An imidazo[5,1-<i>f</i>][1,2,4]triazine derived dual IGF-1R/IR inhibitor
Authors: Meizhong Jin, Prafulla Gokhale, Andy Cooke, Kenneth Foreman, Elizabeth Buck, Earl May, Lixing Feng, Mark Bittner, Mridula Kadalbajoo, Darla Landfair, Kam Siu, Kathryn Stolz, Douglas Werner, Radoslaw Laufer, An-Hu Li, Hanqing Dong, Arno Steinig, Andrew Kleinberg, Yan Yao, Jonathan Pachter, Robert Wild, Mark Mulvihill
Journal: Cancer Research (2012)

Abstract Insulin-like growth factor-1 receptor (IGF-1R) has been recognized as a major target in cancer drug discovery due to its strong implications in various stages of tumorigenesis based on accumulated preclinical data over the years. Recent research on compensatory crosstalk between IGF-1R and insulin receptor (IR) signaling pathways suggests that targeting both receptors is critical to fully blocking the IGF signaling axis. Therefore, inhibition of both receptors is anticipated to result in a more therapeutically beneficial response than targeting IGF-1R alone (e.g. IGF-1R specific antibodies). These findings provided the biological rationale as well as set the foundation for the pursuit and ultimate discovery of OSI-906 (linsitinib), a small molecule dual IGF-1R/IR inhibitor currently in clinical development. As part of OSI's ongoing investment in a small molecule drug discovery platform targeting IGF-1R and IR, a new series of potent and selective imidazo[5,1-f][1,2,4]triazine derived inhibitors of IGF-1R and IR have been identified. Structure-activity relationships and optimization driven by structure-based drug design (SBDD) leading to the discovery of FQIT, a potent, highly selective, well-tolerated and orally bioavailable dual inhibitor of IGF-1R and IR with in vivo efficacy in multiple tumor xenograft models will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3900. doi:1538-7445.AM2012-3900
AB0914 Bone mass and MMP3/TIMP in ankylosing spondylitis
Authors: V. Dhir, R. Srivastava, A. Aggarwal
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> There is some data to suggest that bone mineral density is lower in patients with ankylosing spondylitis. The mechanism could be increased matrix metalloproteinase 3 (MMP-3) activity and/or lower inhibitor levels (TIMP). <h3>Objectives</h3> To compare bone mineral density of ankylosing spondylitis patients with published Indian standards. Also to compare MMP-3/TIMP ratio with controls. <h3>Methods</h3> Patients who fulfilled modified New York criteria and gave consent were recruited. Bone mineral density was done using a Hologic DXA system. These were compared to published Indian standards (ICMR) of healthy young individuals (1). Levels of MMP-3 and TIMP in serum were determined using ELISA in both patients as well as 20 healthy controls (RnD Duo Set). Statistical analysis was done by using student t test for difference in means, correlation by pearsons correlation. Values are in mean (±SD). <h3>Results</h3> 48 patients (M: F=46:2) of ankylosing spondylitis with age 33.7 (±10.1) years were enrolled. Disease duration was 11.2 (±6.0) years and duration of diagnosis 3.3 (±4.1) years. Mean BASDAI was 3.5 (±2.0), BASFI 3.2 (±2.3) and BASMI 2.3 (±2.3). Bone mineral density in patients compared to published Indian standards was not different in the spine (0.907±0.39, 0.976±0.105g/cm<sup>2</sup>, p=0.34) or forearm (0.604±0.063, 0.611±0.052 g/cm<sup>2</sup>, p=0.35) but was lower in the hip (0.846±0.130, 0.988±0.131 g/cm<sup>2</sup>, p=0.02). In patients as compared to controls, both serum MMP-3 (90.5±95.8, 55.9±37.1 ng/ml, p=0.04) and TIMP levels were higher (622.8±551.1, 296.5±114.2 ng/ml, p&lt;0.001). However, there was no difference in the MMP-3/TIMP ratio (0.20±0.22, 0.20±0.14, p=0.95). Among patients, there was a negative correlation between the BMD of the hip and MMP/TIMP (r=-0.29, p=0.04) and BMD of forearm with MMP3/TIMP (r=-0.43, p=0.002). But there was a positive correlation with the BMD spine (r=0.41, p=0.003). There was no significant correlation between the ESR or BASDAI with MMP-3, TIMP or MMP-3/TIMP ratio. <h3>Conclusions</h3> There is mild reduction of bone mineral density only in the hip in patients of ankylosing spondylitis compared to published Indian standards. Although both MMP-3 and TIMP are higher in patients, there is no difference in the MMP3/TIMP ratio compared to controls. <h3>References</h3> New Delhi: ICMR: Published by Director General; 2010. Population based reference standards of Peak Bone Mineral Density of Indian males and females – an ICMR multi-center task force study; pp. 1–24. <h3>Disclosure of Interest</h3> None Declared
INCREASED RELIANCE ON RIGHT ATRIAL ACTIVE EMPTYING FRACTION IS ASSOCIATED WITH DECREASED EVENT FREE SURVIVAL IN CHILDREN WITH PULMONARY ARTERIAL HYPERTENSION
Authors: Shine Kumar, Prashant Bobhate, Shreepal Jain, Long Guo, Timothy Colen, Jean Trines, Nee Scze Khoo, Ian Adatia
Journal: Journal of the American College of Cardiology (2015)
A10.26 Synovial Wnt and WISP1 Expression Induces Expression of Cartilage-Degrading Metalloproteinases in the Synovium
Authors: M van den Bosch, A Blom, A van Erp, F van de Loo, E Blaney Davidson, P van der Kraan, P van Lent, W van den Berg
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Many osteoarthritis (OA) patients show synovial involvement. We found strong upregulation of Wnts 2b and 16 and the downstream protein WISP1 in knee joints in experimental OA. The role of the synovium in the induction of OA pathology under the influence of Wnt signalling is unclear. Here we investigated the potential of Wnt signalling to increase the expression of cartilage-degrading enzymes in the synovium. <h3>Methods</h3> Pathway analysis of microarray data from the synovium of a collagenase-induced OA mouse model was done using DAVID software. In vivo synovial overexpression of genes from the canonical Wnt signalling pathway was achieved by intra-articular injection of adenoviral vectors. Joint pathology was assessed by histology. Gene expression was analysed by qPCR. Human OA synovial specimens were collected from joint replacement surgery and stimulated or used for outgrowth of fibroblasts. <h3>Results</h3> Pathway analysis showed that the Wnt signalling pathway was enriched in the synovium during experimental OA. To determine the effects of Wnt signalling on synovial tissue, we stimulated human OA synovial specimen with Wnt3a or WISP1, which resulted in increased expression of MMP3, MMP9 and MMP13, whereas expression of TIMP1 and 3 was not altered. Next, we investigated which cell-type in the synovium may cause the increased MMP expression. Stimulation of synovial OA fibroblasts with Wnt3a increased the expression of MMP3 and MMP13, whereas WISP1 led to increased MMP3 expression. Stimulation of THP-1 cells with Wnt3a resulted in highly increased MMP3, MMP9 and MMP13 expression. WISP1 stimulation led to increased expression of MMP3. TIMP1 and 3 expression was not altered. Synovial overexpression of Wnt8a, Wnt16 and WISP1 in murine knee joints with use of adenoviral vectors led to cartilage damage in vivo. 7 days after overexpression, we found a significant induction of OA pathology at the medial margin of the medial tibial plateau, a preferential site for damage in experimental OA. Lesions were found in 92% (n = 12) of the knee joints after Wnt8a overexpression compared to 17% (N = 12) for the control virus and 80% (N = 5) for Wnt16 overexpression, but only 20% (N = 5) for the control virus. In addition, overexpression of WISP1 led to significantly increased cartilage damage after 7 days. <h3>Conclusions</h3> Canonical Wnts produced in the synovium may play an important role in OA pathology by increasing the expression of cartilage-degrading MMPs in synovial tissue, where fibroblasts and macrophages showed comparable patterns of MMP induction. Synovium-specific overexpression of Wnt signalling members induces cartilage damage.
PTU-051 Odynophagia – A Symptom Worth Asking About?
Authors: S Subramaniam, G Goodchild, K Besherdas
Journal: Gut (2014)

<h3>Introduction</h3> Odynophagia can be defined as a painful sensation in the oesophageal region that occurs in relation to swallowing. Unlike dysphagia, which has historically been an alarm symptom or warning sign of oesophageal cancer, odynophagia is not classified as an alarm symptom and does not form part of the suspected upper gastrointestinal (GI) cancer referral form in the UK. Endoscopy is the gold standard imaging modality for the diagnosis of mucosal lesions in the oesophagus. However, there is no clear data regarding the findings at endoscopy in patients scoped for odynophagia. Mucosal abnormalities even in the presence of typical symptoms of gastro-oesophageal reflux disease, namely heartburn and regurgitation are absent in up to 70%. We hypothesise that the presence of odynophagia has a high predictive value of mucosal abnormality at endoscopy and aimed to assess the findings at endoscopy for patients scoped for odynophagia. <h3>Methods</h3> A retrospective analysis of all patients who underwent upper GI endoscopy for odynophagia as a primary symptom over an 8-year period (2005–2013) within an NHS Trust in north London was performed. Data was obtained from the Unisoft Endoscopy reporting software. The findings at endoscopy in patients with odynophagia were scrutinised. <h3>Results</h3> 50 patients were endoscoped for odynophagia during the study period. 34 of 50 patients (68%) had oesophageal mucosal lesions (4 Barrett’s mucosa, 2 candida oesophagitis, 14 reflux oesophagitis, 6 malignant tumour, 5 oesophageal stricture, 3 oesophageal ulcers). 12% (6 of 50) had oesophageal cancer. A further 10 had hiatus hernia, 1 had a motility disorder and 1 had oesophageal diverticulum. <h3>Conclusion</h3> From this study, 68% of patients endoscoped for odynophagia have a positive endoscopic mucosal abnormality. Odynophagia as a symptom has a high sensitivity for abnormal endoscopy. 12% of patients endoscoped for odynophagia had oesophageal cancer. This prevalence is similar to the diagnosis of cancer in patients referred on the ‘two week wait upper GI cancer referral form’. We recommend the symptom of odynophagia be classified as an alarm symptom and those presenting with odynophagia all undergo upper GI endoscopy to define the exact mucosal abnormality and exclude oesophageal cancer. <h3>Disclosure of Interest</h3> None Declared.
Abstract A61: 14-3-3gamma transforming ability is determined by a motif outside the conserved phosphoamio-acid binding domain
Authors: Vijayababu M. Radhakrishnan, Charles W. Putnam, Jesse D. Martinez
Journal: Cancer Research (2011)

Abstract The 14-3-3 proteins are a set of seven highly conserved scaffolding proteins that have been implicated as having a role in human tumorigenesis. However, despite the striking similarity of amino acid sequences and structures of the eukaryotic 14-3-3 family of proteins, there is increasing evidence that the seven human isoforms manifest disparate functions. For instance 14-3-3gamma functions as an oncogene and 14-3-3sigma acts as a tumor suppressor. To gain insight into how specific functions are manifested we constructed chimeric proteins by swaping various regions between gamma and sigma. Chimeric proteins were then utilized in NIH3T3 cell transformation assays. We found that transforming ability was associated with a small variable 40 amino acid region in the N-terminus of the gamma protein and that the transforming ability of gamma was dominant to the tumor suppressor activity of sigma. Importantly, the transforming motif was located outside the conserved 14-3-3 phosphoamino acid binding motif. Hence, transforming ability of 14-3-3 proteins is determined by a variable region that does not involve the phosphoamino acid binding site. 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 A61.
Endoscopic retrieval of a toothbrush in the esophagus
Authors: Benjamin Disney, Sharanabasappa Shetty
Journal: Endoscopy (2014)

A 55-year-old woman presented to the hospital following the unintentional swallowing of a toothbrush. The patient had been feeling nauseous and had tried to self-induce vomiting by inserting the toothbrush, having failed with her fingers. The patient had introduced the toothbrush into the oropharynx, which initiated a swallow during which the patient lost her grip of the toothbrush handle. The patient developed subsequent chest discomfort. She was still able to swallow fluids and saliva. There were no underlying medical or psychiatric problems.