tbuckley/cabot-search huggingface dataset:
Abstract SY21-02: DNA methylation and epigenetic instability in human cancer
Authors: Andrew P. Feinberg
Journal: Cancer Research (2012)

Abstract Alterations in DNA methylation in human cancer were identified 30 years ago but a comprehensive view has emerged with the advent of whole genome bisulfite sequencing. While cancer can be viewed as over 200 distinct diseases that are organ-specific in their pathology, and mutation-specific in their molecular mechanism, recent discoveries in cancer epigenetics suggest a different but complementary view. Epigenetically, cancer may approach a single disorder with certain common features underlying the major reasons for cancer morbidity and mortality. Specifically, several common solid tumor types show increased epigenetic instability in DNA methylation at specific loci but involving the same loci in many different tumor types, and these loci appear to be critical for unregulated cell growth and tissue invasion and metastasis, and they involve the boundaries between CpG islands and shores, as well as large hypomethylated genomic blocks. These blocks correspond to large organized chromatin lysine (K) -modified domains (LOCKs) that are normally modulated during cellular reprogramming in development and epithelial-mesenchymal transition. We suggest a unifying model for the epigenetic basis of cancer in which increased instability in gene expression is mediated by loss in cancer of nuclear structures that control variance during normal development, such as LOCKs and CpG island boundaries. By this view, stochastic noise is a necessary part of cell fate determination leading to Waddingtonian canalization, and cancer is a disease, at least epigenetically, in which these canals are shallower, with increasing noise and the probability of cell type transitions that should not appear in differentiated tissues. At the same time, this increased noise increases the fitness of cancer cells and their resistance to any given therapy. 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 SY21-02. doi:1538-7445.AM2012-SY21-02
DIFFERENCES IN LEFT VENTRICULAR GLOBAL LONGITUDINAL STRAIN ASSESSED BY TWO-DIMENSIONAL AND THREE-DIMENSIONAL SPECKLE TRACKING ECHOCARDIOGRAPHY: THE CORONARY ARTERY RISK DEVELOPMENT IN YOUNG ADULTS (CARDIA) STUDY
Authors: Henrique Turin Moreira, Chike Nwabuo, Guilherme Yared, Vasconcellos D. Henrique, Anderson Armstrong, Satoru Kishi, Bharath Ambale Venkatesh, Cora Lewis, Pamela Schreiner, Stephen Sidney, Donald Lloyd-Jones, Samuel Gidding, Joao Lima
Journal: Journal of the American College of Cardiology (2016)
Longitudinal Study of the Effects of Maternal Smoking on Pulmonary Function in Children
Authors: Ira B. Tager, Scott T. Weiss, Alvaro Muñoz, Bernard Rosner, Frank E. Speizer
Journal: New England Journal of Medicine (1983)

We investigated the effects of maternal cigarette smoking on pulmonary function in a cohort of children and adolescents observed prospectively for seven years. A multivariate analysis revealed that after correction for previous forced expiratory volume in one second (FEV1), age, height, change in height, and cigarette smoking in the child, or adolescent, maternal cigarette smoking significantly lowered the expected average annual increase in FEV1 (P = 0.015). On the basis of this analysis, it is estimated that if two children have the same initial FEV1, age, height, increase in height, and personal cigarette-smoking history, but the mother of one has smoked throughout the child's life whereas the mother of the other has not, the difference in the change in FEV1 over time in the exposed child, as compared with that in the unexposed child, will be approximately 28, 51, and 101 ml after one, two, and five years, respectively, or a reduction of 10.7, 9.5, and 7.0 per cent, respectively, in the expected increase. These results suggest that passive exposure to maternal cigarette smoke may have important effects on the development of pulmonary function in children.The authors investigated the effects of maternal cigarette smoking on pulmonary function in a cohort of children and adolescents observed prospectively for 7 years. A multivariate analysis revealed that after correction for previous forced expiratory volume in 1 second (FEV1), age, height, change in height, and cigarette smoking in the child or adolescent, maternal smoking significantly lowered the expected average annual increase in FEV1 (P=0.015). On the basis of this analysis, it is estimated that if 2 children have the same initial FEV1, age, height, increase in height, and personal cigarette smoking history, but the mother of 1 smoked throughout the child's life whereas the mother of the other has not, the difference in the change in FEV1 over time in the exposed child, as compared with that in the unexposed 1, will be approximately 28, 51, and 101 ml after 1, 2, and 5 years, respectively, or a reduction of 10.7, 9.5, and 7.0%, respectively, in the expected increase. These results suggest that passive exposure to maternal cigarette smoke may have important effects on the development of pulmonary function in children.
THU0124 Relationship Between the Level of Antibodies to Modified Citrullinated Vimentin (Anti-MCV) and Bone Destruction in Patients with Rheumatoid Arthritis (RA)
Authors: A. S. Avdeeva, E. N. Alexandrova, A. V. Smirnov, A. A. Novikov, M. V. Cherkasova, E. L. Nasonov
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The destruction of bone and cartilage tissue is one of the main manifestations of RA, which is related to the production of proinflammatory cytokines (TNF-α, IL-1 and IL-6) and making of cells synovium proteolytic enzymes (matrix metalloproteinases –MMP). The presence of anti-citrullinated proteins antibodies is also a risk factor of heavy destructive defeat of joints. Anti-MCV bound to the osteoclast surface, lead to a induction of osteoclastogenesis and bone resorption in vitro. <h3>Objectives</h3> To evaluate the intercommunication between the level of anti-MCV and bone destruction in patients (pts) with RA. <h3>Methods</h3> The study included 105 RA patients (85 women, mean age 53,0; 42,0-60,0, mean disease duration 60,0; 28,0-108,0 months, mean DAS 28 5,9; 5,2-6,7). All pts received disease-modifying antirheumatic drugs (DMARD) (75,4% - methotrexate, 16,7% - leflunomide, and 7,9% - other DMARDs) and glucocorticoids (61,4%). Radiographs of the hands and feet was estimated by using van der Heijde-modified Sharp scores. Erythrocyte sedimentation rate – ESR (mm/hr) was determined by Westergren method; serum concentrations of anti-MCV (U/ml) and - MMP 3 (ng/ml) were tested using ELISA. The levels of IL-1β, IL-6 and TNF-α (pg/ml) were assayed by multiplex technology xMAP. <h3>Results</h3> Mean [Me (interquartile range)] total modified Sharp score (mTSS) were 89 (58-116), erosion score - 9 (3-27), the level of anti-MCV- 470,2 (106,9-1000), IL-1β- 4,6 (2,1-10,2), IL-6 -125,6 (60,1 -370,7), TNF-α- 87,2 (39,4-391,2). Depending on the level of anti-MCV all pts were divided into two groups. Among the high positive RA pts there were a higher value of mTSS and often detected elevated levels of MMP-3 (56%) compared to negative/low positive pts (31%, p=0,038), table 1. The level of proinflammatory cytokines was also higher in the first group (table 1). Significant differences between the groups according to the age, disease duration, activity, DMARDs therapy was not found. <h3>Conclusions</h3> High positive level anti-MCV is associated with more pronounced destructive changes in the joints due to higher levels of MMP-3 and proinflammatory cytokines among this group of patients with RA. <h3>Disclosure of Interest</h3> None Declared
<i>Treponema pallidum</i> — The Great Imitator
Authors: Helga Militz, Christine Hungerer
Journal: New England Journal of Medicine (2015)

A 50-year-old woman was admitted to the hospital with swelling of the left lateral malleolus after an ankle sprain and rupture of the Achilles tendon. Examination was notable for ulcerated lesions with sanguineous secretions on the left breast, back, and left shoulder.
S83 The use of indwelling pleural catheters (IPC) with or without concurrent talc poudrage (TP) at medical thoracoscopy (MT) for cases of suspected trapped lung (TL): Abstract S83 Table 1.
Authors: S Chatterji, T Pulimood, E Reid, J Herre, P Sivasothy
Journal: Thorax (2013)

<h3>Background</h3> Recurrent symptomatic non-infectious pleural effusions can be effectively treated with MT and TP with pleurodesis rates approaching 85% in variety of malignant and benign aetiologies. When TL is likely at MT, management is uncertain. <h3>Aim</h3> We report on a single centre experience of inserting an IPC at MT with or without talc poudrage for suspected trapped lung. TL was suspected if any of the following were observed (a) failure of lung to inflate on voluntary coughing at MT, (b) visceral involvement of more than 25%, (c) radiological evidence of endobronchial compromise and (d) hydropneumothorax following previous thoracocentesis. <h3>Method</h3> A review of all IPC insertions at MT performed at our institution between March 2009 and Feb 2013 assessing indications, length of stay (LoS) after procedure, use of concurrent TP, IPC removal rates and recorded complications. All cases had been performed using rigid thoracoscopy. TP was performed with 4g sterile graded talc. Rocket 16F IPC were used in all cases. <h3>Results</h3> All IPCs were inserted during MT for likely or possible TL. N = 36cases. 14 male. Diagnoses–10 benign recurrent effusions; 26 malignant. See table 1 for details. Median age 73yrs (45–92). Median LoS post procedure–non-elective 7 days (1–23); elective 2.5 days (0–6). 22 (56%) had concurrent TP (18 for malignancy). 14 (36%) had their IPC removed with median time to removal 40 days (28–119) and of these, 11 had received TP during MT. 20 patients have died during follow up (none procedure-related) of which 11 still had their IPC <i>in situ</i>. Complications–2 blocked drains (not talc group, 1 case needing additional thoracocentesis), 2 leaking caps (replaced). <h3>Discussion</h3> IPC insertion at MT with or without TP for cases of suspected TL appears to be safe, effective and obviates the need for further pleural intervention at a later date. This potentially has significant benefits to the patient as well as a reduction in overall healthcare costs to the NHS. Using the above criteria predicted TL in 78% of patients. This single centre observation needs to be investigated by a larger multi-centre study in patients with suspected TL at MT.
184 PREDICTIVE FACTORS OF SURVIVAL AND PROGNOSTIC SCORE VALIDATION IN LIVER RETRANSPLANTATION FOR SEVERE HEPATITIS C RECURRENCE: THE IMPORTANCE OF HCV THERAPY BEFORE AND AFTER RETRANSPLANTATION
Authors: A.T.W. Song, R. Sobesky, C. Vinaixa, J. Dumortier, S. Radenne, G. Rousseau, V. Delvart, S. Haim-Boukobza, A.-M. Roque-Afonso, B. Roche, E. Vibert, D. Castaing, E. Abdala, M. Berenguer, J.-C. Duclos-Vallée, D. Samuel
Journal: Journal of Hepatology (2013)
Reply to Chiu et al. and Lasa et al.
Authors: Karoline Reinhart, Monika Ferlitsch
Journal: Endoscopy (2013)

We thank Dr. Chiu et al. for their thoughtful comments on the classification of flat polyps in our large, nationwide screening colonoscopy study [1]. As stated in our discussion, we agree that a major limitation of the study was the lack of further more detailed classification of flat polyps to distinguish between flat depressed and other flat polyps. Nevertheless, the flat polyp detection rate included depressed polyps, as the endoscopists were asked to classify flat and depressed lesions (Paris 0-IIa, 0-IIb, 0-IIc) together. Therefore, these lesions were indeed not described separately and statistically evaluated, but neither were they neglected. As discussed, the aim of the study was to estimate the risk of all flat polyps with regard to high grade dysplasia in screening colonoscopy, irrespective of their location. Furthermore, as we have pointed out in the paper, the macroscopic classification of a lesion is based on the endoscopist’s interpretation and remains subjective. Regarding the training of the participants, only endoscopists who were performing at least 100 colonoscopies and 10 polypectomies per year participated in the project. The goal of the study was not to show the effects of training in the detection of flat lesions, but to evaluate “the real life” data from screening colonoscopy. In our opinion, most of the screening colonoscopies in Europe are performed in general, rather than specialized centers, or in private practice. Thus, we think that the study design, in particular, has a strong advantage; the study included 52 000 patients, which provides the opportunity to present a representative overview of colonoscopy in daily practice. We consider our results to therefore be a valuable contribution to epidemiology data and screening colonoscopy outcome.
Umesh Chandra Sharma
Authors: Devesh Sharma
Journal: BMJ (2015)

Umesh Chandra Sharma was born in Bhawan Bahadur Nagar, India, on 15 January 1931. His father, Ramchandra Sharma, was an officer in sales tax and his mother was Kishan Devi. He was one of four siblings; two brothers and two sisters. He attended Nagpur medical college. He came to the UK in 1961 and worked in Aberystwyth, Edinburgh, Newcastle, North Shields, Liverpool, and Leicester, before being appointed as a consultant in orthopaedics at Stonehouse Hospital, …
Abstract 3443: Novel small molecule CRM1 inhibitors induce nuclear accumulation of p53, phosphorylated ERK and apoptosis in human melanoma cells.
Authors: Jennifer Yang, Matthew A. Bill, Gregory S. Young, Yosef Landesman, Sharon Shacham, Michael Kauffman, William Senapedis, Trinayan Kashyap, Jean-Richard Saint-Martin, Gregory Lesinski
Journal: Cancer Research (2013)

Abstract Inhibition of nuclear export can promote re-activation of tumor suppressor proteins (TSPs) by restoring them to the nucleus. CRM1 (chromosome region maintenance 1, XPO1) is the exclusive exporter of many TSPs. We hypothesized that CRM1 inhibition can be used as a therapeutic target in melanoma. The growth inhibitory and pro-apoptotic effects of KPT-185, KPT-276 and KPT-330, potent, small molecule, selective inhibitors of nuclear export (SINEs) were evaluated in a panel of human metastatic melanoma cell lines using an MTS assay and Annexin V/PI staining, respectively. The weak CRM1 inhibitor, KPT-185 trans-isomer, and DMSO vehicle were controls in all assays. CRM1 protein was expressed in melanoma cell lines regardless of molecular profile (BRAF, NRAS, TP53) as determined by immunoblot. SINEs inhibited cell growth in a concentration-dependent manner and induced apoptosis at nanomolar concentrations (range=139.7nM - 2.41μM). Both BRAF wild type (WT) and BRAF V600E mutant lines were sensitive to apoptosis by SINE, but BRAF V600E lines had an 8.8-fold lower IC50s as compared to BRAF (WT) lines (p=0.018). The cytostatic and pro-apoptotic effects of CRM1 inhibition were associated with nuclear accumulation of p53, and p21 induction in A375 and CHL-1 melanoma cell lines with functional p53 at time points prior to apoptosis, while pERK accumulated in melanoma cells regardless of p53 status. In pharmacokinetic studies in mice, KPT-276 and KPT-330 showed &amp;gt;50% oral bioavailability with Cmax &amp;gt;5μM. Mice bearing either A375 (BRAF V600E) or CHL-1 (BRAF WT) melanoma xenografts were given KPT-276 or KPT-330 SINE by oral gavage. A375 xenografts (p&amp;lt;0.0001 for both drugs) and CHL-1 xenografts (p=0.0087 and 0.0002 respectively) showed significant growth inhibition as compared to vehicle-treated controls with good tolerability. KPT-330 is currently in Phase 1 clinical trials in patients with advanced cancers including melanoma as the first orally bioavailable, SINE CRM1 antagonist. Citation Format: Jennifer Yang, Matthew A. Bill, Gregory S. Young, Yosef Landesman, Sharon Shacham, Michael Kauffman, William Senapedis, Trinayan Kashyap, Jean-Richard Saint-Martin, Gregory Lesinski. Novel small molecule CRM1 inhibitors induce nuclear accumulation of p53, phosphorylated ERK and apoptosis in human melanoma cells. [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 3443. doi:10.1158/1538-7445.AM2013-3443
Abstract 1857: 3p12.3 and 7q36.3 harbor genes associated with hereditary breast and colorectal carcinomas
Authors: Francine B. Abreu, Erika M.M. Santos, Benedito M. Rossi, Luiz P. Kowalski, Ricardo R. Brentani, Silvia R. Rogatto
Journal: Cancer Research (2010)

Abstract Lynch syndrome (LS) is the most common hereditary syndrome that predisposes to colorectal cancer (CRC). LS is associated with susceptibility to proximal colon cancer, multiple primary (CRC) and extra-colonic tumors. According to Registration of Hereditary Colorectal Cancer (RHCC) of AC Camargo Hospital of Brazil, breast cancer is the most frequent extra-colonic tumor among women with suspicion of hereditary CRC, suggesting the possibility of a new syndrome known as Hereditary Breast and Colorectal Cancer (HBCC). Array comparative genomic hybridization (array CGH) is the high-resolution laboratory technique of choice for the detection of chromosomal DNA copy number alterations on a genome-wide scale. The aim of the present study was to identify copy number alterations in genes related to predisposition in HBCC syndrome. Array comparative genomic hybridization was performed using Human 4 × 180K Oligoarrays (G4449A, Agilent) in 47 individuals from families showing HBCC phenotype. For each sample, 800 ng of DNA were fragmented by a double enzymatic digestion (AluI + RsaI). DNA from peripheral blood leukocytes and control DNA from Promega (Human Genomic DNA Female G1521) were labeled with CY3-dCTP and CY5-dCTPs, respectively, and hybridized at 65°C for 17 h. The chips were scanned on an Agilent DNA Microarray Scanner and image analysis was done using the Feature-Extraction version 10.1.1.1 software (Agilent Technologies). Raw copy number ratio data were transferred to the Agilent Genomic Workbench Software (version 5.0.14) for further analysis. It was detected copy number variations involving 36 regions previously described in genome databases. Furthermore, it was observed loss at 3p12.3 in two individuals. One patient presented breast cancer and CCR while the other one had breast carcinoma. Both of them had breast cancer around the 50 years. In both families, their relatives had CCR, breast cancer and endometrial cancer, which is another extra-colonic tumor found among patients with LS. In a third women with breast and colorectal carcinomas was detected deletion at 7q36.3. Germline copy number alterations may indicate new genes associated with cancer predisposition. Our results suggest that 3p12.3 and 7q36.3 harbor genes associated with hereditary breast and colorectal carcinomas. Additional members of these families are being evaluated to confirm the involvement of these regions as candidate genes. Financial Support: FAPESP (2008/57887-9) and CNPq (57589/2008-9). 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 1857.
HMGB1 mediates muscle fatigue via TLR4 - a possible mechanism for muscle fatigue in patients with inflammatory myopathies
Authors: Mei Zong, Joseph D Bruton, Cecilia Grundtman, Huan Yang, Jian Hua Li, Karin Palmblad, Helena Erlandsson Harris, Ulf Andersson, Håkan Westerblad, Ingrid E Lundberg
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> Idiopathic inflammatory myopathies (IIMs) are chronic inflammatory diseases characterised by muscle weakness and the mechanisms are still unclear. High mobility group box protein 1 (HMGB1) is often found together with aberrant expression of major histocompatibility complex (MHC) class I in muscle fibres of patients with IIMs but not in healthy individuals. Exogenous HMGB1 can accelerate development of muscle fatigue and increase MHC-class I expression in adult mice skeletal muscle fibres. In other tissues it has been shown that HMGB1 could mediate functions via different receptors including the receptor for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4). In this study, the authors set out to investigate whether HMGB1 contribute to increased muscle fatigue and MHC-class I expression in muscle fibres via RAGE or TLR4 in adult skeletal muscle fibres. <h3>Materials and methods</h3> Intact single fibres were dissociated from flexor digitorum brevis (FDB) of wild type (WT), RAGE knockout (RAGE-/-) and TLR4 knockout (TLR4-/-) mice and cultured in the absence or presence of 10 µg/ml recombinant HMGB1. Decrease in sarcoplasmic reticulum (SR) Ca<sup>2+</sup> release, which reflects the development of muscle fatigue, was determined by measuring myoplasmic free tetanic Ca<sup>2+</sup> ((Ca<sup>2+</sup>)<sub>i</sub>) during a series of 300 tetanic contractions. MHC-class I and TLR4 expression in FDB fibres was investigated by immunofluorescence and confocal microscopy. Immunohistochemistry was used to investigate TLR4, MHC-class I and myosin heavy chain expression in muscle fibres of patients with IIMs. <h3>Results</h3> Intact single muscle fibres from WT and RAGE-/- but not from TLR4-/- mice showed a greater decline in tetanic (Ca<sup>2+</sup>)<sub>i</sub> at the end of a series of 300 tetanic contractions when cultured with rHMGB1 compared to without rHMGB1; MHC-class I was detected on the membrane of single fibers from WT but not TLR4-/- mice when exposed to rHMGB1; TLR4 expression was detected on the sarcolemma of muscle fibres from WT mice. TLR4 and MHC-class I co-expression was observed in muscle fibres from patients with IIMs and this staining was essentially confined to skeletal type II fast twitch muscle fibers. <h3>Conclusions</h3> TLR4 mediates muscle fatigue and MHC-class I expression in differentiated skeletal muscle fibres after exposure to the alarmin HMGB1. TLR4, MHC-class I and HMGB1 co-localisation is frequently observed in muscle fibres of patients with IIMs, thus HMGB1-TLR4 pathway may play a role in causing muscle weakness in patients with IIMs and is thus a possible novel target for therapy in IIM patients.