tbuckley/cabot-search huggingface dataset:
Abstract P016: Human Mesenchymal Bone Marrow--Derived Stem Cells Require Connexin 43 to Form Beating 3-Dimensional Tubes When Cocultured with Neonatal Rat Cardiomyocytes
Authors: Cristina Sanina, Claudia O Rodrigues, Ivonne H Schulman, Irene Margitich, Wayne Balkan, Joshua M Hare
Journal: Circulation Research (2011)

Mesenchymal stem cells (MSCs) have begun to manifest themselves as a safe and beneficial therapy for restoring cardiac function in failing hearts. However, the mechanism underlying this function is unclear. The present study was initiated to investigate the role of Connexin 43 (Cx43) in hMSC integration, migration and differentiation in co-culture with neonatal rat cardiomyocyte (NRVMs) in vitro. Cx43 is a gap junction connexin which is required for proper heart development and heart electrophysiology. We generated lentiviral constructs for Cx43 knockdown and Cx43 overexpression and used them to alter the level of Cx43 in hMSCs. The effectiveness of these vectors was confirmed by assessing Cx43 levels in hMSCs by Western Blot analysis and by Real Time-PCR. These hMSCs were co-cultured with NRVMs for up to 1 month on poly-lysine and collagen I coated glass cover slips. Co-cultures containing MSCs overexpressing Cx43 exhibited coordinated beating and three-dimensional tube formation in 10 days, whereas 14 days were required for control cells. The hMSCs were integrated into these beating three dimensional tubes. No tubes were observed in co-cultures with Cx43 knockdown hMSCs, rather we observed the formation of small, unconnected beating spheres after 30 days in co-culture. Human MSC-Cx43 knockdown cells were integrated into these spheres and immunofluorescence staining demonstrated that Cx43 expression in hMSC-Cx43 knockdown remained reduced when compared to the control group. Real Time-PCR analysis using human specific primers showed significant upregulation of KDR, smooth muscle actin, Pecam1, CD34, CDH2, and CaCNA1C. Several genes, not initially seen in hMSCs, including Gata4, CDH5, SCN5A, SLC8A1, and KCNQ1, appeared in co-cultures with hMSCs with normal and elevated expression levels of Cx43. However, in co-culture of cardiomyocytes with Cx43 knockdown MSCs we observed downregulation of KDR, CHD2, SCN5A, SLC8A1, KCNQ1 compare to control. These results suggest a strong correlation between the presence of Cx43 and the ability of hMSCs to differentiate into cardiac and endothelial lineages.
Determination of lung cancer risk based on a biomarker comprising transcript abundance levels of 15 antioxidant and DNA repair genes
Authors: Thomas Blomquist, Erin Crawford, D'Anna Mullins, Dawn-Alita Hernandez, Jaime Ruiz, mohammed Al-Baghdadi, youngsook Yoon, Sadik Khuder, James Willey
Journal: Clinical Cancer Research (2007)

A12  Lung cancer is the leading cancer killer of both men and women in the United States and approximately 90% of cases can be attributed to cigarette smoking. The high death rate is in part because the disease typically is in advanced stage at time of diagnosis. The personal and financial cost of lung cancer in our society is high and likely to remain so for at least a generation because, even after smoking cessation, risk remains high for many years. Recently developed screening tools such as high resolution coaxial tomography (HRCT) offer promise to markedly increase survival through diagnosis at early stage. However, the potential cost of screening is very high because there are greater than 40 million active or ex-smokers. Because only 10-15% of heavy smokers develop lung cancer, a biomarker that accurately predicts individuals at greatest risk could substantially reduce cost of screening. Previously, we published data supporting the hypothesis that individuals with low transcript abundance (TA) levels of certain antioxidant enzyme genes in their normal bronchial epithelial cells were more likely to have developed bronchogenic carcinoma than those with higher, presumably protective, levels and that these TA levels were correlated with TA levels of certain transcription factors. Here we measured TA levels of these antioxidant genes and transcription factors along with TA levels of a set of DNA repair genes in the normal bronchial epithelial cells of 25 lung cancer and 24 non-lung cancer individuals using standardized, quantitative RT-PCR. A biomarker comprising TA levels of 15 genes was developed that accurately predicted which individuals were cancer patients. The 15 genes are CEBPG, E2F1, E2F6, XRCC1, ERCC4, ERCC5, GPX1, GPX3, GSTM3, GSTP1, GSTT1, GSTZ1, MGST1, SOD1 and CAT. For each gene, a threshold level of TA that most accurately separated lung cancer from non-lung cancer individuals was determined empirically. Depending on whether the TA level for a gene was above or below the threshold, the subject was assigned a value of 1 or 0. The values for each of the 15 genes were totaled for each subject. Using a total value cut-off of greater than or equal to 7 as a biomarker for lung cancer individuals, one false negative and seven false positives were observed among the 49 individuals assessed, yielding a sensitivity of 96% and specificity of 71%. We hypothesize that at least some of the non-lung cancer individuals with positive result are at increased risk and that this will become manifest with additional time. These results justify a larger, prospective study to determine whether this biomarker will be useful in predicting risk for lung cancer in current and former smokers.
Reduced radiotherapy is as effective as whole breast treatment for early breast cancer, study finds
Authors: Susan Mayor
Journal: BMJ (2017)

Targeting radiotherapy to the original tumour site or using a reduced dose to treat the whole breast is associated with a similarly low rate of local relapse as standard radiotherapy to the whole breast and fewer long term adverse effects in women treated for early breast cancer, a large randomised UK trial has found.1

Breast radiotherapy after breast conserving surgery halves the risk of recurrence of the cancer in patients with early breast cancer. Whole breast radiotherapy is the current standard of care in the UK, as well …
PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy
Authors: Junyu Long, Jianzhen Lin, Anqiang Wang, Liangcai Wu, Yongchang Zheng, Xiaobo Yang, Xueshuai Wan, Haifeng Xu, Shuguang Chen, Haitao Zhao
Journal: Journal of Hematology & Oncology (2017)

Gastrointestinal (GI) malignancies are the most prevalent tumors worldwide, with increasing incidence and mortality. Although surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy have led to significant advances in the treatment of GI cancer patients, overall survival is still low. Therefore, alternative strategies must be identified to improve patient outcomes. In the tumor microenvironment, tumor cells can escape the host immune response through the interaction of PD-1 and PD-L, which inhibits the function of T cells and tumor-infiltrating lymphocytes while increasing the function of immunosuppressive T regulatory cells. The use of an anti-PD-1/PD-L blockade enables reprogramming of the immune system to efficiently identify and kill tumor cells. In recent years, the efficacy of PD-1/PD-L blockade has been demonstrated in many tumors, and this treatment is expected to be a pan-immunotherapy for tumors. Here, we review the signaling pathway underlying the dysregulation of PD-1/PD-L in tumors, summarize the current clinical data for PD-1/PD-L inhibitors in GI malignancies, and discuss road toward precision immunotherapy in relation to PD-1/PD-L blockade. The preliminary data for PD-1/PD-L inhibitors are encouraging, and the precision immunotherapy of PD-1/PD-L inhibitors will be a viable and pivotal clinical strategy for GI cancer therapy.
THE DEVELOPMENT OF A WEEKLY E-DIARY FOR SELF-REPORTED INJURIES AND ILLNESSES IN PARALYMPIC SPORTS: THE SPORTS-RELATED INJURIES AND ILLNESSES IN PARALYMPIC SPORT STUDY (SRIIPSS)
Authors: Kristina Fagher, Jenny Jacobsson, Toomas Timpka, Örjan Dahlström, Jan Lexell
Journal: British Journal of Sports Medicine (2017)

Background Few studies have longitudinally assessed the epidemiology of sports-related injuries and illnesses in Paralympic sport (SRIIPS). Objective The objective of this study was to develop and test a weekly e-diary for self-reports of SRIIPS in an electronic system specifically adapted for Paralympic athletes with various impairments. Design Prospective cohort pilot study. Setting Paralympic athletes. Patients (or Participants) Twenty-eight Swedish Paralympic athletes with vision (n=11), physical (n=15) and intellectual impairments (n=2) active in in 11 sports. Interventions (or Assessment of Risk Factors) The athletes were asked to self-report SRIIPS, pain, anxiety, training load and exposure weekly during 4 weeks. Main Outcome Measurements System usability indicators and SRIIPS. Results The average weekly response rate was 95%. One athlete dropped out. There were few missing data and a majority could respond to all questions. The system worked well for athletes with physical and intellectual impairment. Some visually impaired athletes perceived it difficult to respond to multiple-choice questions. Ten of the athletes found it partly difficult to define a new injury. Fifteen new injuries and fourteen new illnesses were reported, giving a cumulative incidence of 1.8 injuries/100 hours and 1.7 illnesses/100 hours of athlete exposure. A total of 80% of the injuries were related to overuse. The typical injury severity was 1–3 days time loss of training. In 20% of the injuries and 21% of the illnesses the impairment was involved in the cause. Conclusions This is the first study of self-reported SRIIPS. Overall, the proposed method and variables worked satisfactory. The electronic data collection system needs to be adjusted to visually impaired athletes and injury definitions need to be explained in more detail and examples provided. Based on this, we prepare a prospective longitudinal study (1 year) with the aim to estimate the annual self-reported incidence of SRIIPS.
High-Resolution Mapping of Chromatin Conformation in Cardiac Myocytes Reveals Structural Remodeling of the Epigenome in Heart Failure
Authors: Manuel Rosa-Garrido, Douglas J. Chapski, Anthony D. Schmitt, Todd H. Kimball, Elaheh Karbassi, Emma Monte, Enrique Balderas, Matteo Pellegrini, Tsai-Ting Shih, Elizabeth Soehalim, David Liem, Peipei Ping, Niels J. Galjart, Shuxun Ren, Yibin Wang, Bing Ren, Thomas M. Vondriska
Journal: Circulation (2017)

Background: Cardiovascular disease is associated with epigenomic changes in the heart; however, the endogenous structure of cardiac myocyte chromatin has never been determined. Methods: To investigate the mechanisms of epigenomic function in the heart, genome-wide chromatin conformation capture (Hi-C) and DNA sequencing were performed in adult cardiac myocytes following development of pressure overload–induced hypertrophy. Mice with cardiac-specific deletion of CTCF (a ubiquitous chromatin structural protein) were generated to explore the role of this protein in chromatin structure and cardiac phenotype. Transcriptome analyses by RNA-seq were conducted as a functional readout of the epigenomic structural changes. Results: Depletion of CTCF was sufficient to induce heart failure in mice, and human patients with heart failure receiving mechanical unloading via left ventricular assist devices show increased CTCF abundance. Chromatin structural analyses revealed interactions within the cardiac myocyte genome at 5-kb resolution, enabling examination of intra- and interchromosomal events, and providing a resource for future cardiac epigenomic investigations. Pressure overload or CTCF depletion selectively altered boundary strength between topologically associating domains and A/B compartmentalization, measurements of genome accessibility. Heart failure involved decreased stability of chromatin interactions around disease-causing genes. In addition, pressure overload or CTCF depletion remodeled long-range interactions of cardiac enhancers, resulting in a significant decrease in local chromatin interactions around these functional elements. Conclusions: These findings provide a high-resolution chromatin architecture resource for cardiac epigenomic investigations and demonstrate that global structural remodeling of chromatin underpins heart failure. The newly identified principles of endogenous chromatin structure have key implications for epigenetic therapy.
SAT0697 Prevalence of hepatitis b and c infection and reactivation in patients receiving biologic iv therapies
Authors: K Arévalo Ruales, B Soler Bas, J Ivorra Cortes, E Grau Garcia, E Vicens Bernabeu, E Sánchez Labrador, JJ Fragio Gil, R Mazarío González, C Alcañiz Escandell, I Cánovas Olmos, I Chalmeta Verdejo, CM Feced Olmos, L Gonzalez Puig, I Martínez Cordellat, C Nájera Herranz, R Negueroles Albuixech, JE Oller Rodriguez, FM Ortiz-Sanjuan, JA Román Ivorra
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> With the use of biological therapy, cases of reactivation of hepatitis B (HBV) and C (HCV) have been described, consequently its use has to be carefully evaluated. In some cases these therapies have to be administered together with antiviral treatment. Despite the fact that before the beginning of the biological therapy the screening of HBV and HCV virus is done, during the course of treatment serologies are no longer used to detect serovonversions. <h3>Objectives</h3> To analyze the prevalence of HBV and HCV in patients with rheumatic disease at the beginning of biological therapies. To identify the cases of hepatitis reactivation. <h3>Methods</h3> Retrospective observational analysis of the biological treatments administered to patients with rheumatic Disease of the rheumatology department of La Fe hospital, during the period 2000–2015 who had HBV and/or HCV serology at the beginning of treatment. Demographic data and diagnosis of the patient, months of treatment and the results of the serologies performed at the beginning and in the follow-up of the treatment, and the cases of reactivation of hepatitis have been collected. <h3>Results</h3> A total of 388 patients were selected of which 62.4% were female; the mean age at diagnosis of was 38.96±14.36 years. 49.5% of the patients were diagnosed with rheumatoid arthritis (RA), 25.3% of ankylosing spondylitis (AE), 18.6% of psoriatic arthritis (APSO) and 6.7% with other diagnoses. The mean treatment time with patients9 biological therapy is 200±118 months (3–464 months), and the mean time between the two serologies is 172±102 months (18–460 months). An incidence of 10% of cases with HBV infection (39 patients) is observed. The serological pattern was 8 cases with Ac-core (+) HBV/Ac-surface (-)/Ag-surface (-) HBV and 31 HBV/Ac- surface (-). The incidence of HCV at the start of treatment was 1.1% (4 patients). A case of reactivation (12.5%) was detected among the 8 patients with Ac-core (+)/Ac-surface (-)/Ag-surface (-) HBV. The patient had infliximab and methotrexate, and reactivation was observed after 12 years of treatment. No reactivation of HCV has been detected. <h3>Conclusions</h3> In our series of patients the incidence of HBV and HCV has been 10% and 1.1%, respectively. One of the 8 patients with Ac-core (+)/Ac-surface (-)/Ag-surface (-) HBV, had reactivation of the virus. <h3>Disclosure of Interest</h3> None declared
食後のマクロファージ由来IL‐1βは,インスリンを刺激し,両者が相乗的にグルコースの除去と炎症を促進する
Authors: Dror Erez, Dalmas Elise, Meier Daniel T, Wueest Stephan, Thevenet Julien, Thienel Constanze, Timper Katharina, Nordmann Thierry M, Traub Shuyang, Schulze Friederike, Item Flurin, Vallois David, Pattou Francois, Kerr‐Conte Julie, Lavallard Vanessa, Berney Thierry, Thorens Bernard, Konrad Daniel, Boeni‐Schnetzler Marianne, Donath Marc Y
Journal: Nature Immunology (2017)
<i>KIT</i> and <i>PDGFRA</i>mutation status and their immunohistochemical (IHC) expression profile of gastrointestinal stromal tumor (GIST) patients treated with imatinib (IMT): Seven-year single-center experience
Authors: Y. Koh, H. Kim, H. Lee, K. Lee, D. Oh, J. Kim, S. Im, T. Kim, W. Kim, Y. Bang
Journal: Journal of Clinical Oncology (2009)

10558 Background: Previous studies suggested the role of KIT and PDGFRAmutations on treatment outcome of GIST with IMT, but results are heterogeneous. IHC value of PDGFRA and PDGFRB is not established. Methods: We included patients (pts) treated with IMT as a first line therapy for metastastic or relapsed GIST between 2001 and 2008. Tumor DNA was extracted to investigate the mutation status of KITexon 9, exon 11, PDGFRA exon 12 and 18. IHC stain of c-KIT and PDGFRA/B was performed. We assessed the correlation between the treatment outcome, genetic status and IHC results. Results: A total of 85 pts (M:F=49:36, median age 58.4 years) received IMT 400 mg daily. Location of primary disease included stomach (33), small bowel (34), rectum (10), esophagus (1), and omentum/mesentery (7). Complete and partial responses were achieved in 6% and 62% of pts respectively, while 5% of pts had progressive disease. During median follow up of 28.1 months, estimated median PFS was 39.8 months. KIT exon 11 and 9 mutations were detected in 64% and 5% respectively. Exon 11 mutations included 44 deletions, 2 insertions, 5 substitutions and 3 deletion/insertions. PDGFRA exon 12 and 18 mutations were detected in 2% respectively. Positive rate of c-KIT, PDGFRA and PDGFRB using IHC was 96%, 21%, and 26% respectively. PDGFRA and PDGFRB were co-expressed (p=0.001). PDGFRA mutation did not correlate with PDGFRA/B expression. Clinical response was not different according to the mutation status or IHC expression. PFS of KIT exon 11, KITexon 9, PDGFRA mutants and pts without detectable mutations were not different (p=0.397). Pts with KIT exon 11 balanced mutations (substitution or deletion/insertion) showed longer PFS compared with pts with unbalanced mutations (deletion or insertion) (p=0.014) or pts without exon 11 mutations (p=0.033). Median PFS was shorter in pts lacking c-KIT (p=0.001) expression. PDGFRA/B expression did not influence PFS. Conclusions: Balanced mutation of KIT exon 11 predicted longer PFS, while lack of c-KIT protein expression predicted shorter PFS for GIST pts treated with first line IMT. PDGFRA and B were co-expressed without predictive value. No significant financial relationships to disclose.
Whole-Exome Sequencing Identifies the 6q12-q16 Linkage Region and a Candidate Gene, <i>TTK</i>, for Pulmonary Nontuberculous Mycobacterial Disease
Authors: Fei Chen, Eva P. Szymanski, Kenneth N. Olivier, Xinyue Liu, Hervé Tettelin, Steven M. Holland, Priya Duggal
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Pulmonary nontuberculous mycobacterial disease (PNTM) often affects white postmenopausal women, with a tall and lean body habitus and higher rates of scoliosis, pectus excavatum, mitral valve prolapse, and mutations in the CFTR gene. These clinical features and the familial clustering of the disease suggest an underlying genetic mechanism.To map the genes associated with PNTM, whole-exome sequencing was conducted in 12 PNTM families and 57 sporadic cases recruited at the National Institutes of Health Clinical Center during 2001-2013.We performed a variant-level and a gene-level parametric linkage analysis on nine PNTM families (16 affected and 20 unaffected) as well as a gene-level association analysis on nine PNTM families and 55 sporadic cases.The genome-wide variant-level linkage analysis using 4,328 independent common variants identified a 20-cM region on chromosome 6q12-6q16 (heterogeneity logarithm of odds score = 3.9), under a recessive disease model with 100% penetrance and a risk allele frequency of 5%. All genes on chromosome 6 were then tested in the gene-level linkage analysis, using the collapsed haplotype pattern method. The TTK protein kinase gene (TTK) on chromosome 6q14.1 was the most significant (heterogeneity logarithm of odds score = 3.38). In addition, the genes MAP2K4, RCOR3, KRT83, IFNLR1, and SLC29A1 were associated with PNTM in our gene-level association analysis.The TTK gene encodes a protein kinase that is essential for mitotic checkpoints and the DNA damage response. TTK and other genetic loci identified in our study may contribute to the increased susceptibility to NTM infection and its progression to pulmonary disease.
Tropomyosin Receptor Kinase A Expression on Merkel Cell Carcinoma Cells
Authors: Ulrike Wehkamp, Sophie Stern, Sandra Krüger, Axel Hauschild, Christoph Röcken, Friederike Egberts
Journal: JAMA Dermatology (2017)

<h3>Importance</h3> Merkel cell carcinoma (MCC) is a malignant neuroendocrine skin tumor frequently associated with the Merkel cell polyomavirus. Immune checkpoint therapy showed remarkable results, although not all patients are responsive to this therapy. Anti–tropomyosin receptor kinase A (TrkA)–targeted treatment has shown promising results in several tumor entities. <h3>Objective</h3> To determine TrkA expression in MCC as a rationale for potential targeted therapy. <h3>Design, Setting, and Participants</h3> This case series study investigated the MCC specimens of 55 patients treated at the Department of Dermatology, University Hospital of Schleswig-Holstein, Kiel, Germany, from January 1, 2005, through December 31, 2015. Thirty-nine of the 55 samples were suitable for further histopathologic examination. Expression of TrkA was explored by immunohistochemical analysis. <h3>Exposure</h3> Diagnosis of MCC was confirmed by staining positive for cytokeratin 20 (CK20) and synaptophysin. <h3>Main Outcomes and Measures</h3> Expression of TrkA on the tumor cells. <h3>Results</h3> Specimens of 39 patients (21 women and 18 men; mean [SD] age, 75.0 [7.8] years) underwent immunohistochemical investigation. Thirty-eight of 38 specimens expressed CK20 and synaptophysin on the MCC tumor cells (100% expression). Merkel cell polyomavirus was detected in 32 of 38 specimens (84%). Tropomyosin receptor kinase A was found in all 36 evaluable specimens on the tumor cells; 34 (94%) showed a weak and 2 (6%) showed a strong cytoplasmic expression. In addition, strongly positive perinuclear dots were observed in 30 of 36 specimens (83%). <h3>Conclusions and Relevance</h3> Tropomyosin receptor kinase A was expressed on MCC tumor cells in 100% of evaluable specimens. This result may lead to the exploration of new targeted treatment options in MCC, especially for patients who do not respond to anti–programmed cell death protein 1 treatment.