tbuckley/cabot-search huggingface dataset:
Abstract 1311: ATR inhibition sensitizes p53-deficient cancer cells to chemotherapeutic drugs
Authors: Niquiche Sangster-Guity, Bogdan H.M. Conrad, Fred Bunz
Journal: Cancer Research (2010)

Abstract PURPOSE: We sought to determine whether genetic inhibition of the ATR kinase would preferentially sensitize p53-deficient cancer cells to therapeutic agents that cause replication stress. EXPERIMENTAL PROCEDURES: Previous studies have shown that p53-deficient cancer cells harboring hypomorphic ATR alleles are highly sensitive to DNA damaging agents and DNA replication inhibitors that are commonly used in the clinic. We hypothesize that p53-dependent cell cycle checkpoints would prevent damaged, ATR-deficient cells from entering S-phase and mitosis, and thereby enhance cell survival. To test this hypothesis, we used a gene targeting approach to knock-in wild type p53 into cells with wild type and hypomorphic ATR alleles. The combined effects of ATR and p53 were determined by clonogenic survival assays, flow cytometry and analysis of apoptotic proteins. SUMMARY: RNAi-mediated knockdown of ATR in p53-deficient cells caused reduced survival after cisplatin treatment, compared with knockdown of ATR in isogenic p53-proficient cells. To unambiguously test whether ATR inhibition preferentially sensitizes p53-deficient cancer cells, we used a knock-in vector to replace a p53-mutant allele with a wild type allele. Homologous recombinant cells expressed wild type p53 protein and the p53 target proteins p21 and p53R2, demonstrating restoration of a functional p53 pathway. Knock-in of wild type p53 restored the G1/S checkpoint induced by ionizing radiation. Most significantly, genetic restoration of the p53 pathway rescued the survival defect of the ATR-deficient cells in response to chemotherapeutic drugs. CONCLUSIONS: Our data provide genetic evidence that p53 and ATR function synergistically to enhance the survival of human cancer cells treated with agents that cause DNA replication stress. We propose that pharmacologic inhibition of ATR would cause enhanced killing of cells with loss of p53 function following treatment with DNA replication inhibitors and DNA crosslinking agents, thereby increasing their therapeutic index. 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 1311.
A9.18 Potential Therapeutic Application of Human Umbilical Cord wharton Jelly Derived Mesenchymal Stem Cells in Primary Sjögren’s Syndrome
Authors: Alessia Alunno, Pia Montanucci, Sara Caterbi, Onelia Bistoni, Giuseppe Basta, Elena Bartoloni, Teresa Pescara, Ilaria Pennoni, Riccardo Calafiore, Roberto Gerli
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and Objectives</h3> hUCMS are adult stem cells easy to retrieve in bulk, under acceptable ethical conditions. Their immune-modulatory and pro-differentiation properties have been widely demonstrated. Modulation of the immune system is mediated by both cell contact and soluble factors such as interferon (IFN)-γ produced by hUCMS. Very few evidence is currently available with respect to potential therapeutic application of hUCMS in systemic autoimmune disorders. In particular, no data have been published in primary Sjögren’s syndrome (pSS) to date. Furthermore, we have recently developed an endotoxin-free alginate matrix which can be used to microencapsulate (CpS) different cell types and transfer them into a non-immunosuppressed host. These microcapsules containing pancreatic islets, upon approval by the Italian Ministry of Health for in vivo use, have been grafted into a cohort of patients with type 1 diabetes mellitus with no adverse effects, while proving to be immunoprotective. On this background, we aimed to assess the in vitro immune system modulation by IFN-γ pretreated CpS-hUCMS on T cells from pSS, with special regard to Th17- and Treg-cell subsets. <h3>Materials and Methods</h3> Ten pSS patients and 5 healthy donors (HD) were enrolled. Peripheral blood mononuclear cells (PBMC) were obtained by density gradient from heparinised venous blood. Co-cultures of CpS-hUCMS and PBMCs were arranged at different ratios. Lymphocyte proliferation was assessed by CFSE dilution assay. Phenotypic analysis by flow cytometry for regulatory and effector T cell subpopulations was performed after culture. Real time PCR analysis and the evaluation of culture supernatants for cytokine expression are currently ongoing. <h3>Results</h3> CpS-hUCMS were able to inhibit HD and pSS PBMC cell proliferation and this effect was inversely correlated to hUCMS number. Phenotypic analysis revealed a predominant Th17-cell response in SS which was promptly hampered by CpS-hUCMS Moreover, Th1-cell proliferation was fair and reduced Cps-hUCMS FoxP3 and IL-17 expression among CD4<sup>+</sup> T cells was also modulated by CpS-hUCMS, thereby suggesting that a Treg/Th17 rebalance. <h3>Conclusions</h3> This is the first study evaluating the effects of hUCMSS on T cells in pSS. It appeared that CpS-hUCMS rebalance Treg/Th17 ratio and therefore may exert therapeutic effects in such disease. Furthermore, it is the first study that employs a new technology of drug delivery which may be applied in vivo in pSS patients.
Abstract 4248: A high-fat diet induces an inflammatory tumor microenvironment in MNU-induced estrogen receptor positive mammary tumors
Authors: Shuangping Zhao, Jonna Frasor
Journal: Cancer Research (2012)

Abstract The link between obesity and breast cancer has received much attention because it is associated with an increased risk of breast cancer, an increased incidence of recurrence, higher death rates, and reduced sensitivity to anti-hormonal therapy in post-menopausal women. In addition, obesity is associated with a chronic, low grade inflammatory status. Surprisingly, obesity can have different effects in pre-menopausal women where patient outcome is actually better in obese than lean women. This study was conducted to create an animal model to examine the effects of high-fat (HF) diet on estrogen-dependent mammary tumors in cycling rats. Sprague-Dawley rats were injected with N-Methyl-N-Nitrosourea (MNU) at 6 weeks of age to induce mammary tumors. The next day they received HF diet (45% kcal from fat) or normal fat (NF) diet (10% fat) (n=6-7) and animals were kept on these diets for an average of 15 weeks. Ninety-six percent of rats developed mammary tumors and all the tumors were ER positive. The tumor volume, tumor weight and tumor growth rate were not different between the HF or NF diet groups. Also, the HF diet did not influence the body weight, liver weight and adipose mass weight. However, the expression of pro-inflammatory cytokines, such as TNFa and IL-1b, was significantly up-regulated in tumors of the HF diet group compared to control. Macrophage infiltration was also increased in the tumors of the HF diet group. There was also a tendency of increased NFkB DNA binding activity in the HF diet group. Moreover, macrophage infiltration was significantly correlated with the amount of proinflammatory cytokine gene expression in the HF but not the NF diet group. In agreement with clinical data, cycling rats on the HF diet responded better to tamoxifen than did rats on the NF diet, with a greater reduction in tumor size over 20 days of treatment. Taken together, these results indicate that a HF diet induces a pro-inflammatory tumor microenvironment without causing obesity in cycling rats and that these tumors may be more responsive to endocrine therapy. Our findings also provide a model for future studies into the mechanism by which high fat diet may affect tumor growth and response to therapy in premenopausal women. 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 4248. doi:1538-7445.AM2012-4248
Abstract 198: Identification of differentially expressed microRNAs and other non-coding RNAs in ependymomas
Authors: Fabricio F. Costa, Jared M. Bischof, Elio F. Vanin, Rishi R. Lulla, Simone T. Sredni, Veena Rajaram, Min Wang, Gabriel Renaud, Fabio Passetti, Tadanori Tomita, Stewart Goldman, Maria F. Bonaldo, Marcelo B. Soares
Journal: Cancer Research (2012)

Abstract Ependymomas are tumors that present great challenges in treatment despite the advances in neurosurgical techniques and adjuvant therapy. In order to identify possible molecular markers that could improve clinical management and better treatment, we have profiled ependymomas for the expression of microRNAs (miRNAs) and other non-coding RNAs (ncRNAs). miRNAs are ncRNAs that can block mRNA translation and affect mRNA stability. Several lines of evidence have recently shown that up or down-regulation of miRNAs correlate with many human cancers indicating that they can function as classical tumor suppressors and/or oncogenes. In this study, we have evaluated with the use of TaqMan Low Density Arrays (TLDAs) and RNA-Seq the expression profiles of non-coding RNAs in ependymoma samples and normal brain tissue. We analyzed the miRNA expression profile of 34 ependymoma samples using paraffin tissue compared to 6 normal brain control samples enriched for ependymal cells. miRNA expression profiles were correlated with clinico-pathological parameters, morphological features and the location of the tumor in the brain. We have been able to classify the tumors based on the miRNA expression profile and to identify miRNAs that are differentilly expressed in ependymomas when compared to normal samples. For example, miR-135a, miR-594 and miR-34a were identified as over-expressed and miR-485-5p and miR-383 as down-regulated (p&amp;lt;0.01; FDR&amp;lt;0.05). We have also identified and are currently confirming some of the targets for these miRNAs. Finally, we have utilized high-throughput Whole Transcriptome (WT) analyses with the SOLiD system to identify other differentially expressed miRNAs and long ncRNAs in ependymomas. The transcriptome of 3 ependymomas and 2 controls were sequenced, thus generating approximately 5 Gb of data. In conclusion, using different strategies, we have been able to identify ncRNAs that are differentially expressed in ependymomas compared to normal ependymal tissue, some of which are of clinical importance. Financial Support: Children's Memorial Research Center, The Falk Brain Tumor Foundation and The Maeve McNicholas Memorial Foundation. 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 198. doi:1538-7445.AM2012-198
Levels of Antibodies to Cow's Milk and Β-Lactoglobulin Associate With the Age at Onset of Clinical IDDM and the Type of Infant Feeding: Reply to Lorini et al
Authors: Erkki Savilahti, Tero T Saukkonen, Hans K Åkerblom, Suvi M Virtanen, Gisela Dahlquist
Journal: Diabetes Care (1994)
Correlation of Growth Capacity of Human Tumor Cells in Hard Agarose With Their In Vivo Proliferative Capacity at Specific Metastatic Sites
Authors: L. Li, J. E. Price, D. Fan, R.-d. Zhang, C. D. Bucana, I. J. Fidler
Journal: JNCI Journal of the National Cancer Institute (1989)

The purpose of this study was to determine whether the degree of anchorage-independent growth of human tumor cells in increasing concentrations of agarose correlated with the capacity of the cells to produce experimental metastases in nude mice. Human melanoma, breast carcinoma, and colon carcinoma cells from parental lines and variants selected in vivo for metastasis and in vitro cloned lines were plated into medium containing 0.3%, 0.6%, 0.9%, or 1.2% of agarose. These cells were also injected into nude mice: intravenously for melanoma, into the mammary fat pad for breast carcinoma, and into the spleen for colon carcinoma. Production of tumor cell colonies in dense agarose (greater than 0.6%) correlated with production of experimental metastases in the lung (melanoma, breast carcinoma) or liver (colon carcinoma). We conclude that the degree of anchorage-independent growth of tumor cells can predict their biological behavior and metastatic potential in vivo. Thus, this technique may be useful for the isolation of metastatic cells from heterogeneous human neoplasms.
SC-04 * NON-UNIFORM NOTCH SIGNALING UNDERLIES HETEROGENEITY WITHIN THE GLIOBLASTOMA STEM CELL POPULATION
Authors: N. Sumru Bayin, S. Si, A. Modrek, H.-R. Song, D. Zagzag, D. M. Hoang, Y. Z. Wadghiri, I. Dolgalev, M. Baysan, A. Heguy, M. H. Barcellos-Hoff, D. Placantonakis
Journal: Neuro-Oncology (2014)

Glioblastoma stem cells (GSCs) have the ability to self-renew, differentiate into tumor lineages, and give rise to tumors in immunodeficient animal models. More importantly, GSCs are resistant to current therapies, leading to tumor recurrence. Glioblastoma (GBM) is highly heterogeneous at the molecular and cellular level. This heterogeneity also exhibits itself within the stem cell compartment, further impairing the development of effective therapies. CD133+ GSCs cells have increased tumorigenicity. However, the facts that CD133- cells also give rise to tumors in animal models and that some tumors do not have a CD133+ cell population suggest that CD133 is not a universal GSC marker. The Notch signaling pathway, previously believed to be activated in CD133+ GSCs, is important for GSC self-renewal and therapy resistance. To study GSC heterogeneity, we used genetic reporters for Notch activation and made the surprising observation that Notch signaling is active in small populations of cells that do not express CD133 (CD133-/Notch + ; n = 3 primary GBM cultures). Our in vitro tumorsphere formation and in vivo tumor formation assays showed that both CD133 + /Notch- and CD133-/Notch+ cells have stem cell properties. Global transcriptome analysis revealed that CD133 + /Notch- and CD133-/Notch+ GSCs utilize differential transcriptional programs, which prime CD133 + /Notch- GSCs to rely on anaerobic glycolysis. Furthermore, CD133/-Notch+ cells are able to give rise to CD133 + /Notch- cells, although the converse does not occur. This finding suggests that the two cell types have distinct differentiation potentials. Finally, preliminary data suggest that these two GSC subtypes behave differentially in response to temozolomide and radiation treatment, which are the standard of care for GBM. We are currently testing the contribution of distinct GSCs to tumor heterogeneity in vivo, using lineage-tracing systems. Understanding the biology of GSCs and the functional importance of heterogeneity within GSC populations is critical for the design of novel therapies.
Transitions to different patterns of interstitial lung disease in scleroderma with and without treatment
Authors: Hyun J Kim, Donald P Tashkin, David W Gjertson, Matthew S Brown, Eric Kleerup, Semin Chong, John A Belperio, Michael D Roth, Fereidoun Abtin, Robert Elashoff, Chi-Hong Tseng, Dinesh Khanna, Jonathan G Goldin
Journal: Annals of the Rheumatic Diseases (2016)

The aim is to investigate whether the 12-month quantitative changes in high-resolution CT (HRCT) measures of interstitial lung disease (ILD) are different, and to understand how they change, in patients with scleroderma-related ILD who receive drug therapy versus placebo.HRCT images were acquired at baseline and at 12 months in 83 participants in Scleroderma Lung Study I, a clinical trial comparing treatment with oral cyclophosphamide versus placebo. A computer-aided model was used to quantify the extent of fibrotic reticulation, ground glass and honeycomb patterns and quantitative ILD (QILD: sum of these patterns) in the whole lung and the lung zone (upper, middle or lower) of maximal disease involvement.Mean QILD score decreased by 3.9% in the cyclophosphamide group while increasing by 4.2% in the placebo group in the most severe zone (p=0.01) and decreased by 3.2% in the cyclophosphamide group while increasing by 2.2% in the placebo group in the whole lung (p=0.03). Transitional probabilities demonstrated greater changes from a fibrotic to either a ground glass or normal pattern in the cyclophosphamide group and the reverse in the placebo group.Changes in quantitative HRCT measures of ILD provide a sensitive indication of disease progression and response to treatment.NCT00004563; Post-results.
AB1363 Consequences of inflammatory arthritis for productivity loss at work and sick leave: A systematic review
Authors: M.-L.B. Lenssinck, A. Burdorf, A. Boonen, M.A. Gignac, J.M. Hazes, J.J. Luime
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> From onset of IA onwards, the consequences for participation are substantial for the individual patient. Reduced work participation frequently occurs early in the course of the disease.Research in the field of arthritis and employment has focused mainly on permanentwork disability (i.e. arthritis related unemployment, early retirement, or disability pension) and its underlying risk factors (1-4). <h3>Objectives</h3> To review research on the occurrence and magnitude of productivity loss at work and sick leave in inflammatory arthritis (IA) patients and to identify its determinants. <h3>Methods</h3> PubMed, EMbase, PsycINFO and CINAHL articles to November 2011on IA and productivity loss at work or sick leave were reviewed. Methodological quality was assessed usinga criteria list developed by the authors. <h3>Results</h3> Forty-one original studies were identified. Sick leave in IA patients varied from 3.7% in the past four days to 84% in the past 2.5 years. Total duration of sick leave ranged from 0.33 days to 11 days per patient over one month. Six studies reported on 29 different determinants of sick leave of which pain and functional disability were consistently associated. About 17% to 88% of IA patients experienced productivity loss at work. Three studies investigated determinants. Tumor necrosis factor inhibitors (TNFi) were associated with reduced productivity loss at work and sick leave in the trials evaluated. The included studies showed heterogeneity in populations, definitions and measurements of productivity loss at work and sick leave. <h3>Conclusions</h3> Early inflammatory arthritis impacts on worker productivity but its estimated magnitude varies. Higher levels of sick leave and productivity loss at work were reported for increased levels of pain and decreased levels of functional ability. TNFi use decreased both sick leave and productivity loss at work. <h3>References</h3> Burton W, Morrison A, Maclean R, Ruderman E. Systematic review of studies of productivity loss due to rheumatoid arthritis. Occup Med (Lond) 2006;56(1):18-27. de Croon EM, Sluiter JK, Nijssen TF, Dijkmans BA, Lankhorst GJ, Frings-Dresen MH. Predictive factors of work disability in rheumatoid arthritis: a systematic literature review. Ann Rheum Dis 2004;63(11):1362-7. Detaille SI, Heerkens YF, Engels JA, van der Gulden JW, van Dijk FJ. Common prognostic factors of work disability among employees with a chronic somatic disease: a systematic review of cohort studies. Scand J Work Environ Health 2009;35(4):261-81. Lacaille D. Arthritis and employment research: where are we? Where do we need to go? J Rheumatol Suppl 2005;72:42-5. <h3>Disclosure of Interest</h3> None Declared
FRI0451 Extra-Corporeal Membrane Oxygenation and Diffuse Alveolar Haemorrhage - A Single Centre CASE Series and Analysis of the ELSO Database: Table 1
Authors: C.Y. Ling, T. Simpson, G. Glover, B. Nicholas, D. D'Cruz
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Diffuse alveolar haemorrhage (DAH) is a rare and potentially fatal complication of the systemic vasculitides<sup>1</sup>. DAH may present as a severe acute respiratory distress syndrome (ARDS) with reported mortality of 12- 60%<sup>1.</sup> Whilst extracorporeal membrane oxygenation (ECMO) improves outcomes in ARDS<sup>2</sup>, use of ECMO in DAH may be considered to be relatively contraindicated due to the requirement for systemic anticoagulation. <h3>Methods</h3> A case series of 4 patients with DAH due to ANCA vasculitides diagnosed and or managed by a standardised diagnostic pathway and ARDS treatment algorithm in a single, UK SRF centre, between 2012-13. Analysis of the Extracorporeal Life Support Organisation (ELSO) database using ICD-9 codes 446.2,446.21,446.4,446.6 to report the current international experience of DAH and ECMO<sup>3</sup>. <h3>Results</h3> 4 patients with ARDS due to systemic vasculitides were referred via the SRF pathway, but only 3 patients required ECMO (range 120 – 208 hours). 1 patient received a normal protocol heparin regime to target an APTTr of 1.5-2 whilst two patients had 48 hours of ECMO with no heparin followed by low-dose heparin. ICU survival and six months survival were 100% and there were no exacerbations of pulmonary haemorrhage and no clotting complications. The ELSO database contains 78 patients (adult,59; paediatric,19) with pulmonary vasculitides who received ECMO. 43 had GPA, whereas the remaining diagnoses included hypersensitivity angiitis, Goodpasture9s syndrome and thrombotic microangiopathy. The median age was 23 years old (IQR: 16-47). The median duration of ECMO was 190 hours (IQR: 146-282) and ICU survival was 82%. Twelve patients (15%) were reported to have thrombotic ECMO circuit complications in the context of likely conservative heparinisation. <h3>Conclusions</h3> In this case series, ECMO offers an excellent survival rate and clinical outcomes in SRF due to ANCA-associated DAH. ELSO data supports our case series and suggests that DAH related to vasculitides should not be considered a contraindication. ECMO should be considered as supportive therapy in DAH patients with SRF not responsive to conventional therapy. <h3>References</h3> Sugimoto T et al. Pulmonary-renal syndrome, diffuse pulmonary haemorrhage and glomerulonephritis, associated with Wegener9s granulomatosis effectively treated with early plasma exchange therapy. Intern Med 2007;46:49-53. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet 2009;374:1351-63. ECMO Registry of the Extracorporeal Life Support Organization (ELSO), Ann Arbor, Michigan,June (2013). <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4191
Arthritis in the Mediterranean Theater of Operations
Authors: Charles L. Short
Journal: New England Journal of Medicine (1947)

LIKE other organs of the body, the joints are subject to many different forms of disease and injury of both known and unknown etiology. Since this paper deals chiefly with the medical aspects of joint disorders, strictly surgical conditions, such as the immediate effects of trauma and articular infection associated with wounds, have been excluded. Diseases and injuries of the bones, muscles, tendons, bursas and other supporting structures were not studied unless there was subjective or objective evidence pointing toward joint involvement. The conditions variously labeled arthralgia, myositis, myalgia and fibrositis, although not strictly forms of arthritis, were included, since . . .