tbuckley/cabot-search huggingface dataset:
S70 Mesenchymal Stem Cell Conditioned Media (MSC-CM) Suppress Wnt-3A and TGF-β1-Induced Myofibroblastic Differentiation
Authors: S Samad, KM Akram, NR Forsyth, M Spiteri
Journal: Thorax (2012)

<h3>Hypothesis</h3> Idiopathic pulmonary fibrosis (IPF) remains an incurable fibrotic lung disease. A mesenchymal stem cell (MSC)-mediated regenerative approach has been proposed; MSC-mediated anti-fibrotic effects have been demonstrated in animal lung-fibrosis models. However the mechanism of action and effect on myofibroblastic differentiation are unknown. The Wnt family member, Wnt-3a, has been implicated as an inducer of myofibroblastic differentiation in fibroblast cell models. This study explores the influence of MSC secreted factors on Wnt-3a and TGF-β1-induced lung myofibroblastic differentiation. <h3>Method</h3> Human normal lung (CCD-8Lu) and IPF (LL29) fibroblasts were differentiated with Wnt-3a for 72-hours and TGF-β1 for 24-hours. MSC-mediated differentiation inhibition was assessed by co-incubation of fibroblasts with MSC-CM and either Wnt-3a for 72-hours or TGF-β1 for 24-hours. TGF-β1-induced myofibroblastic differentiation reversal was explored with MSC-CM incubation for 24, 48 and 72-hours. Myofibroblast differentiation was assessed by immunocytochemical detection of α-smooth muscle actin expression. <h3>Results</h3> Myofibroblastic differentiation following TGF-β1 treatment was achieved in 86.27+2.57% CCD-8Lu cells and 86.69+2.51% LL29 cells respectively. Similar, though reduced, levels of myofibroblastic differentiation were achieved in 52.9±0.2% CCD-8Lu and 55.6±5.9% LL29 cells respectively following Wnt-3a treatment. In contrast, a percentage reduction in myofibroblastic differentiation was achieved in CCD-8Lu 31.40+1.44% and LL29 35.69+7.47% cells following exposure to TGF-β1 in the presence of MSC-CM versus TGF-β1 alone (p&lt;0.001). Similarly, we observed a striking percentage reduction in myofibroblastic differentiation following co-incubation with Wnt-3a and MSC-CM versus Wnt-3a alone (p&lt;0.001); 80.76±3.64% of CCD-8Lu and 79.67±3.94% of LL29 cells. A reversal of TGF-β1-induced myofibroblastic differentiation was observed following 72-hours administration of MSC-CM compared to serum-free culture media (p&lt;0.001). Interestingly, we observed a MSC-CM exposure duration effect on the total myofibroblast percentage present in both CCD8-Lu and LL29 cells; 81.7+0.43% and 73.26+0.70% respectively at 24-hours, 72.15+0.81% and 60.57+4.27% at 48-hours, 57.63+4.54% and 60.65+4.9% at 72-hours. <h3>Conclusion</h3> MSC-CM appears to inhibit fibroblast to myofibroblast differentiation, over-riding the pro-differentiation effects of Wnt-3a and TGF-β1. Whilst both TGF-β1 and Wnt-3a have emerged as key players in IPF pathogenesis, we are the first to demonstrate that MSC-CM may be crucial in modulating their pro-fibrogenic effects. These actions of MSC-CM demonstrate exploitative potential for future anti-IPF therapeutic strategies.
Reanalysis and Results after 12 Years of Follow-up in a Randomized Clinical Trial Comparing Total Mastectomy with Lumpectomy with or without Irradiation in the Treatment of Breast Cancer
Authors: Bernard Fisher, Stewart Anderson, Carol K. Redmond, Norman Wolmark, D. Lawrence Wickerham, Walter M. Cronin
Journal: New England Journal of Medicine (1995)

Previous findings from a clinical trial (Protocol B-06) conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) indicated the worth of lumpectomy and breast irradiation for treating breast cancer. After the discovery by NSABP staff members of falsified information on patients enrolled in the study by St. Luc Hospital in Montreal, separate audits were conducted at St. Luc Hospital and other participating institutions. We report the results of both audits and update the study findings through an average of 12 years of follow-up.
Managed Care Slowly Capturing A Share of Medicare
Authors: H. Mclntosh
Journal: JNCI Journal of the National Cancer Institute (1995)

Journal Article Managed Care Slowly Capturing A Share of Medicare Get access Hugh Mclntosh Hugh Mclntosh Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 87, Issue 18, 20 September 1995, Pages 1355–1357, https://doi.org/10.1093/jnci/87.18.1355 Published: 20 September 1995
PWE-021 Mtorc1 Mediated Translational Elongation Is Limiting For Intestinal Tumour Initiation And Growth
Authors: WJ Faller, TJ Jackson, RA Ridgway, JR Knight, T Jamieson, M Pende, AG Ryazanov, N Sonenberg, O Meyuhas, M Bushell, MN Hall, AE Willis, OJ Sansom
Journal: Gut (2014)

<h3>Introduction</h3> The loss of Apc, causing Wnt-mediated epithelial proliferation, is an early event in colorectal cancer (CRC) development. This hyperproliferative state requires signalling though the mTOR pathway, with the current paradigm suggesting that upregulation of translation initiation via phosphorylation of 4EBP1 is crucial. This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 function, would be ineffective in limiting development and progression of intestinal adenomas. <h3>Methods</h3> The inducible <i><i>in vivo</i></i> mouse models Lgr5Cre<sup>ER</sup> and VillinCre<sup>ER</sup> were used to selectively flox genes from intestinal stem cells and crypts respectively. mTOR complex 1 signalling was inhibited in Apc<sup>fl/fl</sup> mice either by rapamycin treatment or co-floxing the mTORC1 essential component Raptor. Translational status was assessed by sucrose gradient ultracentrifugation of intestinal epithelial extract from these mice and <sup>35</sup>S methionine incorporation and harringtonine chase assays on organoid cultures. The role of downstream mTORC1 effectors was established by assessing the intestinal regeneration following IR irradiation of 4EBP1/2<sup>DKO</sup>, S6K1/2<sup>DKO</sup>, rpS6<sup>mut</sup> and eEF2k<sup>-/-</sup> mice. Survival studies for Apc<sup>fl/fl</sup> mice treated with rapamycin were performed both prior to, and on development of, symptoms <h3>Results</h3> mTORC1 activity is absolutely required for the proliferation of Apc deficient, but not wild type, intestinal crypts. Surprisingly, although protein synthesis is increased in Apc<sup>fl/fl</sup> crypts, it is translation elongation and not initiation that is the rate limiting step. Mechanistically, the inhibition of eukaryotic elongation factor (eEF2) kinase, to increase eEF2 activity downstream of mTORC1 and S6K is required for Wnt-mediated proliferation after IR irradiation. Treatment of established Apc<sup>fl/fl</sup> adenomas with rapamycin (which inhibits the mTORC1-S6K-eEF2k-eEF2 axis) arrests tumour growth and prolongs life. Furthermore, rapamycin treatment of mice immediately following homozygous Apc loss prevents the onset of symptoms. <h3>Conclusion</h3> These data show that intestinal adenoma formation and growth requires an mTOR mediated increase in translation elongation. Treatment of patients at high risk of developing CRC, such as those with Familial Adenomatous Polyposis, with Rapalogs may therefore be of therapeutic value. <h3>Disclosure of Interest</h3> None Declared.
FRI0416 Remission definitions affect cost savings estimates in anti-TNF treated rheumatoid arthritis patients:
Authors: C. Barnabe, N.X. Thanh, A. Ohinmaa, S.G. Barr, J. Homik, L. Martin, W.P. Maksymowych
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Multiple remission definitions have been proposed for rheumatoid arthritis (RA), including the 2011 ACR/EULAR Boolean Definition, SDAI ≤3.3, CDAI ≤2.8, and DAS28 ≤2.6. The stringency of the definition affects the proportion of patients classified as being in remission. We hypothesized that the remission definition used will also affect the estimates of cost-savings observed in anti-TNF treated patients. <h3>Objectives</h3> To compare total healthcare costs, RA-attributable costs, and non-RA attributable costs across different definitions of remission. <h3>Methods</h3> We determined healthcare utilization (physician visits, outpatient department visits, and hospitalizations) from a provincial administrative database (years 2004-2009) for a prospective cohort of anti-TNF treated RA patients (n=1,086, mean age 54 years). We compared the mean annual costs (standardized to 2008 Canadian dollars) for individuals achieving a minimum 1 year period of remission for each definition above. A propensity score matching technique was used to account for confounding by individual variables affecting healthcare utilization (including therapy received, baseline function, smoking, age, sex, disease duration and medical comorbidities). <h3>Results</h3> The proportion of patients attaining a 1 year remission period by the DAS28 definition was 16%, compared to 9% for the ACR/EULAR Boolean definition, 6% for the CDAI definition, and 4% for the SDAI definition. The mean reduction in HAQ score was similar across remission definitions, (0.85 for DAS28 remission, 0.80 for ACR/EULAR remission, 0.60 for SDAI remission, and 0.84 for CDAI remission). The estimated cost savings observed varied by the remission definition that was used. The mean annual total cost difference between patients attaining SDAI remission relative to those that did not was estimated at $1904 (95%CI 112,2964), compared to $1630 (95%CI 1016,2508) for DAS28 remission, and $1266 (95%CI 517,2138) for the ACR/EULAR Boolean definition. The difference in cost for for those patients achieving CDAI remission relative to those that did not was not significant at $430 (95%CI -3319, 2214). These savings occurred predominantly in non-RA attributable costs for all definitions except the CDAI (Table 1). <h3>Conclusions</h3> The magnitude of the cost savings observed with anti-TNF treatment varies according to the remission definition used in classifying patient disease status. The best cost-savings was observed in patients attaining SDAI remission, and the least was with the CDAI. Improvements in physical function likely contribute to these savings. Cost-effectiveness evaluations should consider various remission definitions in their analyses. <h3>Disclosure of Interest</h3> None Declared
SAT0535 Sensitivity and Reproducibility of Ultrasonography in Calcium Pyrophosphate Crystal Deposition: A Case-Control Study
Authors: P.-A. Juge, S. Ottaviani, A. Aubrun, E. Palazzo, P. Dieudé
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Calcium pyrophosphate disease (CPPD) is a common disease characterized by deposition of calcium pyrophosphate (CPP) crystals in joints and tendons. The diagnosis is made by identification of CPP crystal in synovial fluid analysis or by imaging such as X-rays or ultrasound (US). However, the performance of the two imaging procedures in the diagnosis of CPPD was poorly studied. <h3>Objectives</h3> The aim of the study was to investigate the reproducibility of US and its ability to detect CPP deposition in comparison to conventional X-rays. <h3>Methods</h3> To be included in this single-centre case-control study, patients needed to have painful knee effusion. The final diagnosis of CPPD was proven by identification of CPP crystals in synovial fluid analysis. All patients underwent a clinical evaluation, X-rays of knees in both anteroposterior and lateral views and US evaluation. All US exams were bilaterally performed by 2 rheumatologists blinded to clinical, laboratory, US and radiographic results. Knees cartilage was explored on the transversal and longitudinal suprapatellar plane in maximal flexion. Lateral and medial menisci of the knees were assessed in moderate flexion (30°) and complete extension. Presence of hyperechoic spots in cartilage and menisci were assessed for both knees. Interobserver agreement between the 2 sonographers was estimated using the k coefficient. <h3>Results</h3> A total of 32 patients (56% of males, mean age: 66.5±15.6 years) with knee effusion were included. Synovial fluid analysis revealed CPP crystals in 16 (50%) patients. Control patients were diagnosed gout (n=6), osteoarthritis (n=6), rheumatoid arthritis (n=2) and spondyloarthritis (n=2). Among the 16 patients with CPP crystals, US revealed hyperechoic spots in menisci and/or cartilage in all patients (Se: 100%, Sp=87.5%) whereas X-rays showed CPPD in 9 patients (Se: 56%, Sp: 100%) (<i>P</i>=0.002). Accuracy of US and X-rays was 93.8% and 78.1%, respectively. Calcifications of menisci were detected by US in 15 (93.7%) of the 16 CPPD patients and in 2 (13.5%) of 16 control patients. Hyperechoic spots of cartilage were noted among CPPD and control group, in 12 (75%) and 1 (6.2%) patients, respectively. Agreement between the 2 sonographers was almost perfect for US CPPD (menisci and/or cartilage calcifications) diagnosis (k=0.87), menisci (k=0.81) and cartilage calcification (k=0.81). <h3>Conclusions</h3> Our study confirms that US of knees is more sensitive than X-rays for the diagnosis of CPPD despite lower specificity. Additionally, the reproducibility of US was good. Thus, US appears to be useful for the diagnosis of CPPD. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3849
AB0588 Experience of tocilizumab using for resistant adult-onset still’s disease
Authors: Y. Muraviev, M. Podryadnova, E. Nasonov
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Adult onset Still's disease (AOSD) is the systemic inflammatory disease. Blockade of interleukin receptors (IL-6) neutralizes the induction of acute phase reaction, which could be used in the therapy of the resistant AOSD. <h3>Objectives</h3> To assess Tocilizumab efficacy in the resistant AOSD. <h3>Methods</h3> The study included 6 women and 1 man with AOSD adopted to clinical department of the Institute, corresponding to Yamaguchi et al criteria, average age 34.2±10.7 y/o, average disease duration – 4.7±4.0 years who regularly had NSAIDs, prednisolone 17.5-50 mg/day, methotrexate 10-15 mg/week. <h3>Results</h3> All included into the study pts, in spite of drug treatment, demonstrated fever &gt;39°C, typical rush, arthritides, leukocytosis &gt;10×10<sup>9</sup>/l, in 5 –throat pain, in 4 – hepatic disturbances and lymphadenopathy, which was the basis for Tocilizumab prescription in doses 8mg/kg of body weight every 4 weeks. After the first Tocilizumab infusion: temperature was normal in 6 pts in 24 hrs and in 1 in 48 hrs; arthritis symptoms disappeared in 2 pts and significantly subsided in 5; CRP level subsided in all pts. Therapy is continued in 6 pts (2-11 infusions). AOSD remission was noticed in 1 patient, improvement in 56. <h3>Conclusions</h3> Tocilizumab can be the drug of choice in the resistant AOSD. <h3>Disclosure of Interest</h3> None Declared
Abstract 2370: A novel Src/Ezrin pathway regulates local invasion and metastasis of breast
Authors: Hannah Mak, Alexandra Naba, Sonal Varma, Jalna Meens, Monique Arpin, Sandip SenGupta, Bruce E. Elliott
Journal: Cancer Research (2010)

Abstract The membrane cytoskeletal crosslinker, ezrin, is frequently over-expressed in human breast cancer, and is required for motility and invasion of epithelial cells. Our group recently showed that ezrin acts co-operatively with the non-receptor tyrosine kinase, Src, in transformation of epithelial cells, requiring phosphorylation of specific tyrosines on ezrin by Src (Srivistava et al. MBC, 16:1481-90, 2005; Naba et al. EMBO J. 27:38-50, 2008). We showed that Src binds to ezrin Y190 via its SH2 domain and that ezrin Y145 and Y477 are phosphorylated by Src. Expression of Y145F or Y477F ezrin mutants, which cannot be phosphorylated by Src, delays cell spreading of epithelial cells on fibronectin substratum. Furthermore, ezrin is required for metastasis in a breast tumor xenograft model (Elliott et al. BCR 7:R365-73, 2005). We therefore examined whether Src/ezrin interaction regulates invasion and metastasis of breast cancer, using a mouse breast tumor (AC2M2) xenograft model. Transplanted tumor cells expressing vector alone rapidly infiltrated into surrounding stroma, underlying abdominal muscle, visceral organs and metastasized to lung and other sites. Interestingly, both Y145F and Y477F ezrin mutants had little effect on primary tumor growth rate. However, Y145F ezrin showed a marked attenuating effect on pulmonary metastasis. Furthermore, transplanted mouse breast carcinoma cells over-expressing Y477F ezrin formed cohesive tumors that were circumscribed by normal stroma with no detectable infiltration into underlying muscle. Marked lymphovascular involvement, a prognostic indicator of relapse in clinically advanced human breast cancers, was evident in control tumors but not in tumors expressing Y477F ezrin. In a preliminary IHC analysis, total ezrin showed strong cytoplasmic and weak membranous staining in the cortical region of control primary tumors, but showed strong membranous and weak cytoplasmic staining in Y477F ezrin-expressing primary tumors. The cohesive phenotype of Y477F ezrin is likely a consequence of a defect in cell adhesion as described by Naba et al. Thus, the precise state of ezrin phosphorylation may elicit different effects on local invasion and metastasis. Our study implicates a role of the Src/ezrin pathway in regulating local invasion and metastasis of breast carcinoma cells, and provides a clinically relevant model for assessing the Src/ezrin pathway as a potential prognostic marker and treatment target for invasive breast cancer. (Funded by CBCRA 17374 and ARC 4823) 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 2370.
Secondary Disaccharidase Deficiency in Adult Celiac Disease (Nontropical Sprue) and Other Malabsorption States
Authors: Gerald R. Plotkin, Kurt J. Isselbacher
Journal: New England Journal of Medicine (1964)

IN the absorption of disaccharides from the intestine, hydrolysis of the sugars into their component monosaccharides is necessary. Largely through the elegant studies of Crane and his associates,1 , 2 it is now recognized that this hydrolysis occurs not primarily in the lumen of the intestine as previously believed but more probably just within the epithelial cells of the mucosa. It has been demonstrated that the various specific hydrolytic enzymes (disaccharidases) are localized predominantly in the brush-border region (microvilli) of the mucosal cells.Over the past five years reports from a number of laboratories have shown the occurrence of primary or hereditary . . .
Final analysis of the ECOG I-COPA trial (E6484) in patients with non-Hodgkin's lymphoma treated with interferon alfa (IFN-α2a) plus an anthracycline-based induction regimen
Authors: RV Smalley, E Weller, MJ Hawkins, MM Oken, MJ O'Connell, S Haase-Statz, EC Borden
Journal: Leukemia (2001)
Abstract 3732: Inflammatory breast cancer rates among different ethnic and racial groups in the United States
Authors: Sharareh Reihani, Igor Akushevich, Joellen Schildkraut, Dora Il'yasova
Journal: Cancer Research (2011)

Abstract Inflammatory breast cancer (IBC) is considered to be the most aggressive form of breast cancer. In the US, the proportion of incidences of IBC cases ranges from 2% to 5%. Understanding the determinants of IBC rates among different populations may help to design prevention strategies. Internationally, IBC rates have been linked to socioeconomic status (SES). In the US, the analysis of the National Cancer Institute Surveillance Epidemiology and End Results (SEER) data for the period of 1988-2000, and data for 1994-1998 from the North American Association of Central Cancer Registries demonstrated greater IBC rates among Blacks compared to Whites and similar rates among Whites and Hispanics. However, the Hispanic population in the US has grown significantly in the last decade and its SES status is generally lower compared to non-Hispanic Whites. Therefore, we hypothesized that IBC rates in Hispanics have increased since the reported rates from 1994-1998 and are higher than among Whites. We used the SEER database to estimate age-adjusted and age-specific rates of IBC among ages 20-84 in three racial/ethnic groups: Whites, Blacks, and Hispanics (including both Whites and Blacks). IBC cases were categorized using Common Stage Extension Codes 71-73. Age-specific IBC rates were estimated for three age-groups: 20-45 (pre-menopausal), 45-60 (peri-menopausal), and 60-84 (post-menopausal). During 2004-2007, a total of 3107 IBC cases were diagnosed among the 20-84 year old population covered by the SEER registries. Among them, 2436 cases were diagnosed in Whites, 470 in Blacks, and 403 in Hispanics. Age-adjusted rates among Blacks were ∼ 1.4-fold greater than in Whites, whereas rates among Hispanics were ∼1.4-fold lower than Whites and ∼2-fold lower than Blacks. Age-specific rates among Blacks were greater than among Whites at all ages. Age-specific rates among Hispanics in pre- and peri-menopausal groups were similar to Whites, but became lower after menopause, which could account for overall lower age-adjusted rates among Hispanics. In summary, our analysis indicates different IBC rates in Whites, Blacks, and Hispanics. New information about lower IBC rates among Hispanics poses a question of what accounts for these differences. Further investigations of the ethnic/racial rates disparities may elucidate the underlying risk factors for IBC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3732. doi:10.1158/1538-7445.AM2011-3732