tbuckley/cabot-search huggingface dataset:
Regulation of Early Cartilage Destruction in Inflammatory Arthritis by Death Receptor 3
Authors: Eddie C. Y. Wang, Zarabeth Newton, Olivia A. Hayward, Stephen R. Clark, Fraser Collins, William V. Perks, Ravinder K. Singh, Jason P. Twohig, Anwen S. Williams
Journal: Arthritis & Rheumatology (2014)

To investigate the role of death receptor 3 (DR-3) and its ligand tumor necrosis factor-like molecule 1A (TL1A) in the early stages of inflammatory arthritis.Antigen-induced arthritis (AIA) was generated in C57BL/6 mice deficient in the DR-3 gene (DR3(-/-) ) and their DR3(+/+) (wild-type) littermates by priming and intraarticular injection of methylated bovine serum albumin. The joints were sectioned and analyzed histochemically for damage to cartilage and expression of DR3, TL1A, Ly-6G (a marker for neutrophils), the gelatinase matrix metalloproteinase 9 (MMP-9), the aggrecanase ADAMTS-5, and the neutrophil chemoattractant CXCL1. In vitro production of MMP-9 was measured in cultures from fibroblasts, macrophages, and neutrophils following the addition of TL1A and other proinflammatory stimuli.DR3 expression was up-regulated in the joints of wild-type mice following generation of AIA. DR3(-/-) mice were protected against cartilage damage compared with wild-type mice, even at early time points prior to the main accumulation of Teff cells in the joint. Early protection against AIA in vivo correlated with reduced levels of MMP-9. In vitro, neutrophils were major producers of MMP-9, while neutrophil numbers were reduced in the joints of DR3(-/-) mice. However, TL1A neither induced MMP-9 release nor affected the survival of neutrophils. Instead, reduced levels of CXCL1 were observed in the joints of DR3(-/-) mice.DR-3 drives early cartilage destruction in the AIA model of inflammatory arthritis through the release of CXCL1, maximizing neutrophil recruitment to the joint and leading to enhanced local production of cartilage-destroying enzymes.
Effect of modest delays in primary surgical treatment on progression of tumor size in breast cancer patients
Authors: J. L. Wagner, C. Warneke, I. Bedrosian, E. Mittendorf, G. Babiera, H. Kuerer, K. Hunt, W. Yang, A. Sahin, F. Meric-Bernstam
Journal: Journal of Clinical Oncology (2009)

622 Background: Evaluation of medical co-morbidities, coordination of reconstructive surgery and referral to tertiary care centers can delay surgical treatment in breast cancer. These delays raise concerns for tumor progression in the interim. We evaluated the time from initial imaging at a cancer center to surgical treatment and the change in tumor size. Methods: We identified 823 patients who underwent surgery as their first therapeutic modality for invasive breast cancer diagnosed from December 2003 to September 2005. Baseline tumor size was determined by mammogram (MMG) and ultrasound (US) reports, and tumor size at surgery was determined by pathology reports. Results: The median time from imaging at our facility to surgery was 0.69 months (range 0.03 to 4.34). Multivariate modeling indicated that older patient age, undergoing total mastectomy, and undergoing reconstruction predicted a longer time from initial imaging to surgery. Comparing radiographic to pathologic size, a moderate correlation was demonstrated for both MMG (Spearman r = 0.58; p &lt; 0.0001) and US (Spearman r = 0.66, p &lt; 0.0001). Pathologic size was the same as MMG size in 14%, smaller in 49%, and larger in 37% of patients. Differences in tumor size estimates were not significantly associated with time lapse between MMG and surgery, but in a multivariate model, MMG tumor size, tumor histology, and tumor grade were significant predictors (p &lt; 0.0001 for all) of differences in mammographic and pathologic size. The pathologic tumor size was the same as US in 10%, smaller in 38%, and larger in 52% of patients. Time lapse to surgery was not significantly associated with differences in US and pathologic tumor size. In a multivariate model, US tumor size (p &lt; 0.0001), tumor histology (p = 0.0006) and tumor grade (p = 0.005) were significant predictors of differences in US and pathologic tumor size estimates. Conclusions: There is no evidence that time lapse from initial imaging to surgical intervention leads to significant changes in tumor size thus allowing patients to complete preoperative workup and planning without significant clinical disease progression. No significant financial relationships to disclose.
Abstract P1-12-12: The insulin like growth factor axis and development of tamoxifen resistance in breast cancer
Authors: Yousef M Hawsawi, James Beattie, Reem El-Gendy, Valerie Speirs, Christopher Twelves
Journal: Cancer Research (2015)

Abstract Background Insulin-like growth factors (IGF). IGFs are potent mitogens for breast epithelial cells that modulate the action of AKT, which has been reported to be associated with tamoxifen resistance. To date, however, anti-IGF strategies have proved disappointing in clinical trials We have investigated whether the IGFBP family of proteins, which modulate the activity of IGF, may play a role in tamoxifen resistance, opening up the route for alternative anti-IGF based therapies. Methodology We investigated the expression of IGF axis genes in parental and tamoxifen-resistant (TamR) MCF-7 cells using qRT-PCR. Gene and protein expression was confirmed using ELISA, Western, and ligand blotting. shRNA transfection was used to silence candidate IGF axis genes in both cell lines. Cell sensitivity 4-hydroxytamoxifen (4-HT) was investigated by WST-1 cell proliferation assay. Results IGF-IR, IGF-2R, IGFBP-2, -4 and -5 genes had the highest expression levels. IGFBP-5 was down-regulated 7-fold while IGFBP-2 was up-regulated by 2-fold in TamR v wt cells. Changes in IGFBP-5 and IGFBP-2 gene expression were mirrored in protein levels measured in conditioned media by ELISA, Western and Ligand blot. Importantly knock down of IGFBP-2 in TamR cells restored sensitivity to 4-HT suggesting a causal role for IGFBP-2 in the acquisition of tamoxifen resistance. Conclusion IGFBP-5 and IGFPB-2 are reciprocally regulated on the acquisition of tamoxifen resistance by MCF-7 cells. Preliminary studies suggest that IGFBP-2 may play a role in the development of tamoxifen resistance in vitro. Citation Format: Yousef M Hawsawi, James Beattie, Reem El-Gendy, Valerie Speirs, Christopher Twelves. The insulin like growth factor axis and development of tamoxifen resistance in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-12.
Effect of vitamin D levels on natural killer cells in diabetes mellitus patients with tuberculosis
Authors: Meenakshi Ponnana, Ramya Sivangala, Lavanya Joshi, Shruthi Thada, Vijaya Lakshmi Valluri, Suman latha Gaddam
Journal: European Respiratory Journal (2014)

It is increasingly apparent that Natural Killer(NK) cells play crucial role in innate defense mechanism against Mycobacterium tuberculosis(M.tb).Diabetes mellitus (DM) is a predisposing factor that alters immunity to Tuberculosis(TB).Further NK cell function depends on adequate levels of Vitamin D, an important regulator of immune system.A total of 150 subjects,TB patients(TB),DM patients with TB(TBDM),their household contacts (HHC),DM patients and Healthy Controls(HC) 25 each in which,CD4,CD8,CD16 & CD56 cell counts were enumerated.Vitamin D levels in serum, IFN-γ & IL-10 levels in M.tb antigen (Ag 85A)stimulated culture supernatants were estimated by ELISA(pg/ml) and ARMS-PCR was carried out to study the SNP's using specific primers. CD56 & CD16 NK cells were significantly low in TBDM patients,their HHC & and DM patients with deficient levels of vitamin D compared to HC (p<0.005) indicating that HHC are prone to develop the disease.The mean IFN-γ cytokine levels were significant for (TB 6.74±4.1423.66±14.96; p<0.0004 & TBDM 6.17±4.42; 32.08±8.8 p<0.03); for IL-10 (9.88±3.45; 34.18±11.74 p<0.04 in TB 70.74±16.5; 14.37±4.14 p<0.01 in TBDM & 69.01±15.29; 13.99±3.9; p<0.01 in DM) compared to HC. AA & AT genotypes of IFN-γ (p<0.009; 95% C.I 0.266-0.853; P<0.032 95% C.I 1.038-2.653 in TB & P< 0.037 95% C.I. 0.261-0.991; p<0.001 95% C.I. 1.349-4.208 in DM); GA & GG genotypes of IL-10 -1082G/A were significantly associated in all the subjects (p< 0.0001). In HHC of the patients, low serum Vitamin D levels and decrease cell count may predispose to TB infection. Hence the study may help in identifying the high risk individuals.
Reply to Jérôme Verine, Christophe Leboeuf and Philippe Ratajczak's Letter to the Editor re: Jimsgene Sanjmyatav, Sven Hauke, Mieczyslaw Gajda, et al. Establishment of a Multicolour Fluorescence In Situ Hybridisation-based Assay for Subtyping of Renal Cell Tumours. Eur Urol 2013;64:689–91
Authors: Jimsgene Sanjmyatav, Arndt Hartmann, Holger Moch, Sven Hauke, Mieczyslaw Gajda, Britta Meyer, Alexey Pryalukhin, Marc-Oliver Grimm, Kerstin Junker
Journal: European Urology (2013)
Cost-effectiveness of Lung Cancer Screening in Canada
Authors: John R. Goffin, William M. Flanagan, Anthony B. Miller, Natalie R. Fitzgerald, Saima Memon, Michael C. Wolfson, William K. Evans
Journal: JAMA Oncology (2015)

The US National Lung Screening Trial supports screening for lung cancer among smokers using low-dose computed tomographic (LDCT) scans. The cost-effectiveness of screening in a publically funded health care system remains a concern.To assess the cost-effectiveness of LDCT scan screening for lung cancer within the Canadian health care system.The Cancer Risk Management Model (CRMM) simulated individual lives within the Canadian population from 2014 to 2034, incorporating cancer risk, disease management, outcome, and cost data. Smokers and former smokers eligible for lung cancer screening (30 pack-year smoking history, ages 55-74 years, for the reference scenario) were modeled, and performance parameters were calibrated to the National Lung Screening Trial (NLST). The reference screening scenario assumes annual scans to age 75 years, 60% participation by 10 years, 70% adherence to screening, and unchanged smoking rates. The CRMM outputs are aggregated, and costs (2008 Canadian dollars) and life-years are discounted 3% annually.The incremental cost-effectiveness ratio.Compared with no screening, the reference scenario saved 51,000 quality-adjusted life-years (QALY) and had an incremental cost-effectiveness ratio of CaD $52,000/QALY. If smoking history is modeled for 20 or 40 pack-years, incremental cost-effectiveness ratios of CaD $62,000 and CaD $43,000/QALY, respectively, were generated. Changes in participation rates altered life years saved but not the incremental cost-effectiveness ratio, while the incremental cost-effectiveness ratio is sensitive to changes in adherence. An adjunct smoking cessation program improving the quit rate by 22.5% improves the incremental cost-effectiveness ratio to CaD $24,000/QALY.Lung cancer screening with LDCT appears cost-effective in the publicly funded Canadian health care system. An adjunct smoking cessation program has the potential to improve outcomes.
Induction Regimens for ANCA-Associated Vasculitis
Authors: Andreas Kronbichler, Julia Kerschbaum, Michael Rudnicki
Journal: New England Journal of Medicine (2013)

In the 18-month follow-up report of the Rituximab in ANCA-Associated Vasculitis (RAVE) trial, Specks et al. (Aug. 1 issue) 1 reported a noninferiority of intravenous rituximab (375 mg per square meter of body-surface area administered weekly for 4 weeks) as compared with oral cyclophosphamide (taken daily) followed by azathioprine.Complete remission was maintained in 39% of the patients in the rituximab group and in 33% of the patients in the comparison group.As compared with the results of the CYCLOPS trial, the relapse rate in the control group exceeded expectations (20.8% in the CYCLOPS trial vs. 29% in the RAVE trial), although the median follow-up in the CYCLOPS trial was 4.3 years. 1,2One explanation might be the rigorous tapering of glucocorticoids in the RAVE trial, because early discontinuation of glucocorticoids is one of the most significant risk factors for relapse. 3These differences were not discussed thoroughly, but clinical trials should address the need to prevent relapses in order to reduce treatment-related adverse events.Repeated administration of rituximab has shown encouraging results. 4Further trials that are now being conducted will reassess these preliminary data.Nonetheless, the results of the RAVE trial have disproved the hypothesis that prolonged immunosuppressive treatment is absolutely necessary in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
Comparative influence of load versus inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure-volume relationships.
Authors: D A Kass, W L Maughan, Z M Guo, A Kono, K Sunagawa, K Sagawa
Journal: Circulation (1987)

We examined the quantitative influence of carefully controlled alterations in end-diastolic volume and afterload resistance on multiple simultaneously determined ejection and isovolumetric phase indexes of left ventricular contractile function in 23 isolated supported canine ventricles. The influence of load change on each index was compared with its sensitivity to inotropic stimulation, and this sensitivity was in turn contrasted to the response of the end-systolic pressure-volume relationship (ESPVR). Experimental data demonstrated various degrees of load sensitivity among the indexes, with a generally curvilinear relationship between load and index response for both preload and afterload alterations. The curvilinear nature of these relationships meant that over a select range of loading, many indexes demonstrated relative load independence. They also often displayed greater sensitivity to inotropic change than the ESPVR, and both factors help explain their enduring clinical utility. To further explore the influence of load and contractile state on several of the indexes, we developed a theoretical analysis, using variables common to pressure-volume relationships, in which these dependencies could be derived. The theoretical models fit very well with the experimental data, and reaffirmed the frequently curvilinear nature of the relationships. We conclude that while many clinical indexes of ventricular contractile function show significant load dependence, the information they provide can be reasonably interpreted within defined ranges of load and inotropic alteration. Any advantage of the ESPVR will derive not from the magnitude of its response to inotropic change, which is smaller than most other indexes, but from its relative insensitivity to load alteration over a wider range of load.
Clinical Laboratory Methods.
Authors: John R. Paul
Journal: JAMA (1923)

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Abstract 860: Carbon ion radiotherapy for recurrent basal cell carcinoma: preliminary report of six cases and review of the literature
Authors: Yingtai Chen, Feng Dong, Yantao Tian, Chengfeng Wang, Liang Cui, Xuezhong Chen
Journal: Cancer Research (2014)

Abstract Abstract Background: Basal cell carcinoma (BCC) is the most common malignant skin carcinoma. Although mortality is low as BCC rarely metastasizes, this malignancy has a tendency for local recurrence. As such, it is of great practical utility to assess which is the best therapeutic choice in the management of BCC recurring after different treatments. Here, we describe six cases of recurrent BCC treated with carbon ion radiotherapy and review the cases previously reported in the literature. Methods: Case records of six patients with biopsy-proved, recurrent BCC, who were given total doses of 60-70 GyE, administered in 6-11 fractions over 6-11 days, with a fraction dose of 7-10 GyE in the therapy terminal at Heavy Ion Research Facility in Lanzhou (HIRFL) at the Institute of Modern Physics, Chinese Academy of Sciences (IMP-CAS), China, were retrospectively reviewed. Results: Tumor response rate was 100%, including 6 CR, at 12 months after completion of carbon ion radiation. In a minimum follow-up period of 55 months, overall survival and no recurrence were achieved. No grade 3 or higher toxicity and complication occurred. Conclusions: Carbon ion radiotherapy is well tolerated and should be considered as a potential salvage modality for recurrent BCC in certain cases. Note: This abstract was not presented at the meeting. Citation Format: Yingtai Chen, Feng Dong, Yantao Tian, Chengfeng Wang, Liang Cui, Xuezhong Chen. Carbon ion radiotherapy for recurrent basal cell carcinoma: preliminary report of six cases and review of the literature. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 860. doi:10.1158/1538-7445.AM2014-860
Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma: The egg of columbus or another illusion?
Authors: Amy K. Kim, James Dziura, Mario Strazzabosco
Journal: Hepatology (2013)

Abstract Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated. Methods: We analyzed prospective data on 300 504 men and women aged 50 to 71 years in the National Institutes of Health–AARP Diet and Health Study cohort and linked self-reported aspirin and non-aspirin NSAID use with registry confirmed diagnoses of HCC and death due to CLD. We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided. Results: Aspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of non-aspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI = 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use non-aspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of non-aspirin NSAIDs compared to non-users. Conclusions: Aspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.
Notch signaling controls self-renewal and lineage differentiation of human mammary stem and progenitor cells
Authors: Gabriela Dontu, Kyle W. Jackson, Erin McNicholas, Mari J. Kawamura, Wissam M. Abdallah, Max S. Wicha
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2782 

There is increasing evidence that stem and progenitor cells are the primary targets for transformation. Therefore, defects in pathways that regulate stem cell function, such as self-renewal and differentiation, may play an important role in carcinogenesis. The Notch signaling pathway plays a critical role in cell fate determination in a variety of developmental systems. Furthermore, deregulation of this pathway has been shown to effect mammary development and induce carcinomas in transgenic mouse models. In order to determine the role of Notch signaling in mammary cell fate determination, we have utilized a newly-described in vitro system in which mammary stem/progenitor cells derived from reduction mammoplasties can be cultured in suspension as “mammospheres.” Although less than 1% of primary mammary cells express Notch-4 protein as determined by immuno-florescence, greater than 60% of mammosphere forming cells are Notch-4 positive. Furthermore, we demonstrate that Notch signaling can act on mammary stem cells to promote their self-renewal, as demonstrated by a 10-fold increase in secondary mammosphere formation upon addition of a Notch activating DSL peptide. In addition to acting on stem cells, Notch signaling is also able to act on multi-potent progenitor cells, facilitating myoepithelial lineage-specific commitment and proliferation. Stimulation of this pathway also promotes branching morphogenesis in three-dimensional Matrigel cultures. These effects are completely inhibited by a Notch 4 blocking antibody or a gamma secretase inhibitor that blocks Notch processing. In contrast to the effects of Notch signaling on mammary stem/progenitor cells, this pathway has no discernable effect on fully committed, differentiated mammary epithelial cells. These studies suggest that Notch signaling plays a critical role in normal human mammary development by acting on both stem and progenitor cells, effecting self-renewal and lineage specific differentiation. Deregulation of Notch signaling resulting in aberrant self-renewal may be an important early event in mammary carcinogenesis.