tbuckley/cabot-search huggingface dataset:
Abstract LB-350: Tissue and serum miRNA profiling for detection of bladder, breast and prostate cancer
Authors: Patricia A. Porter-Gill, Yi-Ping Fu, Alpana Kaushiva, Douglas Price, William Dahut, William Figg, Ludmila Prokunina-Olsson
Journal: Cancer Research (2011)

Abstract Biomarkers that can differentiate between normal and tumor state, and can be measured in easily accessible body fluids such as blood and urine, can be very important for cancer diagnostics and disease monitoring. MicroRNAs (miRNAs), short non-coding regulatory RNA molecules, are attractive as biomarkers because they are stable in different conditions and are easy to measure with quantitative PCR (qPCR) methods. In this study we aimed to identify a universal panel of miRNAs for cancer screening that can be easily tested in the serum of healthy individuals and patients with different types of cancer. First, we measured expression of ∼800 miRNAs in 40 controls and 60 patients with bladder, breast or prostate cancer using the low density TaqMan expression arrays (Applied Biosystems) and starting from 250 ul of serum. Based on these results we selected a panel of 24 miRNAs that showed best discrimination between normal and cancer samples. These miRNAs were then re-tested as a custom-designed mini-panel in serum samples of 44 healthy controls and cancer patients (31 bladder, 25 breast and 28 prostate) and in relevant normal and tumor tissue samples (42 normal bladder and 43 bladder tumors, 44 normal breast and 42 breast tumors and in 50 normal prostate and 20 prostate tumors). Only miRNAs that expressed in the same direction in serum and tissue samples and showed significant association with cancer in both sample types were used for further analysis. The current panel consists of 16 miRNAs – 14 targets, one positive control and one negative control. Using this panel on serum samples from 44 controls, 31 bladder cancer patients, 25 breast cancer patients and 28 prostate cancer patients we performed ROC analysis and achieved complete discrimination (AUC ∼1.0) between all types of cancers and controls and good discrimination between different types of cancers (minimal AUC 0.89 for breast and bladder samples). Our results prove that miRNA detection from serum might be a promising method of cancer detection. Currently, we are performing validation studies in independent sets of samples. A combination of information on genetic susceptibility factors identified by genome-wide association studies (GWAS), other cancer-specific factors such as PSA for prostate cancer and miRNA expression profiling, might provide additional tools for early disease diagnostics and help to guide treatment options. 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 LB-350. doi:10.1158/1538-7445.AM2011-LB-350
Role of the insulin receptor in IGF-system signaling and biology.
Authors: DH Oberg, H Zhang, D Yee
Journal: Cancer Research (2009)

Abstract Abstract #4055 The role of the type I insulin-like growth factor (IGF) receptor (IGF1R) in breast cancer has been extensively studied, and has led to the development of several IGF1R inhibitors currently in clinical trials. The closely related insulin receptor (IR) has been shown to contribute to IGF signaling through the formation of IGF1R/IR-hybrid receptors and through a homodimer of an alternatively spliced form of the IR (IR-A). Understanding the role of the IR in cancer biology will help determine which receptor(s) in the IGF system should be targeted to efficiently inhibit IGF signaling. Our previous work has shown that selective downregulation of IGF1R by siRNA resulted in enhanced sensitivity to insulin through increasing the numbers of insulin receptor homodimers. To determine how downregulation of IR affected IGF1R signaling, we used T47D cells, a breast cancer cell line expressing both the IR and IGF1R, as our model system. We transiently downregulated IR levels using siRNA and evaluated signaling. 5 nM of insulin activated downstream signaling molecules, such as insulin receptor substrate 1(IRS-1) and Akt in control cells, but this response was diminished in the IR-downregulated cells. In contrast, 5 nM of IGF-I did not result in differences in signaling between IR-downregulated cells and control cells. Using IR shRNA, we created stable clones with IR levels reduced by more than 72%. IR shRNA clones demonstrated decreased insulin binding, as measured by 125I-insulin binding assay. Additionally, clones showed decreased response to insulin signaling. 5 nM of insulin activated IRS-1 and Akt in parental T47D cells, but this response was attenuated in the IR-downregulated clones. Proliferation was also decreased in response to 5 nM insulin in the clones compared to parental cells. In contrast, IGF-I mediated signaling was not altered in clones when compared to vector control cells. Further, no change in proliferation was observed in response to IGF-I between wild-type and IR shRNA clones. We also generated stable IR shRNA clones using LCC6 cells. Insulin signaling was reduced in LCC6 clones when compared to wild-type LCC6 cells. However, in contrast to the T47D clones, IGF-I signaling was increased in LCC6 IR shRNA clones. Thus, the role of the insulin receptor in cancer biology may be dependent upon the ratio of IR, IGF1R, and the hybrid receptor. If cells contain mostly homodimers of IGF1R and IR, then downregulation of IR may affect only insulin response. However, if there are high levels of hybrid receptor, then downregulation of IR could affect, and even augment, IGF1R signaling. Our data suggest that the ratio and confirmation states of both IR and IGF1R should be understood to predict the effect of receptor downregulation. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4055.
578 ALBUMIN INFUSION IMPROVES SYSTEMIC AND RENAL BLOOD FLOW AUTOREGULATION BY RESTORATION OF ENDOTHELIAL DYSFUNCTION
Authors: R. Garcia Martinez, F. Andreola, G. Mehta, K. Poulton, L. Noiret, A. Habtesion, M. Jover, N.A. Davies, R.P. Mookerjee, R. Jalan
Journal: Journal of Hepatology (2013)
Abstract 3329: Magnetic isolation and rare cell gene expression analysis of breast cancer stem cells
Authors: Olaf Hardt, Stefan Wild, Kay Hofmann, Shujun Luo, Yvonne Wiencek, Eva Kantelhardt, Geoffrey P. Smith, Gary P. Schroth, Andreas Bosio, Jürgen Dittmer
Journal: Cancer Research (2011)

Abstract Solid tumors consist of heterogeneous cell types including a subpopulation of stem like cells. Starting from bulk tumor mass, the analysis of these cancer stem cells (CSCs) is hampered by their rare frequency and their characteristics remain hidden. To address this issue, we have developed a method for the semi-automated dissociation of human tumor tissue yielding a viable single cell suspension. Subsequently, a magnetic cell sorting (MACS) strategy was established allowing for the isolation of CD24-/CD44+ breast CSCs. Using these methods, we isolated breast CSCs from an invasive ductal carcinoma at a purity of 94%. Due to the limited starting material, a few hundred CSCs as well as bulk tumor cells were used for global PCR based RNA amplification. The amplified cDNA was sheared, size selected, and processed for high throughput gene expression analysis on the Illumina Genome Analyzer system. Samples were prepared in triplicate and over 10 million individual purity-filtered reads were analyzed per sample. In addition, Agilent whole genome microarrays were used for validation of expression differences. Analysis of the sequence tags allowed us to identify novel putative markers overexpressed in breast CSCs. GeneOntology analysis was used to determine functional groups of genes which are differentially regulated between CSCs and bulk tumor cells. We found a strong overrepresentation of genes connected to TGF-beta as well as Wnt/GSK3 signaling supporting the correlation of the CSC phenotype with epithelial-mesenchymal-transition (EMT). Other differentially expressed genes are known to be involved in pluripotency, cell migration, and apoptosis further indicating a stem cell-like fate.Our proof of principle experiment demonstrates the advantage of isolating rare cell populations for subsequent molecular analysis by high throughput sequencing. The analysis of purified CSCs revealed new insights on the regulation, maintenance, and biology that would not have been observed when assessing only the bulk tumor mass. Analyzing the genetic set up of defined tumor subpopulations by Next Generation Sequencing can improve our understanding of cancer and could pioneer targeted diagnostic and therapeutic approaches. 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 3329. doi:10.1158/1538-7445.AM2011-3329
SAT0122 Reduction of Peripheral Blood G-Ifn and IL-17 Producing T Cells After Therapy with Abatacept for Rheumatoid Arthritis
Authors: M. Scarsi, C. Zanotti, M. Chiarini, S. Piantoni, L. Imberti, M. Frassi, C. Bosio, D. Rossi, A. Paletti, A. Tincani, P. Airò
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Abatacept (ABA) is a fusion molecule used in the treatment of Rheumatoid Arthritis (RA), which is able to compete with the engagement of CD28, the receptor for most important costimulatory signal for T cells. CD28-mediated signaling regulate several T-cell functions, including inflammatory cytokine production and Treg differentiation. <h3>Objectives</h3> The aim of our study was to evaluate the effect of therapy with ABA on peripheral blood T lymphocyte cytokine production and on the number of circulating Treg. <h3>Methods</h3> In 24 RA patients treated with ABA for at least 6 months the proportion and absolute number of peripheral blood T cells producing γ-interferon (γ-IFN) and interleukin-17 (IL-17) after <i>in vitro</i> stimulation, as well as those of Treg were longitudinally evaluated by flow-cytometry at baseline and after 6 and 12 months. The EULAR response criteria were applied to evaluate the clinical response to treatment. Sixteen healthy donors (HD) of comparable age were used as controls. <h3>Results</h3> At baseline, compared with HD, RA patients had a higher percentage of circulating Treg (median percentage of CD4+ T cells 6.4 (25<sup>th</sup>-75<sup>th</sup> percentile: 4.8-7.5) vs 4.7 (4.0-4.8); p: 0.041), as well as of CD4+ and CD8+ T-cells producing IL-17 (1.1% of CD4+ T cells (0.4-2.0) vs 0.5 (0.3-0.8); p: 0.021; 1.2% of CD8+ T cells (0.7-1.8) vs 0.7 (0.5-0.8); p:0.006). After 6 months of therapy with ABA, there was a decrease of the percentage of Treg (from 6.4% of CD4+ T cells (4.8-7.5) to 4.8 (3.0-6.3); p: 0.008), of γ-IFN- and IL-17- producing CD8+ T cells (from 25.6% (12.9-34.4) to 17.2 (11.9-28.7), p:0.033; and from 1.2% (0.7-1.8) to 1.0 (0.6-1.3), p:0.035, respectively), while that of IL-17-producing CD4+ T cells decreased at 12 months (from 1.1% of CD4+ T cells (0.4-2.0) to 0.3 (0.2-0.5); p:0.005). The number of Treg and of IL-17 producing T-cells that were higher than in HD at baseline normalized after ABA therapy. All these variations were statistically significant only in RA patients with good clinical response (n:17), whereas the variations were milder and not significant in the other group of patients (n:7). The reduction of IL-17 producing CD4+T cells absolute number was correlated with the reduction of disease activity, evaluated with the DAS28-CRP (r: 0.477; p: 0.039). <h3>Conclusions</h3> These findings enhance our understanding of the mechanism of action of ABA underlying the relevance of the CD28-mediated signaling as pharmacological target for RA. <h3>Acknowledgements</h3> We acknowledge Bristol-Myers-Squibb Italia for the support to our study <h3>Disclosure of Interest</h3> None Declared
SAT0248 Evolution of Radiographic Damage in Ankylosing Spondylitis Over 12 Years of Follow-Up
Authors: S. Ramiro, C. Stolwijk, A. van Tubergen, D. van der Heijde, M. Dougados, F. van den Bosch, R. Landewé
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Radiographic damage is one of the core outcomes recommended by the ASAS for follow-up of patients with AS. So far, the evolution of radiographic damage over a long period has not been described. <h3>Objectives</h3> To describe the evolution of radiographic abnormalities in patients with AS. <h3>Methods</h3> The modified Stoke AS Spine Score (mSASSS) was calculated using 2-yearly radiographs of patients followed for 12 years in the Outcome in AS International Study (OASIS). Two readers (R1 and R2) independently scored the x-rays and scores were averaged. Status and progression scores (2-year and 12-year-progression) were computed for patients with at least one 2-year interval available (n=186) and for those also with an mSASSS at 12-years (n=68). New syndesmophytes at vertebral corners (VCs) at risk (i.e. without a previous syndesmophyte or bridge) were computed. Radiographic progression over time was investigated using generalized estimating equations. Relevant interactions with time were explored. Time was modeled in different forms (linear and non-linear). <h3>Results</h3> 809 radiographs of 186 patients (70% males, mean(SD) age 43(12) years, mean disease duration 11.0(8.8) years and 83% HLA-B27 positive) were included. The mean(SD) mSASSS at baseline was 11.6(16.2) [11.2(15.7) in patients with mSASSS at 12-years]. The mean(SD) 2-year progression (in 520 intervals) was 2.0(3.5) [2.2(3.9) for the subset of 12-year-completers]. Over the 12 years, the mean(SD) progression was 11.7(11.5). A new syndesmophyte was assessed in 38% (R1) and 39% (R2) of all 2-year intervals and, throughout follow-up, in 55% (R1) and 63% (R2) of the patients with at least one VC "at risk". In 24% of the patients (39% of the 2-year intervals) there was no progression in mSASSS. A progression≥5 mSASSS units occurred in 22% of the patients (12% of the intervals). At the group level, a linear time course model fitted the observed data the best. Time was positively associated with radiographic progression, with an increase of 0.98 mSASSS/year. Radiographic progression occurred faster in males, in HLA-B27 positive patients and in patients with a baseline mSASSS≥10. HLA-B27 positive male (but not female) patients had a significantly higher progression than HLA-B27 negative males. Progression was independent of disease- and symptom duration. <h3>Conclusions</h3> Long-term radiographic progression in AS is more severe in HLA-B27 positive males. About 60% of all patients have at least one new syndesmophyte over a period of between 2 and 12 years. Radiographic progression is dependent on time and, at the group level, linear. <h3>Disclosure of Interest</h3> None Declared
OP0014 Care Patterns for Chronic Low Back Pain Patients Included in Functional Restoration Programs in France: Pejorative Professional Factors Delay Access: Table 1
Authors: L. Marson, S. Dadoun, F. Roure, B. Fautrel, L. Gossec, V. Foltz
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Chronic low back pain is a major cause of disability and work loss. Functional restoration programs (FRPs) are effective multidisciplinary programs in terms of return to work. However, the effectiveness of such programs appears greater if work interruption is semi-recent (&lt;6 months) [1]. <h3>Objectives</h3> To explore FRP access in France, with a specific focus on duration of the work interruption before inclusion in the FRPs, and the determinants of a late/delayed access. <h3>Methods</h3> A census of FRPs centers in France was made in 2011. In centers agreeing to participate, a cross sectional study with prospective inclusion of all patients starting the FRPs was conducted over a period of three months. For each patient, socio-professional data, pain characteristics, socio-professional and psychological aspects were collected. Late/delayed access to the FRP was defined as a work interruption of more than 6 months before the FRP (ie sick leave or permanent disability). Factors associated with late access were analyzed by univariate and multivariate logistic regression analysis. <h3>Results</h3> Of the 62 FRPs centers identified, 21 (35%) participated: 185 patients were included (mean age 43 years, 61% men), pain VAS (0-100) was 45.8 (±23.2 SD)). Only 66% of patients had consulted a rheumatologist, with an average time between pain onset and consultation of 7.4 months. 54% of patients had consulted a surgeon. In 120 (65%) patients on sick leave or work disability, the average duration of work interruption was 9.4 (±7.4) months, 62% were off for more than 6 months. In the univariate analysis, factors associated with late/delayed access were low income, low education level, low perceived support of the occupational physician and hierarchical support at work (table 1). In multivariate analysis, hierarchical support (Karasek Score) was associated with late access (OR=0.85 (0.72 to 1.0), p=0.049). <h3>Conclusions</h3> Access of low back pain patients to FRP centers is often delayed. Factors associated with this delay in our study were mainly work-related factors. Therefore it seems necessary to strengthen cooperation between the health care teams and occupational medicine health professionals. <h3>References</h3> Bontoux L, et al. Prospective study of the outcome at one year of patients with chronic low back pain in a program of intensive functional restoration and ergonomic intervention. Factors predicting their return to work. Ann Readapt Med Phys 2004;47(8):563-72. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3723
The misapplication of medical science to literature
Authors: Peter Perkins
Journal: Journal of the Royal Society of Medicine (2013)

In seeking to apply a diagnosis to speech defects described in classic novels, Sainsbury et al.1 trespass into the world of literature at their peril. It is not their conclusions I wish to question, rather that these fictional characters are constructs and therefore the interpretation of their symptoms into neat medical diagnoses is meaningless. Such characters will always remain at the mercy of their author's pen and plot. Even an aphasic subject may ‘speak’ through their thoughts depending on the story's narrator.

Conversely, the author's background maybe very relevant. As a fictional doctor, John Watson, M.D., was at perfect liberty to diagnose and treat fictional characters in the Sherlock Holmes novels written by Sir Arthur Conan Doyle who first trained as a doctor. Indeed, these stories list no less than 68 diseases, 32 medical terms, 38 doctors, 22 drugs, 12 medical specialties, six hospitals and even three medical journals.2 Thomasson3 makes the case that fictional characters should be treated as such. For example, Sherlock Holmes was not a real consulting detective and neither did he really live at 221B, Baker Street. We cannot meet him as he did not exist. Equally, his immortality as a character long after the author's death, is testament to his popularity and not some rare medical longevity condition. Applying 21st Century medical knowledge to imaginary characters is taking fictional realism a step too far.
P27 Does a direct Radiology referral system to a rapid access Tuberculosis clinic improve TB diagnosis?: Abastract P27 Table 1.
Authors: CA Lynch, S Sabah, M Dedicoat, H Kunst
Journal: Thorax (2013)

<h3>Introduction</h3> Delayed diagnosis of active pulmonary tuberculosis (TB) is common and significantly contributes to transmission especially in smear-positive pulmonary TB. Persons with symptoms suggestive of pulmonary TB often have chest radiographs prior to sputum examination and clinical assessment by a specialist. There is no NICE guidance on direct radiology referral pathways to a rapid access TB clinic. This question prompted us to examine all cases referred by the radiology department to our rapid access TB clinic at a centre of England tertiary referral centre. <h3>Method</h3> We conducted a retrospective study of consecutive patients with features of active TB on chest radiograph referred by the radiologists to the rapid access TB clinic from 2008 to 2013. All chest radiographs were reviewed by TB consultants who arranged clinic appointments according to the degree of clinical suspicion of active disease. <h3>Results</h3> 223 cases were referred during the period of November 2008 to May 2013. All patients were requested to attend the TB clinic, 4 patients did not attend clinic. Of 223 cases, 111 patients (50%) were diagnosed with active TB. Mean age of all active cases was 38 years (range 16–83 years) with a male predominance (62, 56%). Of 111 cases, 61 (55%) were from Indian subcontinent, 22 (19%) from Africa, 25 (22%) were UK born and 3 cases were born in other countries. 80 cases had pulmonary TB (72%), of whom 47 (59%) were smear positive. 28 cases (25%) had extra pulmonary disease, two cases had disseminated miliary disease and one case was diagnosed clinically. Table 1 indicates that 102 (92%) cases were seen in clinic within 14 days of rapid access radiology referral and 80 (72%) were started on anti-TB treatment within 28 days of radiology referral. 103 patients (93%) had fully sensitive TB with 8 resistant cases. <h3>Conclusion</h3> Direct radiology referral of cases with chest radiographs suggestive of pulmonary TB to a rapid access TB clinic can hasten diagnosis of active TB and should be included in NICE guidance.
Abstract LB-207: Dissecting the functional landscape of triple-negative breast cancer.
Authors: Kimberly Maxfield, Aleix Prat, Kathleen Corcoran, Angelique Whitehurst
Journal: Cancer Research (2013)

Abstract Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer with poor patient prognosis. Patients who respond poorly to the current standard of care cytotoxic chemotherapeutic regimens only have about a 55% five-year survival rate due to the lack of other effective TNBC therapeutics. To uncover new therapeutic entry points for TNBC, we employed a pangenomic loss of function siRNA screening approach. To account for heterogeneity within the patient population, we screened 4 triple negative tumor-derived breast cancer cell lines that represent the spectrum of oncogenic aberrations and molecular subtypes in TNBC. By intersecting the datasets from these 4 cell lines, we revealed core modulators of viability and chemotherapy-induced cellular stress that have not been previously implicated in TNBC biology. For example, our screen uncovered a tractable energy-sensing AMPK family member that supports tumor cell viability in a subset of TNBC tumors. We also discovered tumor cell vulnerabilities unique to the Basal-Like and Claudin-Low TNBC molecular subtypes. In particular, Basal-Like tumor cell division is sensitive to perturbations in specific cytokine signaling. With respect to Claudin-Lows, we found an increased sensitivity to depletion of transcriptional modulators and downstream targets of TGFβ signaling, which suggests that TGFβ signaling may not only be required for a mesenchymal phenotype but also for Claudin-Low tumor cell survival. Our findings suggest that a set of tumor cell vulnerabilities can partition TNBC into functional subgroups and these vulnerabilities could lead to new therapeutics improving overall TNBC patient prognosis. Citation Format: Kimberly Maxfield, Aleix Prat, Kathleen Corcoran, Angelique Whitehurst. Dissecting the functional landscape of triple-negative breast cancer. [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 LB-207. doi:10.1158/1538-7445.AM2013-LB-207