tbuckley/cabot-search huggingface dataset:
Good news for a change: receipt of adjuvant chemotherapy in diverse populations.
Authors: JJ Griggs, PH Abrahamse, ST Hawley, AS Hamilton, JJ Graff, SJ Katz
Journal: Cancer Research (2009)

Abstract Abstract #2092 Background: Racial, ethnic, and social disparities in the use of chemotherapy have been demonstrated in women with breast cancer in numerous clinical settings. The purpose of this study was to investigate patterns and correlates of chemotherapy use in a recently-treated population-based sample of black, Latina, and non-Hispanic white women with invasive breast cancer. Methods: A sample of women diagnosed with breast cancer between August 2005 and March 2007 and reported to the Los Angeles County and Detroit Metropolitan Surveillance Epidemiology and End Results (SEER) Registries was identified and invited to complete a survey about their breast cancer treatment. Patient responses were linked to SEER data. Black women and Latinas were oversampled. Bivariate and multivariate analyses examined the use of adjuvant chemotherapy according to clinical, disease, and sociodemographic characteristics, including self-reported height and weight, comorbidity, educational attainment, income, insurance, marital status, and employment factors. Results: Of the 1655 respondents, 1041 (60.8%) received chemotherapy. Black women (65.4%) and Latinas (69.5%) were more likely than non-Hispanic white women (57.1%) to receive adjuvant chemotherapy (p = 0.0001). In multivariate models, only younger age (p &amp;lt; 0.0001), increasing tumor size (p &amp;lt; 0.0001), increasing number of involved lymph nodes (p &amp;lt; 0.0001), and negative hormone receptor status (p &amp;lt; 0.0001) were significantly associated with receipt of chemotherapy. In addition, severely obese women were significantly more likely to receive adjuvant chemotherapy than healthy weight women (odds ratio 1.63, 95% confidence interval 1.04, 2.57). Comorbidity, education, income, insurance, marital status, and employment status were not associated with receipt of chemotherapy. Conclusion: Use of adjuvant chemotherapy in this population-based sample was higher among patients who were more likely to benefit from chemotherapy. In contrast to practice-based studies of chemotherapy use in cohorts treated in older time periods, this study using patient report of chemotherapy and of sociodemographic information demonstrates no evidence of racial, ethnic, or social disparities in chemotherapy use in this diverse population-based sample of recently-treated women. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2092.
Abstract 603: CAL-101 acts synergistic with arsenic trioxide in chronic lymphocytic leukemia by preventing p21 phosphorylation through AKT1.
Authors: Olaf Merkel, Eveline Sifft, Simone Schweiggl, Daniela Asslaber, Nathalie Wacht, Richard Greil
Journal: Cancer Research (2013)

Abstract Chronic lymphocytic leukemia (CLL) is the most abundant leukemia of the elderly in the Western world and characterized by the accumulation of CD5/CD19/CD23 positive cells in the peripheral blood, lymph nodes and spleen. It has a very heterogeneous course of disease with patients living longer than 10 years after diagnosis and others needing immediate treatment. CLL cells of the latter often bear aberrations in the p53 tumor suppressor gene. We have shown before that arsenic trioxide preferentially induces apoptosis in CLL cells deficient for p53 (n = 51, P = 0.029). We now reproduced this finding in mouse embryo fibroblasts (MEF) that are p53 deficient. Next we wanted to clarify the role of p53 downstream targets p21 and PUMA and found that p21 but not PUMA knockout led to increased arsenic trioxide susceptibility. When localized in the cytosol p21 has been described to have and anti-apoptotic function and accordingly is associated with negative prognosis in breast, ovarian and prostate cancer. To clarify p21’s localization in CLL cells we used differential detergent cell fractionation and demonstrate that upon arsenic trioxide treatment p21 is induced, but accumulates in the cytoplasm. This is in contrast to fludarabine treated cells, where p21 is strongly induced and shuttles to the nucleus. Moreover, we show here that arsenic trioxide leads to transient AKT activation and AKT phosphorylation of p21 has been shown to promote cytosolic localization. We next hypothesized that by combining the PI3Kdelta/AKT inhibitor CAL-101 with arsenic trioxide we might prevent cytosolic accumulation of p21. Recently, the idea of therapeutic inhibition of tyrosinse kinases in the B-cell receptor pathway has gained new momentum through pivotal phase-2 clincal studies with CAL-101 and ibrutinib targeting the PI3Kdelta- and the Bruton's tyrosine-kinase, respectively. We show here, that the PI3K inhibitor CAL-101 abrogates AKT activation through arsenic trioxide. This leads to strongly, synergistic apoptosis induction when CAL-101 and arsenic trioxide are combined irrespective of p53 status of CLL cells. Thus, we think that these findings not only shed light on the role of p21 in apoptosis induction in CLL, but open the path to novel therapeutic combination regimens. Citation Format: Olaf Merkel, Eveline Sifft, Simone Schweiggl, Daniela Asslaber, Nathalie Wacht, Richard Greil. CAL-101 acts synergistic with arsenic trioxide in chronic lymphocytic leukemia by preventing p21 phosphorylation through AKT1. [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 603. doi:10.1158/1538-7445.AM2013-603
PREVENCION DE LA PANCREATITIS AGUDA POST-CPRE
Authors: M Millán Lorenzo, P Ferrero León, R Calle Sanz, J Ampuero Herrojo, R Llorca Fernández, A Martínez-Alcalá García, A Garrido Serrano, M Romero Gómez
Journal: Endoscopy (2013)

Objetivos: Analizar las CPRE realizadas en nuestro hospital durante un periodo de 10meses. Evaluar las complicaciones y el uso de medidas preventivas para la pancreatitis aguda (PA) post-CPRE. Métodos: Se incluyeron 157 pacientes a los que se realizó CPRE entre junio-2012 y abril-2013. Se estudiaron las características de los pacientes, indicaciones, procedimientos, resultados, y complicaciones. En pacientes de riesgo para PA post-CPRE (repetidos intentos de canulación o canulación del Wirsung) se empleó diclofenaco o indometacina por vía rectal asociado a la colocación de prótesis plástica pancreática, cuando por técnica de doble guía no se consiguía la canulación biliar. Resultados: 49.7% (78/157) eran hombres con edad media de 66.52 años. Las indicaciones fueron: coledocolitiasis 67.5% (106/157), estenosis de la vía biliar 15.3% (24/157), colangitis 8.9% (14/157) y otras 8.3% (13/157). Se canuló la vía biliar en el 84.1%, al primer intento en el 50.3%. Se realizó esfinterotomía 46.5%; esfinteroplastia 9.6%; precorte 2.5% y se colocaron prótesis 34.3%. Se utilizó supositorio de AINE como profilaxis de PA post-CPRE en 36,30%, siendo la causa más frecuente la canulación del conducto pancreático 92.9% (53/57) y a 33.96% (18/53) se les colocó una prótesis plástica en Wirsung. Presentaron complicaciones 17 pacientes: hemorragia post-esfinterotomía 5.1% (8/17), todas leves; PA 3.8% (6/17), 1 en el grupo de no profilaxis y 5 en el grupo de profilaxis, 5 leves y 1 moderada; colangitis 1.3% (2/17) y alergia al contraste 0.6% (1/17); no hubo mortalidad. La PA no se relacionó con el sexo, edad, indicación, procedimiento y vía biliar normal (p > 0.05). Observamos diferencia significativa al canular en primera instancia el Wirsung y no vía biliar (OR = 8.12, p = 0,38). Conclusión: La aparición de PA post-CPRE en nuestra serie es inferior a lo descrito. La canulación del Wirsung es el principal factor de riesgo. El empleo de supositorios de AINE y de prótesis pancreática en pacientes de riesgo disminuyen la incidencia y severidad de esta complicación.
PTU-058 Machine Learning Creates A Simple Endoscopic Classification System For Detecting Dysplasia In Barrett’s Oesophagus With I-scan Imaging And Opens The Way To Standardised Training And Assessment Of Competence
Authors: V Sehgal, A Rosenfeld, DG Graham, MR Banks, RJ Haidry, LB Lovat
Journal: Gut (2014)

<h3>Introduction</h3> Barrett's oesophagus (BE) is the pre-cursor for oesophageal adenocarcinoma. Endoscopic surveillance is performed to detect dysplasia in BE as it is likely to be amenable to curative treatment. Current surveillance relies on white-light endoscopy to obtain 4-quadrant biopsies through every 2cm of the BE segment. This samples less than 5% of the BE epithelium and is likely to miss dysplasia. A novel endoscopic image enhancement technology, <i>i-Scan</i> (PENTAX HOYA, Japan), has been developed to improve lesion recognition in the gastrointestinal tract (GIT). i-Scan uses post-processing light filtering to provide real-time analysis and enhancement of the mucosa and microvasculature. We evaluated the accuracy of i-Scan using a mucosal (M) and vascular (V) classification system for BE amongst 3 expert (consultant) endoscopists. Machine learning (ML) generates simple rules, known as a decision tree, to improve dysplasia detection and validate our classification system. To our knowledge, ML has never been applied for dysplasia detection in the GIT. <h3>Methods</h3> High definition video recordings were collected from patients with non-dysplastic (ND-BE) and dysplastic (D-BE) BE undergoing endoscopy at UCLH. A protocol was used to record areas of interest after which a matched biopsy was taken to confirm the histological diagnosis. In a blinded manner, videos were shown to 3 expert endoscopists who interpreted them based on their M and V patterns, presence of nodularity, ulceration and suspected diagnosis. Acetic acid (ACA) was used in some cases. Data was inputted into the WEKA package to construct a decision tree for dysplasia prediction. <h3>Results</h3> Videos from 47 patients (13 before and after ACA) were collected (24 ND-BE, 23 D-BE). Cases in which ACA was used, 7 had ND-BE and 6 D-BE. Experts' average accuracy for dysplasia prediction was 72.2% (66.7–76.7%). ACA did not improve dysplasia detection. In 5 cases all 3 experts failed to detect D-BE. Using ML, the most important attribute was the lesions' V pattern. If this was reported abnormal (irregular, dilated vessels) by more than one doctor, the lesion was D-BE (accuracy 79%). If D-BE was predicted despite the V pattern being reported abnormal by one or fewer experts, the lesion was still D-BE and vice versa. <h3>Conclusion</h3> Experts can diagnose D-BE in up to three-quarters of cases using i-Scan. ML can define rules learnt from expert opinion that predict dysplasia with a similar level of accuracy and are easier to learn than conventional classification systems. They could be used to train non-expert endoscopists in dysplasia detection and then used for blinded assessment of accuracy. <h3>Disclosure of Interest</h3> None Declared.
Antibodies to HTLV-III in Swiss Patients with AIDS and Pre-AIDS and in Groups at Risk for AIDS
Authors: Jörg Schüpbach, Otto Haller, Markus Vogt, Rudolf Lüthy, Helen Joller, Oswald Oelz, Mikulas Popovic, M.G. Sarngadharan, Robert C. Gallo
Journal: New England Journal of Medicine (1985)

We tested serum samples from Swiss subjects by three different assays based on enzyme-linked immunosorbent assay (ELISA) and Western blot techniques for antibodies to proteins associated with the recently discovered human T-cell leukemia/lymphoma virus HTLV-III, the putative etiologic agent for the acquired immunodeficiency syndrome (AIDS). Of 10 patients with AIDS and 10 with pre-AIDS, all were antibody-positive. Furthermore, 37 of 103 intravenous-drug addicts (36 per cent), 4 of 40 healthy homosexual men (10 per cent), 7 of 83 patients with various types of hepatitis (8.4 per cent), but none of 83 healthy blood donors or 10 other controls were antibody-positive. Antibodies to the major viral protein p24 were found consistently and at high titers in the seropositive members of the groups at risk and in those with pre-AIDS but were dramatically reduced in patients with AIDS. In contrast, antibodies to another virus-associated protein, p41, were present in all cases of AIDS and pre-AIDS but were absent in nearly 10 per cent of seropositive persons at risk. Whereas p41 and p24 thus appear to be the targets of choice for future screening tests, the ELISA test that is currently available is a useful screening tool.
THU0034 CD19 Distinguishes Memory and Pre-Memory Antibody Secreting Cells
Authors: R. Herbst, B. Rajan, C. A. Morehouse, R. Rayanki, Y. Yao, R. Ettinger, Y. Wang, C. J. Groves
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Plasma cells (PC), are differentiated B cells that play a major role in humoral immunity as they actively secrete antibodies which identify and neutralize foreign antigens. Normally, plasma cells develop in response to immune challenges such as infection or vaccination. In autoimmune diseases, however, PCs develop which secrete anti-self antibodies that may play a role in disease pathogenesis. Therefore, PCs are potential targets for therapeutic intervention in autoimmune disease. However, consideration must be given to the potential impact on protective immunity of PC targeted therapy. <h3>Objectives</h3> A recent report has identified long-lived PC in autoimmune patients which secrete Ig specific for self-antigen (1). These autoreactive cells represent a novel therapeutic target. The self-reactive PCs in the study were identified by commonly known cellular markers including the surface expression of CD19. CD19 is a molecule that is present on B cells from the earliest stages of development through the memory and plasma cell stage. Therefore, our goal was to characterize in detail the expression of CD19 on plasmablasts and plasma cells from human blood and tissues, and relate the phenotype of PCs from different tissues to production of antigen-specific immunoglobulin. <h3>Methods</h3> PCs were isolated from peripheral blood, tonsil, spleen, and bone marrow (BM) from human donors and characterized for surface antigen expression by flow cytometry. Samples of sorted cells were further characterized by mRNA expression profiling and by ELISPOT to determine total as well as antigen-specific production of immunoglobulin. <h3>Results</h3> Here we show that CD19 is expressed on normal PC found in human blood, tonsil, spleen, and bone marrow. However, we have identified a population of CD19- PC which exists in the spleen and bone marrow as a sub-population of PC in these tissues. We show that the bone marrow CD19- PC and CD19+ PC have nearly identical morphology, immunophenotype, mRNA expression, and function. However the CD19- PC fraction has a significantly increased frequency of cels which secrete antibodies specific for tetanus/diptheria toxin and influenza vaccine antigens when compared to CD19+ PC in human BM. <h3>Conclusions</h3> The results demonstrate that most PC from human blood and tissue are CD19+, although cell surface levels of CD19 can vary. Importantly, there exists a distinct CD19- population of PC in spleen and BM. These cells appear to be of a long-lived memory phenotype and secrete antibodies to vaccine antigens. The results have significant implications for the targeting of PC in autoimmune disease, especially with depleting antibodies against CD19, such as MEDI-551. <h3>References</h3> Mahévas M. et al (2013) B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells. J Clin Invest 123(1):432-42. <h3>Disclosure of Interest</h3> None Declared
MULTIPLE BIOMARKERS OF CARDIOVASCULAR STRESS RISK STRATIFY PATIENTS WITH AORTIC STENOSIS AND A PRESERVED EJECTION FRACTION UNDERGOING AORTIC VALVE REPLACEMENT
Authors: Marc Sintek, Nishath Quader, Hersh Maniar, Alan Zajarias, Eric Novak, Anna Vatterott, Cassie Lawler, Alejandro Aquino, John Lasala, Jared Breyley, Jennifer Lawton, Marc Moon, Spencer Melby, Ralph Damiano, Brian Lindman
Journal: Journal of the American College of Cardiology (2016)
A2.10 Increased Immunologic Exposure to Necrotic Cell Remnants in Patients with Primary SJögren’s Syndrome Owing to Defective Dnase-I Activity and The Presence of Opsonizing IgG Autoantibodies in Serum
Authors: Aigli G Vakrakou, George Fragoulis, Menelaos N Manoussakis
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and Objectives</h3> Our recent experiments have suggested that similarly to SLE, patients with primary Sjögren's syndrome (SS) manifest significantly increased phagocytosis of necrotic cell debris (secondary necrotic cell material, SNEC). This pheno-menon has been attributed to serological aberrations of these patients, as indicated by the capacity of patients' sera to promote the uptake of SNEC by healthy phagocytes. In this study, we comparatively investigated the role of serum DNAse-I activity and IgG immunoglobulins from SS, SLE and RA patients in the promotion of SNEC-phagocytosis by healthy monocytes. <h3>Materials and Methods</h3> The activity of DNase-I was assessed by single radial enzyme-diffusion assay (SRED) in the serum of patients with SS (n = 60), SLE (n = 22) and RA (n = 14) and healthy donors (HBD, n = 52). Total IgG immunoglobulins were isolated by negative selection from the serum of patients and controls using Melon Gel Resin columns. SNEC were prepared by heat-induced necrosis of normal lymphocytes and labelling with propidium iodide. The influence of serum components on SNEC-phagocytosis was assessed by flow cytometry in admixture experiments using normal phagocytes and SNEC pre-incubated with whole sera or purified serum IgG from patients or HBD. <h3>Results</h3> Serum DNase-I activity in patients with SS and SLE was found significantly reduced compared to HBD and RA patients (p &lt; 0.0001) and correlated inversely with the ability of these sera to promote SNEC-phagocytosis by healthy monocytes (p = 0.0003). The capacity of HBD sera to promote SNEC-phagocytosis by normal monocytes was significantly increased (by 90%) following the addition of the DNase-I-specific inhibitor G-actin (800 µg/ml), supporting the important physiological role of DNA degradation by serum DNase-I in the prevention of SNEC-phagocytosis. SNEC opsonised with IgG isolated from autoimmune patients or from HBD were found to be similarly ingested by normal monocytes. However, in the presence of normal serum, the opsonisation of SNEC with IgG isolated from SS or SLE sera was found to induce significantly increased SNEC-phagocytosis, compared to that observed with SNEC opsonised with IgG isolated from HBD sera (p = 0.001). <h3>Conclusions</h3> Our results indicate that, in a manner similar to SLE, SS patients are characterised by deficient serum DNase-I activity. Such reduced serum capacity for degradation of nucleic acids, in conjunction with the opsonisation of SNEC by serum autoantibodies appears to lead to increased exposure of the immune system of these patients to necrotic cell debris, to enhanced SNEC-phagocytosis and consequently to the inflammatory responses that characterise the disorder.
A2.25 TIE2 signalling induces a pro-inflammatory phenotype in rheumatoid arthritis and psoriatic arthritis macrophages
Authors: S García, B Malvar-Fernández, DL Baeten, PP Tak, KA Reedquist
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Tie2 is a tyrosine kinase receptor with an essential role in blood vessel remodelling and angiogenesis, through its activation by angiopoietin (Ang)-1 and Ang-2. We have found that Tie2 is mainly expressed and activated in RA synovial macrophages, that Ang-2 plays a crucial role in the murine arthritis and that Tie2 signalling promotes the inflammatory activation of human macrophages. However, the effect of Tie2 signalling on macrophages in the RA synovial environment has not been assessed yet. The aim of this study was examine how differentiation stimuli present in the RA and psoriatic arthritis (PsA) synovial microenvironment regulate Tie2 expression and signalling on macrophages, and the role of Tie2 signalling in macrophages from RA and PsA patients. <h3>Material and methods</h3> Monocytes were isolated from blood buffy coats (HD) and from RA and PsA patients and differentiated into macrophages with IFN-γ (10 ng/ml), IL-10 (10 ng/ml), or with 20% synovial fluid from RA or PsA patients (RA SF and PsA SF). Tie2 expression was analysed by flow cytometry and quantitative PCR. Macrophages were stimulated with TNF (10 ng/ml) in the presence or absence of Ang-1 or Ang-2 (200 ng/ml) for 4 h, the RNA was isolated and reverse-transcribed to cDNA. Macrophage mRNA expression of inflammatory mediators and angiogenic factors was analysed by qPCR and qPCR Array. <h3>Results</h3> Tie2 protein and mRNA expression was observed in RA and PsA SF macrophages and expression levels where similar those found in IL-10 and IFN-g HD macrophages. Gene expression analysis of angiogenic factors demonstrated distinct expression profiles under each condition, although unsupervised clustergram analysis demonstrated a high relationship between IL-10, RA SF and PsA SF macrophages. TNF stimulation of RA SF and PsA SF macrophages enhanced expression of the pro-inflammatory cytokines IL-6, IL-8 and TNF and the chemokines CCL-2, CXCL-2, -3, -5, -6 and -10. Ang-1 and Ang-2 stimulation significantly synergized with TNF to promote IL-6, IL-8, CCL-2, CXCL-2, -3, and -6 expression. In RA and PsA macrophages differentiated in IL-10 and IFN-g, Ang-1 and Ang-2 stimulation significantly synergized with TNF to enhance the expression of IL-6, IL-12B and IL-8 and the chemokines CCL-2 and CXCL-6. <h3>Conclusion</h3> Tie2 is functionally expressed by both RA and PsA macrophages. In RA and PsA SF-differentiated macrophages, and IL-10 and IFN-g -differentiated macrophages from RA and PsA patients, Angiopoietin stimulation enhances TNF induced pro-inflammatory cytokine and chemokine expression. These results suggest that Tie2 signalling, in combination with TNF, induces a pro-inflammatory profile in arthritic macrophages, and provides a molecular basis for the role of Tie2 signalling in promoting disease progression in both early and established RA.