tbuckley/cabot-search huggingface dataset:
THU0102 The Involvement of Toll-Like Receptor 9 in the Pathogenesis of Erosive Arthritis
Authors: S. Herman, A. Fischer, C. Böhm, D. Dudziak, W. VandenBerg, G. Steiner
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Toll-like receptors (TLR) such as TLR7 and TLR9 that are activated by nucleic acids are known to be involved in the pathogenesis of systemic lupus erythematosus (SLE) while their role in the initiation and perpetuation of rheumatoid arthritis (RA) is unknown. To address this issue we applied oligonucleotides specifically antagonizing one or both TLRs in two different disease models: (i) pristane-induced arthritis (PIA) in DA rats which is driven by autoimmune processes induced by subcutaneous injection of the mineral oil pristane and (ii) the KRN serum transfer model in C57Bl/6 mice reflecting the late effector phase of erosive arthritis. In addition, involvement of TLR9 was also investigated in TLR9 knock-out mice. <h3>Objectives</h3> To investigate the role of TLR9 in the pathogenesis of autoimmune arthritis both in the early and in the effector disease phase. <h3>Methods</h3> Arthritis was induced in rats with the mineral oil pristane, in C57Bl/6 and TLR9 <sup>-/-</sup> mice by injection of KRN serum. Immunoregulatory oligodeoxynucleotide (ODN) sequences (IRS) antagonizing TLR7 or TLR9 were applied either subcutaneously (PIA) or intra-peritoneally (KRN). A non-inhibitory ODN was used as control and PBS served as placebo. Arthritis was scored using established scoring systems, inflammation and bone erosion were quantified by histology. Serum and cell culture cytokine levels were measured by ELISA. <h3>Results</h3> In the PIA model the TLR7 inhibitor and a TLR7/9 dual inhibitor showed no effect on arthritis development and severity. In contrast, arthritis severity was significantly reduced (p&lt;0.05) by the TLR9 antagonist and bone erosion was almost completely abolished (p&lt;0.01). Furthermore, IL-6 serum levels were significantly lower than in mice treated with the TLR7 antagonist or a control oligonucleotide. However, these effects were only seen when the inhibitor was applied before disease onset. In line with this observation, neither inhibitor affected arthritis onset and severity in the serum transfer model which is independent of the adaptive immune system and arthritis appeared to be even aggravated and osteoclastogenesis enhanced in mice lacking a functional TLR9 gene. <h3>Conclusions</h3> TLR9 inhibition significantly reduced inflammation and bone erosion in PIA, but not in the KRN serum transfer model. These results suggest an important involvement of the DNA (CpG) recognizing TLR9 in the initiation of autoimmune arthritis whereas in the later disease phases TLR9 may even play a beneficial role similar to what has been found in models of SLE and other models for autoimmune diseases such as diabetes. Antagonizing TLR9 in human RA may therefore show beneficial effects only in the very earliest phase of the disease while its activation may have therapeutic effects in established disease. <h3>Disclosure of Interest</h3> None Declared
893 EARLY VIROLOGICAL RESPONSE RATES IN MONOINFECTED PATIENTS WITH HCV AND COINFECTED WITH HCV/HIV, GENOTYPES 1&amp;4 TREATED WITH PEGINTERFERON alpha 2a AND RIBAVIRIN. OPTIM STUDY
Authors: M. Romero-Gómez, B. de Cuenca, E. Baeyens, J. García- Samaniego, J. Salmerón, M.D.M. Alonso, J. Buenestado, R. Muñoz, M. Diago, A. García, C. Mínguez, L. Morano, J.A. Girón, J.J. Sa'nchez, J.J. González-García, R. Solá
Journal: Journal of Hepatology (2013)
Abstract 18503: Geranylgeranylacetone (gga) And Gga-derivatives Inhibit Acetylcholine-activated K+ Current In Mouse Atrial Cardiomyocyte ; Possible Mechanism For Af Suppression
Authors: Tae-Joon Cha, Eun Kyoung Choi, Hye Jin Yun, Ga-In Yu, Sung-Il Im, Bianca Brundel
Journal: Circulation (2015)

Atrial fibrillation (AF) is the most common sustained arrhythmia. AF is caused by inflammation, oxidative stress, and various structural heart diseases. An important key factor in AF promotion is that atrial cardiomyocytes have constitutively active acetylcholine-activated K+ (IKACh) current that is enhanced by the tachycardia. Furthermore, it is known that heat shock proteins (HSPs) are involved in the protection against different forms of cellular stress and recent investigators reported that the HSP inducing compound geranylgeranylacetone (GGA, also known as teprenone) prevents atrial remodeling and attenuates the promotion of AF. Whether GGA and GGA-derivatives prevent the acetylcholine-activated K+ current is unknown. Methods: We examined the effect of HSP inducer GGA and 5 derivatives on IKACh current in mouse atrial cardiomyocytes. In the present study, the IKACh current was recorded using a nystatin-perforated whole cell patch-clamp technique following activation by acetylcholine (10 μM for 2 min). After the measurement of the baseline IKACh current, atrial cardiomyocytes were treated with GGA 10μM or a derivative of GGA (NYK9274, NYK9308, NYK9354, NYK9356 or NYK9376) for 10min and the IKACh current was re-measured. Results: IKACh current in mouse atrial cardiomyocyte treated with acetylcholine (10 μM) was significantly increased, which was markedly attenuated by GGA 10μM treatment (n=5, peak; 54±11.2%, quasi-steady-state; 58±11.4%, p&lt;0.001). In addition, the effects of the GGA derivatives on IKACh were evaluated with same experimental protocol. Our results showed that next to GGA, also NYK9308 and NYK9356 significantly inhibit both peak and quasi-steady-state IKACh. In contrast, NYK9274, NYK9354 and NYK9376 had no effect on IKACh. Conclusion: This study provides important evidences that the HSP inducer GGA facilitates its potent antiarrhythmic effect by inhibiting IKAch, which underlies electrical remodeling in mammalian atrial cardiomyocytes. Furthermore, two GGA derivatives, NYK9308 and NYK9356, with improved pharma-chemical properties compared to GGA, reveal similar protective effects compared to GGA, and provide important background information for the use of GGA and GGA-like compounds in patients with AF.
OC-005 The Early Expansion of Intrahepatic NK Cells is Associated with Clearance of HCV after IFN-Alpha -Based Treatment
Authors: T Pembroke, A Gallimore, A Godkin
Journal: Gut (2013)

<h3>Introduction</h3> Chronic hepatitis C virus (HCV) infection is a major cause of liver failure, cirrhosis and hepatocellular carcinoma. Current treatments are evolving but still largely rely on IFNα in combination with ribavirin +/- protease inhibitors. IFNa can activate Natural killer (NK) cells: large granular lymphocytes that can target virally-infected cells. NK cells may play a role in the immune response to chronic HCV. We examined whether the kinetics of NK cell expansion and activation affected long-term treatment success. <h3>Methods</h3> Repeated matched blood and intrahepatic (IH) NK cells were obtained from 9 patients before treatment and on days 1, 3, 7, 14, 28 and 86 of treatment. IH samples were obtained by fine needle aspirations. NK cell phenotype (CD16, NKp30, NKp46 &amp; NKG2D) and functional markers (CD107a, IFNg &amp; granzyme B) were assessed by flow cytometry. Rate of viral clearance (k) was calculated from serial serum viral loads during treatment. <h3>Results</h3> Multiple IH samples were obtained from 9 subjects. 5 of the 9 patients achieved viral clearance i.e. SVR; 4 failed treatment. The proportion of IH lymphocytes that were NK cells increased from mean 10% (+/-0.97% SEM) at baseline to 16.1% (+/- 2.43% SEM) after 24 hours (p = 0.021) and 17.9% (+/-4.75% SEM) after 72 hours (p = 0.023). The proportions returned to baseline levels from day 7 onwards. The proportion of IH NK cells was greater in patients who achieved SVR (18.6%) than those who failed treatment (11.9%). The rate of viral clearance correlates with IH NK cells at day 1 (p = 0.036). IH NK cells at 24 hours demonstrated an increase in activation i.e. increase CD107a externalisation, decreased granzyme B and CD16 expression. <h3>Conclusion</h3> IH NK cells are cytotoxically active during the early phase of treatment when reduction in viral load is most pronounced. The rate of expansion of these activated NK cells in the first 24 hours indicates treatment success or failure. These findings suggest that strategies to improve early NK cell migration to the liver during treatment may lead to better treatment outcomes. <h3>Disclosure of Interest</h3> None Declared
The Early Prediction of Response to Neoadjuvant Chemotherapy Using MRI.
Authors: H. Kim, E. Ko, E. Kim, E. Jo, M. Kim, W. Noh
Journal: Cancer Research (2009)

Abstract Purpose: Neoadjuvant chemotherapy is an effective method for down-staging the primary tumor before surgery. However, some of patients do not respond. In these patients, neoadjuvant chemotherapy is just an ineffective, toxic and expensive procedure. Therefore, it is very important to find the reliable method to differentiate the responder from non-responder as early as possible. In order to evaluate the role of magnetic resonance imaging (MRI) for the assessment of tumor response, we examined the correlation between the early MRI changes after the 1st cycle of neoadjuvant chemotherapy and later pathologic response after the 3rd cycle of neoadjuvant chemotherapy.Patients and method: 31 breast cancer patients who underwent neoadjuvant chemotherapy prior to surgery were analyzed. The baseline MRI was taken before neoadjuvant chemotherapy. Anthracycline plus taxane were administered to all patients. Post-chemotherapy MRI assessment was done just before the 2nd cycle of neoadjuvant chemotherapy. If the primary tumor was reduced more than 20% in the product of the longest and perpendicular diameter, those cases were classified as responders. Surgery was performed after the 3rd cycle of neoadjuvant chemotherapy. The pathologic response was assessed by measuring pathologic tumor size of viable tumor cells. Sensitivity, specificity, positive predictive value, and negative predictive value of MRI findings were calculated on the basis of histopathological examination.Results: Total 31 patients were examined. Of these patients, 2 patients had bilateral breast cancer. Therefore, a total of 33 lesions were evaluated. The median tumor size on baseline MRI was 4.5cm (range:2.1-10.0cm). 27 cases were classified as responders on early MRI findings. Of these cases, pathologic response was confirmed in 26 cases after surgery. Six cases were classified as non-responder on MRI. In this group, 3 cases showed pathologic response and 3 cases did not. Sensitivity, specificity, positive predictive value and negative predictive value of early MRI findings for the prediction of pathologic response were 89.7%, 75.0%, 96.3% and 50.0%, respectively.Conclusion: Post-chemotherapy MRI after the 1st cycle of neoadjuvant chemotherapy could differentiate responders from non-responders with high accuracy. It would be helpful to determine whether the chemotherapy regimen should be continued or not in the early phase of neoadjuvant therapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6057.
Chemotherapy, Immunocompetence, Immunosuppression and Prognosis in Acute Leukemia
Authors: Evan M. Hersh, John P. Whitecar, Kenneth B. McCredie, Gerald P. Bodey, Emil J. Freireich
Journal: New England Journal of Medicine (1971)

Immunologic competence was evaluated in 25 patients with acute myelogenous leukemia before and after intensive combination chemotherapy for induction of remission. Cell-mediated immunity correlated with the response to chemotherapy; 86 per cent of patients with normal delayed hypersensitivity to a battery of antigens achieved remission as compared to 25 to 50 per cent of anergic patients. In vitro lymphocyte responses to phytohemagglutinin before and after therapy showed 41,000 and 42,000 counts per minute in patients achieving remission and of 15,000 and 9000 counts per minute in patients not achieving remission. Sixty per cent of patients showing delayed hypersensitivity after immunization entered complete remission as compared to only 37 per cent of those without this reactivity. Patients converting from immunoincompetence to immunocompetence during therapy achieved remission, whereas those converting from immunocompetence to immunoincompetence did not. Prior treatment had no effect on immune competence. Serial immunologic evaluation may predict prognosis in acute leukemia.
Abstract 619: Dual targeted therapies to overcome tyrosin kinase inhibitors resistant in epidermal growth factor receptor (EGFR) expression of lung cancer
Authors: Wen-Chien Huang
Journal: Cancer Research (2010)

Abstract Background: Non-small cell lung cancer (NSCLS) comprises about 80% of all lung cancers. The regular treatments for NSCLC are surgery, chemotherapy, radiotherapy and EGFR-targeted therapy. EGFR is frequently mutated and amplified in lung adenocarcinom as sensitive to EGFR inhibitors. The EGFR-targeted therapy, Gefitinib and Erlotinib, significantly improves disease free survival. However, it was not possible to predict super-responder of gefitinib degree of EGFR expression as a single agent. There is an imposing need for new rationally designed regimens to overcome Gefitinib resistance. The other tyrosine kinase inhibitor, Lapatinib, is a small-molecule inhibitor targeting both the HER2 and the epidermal growth factor receptor (EGFR) in solid tumors. We hypothesized that this aberrant activation of EGFR may contribute to Gefitinib resistance and dual blocking EGFR activation with EGFR and ERBB2 inhibitor will re-sensitize HER family in lung cancers. Experimental Design: In the in vitro study, cancer cells with EGFR wild type or mutation type were treated with Tyrosine kinase inhibitor, Gefitinib, Lapatinib, or combined treatments. The responses of cells to Gefitinib or/and Lapatinib treatments were evaluated by MTS proliferation, apoptosis assay, soft agar colony formation assay and western blot. In the in vivo study, pulmonary xenograft tumors were established in ICR/SCID mouse and treated with vehicle control, Gefitinib, Lapatinib, or Gefitinib plus Lapatinib for 4 weeks. Tumor volume were monitored and further studied by immunohistochemistry on collected tumors. Results: We selected multiple pairs of EGFR wild type and mutation type. The EGFR mutation cells have more effect under single tyrosine kinase inhibitor (Gefitinib) treatment compared with EGFR wild type cells. Dual inhibition of EGFR activation sensitized EGFR expression pulmonary cancer cells to Gefitinib treatment. Compared with single treatment, combined treatment led to a significantly more effective inhibition of cell proliferation and induced apoptosis. In a mouse pulmonary xenograft model, combination therapy with Gefitinib and Lapatinib dramatically inhibited EGFR wild type tumor growth. Conclusions: Since the EGFR family inhibitor, Lapatinib is currently under Phase III clinical trial, combining Gefitinib with this Lapatinib, dual EGFR inhibitors is a clinically applicable strategy and a promising combinatory targeted anti-cancer therapy to overcome EGFR wild type mediated Gefitinib resistance. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 619.
Prevention of Typhoid Fever in Nepal with the VI Capsular Polysaccharide of<i>Salmonella Typhi</i>
Authors: I L Acharya, C U Lowe, R Thapa, V L Gurubacharya, M B Shrestha, M Cadoz, D Schulz, J Armand, D A Bryla, B Trollfors
Journal: New England Journal of Medicine (1987)

We conducted a pilot study followed by a large clinical trial in Nepal of the use of the capsular polysaccharide of Salmonella typhi (Vi) as a vaccine to prevent typhoid fever. In the pilot study, involving 274 Nepalese, there were no significant side effects of the Vi vaccine; about 75 percent responded with a rise in serum antibodies of fourfold or more. In the clinical trial, residents of five villages were given intramuscular injections of either Vi or, as a control, pneumococcus vaccine dispensed in coded, randomly arranged, single-dose syringes. There were 6907 participants, of whom 6438 were members of the target population (5 to 44 years of age); each was visited every two days. Those with temperatures of 37.8 degrees C or higher for three consecutive days were examined and asked to give blood for culture. Typhoid was diagnosed as either blood culture-positive or clinically suspected on the basis of bradycardia, splenomegaly, and fever, with a negative blood culture. Seventeen months after vaccination, the codes were broken for the 71 patients meeting the criteria for either culture-positive or clinically suspected typhoid. The attack rate of typhoid was 16.2 per 1000 among the controls and 4.1 per 1000 among those immunized with Vi (P less than 0.00001). The efficacy of Vi was 72 percent in the culture-positive cases, 80 percent in the clinically suspected cases, and 75 percent in the two groups combined. These data provide evidence that Vi antibodies confer protection against typhoid. Surveillance continues to determine the duration of Vi-induced immunity.
FRI0250 Are rheumatoid arthritis patients who receive abatacept comparable with those on other biologics?
Authors: K. Michaud, S. Pedro, T. Simon, F. Wolfe
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Observational studies are critical in assessing medication safety and effectiveness. Non-random assignment can potentially lead to channeling bias. Understanding the characteristics of patients receiving similar treatments is important for addressing these biases prior to performing comparative effectiveness analyses. Abatacept (ABA) was one of the first efficacious non-TNF-targeting biologic treatments available. To date, little is known about the patients receiving it. <h3>Objectives</h3> To assess characteristics of patients receiving ABA as their first, second, or third or more biologic compared to all other biologics. <h3>Methods</h3> Participating RA patients in the National Data Bank for Rheumatic Diseases (NDB) provided treatment and other characteristics (demographic including social, RA-related and comorbidities) through self-reported biannual questionnaires. Only responses from 2005-2012 were used for greater comparability since that is when ABA was available. Initiators of biological therapies were stratified by type of biologic (ABA vs. all others) and by number exposed to previously. <h3>Results</h3> A total of 6,682 RA patients initiated at least one new biologic after 2005. A total of 272 received ABA without any prior biologic experience: they were older, had more experience with smoking, diabetes, cancer, hypertension, and other comorbidities, although they used less prednisone in comparison (see Table). Some trends were found in the 1<sup>st</sup> to 4<sup>th</sup> biologic used: increasing HAQ, cormorbidities, pain, RA duration, and prednisone use (all p&lt;0.01). ABA patients with no prior biologics were less exposed to MTX. When ABA was the 2<sup>nd</sup> biologic, patients were most likely to have prior exposure to infliximab; this is in contrast to 1<sup>st</sup> biologic users who started etanercept and adalimumab before infliximab. When ABA was the 3<sup>rd</sup> biologic, the anti-TNFs were the most frequent biologic previously administered. Few ABA patients had previous exposure to rituximab compared to other biologics. <h3>Conclusions</h3> There appears to be a trend of channeling bias with ABA use in our RA cohort. ABA users were generally older and had more comorbidities including a history of cancer when they had less other biologic experience. Early intravenous ABA use often followed intravenous infliximab use. Careful examination of baseline characteristics will be critical in future comparative effectiveness analyses. <b>Disclosure of Interest</b>: K. Michaud Grant/research support from: ACR Rheumatology Research Foundation, S. Pedro: None Declared, T. Simon Employee of: Bristol-Myers Squibb, F. Wolfe Grant/research support from: NDB receives grant funding from BMS, Amgen, UCB, Pfizer, and AstraZeneca.
195 HEPATIC VEINS DOPPLER PROFILE MODIFICATIONS DURING ACUTE PORTAL PRESSURE INCREASE INDUCED BY PARAUMBILICAL VEIN COMPRESSION
Authors: P. Bizzotto, G. Bombonato, S. Tonello, A. Verardo, S. Brocco, P. Pesce, M. Bolognesi, C. Merkel, D. Sacerdoti
Journal: Journal of Hepatology (2013)
MOF as Control Arm for NSABP Adjuvant Chemotherapy Trial
Authors: K. HELLMANN, J. GILBERT
Journal: JNCI Journal of the National Cancer Institute (1988)

Journal Article MOF as Control Arm for NSABP Adjuvant Chemotherapy Trial Get access K. HELLMANN, K. HELLMANN 1Department of Radiotherapy and Oncology, Riverside Health Authority, Westminster HospitalDeal Ryle, St. Horseferry Rd., London SWIP 2AP, England Search for other works by this author on: Oxford Academic PubMed Google Scholar J. GILBERT J. GILBERT 2St. Mark's HospitalLondon ECI, England Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 80, Issue 14, 21 September 1988, Pages 1173–1174, https://doi.org/10.1093/jnci/80.14.1173 Published: 21 September 1988
Abstract P2-02-02: Prognostic significance of the ratio of absolute neutrophil to lymphocyte counts for breast cancer patients in neoadjuvant setting
Authors: YW Koh, HJ Lee, J-H Ahn, JW Lee, G Gong
Journal: Cancer Research (2012)

Abstract Background: The baseline absolute neutrophil count/absolute lymphocyte count ratio (NLR) has potential prognostic importance in solid tumors, including breast cancer. However, NLR as a predictive factor of the pathologic complete response (pCR) or as a prognostic factor has not been fully studied in breast cancer patients who have received neoadjuvant chemotherapy. Materials and Methods: Using receiver operating characteristic curve analyses, we retrospectively examined the predictive and prognostic impact of the NLR at the diagnosis in 401 patients with primary breast cancer who were treated with neoadjuvant chemotherapy, followed by definitive surgical resection. Of the 401 included patients, 72 (18%) received anthracycline-based, 285 (71%) received anthracycline- and taxane-based, 37 (9.2%) received herceptin-based, and 7 (1.7%) received fluorouracil-based regimens. The significance of NLR was analyzed according to clinicopathologic variables and clinical outcomes. Results: Forty-three (10.7%) patients achieved pCR. On univariate analysis, high NLR (&amp;gt; 2.2) correlated with poor recurrence-free survival (RFS; P = 0.001) and overall survival (OS; P = 0.003). Subgroup analysis of the non-pCR group showed that NLR was significant for RFS and OS (P = 0.002 and P = 0.007, respectively). Multivariate analysis showed NLR to be an independent prognostic factor for RFS and OS (P = 0.002 and P = 0.007, respectively). Subgroup analysis of the pCR group showed that patients with high NLR have a higher recurrent rate than low NLR (30.8% vs. 13.3%). The NLR was not related to pCR (P = 0.098). Conclusion: Our results suggest that the NLR is an independent prognostic factor for RFS and OS in breast cancer patients receiving neoadjuvant chemotherapy and may provide additional prognostic information for patients not achieving a pCR to determine who might profit from further therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-02-02.