tbuckley/cabot-search huggingface dataset:
P23 Effect of omalizumab on oral corticosteroid requirements of young children with severe asthma; results of a UK survey
Authors: A. Kirk, D. Spencer, A. Radwan
Journal: Thorax (2010)

<h3>Introduction and Objectives</h3> Some children with severe chronic asthma require long-term oral corticosteroids (OCS) to maintain disease control which places them at risk of potentially serious adverse effects. Omalizumab is a recombinant, humanised, monoclonal anti-IgE antibody indicated in the EU for use in patients of ≥6 years of age with inadequately controlled severe allergic asthma. This agent improves disease control in children, adolescents and adults. We conducted an observational survey in UK clinical centres to evaluate whether omalizumab enabled reduction of OCS dose in children with severe, persistent, allergic asthma. <h3>Methods</h3> Seven UK clinical centres were identified in which children (6 to &lt;12 years of age) with severe persistent allergic asthma were being treated with omalizumab. Lead clinicians at each centre were approached to request their participation and, if they agreed, they were sent a short questionnaire. Participating clinicians provided information on children who had continued treatment with omalizumab beyond the 16-week responder assessment. Information collected included the number of children receiving omalizumab, OCS use, OCS dose at omalizumab initiation, numbers of children stopping, reducing or increasing OCS use, and current OCS doses. <h3>Results</h3> Information was provided from four sites for 18 children receiving omalizumab, all of whom were on maintenance OCS at baseline. All patients were able to stop or reduce their OCS dose after initiating omalizumab. Four patients (22%) on a mean baseline OCS dose of 8.8 mg/day stopped using OCS altogether. In the remaining fourteen patients (78%) the OCS dose was reduced by a mean of 15.4 mg (from 22.0 mg to 6.5 mg; mean 70.2% reduction). The mean dose reduction across all patients of 77% was achieved in a mean time of 14.6 weeks. <h3>Conclusions</h3> In this observational survey, all paediatric patients with severe allergic asthma who were commenced on omalizumab were able to stop or reduce OCS use, potentially reducing the risk of OCS-related adverse effects. The reductions in OCS use occurred over a short period, raising the possibility that further reductions in OCS dose might be feasible in some patients over a longer period of time.
The Guillain–Barré Syndrome and the 1992–1993 and 1993–1994 Influenza Vaccines
Authors: Tamar Lasky, Gina J. Terracciano, Laurence Magder, Carol Lee Koski, Michael Ballesteros, Denis Nash, Shelley Clark, Penina Haber, Paul D. Stolley, Lawrence B. Schonberger, Robert T. Chen
Journal: New England Journal of Medicine (1998)

The number of reports of influenza-vaccine–associated Guillain–Barré syndrome to the national Vaccine Adverse Event Reporting System increased from 37 in 1992–1993 to 74 in 1993–1994, arousing concern about a possible increase in vaccine-associated risk.
Abstract 2491: High-dose acetaminophen with N-acetylcysteine rescue enhances the efficacy of cisplatin chemotherapy
Authors: Tam Nguyen, Alexander J. Neuwelt, Jeffrey Wu, Nicholas K. Foreman, Edward A. Neuwelt, Louis B. Rapkin
Journal: Cancer Research (2012)

Abstract Acetaminophen (AAP) has been shown to enhance cisplatin (CDDP) cytotoxicity in hepatoblastoma cell lines. Further, one published case report demonstrated clinical efficacy of administering acetaminophen in conjunction with cisplatin and followed 6 hours later with n-acetylcysteine (NAC) rescue. In this study, atypical rhabdoid tumor (ATRT) and germinoma cells were treated with CDDP and AAP with or without NAC rescue. We then evaluated the cells with western blots for cleaved PARP and caspase 3 to demonstrate effects on apoptosis. Further, MTS assays were performed to evaluate cell viability of treated cells. To evaluate the effects of the various treatments on oxidative stress, dihydroethidium (DHE) and 2′,7′-dichlorofluorescin (DCFH) assays were performed to test for superoxide and hydrogen peroxide levels, respectively. It was demonstrated that AAP enhances CDDP cell kill and apoptosis in germinoma and ATRT cell lines. Further, both AAP and CDDP, independently and together, cause increased oxidative stress as measured by DHE and DCFE, but this oxidative stress is only reversed by NAC in the DCFE assay. This makes sense because NAC, a glutathione precursor, detoxifies peroxide but not superoxide. Further, our group has learned of five previously unpublished patients with recurrent liver tumors (hepatocellular carcinoma and hepatoblastoma) treated with AAP and CDDP with delayed NAC rescue. All patients tolerated the treatment well. Two of the five patients responded to the treatment, suggesting the potential of this approach. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2491. doi:1538-7445.AM2012-2491
AB0474 Joint manifestations in behcet’s disease : a review of 100 cases
Authors: R. Dhahri, L. metoui, I. Gharsallah, Ajili Fadia, Najeh bousetta, Nadia Abdelhafidh, B. Louzir, S. Othmeni
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To gain additional knowledge on the joint manifestations of Behcet's disease, with special attention to epidemiological and clinical aspects. <h3>Methods</h3> Retrospective review of 100 cases collected over a period of 13 years. All the patients met International Study Group for Behcet's disease criteria. 60 % of patients had rheumatic manifestations. Ophthalmic examination and the pathergy test were performed in all patients, sacroiliac radiographs were taken in 58 patients. HLAB51 and B27 antigens were investigated in 70 patients, antinuclear antibodies were sought in in 57 patients, C3, C4 in 44 patients. <h3>Results</h3> Joint manifestations were present in more than half of the patients (60%) and were inaugural in 38% of cases. The knees and ankles were the joints most commonly affected. Monoarthritis and oligoarthritis polyarthritis are denoted respectively in 26%, 19%, 14% of cases. arthralgias occured in 80% of cases. Two patients showed a sacroilite isolated. Furthermore, popliteal cyst was noted in 4 cases, broken in 2 cases. The arthritis is associated with erythema nodosum in 55% of cases and in 70% pseudofolliculitis cases. The HLA B51 and HLA-B27 were found in 13.8% and 36.9% of cases, these joint manifestations were benign, limiting and never evolved to deformation or destruction. <h3>Conclusions</h3> Joint manifestations are common in Behcet's disease. The unusual forms deserve to be known since they can raise diagnostic problems when they are inaugural. Rheumaticmanifestations of Behcet's disease are the most frequently associated with erythema nodosum and pseudofolliculitis <h3>Disclosure of Interest</h3> None Declared
Abstract 1693: Intracellular hypoxia is dominantly determined by mitochondrial respiratory activity.
Authors: Sara Prior, Ara Kim, Seiji Tobita, Toshiyuki Takeuchi, Masahiro Higuchi
Journal: Cancer Research (2013)

Abstract Intracellular oxygen concentration ([O2]i.c.) regulates key biological functions such as HIF-1α activation, glucose transport, potassium pumps, intracellular calcium concentration, P450 family enzymes and HMGR expression. However, the mechanisms regulating [O2]i.c remain to be defined. Here, we provide direct evidence of the mitochondrion's role in [O2]i.c. regulation. We used bis(2-(2′-benzothienyl)-pyridianto-N,C3’irridium(acetylacetonate) (BTP) to measure [O2]i.c. in living cells via microscopy.5 Well-differentiated cancers, LNCaP and MCF-7 showed intracellular hypoxia without exogenous hypoxia. In contrast, poorly-differentiated cancers exhibited intracellular normoxia, and exogenous hypoxia could induce hypoxia. The specific complex I inhibitor, rotenone, and the reduction of mitochondrial DNA (mtDNA) content increased in [O2]i.c,, indicating that [O2]i.c. is regulated by mitochondrial respiratory activity. [O2]i.c. is additionally regulated by glucose, but the dose-dependent relationship is parabolic. The no glucose condition induced normoxia, and the low concentration glucose condition (0.045mg/ml) induced strong hypoxia. [O2]i.c. was found to be additionally determined by the presence of FCS in the growth medium, and this effect was mimicked by an androgen analog, R1881, suggesting that androgen, glucose concentration and respiratory function are important regulators of [O2]i.c.. Citation Format: Sara Prior, Ara Kim, Seiji Tobita, Toshiyuki Takeuchi, Masahiro Higuchi. Intracellular hypoxia is dominantly determined by mitochondrial respiratory activity. [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 1693. doi:10.1158/1538-7445.AM2013-1693
A6.41 IgM and IgA rheumatoid factors from rheumatoid arthritis patients boost the F<sub>c</sub>receptor- and complement-dependent effector functions of ACPA
Authors: F Anquetil, C Clavel, G Offer, G Serre, M Sebbag
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Rheumatoid factors (RF) and the disease-specific anti-citrullinated protein autoantibodies (ACPA) coexist in the joints of rheumatoid arthritis (RA) patients were they probably contribute to synovitis. We showed that monoclonal IgM paraproteins with RF activity from patients with mixed cryoglobulinemia enhance the FcγR-mediated proinflammatory response of macrophages to ACPA immune complexes (ACPA-IC). Our aim was to investigate the influence of IgM RF from RA patients on the FcR- and complement-dependent effects of ACPA-IC and to examine that of RA-associated IgA RF. <h3>Materials and methods</h3> M-CSF-differentiated macrophages were stimulated in a serum-free medium by ACPA-IC formed with plate-bound citrullinated fibrinogen in the absence or presence of one of 5 IgM RF or 3 IgA RF fractions purified from RA serum pools by sequential affinity chromatography. Pro-inflammatory and immunoregulatory cytokines were assayed in the culture supernatants. The expression of IgM and/or IgA receptors was analysed by flow cytometry and their contribution to TNF-α secretion prompted by RF-containing ACPA-IC was evaluated. The complement activation capacity of ACPA-IC formed in the absence or presence of IgM or IgA RF was compared by ELISA measuring deposition of the terminal C5b–9 complex. <h3>Results</h3> When stimulated by ACPA-IC formed in the presence of IgM RF or IgA RF fractions, M-CSF-generated macrophages skewed their cytokine response toward inflammation, with an increase of the TNF-α:IL-10 ratio and of the IL-6 and IL-8 secretions, and a decrease of the IL-1Ra:IL 1β ratio. The participation of an IgM receptor in the IgM RF-mediated amplification of the inflammatory response of macrophages was excluded, notably as they did not express any established receptor for IgM. However, the macrophages expressed FcαRI and blocking its interaction with IgA inhibited the IgA RF-mediated amplification of TNF-α secretion induced by ACPA-IC. LPS further amplified the TNF-α response of macrophages to IgM or IgA RF-containing ACPA-IC. Finally, the presence of IgM RF or of IgA RF increased the capacity of ACPA-IC to activate the complement cascade. <h3>Conclusions</h3> Specifically using autoantibodies found in RA patients, the strong complement-dependent and FcR-mediated proinflammatory effect of macro-IC including both ACPA and IgM RF or IgA RF is established, strongly reinforcing the hypothesis of their high pathogenic potential. Simultaneous FcR triggering by these macro-IC and TLR4 ligation possibly makes a major contribution to RA synovitis.
RAP-011, a soluble activin receptor type IIA IgG-Fc fusion protein, is a novel bone anabolic agent that prevents bone loss and skeletal metastases in a mouse model of metastatic breast cancer.
Authors: AW Mulivor, D Barbosa, R Kumar, AE Pearsall, KW Underwood, JA Ucran, J Seehra, R Pearsall
Journal: Cancer Research (2009)

Abstract Abstract #1158 Breast cancer cells have a strong propensity to metastasize to bone, resulting in debilitating complications such as intractable bone pain, spinal compression, pathological fractures, or loss of mobility and function. Anti-resorptive agents, such as bisphosphonates, are commonly used to halt the additional loss of bone, but fail to stimulate the formation of new bone to repair lost or damaged bone. Previous data demonstrated that treatment with an activin antagonist, a soluble form of the extracellular domain of the activin type IIA receptor (ActRIIA) fused to a murine IgG-Fc fragment (RAP-011), can restore bone mass in ovariectomized mice with established bone loss and prevent bone loss in a murine model of multiple myeloma.&amp;#x2028; To investigate the ability of RAP-011 to prevent skeletal metastases in an experimental model, bioluminescent breast cancer cells (MDA-MB-231-luc-D3H2LN) were administered by intracardiac injection into athymic nude mice that had been pretreated for 2 weeks with RAP-011 (10 mg/kg S.C. twice weekly) or vehicle (VEH). At 3 and 5 weeks post-inoculation, RAP-011 treated mice displayed lower levels of hind limb, mandible and lung metastases compared to VEH-treated mice. RAP-011 treated mice had reduced tumor burden (-70%) and increased overall survival by 11 days compared to VEH-treated mice. It was also shown that RAP-011 preserved bone mineral density and increased both trabecular volume (BV/TV +140%, P&amp;lt;0.001) and trabecular number (+15%, P&amp;lt;0.001), compared to VEH. In the VEH-treated mice, BV/TV was lower in bones with a tumor present (0.191) than bones without a tumor (0.276, p=0.1). However, RAP-011 treated mice increased BV/TV to a similar extent in both bones with a tumor (0.598) and bones without a tumor (0.599, p=0.98) compared to the VEH controls (p&amp;lt;0.001).&amp;#x2028; Taken together, these data suggest that inhibition of activin has the potential therapeutic benefit of improving bone health in patients with cancer related bone loss as well as preventing metastasis of breast cancer. Towards this end, ACE-011, the human analog of RAP-011, is currently in clinical development for the treatment of cancer-related bone loss. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1158.
A10.18 Lack of Association of Serum Interleukin-17 and Interleukin-23 Levels with Disease Activity in Patients with Ankylosing Spondylitis in Latvia
Authors: Zepa Julija, Bulina Inita, Nikitina-Zake Liene, Klovins Janis, Jurka Anita, Tretjakovs Peteris, Lejnieks Aivars, Andersone Daina
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Ankylosing spondylitis (AS) is a clinically well-known chronic inflammatory disease of the axial skeleton and peripheral joints. The pathogenesis of this disease still remains a challenge. Determination of cytokine profile and its role involved in AS pathogenesis give an opportunity to extend the targeted therapeutic approach. Interleukin-17 (IL-17) and interleukin-23 (IL-23) are cytokines of interest in the investigation of the pathogenesis of spondyloarthritides although their importance in AS is not clearly defined. <h3>Objectives</h3> to investigate levels of IL-17 and IL-23 in a group of AS and in a demographically matched group of healthy subjects and its association with the disease activity measured by relevant clinical and biochemical parameters. <h3>Materials and Methods</h3> 39 AS patients classified by the modified New York and ASAS criteria were assessed clinically and 6 ml of serum were collected from each patient. 39 healthy subjects as control group were included in this study. The serum IL-17 and IL-23 levels were tested using xMAP multiplex immunobead assay technology. At the same time the disease activity was measured by using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS) using C-reactive protein (CRP), erythrocyte sedimentation rate (ESR). <h3>Results</h3> The mean serum IL-17 and IL-23 level in AS group was respectively 18.9 (SD 39.6) and 194.6 (SD 261.4) pg/ml. In the healthy control group the mean serum IL-17 level was 15.4 (SD 26.0) and IL-23 level – 200.3 (SD 256.3) pg/ml. The serum levels of IL-17 and IL-23 were not statistically significantly different from the healthy subjects and the levels did not correlate with the disease activity measured by BASDAI and ASDAS (using the CRP and ESR). <h3>Conclusions</h3> These results suggest that IL-17 and IL-23 are not major components of the pathogenesis of inflammation in AS patients. Our data differ from <i>Chen W S et al</i>, in 2012 published data of the serum IL-17 and IL-23 level association with the disease activity in Chinese patients with AS. This difference is probably due to the various genetic aspects characterising AS as geographically matched disease.
THU0351 The Role of Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) in the Pathogenesis of Ankylosing Spondylitis
Authors: M. Cinar, H. Akar, S. Yilmaz, I. Simsek, M. Karkucak, R. I. Sagkan, H. Erdem, I. Y. Avci, C. Acikel, U. Musabak, Y. Tunca, S. Pay
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Although genetic factors known to play crucial role in the pathogenesis of ankylosing spondylitis (AS), little is known about the molecular mechanisms that are responsible. In that context, endoplasmic reticulum aminopeptidase 1 (ERAP1) gene has been suggested as the most important factor in genetic susceptibility, with the exception of HLA-B27. <h3>Objectives</h3> To investigate the role of ERAP1 in the pathogenesis of AS and its relationship with clinical findings. <h3>Methods</h3> We included 150 consecutive AS patients who were fulfilling the Modified New York classification criteria and 150 blood donors as healthy control. DNA isolation from the participants' blood samples was performed automatically by the BioRobot<sup>®</sup> EZ1 station and we investigated the presence of ERAP1 gene single nucleotide polymorphisms (SNPs) (rs30187, rs27044, rs26653, rs27037, rs2287987, rs10050860, rs17482078, rs7711564, rs27980, rs27529) by using the method of competitive allele-specific PCR. We also determined the subgroups of HLA-B27 by PCR-Sequence Specific Primer (SSP). The differences between genotype and allele frequencies were compared by Pearson Chi-square test. <h3>Results</h3> The mean age of patients and controls were 34.6 and 29.4 years, respectively. In the patient group, the rate of HLA-B27 positivity was 66.7%, while this was 4.7% in the control group. We detected rs26653 SNP C/C homozygotes in 36 patients (24.0%) and 21 controls (14.0%). The frequency distribution of rs26653 SNP C/C homozygous genotype between the groups was found to be statistically significant (p=0.015). We identified that the frequency of rs26653 SNP's risky C allele was higher in the patient group (50.0%) than the control group (38.3%) (OR 1.609, %95 CI 1.163-2.226, p=0.004). The contribution of rs26653 SNP's risky C allele to the total AS genetic risk was calculated as 23.4%. The differences between genotype and allele frequency distribution of other SNPs were not statistically significant. <h3>Conclusions</h3> In our study, only rs26653 SNP, out of 10 ERAP1 gene SNPs, which were suggested as genetic susceptibility factors in AS at previous studies, was found to be associated with the risk of genetic predisposition in our AS group. The contribution of rs26653 SNP to the total AS genetic risk in the present study was found as 23.4% and it was compatible with the literature (26%). Since there was no relation between HLA-B27 positivity and rs26653 SNP, the contribution of both factor to the pathogenesis of AS seems to be independent from each other. <h3>Disclosure of Interest</h3> None Declared
Protein Patterns of Brush-Border Fragments in Congenital Lactose Malabsorption and in Specific Hypolactasia of the Adult
Authors: Andreas U. Freiburghaus, Jacques Schmitz, Marianne Schindler, Hans W. Rotthauwe, Pekka Kuitunen, Kari Launiala, Béat Hadorn
Journal: New England Journal of Medicine (1976)

Brush-border membrane proteins of the small-bowel mucosa were separated on polyacrylamide gels from intestinal biopsy specimens obtained from four children with congenital lactose malabsorption and from two adults with specific hypolactasia. In three patients with the congenital type of lactase deficiency the protein band corresponding to brush-border lactase was reduced in intensity, but was never completely absent. No difference in gel patterns was detected when this pattern in congenital deficiency was compared to that obtained from the two patients with adult-type selective hypolactasia. In one patient with congenital lactose malabsorption the protein band corresponding to lactase activity was not detectable. The findings suggest that the mechanisms leading to low lactase activity in the congenital and adult forms of lactose intolerance are similar.