tbuckley/cabot-search huggingface dataset:
AB0119 Fully Human Monoclonal Antibodies to Phosphorylcholine Inhibit Basal and Tnf-Induced IL-6 and ICAM-1 in Synovial-Like Fibroblasts from A Rheumatoid Arthritis
Authors: D. Thiagarajan, V. Malmstrom, J. Frostegård, R. Fiskesund, J. Steen, A. Frostegård
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Recently, we described that non-responders to anti-TNF therapy in rheumatoid arthritis (RA) had significantly lower levels of antibodies targeting phsphorylcholine (anti-PC) Since we had observed anti-inflammatory properties of human polyclonal anti-PC vitro, we generated a panel of fully human monoclonal antibodies to PC (anti-PC mAbs). <h3>Objectives</h3> In this study we aimed at investigating effect of anti-PC mAbs on basal and TNF-induced IL-6 secretion and ICAM-1 expression in synovial-like fibroblasts from a healthy and a RA donor. <h3>Methods</h3> Fully human monoclonal antibodies targeting PC of IgG1 isotype were generated from healthy human donors via single-cell sorting of PC-reactive B-cells and consequent cloning/production in human embryonic kidney (HEK) cell system. Synovial-like fibroblasts from a healthy and a RA donor at passage 3 were cultured under serum-free conditions for 12 hrs, pre-incubated with 2 clones of anti-PC mAbs (A01 and E01) at 5 μg/ml for 1 hr. TNF was added at 10 ng/ml. IL-6 levels in cell culture supernatants were measured after 12 hrs by high-sensitivity commercial ELISA. ICAM-1 and VCAM-1 was analysed by flow cytomery. <h3>Results</h3> A significant decrease in both basal and TNF-induced IL-6 level in cell supernatants of RA synoviocyte-like fibroblasts was observed with anti-PC mAbs Simultaneously, a significant decrease in surface expression of both ICAM-1 and VCAM-1 was observed. Anti PC mAbs excerted similar effect on TNF-induced Il-6 adn ICAM- 1 expression in healthy synoviocytes. <h3>Conclusions</h3> Fully human anti-PC mAbs could be produced by single-cell sorting of PC-reactive B-cells and consequent cloning/production in a human cell system. Anti-PC mAbs inhibit both basal and TNF-induced IL-6 levels in cultured synoviocyte-like fibroblasts from rheumatoid arthrtis. Further, there was a variation in the effects between clones. Our data suggest that anti PC mAbs could be of therapeutic interest. <h3>Disclosure of Interest</h3> D. Thiagarajan: None declared, V. Malmstrom: None declared, J. Frostegård Shareholder of: JF is named as co-inventor in patents/patent applications in relation to anti-PC, R. Fiskesund Shareholder of: RF is named as a co inventor on a pending patent application in rleation to anti OC mAbs, J. Steen: None declared, A. Frostegård Shareholder of: AF is named as a co-inventor in pending patent application in relation to anti PC <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6090
FRI0033 The inhibitory effects of the yersinia outer protein m (YOPM) on osteoclastogenesis and bone destruction
Authors: C. Cromme, C. Rüter, J. Scharnert, G. Kollias, M.A. Schmidt, T. Pap, J. Bertrand
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The severe bone destruction during rheumatoid arthritis (RA) is mainly mediated by osteoclasts and thus, reducing osteoclast number is a keystep in ameliorating the outcome of the disease. Yersinia strains are secreting a broad number of effector proteins. The yersinia outer protein M (YopM) has the ability to translocate into host cells by two N-terminal alpha-helices and subsequently down-regulates inflammatory response in infected host tissues. <h3>Objectives</h3> We investigated the effect of recombinant YopM on osteoclastogenesis in vitro and bone destruction in the hTNFtg mouse model in vivo. <h3>Methods</h3> After cloning recombinant YopM into pET-24 b (+) expression vector, it was expressed in Bl21 cells and purified. The uptake of YopM into bone marrow macrophages (BMMs) and osteoclasts was analysed using Cy3-coupled YopM and laser scanning microscopy. The effect of YopM on osteoclastogenesis in an <i>in vitro</i> osteoclast formation assay was studied. The effects of YopM on the activation of ERK, p-38, AKT and NFkappaB signalling was determined by Western Blot analysis. With respect to a potential <i>in vivo</i> application of YopM, we analysed the distribution of YopM-Cy5 injected in the hindpaws of hTNFtg mice by fluorescence reflection imaging (FRI). Finally, we treated hTNFtg mice with YopM and an inactive deletion mutant of YopM. Clinical parameters were recorded and histomorphometric analyses of joint destruction were performed in hind paw sections. <h3>Results</h3> In contrast to mature osteoclasts, YopM penetrated the cell membrane of BMMs <i>in vitro</i> and accumulated in the cells. The incubation of BMMs with YopM resulted in a strong reduction of osteoclast precursors and mature osteoclasts. We found that YopM reduced the activation of NF-kB by reducing the phosphorylation of IkB alpha. Phosphorylation of MAP kinases and AKT, however, was not altered by YopM. YopM-Cy5 injected into the hind paws was detectable by FRI during the monitored time of 48 houres. The treatment of hTNFtg mice with YopM showed a delayed onset of paw swelling and reduced bone destruction and inflammation in YopM treated hTNFtg mice in comparison to untreated hTNFtg mice. <h3>Conclusions</h3> These results suggest that YopM has the potential to reduce inflammation and bone destruction <i>in vivo</i>. Therefore, the underlying mechanisms and functional properties of YopM may serve as basis for the development of novel strategies for the treatment of RA. <h3>Disclosure of Interest</h3> None Declared
Phase I trial of pegylated liposomal doxorubicin (PLD) and cyclophosphamide (CPM) in patients with relapsed platinum- resistant epithelial ovarian carcinoma (EOC)
Authors: A. Floquet, L. Cany, J. P. Dutin, D. Jaubert, C. Dupouy, V. Brouste, S. Mathoulin-Pélissier
Journal: Journal of Clinical Oncology (2007)

16057 Background: Most patients (pts) with EOC recur despite platinum-taxane based first line chemotherapy. Response to second line chemotherapy is limited, and usually related to time between the end of first line treatment and relapse. For early relapses, treatment with non cross resistant drugs or treatment with a different toxicity profile is necessary. Thus, following results of the Gordon study (JCO 2001 Jul 15;19(14):3312–22), a phase I trial of PLD and CPM was planned in patients with EOC who relapsed within 12 months of first line therapy. Methods: This multicenter phase I included 21 pts, PS &lt; 2, age = 18 and = 70, no previous anthracycline, with recurrent EOC (one measurable lesion and/or CA125 elevation RECIST criteria) within 12 months after platinum-taxane first line chemotherapy. Six dose levels were planned : Twenty-one patients were included (3 each at L1, 2, 3 and 4 at L4, 5 and 4 more at L3 ; 18 evaluable patients, 3 excluded due to early PD). No intra patient dose escalation was allowed. Cycles are repeated every 28 days. Toxicity observed on the first 2 cycles. Results: Median age of pts: 59 yrs (22–70). Median platinum-free interval: 6.4 months (0.9–11.7); 71 cycles were administered; 2 DLT NCI G3 were observed at level 4: 1 oesophagitis and 1 stomatitis. No limiting haematological nor skin toxicity was observed. Median follow-up was 25.7 months, 4 surviving pts, 1 with a CR and 3 pts with disease. Conclusions: The combination of CPM and PLD is feasible. The recommended dose for further phase II trial is PLD 40 mg/m2 and CPM 600 mg/m 2 every 28 days. [Table: see text] No significant financial relationships to disclose.
THU0332 Use and Reasons for Non-Use of Antimalarial Drugs in a Dutch Cohort of Patients with Systemic Lupus Erythematosus
Authors: M. W.-P. Tsang-A-Sjoe, I. E. M. Bultink, A. E. Voskuyl
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Antimalarials (AMs) have been demonstrated to reduce disease activity and prevent damage accrual in SLE. Recent guidelines advice to prescribe AMs in all patients with SLE. However, AM related retinopathy is a severe complication of AM use with a reported prevalence of about 1% after 5 years of use. <h3>Objectives</h3> To investigate the use and reasons for non-use of AMs in the Amsterdam Lupus Cohort, as well as disease related variables associated with non-use. Secondly, to assess the occurrence of severe side-effects due to AM use. <h3>Methods</h3> Patients were asked for AM-use at their last visit in our longitudinal cohort study. Reasons for non-use were recorded. Demographic and disease characteristics were compared between users and non-users of AMs. Damage was assessed by SLICC damage index (SDI). Daily dosages of hydroxychloroquine (HCQ) according to lean body weight were calculated. Patient records were checked for the presence of ophthalmologic screening for AM-related retinopathy. <h3>Results</h3> Out of 190 SLE patients in our cohort, 139 (73.2%) were using AMs at their last visit, predominantly HCQ (136/139, 97.8%), while 92.1% (175/190) had ever used AMs. Daily dosage of HCQ was 400 mg in 115/136 (84.6%) patients. Patients did not use AMs (n=51) for the following reasons: intolerance (n=16), discontinued without a documented reason (n=11), never initiated (n=9), quiescent disease (n=7), contraindication (n=2), other (n=6). Only one patient discontinued HCQ due to AM-related retinopathy. Another patient discontinued HCQ due to cardiomyopathy, possibly related to HCQ. Compared to AM users, non-users of AMs had a longer disease duration (median (range) 13 (2-35) vs 10 (2-37) years; p=0.004), higher SDI (mean SDI 2.4 ± 2.5 vs 1.2 ± 1.8; p&lt;0.001) and a history of lupus nephritis (47% vs 29.5%; p=0.002). Logistic regression showed that SDI and lupus nephritis, but not disease duration, were independently associated with non-AM use. Ophthalmologic screening was performed in 84.9% (118/139) of patients, of whom 78.4% (109/139) in the past 2 years. According to lean body weight, 119/136 (87.5%) had daily dosages of HCQ above the recommended 6.5 mg/kg body weight. <h3>Conclusions</h3> Despite increased awareness of the importance of AM treatment in SLE, there is still room for improvement, especially in patients with lupus nephritis and/or long-standing disease. Daily dosages of hydroxychloroquine often exceeded recommendations from guidelines. However, the occurrence of severe side effects is limited. <h3>Disclosure of Interest</h3> None Declared
AB0729 Analysis of short and long term survival in patients with systemic lupus erythematosus
Authors: T. Tarr, E. Kiss, N. Gyori, G. Szegedi, M. Zeher
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Survival of patients with systemic lupus erythematosus has progressively improved wordwide. <h3>Methods</h3> The authors analyse retrospectively the results of 550 lupus patients followed during 40 years between 1970 and 2009 in a single center. All important clinical and serologic parameters were evaluted and considered as prognostic risk factors. Survival was calculated from the time of diagnosis by Kaplan-Meier method. Present data were compared to previous results from the same centre and published in international studies. <h3>Results</h3> Systemic lupus erythematosus survival was found to be increased in he study population. The survival rates at 5, 10, 15 and 20 years after the diagnosis were 98%, 94%, 90%, 89%, respectively. The outcome was significant unfavourable for patients who are older then 50 at the time of diagnosis, have a severe disease or have neuropsychiatric manifestations. Other clinical symptoms or immunosupressive treatments did not influence the survival. A total of 57 out of the 550 patients died. The main causes of death were cardiovascular compilcations (49%), infections (19%), and malignancies (12%). <h3>Conclusions</h3> Present study confirms the improvement of long-term survival in patients with SLE. Regular follow-up regarding mainly to cardiovascular complications is an important factor in lupus survival. <h3>Disclosure of Interest</h3> None Declared
Care of Patients Undergoing Hemodialysis
Authors: Onyekachi Ifudu
Journal: New England Journal of Medicine (1998)

The objectives in caring for patients who are undergoing hemodialysis include providing sufficient dialysis, ensuring adequate nutrition, maintaining vascular access, correcting hormonal deficiencies, minimizing hospitalization, and prolonging life while enhancing its quality.Dose of HemodialysisThe dose of dialysis, which depends on the length of treatment, the type of dialyzer membrane, and solute clearance, is the most important modifiable determinant of survival in patients with end-stage renal disease who are receiving hemodialysis.15 In the United States, the mean length of hemodialysis treatment is 3.5 hours three times a week and the mean rate of urea clearance is about 188 . . .
Abstract 940: Mucin depleted foci as a biomarker for colon precancerous lesions in estrogen receptor β knockout mice
Authors: Diana Saleiro, Genoveva Murillo, Levy Kopelovich, Rajendra G. Mehta
Journal: Cancer Research (2010)

Abstract The role of the estrogen receptor β (ERβ) in the colon has received considerable interest, yet in vivo models are needed to better define its protective actions. In the present study, wild-type (WT), ERα and ERβ knockout (αERKO and βERKO) mice were injected with azoxymethane (AOM). Fourteen weeks after the AOM exposure the incidence of aberrant crypt foci (ACF) was assessed by methylene blue staining. βERKO mice showed significantly higher incidence (p &amp;lt; 0.001) of ACF (15.0 ± 5.5) as compared to αERKO (3.4 ± 2.2) and WT (4.6 ± 2.8) mice. The colons in some βERKO mice had increased thickness and loss of normal morphology. It has been reported that ERβ has a role in maintenance of the colonic crypt architecture; this may explain the loss of crypt organization in the colonic epithelium of βERKO mice. The presence of mucin depleted foci (MDF) has been reported, both in humans and in rodents, as an early event in colon cancer. Therefore, in order to surpass the limitations with ACF scoring, we performed alcian blue-neutral red staining to assess the presence of MDF. This staining allowed the assessment of precancerous lesions on all the βERKO mice colons (38.3 ± 8.2; p &amp;lt; 0.001), comparing to WT and αERKO mice (6.9 ± 3.6, and 10.0 ± 4.3, respectively), and served to confirm the ACF results. Together these results support the use of MDF staining as a biomarker for precancerous lesions, and the protective role of ERβ in colon carcinogenesis. (Supported by NIH K01 CA103861, Fulbright Portugal Commission, and FCT (MCET and FSE). 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 940.
SAT0353 Meta-Analysis Comparing the Efficacy of Tnf-Blockers in as and Nr-Axspa Patients
Authors: J. Callhoff, J. Sieper, A. Weiß, A. Zink, J. Listing
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Tumor necrosis factor α (TNFα) blockers are known to reduce disease activity in patients with ankylosing spondylitis (AS). Data from a growing number of randomised controlled trials (RCTs) suggest them to be efficacious for patients with non-radiographic axial spondylarthritis (nr-axSpA), too. So far there is no meta-analyses comparing the efficacy of TNFα blockers between patients with AS and nr-axSpA. <h3>Objectives</h3> In this meta-analysis we aimed to evaluate if TNFα blockers have a clinically meaningful effect on disease activity and function in patients with AS and nr-axSpA. It was also compared if there were differences in the efficacy of TNFα blockers between these patient groups. <h3>Methods</h3> A systematic literature search in Pubmed and Web of Knowledge was performed to identify double blind randomized controlled trials (RCTs) comparing treatment with TNFα blockers in an approved dosage to placebo (and concomitant NSAIDs). We investigated the efficacy of TNFα blockers by assessing a) the standardized mean difference (SMD) in the outcome between verum and placebo and b) the odds ratio (OR) for ASAS40-response. In mixed effects meta-regression models the effect of the publication year was considered, and efficacy for AS and nr-axSpA patients was compared. <h3>Results</h3> 21 studies with data from 3662 patients were included in the analysis: 16 studies with AS patients, 4 with nr-axSpA patients and one with both. There were 6 eligible studies with adalimumab, 1 with certolizumab, 8 with etanercept, 1 with golimumab and 5 with infliximab. For AS patients, TNFα blockers showed better efficacy than placebo for BASDAI (SMD 0.96, [95% CI: 0.83, 1.10]), BASFI (SMD 0.66, [0.59, 0.74]) and ASAS40 response (OR 4.3, [3.4, 5.4]). For nr-axSpA patients the differences were smaller (SMDs: 0.73, [95% CI: 0.44, 1.01], 0.59, [95% CI: 0.30, 0.88]; OR: 3.6, [95% CI: 2.5, 5.3]). Between 2000 and 2013 there was an overall trend to include AS patients with shorter symptom duration and less functional limitations in the RCTs. Taking this into account by including the year of publication as a proxy for disease severity in the statistical model we did not observe significant differences in the outcome (BASDAI, BASFI, ASAS40 response) between the AS and nr-axSpA trials. <h3>Conclusions</h3> Compared to placebo, TNFα blockers improve disease activity and functional capacity clinically meaningful for both AS and nr-axSpA patients. We found only small and not significant differences in efficacy between these patient groups. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2902
Abstract LB-178: A novel chemopreventive molecular mechanism of selenium: p53-mediated DNA repair
Authors: Young Rok Seo
Journal: Cancer Research (2012)

Abstract Selenium is an essential trace element which has been considered as chemopreventive agent against cancer, due to its antioxidant activity. Among several selenium compounds, selenomethionine (SeMet) has significant protective effect toward various genotoxic stresses via stimulating DNA repair process. However, its mechanism is still not well elucidated. In this study, we examined the mechanism of SeMet in terms of p53-mediated base excision repair (BER). Our data showed that the amount of DNA damage was rapidly decreased in the presence of SeMet when methyl methanesulfonate (MMS), a BER-inducing agent, was treated in the cells. In addition, the removal of apurinic/apyrimidinic sites was significantly enhanced in p53 wild type cells in response to SeMet. Furthermore, we observed the Gadd45a, known to involve BER as one of the p53 downstream genes, was accumulated by SeMet in p53 wild-type RKO cells. Indeed the interaction of BER-mediated repair proteins including PCNA (proliferating cell nucleus antigen) and APE/Ref-1 with Gadd45a was notably decreased by SeMet in p53 siRNA-treated cells. In in vivo study, the frequency and size of polyp in AOM/DSS model as an animal model for colitis-related carcinogenesis was decreased in response to SeMet. Moreover, proteins related with DNA repair including Trx (thioredoxin), p53 and Gadd45a were increased in SeMet treated AOM/DSS model. Those results suggested that BER activity might be dependent on wild-type p53 under the modulation of protein complexes with Gadd45a and repair protein including PCNA and APE/Ref-1 as a distinct chemopreventive mechanism of SeMet. Our study might provide an important evidence to develop the chemopreventive strategies against various oxidative stresses. 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 LB-178. doi:1538-7445.AM2012-LB-178
Cinacalcet for Symptomatic Hypercalcemia Caused by <i>AP2S1</i> Mutations
Authors: Sarah A Howles, Fadil M Hannan, Valerie N Babinsky, Angela Rogers, Caroline M Gorvin, Nigel Rust, Tristan Richardson, Malachi J McKenna, M Andrew Nesbit, Rajesh V Thakker
Journal: New England Journal of Medicine (2016)

The authors show that cinacalcet, which mediates allosteric modulation of the calcium-sensing receptor, corrects loss of function of AP2S1 mutations that cause familial hypocalciuric hypercalcemia type 3 and ameliorates symptomatic hypercalcemia.
Lowering of Plasma Cholesterol and Enhanced Sterol Excretion with the Consumption of Polyunsaturated Ruminant Fats
Authors: Paul J. Nestel, Nathalie Havenstein, H. Malcolm Whyte, Trevor J. Scott, Len J. Cook
Journal: New England Journal of Medicine (1973)

A substantial increase in the linoleic acid content of the milk and meat fat of cattle can be achieved if the ruminal hydrogenation of seed-oil linoleic acid is prevented, thereby increasing the ratio of polyunsaturated to saturated fatty acids in cattle meat and milk 10 times. In a comparison of these and of conventional ruminant fats a significant reduction (10 per cent) in plasma cholesterol was observed in five of six subjects on such diets over periods of three to four weeks. In five subjects, the total excretion of sterols increased by an average of 18 per cent when polyunsaturated ruminant fats were eaten. The significant increase in both mean neutral sterol and bile acid excretion coincided with the fall in plasma cholesterol. Thus, increasing unsaturated fats in the diet of cattle lowered plasma cholesterol of subjects on diets containing food products from such cattle.
Abformation
Authors: J. O. Hourihane
Journal: BMJ (2008)

The verb “to inform” can be either transitive or intransitive. I think transitive basically means a transaction takes place: “I informed the patient that he had cancer” [the transaction being that I gave the patient important information]. The intransitive use is to inform on someone, such as to the police, about a crime. 

Considering the transactional nature of informing someone, it therefore seems that information needs both donation and receipt. Data or details that are put somewhere for someone to find later for themselves do not fit this description of “information.” In our electronic world many extra pieces of crucial “information” are put on a website (“if you want more details see www.we_ don’t_care_if_you_read_it_but_if_we_put_it_there_then_we_are_covered_and_all_liability_is_yours/you_loser.com”) or in tiny writing in a patient information sheet. The new word “abformation” seems to fit better these corporate acts of Pilate-like divestment of responsibility, akin to tossing a lifebuoy approximately in the direction of a drowning man and claiming you did your best to save him. 

As patient advocates, doctors need to fight this scourge of abdication of responsibility from those (including ourselves) who have important data or advice to those who need the advice but don’t yet have it. And don’t get me started on nursing notes that say “Dr informed” when same Dr never heard anything about it. “Nurse abformed,” anyone?