tbuckley/cabot-search huggingface dataset:
OP0143 Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients
Authors: C. Krieckaert, M.T. Nurmohamed, G. Wolbink
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Immunogenicity of adalimumab could impair important treatment outcomes in patients with rheumatoid arthritis (RA). Previously, we observed that patients who developed anti-adalimumab antibodies (AAA) during a three year time period achieved less often minimal disease activity or remission and more often treatment failed than in patients without AAA.[1]. In addition, we observed remarkable baseline differences between AAA positive and negative patients, including the use and dose of methotrexate. <h3>Objectives</h3> To examine whether the use and dose of concomitant methotrexate influenced the development of AAA. <h3>Methods</h3> Patients of the adalimumab cohort (n=272) at the Jan van Breemen Research Institute | Reade, were stratified according to the baseline methotrexate dose: no concomitant methotrexate (n=70), low (5-10 mg/wk, n=40), intermediate (12.5-20 mg/wk, n=54), or high dose methotrexate (&gt;22.5 mg/wk, n=108). Percentages of patients developing AAA per methotrexate dose group were calculated and compared over time using General Estimation Equations (GEE). <h3>Results</h3> In figure 1 the percentages of patients developing AAA per methotrexate dose group during follow-up are shown. The statistical GEE model revealed that patients using methotrexate developed AAA less often compared to patients without methotrexate: low dose vs. no methotrexate OR 0.36 (95%CI 0.18-0.74); intermediate dose vs. no methotrexate OR 0.22 (95%CI 0.10-0.46); high dose vs. no methotrexate OR 0.14 (95%CI 0.07-0.28). Additional odds ratios for intermediate vs. low dose were 0.60 (95%CI 0.25-1.44), 0.39 (95%CI 0.17-0.88) for high vs. low dose, and 0.65 (95%CI 0.28-1.50) for high vs. intermediate dose. <h3>Conclusions</h3> Methotrexate abolishes immunogenicity in a dose-dependent manner.This has implications for other biological therapeutics and inflammatory diseases in which concomitant methotrexate administration is less common. Altogether, the immune-tolerating ability of methotrexate as well as assessment of the optimal dose should be investigated further and the results of our present study are promising for the optimization of treatment responses and easy applicable in clinical practice. <h3>References</h3> [1]Bartelds et al. JAMA 2011;305(14):1460-8. <h3>Disclosure of Interest</h3> C. Krieckaert: None Declared, M. Nurmohamed Grant/Research support from: Abbott, Roche, Pfizer, Consultant for: Abbott, Roche, MSD, UCP, SOBI, BMS, Speakers Bureau: Abbott, Roche, Pfizer, G. Wolbink Grant/Research support from: Pfizer, Speakers Bureau: Pfizer, Amgen
Case 13-1998
Authors: Stasha C. Gominak, Didier P. Cros
Journal: New England Journal of Medicine (1998)

Presentation of CaseA 23-year-old man was seen in the clinic because of progressive weakness and paresthesias.He had been well until six months earlier, when he began to have difficulty climbing a flight of stairs quickly and noted intermittent tingling of the soles of his feet and toes. Two months later, he had increasing weakness in his legs, pain in the lower back, stiffness of the hands, and intermittent numbness of the toes and fingertips. Three months before this visit to the clinic, a tremor developed in the arms. The weakness worsened, and the feet and calves became numb, . . .
A Comparison of Nebulized Budesonide, Intramuscular Dexamethasone, and Placebo for Moderately Severe Croup
Authors: David W. Johnson, Sheila Jacobson, Peter C. Edney, Pat Hadfield, Marianne E. Mundy, Suzanne Schuh
Journal: New England Journal of Medicine (1998)

In children with croup, treatment with nebulized budesonide decreases symptoms, but it is uncertain how budesonide compares with dexamethasone, the conventional therapy for croup, and whether either reduces the rate of hospitalization.
Altered renal hemodynamic and urinary prostaglandin response to acute hypoxemia after inhibition of prostaglandin synthesis in the anesthetized dog.
Authors: D N Weismann
Journal: Circulation Research (1981)

Anesthetized dogs were studied to characterize the renal hemodynamic response to acute, transient hypoxemia and to determine the role of renal prostaglandins (PGE and PGF) in that response.Acute hypoxemia of 10 minutes duration (mean arterial Po 2 32 ± 9 torr) induced a reversible increase in renal blood flow (RBF) (measured by electromagnetic flow probe) and mean arterial pressure (MAP) with a decreased urinary flow rate (V) and no change in glomerular filtration rate (GFR) or renal vascular resistance (RVR).Urinary excretion of PGE (UPGE) and PGF (UPGF) (measured by radioimmunoassay) was not significantly changed by hypoxemia under these conditions.After inhibition of the prostaglandin system by administration of indomethacin (5 mg/kg) or meclofenamate (5 mg/kg) intravenously, a significant decrease in RBF and GFR with an increase in RVR occurred in response to hypoxemia.Furthermore, there was a significantly greater decline in URGE and UPGF with hypoxemia after prostaglandin inhibition than before treatment.Control (non-drug treated) animals demonstrated no difference in response to a second episode of hypoxemia relative to the first hypoxemic response.The significant changes in URGE (AUPGE), UPGF (AUPGF), and GFR with hypoxemia after treatment were not secondary exclusively to a decline in RBF, as shown by the similar response of AUPGE and GFR to hypoxemia in dogs in which RBF was enhanced with hypoxemia after treatment by means of an adjustable aortic clamp.Inhibition of prostaglandin synthesis, therefore, unfavorably altered the ability to maintain normal renal perfusion and function during acute hypoxemia in these animals.This renal response to hypoxemia may be mediated by decreased renal prostaglandin production under these conditions.
IMPACT OF CHRONIC CALCIUM CHANNEL BLOCKER THERAPY ON DEVELOPMENT OF NEW-ONSET DIABETES MELLITUS IN ASIAN POPULATION
Authors: Seung-Woon Rha, Byoung Geol Choi, Se Yeon Choi, Sung Il Im, Sunwon Kim, Jin Oh Na, Cheol Ung Choi, Hong Euy Lim, Jin Won Kim, Eung Ju Kim, Chang Gyu Park, Hong-Seog Seo, Dong Joo Oh
Journal: Journal of the American College of Cardiology (2013)
P371Role of the N- and distal C-terminal domains in Nav1.5 alpha-subunit interaction
Authors: N Neyroud, A Ziyadeh-Isleem, J Clatot, I Deschenes, A Coulombe, P Guicheney
Journal: Cardiovascular Research (2014)

Identification of numerous mutations in SCN5A, the gene encoding the cardiac sodium channel α-subunit Nav1.5, in various arrhythmias highlights the key-role played by Nav1.5 in cardiac pathophysiology. Nav1.5 function and regulation are complex. Nav1.5 is regulated by numerous interacting proteins, but we recently also demonstrated that Nav1.5 α-subunits were unexpectedly able to interact with each other, a new functional mechanism that increases the complexity of interpretation of SCN5A mutation expression studies. Purpose: Since the site of interaction between Nav1.5 α-subunits remains unknown, the aim of this study was to test whether the N- and the distal C-termini of Nav1.5 are involved in this interaction. Methods and Results: We designed a Nav1.5 construct missing the cytoplasmic N-terminal domain of the channel (first 126 amino acids), ΔNter, and a construct where the N-terminal domain of Nav1.5 was fused to three Flag tags, Nter. In addition, we used the R1860Gfs*12 truncating mutation identified in the C-terminus of Nav1.5 in a family with cardiac atrial arrhythmias (truncation of the last 144 amino acids). Co-immunoprecipitation in HEK cells co-expressing ΔNter or the R1860Gfs*12 mutant channel with wild-type (WT) channels demonstrated that the N- and C-terminal truncated channels were still able to interact with WT Nav1.5 channels. In addition, we showed that the Nter fragment did not interact with the full WT channel in HEK cells, and did not traffic to the cell surface. Moreover, patch clamp recordings revealed that, when expressed alone, ΔNter was unable to produce any sodium current, while the R1860Gfs*12 mutant channel carried a small sodium current (mutant: -80.3±16.4 pA/pF vs WT: -280.8±22.2 pA/pF, n= 13, P≤0.001) with altered biophysical properties (positive shift of activation and negative shift of steady-state inactivation). Moreover, both truncated channels were able to traffic to the plasma membrane. Interestingly, when co-expressed in HEK cells, neither ΔNter nor the R1860Gfs*12 mutant channel exerted a dominant-negative effect on WT channels. Conclusion: Altogether, our results showed that the deletion of the cardiac sodium channel α-subunit N-terminus or the distal C-terminus did not prevent the interaction between α-subunits. This suggests that the site of interaction between Nav1.5 α-subunits remains to be identified in the intra- or extra-cytoplasmic loops, or in the proximal C-terminus of the channel.
P723The relationships of leptin and adiponectin with myeloperoxidase in coronary artery disease
Authors: A Emami Razavi, G Basati, S Abdi, P Assa
Journal: Cardiovascular Research (2014)

Propose: The adipokines, leptin and adiponectin have a permissive role in the pathogenesis of coronary artery disease (CAD). The inflammatory enzyme, myeloperoxidase (MPO) has also a determinant role in the pathogenesis of CAD. The relationships of the adipokines with the inflammatory enzyme need to be resolved in patients with CAD. Methods: For the case-control study 100 patients with CAD and 100 control subjects were appropriately recruited. The presence of CAD was assigned by angiographic evaluation. Plasma leptin, adiponectin and MPO levels were measured using immunoassay methods. Other conventional cardiovascular risk factors were also determined. Results: Leptin and MPO levels were significantly increased in CAD patients compared to control subjects (25.37 ± 5.83 ng/ml vs. 3.68 ± 1.95 ng/mL and 52.85 ± 13.20 ng/mL vs. 23.00 ± 3.60 ng/mL, p=0.001, respectively). In contrast, adiponectin was significantly decreased in CAD patients compared to control subjects (5.62 ± 1.15 μg/mL vs. 9.25 ± 1.8, p = 0.001). There was a strong positive association between leptin and MPO levels only in CAD patients (p =.001). There was also a significant inverse association between adiponectin and MPO in CAD patients (p =0.001). The associations were continued after adjustment for other conventional risk factors (p =0.001). Conclusions: Given the presence of significant associations between leptin and MPO as well as adiponectin and MPO in CAD patients, it may infer that the pathogenesis effects of the adipokines may be, in part, through the affecting of MPO levels.
IMPACT OF INDIVIDUAL COMPONENTS OF THE CHA2DS2-VASC SCORE COMPARED WITH ATRIAL FIBRILLATION ON LEFT ATRIAL FIBROSIS PROGRESSION
Authors: Jordan King, Mohamed Labedi, Robert White, Mihail Chelu, Gagandeep Kaur, Kara Johnson, Christina Pacchia, Nassir Marrouche
Journal: Journal of the American College of Cardiology (2016)
Abstract 4119: High-throughput proteomics reveals that enzymes of the ketogenic pathway are upregulated during prostate cancer progression
Authors: Punit Saraon, Daniela Cretu, Keith Jarvi, Eleftherios P. Diamandis
Journal: Cancer Research (2012)

Abstract Prostate cancer is the most common malignancy and the second leading cause of cancer related deaths in men. One common treatment is androgen-deprivation therapy, which reduces symptoms in most patients. However, over time, patients develop tumours that are androgen-independent and ultimately fatal. The mechanisms that cause this transition remain largely unknown, and as a result, there are no effective treatments against androgen-independent prostate cancer. As a model platform, we used the LNCaP cell line, and its androgen independent derivative, LNCaP-SF. By using stable isotope labelling with amino acids in cell culture (SILAC) coupled to mass spectrometry, we assessed the differential global protein expression between the two cell lines. Our proteomic analysis resulted in the quantification of 3355 proteins, in total. Bioinformatic prioritization resulted in 42 up-regulated and 46 down-regulated proteins in LNCaP-SF cells, compared to LNCaP cells. Our top candidate was HMGCS2, an enzyme involved in ketogenesis, was found to be 9-fold elevated in LNCaP-SF cells, based on peptide ratios. After analyzing the remaining enzymes of this pathway (ACAT1, BDH1, HMGCL, OXCT1), we observed increased expression of these proteins in the LNCaP-SF cells. This was further verified using western blotting, indicating the importance of this pathway during the progression of prostate cancer to androgen-independence. To determine whether these enzymes are up-regulated in clinical samples, we performed qPCR analysis on human prostate cancer tissues, from which we observed significantly increased transcript levels of HMGCS2 (p&amp;lt;0.05), OXCT1 (P&amp;lt;0.05), ACAT1 (p&amp;lt;0.001), and BDH1 (p&amp;lt;0.001). In addition, the protein expression of all five ketogenic pathway enzymes was elevated in high grade prostate cancer (Gleason Grade &amp;gt;8) based on immunohistochemistry analysis. ACAT1 displayed the most prominent protein expression patterns, as it exhibited very minimal staining in normal samples, moderate levels in low grade cancer, and high expression during high grade disease. Further assessment of ACAT1 expression demonstrated significantly greater ACAT1 expression in bone metastatic lesions (P&amp;lt;0.001). Altogether, our results indicate that enzymes belonging to the ketogenic pathway become up-regulated during high grade prostate cancer, and could serve as potential biomarkers for diagnosis of high grade disease. 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 4119. doi:1538-7445.AM2012-4119
Letting the job get to you:
Authors: T. Burns
Journal: BMJ (1997)

It is commonplace to say that pet owners become like their pets. We also assume that professional people become affected by what they do. Surgeons become more incisive, philosophers more thoughtful, lawyers more pedantic, and so on. What happens to psychiatrists?

I recently spent a month as Lundbeck visiting professor from the Royal College of Psychiatrists at the Indian National Institute of Mental Health Sciences in Bangalore. My hosts, Srinivasa Murthy and Mohan Isaacs, had prepared an extensive and demanding schedule in their renowned community mental health services so I readily accepted accommodation in the guest house on the institute campus rather than commute from a hotel.

I arrived exhausted at Bangalore after a stressful flight via Bombay …
Abstract 4531: Molecular determinants of sensitivity to pralatrexate in a panel of human cancer cell lines
Authors: Maria Serova, Gijsbertus J. Pronk, Ivan Bieche, Michel Vidaud, Esteban Cvitkovic, Sandrine Faivre, Eric Raymond
Journal: Cancer Research (2011)

Abstract Background: Pralatrexate (FOLOTYN®), an antifolate inhibiting dihydrofolate reductase (DHFR), is a high affinity substrate for cellular uptake via reduced folate carrier-1 (RFC-1) and polyglutamation by folyl-polyglutamyl synthetase (FPGS). This study evaluated the sensitivity of human cancer cell lines to pralatrexate and methotrexate, and investigated molecular determinants of primary sensitivity and acquired resistance. Materials and Methods: Anti-proliferative activity was evaluated in a panel (N=15) of human cancer cell lines using the MTT assay. mRNA expression was analyzed by qRT-PCR and protein expression by Western blot. Results: Two groups of cell lines with at least 100-fold difference in sensitivity to pralatrexate were identified. Pralatrexate was 3- to 19-fold (mean: 9-fold) more potent than methotrexate in the sensitive lines (N=9). Sensitivity to pralatrexate correlated with higher FPGS mRNA expression. Two pralatrexate-resistant cell lines (DU-PDX &amp; HEP-PDX) and two methotrexate-resistant cell lines (DU-MTX &amp; HEP-MTX) were established from DU-145 (prostate) and HEP2 (head &amp; neck) cell lines. DU-PDX and HEP-PDX cells were cross-resistant to methotrexate. DU-MTX and HEP-MTX cells showed partial cross-resistance to pralatrexate but remained more sensitive to pralatrexate compared to methotrexate (7.5- and 11-fold, resp.). Acquired resistance to pralatrexate was associated with decreased RFC-1 expression in both DU-PDX and HEP-PDX cell lines, suggesting that reduced pralatrexate uptake may be an important mechanism of acquired resistance. No change in DHFR mRNA expression was found in the pralatrexate-resistant cells. In contrast, significant increases in DHFR mRNA and protein expression were seen in the methotrexate-resistant HEP-MTX cells, suggesting different mechanisms of resistance for these two antifolates. Conclusions: Consistent with prior findings, pralatrexate was more potent than methotrexate against a panel of human cancer cell lines. Primary sensitivity to pralatrexate was associated with higher FPGS expression whereas acquired resistance was associated with decreased RFC-1 expression. Increased DHFR expression correlated with resistance to methotrexate, but not pralatrexate. The marked differences in potency and molecular determinants of tumor response observed in these preclinical models provide rationale for development of pralatrexate in methotrexate-sensitive cancers as well as in settings of acquired methotrexate resistance. 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 4531. doi:10.1158/1538-7445.AM2011-4531
Abstract P3-11-11: A Comparison of Breast Cancer Treatment Rates in British Columbia, Scotland, and Western Australia, and a Comparison with Models of “Optimal” Therapy
Authors: A Fong, J Shafiq, C Saunders, A Thompson, S Tyldesley, MB Barton, JA Dewar, W Ng, S Jacob, C Speers, I Olivotto, GP. Delaney
Journal: Cancer Research (2010)

Abstract Background: Evidence-based optimal utilization models provide estimates of optimal radiotherapy, chemotherapy and hormonal therapy utilization by stage and other clinically relevant patient sub-groups. We therefore compared predicted utilization with actual utilization of radiotherapy, hormone therapy and chemotherapy in 3 jurisdictions with population-based stage and treatment data: British Columbia, Canada; Dundee, Scotland; and Perth, Western Australia. Methods: Previously published optimal radiotherapy, chemotherapy, and endocrine therapy treatment utilization trees for an Australian population were modified to incorporate epidemiological data from British Columbia, Dundee, and Perth, such that the optimal trees for each region reflected the casemix for each region. Frequency data on patient, tumour, and surgical factors were used to calculate optimal treatment rates for each region. Optimal rates were then compared with actual rates of surgery, radiotherapy, chemotherapy, and endocrine therapy use obtained from 2 population-based and 1 institution-based cancer registries for patients diagnosed with breast cancer between 2000 to 2004. Information on region-specific treatment guidelines was also collected. Results: Region-specific optimal treatment utilization rates at diagnosis varied between 80% and 81% for radiotherapy (62 to 64% when patient preference is taken into account), 53% to 56% for chemotherapy, and 49% to 54% for endocrine therapy. The predicted ranges were due to local variations in demographics, and tumour stage. Actual radiotherapy utilization was 57%, 49%, and 52%; chemotherapy utilization was 32%, 24%, and 29%; and endocrine therapy utilization was 56%, 64%, and 52% for British Columbia, Dundee, and Perth, respectively. Conclusion: There are significant differences in actual treatment utilisation rates between the study populations. It is unlikely that all of this variation is due to differences in tumour characteristics alone. Actual utilization rates were lower than the calculated optimal rates for radiotherapy and chemotherapy, and higher for endocrine therapy. Differences between actual regional rates of treatment utilization were seen, and were associated with differences in mastectomy rates, and guideline recommendations for treatment use in that region. This methodology allows comparison of the treatment that occurs in a jurisdiction against what would be considered optimal based on evidence. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-11-11.
In Vivo Effects of Diagnostic X-Irradiation on Human Chromosomes
Authors: Arthur D. Bloom, J. H. Tjio
Journal: New England Journal of Medicine (1964)

CHROMOSOMAL aberrations have been shown to persist for eighteen years in the peripheral leukocytes of patients exposed to therapeutic doses of x-irradiation for ankylosing spondylitis.1 Accidental exposure to mixed gamma and neutron radiation at doses of 23 to 365 rads was found by Bender and Gooch2 to produce chromosome effects lasting up to three and a half years after irradiation. Isolated case reports have described abnormally structured chromosomes in persons undergoing diagnostic x-ray examinations, in 1 case at a dose of 0.8 rad.3 , 4 The present study was designed to evaluate the possible chromosomal effects of different diagnostic x-ray procedures at . . .
Paired Immunophenotype Comparison Of Diagnosis and Relapse Samples In B-Lineage Acute Lymphoblastic Leukemia
Authors: Marion Eveillard, Richard Garand, Nelly Robillard, Soraya Wuilleme, Caroline Thomas, Marion Strullu, Fanny Rialland, Jacques Delaunay, Patrice Chevallier, Philippe Moreau, Nicolas Blin, Marie-Christine Bene
Journal: Blood (2013)
A1.9 Among patients with venous thrombo-embolism, B cell subset disturbances characterise those with primary antiphospholipid syndrome
Authors: L Simonin, E Pasquier, C Leroyer, D Cornec, B Bendaoud, S Hillion, F Couturaud, Y Renaudineau
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Lymphocytes subset distribution is altered in numerous autoimmune diseases, and our aim was to evaluate lymphocyte distribution in well-characterised primary antiphospholipid syndrome (pAPS) patients selected from a venous thromboembolism (VTE) cohort. <h3>Materials and methods</h3> Cases of pAPS VTE patients (n = 11) and matched non-APS VTE patients were selected during their follow-up from the data base EDITH (study of determinants interactions of venous thrombosis), which is a monocentric case-control cohort (n = 5,539). In addition, matched autoimmune disease patients (Sjögren's syndrome and systemic lupus erythematosus) and controls were also included. Using a 4 colours flow cytometer, peripheral blood B cell subsets (B1, transitional, naïve, and memory), T cell subsets (CD3, CD4, CD8) and NK-cells were explored. <h3>Results</h3> In contrast to non-APS VTE patients and controls, pAPS VTE patients displayed total CD3 and CD8 naïve (CD45RA<sup>+</sup>CD27<sup>+</sup>) T cell reduction, and disturbance in B cell homeostasis with increased proportions of B1 cells, transitional B cells (CD24<sup>+</sup><sup>+</sup>CD38<sup>+</sup><sup>+</sup>) and naïve B cells, while memory B cells were reduced. The unswitch memory B cell percentage (IgD<sup>+</sup>CD27<sup>+</sup>), and even better the naïve (IgD<sup>+</sup>CD27<sup>-</sup>)/unswitched memory B cell ratio were both effective to distinguish pAPS VTE patients from non-APS VTE patients, and from patients with autoimmune diseases. Moreover, the absolute number of CD4 T cells was positively correlated with IgG anti-cardiolipin antibody levels. <h3>Conclusions</h3> Disturbances of B cell homeostasis characterised, within VTE patients, those with pAPS during their follow-up and an elevated naïve/unswitched memory B cell ratio represent a useful biomarker to characterise them.