tbuckley/cabot-search huggingface dataset:
A6.32 1,25(OH)<sub>2</sub>D<sub>3</sub>suppresses the pro-inflammatory TH17-RASF feedback loop via IL-4-dependent and –independent mechanisms
Authors: W Dankers, JP van Hamburg, W Razawy, N Davelaar, AMC Mus, PS Asmawidjaja, van Leeuwen JPTM, EM Colin, E Lubberts
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objectives</h3> Vitamin D has suppressive effects on autoimmune diseases, such as rheumatoid arthritis (RA). Within these diseases, Th17 cells are considered to play a crucial role in the processes underlying chronic inflammation. We have shown that Th17 cells from RA patients induce a pro-inflammatory feedback loop upon interaction with RA synovial fibroblasts (RASF). Interestingly, 1,25(OH)<sub>2</sub>D<sub>3</sub> is able to inhibit this feedback loop by modulating Th17 cell activity. However the molecular mechanisms underlying this inhibition by vitamin D are currently unclear. <h3>Materials and methods</h3> CD4<sup>+</sup>CD45RO<sup>+</sup> (memory) and CCR6+ memory T-helper cells were sorted from peripheral blood of patients with early RA and healthy volunteers. They were cultured for three days in the presence or absence of 1,25(OH)<sub>2</sub>D<sub>3</sub> together with synovial fibroblasts from RA patients. The expression of cytokines and transcription factors of interest was analysed using microarray based gene expression profiling, flow cytometry, ELISA and/or RT-PCR. <h3>Results</h3> In the presence of 1,25(OH)<sub>2</sub>D<sub>3</sub> the pro-inflammatory cytokines IL-17A, IL-17F and IL-22 were inhibited. Also the expression of Th17 signature genes like RORgt and IL-23R was reduced. On the other hand we find an increase in IL-4 and IL-10 expression. Interestingly neutralisation of IL-4 partly reversed the effect of 1,25(OH)<sub>2</sub>D<sub>3 </sub>on the inhibition of IL-17A, IL22 and RORγt expression. In addition, the inhibition of IL-17F by 1,25(OH)<sub>2</sub>D<sub>3 </sub>was almost completely absent when IL-4 was blocked. In contrast to IL-4, IL-10 neutralisation had limited effects in these cultures. Because the effect of 1,25(OH)<sub>2</sub>D<sub>3</sub> is only partially dependent on IL-4, we examined factors that could play a role independent of IL-4. Gene expression profiling revealed that two transcription factors that are known to play a role in Th17 differentiation, EOMES and IRF8, are upregulated by 1,25(OH)<sub>2</sub>D<sub>3</sub>. EOMES and IRF8 are direct regulators of RORgt expression. Blocking IL-4 does not affect this up regulation, indicating that EOMES and IRF8 might be important in the IL-4 independent regulating of Th17 polarisation by 1,25(OH)<sub>2</sub>D<sub>3</sub>. <h3>Conclusions</h3> From these findings, we conclude that 1,25(OH)<sub>2</sub>D<sub>3</sub> inhibits the pro-inflammatory feedback loop between Th17 cells and synovial fibroblast. This modulation is partly dependent on up regulation of IL-4. IL-4 independent mechanisms may include the down-regulation of RORgt expression via up regulation of IRF8 and EOMES.
Transferrin and HLA: Spontaneous Abortion, Neural Tube Defects, and Natural Selection
Authors: Lowell R. Weitkamp, Bernice Z. Schacter
Journal: New England Journal of Medicine (1985)

We report evidence that transferrin C3, a gene present in 9 to 10 per cent of whites, is associated with recurrent spontaneous abortion (P = 0.001) and that maternal transferrin genotype has an effect on the transmission ratio of the common transferrin genes (C1, C2, and C3) from heterozygous fathers to normal offspring (P<0.002). The effect of maternal genotype on paternal gene transmission is an unusual example of the operation of selection in the human reproductive process. This effect, together with the separate evidence for association of the transferrin C3 allele with spontaneous abortion, indicates that transferrin is a second marker (in addition to HLA) of genes important in reproduction. On the basis of comparison of the frequencies of transferrin (chromosome 3) and HLA (chromosome 6) mating types in 348 control couples and in 81 couples who had had a child with a neural tube defect, we hypothesize that some combinations of maternal and fetal genes on these two chromosomes may be associated with neural tube defects. (N Engl J Med 1985; 313:925–32.)
AB0620 Effects of zoledronic acid for glucocorticoid-induced osteoporosis in patients with inflammatory joints disease
Authors: O. Mytrokhina, O. Kuryata, T. Lysunets
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> As known, glucocorticoid-induced osteoporosis is the most common form of osteoporosis. The most pressing issue remains the prevention of osteoporosis in patients with prolonged therapy by glucocorticosteroid. The role of Zoledronic acid (ZOL) for glucocorticoid-induced osteoporosis in patients with inflammatory joints disease remains debatable. <h3>Objectives</h3> we aimed to evaluate the effects of Zoledronic acid for glucocorticoid-induced osteoporosis in patients with inflammatory joints disease. <h3>Methods</h3> 20 patients (mean age – 57,20±4,46 years) with inflammatory joints disease were enrolled. All patients were women and received glucocorticoid during more than 5 years (mean duration of treatment – 3,20±0,46 years). Women had osteoporosis documented by either a lumbar spine T-score ≤–2.5 or lumbar spine T-score ≤–1.5 with 2 mild or 1 moderate prevalent vertebral fracture. 10 (50%) patients received the standard treatment and Zoledronic acid 5 mg infusion once a year (study group), while 20 (50%) (control group) – received only the standard treatment for 3 years. Visual Analog Scale (VAS), <i>bone mineral density (BMD)</i> were performed in all patients at baseline and at the end of the study. <h3>Results</h3> VAS and <i>BMD</i> did not differ significantly between the groups. After 3 years of treatment with Zoledronic acid the incidence of symptoms, including arthralgia were significantly lower in the study in comparison of control groups (P = 0.05). The increase in BMD was greater in the study group than in the control group (P = 0.01). During 3 years among patients in the control group 30% have compression fractures in compare with study group (P = 0.05). <h3>Conclusions</h3> Zoledronic acid is effective and safe for patients with glucocorticoid-induced osteoporosis in patients with inflammatory joints disease. Its administration may provide benefits for the reduction of hospitalizations and mortality in its population. <h3>Disclosure of Interest</h3> None Declared
138 IDENTIFICATION OF HDAG-L VARIANTS IN COVERT HEPATITIS D AMONG AMERINDIANS OF ARGENTINA WITH MAINLY OCCULT INFECTIONS OF HBV
Authors: C.M. Delfino, C. Berini, M.E. Eirin, R. Malan, E. Gentile, A. Castillo, W. Pedrozo, R. Krupp, J. Oubiña, V. Mathet, M. Biglione
Journal: Journal of Hepatology (2012)
Abstract P6-05-06: Serum estradiol levels in postmenopausal ER+/PR- breast cancer are lower than those in postmenopausal ER+/PR+
Authors: Y Yamamoto, M Ibusuki, H Goto, K Murakami, H Iwase
Journal: Cancer Research (2012)

Abstract (Background) Activation of growth factor receptor (GFR) signaling is related with ER+/PR- breast cancer (BC). Proportion of ER+/PR- phenotype in ER+ BC in postmenopausal patients is higher than that in premenopausal. However, this phenomenon cannot be explained by only GFR signaling activation. We hypothesized that ER+/PR- phenotype in postmenopausal patients has at least two subtypes, one is related with activation of GFR signaling and the other is related with suppression of PR expression due to low estrogenic stimulation. (Purpose) The aim of this study is to clarify out hypothesis. (Patients and methods) We measured serum E2 levels with radioimmuno assay (range of E2 levels: 1.3 to 50 pg/ml) in 154 postmenopausal ER+ BC patients. Cut-off levels of ER and PR were used 10% or more expression in tumor cells. We analyzed the correlation between serum levels of E2 and clinicopathological factors including PR expression. We also examined the relationship between HER2 expression levels and ki67 labeling index in ER+/PR- BC. In addition, we analysed the difference in ki67 LI between in premenopausal patients (n = 65) and in postmenopausal patients. (Results) Median serum levels of E2 in ER+/PR+ phenotype (6.7 pg/ml) were significantly higher than in ER+/PR- phenotype (4.5 pg/ml)(p = 0.036). Serum levels of E2 was positively associated with body mass index (p = 0.01). However, there was no significant difference between serum E2 levels and other clinicopathological factors including tumor size, nodal status, nuclear grade, levels of ER expression and ki67 LI. In ER+/PR- phenotype, ki67 LI were varied (Median: 7.5%, range: 0.5 to 85%). Ki67 LI in Postmenopausal patients with ER+/PR- phenotype was significantly lower than that in premenopausal patients with ER+/PR- phenotype (p = 0.0022). Expression levels of HER2 was positively associated with ki67 LI(p = 0.002). (Conclusions) ER+/PR- cancer in postmenopausal patients may have two types of phenotype. One is highly proliferative phenotype that is stimulated with GFR signaling. The other is low proliferative one that PR expression is suppressed by without sufficient estrogen supply. Serum levels of E2 might affect development of ER+ BC in postmenopausal women, especially in case of no activation of GFR signaling. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-06.
Endoloop/clip technique for gastrointestinal hemorrhage: rescue or first-line line therapy?
Authors: Gabriele Curcio, Mario Traina, Neville Azzopardi, Luca Barresi, Ilaria Tarantino, Antonio Granata
Journal: Endoscopy (2013)

We read with interest the study by Lee et al. [1]. The authors describe their experience with the use of clipping and detachable snaring (CDS) for rescue endoscopic control of nonvariceal upper gastrointestinal bleeding (UGIB). They report a case series of seven patients who underwent endoscopic hemostasis using the combined method of CDS. The success rate of endoscopic hemostasis with CDS was 86 %: six of the seven patients who had experienced primary endoscopic treatment failure or recurrent bleeding after endoscopic hemostasis were treated successfully.
PWE-075 Anti-tnf Therapy Reduces Ionising Radiation Exposure In Patients With Ulcerative Colitis
Authors: D Aggarwal, JK Limdi
Journal: Gut (2014)

<h3>Introduction</h3> Patients with Ulcerative Colitis [UC] may be exposed to ionising radiation for evaluation of disease with inherent risks from protracted exposure. Meanwhile, bolder definitions of disease control with evolving treatment paradigms have led to earlier introduction of biological therapy. Our aim was to compare the effective radiation dose prior to and a year and 3 years after initiating anti-TNF therapy or corticosteroid in patients with UC. <h3>Methods</h3> We performed a retrospective review of UC patients treated with anti-TNF therapy (infliximab or adalimumab) or corticosteroids at our institution from 2005 to 2013. Clinical data (demographics, disease characteristics, treatment) were obtained from case notes and electronic patient records. All instances of imaging in the previous year, 1 and 3 years after initiation of anti-TNF therapy were recorded. The effective and cumulative radiation doses were calculated from published tables [Royal College of Radiologists, UK]. <h3>Results</h3> We analysed 102 patients with ulcerative colitis (66 anti-TNF and 36 corticosteroid treated). In the anti-TNF group, 68% were males (median age 47 yrs; range 25–76; mean disease duration 9.5 yrs). Forty seven per cent had left sided disease [Montreal E2] and 55% had pancolitis [Montreal E3]. In the corticosteroid treated patients, 55% were males (median age 51 yrs; range 17–90; mean disease duration 7.7 yrs). Montreal classification of disease was E1 in 11%, E2 in 46% and E3 in 43% respectively. The anti-TNF cohort had a significant reduction in the number of imaging studies (4.0 <i>vs.</i> 1.5, p &lt; 0.0001) and cumulative radiation dose (4.1 vs. 1.1 mSv, p &lt; 0.0001) a year after treatment. The corticosteroid group had no significant change in the number of imaging studies (1.9 vs. 1.3, p = 0.1 or cumulative radiation dose (3.2 vs. 2.0 mSv, p = 0.5). After 3 years of anti-TNF (n = 22), there was a reduction in the cumulative radiation dose (1.6 <i>vs.</i>1.0 mSv, p = 0.3) and number of imaging studies (2.7 <i>vs.</i>1.9, p = 0.3). In the corticosteroid group, there was a reduction noted in the cumulative radiation dose (2.5 <i>vs.</i> 1.1 mSv, p &lt; 0.3) and no change in the number of imaging studies (1.6 vs. 1.7, p = 0.5). Linear regression analysis showed a decrease in cumulative radiation dose by 3.1 mSv (CI= -4.9 to +0.2, p = 0.07) and number of CT imaging scans by 1 (CI= +1.5 to -1.2, p &lt; 0.08) in the anti-TNF group compared to the corticosteroid group within a year of therapy after adjusting for age, gender, disease duration, disease location and disease behaviour. <h3>Conclusion</h3> Anti-TNF therapy is associated with a significant reduction in cumulative radiation dose and diagnostic imaging studies a year after anti-TNF therapy but not with corticosteroids. The decrease in radiation dose exposure in both groups was similar three years after treatment. <h3>Disclosure of Interest</h3> None Declared.
Uncomplicated Cystitis — Not So Simple
Authors: Michael S. Donnenberg
Journal: New England Journal of Medicine (2013)

Most women have had at least one symptomatic urinary tract infection,1 and many have had multiple recurrences.2,3 In the United States, billions of dollars are spent annually and tens of millions of courses of antimicrobial therapy are prescribed for urinary tract infections.1 The majority of these infections are caused by bacteria that colonize and induce inflammation in the bladder. Although complications are rare, acute cystitis can be extremely uncomfortable and result in lost productivity.The voided midstream urine culture represents a convenient, noninvasively obtained specimen that can aid in the diagnosis of urinary tract infection. However, such cultures do . . .
Utilisation du dossier médical électronique (DME) par les hépato-gastroentérologues (HGE) en France
Authors: C Altman, G Bonnaud, I Ingrand, S Beorchia, JC Letard
Journal: Endoscopy (2011)

Introduction: Le DME permet une acquisition et une conservation structurées des données médicales, en remplacement du dossier traditionnel „papier„. Ces données restent par la suite facilement accessibles au médecin et peuvent être, éventuellement, partagées entre les soignants. L'utilisation du DME pourrait permettre une amélioration de la qualité des soins et une diminution de leur coût (1). L'utilisation réelle, en pratique quotidienne, du DME par les médecins n'a cependant jamais été étudiée en France, en particulier chez les HGE.
Abstract LB-356: An siRNA screen identifies Rsk1 as a key modulator of lung cancer metastasis
Authors: Romain Lara, Francesco A. Mauri, Harriet Taylor, Rita Derua, Alice Shia, Colin Gray, Alastair Nicols, Robert J. Shiner, Edward Schofield, Paul A. Bates, Etienne Waelkens, Maggie Dallman, Jonathan Lamb, Daniel Zicha, Julian Downward, Michael J. Seckl, Olivier E. Pardo
Journal: Cancer Research (2011)

Abstract Lung cancer is the commonest cancer killer worldwide. The appearance of distant metastasis is one of the main reasons for failing to cure patients with this disease. To address the underlying molecular mechanisms that regulate cancer cell motility, we performed an automated kinome-based RNA interference screen in the non-small cell lung cancer (NSCLC) cell line A549. We studied changes in cell migration patterns using timelapse microscopy and automatic tracking. Mathematical analysis of the obtained cell tracks provided information on migration speed and distance. 48 kinases were identified that were previously unknown to regulate cell motility. Among our candidates, were several members of the ribosomal S6 kinase (Rsk) family. In particular, Rsk1 silencing increased, while Rsk2 and 4 downregulation decreased, cell motility. These effects correlated with changes to the actin cytoskeleton as well as decreased E-cadherin and increased Vimentin expression levels. A secondary 3-dimensional invasion screen for our candidates confirmed that Rsk1 downregulation increased the invasiveness of A549 cells. In silico analysis and biochemical experimentation revealed that Rsk1 interacted with the actin regulators Vasp and Mena. This correlated with the ability of Rsk1 to phosphorylate Vasp on Thr-278, a site regulating Vasp-mediated actin dynamics. Moreover, Rsk1 silencing enhanced the metastatic behaviour of A549 cells in vivo using a zebrafish xenograft model. Importantly, immunohistochemical staining validated Rsk1 down regulation in metastatic lung cancer samples compared to isogenically matched primary tumours. Moreover, patients with Rsk1-negative lung primary tumours showed an increased number of metastatic lesions as well as an increase in Rsk2 and/or Rsk4 staining establishing Rsk family members as strong determinants of lung cancer cell metastasis and potential predictive markers for the progression of this disease. 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 LB-356. doi:10.1158/1538-7445.AM2011-LB-356
PWE-133 Hepatocellular Carcinoma: Impact Of Nice Guidelines On Assessing And Optimising Surveillance
Authors: E Johnston, R Khan, J Ingoe, G Tritto
Journal: Gut (2014)

<h3>Introduction</h3> Screening for hepatocellular carcinoma (HCC) is only deemed cost-effective in patients at high risk. However, the criteria for identifying patients at risk, particularly in relation to non-cirrhotic hepatitis B, remains ill defined and different international guidelines are not consistent. Recent NICE guidelines proposed offering surveillance to patients with significant fibrosis (≥F2) or age &gt;40 with either high viral load or family history of HCC. The aim of this study was to evaluate how the new NICE guidelines can impact on current practice and on the effectiveness of our surveillance program. <h3>Methods</h3> All patients who underwent an abdominal ultrasound for HCC surveillance from 1<sup>st</sup> September 2012–31<sup>st</sup> August 2013 were identified and the indications evaluated. In a subgroup of these patients with hepatitis B the appropriateness of screening was assessed according to the 2013 NICE guidelines. From the same period, all HCC diagnosed were identified and cross matched with our surveillance list. <h3>Results</h3> In the period under study, 1280 surveillance ultrasounds (606 in cirrhosis, 628 in non cirrhotic hepatitis B or C, 46 other) led to 5 diagnoses of HCC. All HCC were found in cirrhotic patients (annual incidence 1.65%). Seventeen further HCC were diagnosed from emergency admissions or referred from elsewhere. One patient had non cirrhotic hepatitis B (78yr old male with a long history of hepatitis B) whilst all the remaining were cirrhotic (2 with hepatitis B). In a randomly selected sample of 200 patients undergoing surveillance ultrasounds, 62% (n = 124) had hepatitis B and 76 had cirrhosis of other aetiology. Of the patients with hepatitis B, an assessment of specific risk factors, particularly level of fibrosis, was not documented in 50 (40%). A further 48 (39%) patients were retrospectively deemed low risk according to NICE guidance. <h3>Conclusion</h3> The number of HCC diagnosed through surveillance was low, but still cost effective in cirrhotic patients. The main risk factor for HCC in this cohort was cirrhosis (96.5%). In fact, only 1 non cirrhotic patient with hepatitis B developed HCC and this was on a background of likely advanced fibrosis. None of the HCC from surveillance would have been missed if NICE criteria were used. It is important that patients with chronic hepatitis B all undergo assessment of fibrosis, along with clear documentation of other known risk factors in order to enable better risk stratification. In our experience following NICE guidance to identify high risk patients for surveillance will pick up all cases of HCC and decrease cost by reducing the number of unnecessary ultrasound scans being carried out. <h3>Reference</h3> NICE clinical guideline 165 – Hepatitis B (chronic) June 2013 (http://www.nice.org.uk/nicemedia/live/14191/64234/64234.pdf) <h3>Disclosure of Interest</h3> None Declared.
Abstract 871: Dermatofibrosarcoma protuberans in a black African population: A clinicopathologic study with emphasis on the predictors of recurrence and outcome
Authors: Gabriel O. Ogun, Adebola O. Ogunbiyi
Journal: Cancer Research (2010)

Abstract Background: Dermatofibrosarcoma protuberans are relatively rare in our environment. Detailed studies on the subject in homogenous black African population are rare in literature. The aim of the study was to retrospectively analyze the clinical and histopathologic features of the tumor and identify the factors that directly influence recurrence, outcome and prognosis in the setting of a developing country with limited resources. Materials and Methods: All cases of Dermatofibrosarcoma protuberans histopathologically diagnosed and available from the files and records of Department of Pathology, University College Hospital, Ibadan, Nigeria between January 1989 and December 2007 were identified, reviewed and included in the study. The detailed clinical parameters like age at presentation, gender, size and site of tumor, stage at presentation, treatment modalities, recurrence and follow up details; also details of histopathologic features like mitotic count and presence of tumor at the resection margins were analyzed. Results: A total of 58 cases were identified and are presented. All the patients were Nigerians. Patient's age ranged from 5-74 years (median, 35years) with a modal age group of 30-39 years. The male/ female ratio had a male preponderance of 2.2:1. Tumor site distribution was trunk (39.5%), lower limb (27%), Upper limb (21%) and head and neck (12.5%). Tumor size ranged from 1.5 to 21cm. Seventy four percent presented with pT2 (TNM) stage tumor. Size of tumor larger than 7cm, mitotic count of greater than 7 per 10hpf and involvement of the subcutaneous tissue were strong indicators of the likelihood of recurrence. Forty five percent of our patients had recurrence with a patient having eight recurrences. The cost implications significantly delayed adjuvant therapy after surgical resection in our patients. This is because the cost of management is borne directly by patients in our environment. About 50% of our patients especially those with pT1 stage tumors were lost to follow up in less than 6 months. Two of our patients had features with fibrosarcoma-like transformation. Conclusion: The trunk and the lower limb accounted for 66.5% of location of tumor. The follow up data was poor in patients with small sized tumors. Large tumor size and high mitotic count increased the rate of recurrence. The cost implication of care, which is directly borne by patients due to out-of pocket payment lead to poor follow up and outcome. 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 871.
Oral Ganciclovir for the Prevention of Cytomegalovirus Disease in Persons with AIDS
Authors: Stephen A. Spector, George F. McKinley, Jacob P. Lalezari, Tobias Samo, Robert Andruczk, Stephen Follansbee, Paula D. Sparti, Diane V. Havlir, Gail Simpson, William Buhles, Rodney Wong, Mary Jean Stempien
Journal: New England Journal of Medicine (1996)

In the advanced stages of the acquired immunodeficiency syndrome (AIDS), cytomegalovirus (CMV) disease, particularly vision-damaging retinitis due to CMV, is common. We evaluated prophylactic treatment with orally administered ganciclovir as a way to prevent CMV disease.