tbuckley/cabot-search huggingface dataset:
Abstract 3078: Effects of neuregulins in the regulation of EGFR in breast cancer cell lines
Authors: Laurimer Kuilan-Torres, Marianela Perez-Torres
Journal: Cancer Research (2012)

Abstract The epidermal growth factor receptor (EGFR) is a member of the ERBB family of oncoproteins which consist of four related receptors: EGFR/ErbB1, ErbB2, ErbB3 and ErbB4. Overexpression of EGFR and other members of ERBB family were found to induce erroneous development and unrestricted proliferation in human malignancies including breast cancer. Neuregulins (NRG) are signaling proteins that produce cell-cell interactions and can bind to the extracellular domain of ErbB3 or ErbB4, activating signaling pathways leading to cellular responses that include stimulation or inhibition of proliferation, apoptosis, and gene regulation. Previous studies showed that constitutive expression of neuregulin 1-beta (NRG-1α) in MCF-7 cells decreased the levels of estrogen receptor (ER) and progesterone receptor (PR), which may contribute to the transformation from estrogen-responsive into a hormone-independent phenotype. An inverse correlation between expression of ER and EGFR has been demonstrated. Our hypothesis is that EGFR levels are regulated by neuregulins in breast cancer cell lines. We treated the breast cancer cell lines ZR-75-1 and MDA-MB-231 with NRG-1α or NRG-1α at different concentrations for 4 hours. In addition, both cells lines were treated with selected concentrations of NRG-1α or NRG-1α at different time points. Isolated mRNA was used to measure EGFR expression using reverse-transcriptase real-time PCR and levels of protein were determined by western blot analysis. Our results show that EGFR mRNA levels increased when ZR-75-1 cells were treated with increasing concentrations of neuregulins. In this regard, treatment with 100 ng/mL of NRG-1α increased EGFR expression by 10-fold in ZR-75-1 cells. However, when MDA-MB-231 cells were treated with NRG-1α or NRG-1α, the expression of EGFR mRNA levels did not change. Western blots analysis of ZR-75-1 cells treated with NRG-1α shows activated ErbB3, confirming that this activation is related to the increase in EGFR mRNA levels. Our data suggest a role for neuregulins in the EGFR up-regulation. One of the mechanisms related to ErbB3 activation is the activation of phosphatidylinositol 3-kinases (PI3K) and mitogen-activated protein kinase (MAPK), thus current efforts are directed towards elucidating the role of these pathways in the NRG-upregulation of EGFR. Supported by NIH/NIGMS Grant #SC2GM084789, NIH-RCMI Grant #G12 RR 03051. 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 3078. doi:1538-7445.AM2012-3078
SP0092 Osteoporosis. Whom, When and How to Treat
Authors: P. Peris
Journal: Annals of the Rheumatic Diseases (2014)

<h3></h3> The evaluation and treatment of osteoporosis differ depending on several conditions such as the associated risk factors for the development of osteoporosis and fragility fractures, gender, age and menopausal status of the individual, and the presence of other secondary associated processes, among others. In addition, some types of secondary osteoporosis, such as glucocorticoid induced osteoporosis, present fractures with relatively higher bone mineral density values, whereas other metabolic bone diseases, such as osteomalacia, can easly be misdiagnosed with this condition. All these data should be taken into account when evaluating the diagnosis and treatment of these patients. Besides general measures, the pharmacological management of osteoporosis, including the type of antiosteoporotic drug, administration route, optimal treatment duration and monitoring, depend on the characteristics of the patient, the fracture risk and the type of treatment. Thus, whereas bisphosphonates are commonly used in postmenopausal osteoporotic women and men, they should be used with caution in premenopausal women. Moreover, additional non-pharmacologic therapies, such as the use of percutaneous vertebroplasty for the treatment of painful vertebral fractures need appropriate patient selection. In summary, the therapeutic approach of osteoporosis managment involves several aspects that include the identification of individuals at risk of fracture, the correction of modifiable risk factors and, when indicated, the selection of the most appropriate drug therapy. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.6220
SP0128 The Melanocortin Anti-Inflammatory Paradigm
Authors: M. Perretti
Journal: Annals of the Rheumatic Diseases (2013)

<h3></h3> Substantial evidence now signifies that resolution of inflammation is a highly coordinated, active process dictated by the spatial-temporal generation of pro-resolving mediators that act on specific receptors to modulate cell and tissue reactivity. Thus, in contrast to current anti-inflammatories that typically target the 'heating-up' period of the immune response, new therapeutics based on pro-resolution mediators would accelerate the way our body naturally regulates an inflammatory reaction, prompting the regain of physiological tissue function. Melanocortins are a group of endogenous pro-resolving mediators; these include α- and γ-melanocyte-stimulating hormone (MSH) and adrenocorticotrophin (ACTH). These polypeptides block neutrophilic infiltration and the production of pro-inflammatory cytokines from target cells, yet also activate pro-resolving processes including the induction of heme oxygenase 1 via signaling through specific melanocortin (MC) receptors. Definition of the receptors regulating melanocortin anto-arthritic effects can guide innovative drug discovery programmes. We have observed high and relatively stable expression of melanocortin receptor type 1 (MC1) in macrophages, synovial tissue and sub-endothelial tissue in the mesenteric vasculature, with little expression of the MC3 receptor. However, upon application of an insult such as an ischemia-reperfusion procedure or induction of joint arthritis, marked upregulation of MC3 gene product occurred, with MC1 remaining stable. We postulate that in these settings MC3 mRNA is over-expressed in the affected tissue not only in view of the marked influx of myeloid cells, but also through genuine gene promoter activation, and that this is part of a homeostatic process aiming at directing the host response through resolution pathways. On going work in the synovia of patients suffering from Rheumatoid Arthritis will indicate the relevance of MC1 and MC3 expression to man. I acknowledge the contribution of my colleagues Prof C Pitzalis, Drs M Bombardieri, T Montero-Melendez and HB Patel. Our work on Melanocortin receptors is funded by The British Heart Foundation (PG/11/48/28981) and the Medical Research Council (MR/K013068/1). <h3>Disclosure of Interest</h3> M. Perretti Grant/research support from: Action Pharma AS; SynactPharma ApS
FRI0566-HPR Effect of a Thin Dynamic Insole on Pain and Walking Ability in Rheumatoid Arthritis
Authors: B.H. Linberg, A.M. Mengshoel
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Forefoot pain occurs often in rheumatoid arthritis (RA), also among patients that are in remission (1). Such pain may limit walking and activities of daily life. Earlier studies on different insoles have shown effect on pain, but there are various results concerning walking ability (2). The insole in this study is thin and can fit into most shoewear. <h3>Objectives</h3> To investigate the immediate effects of a customized thin dynamic insole on pain and walking ability in patients with RA and forefoot pain and whether the insoles were in use one year afterwards. <h3>Methods</h3> An experimental study was performed on twenty-one patients with RA and forefoot pain in either one or both feet. Eighty-one percent of the participants were women. Their mean age (SD) was 54 (11) years and median (iqr) disease duration was 4 (8.3) years. The patients walked as fast as they could in 6 minutes (6MWT) with either insoles (situation A) and without insoles (situation B). The order of situation A and B was randomized, and the assessor was blinded for the order of the two situations. Both tests were conducted the same day. Walking ability was assessed by the 6MWT. Foot pain was assessed by a ten centimeter visual analog scale (VAS) anchored with no or worst pain immediately after situation A and B. A one-year follow-up was conducted by a telephone interview. <h3>Results</h3> The median (iqr) in VAS pain was 19 (15) in situation A and 36 (27) in situation B (p&lt;0.001). The effect size was 0.6, and the result is considered to be of high clinical relevance. The difference between the two situations in 6MWT was not statistically significant (p=0.07). After one year, 86% of the participants were still using the insoles, 71% experienced that the insoles relieved their foot pain and 57% of the participants reported increased walking ability using the insoles. <h3>Conclusions</h3> The use of a thin dynamic insole showed an immediate forefoot pain relief during walking. The pain modifying effect of the insoles can be supported by the high number of patients still using the insoles after one year. <h3>References</h3> Otter SJ, Lucas K, Springett K, Moore A, Davies K, Young A, et al. Comparison of foot pain and foot care among rheumatoid arthritis patients taking and not taking anti-TNFalpha therapy: an epidemiological study. Rheumatol Int 2001 Nov;31(11):1515-9 Hennessy K, Woodburn J, Steultjens MP. Custom foot orthoses for rheumatoid arthritis: A systematic review. Arthrtis Care Res (Hoboken) 2012 Mar;64(3):311-20 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2344
THU0577 Protocol-Bvased Pharmacotherapy in Gout Delivered by Specialised Health Care Professional Under Supervision of a Rheumathologist is Similar but not Significantly Superior to Care as Usual
Authors: R. Bakker, A. V. Ede, F. Lamers-Karnebeek, I. Meek, T. Jansen
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Currently there is no guideline in treating gout in the Nederlands. The Outpatient Department of Rheumatologyof the University Hospital St. Radboudhasmade guidelines based on the Eular/British guidelinesand followed by a health care professional. The targets are-Attack free without profylaxis at 6 months; -serum uric acid concentration ≤ 0.30 mmol/l. <h3>Objectives</h3> The purpose of this study is to gain insight in conventional gout care by different rheumatologists versus care by onehealth care professional. <h3>Methods</h3> Usinganobservational study, 2patient cohorts arecompared during a follow-up of one year. A retrospective medical files study was performed for the control group (n=30) whom received conventional specialist care. Starting the gout clinic at November 2011 (n 53) consecutive patients are included in the intervention group. <h3>Results</h3> Demographic data are similar in both groups. Medical file analysis of the control group showed limited documentation about frequency and duration of the gout attacks or patient compliance. There are less frequent and also shorter gout attacks at t=12 (weeks) and t=52 in the intervention group. Allopurinol has been prescribed more frequently and higher-dosed within the intervention group at t=12. Colchicine use was lower in the intervention group. Dosing and administration methods of steroids were not uniform. In both groups NSAIDs are rarely prescribed. <h3>Conclusions</h3> Despite thelimitations of this study (small patient numbers, short follow-up period and suboptimal documentation in the control group), there is a clear trend to more intensive monitoring and care in the intervention group. This can be done by a specialist nurse under supervision from a rheumatologist versus gout care as usual. This also suggests that treating to a predefined target according to guidelines may well lead to improved treatment results in gout patients. A decrease in disease burden (a lower frequency and shorter duration of gout attacks) and lower serum urate were achieved. This study invites further research with a larger number of gout patients and extendedfollow-up, preferably within a multi-centre prospective cohort of gout patients. This could lead to a Dutch guideline allowing a more uniform and effective treatment of gout to be achieved. <h3>References</h3> EULAR evidence based recommendations for gout (2006). Part I. - EULAR evidence based recommendations for gout (2006). Part II.- BSR British Society for Rheumatology and British Health Professionals in Rheumatology Guideline for the Management of Gout (2007). <h3>Disclosure of Interest</h3> None Declared
Abstract 5620: Polymorphisms in steroid hormone genes and endometrial cancer risk
Authors: Jennifer A. Doherty, Noel S. Weiss, Sherianne Fish, Wenhong Fan, Melissa M. Loomis, Mary Anne Rossing, Lue Ping Zhao, Chu Chen
Journal: Cancer Research (2011)

Abstract The incidence of endometrial cancer is increased in the presence of elevated circulating levels of estrogens, especially when inadequately opposed by progestins. Estrogens are catabolized via catechol estrogen formation, oxidation, glucuronidation, and sulfation. Thus, it is possible that interindividual variation in these pathways might influence a woman's risk of endometrial cancer. To test this hypothesis, we examined whether the presence of the minor alleles in 26 SNPs in the genes CYP17, CYP1A1, CYP1B1, CYP3A4, CYP3A5, COMT, SULT1A1, UGT1A1, UGT1A8, UGT2B4, UGT2B7, and UGT2B15 was associated with risk of endometrial cancer in a population-based case-control study in Washington State, with 727 cases ages 50-74 years diagnosed between 1994-2005, and 736 controls frequency-matched to the cases by age, county and reference year. Analyses were restricted to non-Hispanic white women and adjusted for frequency matching variables. Only SNPs in CYP1A1 (involved in the formation of 2-hydroxyestrogens) and SULT1A1 (involved in estrogen sulfation) were associated with endometrial cancer risk. The CYP1A1 rs4646903 C allele was associated with a decreased risk of endometrial cancer (per C allele odds ratio (OR) 0.75, 95% confidence interval (CI) 0.58-0.95; ORs and 95% CIs for CT and CC vs TT were, respectively: 0.81, 0.61-1.07, and 0.38, 0.15-0.93). The SULT1A1 rs9282861 A allele was associated with increased risk of endometrial cancer (per A allele OR 1.22, 95% CI 1.04-1.42; ORs and 95% CIs for AG and AA vs GG were, respectively: 1.20, 0.96-1.50, and 1.50, 1.06-2.12). Both of these polymorphisms have been reported to be associated with alterations in the ability to metabolize estrogens; the CYP1A1 rs4646903 C allele may be associated with increased inducibility and increased endometrial expression of CYP1A1, and therefore could be associated with potentially higher levels of the 2-hydroxyestrogens in the target tissue. The SULT1A1 rs9282861 A allele is associated with reduced sulfotransferase activity, which could possibly allow the accumulation of estrogens. Thus, the observed associations with each SNP are consistent with their putative biologic function. However, several studies have examined variation in these and other genes in the steroid hormone metabolism pathways and endometrial cancer risk, and there are reports of both positive and negative findings for many of the SNPs studied. If a small effect size is expected, then additional studies and pooled analyses are needed to clarify possible associations with each of these polymorphisms. 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 5620. doi:10.1158/1538-7445.AM2011-5620
Impaired Insulin Action in Puberty
Authors: Stephanie A. Amiel, Robert S. Sherwin, Donald C. Simonson, Albert A. Lauritano, William V. Tamborlane
Journal: New England Journal of Medicine (1986)

Patients with insulin-dependent diabetes mellitus often have poor metabolic control during puberty. To determine whether puberty is associated with decreased insulin-stimulated glucose metabolism, we compared the results of euglycemic insulin-clamp studies in adults and prepubertal and pubertal children with and without insulin-dependent diabetes. In nondiabetic pubertal children, insulin-stimulated glucose metabolism (201±12 mg per square meter of body surface area per minute) was sharply reduced, as compared with that of prepubertal children and adults (316±34 and 290±21 mg per square meter, respectively; P<0.01), despite comparable hyperinsulinemia (insulin levels of 80 to 90 μU per milliliter). Similarly, the response to insulin was 25 to 30 percent lower in the diabetic pubertal children than in the diabetic prepubertal children (P<0.05) and adults (P = 0.07). At each stage of development, the stimulating effect of insulin on glucose metabolism was decreased by 33 to 42 percent in the children with diabetes (P<0.01). In all the groups of children studied, the response to insulin was inversely correlated with mean 24-hour levels of growth hormone (r = -0.52, P = 0.01). Among the diabetic children, the glycosylated hemoglobin levels were substantially higher in the pubertal children than in the prepubertal children (P<0.02), although the daily insulin doses tended to be higher. These data suggest that insulin resistance occurs during puberty in both normal children and children with diabetes. The combined adverse effects of puberty and diabetes on insulin action may help explain why control of glycemia is so difficult to achieve in adolescent patients. (N Engl J Med 1986; 315:215–9.)
It's not the destination, it's the ‘road to load’ that matters: a tennis injury prevention perspective
Authors: Babette M Pluim, Michael K Drew
Journal: British Journal of Sports Medicine (2016)

Consistent training is conducive to reaching performance goals in sport and essential for optimal performance. A study in athletics has shown that the likelihood of achieving a performance goal was seven times higher in those athletes who completed >80% of their planned training weeks and that training availability accounted for 86% of successful seasons.1 This means that the goals of the coaches and strength/conditioning experts and the sports medicine/physiotherapy team are not distinct entities but rather complementary, with the clinical team trying to avoid failure and the coaches improving the chance of success.

How do we keep our athletes injury-free? There is the perception that higher training loads inevitably result in higher injury rates in athletes. Although it is true that high absolute training loads are associated with greater injury risk, there is also evidence that training may have a protective effect and that undertraining increases injury risk.2 

The new ‘train smart AND hard’ paradigm3 suggests that it is not so much the load itself, but an inappropriate transition to …
Low Activities of the Pyruvate and Oxoglutarate Dehydrogenase Complexes in Five Patients with Friedreich's Ataxia
Authors: J.P. Blass, R.A. Pieter Kark, Nirmala K. Menon, Sandra E. Harris
Journal: New England Journal of Medicine (1976)

Since patients with Friedreich's ataxia appear to oxidize pyruvate slowly, we measured the activity of the pyruvate dehydrogenase complex in disrupted fibroblasts from four patients with this syndrome and one patient with a clinical variant. The activity was 43 +/- 4 per cent of that in 16 controls (mean +/- S.E.M., P less than 0.001). The activity of the 2-oxoglutarate dehydrogenase complex was also lower in the patients' cells than in those of controls (50 +/- 2 per cent, P less than 0.001). However, the activity of cytochrome-c oxidase was normal (126 +/- 43 per cent of controls). Mixing experiments gave no evidence of soluble enzyme inhibitors or activators, and the addition of excess substrate or cofactor did not ameliorate the deficiencies. White blood cells from one of the patients had low activities of both complexes. Mutations of these dehydrogenase complexes occur in some patients with Friedreich's ataxia and lead to abnormally low activity of an enzyme of the tricarboxylic acid cycle.
More people in England are dying at home
Authors: Z. Kmietowicz
Journal: BMJ (2013)

The proportion of people dying at home or in care homes in England rose from 38% in 2008 to 44% in 2012, says a report from Public Health England.1

About 450 000 people die in England each year, but the proportion dying in hospital has been gradually falling since 2005. In 2012 just under 200 000 people died at home or in a care home, up from 175 000 in 2008, …
Abstract 3962: Mathematical models for cellular pharmacodynamics of fractionated radiation and radiochemotherapy
Authors: Ardith W. El-Kareh, Leslie Braziel Jones, Timothy W. Secomb
Journal: Cancer Research (2012)

Abstract Cellular response to radiation is generally described by the linear-quadratic equation, but the extension to complicated fractionated schedules, and to combined exposure with chemotherapeutic drugs is not well-established. Mathematical models for cellular response are needed for predictive quantitative modeling of treatment. Here, such models are formulated using the previously developed concepts of peak damage models and additive damage, which in prior studies proved successful in describing cellular pharmacodynamics of single-agent and combination chemotherapy. The exponential form of the linear-quadratic equation is replaced by Hill or cumulative lognormal functions of the peak value over time of a quantity termed “cellular damage.” Damage is a saturating function of radiation dose. Cell survival depends on whether the peak value of cellular damage ever exceeds a threshold value during treatment. This model is tested for a range of data sets for single-dose radiation, and compares favorably with the linear-quadratic. In one data set (Park et al 2008) the dose range was sufficiently wide to show the significant overestimation of cell kill by the linear-quadratic model at high doses; the Hill/lognormal formulation behaves more satisfactorily in this limit. The model is then extended to the case of fractionated radiation through the assumption that damage decays between treatments according to first-order kinetics, and damage from different cycles is additive. The model gives a satisfactory fit to literature data with multiple fractionation schedules for the same drug and cell line. Finally, the principle of additive damage is applied to model cellular response to radiochemotherapy, with damage as a linear superposition of terms from radiation and drug. Overall, the peak cellular damage model with additive damage was found to fit in vitro dose-response data well, and provides a tool for understanding and predicting response as schedule and dose are varied in combination treatments. It is expected that these models will have application in assessment of preclinical cellular pharmacodynamics data, as well as computational simulations of treatment response. 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 3962. doi:1538-7445.AM2012-3962