tbuckley/cabot-search huggingface dataset:
Abstract P2-13-09: Pharmacological impact of endoxifen in a laboratory simulation of tamoxifen therapy in postmenopausal breast cancer patients
Authors: PY Maximov, RE McDaniel, P Bhatta, H Brauch, VC Jordan
Journal: Cancer Research (2012)

Abstract Tamoxifen is a well-established adjuvant drug for the treatment and prevention of Estrogen Receptor (ER) positive breast cancer, effective in both pre- and postmenopausal women. However, the metabolic activation of tamoxifen to endoxifen by the CYP2D6 enzyme system still remains controversial to plan the treatment of patients with breast cancer. Since the discovery and description of the pharmacological properties of endoxifen, clinical trials were undertaken to determine the pharmacological relevance of endoxifen. The results of these trials, however, vary. In this study we demonstrate the pharmacological impact of endoxifen in a laboratory simulation of breast cancer therapy with tamoxifen in postmenopausal women in vitro in a panel of human breast cancer cell lines (MCF-7, T47D, ZR-75-1 and BT474). The concentrations of estrogens (E1/E2) used to simulate postmenopausal women treated with tamoxifen, were obtained from published studies, as well as the concentrations of tamoxifen and its metabolites (N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen) based on the CYP2D6 genotype in postmenopausal breast cancer patients (Murdter TE et al, Clin Pharmacol Ther, 2011). Our results demonstrate that irrespective of CYP2D6 genotype, tamoxifen and its primary metabolites (N-desmethyltamoxifen and 4-hydroxytamoxifen) are able to inhibit completely the estrogen-stimulated growth of breast cancer cells in vitro. Additional endoxifen in any concentration corresponding to CYP2D6 genotype was not able to increase the antiestrogenic effect of tamoxifen and its primary metabolites. Moreover, we demonstrate that 4-hydroxytamoxifen is absolutely essentialforinhibition of estrogen action. Based on our results, we can conclude that endoxifen is pharmacologically supportive but not essential for any genotype of CYP2D6 in a postmenopausal setting. This study (PYM) was supported by Susan G. Komen for the Cure International Postdoctoral Fellowship under Award number SAC100009(VCJ), and the Department of Defense Breast Program under Award number W81XWH-06-1-0590 (VCJ). Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-13-09.
AB0016 Significance of MEFV E148Q mutation in korean patients with adult onset still’s disease
Authors: J.J. Kim, Y.B. Joo, S.C. Shim, J.Y. Choe, T.H. Kim, J.B. Jun, D.H. Yoo
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Adult onset Still's disease (AOSD) is a rare rheumatic disease characterized by high fever, cutaneous rash, articular symptom, lymphadenopathy, leukocytosis and abnormal liver function test. Familial Mediterranean fever (MEFV) is an inherited disorder and one of the periodic fever syndrome and its mutations of MEFV gene, including E148Q have been described. Some contribution of MEFV gene mutation and certain rheumatic disease has been suggested. <h3>Objectives</h3> The purpose of this study is to research the incidence and clinical significance of MEFV gene E148Q mutations in a cohort of patients with AOSD in Korea. <h3>Methods</h3> The study included ninety-four patients with AOSD and one hundred sixty-five healthy controls. In all patients and controls, genomic DNAs were isolated and genotyped using restriction fragment length polymorphism for five MEFV gene mutations such as E148Q, P369S, M680I, V726A and M694V. In the AOSD patients, the clinical significance of MEFV mutation, especially E148Q heterozygote and homozygote were compared with E148 homozygote by the laboratory findings and modified Pouchot's activity score. <h3>Results</h3> P369S was detected in seven (7.4%) of AOSD patient and ten (6.1%) of control group, but M680I, V726A and M694V were not found in both groups. In control group, seventy-seven persons (46.6%) found to carry 148Q allele were consisted with seventy-one E148Q heterozygotes (92.2%) and six E148Q homozygotes (7.8%). In AOSD patients, fifty-one patients (54.3%) were E148 homozygote and forty-three patients (45.7%) were found to carry 148Q allele consisted with fifty-eight E148Q heterozygotes (92.1%) and five E148Q homozygotes (7.9%). The frequency of 148Q allele was not clinical significance between control group and AOSD patients (p value=0.887). In the group of AOSD patients (E148 homozygote versus E148Q heterozygote and homozygote), there were statistical differences of sore throat (p value=0.017) and level of ESR (p value=0.025), but no significant differences of onset-age, leukocytosis, abnormal liver function test, level of CRP and ferritin, fever, arthralgia, activity score and disease pattern. <h3>Conclusions</h3> The high incidence of E148Q mutation among MEFV gene mutations was found in this Korean cohort. But, MEFV E148Q mutation was not associated with the development of AOSD patients in Korea. Eventually E148Q mutation was correlated with only high ESR and sore throat, but we need to look for association with clinical response to certain treatment and longer prognosis. <h3>Disclosure of Interest</h3> None Declared
Oral Manifestation of Crohn’s Disease
Authors: Alfredo Aguirre, Colleen A Nugent
Journal: New England Journal of Medicine (2015)

A 13-year-old boy presented with a 9-month history of episodic unilateral swelling of the face and oral pain. He reported having loose, nonbloody stools. Granulomatous inflammation consistent with Crohn's disease was found on histopathological examination.
From mutualism to moral transcendence
Authors: Scott Atran
Journal: Behavioral and Brain Sciences (2013)

Abstract Baumard et al. attribute morality to a naturally selected propensity to share costs and benefits of cooperation fairly. But how does mundane mutualism relate to transcendent notions of morality critical to creating cultures and civilizations? Humans often make their greatest exertions for an idea they form of their group. Primary social identity is bounded by sacred values, which drive individuals to promote their group through non-rational commitment to actions independently of likely risks and rewards.
719 COMPARISON OF THE NAFLD FIBROSIS SCORE VERSUS 7 OTHER BLOOD TESTS FOR LIVER FIBROSIS IN NAFLD
Authors: A. Guillet, J. Vergniol, J. Boursier, J. Foucher, F. Oberti, F. Chermazk, I. Fouchard-Hubert, N. Dib, P. Calès, V. de Ledinghen
Journal: Journal of Hepatology (2013)
PMO-231 Ileal and colonic mucosal dendritic cell cytokine profiles differ at rest and after in vitro bacteria and pro-biotic challenge in postoperative Crohn's disease patients
Authors: A U Murugananthan, D O Bernardo, E R Mann, C T Tee, A L Hart, N Arebi, S C Knight, H O Al-Hassi
Journal: Gut (2012)

<h3>Introduction</h3> Postoperative Crohn9s disease (CD) recurrence predominantly affects the ileal mucosa at the ileo-colonic anastomosis with the colonic side often spared. Altered immune responses to bacterial flora are thought to be a driving force in the pathogenesis of CD recurrence. Gut dendritic cells (DC) are key in the initiation of immune response, through cytokine production, when stimulated with bacterial antigens. We postulate that differences between ileal and colonic DC resting characteristics and functional responses may be responsible for the propensity of recurrence to occur at the ileal aspect of the anastomosis. We aimed to assess ongoing intracellular cytokine production in DC from ileal and colonic postoperative CD mucosa and assess their functional response to bacterial stimulation and modulation with probiotics. <h3>Methods</h3> Paired ileal and colonic biopsies were taken from postoperative CD patients at colonoscopy (n=11). Lamina propria mononuclear cells were collected after collagenase digestion. DC intracellular cytokine responses (IL-2, IL-6, IL-17a, TGFβ and INFγ) were assessed in basal conditions and after culture with LPS and two probiotic bacterial strains Bifidobacterium Longum; Lactobacillus Casei (<i>B longum</i> and <i>L casei</i>) using multi-colour flow cytometry. <h3>Results</h3> Unstimulated ileal DC showed higher levels of ongoing intracellular production of pro-inflammatory cytokines than unstimulated colonic DC: IL6 (34.21±12.80 vs 10.47±3.574 cells/υl [mean±SEM], p=0.037), IL17a (24.62±12.38 vs 14.94±9.865 cells/υl, p=0.05, n=5) and TGFβ (74.12±17.96 vs 32±16.27 cells/υl, p=0.031). Incubation with LPS resulted in higher DC intracellular cytokine levels of INFγ in ileal derived DC with a borderline p value (27.49±12.61 vs 0.39±0.391 cells/υl p=0.06) but not colonic derived DCs (19.55±10.12 vs 12.40±7.039, p=0.6). <i>L casei</i> incubation, however, led to a larger decrease in ongoing TGFβ (−42.35±16.02 vs 4.42±11.46 cells/υl p=0.023) and INFγ (−14.76 ±7.196 vs 20.33±10.16 cells/υl-, p=0.05) DC cytokine production in colonic tissue compared with ileal. <h3>Conclusion</h3> Ileal mucosa DC demonstrate a cytokine profile implicating a Th17 response compared with colonic mucosa. Upon bacterial stimulation with LPS ileal mucosa demonstrate increased INFγ DC production compared with unstimulated DC. These results suggest a role of for a Th1/Th17 response in driving post-operative CD recurrence. The probiotics <i>L casei</i> and <i>B longum</i> failed to show significant effects in modulation of intracellular cytokine production in ileal DC. <h3>Competing interests</h3> None declared.
Type 1 diabetes is still linked to lower life expectancy
Authors: Jacqui Wise
Journal: BMJ (2016)

The gap in life expectancy between patients with type 1 diabetes and the general population has not closed over the past few decades, two new studies published in Diabetologia show. Although life expectancy has improved for patients with type 1 diabetes, so has that of the general population.

In the first study, researchers analysed mortality data of patients with type 1 diabetes in Australia from 1997 to 2010.1 A total of 5981 deaths were identified during 902 136 person …
Discordance in lymphoid tissue recovery following stem cell transplantation in rhesus macaques: an in vivo imaging study
Authors: Robert E. Donahue, Sharat Srinivasula, Naoya Uchida, Insook Kim, Alexis St. Claire, Gorka Duralde, Paula DeGrange, Marisa St. Claire, Richard C. Reba, Aylin C. Bonifacino, Allen E. Krouse, Mark E. Metzger, Chang H. Paik, H. Clifford Lane, John F. Tisdale, Michele Di Mascio
Journal: Blood (2015)
Cerivastatin and Reports of Fatal Rhabdomyolysis
Authors: Judy A. Staffa, Jennie Chang, Lanh Green
Journal: New England Journal of Medicine (2002)

To the Editor: Bayer's voluntary withdrawal of cerivastatin from the U.S. market led to questions regarding the safety of all hydroxymethylglutaryl–coenzyme A reductase inhibitors, or statins. Myopathy and the rarer severe rhabdomyolysis are considered adverse events of therapy with this class of drugs.1 Concomitant use of drugs that can increase blood levels of statins can increase the risk of myopathy, as can concomitant use of gemfibrozil.2 We summarize the U.S. reports of fatal rhabdomyolysis associated with all six drugs in this class: lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, and cerivastatin. We reviewed reports in the Adverse Event Reporting System of the . . .
792 HBV-HCV COINFECTION: A NOVEL MODEL SYSTEM REVEALS INSIGHTS INTO IMMUNOLOGICAL MECHANISMS OF VIRAL INTERFERENCE
Authors: C. Lass, C. Präg, D. Grimm, J. Gouttenoire, V. Lohmann, J. Köck, M. Nassal, H.E. Blum, R. Bartenschlager, D. Moradpour, R. Thimme, V. Brass
Journal: Journal of Hepatology (2012)
Study Confirms High Rates of Adult T-Cell Leukemia in N.Y.C.
Authors: N. S. Larsen
Journal: JNCI Journal of the National Cancer Institute (1994)

Journal Article Study Confirms High Rates of Adult T-Cell Leukemia in N.Y.C. Get access Natalie S. Larsen Natalie S. Larsen Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 86, Issue 2, 19 January 1994, Pages 85–86, https://doi.org/10.1093/jnci/86.2.85 Published: 19 January 1994
Scintigraphic Detection of an Occult Bleed into a Retroperitoneal Mass Using Tc-99m Labeled Red Blood Cells
Authors: D H Ring, E D Silverman
Journal: Clinical Nuclear Medicine (1997)

A 45-year-old man with chronic lymphocytic leukemia and a retroperitoneal mass underwent Tc-99m labeled red blood cell bleeding imaging to localize a bleeding source. The bleeding scan showed a linear accumulation of radiotracer obliquely oriented along the left upper epigastrium to the right midepigastrium. This area of uptake increased in intensity and assumed a more globular appearance throughout the study, but did not change in location. This is the pattern of a retroperitoneal bleed resulting from active hemorrhage into the retroperitoneal mass.
Abstract 5389: Novel inhibitors of nicotinamide phosphoribosyl transferase (NAMPT).
Authors: Murali Ramachandra, Chetan Pandit, Hosahalli Subramanya, Dinesh Chikkanna, Anirudha Lakshminarasimhan, Vinayak Khairnar, Sunil Panigrahi, Anuradha Ramanathan, Aparna Satyanandan, Narasimha Rao, Arnab Bera, Kishore Narayanan, Sreevalsam Gopinath, Raghuveer Ramachandra
Journal: Cancer Research (2013)

Abstract Nicotinamide phosphoribosyl transferase (NAMPT) is the enzyme that catalyzes the rate limiting step in the salvage pathway of Nicotinamide Adenine Dinucleotide (NAD) biosynthesis. NAMPT is reported to be overexpressed in a number of cancer and inflammatory indications. Because of the requirement of NAD as a co-factor or substrate for a number of key biochemical pathways including those catalyzed by PARP1, Sirtuins and ADP-ribosyl cyclase, inhibition of NAMPT has been shown to result in anti-tumor efficacy in preclinical models. Two NAMPT Inhibitors FK866/APO866 and GMX1778 are currently in clinical trials for oncology indications. In the presence of these clinical agents, cultured cell lines show development of resistance due to mutations underscoring the potential need for inhibitors from distinct chemical series. Here, we report a structure-guided drug design based approach for identification of lead compounds from two chemical series selectively targeting NAMPT. Determination of co-crystal structures with several de novo designed hits greatly aided in the identification of lead compounds that exhibited potent inhibition of NAMPT against both wild type and resistance mutants (G217R and H191R) Lead compounds were highly active in inhibiting proliferation that correlated well with cellular NAD depletion in several cancer cell lines. Normal cells and selected cancer cell lines have an NAMPT independent salvage pathway for biosynthesis of NAD, which is dependent on nicotinic acid phosphoribosyltransferase (NAPRT) and Nicotinic acid (NA). The anti-proliferative activities were fully rescued in NAPRT- proficient cell lines with the addition of NA, confirming the mechanism of action through specific NAD depletion. Lead compounds from both series exhibited excellent drug-like properties including solubility, metabolic stability and permeability, and desired exposure in pharmacokinetic studies. Anti-tumor activities of these compounds including NA rescue in NAPRT-proficient tumor models are currently being evaluated in preclinical models. Citation Format: Murali Ramachandra, Chetan Pandit, Hosahalli Subramanya, Dinesh Chikkanna, Anirudha Lakshminarasimhan, Vinayak Khairnar, Sunil Panigrahi, Anuradha Ramanathan, Aparna Satyanandan, Narasimha Rao, Arnab Bera, Kishore Narayanan, Sreevalsam Gopinath, Raghuveer Ramachandra. Novel inhibitors of nicotinamide phosphoribosyl transferase (NAMPT). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5389. doi:10.1158/1538-7445.AM2013-5389
THU0002 Comparison of Pathways Implicated in Anti-Citrillunated Peptide Antibody Positive and Negative Rheumatoid Arthritis Patients
Authors: P. Martin, S. Viatte, A. Brass, S. Eyre
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid Arthritis (RA) is a chronic autoimmune disease characterised by inflammation and destruction of synovial joints affecting up to 1% of the adult population. GWAS have been successful in identifying SNPs associated with disease. However, previous studies have been under-powered to detect differences between anti-citrillunated peptide antibody (ACPA) positive and negative patients. Using a custom Illumina® Infinium® array, the RA Consortium for Immunochip (RACI) allows comprehensive analysis of disease associations in both ACPA positive and negative patients. Pathway analyses test whether a molecular pathway is associated with disease by testing for enrichment of genes associated with disease. This involves mapping SNP associations to genes which can often be problematic or subjective. <h3>Objectives</h3> The objectives of this study, therefore, were to develop a robust workflow based method to assign genes and to compare the pathways significantly enriched in ACPA positive and negative patients. <h3>Methods</h3> Excluding HLA, the top 100 most associated SNPs from the immunochip analysis were selected for ACPA positive patients along with the top 100 most associated SNPs from the ACPA negative analysis. Genes were assigned to these SNPs using a Taverna workflow which defines an associated region using SNPs in linkage disequilibrium (LD) with the associated SNP. This prevents the bias introduced by researchers assigning SNPs to ‘biologically plausible’ genes and provides a robust, reproducible method for assigning genetic associations to genes. These genes were subsequently tested for enrichment in PANTHER pathways and Gene Ontologies (GO) using the Expression Analysis tool. <h3>Results</h3> Overall 4 pathways were significantly (p&lt;0.05) enriched in the ACPA positive gene list and 6 in the ACPA negative gene list, with 1 pathway significantly associated in both. The interleukin signalling pathway was associated in the ACPA positive (p=0.00322) group, the interferon-gamma signalling pathway in ACPA negative (p=0.0190) patients and the GO JAK/STAT signalling pathway in both (ACPA<sup>+</sup> p=0.00234; ACPA<sup>-</sup> p=0.00243). <h3>Conclusions</h3> Although results are preliminary, this study provides a promising pathway analysis of ACPA positive and negative RA patients. These findings not only suggest shared processes between the two disease sub-groups, such as JAK/STAT signalling, but also identify areas where possible differences exist helping to define patient groups and potentially leading to better targeting of therapies. <h3>Disclosure of Interest</h3> None Declared
Hemolytic Anemia of Mechanical Origin with Aortic-Valve Prosthesis
Authors: William DeCesare, Charles Rath, Charles Hufnagel
Journal: New England Journal of Medicine (1965)

HEMOLYTIC anemia that followed the use of prosthetic materials in dogs was reported by Stohlman and his associates,1 who described the development of anemia accompanied by hemoglobinemia, hemoglobinuria, hemosiderinuria and a markedly shortened red-cell life-span after the insertion of a lucite ball valve between the apex of the left ventricle and the thoracic aorta. They concluded that the hemolytic process resulted from mechanical trauma to red cells by the impact of the rigid ball against the rigid housing, and they found a substantial decrease in red-cell destruction when an elastic silicone valve with a more resilient housing was employed. Earlier, . . .
Diagnosis and Treatment of Congenital Bladder-Neck Obstruction in Children
Authors: Guy W. Leadbetter, Wyland F. Leadbetter
Journal: New England Journal of Medicine (1959)

CONGENITAL bladder-neck obstruction is a common, and potentially serious, pediatric and urologic problem. Sixty-six per cent of the cases of bladder dysfunction reported by Emmett and Simon1 and 95 per cent of those reported by Burns et al.2 showed some type of bladder-neck obstruction. Congenital valves were rarely found. Neurogenic disturbance of some type accounted for the remainder. Unrecognized and untreated, this pathologic abnormality leads to vesical and upper-urinary-tract changes, and ultimately to progressive renal destruction and death.The explanation for the development of this obstructive lesion appears to be a fault in dissolution of mesenchyme at the bladder neck, . . .
Leydig-Cell Tumors Caused by an Activating Mutation of the Gene Encoding the Luteinizing Hormone Receptor
Authors: Guoquan Liu, Lise Duranteau, Jean-Claude Carel, Jason Monroe, Daniel A. Doyle, Andrew Shenker
Journal: New England Journal of Medicine (1999)

The receptor for luteinizing hormone and chorionic gonadotropin plays a major part in normal and abnormal reproductive function.1–4 In males, activation of the receptor regulates the development and function of Leydig cells.5 Testosterone secreted by Leydig cells promotes male sexual differentiation, pubertal androgenization, and fertility. The human luteinizing hormone receptor is a G protein–coupled receptor with a transmembrane domain composed of seven segments. Activation of the receptor by luteinizing hormone leads to activation of Gs, the G protein that is coupled to adenylyl cyclase, and to an increase in cyclic AMP (cAMP). High concentrations of luteinizing hormone . . .
Orthostatic Renal Arteriography
Authors: J J KAUFMAN, M H MAXWELL
Journal: JAMA (1963)

Orthostatic renal arteriography has served to provide better delineation of the renal arteries, to better define stenotic lesions of these vessels and to point to a possible relationship between excessive renal mobility and the development of mural hyperplasias of the renal artery. It is suggested that where facilities permit, orthostatic renal arteriography be employed as a method of obtaining a better understanding of renal artery architecture and function in patients who are being studied for secondary hypertension.
FRI0546 Pituitary-adrenal function after prolonged glucocorticoid therapy in systemic disorders
Authors: K. Sacre, M. Dehoux, M. Chauchard, D. Gobert, E. Pasqueloni, C. Compain, J.-F. Alexandra, M.-P. Chauveheid, O. Lidove, R. Roussel, T. Papo
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> In showing no correlation between adrenal insufficiency risk and dose or duration of steroid treatment, previous reference papers have blurred our comprehension and practice (1). <h3>Objectives</h3> To determine the extent to which long-term corticosteroid therapy damages the pituitary-adrenal axis in patients treated with prednisone medication for systemic disorders. <h3>Methods</h3> We retrospectively studied all consecutive patients followed in our department from January 2011 to August 2012 in whom short synacthen test (SST) was assessed when withdrawal of prednisone was planned. Age, sex, disease status, duration and cumulative dose of glucocorticoid therapy were systematically recorded. SST was considered blunted when the 60 minutes plasma cortisol concentration was below 550 nmol per liter. <h3>Results</h3> Sixty consecutive patients suffering various systemic diseases were studied (Table 1). The mean daily dose of prednisone at study time was 7 (±2) (range: 5-10) mg. Median duration and cumulative dose of prednisone were 3.8 years (range: 0.3-32) and 16.6 grams (1-132), respectively. The SST response was blunted in 29 patients (48.3%) and normal in 31. Blunted responses were associated with higher cumulative prednisone dose (p=0.04) and treatment duration (p=0.04) (Table1 and 2). Basal cortisol concentrations negatively correlated with both duration (r=-0.33, p=0.01) and cumulative dose (r=-0.28, p=0.03) of prednisone. Steroids were stopped in 29/31 (93.5 %) patients showing a normal response to SST. In this case, no patient required hydrocortisone replacement for a mean follow-up of 10 (± 6) months. <h3>Conclusions</h3> Adrenal insufficiency is frequent in patients treated with long-term glucocorticoid for systemic disorders. Adrenal insufficiency risk may be appraised adequately on the basis of cumulative dose and duration of glucocorticoid therapy. <h3>References</h3> Schlaghecke R, et al. N Engl J Med 1992;326:226-230. <h3>Disclosure of Interest</h3> None Declared