tbuckley/cabot-search huggingface dataset:
THU0182 Waste Not, Want Not: Is Anti-TNF Wastage Preventable?
Authors: C. Bell, S. Petford, L.-M. Tibbetts, K. M. Douglas
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Anti-TNF therapy (αTNF) has revolutionised rheumatology with undeniable improvements in patients' care, but also made it an expensive speciality. Humira, Enbrel and Infliximab are independently within the top 10 selling pharmaceutical products 2012 with combined estimated worldwide sales of $9.48, $8.37 and $7.67 billion respectively [1]. Financial accountability is imperative to modern medical practice and this includes minimising drug waste. In much of the UK injectable αTNF is delivered directly to patients' home, with financial benefits for NHS trusts, however any unused stock is wasted. <h3>Objectives</h3> We aimed to quantify injectable αTNF waste, reasons for it and explore options for reduction. <h3>Methods</h3> Patients return unused αTNF to the department as a drug safety measure. Patient details; volume of returned drug; and date are recorded on an Excel database. Returns between October 2011 and October 2012 were identified. Patients' clinical letters were reviewed to establish the timing, reason and a clinical decision made as to the predictability of drug discontinuation. A questionnaire was completed by clinical staff (7 Consultant, 3 SpR, 4 Clinical Nurse Specialist) regarding clinical scenarios of primary/ secondary failure and significant events requiring αTNF cessation. It explored knowledge of the process of stopping αTNF including its delivery. <h3>Results</h3> In total 390 patients received injectable αTNF; 25 stopped (4 inefficacy, 12 side effects, 6 new contraindication, 3 other); 2 were deemed predictable. <h3>Conclusions</h3> Annual un-used αTNF amounted to £35,500 representing 1.4% of our departments £2.5million biologics spend. Whilst this is a small proportion, when dealing with large figures small percentages amount to considerable sums. Wastage was largely unpredictable; simply recognising patients expected to stop is thus unlikely to be beneficial. The questionnaire identified sources of unnecessary drug delivery due to delays in stopping αTNF. Clinical staff need education and a streamlined pathway for αTNF cessation instituted. Currently deliveries are made quarterly; reducing this interval would minimise waste without incurring extra cost to the Trust, but an increased workload preparing and dispensing prescriptions is inevitable. To uncouple any dissociation between decision making and prescribing 'flagging' prescription requests prior to assessment points (e.g. 6 months in RA) would ensure criteria are fulfilled and appropriate prescribing. We have identified local actions to reduce αTNF wastage. However, our experience is unlikely to be unique and consequently represents an area for considerable potential cost savings both within the UK and EU. <h3>References</h3> FiercePharma 9<sup>th October 2012</sup> <h3>Disclosure of Interest</h3> None Declared
A Short-Term Study of Chimeric Monoclonal Antibody cA2 to Tumor Necrosis Factor α for Crohn's Disease
Authors: Stephan R. Targan, Stephen B. Hanauer, Sander J.H. van Deventer, Lloyd Mayer, Daniel H. Present, Tanja Braakman, Kimberly L. DeWoody, Thomas F. Schaible, Paul J. Rutgeerts
Journal: New England Journal of Medicine (1997)

Studies in animals and an open-label trial have suggested a role for antibodies to tumor necrosis factor α, specifically chimeric monoclonal antibody cA2, in the treatment of Crohn's disease.
Direct alkylation of calf thymus DNA by acrylonitrile. Isolation of cyanoethyl adducts of guanine and thymine and carboxyethyl adducts of adenine and cytosine.
Authors: J J Solomon, A Segal
Journal: Environmental Health Perspectives (1985)

Reaction of the rodent carcinogen acrylonitrile (AN) at pH 7.0 for 10 and/or 40 days with 2'-deoxyadenosine (dAdo), 2'-deoxycytidine (dCyd), 2'-deoxyguanosine (dGuo), 2'-deoxyinosine (dIno), and thymidine (dThd) resulted in the formation of cyanoethyl and carboxyethyl adducts. The adducts isolated were 1-(2-carboxyethyl)-dAdo (1-CE-dAdo), N6-CE-dAdo, 3-CE-dCyd, 7-(2-cyanoethyl)-Gua (7-CNE-Gua), 7,9-bis-CNE-Gua, imidazole ring-opened 7,9-bis-CNE-Gua, 1-CNE-dIno, and 3-CNE-dThd. Structures were assigned on the basis of UV spectra and electron impact (EI), desorption chemical ionization (DCI) and Californium-252 fission fragment ionization mass spectra. The carboxyethyl adducts resulted from initial cyanoethylation at a ring nitrogen adjacent to an exocyclic nitrogen followed by rapid hydrolysis of the nitrile moiety to a carboxylic acid. It was postulated that the facile hydrolysis is the result of an intramolecular-catalyzed reaction resulting from the formation of a transient cyclic intermediate between nitrile carbon and exocyclic nitrogen. AN was reacted with calf thymus DNA (pH 7.0, 37 degrees C, 40 days) and the relative amounts of adducts isolated was 1-CE-Ade (25.8%), N6-CE-Ade (7.6%), 3-CE-Cyt (1.3%), 7-CNE-Gua (25.8%), 7,9-bis-CNE-Gua (4.3%), imidazole ring-opened 7,9-bis-CNE-Gua (18.9%) and 3-CNE-Thy (16.3%). Thus a carcinogen once adducted to a base in DNA was shown to be subsequently modified resulting in a mixed pattern of cyanoethylated and carboxyethylated AN-DNA adducts.(ABSTRACT TRUNCATED AT 250 WORDS)
Colonic schistosomiasis and early rectal cancer: coincidence or causal relationship?
Authors: Andreas Probst, Tina Schaller, Alanna Ebigbo, Helmut Messmann
Journal: Endoscopy (2014)

A 74-year-old woman was referred for endoscopic resection of a laterally spreading rectal tumor of the nongranular pseudodepressed subtype ([Fig. 1 a]). The 25-mm lesion had been diagnosed during screening colonoscopy and the patient denied any symptoms. Resection was performed en bloc by endoscopic submucosal dissection (ESD). Histology showed pT1 carcinoma with a submucosal depth of invasion of 200 µm ([Fig. 1 b]). Close to the laterally spreading rectal tumor, a submucosal yellowish lesion 3 mm in diameter was seen ([Fig. 2 a]). A neuroendocrine tumor was suspected macroscopically and ESD was performed. Surprisingly, histopathological examination of the specimen revealed granuloma with calcification containing schistosomal ova ([Fig. 2 b]). The patient recalled a diagnosis of schistosomiasis 27 years earlier when she had travelled to Uganda. Treatment had been performed with praziquantel immediately after diagnosis and her further course was uneventful.
Abstract 4639: Prognostic significance and molecular associations of <i>CDKN2A</i> (p16) promoter methylation and loss of expression in colorectal cancer
Authors: Kaori Shima, Katsuhiko Nosho, Yoshifumi Baba, Mami Cantor, Edward L. Giovannucci, Charles S. Fuchs, Shuji Ogino
Journal: Cancer Research (2010)

Abstract Background: p16 (CDKN2A/Ink4a) is a cyclin-dependent kinase inhibitor and functions as a tumor suppressor. CDKN2A promoter methylation and gene silencing are associated with the CpG island methylator phenotype (CIMP) in colorectal cancer. However, prognostic significance of CDKN2A methylation or loss of p16 expression independent of CIMP status has not been studied. Patients and Methods: Utilizing 940 colorectal cancers (stage I-IV) in two independent cohort studies (the Nurses’ Health Study and the Health Professionals Follow-up Study), we quantified DNA methylation in the CDKN2A promoter real-time PCR (MethyLight) and detected hypermethylation in 269 tumors (29%). By immunohistochemistry, we detected loss of p16 (CDKN2A) expression in 25% (200/804) of tumors. We also analyzed DNA methylation in LINE-1 and 7 other CpG islands (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); microsatellite instability (MSI); KRAS, BRAF and PIK3CA mutations; and expression of β-catenin, p53, p21, p27, cyclin D1, fatty acid synthase (FASN), and cyclooxygenase-2 (PTGS2, COX-2). Results: In multivariate logistic regression analysis, CDKN2A methylation was independently associated with CIMP-high [adjusted odds ratio (OR) 41.6; 95% CI, 21.6-80.0; vs. CIMP-0], CIMP-low (adjusted OR 5.66; 95% CI, 3.75-8.53; vs. CIMP-0), and COX-2 negativity (adjusted OR 0.46; 95% CI, 0.29-0.74; COX-2 -positive vs. negative). Both CDKN2A promoter methylation and loss of p16 were significantly associated with high overall mortality in univariate Cox regression analysis [hazard ratio (HR), 1.31; 95% CI, 1.07-1.60; p=0.009 (CDKN2A methylation), HR, 1.30; 95% CI, 1.03-1.63; p=0.026 (loss of p16)] but not in multivariate analysis [HR, 0.79; 95% CI, 0.57-1.09; p=0.14 (CDKN2A methylation), HR, 1.00; 95% CI, 0.79-1.27; p=0.98]. Conclusion: Both CDKN2A promoter methylation and loss of p16 expression in colorectal cancer are not independently associated with patient survival. However, CDKN2A promoter methylation is independently associated with CIMP and COX-2 negativity. 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 4639.
Case 35-2003
Authors: Andrew L. Warshaw, William R. Brugge, Kent B. Lewandrowski, Martha B. Pitman
Journal: New England Journal of Medicine (2003)

Presentation of CaseA 75-year-old man was evaluated in the clinic because of a cystic lesion of the pancreas.For several years he had had gastroesophageal reflux, which was alleviated by pantoprazole. He continued to have intermittent, mild, vague upper abdominal pain with possible early satiety. The pain did not radiate to the back. He had not lost weight. An ultrasonographic examination performed at another hospital four months before admission showed a hyperechoic mass, 2.9 cm in diameter, in the right hepatic lobe that was eventually determined to be a hemangioma, as well as multiple hepatic cysts. Computed tomographic (CT) . . .
AB0481 Demonstrated, quantifiable benefits in patient reported outcomes supporting a “treat to target” paradigm for infliximab-treated RA patients previously inadequately responsive to prior anti-TNF treatment:
Authors: M. Ingham, L. Tang, D. Decktor, R. Bolce, J. Wang
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> ACR and EULAR jointly released Treat-to-target (T2T) recommendations in 2010. Clinical Disease Activity Index (CDAI) has been recommended for use in practice, if thresholds are applied. CDAI cut points have been previously published. <h3>Objectives</h3> Quantify the relative difference in improvement in pt reported outcomes between RA pts achieving different T2T-related goals vs. those who do not. <h3>Methods</h3> This is a post hoc analysis of the RESTART trial, where mean (SD) CDAI at baseline was 40.1 (12.38) and 95% of pts had a baseline CDAI&gt;22. RESTART is an active switch study. Pts were treated with IFX for 22 wks and clinicians allowed to dose escalate at fixed intervals to achieve a EULAR response. In this analysis, multiple analytical subgroups were defined using published CDAI thresholds. Given the relatively high baseline CDAI scores, subgroup definitions included goals of low or moderate disease activity, with or without significant improvement in CDAI. Subgroup response thresholds at Wk 26 included published specific cut points of: CDAI≤22 (Subgroup A); CDAI≤22 <i>and</i> CDAI reduction of at least 16.1 points (Subgroup B); CDAI≤10 (Subgroup C). Within each sub group, responder vs non-responder cohorts were then compared on HAQ scores and all domains of the SF-36 health status questionnaire. Missing data were not imputed. Descriptive statistics and a non-parametric Wilcoxon test were used to compare the change from baseline to Wk 26 in HAQ or SF-36 domains between cohorts. <h3>Results</h3> Responders in Subgroups A to C typically experienced at least twice the level of absolute improvement from baseline to Wk 26, in 7 of 8 SF-36 domains vs. non-responders, and 2 to 6 times greater improvement in HAQ. Pts attaining low disease activity (Subgroup C) experienced the greatest differences. For Subgroup B (Table 1), where cohorts had the most comparable baseline scores, results were statistically significant for HAQ (p=0.0079) and 5 of 8 SF-36 domains (p&lt;0.05 except, general health, role-emotional and mental health domains). <h3>Conclusions</h3> Pts able to attain T2T-related response achieved significantly greater absolute improvement in health status vs. non-responders, in HAQ and 5 of 8 SF-36 domains. There may be additional value in adding change scores to threshold values in current T2T objectives for severe pts and consideration of pt functionality may be warranted. <h3>References</h3> Smolen JS et al. Ann Rheum Dis; 69:631-637. Aletaha D et al. EULAR/ACR collaborative recommendations, 2008. Ann Rheum Dis; 67:1360-64. Fleischmann R, et al. ACR 2010. Abstract 420 <h3>Disclosure of Interest</h3> None Declared
Abstract 2296: Aldose reductase inhibition prevents human colon cancer cells growth by miR-21 and FOXO3a-mediated regulation of PTEN
Authors: Satish K. Srivastava, Ashish Saxena, Kota V. Ramana
Journal: Cancer Research (2012)

Abstract We have shown earlier that the inhibition of aldose reductase (AR), a NADPH-dependent aldo-keto reductase, prevents growth factor-induced proliferation of colon cancer cells in vitro and in vivo. Recent studies indicate that changes in microRNA (miRNA) expression can contribute to cancer by modulating the functional expression of critical genes involved in cancer growth and metastasis. However, the molecular mechanism(s) by which AR regulates miRNA expression and their dependent mitogenic effects in cancer cells is not known. Therefore, we investigated how AR regulates growth factor -induced expression of miRNAs in colon cancer cells. Our results indicate that inhibition of AR significantly down-regulated growth factor-induced miR-21 expression in HT29, SW480 and Caco-2 human colon cancer cells. Further, AR inhibition also increased PTEN, a direct target of miR-21 that contributes cancer cell growth and invasion. Inhibition of AR also prevented the EGF-induced phosphorylation of PTEN and FOXO3a, which prevents cell proliferation. Treatment of human colon cancer cells with AR inhibitor, fidarestat, prevented the EGF-induced DNA binding activity of AP1, phosphorylation of PI3K, AKT, c-Jun and c-Fos. More importantly, in HT29 human colon adenocarcinoma xenograft tissues, miR-21 expression was lower, and PTEN and FOXO3a levels were significantly higher in AR inhibitor-treated mice compared to controls. Collectively, these results show a novel role of AR in mediation of growth factor-induced colon cancer cell proliferation by increasing miR-21 expression and inactivating or decreasing PTEN and FOXO3a through the ROS/PI3K/AKT/AP1 pathway, indicating that AR inhibitors could be used for the prevention/therapy of colon carcinogenesis. 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 2296. doi:1538-7445.AM2012-2296
PMO-052 Sleeve gastrectomy for obesity: a systematic review
Authors: J Al Shakarchi
Journal: Gut (2012)

<h3>Introduction</h3> Sleeve gastrectomy has become an accepted and popular bariatric procedure world wide. Weight loss is achieved through restrictive and endocrine mechanisms. We aimed to evaluate the efficiency of excess weight loss by sleeve gastrectomy and to compare it to other bariatric procedures. <h3>Methods</h3> We searched the Cochrane Database of Systematic Reviews and Pubmed for studies assessing the efficiency of sleeve gastrectomy. Strict inclusion criteria and thorough appraisal of the reviews was required to ensure comparability of the included papers. <h3>Results</h3> Our dataset comprised of individual data on 1845 patients from 27 different studies. The median difference in excess body weight loss across the 27 studies which reported weight loss was a significant difference of 56.2% (range 33–85). The mean mortality rate reported from the studies was 0.16%. The major postoperative complication rate ranged from 0% to 23.8%. <h3>Conclusion</h3> From the data we have gathered it may be reasonable to conclude that sleeve gastrectomy is an efficient procedure which achieves comparable if not better excess weight loss to both gastric bypass and banding. It may be achieved safely and has similar complication rates to other bariatric procedures. However there is currently little data assessing long term outcomes of the procedure. <h3>Competing interests</h3> None declared.
Successful treatment with anti-tumor necrosis factor alpha for reactive small-bowel amyloidosis
Authors: C. Lee, J. Park, J.-J. Shim, J. Jang
Journal: Endoscopy (2011)

A 62-year-old woman who was taking naproxen, methotrexate, and leflunomide for treatment of long-standing, poorly controlled rheumatoid arthritis was admitted because of a 4-week history of watery diarrhea and abdominal pain. Laboratory studies revealed the following results: leukocytes 16.5 × 109/L, hemoglobin 9.8 g/dL, platelets 899 × 109/L, total protein 62 g/L, albumin 29 g/L, and C-reactive protein 334 mg/L. Tests of renal function were normal. On the second hospital day, she developed fever and received broad-spectrum antibiotics, but she deteriorated clinically over the next three days. Multiple stool tests gave negative results for bacterial infection. Endoscopic examinations showed marked submucosal edema and hemorrhagic erosions in the deep part of the duodenum and ileum ([Fig. 1 a]), and multiple biopsy specimens revealed amyloid A (AA) protein deposition. A diagnosis of small-bowel AA amyloidosis associated with rheumatoid arthritis was made ([Fig. 2]).
ATPS-61NEW SMALL MOLECULES THAT KILL HYPOXICALLY TRANSFORMED GLIOMA STEM-LIKE CELLS
Authors: Nagarekha Pasupuleti, Anthony Valenzuela, Yamini Manohar, Dinesh Mahajan, Sundeep Dugar, Jann Sarkaria, Fredric Gorin
Journal: Neuro-Oncology (2015)

High grade gliomas (HGGs) are lethal brain cancers, accounting for 78% of adult onset primary CNS malignancies. HGGs are resistant to current conventional therapies, including radiation therapy (RT), chemotherapy, and treatment with anti-angiogenic agents. Populations of cancer cells surviving these treatments regenerate leading to recurrence in more than 95% of patients. Spontaneous tumor necrosis within avascular tumor domains imparts poor clinical prognosis as glioma cells are reprogrammed by hypoxic transcription factors to adopt ‘stem-cell’ like properties; commonly referred to as glioma ‘stem-like’ cells (GSCs). GSCs possess several properties of normal stem cells, including self-aggregation, expression of stem cell markers, ability to survive in hypovascularized tumor regions, ability to survive detachment, and most importantly, the ability of tumor regrowth. GSCs can stop proliferating in hypoxic and acidic perinecrotic regions, which increases their resistance to RT and conventional anti-mitotic therapies. Hypoxically reprogrammed GSCs represent an important drug target to prevent the recurrence of HGGs. Drug targeting of hypovascularized GSCs is challenging as acidic and hypoxic tumor domains promote cell cycle arrest. Thus, therapeutic agents must be cytotoxic, not cytostatic, and need to kill independently of proliferative status. We developed novel small molecules that triggers ‘mis-trafficking’ of endosomes containing urokinase protein cargo in HGGs, and killing non-proliferating and proliferating glioma cells by an irreversible caspase-independent necrotic pathway. We identified that more than 90% of glioma cells within 22 patient derived xenografts (PDX) express intracellular PAI-1 and uPA and that 40-80% of these cells co-express the pluripotent stem cell transcription factors Oct4 and Nanog. Our lead small molecule crosses the intact rodent BBB and selectively kills glioma cells within intracerebral PDX glioma xenografts (PDX). The anti-glioma cytotoxicities of these small molecules is cell cycle independent, unaffected by hypoxia, and could represent an effective adjunctive therapy to be combined with radiotherapy, anti-mitotic, and/or anti-angiogenic therapies.
ASSOCIATION BETWEEN GALECTIN-3, RENAL FUNCTION AND NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN IN ISCHEMIC HEART FAILURE PATIENTS
Authors: Evangelos Oikonomou, Gerasimos Siasos, Sotirios Tsalamandris, Christine Chrysohoou, Antigoni Miliou, Aimilios Kalampogias, Alexis Antonopoulos, Christina Mpiri, Theodoros Zografos, Georgios Marinos, Manolis Vavuranakis, Dimitris Tousoulis
Journal: Journal of the American College of Cardiology (2016)
The Intravenous Glucose-Tolerance Test in Liver Disease
Authors: James A. Campbell, Henry J. Tagnon
Journal: New England Journal of Medicine (1946)

THE liver plays an important role in the metabolism of carbohydrates. Clinical investigators have frequently reported observations of disturbed carbohydrate metabolism in the presence of liver disease,1 2 3 4 5 6 and numerous studies have been made of the metabolic alterations found in experimental animals with liver damage induced either by toxic agents or by partial or total hepatectomy.7 8 9 The possibility that alteration of liver function enters into the production of the diabetic syndrome has been considered by many authors, and several reports have been published that emphasize the possible role of the liver in the etiology and pathogenesis of diabetes mellitus in human . . .