tbuckley/cabot-search huggingface dataset:
Abstract 3368: Pre-clinical PK/PD/efficacy characterization of AZD1480, a JAK1/2 kinase inhibitor.
Authors: Patricia Schroeder
Journal: Cancer Research (2013)

Abstract Constitutive activation of the transcription factor STAT3, manifest as Y-705 phosphorylation, is a feature of many hematologically-derived and solid tumor malignancies. Accumulating evidence indicates that JAK kinases are the key mediators of STAT activation in solid tumor models. AZD1480, an inhibitor of Janus kinases 1 and 2 (JAK1/2), is a bioavailable small molecule whose inhibition of the JAK-STAT signalling pathway may provide clinical benefit by suppression of the pleiotropic tumorigenic effects of constitutive STAT3 activation (tumor cell proliferation, motility and survival, tumor angiogenesis, tumor immune suppression). Here we present a pre-clinical population-based effect-compartment pharmacokinetic / pharmacodynamic (PK/PD) model to describe the onset, intensity, and duration of pSTAT3 inhibition as a function of unbound concentration and time in the MDAH-2774 ovarian xenograft mouse model. A mathematical tumor growth inhibition model capturing the relationship between systemic exposure to AZD1480 and tumor growth inhibition was built to provide a pharmacokinetic rationale for tumor growth inhibition. Furthermore, the pSTAT3 inhibition PK/PD relationship for AZD1480 was quantitatively integrated into a tumor growth inhibition model providing a mechanistic pharmacodynamic rationale for tumor growth inhibition pre-clinically. Taken together, these pre-clinical data recommend that increasing inhibition of pSTAT3 correlates with greater tumor growth inhibition and provide a PK/PD/Efficacy platform of evidence for clinical hypothesis testing. Citation Format: Patricia Schroeder. Pre-clinical PK/PD/efficacy characterization of AZD1480, a JAK1/2 kinase inhibitor. [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 3368. doi:10.1158/1538-7445.AM2013-3368 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Mechanism of Adrenal-Steroid Reversal of Hypercalcemia in Multiple Myeloma
Authors: Michael Z. Lazor, Leon E. Rosenberg, Alnora Granger
Journal: New England Journal of Medicine (1964)

HYPERCALCEMIA is a frequent complication in multiple myeloma, occurring in 70 per cent of 72 cases reviewed by Gutman et al.1 It is well established that carbohydrate-active adrenocorticosteroid hormones are effective in reversing the hypercalcemia seen in multiple myeloma, but the mechanism of steroid action in this situation is not known. We have studied a patient with multiple myeloma who provided a unique opportunity to investigate several aspects of calcium metabolism before, during and after the spontaneous appearance of hypercalcemia. Baseline studies were done while the patient was normocalcemic. As shown in Figure 1, the patient became hypercalcemic while on the . . .
A Molecular Basis for Nicotine as a Gateway Drug
Authors: Eric R. Kandel, Denise B. Kandel
Journal: New England Journal of Medicine (2014)

Nearly all cocaine users are also smokers. Nicotine serves as a gateway drug to cocaine abuse. The Shattuck lecturers, Eric Kandel and Denise Kandel, reveal molecular pathways that explain the role of nicotine in enhancing cocaine effects.
Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease
Authors: Ottar Nygård, Jan Erik Nordrehaug, Helga Refsum, Per Magne Ueland, Mikael Farstad, Stein Emil Vollset
Journal: New England Journal of Medicine (1997)

Elevated plasma homocysteine levels are a risk factor for coronary heart disease, but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined.
TREATMENT WITH AN INORGANIC NITRIC OXIDE DONOR RECAPITULATES THE EFFECTS OF SARCOLEMMAL NNOS ON MUSCLE BLOOD FLOW REGULATION IN PATIENTS WITH BECKER MUSCULAR DYSTROPHY
Authors: Michael D. Nelson, O’Neil Mason, Florian Rader, Ryan Rosenberry, Avery Schwartz, Xiu Tang, Sarah Shidban, Neigena Mobaligh, Robert Elashoff, Thomas Stabler, Jason Allen, Evgeny Tsmirinov, Rita Barresi, Ronald Victor
Journal: Journal of the American College of Cardiology (2015)
Continuous Production of Carcinoembryonic Antigen in Hollow Fiber Cell Culture Units: Brief Communication 2 3
Authors: Gary S. David, Ralph A. Reisfeld, Tom H. Chino
Journal: JNCI Journal of the National Cancer Institute (1978)

A line of cultured cells derived from a primary human adenocarcinoma of the colon was grown in the extracapillary spaces of hollow fiber tissue culture units in the absence of serum components of high molecular weight (>10,000). The cells were capable of producing more than 30 μg of carcinoembryonic antigen (CEA) per day, provided that the extracapillary fluid was changed frequently. The concanavalin-A binding and molecular sieve chromatography properties of the tissue culture-derived CEA were similar to those of CEA isolated from metastatic colon cancer tissue.
Abstract 1263: Cellular senescence in Hodgkin's lymphoma
Authors: Jacob Gopas, Udi Zurgil, Estee Zeev, Daniel Benharoch, Jodi Ezratty, Giora Shubinsky, Etta Livneh
Journal: Cancer Research (2015)

Abstract Hodgkin's lymphoma (HL), a B cell originated malignancy of the immune system, is one of the most frequent lymphomas in the Western world. Although the rate of cure is high, about 20-35% of patients relapse, and about half of them eventually die of the disease or treatment-related late toxicities and secondary malignancies. Conceptually novel treatment strategies are thus needed, particularly for this category of patients. The malignant cells, called Hodgkin and Reed-Sternberg (HRS) cells, only make up 1-2% of the total tumor cellularity; the remaining mass comprising a mixed infiltrate population is thought to be recruited to the lymph node by HRS-driven pro-inflammatory signals. The origin of the pro-inflammatory signals remains elusive, and represents a critical gap in our knowledge of the pathogenesis of HL. We propose that a sub-population of HRS cells, which we call herein large RS cells, have characteristics of senescent cells, and, thus produce large amounts of inflammatory mediators (the so-called “senescence-associated secretory phenotype”, or SASP). Senescence is characterized by permanent cell cycle arrest and loss of proliferative capacity, despite continued viability and metabolic activity. We show that the senescence markers the cell cycle inhibitors p16INK4a and p21Cip1 are expressed in large RS cells in all HL biopsies examined. Moreover, the large RS cells are negative for Ki-67 staining, demonstrating that these cells have ceased to proliferate. We also show that large, ‘RS-like’ cells in a HL-derived line, L428, stained for the characteristic senescence marker β-galactosidase (β-gal). Oxidative stress and chemotherapy increased the proportion of β-gal positive large RS cells. Furthermore, we show that the large RS cells secrete high levels of cytokines. We suggest that these senescent RS cells may be responsible, at least in part, for creating a pro-inflammatory microenvironment, promoting HL pathogenesis, and mediating chemo-resistance in relapsed disease. Understanding the pathways important for the establishment of senescence in HRS cells, as well gaining insight into targetable mechanisms for the eradication of these cells, will provide new therapeutic approaches for HL patients with recurrent or chemo-resistant disease. Citation Format: Jacob Gopas, Udi Zurgil, Estee Zeev, Daniel Benharoch, Jodi Ezratty, Giora Shubinsky, Etta Livneh. Cellular senescence in Hodgkin's lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1263. doi:10.1158/1538-7445.AM2015-1263
The Effects of Omalizumab on the Late-Phase Response to Nasal and Skin Allergen Challenge
Authors: M.O. Paterniti, L.M. Breslin, J. Courneya, P.M. Sterba, M.E. Brummet, Y. Park, D.W. MacGlashan, B.S. Bochner, S.S. Saini
Journal: Journal of Allergy and Clinical Immunology (2012)
An Artifact Simulating Urinoma on Renal Transplant Imaging
Authors: A. M. OMAR, R. CUSTODIO, A. A. GAWISH, T. ALSAIED, A. H. ELGAZZAR
Journal: Clinical Nuclear Medicine (1999)

The authors describe a patient who received a renal transplant and had immediate postoperative radionuclide renal imaging that showed accumulation of activity during the study simulating a urine leak, which proved to be due to activity in a blood drainage bag that was in the field of view.
Benign Methylmalonic Aciduria
Authors: Fred D. Ledley, Harvey L. Levy, Vivian E. Shih, Rachel Benjamin, Maurice J. Mahoney
Journal: New England Journal of Medicine (1984)

Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency is usually considered to be a serious, often life-threatening disease. However, through routine screening of urine in neonates or screening of siblings of clinically affected neonates, we have identified eight children who have a benign clinical variant of this disorder. Their urinary methylmalonic acid levels have ranged from 1.0 to 3.4 mg per milligram of creatinine, with serum values ranging from an undetectable level to 1.7 mg per deciliter (130 nmol per liter). The children have not received dietary or vitamin therapy, have had normal growth and development (age range, 18 months to 13 years), and have performed as well as their unaffected siblings on psychometric testing. These children have no evidence of a deficiency of vitamin B12, which acts as a cofactor with methylmalonyl-CoA mutase, and they did not respond to the administration of vitamin B12. Two siblings were found by complementation analysis to have a defect in the methylmalonyl-CoA mutase apoenzyme; complementation analysis was not performed on the other patients. We conclude that the clinical spectrum of methylmalonyl-CoA mutase deficiency is wider than indicated by previously reported cases.
Abstract 4646: Toward engineering of novel anticancer bio-agents
Authors: GOPITKUMAR R. SHAH, Shane Wesener, Yi-Qiang Cheng
Journal: Cancer Research (2012)

Abstract Our research goal is to engineer the next generation of novel anticancer bio-agents that will target and eradicate a broad spectrum of solid tumors including breast cancer. Our research design was based on the hypotheses that (1) the next generation of bio-agents could be engineered to continuously produce doses of an anticancer drug (e.g. FK228 or tryprostatin) at the sites of bacterial spore germination and vegetative growth in the hypoxic/necrotic regions of solid tumors, and (2) the synergistic actions of bacterial consumption of tumor mass and anticancer drug activities could destroy many kinds of solid tumors regardless of cancer genotype, without the need for prodrug injections and could overcome the common side effects and less efficacy of current cancer therapies. Our research focuses on biosynthetic pathways of FK228 and tryprostatins. FK228 is an anticancer drug approved by FDA in 2009 in the name of Istodax® and acts as a potent histone deacetylase (HDAC) inhibitor. Tryprostatins are natural products of Aspergillus fumigatus BM939, with reported bioactivity as potent inhibitor of mammalian cell cycle and as an inhibitor of breast cancer resistance protein (BCRP). The specific aims of the project are (1) reconstitution of FK228 or tryprostatin biosynthetic pathways; (2) integration and expression of FK228 or tryprostatin biosynthetic genes in anaerobic/facultative anaerobic bacteria; (3) evaluation of antitumor efficacy of recombinant bacteria using animal model. In pilot experiments, we have succeeded in reconstituting the FK228 and tryprostatin biosynthetic gene cluster individually into E. coli using plasmid expression system and the engineered E. coli strains were able to express the genes and produced FK228 or tryprostatin under both aerobic and anaerobic fermentation conditions. Integration of the gene clusters into anaerobic/facultative anaerobic bacterial genome is in process. Successful integration and stable expression of anticancer compounds by bacteria would generate a new class of anticancer bio-agents that can target and eradicate solid tumors irrespective of genotypes. Project scheme: 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 4646. doi:1538-7445.AM2012-4646
THU0486 Peroxisome Proliferator Activated Receptorγ Anti-Fibrosis Mechanism in Connective Tissue Disease Related Interstitial Lung Disease
Authors: X. Pan, X. zhang, G. zhang
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Connective tissue disease (CTD) is a disease with a high incidence and a poor therapeutic effect. In recent years, in vitro and in vivo experimental studies have confirmed that the peroxisome proliferator-activated receptor γ (PPARγ) can interfere with the TGFβ1 pathway to play an anti-pulmonary fibrosis effect, but the exact mechanism is to be clarified. <h3>Objectives</h3> To study the anti-fibrotic function and mechanism of PPARγ in connective tissue disease-interstitial lung disease (CTD-ILD). <h3>Methods</h3> The expression of PPARγ in lungs was analyzed in 37 cases with CTD-ILD and 20 normal cases by immunohistochemistry. Changes in α-SMA levels were analyses by Western blot, and acetylation Smad3 and Smad3 or PPARγcombine with P300 were analysed by IP-WB. The data was analysed by One—Way ANOVA or t test. <h3>Results</h3> PPARγ'expression in the lung of CTD-ILD is lower than the control ( 1.341±1.348% vs 3.923±1.978%, p&lt;0.01 ). Different concentration of PPARγ(0, 1,5,10,20,40 ummol/l)ligand inhibited the marked elevation of the protein α-SMA induced by TGF-beta1 in a concentration-dependent manner(0.918±0.062 vs 0.852±0.042,0.725±0.057,0.678±0.042,0.418±0.022,0.456±0.029 ; P&gt;0.05, P&lt;0.05, P&lt;0.01, P&lt;0.01, P&lt;0.01), this response was blocked by a selective antagonist of PPARγsignaling GW9662 ( 0.946+0.087 vs 0.538+0.120, P&lt;0.01 ). Acetylation Smad3 expression was increased when TGFβ1 was putted into lung fibroblast after 60min, 90min and 180min ( 0.565±0.047, 1.127±0.101and 0.873±0.022 vs 0.614±0.407 ; all P&lt;0.05 ) ) the combination of Smad3 with P300 was also increased ( 1.461±0.118 vs 0.982±0.094, P&lt;0.05 ), but the ligand of PPAR γcan block the effect(P&lt;0.05). <h3>Conclusions</h3> PPARγmay play a physiologic role in the regulation of the anti-fibrosis response. Its function may be realized by its competition with Smad3 to combine with P300. <h3>References</h3> Kocheril S V, Appleton B E, Somers E C, et al. Comparison of disease progression and mortality of connective tissue disease-related interstitial lung disease and idiopathic interstitial pneumonia[J]. Arthritis Rheum, 2005,53(4):549-557. Park J H, Kim D S, Park I N, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes[J]. Am J Respir Crit Care Med, 2007,175(7):705-711. de Lauretis A, Veeraraghavan S, Renzoni E. Review series: Aspects of interstitial lung disease: connective tissue disease-associated interstitial lung disease: how does it differ from IPF? How should the clinical approach differ?[J]. Chron Respir Dis, 2011,8(1):53-82. <h3>Acknowledgements</h3> Thanks for my teacher xiaozhang, guangfengzhang <h3>Disclosure of Interest</h3> None Declared
Hypoxia and inflammation synergistically promote bone destruction
Authors: Shankar Revu, Vivekananda Gupta Sunkari, Akilan Krishnamurthy, Ileana Ruxandra Botusan, Sergiu-Bogdan Catrina, Anca I Catrina
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> Rheumatoid arthritis (RA) is a chronic inflammatory disease characterised by synovial inflammation and consecutive local hypoxia, leading to cartilage and bone destruction. Hypoxia promotes osteoclasts formation in vitro but its role in mediating bone destruction in the presence of chronic inflammation has not previously been investigated. The authors aimed to investigate the effect of hypoxia on the RANKL/OPG system and bone destruction in the presence of pro inflammatory stimuli. <h3>Methods</h3> The authors investigated the in vitro effect of hypoxia on RANKL/OPG expression in osteoblast-like (Saos2) cells. Cells were cultured in normoxic (21% pO<sub>2</sub>) or hypoxic (0.5% pO<sub>2</sub>) conditions with or without tumour necrosis factor α (TNFα). Expression of RANKL and OPG mRNA was detected by rtPCR. Cellular and soluble forms of RANKL and OPG proteins were determined by western blot and ELISA respectively. Hypoxia effect on bone resorption was evaluated in a dentine pit formation assay using peripheral blood mononuclear cells from RA patients. Statistical analysis was performed using one-way analysis of variance. <h3>Results</h3> Exposure to hypoxia induced a significant increase in cellular RANKL mRNA and protein expression, with minimal changes of the cellular OPG. In contrast soluble OPG levels significantly decreased following hypoxia exposure with no changes in the soluble levels of RANKL. Concomitant exposure to both hypoxia and TNFα had an additive effect resulting in a further increase of the RANKL/OPG ratio. Small interfering RNA against HIF 2α but not HIF 1α was able to abolish hypoxia effect on cellular RANKL expression. Hypoxia mimicking by prolyl hydroxylases inhibitors acted synergistically with TNF in inducing pit formation and resorption of synthetic osteologic bone discs. <h3>Conclusions</h3> TNF and hypoxia act synergistically to promote bone destruction potentially through a HIF2α dependent mechanism. These findings add on the current understanding of bone destruction in the setting of chronic inflammation.
HEMORRAGIA DIGESTIVA BAJA EN URGENCIAS. RENDIMIENTO DE LA RECTOSIGMOIDOSCOPIA EN UNA CONSULTA DE ALTA RESOLUCIÓN
Authors: P Fernández-Gil, J De la Peña-García, A Díaz-Pérez, J Cabezas-González, MA Bautista Henríquez, B Sampedro-Andrada
Journal: Endoscopy (2011)

Introducción: La hemorragia digestiva baja(HDB) es un frecuente motivo de consulta en Urgencias. La progresiva indicación de colonoscopias está generando listas de espera de difícil gestión. Hemos desarrollado una Consulta de Alta Resolución(CAR) para pacientes atendidos en Urgencias por HDB, que no cumplan criterios de ingreso, con valoración en Consulta(lunes) y exploración endoscópica (rectosigmoidoscopia/colonoscopia)a las 48h.
NO ASSOCIATED RISK OF INFECTIOUS ENDOCARDITIS WITH ROUTINE DENTAL CARE
Authors: Emil Fosbøl, Anders Dahl, Nikolaj Ihlemann, Louise Bruun, Lars Kober, Henning Bundgaard, Søren Fanø, Trine Lauridsen, Gunnar Gislason, Christian Torp-Pedersen
Journal: Journal of the American College of Cardiology (2016)
AB0816-PC Associations of autoimmune deseases with transient or permanent hip destruction
Authors: V. Mandrakos, M. Kyvernitakis, A. Poulis, I. Kyvernitakis, A. Kyvernitakis, S. Poulis, A.-F. Mandrakou
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Associations of autoimmune diseases with transient or permanent hip destructions <h3>ABSTACT</h3> Autoimmune diseases associated with partial or total destruction of bone cartilage and the bone morrow of the hip in high risk patients can lead to a transient or permanent disability of the joint. This condition may indicate a permanent handicap of the patient, an endoprothesis of the hip, insurance and health system costs as well as social restriction. <h3>Methods: METHODS</h3> Our working group including rheumatologists, orthopedic surgeons and gynecologists based on an 8 year experience conducted and investigated the impact of special therapy protocols, questionnaires on family case history and personal history for high risk factors (obesity, dyslipidemia, elevated uric acid and chronic pulmonary diseases) and habits as alcohol and smoking, medical charts of former diseases on patient outcome. Primary aim of this study was to investigate whether our protocol could prevent hip destruction based on diagnosis and therapy on time. <h3>Results: RESULTS</h3> We present: Tables Figures analyzing development of disease Figures presenting radiological findings before and after therapy <b>DISCUSSION</b> Analysis of the results Therapy protocols For cartilage For bone morrow For hip ischemia We investigate a total of 156 high risk patients. 16 patients (10.1%) presented additionally with an autoimmune disease (SLE, A.S., R.A., SJOGREN SYNDROME). Close patient surveillance was conducted over a period of 2 years. We conclude that apart from timely diagnosis, a therapy with the correct indication should include support of the cartilage, anti-resorptive therapy of the bone and prevention of hip ischemia. <h3>Disclosure of Interest</h3> None Declared
P380 EXPRESSION OF THE FIBROBLAST GROWTH FACTOR 19 (FGF19) IN THE LIVER CORRELATES WITH CLINICAL AND LABORATORY MEASURES IN PATIENTS WITH PRIMARY BILIARY CIRRHOSIS
Authors: E. Wunsch, M. Milkiewicz, A. Kempińska-Podhorodecka, J. Raszeja-Wyszomirska, J. Trottier, O. Barbier, P. Milkiewicz
Journal: Journal of Hepatology (2014)
Hepatic artery pseudoaneursym formation following intraductal biliary radiofrequency ablation
Authors: M. Topazian, M. Levy, S. Patel, M. Charlton, T. Baron
Journal: Endoscopy (2013)

A 73-year-old man with a history of liver transplantation developed cholestasis. No abnormality was seen on magnetic resonance imaging. Percutaneous cholangioscopy via a left-sided transhepatic tract ([Fig. 1]) demonstrated carpet-like villous change with biopsies showing high-grade dysplasia in the right and left ducts. Intraductal ultrasound (IDUS) showed a T1 lesion, with bile duct wall thickening to 2.4 mm. Radiofrequency ablation (RFA) was performed in the right and left hepatic ducts with an 8-French catheter (Habib EndoHPB, EMcision, Montreal, Canada) at 10 W for 90 seconds. Sixteen days later the patient presented with melena, requiring transfusion of 6 units packed red blood cells. Angiography showed a 1.2-cm pseudoaneurysm of the right hepatic artery, which was thrombosed with percutaneous thrombin injection. Subsequent cholangioscopy demonstrated successful ablation of the biliary dysplasia ([Fig. 1]). The close temporal relationship of RFA to pseudoaneurysm formation, and the absence of other apparent etiologies, implicate intraductal RFA as the likely cause.
The Importance of Circulating 1,25-Dihydroxyvitamin D in the Pathogenesis of Hypercalciuria and Renal-Stone Formation in Primary Hyperparathyroidism
Authors: Arthur E. Broadus, Ronald L. Horst, Robert Lang, E. Travis Littledike, Howard Rasmussen
Journal: New England Journal of Medicine (1980)

Original Article from The New England Journal of Medicine — The Importance of Circulating 1,25-Dihydroxyvitamin D in the Pathogenesis of Hypercalciuria and Renal-Stone Formation in Primary Hyperparathyroidism