tbuckley/cabot-search huggingface dataset:
Treatment Escalation and Rise in HbA1c Following Successful Initial Metformin Therapy
Authors: Gregory A. Nichols, Charles M. Alexander, Cynthia J. Girman, Sachin J. Kamal-Bahl, Jonathan B. Brown
Journal: Diabetes Care (2006)

OBJECTIVE—To describe secondary failure of initial metformin therapy in patients who achieved initial HbA1c (A1C) &amp;lt;8% and to identify predictors of failure. RESEARCH DESIGN AND METHODS—We identified 1,288 patients who achieved A1C &amp;lt;8% within 1 year of initiating metformin as their first-ever antihyperglycemic drug. Subjects were followed until they added/switched antihyperglycemics, they terminated health plan membership, or 31 December 2004. We defined secondary failure using two separate but overlapping approaches: 1) addition/switch to another antihyperglycemic drug or 2) first A1C measurement &amp;gt;8.0% after at least 6 months on metformin. RESULTS—The best A1C achieved within 1 year of metformin initiation was the most powerful predictor of avoiding secondary failure. Approximately 50% of subjects whose best A1C was 7–7.9% added/switched antihyperglycemic drugs within 36 months, whereas it took &amp;gt;60 months for those in the 6–6.9% A1C category to reach a 50% failure rate. Those who achieved an A1C &amp;lt;6% did not reach a 50% rate of adding/switching drugs until 84 months. For the alternative secondary failure outcome, about half of those whose best A1C was 7.0–7.9% reached an A1C &amp;gt;8% within 24 months. Only ∼25% of subjects in the 6–6.9% category failed by 48 months, and &amp;gt;80% of subjects in the &amp;lt;6% category remained below 8% through 60 months. CONCLUSIONS—Whether defined by adding/switching to another drug or by reaching an A1C of 8%, secondary failure is inversely associated with the reduction of A1C achieved within the 1st year of metformin monotherapy.
Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity
Authors: Katrin S. Reiners, Daniela Topolar, Alexander Henke, Venkateswara R. Simhadri, Jörg Kessler, Maike Sauer, Martina Bessler, Hinrich P. Hansen, Samir Tawadros, Marco Herling, Martin Krönke, Michael Hallek, Elke Pogge von Strandmann
Journal: Blood (2013)
Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus
Authors: Zhan Su, Laura J Gay, Amy Strange, Claire Palles, Gavin Band, David C Whiteman, Francesco Lescai, Cordelia Langford, Manoj Nanji, Sarah Edkins, Anouk van der Winkel, David Levine, Peter Sasieni, Céline Bellenguez, Kimberley Howarth, Colin Freeman, Nigel Trudgill, Art T Tucker, Matti Pirinen, Maikel P Peppelenbosch, Luc J W van der Laan, Ernst J Kuipers, Joost P H Drenth, Wilbert H Peters, John V Reynolds, Dermot P Kelleher, Ross McManus, Heike Grabsch, Hans Prenen, Raf Bisschops, Kausila Krishnadath, Peter D Siersema, Jantine W P M van Baal, Mark Middleton, Russell Petty, Richard Gillies, Nicola Burch, Pradeep Bhandari, Stuart Paterson, Cathryn Edwards, Ian Penman, Kishor Vaidya, Yeng Ang, Iain Murray, Praful Patel, Weimin Ye, Paul Mullins, Anna H Wu, Nigel C Bird, Helen Dallal, Nicholas J Shaheen, Liam J Murray, Konrad Koss, Leslie Bernstein, Yvonne Romero, Laura J Hardie, Rui Zhang, Helen Winter, Douglas A Corley, Simon Panter, Harvey A Risch, Brian J Reid, Ian Sargeant, Marilie D Gammon, Howard Smart, Anjan Dhar, Hugh McMurtry, Haythem Ali, Geoffrey Liu, Alan G Casson, Wong-Ho Chow, Matt Rutter, Ashref Tawil, Danielle Morris, Chuka Nwokolo, Peter Isaacs, Colin Rodgers, Krish Ragunath, Chris MacDonald, Chris Haigh, David Monk, Gareth Davies, Saj Wajed, David Johnston, Michael Gibbons, Sue Cullen, Nicholas Church, Ruth Langley, Michael Griffin, Derek Alderson, Panos Deloukas, Sarah E Hunt, Emma Gray, Serge Dronov, Simon C Potter, Avazeh Tashakkori-Ghanbaria, Mark Anderson, Claire Brooks, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Audrey Duncanson, Hugh S Markus, Christopher G Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas Wood, Gosia Trynka, Cisca Wijmenga, Jean-Baptiste Cazier, Paul Atherfold, Anna M Nicholson, Nichola L Gellatly, Deborah Glancy, Sheldon C Cooper, David Cunningham, Tore Lind, Julie Hapeshi, David Ferry, Barrie Rathbone, Julia Brown, Sharon Love, Stephen Attwood, Stuart MacGregor, Peter Watson, Scott Sanders, Weronica Ek, Rebecca F Harrison, Paul Moayyedi, John de Caestecker, Hugh Barr, Elia Stupka, Thomas L Vaughan, Leena Peltonen, Chris C A Spencer, Ian Tomlinson, Peter Donnelly, Janusz A Z Jankowski
Journal: Nature Genetics (2012)
Childhood eosinophilic fasciitis presenting as inflammatory polyarthritis and associated with selective IgA deficiency.
Authors: D W Ching, J P Petrie
Journal: Annals of the Rheumatic Diseases (1991)

A 13 year old school boy presented with seronegative inflammatory polyarthritis after a flu-like illness. Four months later clinical features of eosinophilic fasciitis became apparent. After histological diagnosis treatment was started with prednisone 40 mg daily, with a good response. Routine investigations showed persistent selective IgA deficiency.
Mutant allele frequency predicts the efficacy of EGFR-TKIs in lung adenocarcinoma harboring the L858R mutation
Authors: A. Ono, H. Kenmotsu, M. Watanabe, M. Serizawa, K. Mori, H. Imai, T. Taira, T. Naito, H. Murakami, T. Nakajima, Y. Ohde, M. Endo, N. Yamamoto, Y. Koh, T. Takahashi
Journal: Annals of Oncology (2014)
Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes
Authors: David K. Finlay, Linda V. Sinclair, Carmen Feijoo, Caryll M. Waugh, Thijs J. Hagenbeek, Hergen Spits, Doreen A. Cantrell
Journal: The Journal of Experimental Medicine (2009)

In normal T cell progenitors, phosphoinositide-dependent kinase l (PDK1)–mediated phosphorylation and activation of protein kinase B (PKB) is essential for the phosphorylation and inactivation of Foxo family transcription factors, and also controls T cell growth and proliferation. The current study has characterized the role of PDK1 in the pathology caused by deletion of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN). PDK1 is shown to be essential for lymphomagenesis caused by deletion of PTEN in T cell progenitors. However, PTEN deletion bypasses the normal PDK1-controlled signaling pathways that determine thymocyte growth and proliferation. PDK1 does have important functions in PTEN-null thymocytes, notably to control the PKB–Foxo signaling axis and to direct the repertoire of adhesion and chemokine receptors expressed by PTEN-null T cells. The results thus provide two novel insights concerning pathological signaling caused by PTEN loss in lymphocytes. First, PTEN deletion bypasses the normal PDK1-controlled metabolic checkpoints that determine cell growth and proliferation. Second, PDK1 determines the cohort of chemokine and adhesion receptors expressed by PTEN-null cells, thereby controlling their migratory capacity.
Association of a Functional Deficit of the BK<sub>Ca</sub>Channel, a Synaptic Regulator of Neuronal Excitability, With Autism and Mental Retardation
Authors: Frédéric Laumonnier, Sébastien Roger, Pascaline Guérin, Florence Molinari, Ridha M’Rad, Dominique Cahard, Ahlem Belhadj, Mohamed Halayem, Antonio M. Persico, Maurizio Elia, Valentino Romano, Sébastien Holbert, Christian Andres, Habiba Chaabouni, Laurence Colleaux, Jacques Constant, Jean-Yves Le Guennec, Sylvain Briault
Journal: American Journal of Psychiatry (2006)

Autism is a complex, largely genetic psychiatric disorder. In the majority of cases, the cause of autism is not known, but there is strong evidence for a genetic etiology. To identify candidate genes, the physical mapping of balanced chromosomal aberrations is a powerful strategy, since several genes have been characterized in numerous disorders. In this study, the authors analyzed a balanced reciprocal translocation arising de novo in a subject with autism and mental retardation.The authors performed the physical mapping of the balanced 9q23/10q22 translocation by fluorescent in situ hybridization experiments using bacterial artificial chromosome clones covering the areas of interest.Findings revealed that the KCNMA1 gene, which encodes the alpha-subunit of the large conductance Ca(2+)-activated K(+) (BK(Ca)) channel, a synaptic regulator of neuronal excitability, is physically disrupted. Further molecular and functional analyses showed the haploinsufficiency of this gene as well as decreased activity of the coded BK(Ca )channel. This activity can be enhanced in vitro by addition of a BK(Ca )channel opener (BMS-204352). Further mutational analyses on 116 autistic subjects led to the identification of an amino acid substitution located in a highly conserved domain of the protein not found in comparison subjects.These results suggest a possible association between a functional defect of the BK(Ca) channel and autistic disorder and raise the hypothesis that deficits in synaptic transmission may contribute to the physiopathology of autism and mental deficiency.
Autoantibodies to Annexin XI-A and Other Autoantigens in the Diagnosis of Breast Cancer
Authors: Félix Fernández-Madrid, Naimei Tang, Huda Alansari, José L. Granda, Larry Tait, Kathryn C. Amirikia, Mihail Moroianu, Xiaoju Wang, Robert L. Karvonen
Journal: Cancer Research (2004)

Abstract We report on the identification of autoantigens commonly recognized by sera from patients with breast cancer. We selected ten sera from patients with invasive ductal carcinoma (IDC) of the breast with high titer IgG autoantibodies for biopanning of a T7 phage breast cancer cDNA display library. A high throughput method involved the assembly of 938 T7 phages encoding potential breast cancer autoantigens. Microarrays of positive phages were probed with sera from 90 patients with breast cancer [15 patients with ductal carcinoma in situ (DCIS) and 75 patients with IDC of the breast], with 51 non-cancer control sera and with sera from 21 patients with systemic autoimmune diseases. A 12-phage breast cancer predictor group was constructed with phage inserts recognized by sera from patients with breast cancer and not by non-cancer or autoimmune control sera (P &amp;lt; 0.0001). Several autoantigens including annexin XI-A, the p80 subunit of the Ku antigen, ribosomal protein S6, and other unknown autoantigens could significantly discriminate between breast cancer and non-cancer control sera. Biopanning with three different sera led to the cloning of partial cDNA sequences identical to annexin XI-A. IgG autoantibodies reacting with the amino acid 41–74 sequence of annexin XI-A were found in 19% of all women with breast cancer but in 60% of sera from women with DCIS of the breast. In addition, partial sequences identical to annexin XI-A, nucleolar protein interacting with the forkhead-associated (FHA) domain of pKi-67, the KIAA1671 gene product, ribosomal protein S6, cyclin K, elongation factor-2, Grb2-associated protein 2, and other unknown proteins could distinguish DCIS from IDC of the breast and appear to be potential biomarkers for the diagnosis of breast cancer.
Effects of Chemotherapy on the Cytogenetic Constitution of Wilms' Tumor
Authors: Thorsten Schlomm, Bastian Gunawan, Hans-Jürgen Schulten, Björn Sander, Karthinathan Thangavelu, Norbert Graf, Ivo Leuschner, Rolf-Hermann Ringert, László Füzesi
Journal: Clinical Cancer Research (2005)

Abstract The management of Wilms' tumors consists of a combination of surgery, chemotherapy, and possibly radiotherapy. To date, chemotherapy is being risk stratified according to histologic subtype and stage. Although the cytogenetic characteristics of Wilms' tumors are well established, the cytogenetic effects related to chemotherapy are widely unknown. We herein report on comparative genomic hybridization findings in 41 primary Wilms' tumors of blastemal type, of which 19 had received preoperative chemotherapy (PCT group) and 22 did not (non-PCT group). Overall, imbalances could be detected in 32 tumors, with +1q (17 cases), +7q (10 cases), +7p (6 cases), and −7p (6 cases) as the most common changes. Among these, +7q and −7p were both significantly associated with metastatic disease at the time of surgery (P = 0.002 and 0.007, respectively), and +7q was also associated with higher stage (stages III + IV; P = 0.003). There were significant differences in the cytogenetic constitution of tumors between the two treatment groups. As a trend, tumors in the preoperative-chemotheraphy group had fewer changes (mean, 2.7) than those in the non-preoperative-chemotheraphy group (mean, 3.8), and the frequencies of imbalances at 7p or +7q, respectively, were significantly lower compared with tumors in the non-preoperative-chemotheraphy group (2 of 19 versus 10 of 22, P = 0.019; 1 of 19 versus 9 of 22, P = 0.011). In contrast, −1q was common in both the preop-CT group (10 of 19) and the non-preop-CT group (7 of 22). The results suggest that Wilms' tumor clones with +1q are not obliterated by preoperative chemotherapy, whereas cytogenetically more complex clones with +7q and/or imbalances at 7p seem more responsive and are more likely to be eliminated by chemotherapeutic treatment.
Mental Stress Induces Prolonged Endothelial Dysfunction via Endothelin-A Receptors
Authors: Lukas E. Spieker, David Hürlimann, Frank Ruschitzka, Roberto Corti, Frank Enseleit, Sidney Shaw, Daniel Hayoz, John E. Deanfield, Thomas F. Lüscher, Georg Noll
Journal: Circulation (2002)

Background — Mental stress is a risk factor for atherosclerosis and may precipitate myocardial ischemia and infarction. Because endothelial dysfunction is an early manifestation of atherosclerosis, we investigated the impact of mental stress on endothelial function. Methods and Results — The effects of a 3-minute mental stress task on endothelium-dependent vasodilation were studied in healthy subjects without cardiovascular risk factors. Flow-mediated (FMD) and nitroglycerin (0.4 mg sublingual)-induced vasodilation were studied before and after mental stress by high-resolution ultrasound of the radial artery. Additionally, FMD was assessed before and 10 to 45 minutes after mental stress during intraarterial infusion of a selective endothelin A receptor antagonist (BQ-123, 1 nmol/min) or saline, respectively. Endothelium-dependent vasodilation was reduced by half for about 45 minutes (8.0±1.1% versus 4.1±1.0%; P &lt;0.002), whereas endothelium-independent vasodilation to nitroglycerin remained unaffected (15.6±1.6 versus 14.3±1.3%; NS). Intraarterial infusion of BQ-123, a selective endothelin-A receptor antagonist, but not saline prevented the impairment of endothelium-dependent vasodilation (8.6±1.2 versus 9.4±1.3%; NS). In contrast, intraarterial infusion of norepinephrine of similar duration as mental stress did not inhibit FMD. Conclusions — Mental stress induces prolonged endothelial dysfunction, which is prevented by selective endothelin-A receptor antagonism. This represents a novel and important link between mental stress and atherosclerotic vascular disease.
Specific action of the lipoxygenase pathway in mediating angiotensin II-induced aldosterone synthesis in isolated adrenal glomerulosa cells.
Authors: J L Nadler, R Natarajan, N Stern
Journal: Journal of Clinical Investigation (1987)

Angiotensin II (AII) in adrenal glomerulosa cells activates phospholipase C resulting in the formation of inositol phosphates and diacylglycerol rich in arachidonic acid (AA). Although glomerulosa cells can metabolize AA via cyclooxygenase (CO), this pathway plays little role in aldosterone synthesis. Recent evidence suggests that the lipoxygenase (LO) pathway may be important for hormonal secretion in endocrine tissues such as the islet of Langerhans. However, the capacity of the glomerulosa cell to synthesize LO products and their role in aldosterone secretion is not known. To study this, the effect of nonselective and selective LO inhibitors on AII, ACTH, and potassium-induced aldosterone secretion and LO product formation was evaluated in isolated rat glomerulosa cells. BW755c, a nonselective LO inhibitor dose dependently reduced the AII-stimulated level of aldosterone without altering AII binding (91 +/- 6 to 36 +/- 4 ng/10(6) cells/h 10(-4) M, P less than 0.001). The same effect was observed with another nonselective LO blocker, phenidone, and a more selective 12-LO inhibitor, Baicalein. In contrast U-60257, a selective 5-LO inhibitor did not change the AII-stimulated levels of aldosterone (208 +/- 11% control, AII 10(-9) M vs. 222 +/- 38%, AII + U-60257). The LO blockers action was specific for AII since neither BW755c nor phenidone altered ACTH or K+-induced aldosterone secretion. AII stimulated the formation of the 12-LO product 12-hydroxyeicosatetraenoic acid (12-HETE) as measured by ultraviolet detection and HPLC in AA loaded cells and by a specific RIA in unlabeled cells (501 +/- 50 to 990 +/- 10 pg/10(5) cells, P less than 0.02). BW755c prevented the AII-mediated rise in 12-HETE formation. In contrast, neither ACTH nor K+ increased 12-HETE levels. The addition of 12-HETE or its unstable precursor 12-HPETE (10(-9) or 10(-8) M) completely restored AII action during LO blockade. AII also produced an increase in 15-HETE formation, but the 15-LO products had no effect on aldosterone secretion. These studies suggest that the 12-LO pathway plays a key role as a new specific mediator of AII-induced aldosterone secretion.
Ischemia and reperfusion-induced arrhythmias in the rat. Effects of xanthine oxidase inhibition with allopurinol.
Authors: A S Manning, D J Coltart, D J Hearse
Journal: Circulation Research (1984)

We have investigated the possibility that xanthine oxidase-linked free radical production has a role in the genesis of arrhythmias during ischemia and reperfusion. In this study, rats were treated with allopurinol (20 mg/kg, orally, 24 hours before study, plus 20 mg/kg, iv, 15 minutes prior to study). Using an anesthetized open-chest preparation with either coronary artery occlusion for 30 minutes, or 5 minutes followed by 10 minutes reperfusion, we monitored and compared the rhythm disturbances in experimental vs. placebo-treated rats (n = 18 in each group). Allopurinol treatment reduced the incidence of ventricular tachycardia during ischemia from 88% to 50% (P less than 0.05) and the number of premature ventricular complexes from 471 +/- 120 to 116 +/- 46 (P less than 0.02), but the treatment had no effect upon the incidence or duration of ventricular fibrillation or upon mortality. In contrast, far more dramatic protection was observed during reperfusion after 5 minutes of ischemia. Allopurinol treatment reduced the incidence of ventricular fibrillation from 67% to 11% (P less than 0.01), reduced the mean duration of fibrillation from 230 +/- 70 to 14 +/- 1 seconds (P less than 0.05), and reduced mortality by half (10/18 to 4/18), although this did not reach a level of statistical significance. In addition, the mean duration of tachycardia was reduced from 83 +/- 26 to 38 +/- 8 seconds (P less than 0.05). Allopurinol pretreatment thus affords some protection against ischemia-induced arrhythmias, but a higher degree of protection against reperfusion-induced arrhythmias. Allopurinol inhibits xanthine oxidase activity, and, in turn, this inhibits superoxide radical production.(ABSTRACT TRUNCATED AT 250 WORDS)
Cancer-causing motifs
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

![Graphic][1] 

A mammary epithelial cell becomes transformed (bottom) after transfection with MMTV envelope protein.A conserved activation motif identified in the envelope (Env) protein of murine mammary tumor virus (MMTV) can drive transformation of mammary epithelial cells, according
Role of Muscular Contraction in the Reflex Vascular Responses to Stimulation of Muscle Afferents in the Dog
Authors: DENIS L. CLEMENT, CONRAD L. PELLETIER, JOHN T. SHEPHERD
Journal: Circulation Research (1973)

The effect of stimulation of somatic afferents from muscle was investigated in 24 anesthetized dogs. The carotid sinuses were isolated and kept at constant pressure, the vagi were cut, and the left iliac artery was isolated and perfused at constant flow. Muscle afferents were stimulated by either inserting electrodes into the muscles of the right thigh or stimulating the central end of the right femoral nerve. Muscle stimulation at 5 Hz decreased perfusion pressure in the iliac artery 76 ± 6 mm Hg (mean ± SE ); the decrease was not prevented by paralysis of the stimulated muscles, administration of atropine or antihistamines, or -receptor blockade. Muscle stimulation at 40 Hz increased perfusion pressure in the iliac artery 28 ± 3 mm Hg. This increase was prevented or changed to a depressor response by muscle paralysis. Similar effects were obtained with femoral nerve stimulation. Both depressor and pressor responses persisted after the leg had been skinned and the muscles had been separated from their tendons, but they were abolished by left sympathectomy. Thus, skeletal muscle contraction is necessary for activation of the muscle afferents which cause reflex vasoconstriction but not for activation of those which cause reflex vasodilatation.
Perturbation of upper gastrointestinal transit and antroduodenal motility by experimentally applied stress: the role of beta-adrenoreceptor mediated pathways.
Authors: J D O'Brien, D G Thompson, S J Day, W R Burnham, E Walker
Journal: Gut (1989)

IgG4-related disease is a rheumatological disorder, affecting multiple organ systems, and displaying dense lymphoplasmacytic inflammatory infiltrate and storiform fibrosis on histology. The pulmonary manifestations of IgG4-related disease are varied. Most commonly, bronchovascular consolidation and perilymphatic parenchymal thickening occur. IgG4-related disease can present as a solitary parenchymal mass and is often mistaken for a primary pulmonary or haematological malignancy. This report presents a case of IgG4-related disease in a patient with 6 months reported haemoptysis symptomatology and CT findings of perihilar lymphadenopathy, multiple pulmonary parenchymal nodules and a single parenchymal mass. Clinician cognisance of the histopathological presentation of IgG4-disease is important. It should be considered as a differential in patients for which investigations have ruled out malignancy, as it is responsive to glucocorticoids in the majority of cases.