tbuckley/cabot-search huggingface dataset:
The Rapid Changes of Hepatic Glycolytic Enzymes and Fructose-1, 6-Diphosphatase Activities after Intravenous Glucagon in Humans
Authors: H. L. Greene, O. D. Taunton, F. B. Stifel, R. H. Herman
Journal: Journal of Clinical Investigation (1974)

Glucagon (0.04-0.09 mg/kg/min) was given intravenously for either 2 or 3 min to eight patients with fasting-induced hypoglycemia. One child had hepatic phosphorylase deficiency, two children had glucose-6-phosphatase deficiency, two children had debrancher enzyme (amylo-1,6-glucosidase) deficiency, and two children and one adult had decreased hepatic fructose-1,6-diphosphatase (FDPase) activity. Liver biopsy specimens were obtained before and immediately after the glucagon infusion. The glucagon caused a significant increase in the activity of FDPase (from 50±10.0 to 72±11.7 nmol/mg protein/min) and a significant decrease in the activities of phosphofructokinase (PFK) (from 92±6.1 to 41±8.1 nmol/mg protein/min) and pyruvate kinase (PK) (from 309±39.4 to 165±23.9 nmol/mg protein/min). The glucagon infusion also caused a significant increase in hepatic cyclic AMP concentrations (from 41±2.6 to 233±35.6 pmol/mg protein). Two patients with debrancher enzyme deficiency who had biopsy specimens taken 5 min after the glucagon infusion had persistence of enzyme and cyclic AMP changes for at least 5 min. One child with glucose-6-phosphatase deficiency was given intravenous glucose (150 mg/kg/min) for a period of 5 min after the glucagon infusion and biopsy. The plasma insulin concentration increased from 8 to 152 μU/ml and blood glucose increased from 72 to 204 mg/100 ml. A third liver biopsy specimen was obtained immediately after the glucose infusion and showed that the glucagon-induced effects on PFK and FDPase were completely reversed. The glucagon infusion caused an increase in hepatic cyclic AMP concentration from 38 to 431 pmol/mg protein but the glucose infusion caused only a slight decrease in hepatic cyclic AMP concentration (from 431 to 384 pmol/mg protein), which did not appear to be sufficient to account for the changes in enzyme activities. Hepatic glucose-6-phosphatase and fructose-1,6-diphosphate aldolase activities were not altered by either the glucagon or the glucose infusion in any patients. Cyclic AMP (0.05 mmol/kg) was injected into the portal vein of adult rats and caused enzyme changes similar to those seen with glucagon administration in humans. Our findings suggest that rapid changes in the activities of PFK, PK, and FDPase are important in the regulation of hepatic glycolysis and gluconeogenesis, respectively, in humans and that cyclic AMP may mediate the glucagon- but probably not the glucose-insulin-induced changes in enzyme activities.
Impact of Viral and Bacterial Infectious Burden on Long-Term Prognosis in Patients With Coronary Artery Disease
Authors: Hans J. Rupprecht, Stefan Blankenberg, Christoph Bickel, Gerd Rippin, Gerd Hafner, Wilfried Prellwitz, Wolfgang Schlumberger, Jürgen Meyer
Journal: Circulation (2001)

The number of infectious pathogens to which an individual has been exposed (infectious burden) may correlate with coronary artery disease (CAD). In a prospective study, we evaluated the effect of 8 pathogens and the aggregate pathogen burden on the risk for future fatal cardiac events among patients with angiographically documented CAD. Methods and Results-In 1018 patients, IgG or IgA antibodies to herpes simplex virus types 1 and 2, cytomegalovirus, Epstein-Barr virus, Haemophilus influenzae, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Helicobacter pylori were determined. Moreover, highly sensitive C-reactive protein was measured. Follow-up information on cardiovascular events was obtained (mean 3.1 years, maximum 4.3 years). Seropositivities to Epstein-Barr virus (P=0.001), H pylori (P=0.002), and herpes simplex virus type 2 (P=0.045) were independently associated with the future risk of cardiovascular death. An increasing number for pathogen burden was significantly predictive of the long-term prognosis (P<0.0001). Infectious burden divided into 0 to 3, 4 or 5, and 6 to 8 seropositivities was associated with an increasing mortality of 3.7%, 7.2%, and 12.6%, respectively. Patients seropositive to >5 pathogens compared with those seropositive to <4 pathogens had a 5.1 (1.4 to 18.3) higher risk of future cardiac death. This result was mainly driven by the pathogen burden of seropositivities to Herpesviridae (P<0.0001). The prognostic impact of total or viral pathogen burden was independent of the C-reactive protein level.These results support the hypothesis that the number of infectious pathogens to which an individual has been exposed independently contributes to the long-term prognosis in patients with documented CAD.
Sequence variation in hepatitis C viral isolates
Authors: Amy J. Weiner, Cindy Christopherson, J.Eric Hall, Ferruccio Bonino, Giorgio Saracco, Maurizia R. Brunetto, Kevin Crawford, Christopher D. Marion, Kenneth A. Crawford, Shyamala Venkatakrishna, Tatsuo Miyamura, John McHutchinson, Theo Cuypers, Michael Houghton
Journal: Journal of Hepatology (1991)
Gonadal Function and Fertility in Survivors After Hodgkin Lymphoma Treatment Within the German Hodgkin Study Group HD13 to HD15 Trials
Authors: Karolin Behringer, Horst Mueller, Helen Goergen, Indra Thielen, Angelika Diana Eibl, Volker Stumpf, Carsten Wessels, Martin Wiehlpütz, Johannes Rosenbrock, Teresa Halbsguth, Katrin S. Reiners, Thomas Schober, Jorg H. Renno, Michael von Wolff, Katrin van der Ven, Marietta Kuehr, Michael Fuchs, Volker Diehl, Andreas Engert, Peter Borchmann
Journal: Journal of Clinical Oncology (2012)

Purpose To optimize fertility advice in patients with Hodgkin lymphoma (HL) before therapy and during survivorship, information on the impact of chemotherapy is needed. Therefore, we analyzed gonadal functions in survivors of HL. Patients and Methods Women younger than age 40 and men younger than 50 years at diagnosis in ongoing remission at least 1 year after therapy within the German Hodgkin Study Group HD13 to HD15 trials for early- and advanced-stage HL were included. Hormone parameters, menstrual cycle, symptoms of hypogonadism, and offspring were evaluated. Results A total of 1,323 (55%) of 2,412 contacted female and male survivors were evaluable for the current analysis (mean follow-up, 46 and 48 months, respectively). Follicle-stimulating hormone, anti-Müllerian hormone, and inhibin B levels correlated significantly with therapy intensity (P &lt; .001). Low birth rates were observed in survivors after advanced-stage treatment within the observation time (women, 6.5%; men, 3.3%). Regular menstrual cycle was reported by more than 90% of female survivors of early-stage HL (recovery time mostly ≤ 12 months). After six to eight cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, menstrual activity was strongly related to age (&lt; v ≥ 30 years: 82% v 45%, respectively; P &lt; .001; prolonged recovery time). Thirty-four percent of women age ≥ 30 years suffered severe menopausal symptoms (three- to four-fold more frequently than expected). In contrast, male survivors had mean levels of testosterone within the normal range and reported no increased symptoms of hypogonadism. Conclusion The present analysis in a large group of survivors of HL provides well-grounded information on gonadal toxicity of currently used treatment regimens and allows risk-adapted fertility preservation and comprehensive support during therapy and follow-up.
Recent Studies on Arthritis and Rheumatism in the United States
Authors: Philip S. Hench
Journal: Annals of the Rheumatic Diseases (1941)

THE RHEUMATIC DISEASES funds and potential are directed solely or chiefly to the rheumatic field.At the University of Michigan the Rackemann Foundation has provided for a comprehensive, long-range study of arthritis, and in New York a large hospital has been built and dedicated to the treatment of, and research in, chronic diseases, arthritis being one of the three diseases selected.In Boston the Lovett and Commonwealth Foundations, with large-scale assistance from the State of Massachusetts, have inaugurated basic studies, already bearing significant results.It is much too soon to attempt to evaluate all that is being accomplished in this connection, but it is fair to state that by the time peace returns to the world, be this soon or late, the members of the American Rheumatism Association will have a full message to deliver.It is at such a time that the postponed meeting of the Ligue Internationale contre le Rhumatisme should be held.Unusual stimulation will derive from renewing interchange of thought, and it is not too much to suppose that added impetus will also be given to those plans, which must then be formulated and executed, to bring about that stability which the world will then everywhere need.
ZNF238 Is Expressed in Postmitotic Brain Cells and Inhibits Brain Tumor Growth
Authors: Valérie M. Tatard, Chaomei Xiang, Jaclyn A. Biegel, Nadia Dahmane
Journal: Cancer Research (2010)

Brain tumors such as medulloblastoma (MB) and glioblastoma multiforme (GBM) can derive from neural precursors. For instance, many MBs are thought to arise from the uncontrolled proliferation of cerebellar granule neuron precursors (GNP). GNPs normally proliferate in early postnatal stages in mice but then they become postmitotic and differentiate into granule neurons. The proliferation of neural precursors, GNPs, as well as at least subsets of GBM and MB depends on Hedgehog signaling. However, the gene functions that are lost or suppressed in brain tumors and that normally promote the proliferation arrest and differentiation of precursors remain unclear. Here we have identified a member of the BTB-POZ and zinc finger family, ZNF238, as a factor highly expressed in postmitotic GNPs and differentiated neurons. In contrast, proliferating GNPs as well as MB and GBM express low or no ZNF238. Functionally, inhibition of ZNF238 expression in mouse GNPs decreases the expression of the neuronal differentiation markers MAP2 and NeuN and downregulates the expression of the cell cycle arrest protein p27, a regulator of GNP differentiation. Conversely, reinstating ZNF238 expression in MB and GBM cells drastically decreases their proliferation and promotes cell death. It also downregulates cyclin D1 while increasing MAP2 and p27 protein levels. Importantly, ZNF238 antagonizes MB and GBM tumor growth in vivo in xenografts. We propose that the antiproliferative functions of ZNF238 in normal GNPs and possibly other neural precursors counteract brain tumor formation. ZNF238 is thus a novel brain tumor suppressor and its reactivation in tumors could open a novel anticancer strategy.
The Lambeth Conventions: guidelines for the study of arrhythmias in ischaemia, infarction, and reperfusion
Authors: M J A WALKER, M J CURTIS, D J HEARSE, R W F CAMPBELL, M J JANSE, D M YELLON, S M COBBE, S J COKER, J B HARNESS, D W G HARRON, A J HIGGINS, D G JULIAN, M J LAB, A S MANNING, B J NORTHOVER, J R PARRATT, R A RIEMERSMA, E RIVA, D C RUSSELL, D J SHERIDAN, E WINSLOW, B WOODWARD
Journal: Cardiovascular Research (1988)

The Lambeth Conventions are guidelines intended to be of practical value in the investigation of arrhythmias induced by ischaemia, infarction, and reperfusion. They cover the design and execution of experiments and the definition, classification, quantification, and analysis of arrhythmias. Investigators are encouraged to adopt the conventions in the hope that this will improve uniformity and interlaboratory comparisons.
A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP
Authors: Gaetana Lanzi, Daniele Moratto, Donatella Vairo, Stefania Masneri, Ottavia Delmonte, Tiziana Paganini, Silvia Parolini, Giovanna Tabellini, Cinzia Mazza, Gianfranco Savoldi, Davide Montin, Silvana Martino, Pierangelo Tovo, Itai M. Pessach, Michel J. Massaad, Narayanaswamy Ramesh, Fulvio Porta, Alessandro Plebani, Luigi D. Notarangelo, Raif S. Geha, Silvia Giliani
Journal: The Journal of Experimental Medicine (2012)

A female offspring of consanguineous parents, showed features of Wiskott-Aldrich syndrome (WAS), including recurrent infections, eczema, thrombocytopenia, defective T cell proliferation and chemotaxis, and impaired natural killer cell function. Cells from this patient had undetectable WAS protein (WASP), but normal WAS sequence and messenger RNA levels. WASP interacting protein (WIP), which stabilizes WASP, was also undetectable. A homozygous c.1301C&amp;gt;G stop codon mutation was found in the WIPF1 gene, which encodes WIP. Introduction of WIP into the patient’s T cells restored WASP expression. These findings indicate that WIP deficiency should be suspected in patients with features of WAS in whom WAS sequence and mRNA levels are normal.
Whole Genome Sequencing versus Traditional Genotyping for Investigation of a Mycobacterium tuberculosis Outbreak: A Longitudinal Molecular Epidemiological Study
Authors: Andreas Roetzer, Roland Diel, Thomas A. Kohl, Christian Rückert, Ulrich Nübel, Jochen Blom, Thierry Wirth, Sebastian Jaenicke, Sieglinde Schuback, Sabine Rüsch-Gerdes, Philip Supply, Jörn Kalinowski, Stefan Niemann
Journal: PLoS Medicine (2013)

Understanding Mycobacterium tuberculosis (Mtb) transmission is essential to guide efficient tuberculosis control strategies. Traditional strain typing lacks sufficient discriminatory power to resolve large outbreaks. Here, we tested the potential of using next generation genome sequencing for identification of outbreak-related transmission chains.During long-term (1997 to 2010) prospective population-based molecular epidemiological surveillance comprising a total of 2,301 patients, we identified a large outbreak caused by an Mtb strain of the Haarlem lineage. The main performance outcome measure of whole genome sequencing (WGS) analyses was the degree of correlation of the WGS analyses with contact tracing data and the spatio-temporal distribution of the outbreak cases. WGS analyses of the 86 isolates revealed 85 single nucleotide polymorphisms (SNPs), subdividing the outbreak into seven genome clusters (two to 24 isolates each), plus 36 unique SNP profiles. WGS results showed that the first outbreak isolates detected in 1997 were falsely clustered by classical genotyping. In 1998, one clone (termed "Hamburg clone") started expanding, apparently independently from differences in the social environment of early cases. Genome-based clustering patterns were in better accordance with contact tracing data and the geographical distribution of the cases than clustering patterns based on classical genotyping. A maximum of three SNPs were identified in eight confirmed human-to-human transmission chains, involving 31 patients. We estimated the Mtb genome evolutionary rate at 0.4 mutations per genome per year. This rate suggests that Mtb grows in its natural host with a doubling time of approximately 22 h (400 generations per year). Based on the genome variation discovered, emergence of the Hamburg clone was dated back to a period between 1993 and 1997, hence shortly before the discovery of the outbreak through epidemiological surveillance.Our findings suggest that WGS is superior to conventional genotyping for Mtb pathogen tracing and investigating micro-epidemics. WGS provides a measure of Mtb genome evolution over time in its natural host context.
<i>PTEN</i> Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR
Authors: Martin L. Sos, Mirjam Koker, Barbara A. Weir, Stefanie Heynck, Rosalia Rabinovsky, Thomas Zander, Jens M. Seeger, Jonathan Weiss, Florian Fischer, Peter Frommolt, Kathrin Michel, Martin Peifer, Craig Mermel, Luc Girard, Michael Peyton, Adi F. Gazdar, John D. Minna, Levi A. Garraway, Hamid Kashkar, William Pao, Matthew Meyerson, Roman K. Thomas
Journal: Cancer Research (2009)

Clinical resistance to epidermal growth factor receptor (EGFR) inhibition in lung cancer has been linked to the emergence of the EGFR T790M resistance mutation or amplification of MET. Additional mechanisms contributing to EGFR inhibitor resistance remain elusive. By applying combined analyses of gene expression, copy number, and biochemical analyses of EGFR inhibitor responsiveness, we identified homozygous loss of PTEN to segregate EGFR-dependent and EGFR-independent cells. We show that in EGFR-dependent cells, PTEN loss partially uncouples mutant EGFR from downstream signaling and activates EGFR, thereby contributing to erlotinib resistance. The clinical relevance of our findings is supported by the observation of PTEN loss in 1 out of 24 primary EGFR-mutant non-small cell lung cancer (NSCLC) tumors. These results suggest a novel resistance mechanism in EGFR-mutant NSCLC involving PTEN loss.
Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a descriptive study
Authors: Lisa F Barcellos, Brinda B Kamdar, Patricia P Ramsay, Cari DeLoa, Robin R Lincoln, Stacy Caillier, Silke Schmidt, Jonathan L Haines, Margaret A Pericak-Vance, Jorge R Oksenberg, Stephen L Hauser
Journal: The Lancet Neurology (2006)
Phase II Multicenter Study of Abiraterone Acetate Plus Prednisone Therapy in Patients With Docetaxel-Treated Castration-Resistant Prostate Cancer
Authors: Daniel C. Danila, Michael J. Morris, Johann S. de Bono, Charles J. Ryan, Samuel R. Denmeade, Matthew R. Smith, Mary-Ellen Taplin, Glenn J. Bubley, Thian Kheoh, Christopher Haqq, Arturo Molina, Aseem Anand, Michael Koscuiszka, Steve M. Larson, Lawrence H. Schwartz, Martin Fleisher, Howard I. Scher
Journal: Journal of Clinical Oncology (2010)

Persistence of ligand-mediated androgen receptor signaling has been documented in castration-resistant prostate cancers (CRPCs). Abiraterone acetate (AA) is a potent and selective inhibitor of CYP17, which is required for androgen biosynthesis in the testes, adrenal glands, and prostate tissue. This trial evaluated the efficacy and safety of AA in combination with prednisone to reduce the symptoms of secondary hyperaldosteronism that can occur with AA monotherapy.Fifty-eight men with progressive metastatic CRPC who experienced treatment failure with docetaxel-based chemotherapy received AA (1,000 mg daily) with prednisone (5 mg twice daily). Twenty-seven (47%) patients had received prior ketoconazole. The primary outcome was > or = 50% prostate-specific antigen (PSA) decline, with objective response by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and changes in Eastern Cooperative Oncology Group (ECOG) performance status (PS) and circulating tumor cell (CTC) numbers. Safety was also evaluated.A > or = 50% decline in PSA was confirmed in 22 (36%) patients, including 14 (45%) of 31 ketoconazole-naïve and seven (26%) of 27 ketoconazole-pretreated patients. Partial responses were seen in four (18%) of 22 patients with RECIST-evaluable target lesions. Improved ECOG PS was seen in 28% of patients. Median time to PSA progression was 169 days (95% CI, 82 to 200 days). CTC conversions with treatment from > or = 5 to < 5 were noted in 10 (34%) of 29 patients. The majority of AA-related adverse events were grade 1 to 2, and no AA-related grade 4 events were seen.AA plus prednisone was well tolerated, with encouraging antitumor activity in heavily pretreated CRPC patients. The incidence of mineralocorticoid-related toxicities (hypertension or hypokalemia) was reduced by adding low-dose prednisone. The combination of AA plus prednisone is recommended for phase III investigations.
Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice
Authors: Moshe Elkabets, Ann M. Gifford, Christina Scheel, Bjorn Nilsson, Ferenc Reinhardt, Mark-Anthony Bray, Anne E. Carpenter, Karin Jirström, Kristina Magnusson, Benjamin L. Ebert, Fredrik Pontén, Robert A. Weinberg, Sandra S. McAllister
Journal: Journal of Clinical Investigation (2011)

Systemic instigation is a process by which endocrine signals sent from certain tumors (instigators) stimulate BM cells (BMCs), which are mobilized into the circulation and subsequently foster the growth of otherwise indolent carcinoma cells (responders) residing at distant anatomical sites. The identity of the BMCs and their specific contribution or contributions to responder tumor growth have been elusive. Here, we have demonstrated that Sca1+ cKit- hematopoietic BMCs of mouse hosts bearing instigating tumors promote the growth of responding tumors that form with a myofibroblast-rich, desmoplastic stroma. Such stroma is almost always observed in malignant human adenocarcinomas and is an indicator of poor prognosis. We then identified granulin (GRN) as the most upregulated gene in instigating Sca1+ cKit- BMCs relative to counterpart control cells. The GRN+ BMCs that were recruited to the responding tumors induced resident tissue fibroblasts to express genes that promoted malignant tumor progression; indeed, treatment with recombinant GRN alone was sufficient to promote desmoplastic responding tumor growth. Further, analysis of tumor tissues from a cohort of breast cancer patients revealed that high GRN expression correlated with the most aggressive triple-negative, basal-like tumor subtype and reduced patient survival. Our data suggest that GRN and the unique hematopoietic BMCs that produce it might serve as novel therapeutic targets.
Uterine leukocytes and decidualization
Authors: A. King
Journal: Human Reproduction Update (2000)

The transformation of endometrium into decidua is an essential feature of normal implantation and pregnancy. There is a close association with an unusual leukocyte population, uterine natural killer (NK) cells, and onset of decidualization. These uterine NK cells are seen in close contact with stromal cells ultrastructurally and are also seen encircling vessels and glands. The possibility that uterine NK cells in the late secretory phase and in early decidua may be important in initiating and maintaining decidualization is raised. In contrast, the death of uterine NK cells could be an early event in the onset of endometrial breakdown at menstruation. The period between implantation and menstruation (7–14 days after luteinizing hormone surge) is the time when implantation is known to be particularly vulnerable. In this review, the possibility that uterine leukocytes might influence the critical decision that the mid- to late secretory endometrium must make either to decidualize or to undergo menstruation is explored.
Increased airway osmolarity inhibits the action of nitric oxide in the rabbit
Authors: M Hogman, J Hjoberg, G Hedenstierna
Journal: European Respiratory Journal (1998)

Inhalation of nitric oxide (NO) is known to dilate preconstricted airways. In asthmatics, there are large variations in the effect of NO on airway tone. One explanation of these variations may be different degrees of airway wall oedema. The effect of NO inhalation on methacholine (meth)-induced airway constriction was investigated in a rabbit model. Oedema and a change in osmolarity of the airways was achieved by hypertonic saline nebulization and hyperventilation with dry gas. There was an increase in resistance to meth at a concentration of 3 mg x mL(-1), of 86+/-14 cmH2O x L(-1) x s (mean+/-SEM) after oedema formation, compared with 46+/-16 cmH2O x L(-1) x s without oedema. Inhalation of 80 parts per million (ppm) NO failed to counter the increase in resistance due to meth, 92+/-14 cmH2O x L(-1) x s after hypertonic saline nebulization. After hyperventilation of dry gas, the increase in resistance due to meth at 1 mg x mL(-1) was 27+/-11 cmH2O x L(-1) x s with 80 ppm NO and 28+/- 5 cmH2O x L(-1) x s without NO. In conclusion, the relaxant effect of nitric oxide-inhalation on the airway smooth muscle can be blocked by an increase in the osmolarity of the airway surface liquid. The mechanism of this inhibition of nitric oxide remains to be established.