tbuckley/cabot-search huggingface dataset:
Abstract LB-81: Conditional deletion of the tumor suppressor Hic1 results in aneuploidy and single-step transformation
Authors: Anette Szczepny, Lisa McKenzie, Samantha Jayesekara, Prue Russell, Gavin Wright, Stephen B. Baylin, Fernando J. Rossello, Jason E. Cain, David N. Watkins
Journal: Cancer Research (2014)

Abstract HIC1 is a zinc-finger transcriptional repressor frequently targeted for deletion and/or epigenetic gene silencing in cancer. In cancer cell lines, re-expression of HIC1 results in the downregulation of target genes thought to promote context-dependent tumor growth, including Sirt1, Atoh1, Efna1 and components of the WNT and STAT3 signalling pathway. In mouse embryonic fibroblasts, we now show that deletion of a conditional loxP allele of Hic1 results in immediate growth arrest without significant overexpression of Hic1 target genes, followed by a prolonged period of cellular quiescence. After several weeks, we then observed the spontaneous emergence of rapidly growing clones that fulfil all the criteria for transformation, associated with aneuploidy and recurrent copy number alterations. By contrast, conditional deletion of p53 using the same experimental protocol resulted in prompt immortalisation without transformation, and a stable tetraploid karyotype resembling that seen in NIH-3T3 cells. These data suggest that inactivation of Hic1 in cells undergoing replication stress in tissue culture can induce complete transformation associated with marked genomic instability. To test this hypothesis in vivo, we employed the inhaled adenoviral Cre recombinase model in order to direct loxP recombination to the airway epithelium of adult mice. As previously described by other groups, Cre activation of a conditional oncogenic KRasG12D mutant resulted in the appearance of multiple lung adenomas within 6-8 weeks following viral inhalation. By contrast, mice carrying this KRasG12D allele, as well as homozygous for the conditional Hic1lox knockout allele, developed highly aggressive adenocarcinomas with prominent pleomorphic and micropapillary histology. These data suggest a novel tumour suppressor role for HIC1 in maintaining genomic stability in replicating cells. HIC1 is known to interact with components of the SWI/SNF and PRC2 complexes, which help maintain genomic integrity by re-establishing constitutive heterochromatin following DNA replication. We therefore speculate that loss of HIC1 function may phenocopy recently described mutations in components of these chromatin-remodelling complexes such as ARID1A and BRG1. Citation Format: Anette Szczepny, Lisa McKenzie, Samantha Jayesekara, Prue Russell, Gavin Wright, Stephen B. Baylin, Fernando J. Rossello, Jason E. Cain, David N. Watkins. Conditional deletion of the tumor suppressor Hic1 results in aneuploidy and single-step transformation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-81. doi:10.1158/1538-7445.AM2014-LB-81
Doctors and children's teeth.
Authors: P Stocker
Journal: BMJ (1979)

months.Three of them had had unsuccessful kidney transplants before CAPD and the fourth, a 3-year old, had Wilms's tumours.Although our experience is still too short to allow us more generalised conclusions, we are convinced that the availability of CAPD in- creases the therapeutic armamentarium in the management of children with end-stage renal disease.
PDGF-D Improves Drug Delivery and Efficacy via Vascular Normalization, But Promotes Lymphatic Metastasis by Activating CXCR4 in Breast Cancer
Authors: Jieqiong Liu, Shan Liao, Yuhui Huang, Rekha Samuel, Tony Shi, Kamila Naxerova, Peigen Huang, Walid Kamoun, Rakesh K. Jain, Dai Fukumura, Lei Xu
Journal: Clinical Cancer Research (2011)

Unlike platelet-derived growth factor-B (PDGF-B), the role of PDGF-D in tumor progression or treatment is largely unknown. To this end, we determined the role of PDGF-D in breast cancer progression, metastasis, and response to chemotherapy.We first examined PDGF-D expression in human breast carcinomas by immunohistochemical (IHC) staining. To mimic high PDGF-D expressing tumors, we stably transfected the breast cancer cell lines MDA-MB-231 and 4T1 with pdgf-d cDNA, and implanted these tumor cells orthtopically into nude mice. We monitored tumor growth by caliper measurement and bioluminescence imaging. We also used short hairpin RNA interference (shRNAi) and imatinib to block PDGF-D/PDGFRβ signaling. Finally, we studied the effect of PDGF-D on doxorubicin delivery and efficacy.Human breast cancers express high levels of PDGF-D. Overexpression of PDGF-D promoted tumor growth and lymph node metastasis through increased proliferation, decreased apoptosis, and induction of CXCR4 expression. Blockade of CXCR4 signaling abolished PDGF-D-induced lymph node metastasis. Furthermore, overexpression of PDGF-D increased perivascular cell coverage and normalized tumor blood vessels. As a result, PDGF-D overexpression facilitated tissue penetration of doxorubicin and enhanced its treatment efficacy.PDGF-D is highly expressed in human breast cancer and facilitates tumor growth and lymph node metastasis, making it a potential target in breast cancer. At the same time, PDGF-D increases drug delivery and hence improves the efficacy of chemotherapy through vessel normalization. Therefore, judicious use of PDGF-D/PDGFRβ blockers would be necessary to minimize the adverse effects on concomitantly administered cytotoxic therapies.
Model studies in cytochrome P-450-mediated toxicity of halogenated compounds: radical processes involving iron porphyrins.
Authors: D Brault
Journal: Environmental Health Perspectives (1985)

Haloalkane toxicity originates from attack on biological targets by reactive intermediates derived from haloalkane metabolism by a hemoprotein, cytochrome P-450. Carbon-centered radicals and their peroxyl derivatives are most likely involved. The reactions of iron porphyrin--a model for cytochrome P-450--with various carbon-centered and peroxyl radicals generated by pulse radiolysis are examined. Competition between iron porphyrin and unsaturated fatty acids for attack by peroxyl radicals is pointed out. These kinetic data are used to derive a model for toxicity of haloalkanes with particular attention to carbon tetrachloride and halothane. The importance of local oxygen concentration and structural arrangement of fatty acids around cytochrome P-450 is emphasized.
Valvular-ventricular interaction: importance of the mitral apparatus in canine left ventricular systolic performance.
Authors: D E Hansen, P D Cahill, W M DeCampli, D C Harrison, G C Derby, R S Mitchell, D C Miller
Journal: Circulation (1986)

As the mitral valvular apparatus tenses during systole, forces transmitted along the chordae tendineae to the left ventricular chamber may influence left ventricular performance. To test this hypothesis, 10 dogs anesthetized with fentanyl were studied during cardiopulmonary bypass. The importance of the mitral apparatus in left ventricular systolic function was assessed independent of load by means of the slope of the contractile state-dependent left ventricular peak isovolumetric pressure-volume relationship (Emax), which was measured at constant heart rate and aortic pressure with a micromanometer inside a left ventricular intracavitary balloon before and immediately after all chordae tendineae were severed. Herniation of the balloon was prevented by a disk secured to the mitral anulus. Emax decreased from 11.97 +/- 3.35 (+/- SD) to 6.38 +/- 0.96 mm Hg/ml (p less than .001) with chordal severing. The volume intercept (Vo) was unchanged. Fluoroscopic studies of the balloon contour in eight additional dogs revealed dyskinesia in the area of the papillary muscle insertion and substantial alterations in chamber geometry during systole after the chordae were severed. Accordingly, we conclude that global left ventricular systolic performance is impaired when chordal attachments of the mitral valve are disrupted. Changes in left ventricular geometry or loss of inward force normally transmitted to the left ventricular wall as the valve tense may underlie these changes. These findings suggest that postoperative left ventricular dysfunction after mitral valve replacement may be attributable, in part, to excision of the native mitral apparatus at the time of surgery and support efforts to spare chordae during mitral valve surgery.
Lead Poisoning: Costs of Care in the United States,1988-1992
Authors: Alfredo E. Vergara
Journal: JAMA (1996)

<h3>To the Editor.</h3> —Lead poisoning remains a major environmental health problem among children in the United States.<sup>1</sup>Recent estimates on the number of childhood lead poisoning hospitalizations and their cost have not been published. Data were obtained from the National Hospital Discharge Survey, a nationally representative probability survey of discharges from short-stay nonfederal hospitals.<sup>2</sup>Analyses included hospitalization records listing lead poisoning (<i>International Classification of Diseases, Ninth Revision, Clinical Modification</i><sup>3</sup>codes 984, E861.5, or E866.0) among children 0 through 5 years of age for 1979 through 1983 and during 1988 through 1992. Direct costs for inpatient care were estimated from daily hospital charges of 1990 statewide billing records for 18 states: Arizona, California, Colorado, Florida, Illinois, Maine, Massachusetts, Maryland, Nevada, New Hampshire, New Jersey, New York, Oregon, Pennsylvania, South Carolina, Vermont, Washington, and Wisconsin (Manon Spitzer, Codman Research Group Inc, written communication, June 29, 1993). National inpatient childhood
P1-10-03: Colony Stimulating Factor Use with Taxane-Based Therapy for Metastatic Breast Cancer: Claims Analysis of Prophylaxis, Treatment, and Costs.
Authors: RW Force, BA Pugmire, VL Culbertson
Journal: Cancer Research (2011)

Abstract Background: The taxanes (paclitaxel, docetaxel, and albumin-bound paclitaxel) are used in women with metastatic breast cancer (MBC). Clinical trials indicate that these drugs may differ in their toxicity profiles, including rates of neutropenia and need for colony stimulating factor (CSF) supportive therapy. Utilizing medical claims data, we evaluated prophylactic and treatment-related CSF use among women receive taxane-based chemotherapy regimens. Objective: To determine if differences exist in rates of CSF use for prophylaxis, treatment and associated costs in women receiving taxane-based chemotherapy for MBC. Methods: Women with MBC were identified with ICD-9-CM codes and by their prior use of adjuvant chemo regimens. Paid medical claims (source: Ingenix Consulting) from May 1, 2006 to April 30, 2009 were analyzed. Study groups were defined according to the first taxane administered. CSF utilization was classified as prophylaxis (0-5 days post-taxane administration), treatment (6-21 days post-taxane,) or non-taxane associated use (&amp;gt;21 days post-taxane). Comparisons were made between the taxane groups. All CSF costs were captured from date of first taxane to end of taxane therapy +21 days and categorized as above. Patients censored if ≥35 days elapsed with no taxane therapy. Two-stage regression analyses were performed. Control variables included age, Romano comorbidity score, and use of prior and other concurrent chemotherapy. Results: 4,503 women (mean age: 53 +/− 10 years) with MBC were identified: 2,599 in the docetaxel group; 1,643 received paclitaxel; and 261 received nab-paclitaxel. More patients receiving docetaxel received any CSF (75.6%) than either paclitaxel (49.8%) or albumin-bound paclitaxel (36.8% P&amp;lt;0.05 for each comparison). For docetaxel 70.5% of women received prophylactic CSF, whereas the rates were 47.0% for paclitaxel and 33.0 for albumin-bound paclitaxel (P&amp;lt;0.05). The rate of women receiving CSF in the albumin-bound paclitaxel group was not different than the other groups. Daily per-patient CSF expenditures during taxane therapy were $176.81 (95% CI, $168.20-$185.52) for docetaxel, $127.71(95% CI, $113.62-$142.60) for paclitaxel, and 46.24 (95% CI, $29.37-$67.25) for albumin-bound paclitaxel. Conclusions: Compared with docetaxel and paclitaxel, patients receiving albumin-bound paclitaxel had significantly lower prophylactic CSF use, yet did not experience any difference in treatment-related use. Daily per-patient CSF expenditures for albumin-bound paclitaxel were significantly lower than the other two taxanes. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-10-03.
Establishment of public health security in Saudi Arabia for the 2009 Hajj in response to pandemic influenza A H1N1
Authors: ZA Memish, SJN McNabb, F Mahoney, F Alrabiah, N Marano, QA Ahmed, J Mahjour, RA Hajjeh, P Formenty, FH Harmanci, H El Bushra, TM Uyeki, M Nunn, N Isla, M Barbeschi
Journal: The Lancet (2009)
Greater-curvature Gastric Ulcers in Patients on Long-term Steroid Therapy
Authors: F. M. Low
Journal: BMJ (1962)

IRON OVERLOAD MEDICALrorua may be beneficial, however; in observations on patients with haemochromatosis it has been noticed on several occasions that the subjective improvement and reduction in pigmentation after desferrioxamine infusions was far greater than expected, in view of the relatively small quantities of iron removed (Ciba, 1961).Finally, the removal of iron by chelation must be considered in relation to other aspects of the patient's iron metabolism.There is evidence that in thalassaemia major iron is absorbed from food in amounts greater than can be used in haemoglobin synthesis.At necropsy iron may be found in quantities far greater than can be accounted for by transfusions (Ellis et a!., 1954).Even when iron overload is present, some degree of iron absorption persists (Erlandson et al., 1962; Bannerman et al., 1962a).It is therefore probable that iron absorption from food makes a significant contribution to the iron overload present in these patients.Means will have to be found to reduce their absorption of food iron ; indeed it might be found that removal of significant amounts of stored iron by parenteral chelating agents was followed by enhanced iron absorption from food, in which case no overall benefit would result.It is clev that a great deal of further work will be require3, particularly in the development of chelating agents which can be taken by mouth, some to bind food iron and prevent its absorption, others to be absorbed unchanged for the purpose of binding excess iron in the body stores. SummaryIron excretion was measured in 17 thalassaemic children and one boy with pure red-cell aplasia after the intravenous or intramuscular administration of desferrioxamine or D.T.P.A.The dose of chelating agent varied between 100 mg. and 2 g. (5-104 mg./kg.body weight).Children with over 80% saturation of the plasma iron-binding capacity excreted (with one exception) 11-40 mg. of iron per g. of desferrioxamine or D.T.P.A. given: those with less than 60% saturation usually excreted less than 8 mg./g., and an intermediate degree of iron excretion was found in children with 60-80% saturation of the plasma iron- binding capacity.The use of these chelating agents for the diagnosis and treatment of conditions associated with iron overloading is discussed.
NT-33 * NAD+ SYNTHESIS INHIBITION AS A THERAPEUTIC STRATEGY FOR GLIOBLASTOMA WITH MYC AMPLIFICATION
Authors: K. Tateishi, N. Lelic, Q. H. Ho, S. Esakl, J. A. Iafrate, D. P. Cahill, A. S. Chi, H. Wakimoto
Journal: Neuro-Oncology (2014)

BACKGROUND AND OBJECTIVE: Oncoprotein Myc is a master transcription factor and plays a crucial role in human cancer pathogenesis and the stem-like phenotype of glioblastoma (GBM). Since dyregulated Myc in cancer drives altered glucose and glutamine metabolism promoting tumor growth, pathways involved in Myc-induced aberrant metabolism could offer therapeutic targets. The coenzyme Nicotinamide Adenine Dinucleotide (NAD+) is essential in redox reactions including glycolysis and the citric acid cycle. We sought to determine whether MYC-amplified GBM, as compared to MYC-non-amplified GBM, utilizes distinct NAD+ biosynthesis pathways and exhibits differential dependence on metabolic pathways that require NAD+. MATERIALS AND METHODS: A total of 11 patient-derived GBM stem-like cell (GSCs) lines established from surgical specimens were used. FISH analysis was performed to determine copy number status of MYC and MYCN. Expression of enzymes involved in NAD+ synthesis [e.g., nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT-1)] was tested with Western blot. NAD+ levels were measured after treating GSCs with FK866, a potent and specific small molecule inhibitor for NAMPT. The effects of pharmacological inhibition of NAMPT on GSC viability were determined by CellTiter Glo cell viability assay. RESULTS: Five (45.5%) GSCs had MYC (1) or MYCN (4) amplification. FK866 depleted NAD+ levels in GSCs. Treatment with FK866 potently inhibited in vitro growth of all the GSCs that harbored MYC/MYCN amplification with IC50 values in a low-nanomolar range (0.7 - 4.6 nM). In contrast, non-amplified GSCs as well as human normal astrocytes showed resistance to FK866. The MYC/MYCN amplified GSCs expressed low or undetectable levels of NAPRT-1, which is involved in the NAD+ synthesis pathway utilizing nicotinic acid. CONCLUSIONS: MYC/MYCN-amplified GSCs, but not non-amplified GSCs, were exquisitely sensitive to NAMPT inhibition. NAMPT may represent a promising therapeutic target for GBM with MYC amplification.
A Mini-intronic Plasmid (MIP): A Novel Robust Transgene Expression Vector In Vivo and In Vitro
Authors: Jiamiao Lu, Feijie Zhang, Mark A Kay
Journal: Molecular Therapy (2013)

The bacterial backbone (BB) sequences contained within a canonical plasmid DNA dampen exogenous transgene expression by tenfold to 1,000-fold over a period of a few weeks following transfection into quiescent tissues such as the liver. Minicircle DNA vectors devoid of bacterial plasmid backbone sequences overcome transgene silencing providing persistent transgene expression. Because, we recently established that the length rather than sequence of the DNA flanking the transgene expression cassette is the major parameter affecting transgene silencing, we developed an alternative plasmid propagation process in which the essential bacterial elements for plasmid replication and selection are placed within an engineered intron contained within the eukaryotic expression cassette. As with the minicircle vector, the mini-intronic plasmid (MIP) vector system overcomes transgene silencing observed with plasmids but in addition provides between 2 and often 10 times or higher levels of transgene expression compared with minicircle vectors containing the same expression cassette in vivo and in vitro. These improved plasmids will benefit all studies involving gene transfer/therapy approaches.
Development and validation of the Food Allergy Quality of Life Questionnaire – Adult Form
Authors: B. M. J. Flokstra‐de Blok, G. N. Van Der Meulen, A. DunnGalvin, B. J. Vlieg‐Boerstra, J. N. G. Oude Elberink, E. J. Duiverman, J. O’B. Hourihane, A. E. J. Dubois
Journal: Allergy (2009)

Background: Health‐related quality of life (HRQL) may be affected by food allergy. Presently, no disease‐specific HRQL questionnaire exists for food allergic adults. Therefore, we developed and validated the Food Allergy Quality of Life Questionnaire – Adult Form (FAQLQ‐AF) in the Dutch language. Methods: Twenty‐two food allergic patients (≥18 years) were interviewed and generated 180 HRQL items. The most important items were identified by 54 food allergic patients using the clinical impact method resulting in the FAQLQ‐AF containing 29 items (score range 1 ‘not troubled’ to 7 ‘extremely troubled’). The FAQLQ‐AF, the Food Allergy Independent Measure (FAIM) and a generic HRQL questionnaire (RAND‐36) were sent to 100 other food allergic adults for cross‐sectional validation of the FAQLQ‐AF. Results: Cross‐sectional validity was assessed by the correlation between FAQLQ‐AF and FAIM (ρ = 0.76, P &lt; 0.001). The FAQLQ‐AF had excellent internal consistency (Cronbach’s α = 0.97). The FAQLQ‐AF discriminated between patients who differ in severity of symptoms (anaphylaxis vs no anaphylaxis, total FAQLQ‐AF score 4.9 vs 4.1; P = 0.041) and number of food allergies (&gt;3 food allergies vs ≤3 food allergies, total FAQLQ‐AF score 5.2 vs 4.2; P = 0.008). The total FAQLQ‐AF score was correlated with one RAND‐36 scale (convergent/discriminant validity). Conclusions: The FAQLQ‐AF is the first disease‐specific HRQL questionnaire for food allergic adults and reflects the most important issues that food allergic patients have to face. The questionnaire is valid, reliable and discriminates between patients with different disease characteristics. The FAQLQ‐AF is short and easy to use and may therefore be a useful tool in clinical research.
Hemodynamic Improvement after Oral Hydralazine in Left Ventricular Failure
Authors: Joseph A. Franciosa, Gordon Pierpont, Jay N. Cohn
Journal: Annals of Internal Medicine (1977)

Hydralazine was administered in a single oral dose of 50 to 100 mg in 16 patients with left ventricular failure due to cardiomyopathy. It produced sustained effects for at least 4 h characterized by a significant increase in cardiac output, a reduction in arterial and pulmonary arterial pressure, and a slight rise in heart rate. When compared to nitroprusside infusion in these same patients, hydralazine produced a similar reduction in systemic vascular resistance but a slightly greater increase in cardiac index (0.74 versus 0.95 litres/min · m2), with a lesser fall in mean arterial pressure (7.8 versus 13.6 mm Hg, P < 0.01), mean pulmonary arterial pressure (4.2 versus 11.3 mm Hg, P < 0.001), and pulmonary wedge pressure (5.5 versus 9.9 mm Hg, P < 0.001). Forearm venous tone decreased and venous compliance increased during nitroprusside infusion, but they were unchanged after hydralazine therapy. These data suggest that hydralazine may be a useful agent in the treatment of chronic left ventricular failure.
[493] ADEFOVIR SALVAGE THERAPY FOR VIROLOGIC BREAKTHROUGH IN TELBIVUDINE-TREATED PATIENTS FROM THE GLOBE STUDY
Authors: E. Pane, C.-L. Lai, A. Min, I. Heathcote, T. Poynard, O.O. Kurdas, J.-D. Grange, N.A. Brown
Journal: Journal of Hepatology (2007)