tbuckley/cabot-search huggingface dataset:
Mixture modeling of transcript abundance classes in natural populations
Authors: Wen-Ping Hsieh, Gisele Passador-Gurgel, Eric A Stone, Greg Gibson
Journal: Genome biology (2007)

Abstract Background Populations diverge in genotype and phenotype under the influence of such evolutionary processes as genetic drift, mutation accumulation, and natural selection. Because genotype maps onto phenotype by way of transcription, it is of interest to evaluate how these evolutionary factors influence the structure of variation at the level of transcription. Here, we explore the distributions of cis -acting and trans -acting factors and their relative contributions to expression of transcripts that exhibit two or more classes of abundance among individuals within populations. Results Expression profiling using cDNA microarrays was conducted in Drosophila melanogaster adult female heads for 58 nearly isogenic lines from a North Carolina population and 50 from a California population. Using a mixture modeling approach, transcripts were identified that exhibit more than one mode of transcript abundance across the samples. Power studies indicate that sample sizes of 50 individuals will generally be sufficient to detect divergent transcript abundance classes. The distribution of transcript abundance classes is skewed toward low frequency minor classes, which is reminiscent of the typical skew in genotype frequencies. Similar results are observed in reported data on gene expression in human lymphoblast cell lines, in which analysis of association with linked polymorphisms implies that cis-acting single nucleotide polymorphisms make only a modest contribution to bimodal distributions of transcript abundance. Conclusion Population surveys of gene expression may complement genetical genomics as a general approach to quantifying sources of transcriptional variation. Differential expression of transcripts among individuals is due to a complex interplay of cis-acting and trans -acting factors.
Failing mouse hearts utilize energy inefficiently and benefit from improved coupling of glycolysis and glucose oxidation
Authors: Waleed G.T. Masoud, John R. Ussher, Wei Wang, Jagdip S. Jaswal, Cory S. Wagg, Jason R. Dyck, Craig A. Lygate, Stefan Neubauer, Alexander S. Clanachan, Gary D. Lopaschuk
Journal: Cardiovascular Research (2013)

To determine whether post-infarction LV dysfunction is due to low energy availability or inefficient energy utilization, we compared energy metabolism in normal and failing hearts. We also studied whether improved coupling of glycolysis and glucose oxidation by knockout of malonyl CoA decarboxylase (MCD-KO) would have beneficial effects on LV function and efficiency.Male C57BL/6 mice were subjected to coronary artery ligation (CAL) or sham operation (SHAM) procedure. After 4 weeks and echocardiographic evaluation, hearts were perfused (working mode) to measure LV function and rates of energy metabolism. Similar protocols using MCD-KO mice and wild-type (WT) littermates were used to assess consequences of MCD deficiency. Relative to SHAM, CAL hearts had impaired LV function [lower % ejection fraction (%EF, 49%) and LV work (46%)]. CAL hearts had higher rates (expressed per LV work) of glycolysis, glucose oxidation, and proton production. LV work per ATP production from exogenous sources was lower in CAL hearts, indicative of inefficient exogenous energy substrate utilization. Fatty acid oxidation rates, ATP, creatine, and creatine phosphate contents were unaffected. Utilization of endogenous substrates, triacylglycerol and glycogen, was similar in CAL and SHAM hearts. MCD-KO CAL hearts had 31% higher %EF compared with that of WT-CAL, and lower rates of glycolysis, glucose oxidation, proton production, and ATP production, indicative of improved efficiency.CAL hearts are inefficient in utilizing energy for mechanical function, possibly due to higher proton production arising from mismatched glycolysis and glucose oxidation. MCD deficiency lessens proton production, LV dysfunction, and inefficiency of exogenous energy substrate utilization.
Primary care referral to a commercial provider for weight loss treatment versus standard care: a randomised controlled trial
Authors: Susan A Jebb, Amy L Ahern, Ashley D Olson, Louise M Aston, Christina Holzapfel, Julia Stoll, Ulrike Amann-Gassner, Annie E Simpson, Nicholas R Fuller, Suzanne Pearson, Namson S Lau, Adrian P Mander, Hans Hauner, Ian D Caterson
Journal: The Lancet (2011)
Prevalence of Hepatitis B Markers and Measles, Mumps, and Rubella Antibodies Among Jewish Refugees From the Former Soviet Union
Authors: Marjorie B. Hurie
Journal: JAMA (1995)

<h3>Objective.</h3> —To assess the prevalence of hepatitis B virus (HBV) infection and immunity to measles, mumps, and rubella among refugees from the former Soviet Union (FSU). <h3>Design.</h3> —Descriptive study. <h3>Setting.</h3> —Soviet Immigrant Health Care Program, Sinai Samaritan Hospital, Milwaukee, Wis. <h3>Patients.</h3> —Consecutive sample of 496 Jewish refugees from the FSU presenting for new arrival screening from December 1, 1990, through January 11, 1993. <h3>Outcome Measures.</h3> —Hepatitis B surface antigen (HBsAg), hepatitis B core antibody, hepatitis B surface antibody, and measles, mumps, and rubella antibodies. <h3>Results.</h3> —At least one hepatitis B marker was detected in 22% of the refugees, and HBsAg was detected in 0.4%. The rate of HBV infection (any marker present) increased with increasing age, ranging from 4% among those aged 0 through 19 years to 31% among those aged 50 through 59 years (χ<sup>2</sup>test for trend, 13.5;<i>P</i>&lt;.001). Among those aged 0 through 19 years, 19% lacked antibody to measles, 8% lacked antibody to mumps, and 13% lacked antibody to rubella. Refugees who were less than 30 years of age were more than twice as likely to lack antibodies to measles, mumps, or rubella compared with those who were 30 years of age or older (relative risk, 2.8; 95% confidence interval, 1.8 to 4.2;<i>P</i>&lt;.001). <h3>Conclusions.</h3> —In our sample of Jewish refugees from the FSU (primarily Ukraine, Russia, and Belorussia), the rate of HBsAg positivity was low, suggesting that routine screening for HBV infection is not needed. Seronegativity to measles, mumps, and rubella was relatively common among those less than 30 years old. Those refugees who were born after 1957 should be given combined measles, mumps, and rubella vaccine unless their written documentation indicates previous receipt of these antigens according to the immunization schedule recommended in the United States. (<i>JAMA</i>. 1995;273:954-956)
Lazaroid U-74389F attenuates phorbol ester-induced lung injury in rabbits
Authors: M Miniati, F Cocci, S Monti, E Filippi, R Sarnelli, M Ferdeghini, V Gattai, M Pistolesi
Journal: European Respiratory Journal (1996)

We examined the effect of the antioxidant lazaroid U-74389F on acute lung injury induced in rabbits by phorbol myristate acetate (PMA). Thirty minutes after receiving either U-74389F (15 mg.kg-1 i.v.) or U-74389F vehicle, rabbits (n = 60) were given PMA (60 micrograms.kg-1 i.v.). PMA vehicle injected rabbits (n = 20) served as controls. Over a 5 h period after PMA or PMA vehicle injection, we measured arterial pH, arterial oxygen tension (Pa,O2), arterial carbon dioxide tension (Pa,CO2), and the plasma concentration of the neutrophil chemoattractant interleukin-8 (IL-8). At postmortem, lungs were inspected for macroscopic injury and examined histologically. Malondialdehyde levels were assayed in lung tissue as an index of lipid peroxidation. In bronchoalveolar lavage (BAL), total and differential cell counts, protein and IL-8 concentrations were measured. Compared to normal controls, rabbits challenged with PMA alone developed arterial acidosis, hypercapnia and hypoxaemia, accompanied by significant rise in plasma IL-8 concentration. U-74389F pretreated animals did not develop significant arterial blood gas abnormalities and had significantly lower IL-8 concentration in plasma. U-74389F did not prevent PMA-induced lipid peroxidation. However, macroscopic signs of lung injury and the degree of alveolar haemorrhage and protein extravasation were significantly less severe in pretreated rabbits than in those given PMA alone. In addition, U-74389F significantly reduced IL-8 concentration and neutrophil number in BAL. By histological assessment, 80% of lung neutrophils were localized in alveolar spaces of animals receiving PMA alone. Conversely, in U-74389F pretreated animals, 75% of neutrophils were distributed within extra-alveolar blood vessels and alveolar septa. We conclude that lazaroid U-74389F attenuates lung injury in rabbits given PMA by preventing neutrophil migration into pulmonary alveoli. This effect may, in part, be related to downregulation of IL-8 production.
Managed care, capitation, and the future of nephrology.
Authors: T I Steinman
Journal: Journal of the American Society of Nephrology (1997)

Within the next decade, it is predicted that more than 90% of the United States population will receive its health insurance through managed care. Capitation will be the reimbursement mechanism to health care providers as the major way of controlling costs. Currently, managed care has had little experience with capitation payments for chronically ill patients, who consume large financial and physical resources. The end-stage renal disease (ESRD) population represents a vulnerable group of patients, and their care may be compromised in a capitated environment. Nephrologists will need to serve as advocates for ESRD patients through a mechanism of quality of care, driven by a continuous quality improvement model. Cost-effective delivery of care will occur as nephrologists join together to form Independent Practice Associations (IPAs). In this article, the role of a nephrologist in a capitated environment is outlined in detail, and background for the basis of managed care growth is provided as a framework for understanding the change in our health care delivery system. After formation of a nephrology IPA, there will most likely be a linkage with a management service organization (MSO). A business plan driven by the highest principles will allow nephrologists to work together as a cohesive force in accepting global risk capitated contracts. The starting point is for ESRD care, and the future includes pre-ESRD care.
Activated d16HER2 Homodimers and SRC Kinase Mediate Optimal Efficacy for Trastuzumab
Authors: Lorenzo Castagnoli, Manuela Iezzi, Gaia C. Ghedini, Valentina Ciravolo, Giulia Marzano, Alessia Lamolinara, Roberta Zappasodi, Patrizia Gasparini, Manuela Campiglio, Augusto Amici, Claudia Chiodoni, Arianna Palladini, Pier Luigi Lollini, Tiziana Triulzi, Sylvie Menard, Patrizia Nanni, Elda Tagliabue, Serenella M. Pupa
Journal: Cancer Research (2014)

Abstract A splice isoform of the HER2 receptor that lacks exon 16 (d16HER2) is expressed in many HER2-positive breast tumors, where it has been linked with resistance to the HER2-targeting antibody trastuzumab, but the impact of d16HER2 on tumor pathobiology and therapeutic response remains uncertain. Here, we provide genetic evidence in transgenic mice that expression of d16HER2 is sufficient to accelerate mammary tumorigenesis and improve the response to trastuzumab. A comparative analysis of effector signaling pathways activated by d16HER2 and wild-type HER2 revealed that d16HER2 was optimally functional through a link to SRC activation (pSRC). Clinically, HER2-positive breast cancers from patients who received trastuzumab exhibited a positive correlation in d16HER2 and pSRC abundance, consistent with the mouse genetic results. Moreover, patients expressing high pSRC or an activated “d16HER2 metagene” were found to derive the greatest benefit from trastuzumab treatment. Overall, our results establish the d16HER2 signaling axis as a signature for decreased risk of relapse after trastuzumab treatment. Cancer Res; 74(21); 6248–59. ©2014 AACR.
Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency
Authors: Neil P. Shah, Brian J. Skaggs, Susan Branford, Timothy P. Hughes, John M. Nicoll, Ronald L. Paquette, Charles L. Sawyers
Journal: Journal of Clinical Investigation (2007)

Molecularly targeted kinase inhibitor cancer therapies are currently administered sequentially rather than simultaneously. We addressed the potential long-term impact of this strategy in patients with chronic myelogenous leukemia (CML), which is driven by the fusion oncogene BCR-ABL. Analysis of BCR-ABL genotypes in CML patients who relapsed after sequential treatment with the ABL inhibitors imatinib and dasatinib revealed evolving resistant BCR-ABL kinase domain mutations in all cases. Twelve patients relapsed with the pan-resistant T315I mutation, whereas 6 patients developed novel BCR-ABL mutations predicted to retain sensitivity to imatinib based on in vitro studies. Three of these patients were retreated with imatinib (or the chemically related compound nilotinib) and responded; however, selection for compound mutants (2 or 3 BCR-ABL mutations in the same molecule) can substantially limit the potential effectiveness of retreating patients with inhibitors that have previously failed. Furthermore, drug-resistant mutations, when compounded, can increase oncogenic potency relative to the component mutants in transformation assays. The Aurora kinase inhibitor VX-680, currently under clinical evaluation based on its activity against the T315I mutation, is also effective against the other commonly detected dasatinib-resistant mutation in our analysis, V299L. Our findings demonstrate the potential hazards of sequential kinase inhibitor therapy and suggest a role for a combination of ABL kinase inhibitors, perhaps including VX-680, to prevent the outgrowth of cells harboring drug-resistant BCR-ABL mutations.
No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group
Authors: K. Behringer, L. Wildt, H. Mueller, V. Mattle, P. Ganitis, B. van den Hoonaard, H.W. Ott, S. Hofer, A. Pluetschow, V. Diehl, A. Engert, P. Borchmann
Journal: Annals of Oncology (2010)
Molecular Profiling Identifies Prognostic Subgroups of Pediatric Glioblastoma and Shows Increased YB-1 Expression in Tumors
Authors: Damien Faury, André Nantel, Sandra E. Dunn, Marie-Christine Guiot, Takrima Haque, Péter Hauser, Miklós Garami, László Bognár, Zoltán Hanzély, Pawel P. Liberski, Enrique Lopez-Aguilar, Elvis T. Valera, Luis G. Tone, Anne-Sophie Carret, Rolando F. Del Maestro, Martin Gleave, Jose-Luis Montes, Torsten Pietsch, Stephen Albrecht, Nada Jabado
Journal: Journal of Clinical Oncology (2007)

Pediatric glioblastoma (pGBM) is a rare, but devastating brain tumor. In contrast to GBM in adults (aGBM), little is known about the mechanisms underlying its development. Our aim is to gain insight into the molecular pathways of pGBM.Thirty-two pGBM and seven aGBM samples were investigated using biochemical and transcriptional profiling. Ras and Akt pathway activation was assessed through the phosphorylation of downstream effectors, and gene expression profiles were generated using the University Health Network Human 19K cDNA arrays. Results were validated using real-time polymerase chain reaction and immunohistochemistry and compared with existing data sets on aGBM.There are at least two subsets of pGBM. One subset, associated with Ras and Akt pathway activation, has very poor prognosis and exhibits increased expression of genes related to proliferation and to a neural stem-cell phenotype, similar to findings in aggressive aGBM. This subset was still molecularly distinguishable from aGBM after unsupervised and supervised analysis of expression profiles. A second subset, with better prognosis, is not associated with activation of Akt and Ras pathways, may originate from astroglial progenitors, and does not express gene signatures and markers shown to be associated with long-term survival in aGBM. Both subsets of pGBM show overexpression of Y-box-protein-1 that may help drive oncogenesis in this tumor.Our work, the first study of gene expression profiles in pGBM, provides valuable insight into active pathways and targets in a cancer with minimal survival, and suggests that these tumors cannot be understood exclusively through studies of aGBM.
Railwaymen and drug side-effects.
Authors: J. S. Grant
Journal: BMJ (1968)

hepatitis was 30,000 cases with nearly 3,600 deaths.No account was taken of the incidence of anicteric hepatitis, and, in general, the accepted ratio is 1 overt case for at least 10 actual infections, although in 1965 it was estimated that the ratio of anic- teric to icteric hepatitis after blood trans- fusion could be greater than 100: 1 (based
Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebo-controlled trial
Authors: John J Bissler, J Christopher Kingswood, Elżbieta Radzikowska, Bernard A Zonnenberg, Michael Frost, Elena Belousova, Matthias Sauter, Norio Nonomura, Susanne Brakemeier, Petrus J de Vries, Vicky H Whittemore, David Chen, Tarek Sahmoud, Gaurav Shah, Jeremie Lincy, David Lebwohl, Klemens Budde
Journal: The Lancet (2013)
Adenoviral Catheter-Mediated Intramyocardial Gene Transfer Using the Mature Form of Vascular Endothelial Growth Factor-D Induces Transmural Angiogenesis in Porcine Heart
Authors: Juha Rutanen, Tuomas T. Rissanen, Johanna E. Markkanen, Marcin Gruchala, Päivi Silvennoinen, Antti Kivelä, Antti Hedman, Marja Hedman, Tommi Heikura, Maija-Riitta Ordén, Steven A. Stacker, Marc G. Achen, Juha Hartikainen, Seppo Ylä-Herttuala
Journal: Circulation (2004)

It is unclear what is the most efficient vector and growth factor for induction of therapeutic vascular growth in the heart. Furthermore, the histological nature of angiogenesis and potential side effects caused by different vascular endothelial growth factors (VEGFs) in myocardium have not been documented.Adenoviruses (Ad) at 2 doses (2x10(11) and 2x10(12) viral particles) or naked plasmids (1 mg) encoding LacZ control, VEGF-A165, or the mature, soluble form of VEGF-D (VEGF-D(DeltaNDeltaC)) were injected intramyocardially with the NOGA catheter system into domestic pigs. AdVEGF-D(DeltaNDeltaC) gene transfer (GT) induced a dose-dependent myocardial protein production, as measured by ELISA, resulting in an efficient angiogenic effect 6 days after the injections. Also, AdVEGF-A165 produced high gene transfer efficacy, as demonstrated with immunohistochemistry, leading to prominent angiogenesis effects. Despite the catheter-mediated approach, angiogenesis induced by both AdVEGFs was transmural, with maximal effects in the epicardium. Histologically, strongly enlarged alpha-smooth muscle actin-positive microvessels involving abundant cell proliferation were found in the transduced regions, whereas microvessel density did not change. Myocardial contrast echocardiography and microspheres showed marked increases in perfusion in the transduced areas. VEGF-D(DeltaNDeltaC) but not matrix-bound VEGF-A165 was detected in plasma after adenoviral GT. A modified Miles assay demonstrated myocardial edema resulting in pericardial effusion with the higher AdVEGF doses. All effects returned to baseline by 3 weeks. Naked plasmid-mediated GT did not induce detectable protein production or vascular effects.Like AdVEGF-A165, AdVEGF-D(DeltaNDeltaC) GT using the NOGA system produces efficient transmural angiogenesis and increases myocardial perfusion. AdVEGF-D(DeltaNDeltaC) could be useful for the induction of therapeutic vascular growth in the heart.
Week 12 EVR predicts EOT in CHC genotype 4 patients treated with peginterferon alfa-2a (40KD)/RBV
Authors: O. Shobokshi, F.E. Serebour, L. Skakni, N. Al-Jasser, A.O. Tantawi, A. Sabah, T. Dinish, M. Al-Quaiz, K. Qahtani, A. Sandokji, A. Al-Blowi, M. Al-Karawi, B. Al-Kayyal, S. Al-Momen, H. Akbar, A. Ayoola, M. El-Hazmi, A. Humaida, I. El-Hazmi, H. Eissa, F. Khawajah, M. Al-Khalifa
Journal: Journal of Hepatology (2003)
Screen Memories in a Pair of Monozygotic Twins Discordant for Involutional Depression and Psychophysiological Disorders
Authors: LORETTA R. LOEB, STANLEY PEAL, FELIX F. LOEB, BRYCE TEMPLETON
Journal: American Journal of Psychiatry (1973)

The authors studied a pair of monozygotic twins who became discordant for mental and physical disorders late in life. Differences in the twins' early histories, earliest memories, and reactions to the loss of their mother when they were children suggest that their early interactions with their environment resulted in different modes of adaptation, which subsequently became internalized as different defensive and characterological patterns. The authors believe that the specific environmentally determined psychodynamic influences described in the paper serve to explain the twins' discordance for disease.
Differential expression of tissue-specific promoters by gene gun
Authors: M.T.S. Lin, F. Wang, J. Uitto, K. Yoon
Journal: British Journal of Dermatology (2001)

Background Tissue‐specific promoters are becoming increasingly important in light of their effects on gene expression in gene therapy experiments. The regulation of gene expression may be as important as the delivery of the gene itself. Objectives To determine the effects of the involucrin (INV), keratin 14 (K14) and cytomegalovirus (CMV) promoters on the expression of the reporter gene β‐galactosidase. MethodsIn vivo, plasmid DNA was introduced to BALB/c mice by gene gun. Skin biopsies were taken after 24 h for histology and β‐galactosidase staining. In tissue culture cells, plasmid DNA was introduced by transient transfection to cell lines 293 (transformed primary human embryonal kidney cells), NIH 3T3 (immortalized mouse fibroblasts) and human keratinocytes. Reporter gene expression was assayed by histochemical staining and chemiluminescence. Results The K14 and INV promoter constructs showed β‐galactosidase gene expression only in the epidermis, while the CMV promoter showed gene expression in both the dermis and epidermis. In cell culture, the INV and K14 promoter constructs demonstrated significant β‐galactosidase expression in human keratinocytes, but minimal expression in 293 and NIH 3T3 cell types. CMV promoter constructs demonstrated significant expression in all cell types. Conclusions Gene expression can be regulated by different promoters both in vivo and in cell culture. Based on the physiological expression of the different promoters, gene expression can be restricted to certain cell types, tissues and skin layers.