tbuckley/cabot-search huggingface dataset:
Genetic Transmission of Congenital Membranous Ventricular Septal Defects in Selectively Inbred Substrains of Rats
Authors: MARJORIE HOPKINS FOX
Journal: Circulation Research (1967)

Two inbred substrains of Long-Evans rats have been maintained under identical laboratory conditions. In one substrain (Olson-Goss) 25% of the neonates have spontaneously occurring membranous ventricular septal defects; in the other (California) only 4% are affected. Since a genetic etiology was indicated, two series of reciprocal crosses were made to evaluate the possibilities that the defects might result from an abnormal fetal genotype, a genetically abnormal intrauterine environment, or both. In both series parents of a highly defective litter ("high-incidence" pairs) were reciprocally mated to parents of a completely normal litter ("low-incidence" pairs). In Series I, all parental pairs were Olson-Goss animals; in Series II, the low-incidence pairs were California animals. Substitution of a low- for a high-incidence male consistently and appreciably decreased the incidence of defects in the progeny of high-incidence females. Conversely, low-incidence females produced a relatively large number of defective pups when mated to high-incidence males. These data suggest that the primary factor responsible for septal malformation is the fetal genotype rather than the intrauterine environment. Patroclinous reciprocal cross differentials, particularly marked in the substrain crosses, suggest, however, that secondary factors may also be implicated.
The molecular foundations of the maternal to zygotic transition in the preimplantation embryo
Authors: R. M. Schultz
Journal: Human Reproduction Update (2002)

The maternal to zygotic transition is the first major transition that occurs following fertilization, and entails a dramatic reprogramming of gene expression that is essential for continued development. Although the major reprogramming of gene expression occurs during the 2-cell stage, transcription is evident in the 1-cell embryo, with the male pronucleus supporting a significantly higher level of transcription than the female pronucleus. This difference is likely due to differences in chromatin structure as a consequence of the protamine-histone exchange. Although the 1-cell embryo is transcriptionally competent, transcription and translation appear uncoupled. This transcription, however, may mark promoters for efficient utilization in the 2-cell embryo. Genome activation in the 2-cell embryo is accompanied by a requirement for an enhancer for efficient transcription and the more efficient utilization of TATA-less promoters. These changes in promoter utilization could contribute substantially to the reprogramming of gene expression. Superimposed on genome activation is the development of a chromatin-mediated transcriptionally repressive state that is relieved by either inducing histone hyperacetylation or inhibiting the second round of DNA replication. Since genome activation appears to be a relatively opportunistic process, the development of the transcriptionally repressive state may be a major determinant in establishing the appropriate gene expression profile that is essential for continued development.
MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man.
Authors: K Peerlinck, I De Lepeleire, M Goldberg, D Farrell, J Barrett, E Hand, D Panebianco, H Deckmyn, J Vermylen, J Arnout
Journal: Circulation (1993)

BACKGROUND Fibrinogen-dependent cross-linking of glycoprotein (GP) IIb/IIIa on activated platelets is the final mechanism leading to platelet aggregation. Inhibition of this mechanism may result in a novel antithrombotic agent. We studied the activity of MK-383 (L-700,462), a new, nonpeptide GPIIb/IIIa antagonist, in vitro and in vivo, in man. METHODS AND RESULTS MK-383, a nonpeptide tyrosine derivative, dose-dependently inhibited fibrinogen-dependent platelet aggregation, in vitro. Binding of 125I-labeled fibrinogen to activated platelets was prevented in a competitive manner with an IC50 of 10 +/- 4.2 nmol/L. The activity and tolerability of MK-383 were evaluated in a two-part double-blind, placebo-controlled, dose-escalation study in healthy male subjects using 1- and 4-hour intravenous infusions. Effects on ADP- and collagen-induced ex vivo platelet aggregation (APA or CPA) and template bleeding time (TBT) were evaluated. Twenty-four subjects participated in the 1-hour part. Six received placebo and 18 MK-383 in doses ranging from 0.05 to 0.40 microgram.kg-1 x min-1. MK-383 inhibited platelet aggregation and prolonged bleeding time in a dose-dependent manner. APA and CPA were totally inhibited at the end of infusion of 0.4 microgram.kg-1 x min-1 and returned to 55% and 89% of baseline, respectively, at 3 hours after infusion. TBT was prolonged at this dose from 5.0 +/- 1.3 minutes predose to 22.7 +/- 6 minutes at the end of the infusion (P &lt; .01) and was normalized by 3 hours after infusion. In the 4-hour infusion part, 15 subjects received MK-383 (0.1 to 0.2 microgram.kg-1 x min-1), and five received placebo. Complete inhibition of ex vivo platelet aggregation was seen at 0.15 and 0.2 microgram.kg-1 x min-1. At 0.2 microgram.kg-1 x min-1, TBT was prolonged from 4.4 +/- 1.2 to 23.9 +/- 4.3 minutes at the end of infusion (P &lt; .01) and remained slightly prolonged 3 hours after infusion (7.2 +/- 1.8 minutes). No adverse effects were observed in any of the 33 subjects receiving MK-383. CONCLUSIONS The results from this study indicate that MK-383 appears to be well tolerated and active in man. It is the first nonpeptide GPIIb/IIIa antagonist that can be used to investigate the antithrombotic potential of this new class of antiplatelet agents.
Magnetic Resonance Spectroscopic Pharmacodynamic Markers of the Heat Shock Protein 90 Inhibitor 17-Allylamino,17-Demethoxygeldanamycin (17AAG) in Human Colon Cancer Models
Authors: Y.-L. Chung
Journal: JNCI Journal of the National Cancer Institute (2003)

17-allylamino,17-demethoxygeldanamycin (17AAG) is a novel anticancer drug that inhibits heat shock protein 90 (Hsp90), resulting in proteasomal degradation of several oncogenic proteins. We used phosphorus magnetic resonance spectroscopy (31P-MRS) to determine whether 17AAG treatment leads to alterations in phospholipids that could serve as pharmacodynamic markers for tumor response to 17AAG.HCT116, HT29, and SW620 colon cancer cells were treated with 17AAG, and extracts were examined by 31P-MRS. HT29 cells were also treated with the active metabolite of 17AAG, 17-amino,17-demethoxygeldanamycin (17AG), or the inactive 17AAG analog NSC683666. MF-1 nude mice carrying HT29 xenografts were examined using in vivo 31P-MRS before and after 17AAG treatment; xenograft tumor extracts were examined by 31P-MRS and proton MRS (1H-MRS). Hsp90 client protein expression was determined by using western blots. Two-tailed t tests were used to compare metabolite concentrations and ratios, and a Mann-Whitney U test was used to compare proportions. All statistical tests were two-sided.17AAG treatment led to statistically significantly increased phosphocholine levels in all three cell lines (P =.02). 17AG treatment also increased phosphocholine levels in HT29 cells, whereas NSC683666 had no effect. The phosphomonoester/phosphodiester ratio was statistically significantly increased in the HT29 xenografts after 17AAG treatment relative to the pretreatment ratio (P =.02), whereas no statistically significant change was observed after vehicle treatment (P =.62). Statistically significant increases in phosphocholine, phosphoethanolamine, and valine levels were also observed in tumor extracts treated with 17AAG.Inhibition of Hsp90 by 17AAG resulted in altered phospholipid metabolism in cultured tumor cells and in tumor xenografts. The increases observed in phosphocholine and phosphomonoester levels suggest that these metabolites may have the potential to act as noninvasive pharmacodynamic markers for analyzing tumor response to treatment with 17AAG or other Hsp90 inhibitors.
Rituximab-related late-onset neutropenia in a patient with severe rheumatoid arthritis
Authors: H Marotte, G Paintaud, H Watier, P Miossec
Journal: Annals of the Rheumatic Diseases (2008)

Rituximab is effective in B-cell lymphomas but also in inflammatory diseases such as rheumatoid arthritis (RA).1 Several cases of late-onset neutropenia (LON) have been described in lymphomas.2–4 Reversible rituximab-related LON tends to occur 2–6 months after rituximab administration. The post-marketing rate of LON appears very low (<0.02% in a total of 300 000 patients).2 Its mechanism is unknown, although several hypotheses have been suggested.

We report one case of rituximab-related LON for the first time outside the lymphoma field and explore some of the proposed …
MicroRNA Biogenesis Is Required for Myc-Induced B-Cell Lymphoma Development and Survival
Authors: Maria Pia Arrate, Tiffaney Vincent, Jessica Odvody, Rekha Kar, Stephen N. Jones, Christine M. Eischen
Journal: Cancer Research (2010)

Many tumor cells express globally reduced levels of microRNAs (miRNA), suggesting that decreased miRNA expression in premalignant cells contributes to their tumorigenic phenotype. In support of this, Dicer, an RNase III-like enzyme that controls the maturation of miRNA, was recently shown to function as a haploinsufficient tumor suppressor in nonhematopoietic cells. Because the Myc oncoprotein, a critical inducer of B-cell lymphomas, was reported to suppress the expression of multiple miRNAs in lymphoma cells, it was presumed that a deficiency of Dicer and subsequent loss of miRNA maturation would accelerate Myc-induced lymphoma development. We report here that, surprisingly, a haploinsufficiency of Dicer in B cells failed to promote B-cell malignancy or accelerate Myc-induced B-cell lymphomagenesis in mice. Moreover, deletion of Dicer in B cells of CD19-cre(+)/Emicro-myc mice significantly inhibited lymphomagenesis, and all lymphomas that did arise in these mice lacked functional Cre expression and retained at least one functional Dicer allele. Uncharacteristically, the lymphomas that frequently developed in the CD19-cre(+)/Dicer(fl/fl)/Emicro-myc mice were of very early precursor B-cell origin, a stage of B-cell development prior to Cre expression. Therefore, loss of Dicer function was not advantageous for lymphomagenesis, but rather, Dicer ablation was strongly selected against during Myc-induced B-cell lymphoma development. Moreover, deletion of Dicer in established B-cell lymphomas resulted in apoptosis, revealing that Dicer is required for B-cell lymphoma survival. Thus, Dicer does not function as a haploinsufficient tumor suppressor in B cells and is required for B-cell lymphoma development and survival.
Potential involvement of the IL-33–ST2 axis in the pathogenesis of primary Sjögren's syndrome
Authors: Ahmad Awada, Charles Nicaise, Sabrina Ena, Liliane Schandéné, Joanne Rasschaert, Iuliana Popescu, Valérie Gangji, Muhammad S Soyfoo
Journal: Annals of the Rheumatic Diseases (2014)

To investigate the role of the interleukin (IL)-33-ST2 axis in the pathophysiology of primary Sjögren's syndrome (pSS).Serum levels of IL-33 and sST2 were determined by ELISA. The expression of IL-33 and ST2 was investigated in salivary glands (SG) by immunohistochemistry. PBMC were isolated and stimulated with IL-33, IL-12 and IL-23 and the cytokine profile response was examined by flow cytometry. Intracellular cytokine detection of IFNγ and IL-17 was performed by flow cytometry.Serum IL-33 and sST2 levels were increased in pSS patients compared with controls and patients with systemic lupus erythematosus. Expression of IL-33 was upregulated in SG with Chisholm scores of 2 and 3 of pSS patients but comparable with controls for SG with Chisholm score of 4. ST2 expression in SG was downregulated in pSS patients. IL-33 at different concentrations did not increase the secretion of pro-inflammatory cytokines but acted synergistically with IL-12 and IL-23 to promote IFNγ production. NK and NKT cells were identified as main producers of IFNγ in vitro and were found in SG of pSS patients.IL-33 is released in pSS, and acts with IL-12 and IL-23 to favour the secretion of IFNγ by NK and NKT cells.
A prospective randomised trial of protracted venous infusion 5-fluorouracil with or without mitomycin C in advanced colorectal cancer
Authors: P. Ross, A. Norman, D. Cunningham, A. Webb, T. Iveson, A. Padhani, J. Prendiville, M. Watson, A. Massey, R. Popescu, J. Oates
Journal: Annals of Oncology (1997)
Dissociation of Pulmonary Vascular Remodeling and Right Ventricular Pressure in Tissue Angiotensin-converting Enzyme-deficient Mice Under Conditions of Chronic Alveolar Hypoxia
Authors: ROBERT J. van SUYLEN, WENDY M. AARTSEN, JOS F. M. SMITS, MAT J. A. P. DAEMEN
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

The present study was designed to characterize the role of tissue angiotensin-converting enzyme (ACE) on pulmonary vascular remodeling and its functional consequences in chronic hypoxia. On the basis of data obtained by pharmacological inhibition of ACE in rats we hypothesized that, under chronic hypoxic conditions, tissue ACE-deficient mice show less remodeling of pulmonary arterioles as compared with wild-type mice, but have equally increased right ventricular pressures. Wild-type and tissue ACE-deficient mice were exposed to chronic hypoxia for 4 wk. Absence of tissue ACE did not affect the increase in the mean right ventricular pressures (MRVP) and the extent of right ventricular hypertrophy under chronic hypoxic conditions. Chronic hypoxia induced significant remodeling of pulmonary arterioles in tissue ACE-deficient mice. The percentage of completely muscularized arterioles was, however, lower in tissue ACE-deficient mice compared with wild-type animals (29 +/- 12 versus 41 +/- 18%, p < 0.05), whereas the percentage of partially muscularized arterioles had increased (48 +/- 11 versus 39 +/- 11%, p < 0.05). No sex-based effects were found. We conclude that the absence of tissue ACE does not prevent the MRVP and right ventricular weight from increasing during chronic hypoxia in the mouse. Also, pulmonary vascular remodeling occurs in hypoxic tissue ACE-deficient mice, albeit to a lower level than in mice that do have an intact ACE gene.
Trial of the Route of Early Nutritional Support in Critically Ill Adults
Authors: Sheila E. Harvey, Francesca Parrott, David A. Harrison, Danielle E. Bear, Ella Segaran, Richard Beale, Geoff Bellingan, Richard Leonard, Michael G. Mythen, Kathryn M. Rowan
Journal: New England Journal of Medicine (2014)

Uncertainty exists about the most effective route for delivery of early nutritional support in critically ill adults. We hypothesized that delivery through the parenteral route is superior to that through the enteral route.
Tissue Culture Assay for Moloney Leukemia Virus&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Bo A. Nordenskjöld, Eva Klein, Takehiko Tachibana, Eva Maria Fenyö
Journal: JNCI Journal of the National Cancer Institute (1970)

Journal Article Tissue Culture Assay for Moloney Leukemia Virus Get access Bo A. Nordenskjöld, Bo A. Nordenskjöld Department of Tumor Biology, Karolinska Institutet, Stockholm 60, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Eva Klein, Eva Klein Department of Tumor Biology, Karolinska Institutet, Stockholm 60, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Takehiko Tachibana, Takehiko Tachibana Department of Tumor Biology, Karolinska Institutet, Stockholm 60, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar Eva Maria Fenyö Eva Maria Fenyö Department of Tumor Biology, Karolinska Institutet, Stockholm 60, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 44, Issue 2, February 1970, Pages 403–412, https://doi.org/10.1093/jnci/44.2.403 Published: 01 February 1970 Article history Received: 15 August 1969 Accepted: 27 October 1969 Published: 01 February 1970
Natural HLA Class I Polymorphism Controls the Pathway of Antigen Presentation and Susceptibility to Viral Evasion
Authors: Danielle Zernich, Anthony W. Purcell, Whitney A. Macdonald, Lars Kjer-Nielsen, Lauren K. Ely, Nihay Laham, Tanya Crockford, Nicole A. Mifsud, Mandvi Bharadwaj, Linus Chang, Brian D. Tait, Rhonda Holdsworth, Andrew G. Brooks, Stephen P. Bottomley, Travis Beddoe, Chen Au Peh, Jamie Rossjohn, James McCluskey
Journal: The Journal of Experimental Medicine (2004)

HLA class I polymorphism creates diversity in epitope specificity and T cell repertoire. We show that HLA polymorphism also controls the choice of Ag presentation pathway. A single amino acid polymorphism that distinguishes HLA-B*4402 (Asp116) from B*4405 (Tyr116) permits B*4405 to constitutively acquire peptides without any detectable incorporation into the transporter associated with Ag presentation (TAP)-associated peptide loading complex even under conditions of extreme peptide starvation. This mode of peptide capture is less susceptible to viral interference than the conventional loading pathway used by HLA-B*4402 that involves assembly of class I molecules within the peptide loading complex. Thus, B*4402 and B*4405 are at opposite extremes of a natural spectrum in HLA class I dependence on the PLC for Ag presentation. These findings unveil a new layer of MHC polymorphism that affects the generic pathway of Ag loading, revealing an unsuspected evolutionary trade-off in selection for optimal HLA class I loading versus effective pathogen evasion.
Long-Term Effects of Surgical Septal Myectomy on Survival in Patients With Obstructive Hypertrophic Cardiomyopathy
Authors: Steve R. Ommen, Barry J. Maron, Iacopo Olivotto, Martin S. Maron, Franco Cecchi, Sandro Betocchi, Bernard J. Gersh, Michael J. Ackerman, Robert B. McCully, Joseph A. Dearani, Hartzell V. Schaff, Gordon K. Danielson, A. Jamil Tajik, Rick A. Nishimura
Journal: Journal of the American College of Cardiology (2005)
53BP1 Is a Haploinsufficient Tumor Suppressor and Protects Cells from Radiation Response in Glioma
Authors: Massimo Squatrito, Fabio Vanoli, Nikolaus Schultz, Maria Jasin, Eric C. Holland
Journal: Cancer Research (2012)

The DNA damage response (DDR) plays a crucial role in tumor development in different tissues. Here, we show that p53-binding protein 1 (53BP1), a key element of the DDR, is heterozygously lost in approximately 20% of human glioblastoma multiforme (GBM) specimens, primarily of the Proneural subtype, and low 53BP1 expression levels are associated with worse prognosis. We present evidence that 53BP1 behaves as haploinsufficient tumor suppressor in a mouse model of platelet-derived growth factor-induced gliomagenesis. We also show that very low level of 53BP1 as found in 53BP1 null gliomas or robust 53BP1 gene silencing in glioma cell lines (but not 53BP1 heterozygous tumors or partial gene knockdown) sensitizes glioma cells to ionizing radiation (IR), both in vitro and in vivo. We further show the 53BP1 gene silencing induces defects in the nonhomologous end-joining (NHEJ) DNA repair pathway. These deficiencies lead to a failure to fully repair the damaged DNA upon exposure of glioma cells to IR with a consequent prolonged cell-cycle arrest and increased apoptosis. Our data suggest that either 53BP1 or other NHEJ components may be critical molecules to be pharmacologically targeted in GBM in combination with standard therapies.
Functional Mineralocorticoid Receptors in Human Vascular Endothelial Cells Regulate Intercellular Adhesion Molecule-1 Expression and Promote Leukocyte Adhesion
Authors: Massimiliano Caprio, Brenna G. Newfell, Andrea la Sala, Wendy Baur, Andrea Fabbri, Giuseppe Rosano, Michael E. Mendelsohn, Iris Z. Jaffe
Journal: Circulation Research (2008)

In clinical trials, aldosterone antagonists decrease cardiovascular mortality and ischemia by unknown mechanisms. The steroid hormone aldosterone acts by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor. In humans, aldosterone causes MR-dependent endothelial cell (EC) dysfunction and in animal models, aldosterone increases vascular macrophage infiltration and atherosclerosis. MR antagonists inhibit these effects without changing blood pressure, suggesting a direct role for vascular MR in EC function and atherosclerosis. Whether human vascular ECs express functional MR is not known. Here, we show that human coronary artery and aortic ECs express MR mRNA and protein and that EC MR mediates aldosterone-dependent gene transcription. Human ECs also express the enzyme 11-β-hydroxysteroid dehydrogenase-2 (11βHSD2), and inhibition of 11βHSD2 in aortic ECs enhances gene transactivation by cortisol, supporting that EC 11βHSD2 is functional. Furthermore, aldosterone stimulates transcription of the proatherogenic leukocyte–EC adhesion molecule intercellular adhesion molecule (ICAM)1 gene and protein expression on human coronary artery ECs, an effect inhibited by the MR antagonist spironolactone and by MR knock down with small interfering RNA. Cell adhesion assays demonstrate that aldosterone promotes leukocyte–EC adhesion, an effect that is inhibited by spironolactone and ICAM1 blocking antibody, supporting that aldosterone induction of EC ICAM1 surface expression via MR mediates leukocyte–EC adhesion. These data show that aldosterone activates endogenous EC MR and proatherogenic gene expression in clinically important human ECs. These studies describe a novel mechanism by which aldosterone may influence ischemic cardiovascular events and support a new explanation for the decrease in ischemic events in patients treated with aldosterone antagonists.
In vitro estrogenicity of polybrominated diphenyl ethers, hydroxylated PDBEs, and polybrominated bisphenol A compounds.
Authors: I A Meerts, R J Letcher, S Hoving, G Marsh, A Bergman, J G Lemmen, B van der Burg, A Brouwer
Journal: Environmental Health Perspectives (2001)

Polybrominated diphenyl ethers (PBDEs) are used in large quantities as additive flame retardants in plastics and textile materials. PBDEs are persistent compounds and have been detected in wildlife and in human adipose tissue and plasma samples. In this study, we investigated the (anti)estrogenic potencies of several PBDE congeners, three hydroxylated PBDEs (HO-PBDEs), and differently brominated bisphenol A compounds in three different cell line assays based on estrogen receptor (ER)-dependent luciferase reporter gene expression. In human T47D breast cancer cells stably transfected with an estrogen-responsive luciferase reporter gene construct (pEREtata-Luc), 11 PBDEs showed estrogenic potencies, with concentrations leading to 50% induction (EC(50)) varying from 2.5 to 7.3 microM. The luciferase induction of the most potent HO-PBDE [2-bromo-4-(2,4,6-tribromophenoxy)phenol] exceeded that of estradiol (E(2)), though at concentrations 50,000 times higher. As expected, brominated bisphenol A compounds with the lowest degree of bromination showed highest estrogenic potencies (EC(50) values of 0.5 microM for 3-monobromobisphenol A). In an ER alpha-specific, stably transfected human embryonic kidney cell line (293-ER alpha-Luc), the HO-PBDE 4-(2,4,6-tribromophenoxy)phenol was a highly potent estrogen with an EC(50) < 0.1 microM and a maximum 35- to 40-fold induction, which was similar to E(2). In an analogous ER beta-specific 293-ER betas-Luc cell line, the agonistic potency of the 4-(2,4,6-tribromophenoxy)phenol was much lower (maximum 50% induction compared to E(2)), but EC(50) values were comparable. These results indicate that several pure PBDE congeners, but especially HO-PBDEs and brominated bisphenol A-analogs, are agonists of both ER alpha and ER beta receptors, thus stimulating ER-mediated luciferase induction in vitro. These data also suggest that in vivo metabolism of PBDEs may produce more potent pseudoestrogens.