tbuckley/cabot-search huggingface dataset:
Moesin Is a Glioma Progression Marker That Induces Proliferation and Wnt/β-Catenin Pathway Activation via Interaction with CD44
Authors: Xiaoping Zhu, Fabiana C. Morales, Nitin Kumar Agarwal, Turgut Dogruluk, Mihai Gagea, Maria-Magdalena Georgescu
Journal: Cancer Research (2012)

Abstract Moesin is an ERM family protein that connects the actin cytoskeleton to transmembrane receptors. With the identification of the ERM family protein NF2 as a tumor suppressor in glioblastoma, we investigated roles for other ERM proteins in this malignancy. Here, we report that overexpression of moesin occurs generally in high-grade glioblastoma in a pattern correlated with the stem cell marker CD44. Unlike NF2, moesin acts as an oncogene by increasing cell proliferation and stem cell neurosphere formation, with its ectopic overexpression sufficient to shorten survival in an orthotopic mouse model of glioblastoma. Moesin was the major ERM member activated by phosphorylation in glioblastoma cells, where it interacted and colocalized with CD44 in membrane protrusions. Increasing the levels of moesin competitively displaced NF2 from CD44, increasing CD44 expression in a positive feedback loop driven by the Wnt/β-catenin signaling pathway. Therapeutic targeting of the moesin–CD44 interaction with the small-molecule inhibitor 7-cyanoquinocarcinol (DX-52-1) or with a CD44-mimetic peptide specifically reduced the proliferation of glioblastoma cells overexpressing moesin, where the Wnt/β-catenin pathway was activated. Our findings establish moesin and CD44 as progression markers and drugable targets in glioblastoma, relating their oncogenic effects to activation of the Wnt/β-catenin pathway. Cancer Res; 73(3); 1142–55. ©2012 AACR.
Studies on Mechanisms of Cerebral Edema in Diabetic Comas. EFFECTS OF HYPERGLYCEMIA AND RAPID LOWERING OF PLASMA GLUCOSE IN NORMAL RABBITS
Authors: Allen I. Arieff, Charles R. Kleeman
Journal: Journal of Clinical Investigation (1973)

To investigate the pathophysiology of cerebral edema occurring during treatment of diabetic coma, the effects of hyperglycemia and rapid lowering of plasma glucose were evaluated in normal rabbits. During 2 h of hyperglycemia (plasma glucose=61 mM), both brain (cerebral cortex) and muscle initially lost about 10% of water content. After 4 h of hyperglycemia, skeletal muscle water content remained low but that of brain was normal. Brain osmolality (Osm) (343 mosmol/kg H(2)O) was similar to that of cerebrospinal fluid (CSF) (340 mosmol/kg), but increases in the concentration of Na+, K+, Cl-, glucose, sorbitol, lactate, urea, myoinositol, and amino acids accounted for only about half of this increase. The unidentified solute was designated "idiogenic osmoles". When plasma glucose was rapidly lowered to normal with insulin, there was gross brain edema, increases in brain content of water, Na+, K+, Cl- and idiogenic osmoles, and a significant osmotic gradient from brain (326 mosmol/kg H(2)O) to plasma (287 mosmol/kg). By similarly lowering plasma glucose with peritoneal dialysis, increases in brain Na+, K+, Cl-, and water were significantly less, idiogenic osmoles were not present, and brain and plasma Osm were not different. It is concluded that during sustained hyperglycemia, the cerebral cortex adapts to extracellular hyperosmolality primarily by accumulation of idiogenic osmoles rather than loss of water or gain in solute. When plasma glucose is rapidly lowered with insulin, an osmotic gradient develops from brain to plasma. Despite the brain to plasma osmotic gradient, there is no net movement of water into brain until plasma glucose has fallen to at least 14 mM, at which time cerebral edema occurs.
Infrared Imaging: a Potential New Tool to Characterize Lymphocytic Infiltration in Human Breast Cancer
Authors: M. Verdonck, S. Garaud, H. Duvillier, N.F. Vermeulen, L. Buisseret, C. Desmedt, R. de Wind, C. Sotiriou, K. Willard-Gallo, E. Goormaghtigh
Journal: Annals of Oncology (2013)
The Steroid Receptor Coactivator-3 Is Required for the Development of Castration-Resistant Prostate Cancer
Authors: Jean C-Y. Tien, Zhaoliang Liu, Lan Liao, Fen Wang, Yixiang Xu, Ye-Lin Wu, Niya Zhou, Michael Ittmann, Jianming Xu
Journal: Cancer Research (2013)

Abstract The transcriptional coactivator SRC-3 plays a key role in enhancing prostate cancer cell proliferation. Although SRC-3 is highly expressed in advanced prostate cancer, its role in castration-resistant prostate cancer (CRPC) driven by PTEN mutation is unknown. We documented elevated SRC-3 in human CRPC and in PTEN-negative human prostate cancer. Patients with high SRC-3 and undetectable PTEN exhibited decreased recurrence-free survival. To explore the causal relationship in these observations, we generated mice in which both Pten and SRC-3 were inactivated in prostate epithelial cells (Pten3CKO mice), comparing them with mice in which only Pten was inactivated in these cells (PtenCKO mice). SRC-3 deletion impaired cellular proliferation and reduced tumor size. Notably, while castration of PtenCKO control mice increased the aggressiveness of prostate tumors relative to noncastrated counterparts, deletion of SRC-3 in Pten3CKO mice reversed all these changes. In support of this finding, castrated Pten3CKO mice also exhibited decreased levels of phospho-Akt, S6 kinase (RPS6KB1), and phosphorylated S6 protein (RPS6), all of which mediate cell growth and proliferation. Moreover, these tumors appeared to be more differentiated as evidenced by higher levels of Fkbp5, an AR-responsive gene that inhibits Akt signaling. Lastly, these tumors also displayed lower levels of certain androgen-repressed genes such as cyclin E2 and MMP10. Together, our results show that SRC-3 drives CRPC formation and offer preclinical proof of concept for a transcriptional coactivator as a therapeutic target to abrogate CRPC progression. Cancer Res; 73(13); 3997–4008. ©2013 AACR.
Determination of key structure–activity relationships in siRNA delivery with a mixed micelle system
Authors: Marta Omedes Pujol, Daniel J.L. Coleman, Christopher D. Allen, Olaf Heidenreich, David A. Fulton
Journal: Journal of Controlled Release (2013)

Short interfering ribonucleic acids (siRNAs) offer a highly specific and selective form of therapy for diseases with a genetic component; however the poor pharmacokinetic properties of the molecule have impeded its development into a therapeutic for use in vivo. Several different approaches have been taken to develop a successful siRNA delivery system but these systems lack the flexibility for easy optimisation. Here, we propose a polymeric nanoparticle (PNP) system consisting of two amphiphilic diblock copolymers which allow for the rapid determination of structure-activity relationships involving gene knockdown and toxicity. The diblock copolymers self-assemble into monodisperse micelles of defined hydrodynamic diameters ranging from 30 to 100 nm dependent on the copolymer ratio. A luciferase-based high throughput assay varying PNP composition, concentration and siRNA concentration allowed the rapid identification of efficient PNP formulations for adherent and suspension cell lines. Optimised PNPs efficiently knocked down a fusion oncogene in hard to transfect human leukaemic cells raising the possibility of targeting malignant cells in a cancer-specific fashion. This approach allows the optimum PNP formulation to be identified for different cell types and conditions.
Epigenetic Inactivation of the Canonical Wnt Antagonist SRY-Box Containing Gene 17 in Colorectal Cancer
Authors: Wei Zhang, Sabine C. Glöckner, Mingzhou Guo, Emi Ota Machida, David H. Wang, Hariharan Easwaran, Leander Van Neste, James G. Herman, Kornel E. Schuebel, D. Neil Watkins, Nita Ahuja, Stephen B. Baylin
Journal: Cancer Research (2008)

Abstract SRY-box containing gene 17 (Sox17) is a member of the high mobility group (HMG) transcription factor superfamily, which plays critical roles in the regulation of development and stem/precursor cell function, at least partly through repression of Wnt pathway activity. Modulators controlling aberrant Wnt signaling activation are frequently disrupted in human cancers through complementary effects of epigenetic and genetic changes. Our recent global analysis of CpG island hypermethylation and gene expression in colorectal cancer (CRC) cell lines revealed that SOX17 gene silencing is associated with DNA hypermethylation of a CpG island in the promoter region. Here, we report that CpG island methylation-dependent silencing of SOX17 occurs in 100% of CRC cell lines, 86% of colorectal adenomas, 100% of stage I and II CRC, 89% of stage III CRC, 89% of primary esophageal cancer, and 50% of non–small cell lung cancer. Overexpression of SOX17 in HCT116 CRC cells inhibits colony growth and β-catenin/T-cell factor–dependent transcription. Structure-based deletion analysis further shows the presence of a Wnt signaling repression domain in the SOX17 HMG box. Together, our studies suggest that SOX17 is a negative modulator of canonical Wnt signaling, and that SOX17 silencing due to promoter hypermethylation is an early event during tumorigenesis and may contribute to aberrant activation of Wnt signaling in CRC. [Cancer Res 2008;68(8):2764–72]
Reprogramming of vascular smooth muscle α-actin gene expression as an early indicator of dysfunctional remodeling following heart transplant
Authors: Sukanya V Subramanian, Robert J Kelm, John A Polikandriotis, Charles G Orosz, Arthur R Strauch
Journal: Cardiovascular Research (2002)

Objective: Chronic rejection in cardiac allografts depletes vascular smooth muscle (VSM) α-actin from the coronary arterial smooth muscle bed while promoting its abnormal accumulation in cardiomyocytes and myofibroblasts. The objective was to determine if the newly discovered TEF1, MSY1, Purα and Purβ VSM α-actin transcriptional reprogramming proteins (TRPs) were associated with development of chronic rejection histopathology in accepted murine cardiac allografts. Methods: A mouse heterotopic cardiac transplant model was employed using H2 locus-mismatched mouse strains (DBA/2 or FVB/N to C57BL/6). Recipients were immunosuppressed to promote long-term allograft acceptance and emergence of chronic rejection. Explanted grafts and isolated heart cells were evaluated for changes in the DNA-binding activity and subcellular distribution of VSM α-actin transcriptional regulatory proteins. Results: The DNA-binding activity of all four TRPs was high in the developing mouse ventricle, minimal in adult donor hearts and increased substantially within 30 days after transplantation. Immunohistologic analysis revealed nuclear localization of Purβ and MSY1 particularly in fibrotic areas of the allograft myocardium demonstrating extravascular accumulation of VSM α-actin. Cardiomyocytes isolated from adult, non-transplanted mouse hearts not only exhibited less VSM α-actin expression and lower levels of TRPs compared to isolated cardiac fibroblasts or neonatal cardiomyocytes, but also contained a novel size variant of the MSY1 protein. Conclusion: Accumulation of TRPs in cardiac allografts, particularly within the fibroblast-enriched myocardial interstitium, was consistent with their potential role in VSM α-actin gene reprogramming, fibrosis and dysfunctional remodeling following transplant. These nuclear protein markers could help stage peri-transplant cellular events that precede formation of graft-destructive fibrosis and coronary vasculopathy during chronic rejection.
A novel mechanism of factor VIII protection by von Willebrand factor from activated protein C–catalyzed inactivation
Authors: Keiji Nogami, Midori Shima, Katsumi Nishiya, Kazuya Hosokawa, Evgueni L. Saenko, Yoshihiko Sakurai, Masaru Shibata, Hiroshi Suzuki, Ichiro Tanaka, Akira Yoshioka
Journal: Blood (2002)
Histopathologic and Molecular Alterations in Bronchial Epithelium in Habitual Smokers of Marijuana, Cocaine, and/or Tobacco
Authors: Sanford H. Barsky, Michael D. Roth, Eric C. Kleerup, Michael Simmons, Donald P. Tashkin
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: Tobacco smoking has been observed to cause molecular alterations in bronchial epithelium that antedate the development of lung carcinoma. The rising prevalence of marijuana and cocaine use among young adults in the United States prompted us to investigate whether similar molecular and histopathologic alterations occur in habitual smokers of marijuana and/or cocaine who may or may not also smoke tobacco. Methods: Bronchoscopy was performed in 104 healthy volunteer subjects, including 28 nonsmokers and 76 smokers of one or more of the following substances: marijuana, tobacco, and/or cocaine. Bronchial mucosa biopsy specimens and brushings were analyzed for histopathologic changes, for immunohistopathologic expression of intermediate or surrogate end-point markers that are linked to an increased risk of cancer (Ki-67 [a marker of cell proliferation], epidermal growth factor receptor, p53, Her-2/neu [also known as erbB-2 and ERBB2], globular actin, and abnormal DNA ploidy). Reported P values are two-sided. Results: Smokers of any one substance or of two or more substances exhibited more alterations than nonsmokers in five to nine of the 10 histopathologic parameters investigated (all P<.05), and they exhibited more molecular abnormalities than nonsmokers. Differences between smokers and nonsmokers were statistically significant (all P⩽.01) for Ki-67, epidermal growth factor receptor, globular actin, and DNA ploidy. There was general agreement between the presence of molecular abnormalities and histopathologic alterations; however, when disagreement occurred, the molecular abnormalities (e.g., Ki-67 and epidermal growth factor receptor) were more frequently altered (all P⩽.01). Conclusions: These findings suggest that smoking marijuana and/or cocaine, like tobacco smoking, exerts field cancerization effects on bronchial epithelium, which may place smokers of these substances at increased risk for the subsequent development of lung cancer. [J Natl Cancer Inst 1998;90:1198–1205]
Transcytosis of Staphylococcal Superantigen Toxins
Authors: Abdel Rahim A. Hamad, Philippa Marrack, John W. Kappler
Journal: The Journal of Experimental Medicine (1997)

Staphylococcus aureus produces a set of proteins (e.g., staphylococcal enterotoxin A [SEA], SEB, toxic shock syndrome toxin 1 [TSST-1]) which act both as superantigens (SAgs) and toxins. Although their mode of action as SAgs is well understood, little is known about how they enter the body via the intestine and cause food poisoning. To examine this problem we used an in vitro culture system to study the capacity of class II MHC-negative human intestinal epithelial cells (Caco-2) to transcytose several staphylococcal toxins. We found that Caco-2 cells are capable of dosedependent, facilitated transcytosis of SEB and TSST-1, but not SEA. We extended these studies in vivo in mice by showing that ingested SEB appears in the blood more efficiently than SEA. Our data suggest that these toxins can cross the epithelium in an immunologically intact form. These results may have important implications for the pathogenesis of food poisoning.
Hypoglycemia and Clinical Outcomes in Patients With Diabetes Hospitalized in the General Ward
Authors: Jen M. Ng, Heidi Cox, David Longbotham, Eric S. Kilpatrick, Stephen L. Atkin, Belinda J. Allan
Journal: Diabetes Care (2009)

We read with interest the article by Turchin et al. (1) on clinical outcomes in patients with diabetes. The investigators show that hypoglycemia while in the hospital leads to an increase in length of stay and higher mortality. In parallel to this, we would also highlight the importance of staffing levels and the time to biochemical resolution of hypoglycemia. Previous studies have shown that low levels of hospital nursing staff lead to an increased incidence of pneumonia, bed sores, andtk;2 overall poorer outcomes (2). We studied the rates of hypoglycemia and the effect of nurse staffing on its resolution on a medical ward …
Disentangling Public Participation In Science and Biomedicine
Authors: Christopher Kelty, Aaron Panofsky
Journal: Genome Medicine (2014)

This article provides a framework for disentangling the concept of participation, with emphasis on participation in genomic medicine. We have derived seven 'dimensions' of participation that are most frequently invoked in the extensive, heterogeneous literature on participation. To exemplify these dimensions, we use material from a database of 102 contemporary cases of participation, and focus here on cases specific to science and medicine. We describe the stakes of public participation in biomedical research, with a focus on genomic medicine and lay out the seven dimensions.
The Prognostic Significance of Phosphatidylinositol 3-Kinase Pathway Activation in Human Gliomas
Authors: Arnab Chakravarti, Gary Zhai, Yoshiyuki Suzuki, Sormeh Sarkesh, Peter M. Black, Alona Muzikansky, Jay S. Loeffler
Journal: Journal of Clinical Oncology (2004)

Purpose The objectives of this study were to examine activation patterns of the phosphatidylinositol 3-kinase (PI3K) pathway in gliomas and to examine the prognostic significance of PI3K pathway activation using snap-frozen clinical specimens. Materials and Methods Levels of expression of PI3K pathway members were assessed in 92 prospectively collected gliomas through quantitative Western analysis using total and phospho-specific antibodies for PI3K, Akt, and p70 s6k . Both expression and expression levels of these PI3K pathway members were correlated with histology, markers of apoptosis (cleaved caspase 3), and with clinical outcome (eg, overall survival). Results It was determined that activation of all three PI3K pathway members were significantly more frequent in glioblastoma multiforme than in non-glioblastoma multiforme tumors. Levels of phospho-PI3K, phospho-Akt, and phospho-p70 s6k were all found to be inversely associated with cleaved caspase 3 levels, suggesting PI3K pathway activation is associated with reduced levels of apoptosis. Perhaps most importantly, activation of PI3K pathway members was found to be significantly associated with reduced survival times when all glioma cases were considered in aggregate. When glioblastoma cases were considered separately, the prognostic value of PI3K activation remained significant, suggesting that PI3K activation may directly be associated with radiation resistance, given that this was the only adjuvant therapy administered to this subset of patients. Conclusion Activation of the PI3K pathway is significantly associated with increasing tumor grade, decreased levels of apoptosis, and with adverse clinical outcome in human gliomas. Molecular pathways regulating PI3K activation would appear to be promising targets in the clinical management of glioma patients.
Effect of temperature on the rise in intracellular sodium caused by calcium depletion in ferret ventricular muscle and the mechanism of the alleviation of the calcium paradox by hypothermia.
Authors: M S Suleiman, R A Chapman
Journal: Circulation Research (1990)

The effects of temperature over the range 37-10 degrees C on the responses of isolated ferret ventricular trabeculae to the depletion and repletion of bathing calcium has been investigated. Cooling is found to reduce the rate of rise of intracellular sodium activity (measured with an ion-sensitive microelectrode) induced by depletion of bathing divalent cations, without affecting the prolonged depolarization. The rate of rise of [Na]i (with the sodium pump inhibited) shows a dependence on temperature (energy of activation, 67 kJ.mol-1; Q10, 2.3-2.8) that increases with increasing temperature. This contrasts with previously published data for the sodium pump for which the temperature dependence falls with increasing temperature. These results offer an explanation for the alleviation of the calcium paradox caused by cooling during the period of calcium depletion, which is similar to other procedures that offer protection by limiting the rise in [Na]i by having effects on the L-type calcium channel.
Autoantibodies Targeting Galactose-Deficient IgA1 Associate with Progression of IgA Nephropathy
Authors: Francois Berthoux, Hitoshi Suzuki, Lise Thibaudin, Hiroyuki Yanagawa, Nicolas Maillard, Christophe Mariat, Yasuhiko Tomino, Bruce A. Julian, Jan Novak
Journal: Journal of the American Society of Nephrology (2012)

Mesangial and circulating IgA1 with aberrantly glycosylated hinge region O-glycans characterize IgA nephropathy (IgAN). Unlike healthy individuals, some IgA1 is galactose deficient in patients with IgAN, leaving terminal N-acetylgalactosamine residues in the hinge region exposed. Circulating autoantibodies that recognize such galactose-deficient IgA1 as an autoantigen, or the levels of the autoantigen itself, may allow prediction of disease progression. Here, we analyzed serum samples obtained at diagnosis for autoantigen and autoantibodies from 97 patients with IgAN selected from our prospective cohort according to their absolute renal risk for progression to dialysis or death (0, very low; 1, low; 2, high; 3, very high). We also analyzed samples from controls comprising 30 healthy volunteers and 30 patients with non-IgAN disease. The mean follow-up was 13.8 years. We found that mean serum levels of total autoantigen, normalized IgG autoantibody, and total IgA autoantibody were significantly higher in patients than in the combined controls (all P≤0.01). Furthermore, increasing levels correlated with worse clinical outcomes. In Cox regression and Kaplan-Meier analyses, IgG autoantibody levels ≥1.33 predicted dialysis or death (both P≤0.01). In conclusion, these data suggest that serum levels of IgG and IgA autoantibodies strongly associate with the progression of IgAN nephropathy.
Sphygmomanometrically Determined Pulse Pressure Is a Powerful Independent Predictor of Recurrent Events After Myocardial Infarction in Patients With Impaired Left Ventricular Function
Authors: Gary F. Mitchell, Lemuel A. Moyé, Eugene Braunwald, Jean-Lucien Rouleau, Victoria Bernstein, Edward M. Geltman, Greg C. Flaker, Marc A. Pfeffer, for the SAVE Investigators
Journal: Circulation (1997)

Background There is increasing evidence of a link between conduit vessel stiffness and cardiovascular events, although the association has never been tested in a large post–myocardial infarction patient population. Methods and Results We evaluated the relationship between baseline pulse pressure, measured by sphygmomanometry 3 to 16 days after myocardial infarction, and subsequent adverse clinical events in the 2231 patients enrolled in the SAVE Trial. Increased pulse pressure was associated with increased age, left ventricular ejection fraction, female sex, history of prior infarction, diabetes, and hypertension and use of digoxin and calcium channel blockers. Over a 42-month period, there were 503 deaths, 422 cardiovascular deaths, and 303 myocardial infarctions. Pulse pressure was significantly related to each of these end points as a univariate predictor. In a multivariate analysis, pulse pressure remained a significant predictor of total mortality (relative risk, 1.08 per 10 mm Hg increment in pulse pressure; 95% CI, 1.00 to 1.17; P &lt;.05) and recurrent myocardial infarction (relative risk, 1.12; 95% CI, 1.01 to 1.23; P &lt;.05) after control for age; left ventricular ejection fraction; mean arterial pressure; sex; treatment arm (captopril or placebo); smoking history; history of prior myocardial infarction, diabetes, or hypertension; and treatment with β-blockers, calcium channel blockers, digoxin, aspirin, or thrombolytic therapy. Conclusions These data provide strong evidence for a link between pulse pressure, which is related to conduit vessel stiffness, and subsequent cardiovascular events after myocardial infarction in patients with left ventricular dysfunction.