tbuckley/cabot-search huggingface dataset:
Quantitative GSTP1 Methylation and the Detection of Prostate Adenocarcinoma in Sextant Biopsies
Authors: S. V. Harden
Journal: JNCI Journal of the National Cancer Institute (2003)

Hypermethylation of the 5′ promoter region of the glutathione S-transferase π gene (GSTP1) occurs at a very high frequency in prostate adenocarcinoma. We compared the results of blinded histologic review of sextant biopsy samples from 72 excised prostates with those obtained using a quantitative methylation-specific polymerase chain reaction assay (QMSP) for GSTP1. Formal surgical pathologic review of the resected prostates was used to determine the number of patients with (n = 61) and without (n = 11) prostate cancer. Histology alone detected prostate carcinoma with 64% sensitivity (95% confidence interval [CI] = 51% to 76%) and 100% specificity (95% CI = 72% to 100%), whereas the combination of histology and GSTP1 QMSP at an assay threshold greater than 10 detected prostate carcinoma with 75% sensitivity (95% CI = 63% to 86%) and 100% specificity (95% CI = 72% to 100%), an 11% improvement (95% CI = 5% to 22%) in sensitivity over histology alone. The combination of histology and GSTP1 QMSP at an assay threshold greater than 5 detected prostate adenocarcinoma with 79% sensitivity (95% CI = 68% to 89%), a 15% improvement (95% CI = 7% to 26%) over histology alone. Thus, GSTP1 QMSP improved the sensitivity of histologic review of random needle biopsies for prostate cancer diagnosis. Further studies should determine whether detection of GSTP1 hypermethylation in a biopsy sample with normal histology indicates the need for an early repeat biopsy at the same site.
Bleomycin and IL-1β–mediated pulmonary fibrosis is IL-17A dependent
Authors: Mark S. Wilson, Satish K. Madala, Thirumalai R. Ramalingam, Bernadette R. Gochuico, Ivan O. Rosas, Allen W. Cheever, Thomas A. Wynn
Journal: The Journal of Experimental Medicine (2010)

Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4+ and γδ+ T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a−/− mice confirmed an essential role for IL-17A. Mechanistically, using ifnγ−/−, il10−/−, il10−/−il12p40−/−, and il10−/−il17a−/− mice and TGF-β blockade, we demonstrate that IL-17A–driven fibrosis is suppressed by IL-10 and facilitated by IFN-γ and IL-12/23p40. BLM-induced IL-17A production was also TGF-β dependent, and recombinant IL-17A–mediated fibrosis required TGF-β, suggesting cooperative roles for IL-17A and TGF-β in the development of fibrosis. Finally, we show that fibrosis induced by IL-1β, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1β were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis.
High-Density Lipoproteins and Their Constituent, Sphingosine-1-Phosphate, Directly Protect the Heart Against Ischemia/Reperfusion Injury In Vivo via the S1P <sub>3</sub> Lysophospholipid Receptor
Authors: Gregor Theilmeier, Christoph Schmidt, Jörg Herrmann, Petra Keul, Michael Schäfers, Ilka Herrgott, Jan Mersmann, Jan Larmann, Sven Hermann, Jörg Stypmann, Otmar Schober, Reinhard Hildebrand, Rainer Schulz, Gerd Heusch, Michael Haude, Karin von Wnuck Lipinski, Christine Herzog, Martina Schmitz, Raimund Erbel, Jerold Chun, Bodo Levkau
Journal: Circulation (2006)

Background— All treatments of acute myocardial infarction are aimed at rapid revascularization of the occluded vessel; however, no clinical strategies are currently available to protect the heart from ischemia/reperfusion injury after restitution of blood flow. We hypothesized that some of the cholesterol transport–independent biological properties of high-density lipoprotein (HDL) implied in atheroprotection may also be beneficial in settings of acute myocardial reperfusion injury. Methods and Results— In an in vivo mouse model of myocardial ischemia/reperfusion, we observed that HDL and its sphingolipid component, sphingosine-1-phosphate (S1P), dramatically attenuated infarction size by ≈20% and 40%, respectively. The underlying mechanism was an inhibition of inflammatory neutrophil recruitment and cardiomyocyte apoptosis in the infarcted area. In vitro, HDL and S1P potently suppressed leukocyte adhesion to activated endothelium under flow and protected rat neonatal cardiomyocytes against apoptosis. In vivo, HDL- and S1P-mediated cardioprotection was dependent on nitric oxide (NO) and the S1P 3 lysophospholipid receptor, because it was abolished by pharmacological NO synthase inhibition and was completely absent in S1P 3 -deficient mice. Conclusions— Our data demonstrate that HDL and its constituent, S1P, acutely protect the heart against ischemia/reperfusion injury in vivo via an S1P 3 -mediated and NO-dependent pathway. A rapid therapeutic elevation of S1P-containing HDL plasma levels may be beneficial in patients at high risk of acute myocardial ischemia.
Tissue Inhibitor of Metalloproteinase 3 Suppresses Tumor Angiogenesis in Matrix Metalloproteinase 2–Down-regulated Lung Cancer
Authors: Chandramu Chetty, Sajani S. Lakka, Praveen Bhoopathi, Sateesh Kunigal, Roger Geiss, Jasti S. Rao
Journal: Cancer Research (2008)

Abstract Matrix metalloproteinase-2 (MMP-2) expression is often up-regulated in advanced cancers and known to play an important role in tumor angiogenesis. We previously showed that adenoviral-mediated delivery of siRNA for MMP-2 (Ad-MMP-2-Si) inhibited lung cancer growth, angiogenesis, and metastasis. In this study, we investigated the signaling mechanisms involved in Ad-MMP-2-Si–mediated inhibition of angiogenesis. Ad-MMP-2-Si treatment inhibited neovascularization in vivo as determined by mouse dorsal air sac model, and conditioned medium from Ad-MMP-2-Si–infected A549 lung cancer cells (Ad-MMP-2-Si-CM) inhibited endothelial tube formation in vitro. Ad-MMP-2-Si-CM decreased proliferation as determined by Ki-67 immunofluorescence and induced apoptosis in endothelial cells as determined by terminal deoxynucleotidyl-transferase–mediated dUTP nick-end labeling (TUNEL) assay. Furthermore, Ad-MMP-2-Si-CM inhibited AKT phosphorylation and induced phosphorylation of extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase in endothelial cells. Overexpression of constitutively active AKT reversed the Ad-MMP-2-Si-CM–mediated inhibition of tube formation and induction of ERK phosphorylation. Conversely, Ad-MMP-2-Si-CM induced tissue inhibitor of metalloproteinase (TIMP) 3 expression, and the interaction of vascular endothelial growth factor 2 and TIMP-3 was determined by coimmunoprecipitation experiments. TIMP-3 induction was mediated by ERK activation. In addition, electrophoretic mobility shift and chromatin immunoprecipitation assays show that Sp1 transcription factor mediated Ad-MMP-2-Si-CM–stimulated increase of TIMP-3. Vasculature destruction was confirmed with colocalization studies with TUNEL and an endothelial marker, CD31, in tumor sections of Ad-MMP-2-Si–treated mice. Our data collectively suggest that MMP-2 inhibition induces endothelial apoptosis in vivo and inhibits endothelial tube formation. These experiments provide the first evidence that inhibition of p-AKT and induction of p-ERK1/2 are crucial events in the induction of TIMP-3–mediated endothelial apoptosis in MMP-2 inhibited lung tumors. [Cancer Res 2008;68(12):4736–45]
Enhancement of Drug Delivery: Enzyme-replacement Therapy for Murine Morquio A Syndrome
Authors: Shunji Tomatsu, Adriana M Montaño, Vu Chi Dung, Amiko Ohashi, Hirotaka Oikawa, Toshihiro Oguma, Tadao Orii, Luis Barrera, William S Sly
Journal: Molecular Therapy (2010)

Mucopolysaccharidosis IVA (MPS IVA, Morquio A disease) is an inherited lysosomal storage disorder that features skeletal chondrodysplasia caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Human GALNS was bioengineered with the N-terminus extended by the hexaglutamate sequence (E6) to improve targeting to bone (E6-GALNS). We initially assessed blood clearance and tissue distribution. Next, to assess the effectiveness of storage clearance and reversal of pathological phenotype, a dose of 250 U/g of enzyme was given weekly to Morquio A mice (adults: 12 or 24 weeks, newborn: 8 weeks). Sulfatase modifier factor 1 (SUMF1) was co-transfected to activate the enzyme fully. The E6-GALNS tagged enzyme had markedly prolonged clearance from circulation, giving over 20 times exposure time in blood, compared to untagged enzyme. The tagged enzyme was retained longer in bone, with residual enzyme activity demonstrable at 48 hours after infusion. The pathological findings in adult mice treated with tagged enzyme showed substantial clearance of the storage materials in bone, bone marrow, and heart valves, especially after 24 weekly infusions. Mice treated from the newborn period showed marked reduction of storage materials in tissues investigated. These findings indicate the feasibility of using tagged enzyme to enhance delivery and pathological effectiveness in Morquio A mice. Mucopolysaccharidosis IVA (MPS IVA, Morquio A disease) is an inherited lysosomal storage disorder that features skeletal chondrodysplasia caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Human GALNS was bioengineered with the N-terminus extended by the hexaglutamate sequence (E6) to improve targeting to bone (E6-GALNS). We initially assessed blood clearance and tissue distribution. Next, to assess the effectiveness of storage clearance and reversal of pathological phenotype, a dose of 250 U/g of enzyme was given weekly to Morquio A mice (adults: 12 or 24 weeks, newborn: 8 weeks). Sulfatase modifier factor 1 (SUMF1) was co-transfected to activate the enzyme fully. The E6-GALNS tagged enzyme had markedly prolonged clearance from circulation, giving over 20 times exposure time in blood, compared to untagged enzyme. The tagged enzyme was retained longer in bone, with residual enzyme activity demonstrable at 48 hours after infusion. The pathological findings in adult mice treated with tagged enzyme showed substantial clearance of the storage materials in bone, bone marrow, and heart valves, especially after 24 weekly infusions. Mice treated from the newborn period showed marked reduction of storage materials in tissues investigated. These findings indicate the feasibility of using tagged enzyme to enhance delivery and pathological effectiveness in Morquio A mice.
Does an oral analgesic protocol improve pain control for patients with cancer? An intergroup study coordinated by the Eastern Cooperative Oncology Group
Authors: C.S. Cleeland, R.K. Portenoy, M. Rue, T.R. Mendoza, E. Weller, R. Payne, J. Kirshner, J.N. Atkins, P.A. Johnson, A. Marcus
Journal: Annals of Oncology (2005)
Chemically induced cosmetic alopecia
Authors: A.G. NICHOLSON, C.C. HARLAND, R.H. BULL, P.S. MORTTMHR, M.G. COOK
Journal: British Journal of Dermatology (1993)

Cosmetic causes of scarring alopecia are poorly documented. They include traction alopecia and hotcombing. Recently, another group has presented in the South London area, related to misuse of chemical hair straightening agents. Affected patients are young, female, of Afro-Caribbean origin, and typically display hair loss on the vertex of the scaip. Histology shows a pattern of fibrosis and inflammation characteristic of the physical damage seen with other cosmetic procedures. This histological pattern is distinguishable from other non-cosmetic causes of scarring alopecia.
Environmental Genotoxicity Evaluation Using Cytogenetic End Points in Wild Rodents
Authors: Angela Maria de Souza Bueno, Carlos Alberto de Braganca Pereira, M. Nazareth Rabello-Gay
Journal: Environmental Health Perspectives (2000)

We analyzed cytogenetic end points in three populations of two species of wild rodents--Akodon montensis and Oryzomys nigripes--living in an industrial, an agricultural, and a preservation area at the Itajai Valley, state of Santa Catarina, Brazil. Our purpose was to evaluate the performance of the following end points in the establishment of a genotoxic profile of each area: the polychromatic/normochromatic cell ratio; the mitotic index; the frequency of micronucleated cells both in the bone marrow and peripheral blood; and the frequency of cells with chromosome aberrations in the bone marrow. Preparations were obtained using conventional cytogenetic techniques. The results showed a) the role of the end points used as biomarkers in the early detection of genotoxic agents and in the identification of species and populations at higher risk; b) the difference in sensitivity of the species selected as bioindicators in relation to the cytogenetic end points analyzed; c) the need to use at least two sympatric species to detect the presence of genotoxins in each locality; and d) the need to use several end points when trying to establish a genotoxic profile of an area.
When can personal best peak flow be determined for asthma action plans?
Authors: H K Reddel
Journal: Thorax (2004)

<b>Background:</b> Written asthma action plans based on personal best peak expiratory flow (PEF) consistently improve health outcomes, whereas those based on predicted PEF do not. Guidelines state that personal best PEF should be assessed over 2–3 weeks during good asthma control, but it is unclear how long to wait after commencing or changing treatment. <b>Methods:</b> Electronically recorded spirometric data from 61 subjects with initially poorly controlled asthma from a 72 week budesonide study were analysed. For each week, average morning pre-bronchodilator PEF was calculated and personal best PEF was determined as the highest PEF in the previous 2 weeks. The time to plateau was defined as the week beyond which no further improvement occurred. <b>Results:</b> At baseline, average morning PEF was 61% predicted and personal best PEF was 87% predicted. Personal best PEF from twice daily monitoring increased to a plateau of 95% predicted (p&lt;0.0001) after only 3 weeks of budesonide treatment. However, average morning PEF continued to improve for 3 months and "as needed" reliever use for 7 months. <b>Conclusions:</b> Personal best PEF is a useful concept for asthma self-management plans when determined as the highest PEF over the previous 2 weeks. With twice daily monitoring, personal best PEF reaches plateau levels after only a few weeks of corticosteroid treatment.
HFEA widens its criteria for preimplantation genetic diagnosis
Authors: Clare Dyer
Journal: BMJ (2006)

Screening embryos for a wider range of genetic conditions was given the go ahead by the Human Fertilisation and Embryology Authority (HFEA), the United Kingdom's fertility watchdog, last week.

Preimplantation genetic diagnosis was already approved for a limited number of conditions with which a baby is born—such as cystic fibrosis—or that it risks developing early in life—for example, the cancers retinoblastoma and familial adenomatous polyposis. Both cancers have “high penetrance”—children born with the genetic mutation have a 90% chance of developing the condition.

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MGMT Promoter Methylation and Field Defect in Sporadic Colorectal Cancer
Authors: Lanlan Shen, Yutaka Kondo, Gary L. Rosner, Lianchun Xiao, Natalie Supunpong Hernandez, Jill Vilaythong, P. Scott Houlihan, Robert S. Krouse, Anil R. Prasad, Janine G. Einspahr, Julie Buckmeier, David S. Alberts, Stanley R. Hamilton, Jean-Pierre J. Issa
Journal: JNCI Journal of the National Cancer Institute (2005)

Sporadic colorectal cancers often arise from a region of cells characterized by a "field defect" that has not been well defined molecularly. DNA methylation has been proposed as a candidate mediator of this field defect. The DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) is frequently methylated in colorectal cancer. We hypothesized that MGMT methylation could be one of the mediators of field cancerization in the colon mucosa.We studied MGMT promoter methylation by three different bisulfite-based techniques in tumor, adjacent mucosa, and non-adjacent mucosa from 95 colorectal cancer patients and in colon mucosa from 33 subjects with no evidence of cancer. Statistical tests were two-sided.MGMT promoter methylation was present in 46% of the tumors. Patients whose cancer had MGMT promoter methylation also had substantial MGMT promoter methylation in apparently normal adjacent mucosa. This methylation was seen with a quantitative assay in 50% (22/44; 95% confidence interval [CI] = 34% to 65%) of normal samples with MGMT promoter methylation in the adjacent tumors, 6% (3/51; 95% CI = 1% to 16%) of samples without MGMT methylation in adjacent tumors, and 12% (4/33; 95% CI = 3% to 28%) of control samples (P < .001 for comparison between each of the latter two groups and the first group). MGMT methylation was detected with a more sensitive assay in 94%, 34%, and 27% of these samples, respectively (P < .001). In grossly normal colonic mucosa of colon cancer patients, methylation was detected 10 cm away from the tumor in 10 of 13 cases. Tumors with MGMT promoter methylation had a higher rate of G-to-A mutation in the KRAS oncogene than tumors without MGMT promoter methylation (10/42 versus 3/46, P = .03). Using a sensitive mutant allele-specific amplification assay for KRAS mutations, we also found KRAS mutations in 12% (3/25; 95% CI = 2.5% to 31%) of colorectal mucosas with detectable MGMT methylation and 3% (2/64; 95% CI = 0.4% to 11%) of colorectal mucosas without MGMT methylation (P = .13).Some colorectal cancers arise from a field defect defined by epigenetic inactivation of MGMT. Detection of this abnormality may ultimately be useful in risk assessment for colorectal cancer.
Myosin Phosphatase Modulates the Cardiac Cell Fate by Regulating the Subcellular Localization of Nkx2.5 in a Wnt/Rho–Associated Protein Kinase–Dependent Pathway
Authors: Tammy Ryan, Michael Shelton, Jean-Philippe Lambert, Barbora Malecova, Sophie Boisvenue, Marc Ruel, Daniel Figeys, Pier Lorenzo Puri, Ilona S. Skerjanc
Journal: Circulation Research (2012)

Nkx2.5 is a transcription factor that regulates cardiomyogenesis in vivo and in embryonic stem cells. It is also a common target in congenital heart disease. Although Nkx2.5 has been implicated in the regulation of many cellular processes that ultimately contribute to cardiomyogenesis and morphogenesis of the mature heart, relatively little is known about how it is regulated at a functional level.We have undertaken a proteomic screen to identify novel binding partners of Nkx2.5 during cardiomyogenic differentiation in an effort to better understand the regulation of its transcriptional activity.Purification of Nkx2.5 from differentiating cells identified the myosin phosphatase subunits protein phosphatase 1β and myosin phosphatase targeting subunit 1 (Mypt1) as novel binding partners. The interaction with protein phosphatase 1 β/Mypt1 resulted in exclusion of Nkx2.5 from the nucleus and, consequently, inhibition of its transcriptional activity. Exclusion of Nkx2.5 was inhibited by treatment with leptomycin B and was dependent on an Mypt1 nuclear export signal. Furthermore, in transient transfection experiments, Nkx2.5 colocalized outside the nucleus with phosphorylated Mypt1 in a manner dependent on Wnt signaling and Rho-associated protein kinase. Treatment of differentiating mouse embryonic stem cells with Wnt3a resulted in enhanced phosphorylation of endogenous Mypt1, increased nuclear exclusion of endogenous Nkx2.5, and a failure to undergo terminal cardiomyogenesis. Finally, knockdown of Mypt1 resulted in rescue of Wnt3a-mediated inhibition of cardiomyogenesis, indicating that Mypt1 is required for this process.We have identified a novel interaction between Nkx2.5 and myosin phosphatase. Promoting this interaction represents a novel mechanism whereby Wnt3a regulates Nkx2.5 and inhibits cardiomyogenesis.
THE PROTEINS IN UNHEATED CULTURE FILTRATES OF HUMAN TUBERCLE BACILLI
Authors: Janet R. McCarter, Ellen B. Bevilacqua
Journal: The Journal of Experimental Medicine (1948)

1. Only two serologically different proteins were found in the unheated culture filtrates of both virulent and slightly virulent tubercle bacilli. One of them was the protein which had a sedimentation constant of 3.4 S, and the other was in filtrate fractions with a constant of 2 S. 2. That these proteins were distinct was demonstrated by three methods: quantitative precipitin and precipitin absorption tests with rabbit antisera, skin tests in guinea pigs actively sensitized with the culture filtrate fractions, and skin tests in passively sensitized guinea pigs. 3. A third antigen of unknown nature was found by means of the precipitin tests, but only in certain fractions from the virulent culture filtrate. 4. The protein with the constant of 3.4 S could not be demonstrated serologically in an O.T. made from the same culture filtrate as the unheated preparation from the virulent organism.
Protein Kinase Cε, which Sensitizes Skin to Sun's UV Radiation–Induced Cutaneous Damage and Development of Squamous Cell Carcinomas, Associates with Stat3
Authors: Moammir H. Aziz, Herbert T. Manoharan, Ajit K. Verma
Journal: Cancer Research (2007)

Abstract Chronic exposure to UV radiation (UVR) is the major etiologic factor in the development of human skin cancers including squamous cell carcinoma (SCC). We have shown that protein kinase Cε (PKCε), a Ca2+-independent, phospholipid-dependent serine/threonine kinase, is an endogenous photosensitizer. PKCε is among the six isoforms (α, δ, ε, η, μ, and ζ) expressed in both mouse and human skin. PKCε transgenic mice, which overexpress PKCε in the basal epidermal cells and cells of the hair follicle, are highly sensitive to UVR-induced cutaneous damage and development of SCC. We now present that PKCε-overexpressing, but not PKCδ-overexpressing, transgenic mice, when exposed to a single (4 kJ/m2) or repeated (four doses, 2 kJ/m2/dose, thrice weekly) UVR, emitted by Kodacel-filtered FS-40 sun lamps, elicit constitutive phosphorylation of signal transducers and activators of transcription 3 (Stat3) at both Tyr705 and Ser727 residues. UVR-induced phosphorylation of Stat3 accompanied increased expression of Stat3-regulated genes (c-myc, cyclin D1, cdc25A, and COX-2). In reciprocal immunoprecipitation/blotting experiments, phosphorylated Stat3 coimmunoprecipitated with PKCε. As observed in vivo using PKCε knockout mice and in vitro in an immunocomplex kinase assay, PKCε phosphorylated Stat3 at Ser727 residue. These results indicate for the first time that (a) PKCε is a Stat3Ser727 kinase; (b) PKCε-mediated phosphorylation of StatSer727 may be essential for transcriptional activity of Stat3; and (c) UVR-induced phosphorylation of Ser727 may be a key component of the mechanism by which PKCε imparts sensitivity to UVR-induced development of SCC. [Cancer Res 2007;67(3):1385–94]