tbuckley/cabot-search huggingface dataset:
Formation of Nitric Oxide–Derived Oxidants by Myeloperoxidase in Monocytes
Authors: Stanley L. Hazen, Renliang Zhang, Zhongzhou Shen, Weijia Wu, Eugene A. Podrez, Jennifer C. MacPherson, David Schmitt, Shome N. Mitra, Chaitali Mukhopadhyay, Yonghong Chen, Peter A. Cohen, Henry F. Hoff, Husam M. Abu-Soud
Journal: Circulation Research (1999)

Protein nitration and lipid peroxidation are implicated in the pathogenesis of atherosclerosis; however, neither the cellular mediators nor the reaction pathways for these events in vivo are established. In the present study, we examined the chemical pathways available to monocytes for generating reactive nitrogen species and explored their potential contribution to the protein nitration and lipid peroxidation of biological targets. Isolated human monocytes activated in media containing physiologically relevant levels of nitrite (NO(2)(-)), a major end product of nitric oxide ((*)NO) metabolism, nitrate apolipoprotein B-100 tyrosine residues and initiate LDL lipid peroxidation. LDL nitration (assessed by gas chromatography-mass spectrometry quantification of nitrotyrosine) and lipid peroxidation (assessed by high-performance liquid chromatography with online tandem mass spectrometric quantification of distinct products) required cell activation and NO(2)(-); occurred in the presence of metal chelators, superoxide dismutase (SOD), and scavengers of hypohalous acids; and was blocked by myeloperoxidase (MPO) inhibitors and catalase. Monocytes activated in the presence of the exogenous (*)NO generator PAPA NONOate (Z-[N-(3-aminopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2- diolate) promoted LDL protein nitration and lipid peroxidation by a combination of pathways. At low rates of (*)NO flux, both protein nitration and lipid peroxidation were inhibited by catalase and peroxidase inhibitors but not SOD, suggesting a role for MPO. As rates of (*)NO flux increased, both nitrotyrosine formation and 9-hydroxy-10,12-octadecadienoate/9-hydroperoxy-10,12-octadecadieno ic acid production by monocytes became insensitive to the presence of catalase or peroxidase inhibitors, but they were increasingly inhibited by SOD and methionine, suggesting a role for peroxynitrite. Collectively, these results demonstrate that monocytes use distinct mechanisms for generating (*)NO-derived oxidants, and they identify MPO as a source of nitrating intermediates in monocytes.
The Integrin αvβ3-5 Ligand MFG-E8 Is a p63/p73 Target Gene in Triple-Negative Breast Cancers but Exhibits Suppressive Functions in ER+ and erbB2+ Breast Cancers
Authors: Chuanwei Yang, Tetsu Hayashida, Nicole Forster, Cuiqi Li, Dejun Shen, Shyamala Maheswaran, Li Chen, Karen S. Anderson, Leif W. Ellisen, Dennis Sgroi, Emmett V. Schmidt
Journal: Cancer Research (2010)

The progression from preinvasive lesion to invasive carcinoma is a critical step contributing to breast cancer lethality. We identified downregulation of milk fat globule-EGF factor 8 (MFG-E8) as a contributor to breast cancer progression using microarray analysis of laser capture microdissected (LCM) tissues. We first identified MFG-E8 downregulation in invasive lesions in transgenic mammary tumor models, which were confirmed in LCM-isolated human invasive ductal carcinomas compared with patient-matched normal tissues. In situ analyses of MFG-E8 expression in estrogen receptor (ER) positive cases confirmed its downregulation during breast cancer progression and small inhibitory MFG-E8 RNAs accelerated ER(+) breast cancer cell proliferation. MFG-E8 also decreased in erbB2(+) human cancers and erbB2 transgenic mice lacking MFG-E8 showed accelerated tumor formation. In contrast, MFG-E8 expression was present at high levels in triple-negative (ER(-), PgR(-), erbB2(-)) breast cancers, cell lines, and patient sera. Knockdown, chromatin immunoprecipitation, and reporter assays all showed that p63 regulates MFG-E8 expression, and MFG-E8 knockdowns sensitized triple-negative breast cancers to cisplatin treatment. Taken together, our results show that MFG-E8 is expressed in triple-negative breast cancers as a target gene of the p63 pathway, but may serve a suppressive function in ER(+) and erbB2(+) breast cancers. Its potential use as a serum biomarker that contributes to the pathogenesis of triple-negative breast cancers urges continued evaluation of its differential functions.
Heterogeneity of tumorigenicity phenotype in murine tumors. I. Characterization of regressor and progressor clones isolated from a nonmutagenized ultraviolet regressor tumor
Authors: M Schmitt, RA Daynes
Journal: The Journal of Experimental Medicine (1981)

We have shown that both regressor and progressor clones can be isolated from a UV regressor tumor, RD-1024. Although the daughter clones are characterized by differences in tumorigenic potential in normal transplant hosts, they nevertheless seem to express the same major tumor rejection antigens, because immunization with either the regressor parent tumor, RD-1024, or with regressor Cl 8 protects against subsequent challenge with progressor C1 4 or Cl 9. Consistent with the in vivo-generated data is the evidence that draining lymph node cells with functional specificity for regressor Cl 8 are capable of cross-reactive cytotoxicity in an in vitro chromium release assay. We have demonstrated an indirect interaction occurring in vivo between regressor and progressor cells, in that Cl 8 cells have the ability to influence the outcome of simultaneous or sequential challenge with Cl 4 or Cl 9 cells. Because 500 rad of gamma irradiation has been shown to compromise the ability of mice to respond to a primary challenge with tumor, an immunological mechanism is implicated in the ultimate rejection of progressor tumor in a doubly challenged host. The importance of these results lies in the knowledge that these interacting subpopulations have been isolated directly from a tumor growing in vivo and that no selection pressure has been exerted on the cells greater than the short in vitro culture period necessary for the isolation and expansion of individual clones. The apparent immunoregulatory potential in a tumor-bearing animal is thus seen to be modified in accordance with the phenotypic heterogeneity of the cells within that tumor.
Evidence that circulating immune complexes remove transfused platelets from the circulation
Authors: Jack Kutti, Charles G. Zaroulis, Soodabeh Safai‐Kutti, Robert E. Dinsmore, Noorbibi K. Day, Robert A. Good
Journal: American Journal of Hematology (1981)

Abstract Fifteen recently diagnosed patients with acute leukemias admitted for induction chemotherapy were selected for study. When thrombocytopenic (venous platelet count &lt;20 × 10 9 /1) these patients received prophylactic platelet transfusions. A total of 67 platelet transfusion therapies were administered and evaluated. Using the Raji cell radioimmunoassay, the serum concentrations of circulating immune complexes (CIC) were measured immediately before and 10–12 hr after each platelet transfusion. In 36 instances, elevated values of CIC were present in the recipient's pretransfusion samples, the corresponding posttrans‐fusion values being significantly lower (P &lt; 0.05). Furthermore, in those 36 instances the mean percentage for the posttransfusion platelet increment was significantly lower (P &lt; 0.001) than in the remaining 31 instances in which normal pretransfusion values of CIC were measured. We conclude that CIC were an important factor in rapidly removing transfused platelets from the circulation, thereby, adversely affecting the benefit of platelet transfusions.
VOLUMETRIC ASSESSMENT OF CORONARY CALCIFICATION USING OPTICAL COHERENCE TOMOGRAPHY
Authors: Emile Mehanna, David Prabhu, Eric Brandt, Hirosada Yamamoto, Daniel Chamie, Guilherme Attizzani, Yusuke Fujino, Satoko Tahara, Nienke Van Ditzhuijzen, Wei Wang, Madhusudhana Gargesha, Hiram Bezerra, David Wilson, Marco Costa
Journal: Journal of the American College of Cardiology (2012)
The Nasal Epithelium as a Factory for Systemic Protein Delivery
Authors: Uta Griesenbach, Robin L. Cassady, Stefano Ferrari, Masayuki Fukumura, Christian Müller, Edgar Schmitt, Jie Zhu, Peter K. Jeffery, Yoshiyuki Nagai, Duncan M. Geddes, Mamoru Hasegawa, Eric W.F.W. Alton
Journal: Molecular Therapy (2002)

We have previously shown that recombinant Sendai virus (SeV) produces efficient in vivo airway epithelial gene transfer. The ability to produce therapeutic levels of circulating proteins following noninvasive gene transfer would have widespread clinical application. Here, we compared nose, lung, and skeletal muscle for the ability to produce circulating levels of the secreted mouse antiinflammatory cytokine interleukin-10 (IL10) following SeV-mediated gene transfer. High levels of serum IL10 were obtained from each site with a potency order of lung > nose > muscle for a given viral titer. Serum levels from each site were within the likely required range for anti-inflammatory effects. The combination of a high-efficiency gene transfer agent (SeV) and sites that can be assessed noninvasively (nose or lung) may circumvent several current challenges to gene therapy. We have previously shown that recombinant Sendai virus (SeV) produces efficient in vivo airway epithelial gene transfer. The ability to produce therapeutic levels of circulating proteins following noninvasive gene transfer would have widespread clinical application. Here, we compared nose, lung, and skeletal muscle for the ability to produce circulating levels of the secreted mouse antiinflammatory cytokine interleukin-10 (IL10) following SeV-mediated gene transfer. High levels of serum IL10 were obtained from each site with a potency order of lung > nose > muscle for a given viral titer. Serum levels from each site were within the likely required range for anti-inflammatory effects. The combination of a high-efficiency gene transfer agent (SeV) and sites that can be assessed noninvasively (nose or lung) may circumvent several current challenges to gene therapy.
Anti-Invasive Adjuvant Therapy with Imipramine Blue Enhances Chemotherapeutic Efficacy Against Glioma
Authors: Jennifer M. Munson, Levi Fried, Sydney A. Rowson, Michael Y. Bonner, Lohitash Karumbaiah, Begoña Diaz, Sara A. Courtneidge, Ulla G. Knaus, Daniel J. Brat, Jack L. Arbiser, Ravi V. Bellamkonda
Journal: Science Translational Medicine (2012)

A novel compound, Imipramine Blue, enhances efficacy of chemotherapy in a single treatment against a rodent astrocytoma model in vivo by inhibiting cell invasion.
Blood-derived angioblasts accelerate blood-flow restoration in diabetic mice
Authors: Gina C. Schatteman, Heather D. Hanlon, Chunhua Jiao, Sherry G. Dodds, Barbara A. Christy
Journal: Journal of Clinical Investigation (2000)

Endothelial cell progenitors, angioblasts, have been detected in the peripheral blood of adult humans, mice, and rabbits. These cells have been shown to incorporate into the endothelium of newly forming blood vessels in pathological and nonpathological conditions. Here we investigated the possibility that the CD34-expressing leukocytes (CD34+ cells) that appear to be enriched for angioblasts could be used to accelerate the rate of blood-flow restoration in nondiabetic and diabetic mice undergoing neovascularization due to hindlimb ischemia. CD34+ cells did not accelerate the restoration of flow in nondiabetic mice, but dramatically increased it in diabetic mice. Furthermore, CD34+ cells derived from type 1 diabetics produced fewer differentiated endothelial cells in culture than did their type 2 diabetic– or nondiabetic-derived counterparts. In vitro experiments suggest that hyperglycemia per se does not alter the ability of angioblasts to differentiate or of angioblast-derived endothelial cells to proliferate. In contrast, hyperinsulinemia may enhance angioblast differentiation but impair angioblast-derived endothelial cell survival or proliferation. Our findings suggest that CD34+ cells may be a useful tool for therapeutic angiogenesis in diabetics.
The potential role of regional and national health observatories in narrowing the knowledge gap in sub-Saharan Africa
Authors: Derege Kebede, Chris Zielinski
Journal: Journal of the Royal Society of Medicine (2014)

A gulf exists between the many potential opportunities to improve health by applying existing research evidence and the current inequalities in health in the World Health Organization (WHO) African Region. The gaps between what could be achieved and what has been achieved need to be closed – or at least narrowed. Closing these gaps is a major challenge – and opportunity – as they are numerous. As described in the WHO global plan of work, gaps exist in social justice, human rights and equality, leadership and accountability, and implementation and delivery of proven health interventions. Importantly, gaps in health knowledge exist where essential answers on how to improve the health of the people in the Region are missing or incomplete, information is not shared effectively, and education is inadequate or is denied to certain groups. The utility of health information, research evidence and knowledge (collectively described as ‘knowledge’) is to:
Glioblastoma-Specific Protein Interaction Network Identifies PP1A and CSK21 as Connecting Molecules between Cell Cycle–Associated Genes
Authors: Jayashree Ladha, Sainitin Donakonda, Shipra Agrawal, Balaram Thota, Mallavarapu R. Srividya, Sambandam Sridevi, Arimappamagan Arivazhagan, Kandavel Thennarasu, Anandh Balasubramaniam, Bangalore A. Chandramouli, Alangar Sattiyaranjandas Hegde, Paturu Kondaiah, Kumaravel Somasundaram, Vani Santosh, Satyanarayana M.R. Rao
Journal: Cancer Research (2010)

Glioblastoma (GBM; grade IV astrocytoma) is a very aggressive form of brain cancer with a poor survival and few qualified predictive markers. This study integrates experimentally validated genes that showed specific upregulation in GBM along with their protein-protein interaction information. A system level analysis was used to construct GBM-specific network. Computation of topological parameters of networks showed scale-free pattern and hierarchical organization. From the large network involving 1,447 proteins, we synthesized subnetworks and annotated them with highly enriched biological processes. A careful dissection of the functional modules, important nodes, and their connections identified two novel intermediary molecules CSK21 and protein phosphatase 1 alpha (PP1A) connecting the two subnetworks CDC2-PTEN-TOP2A-CAV1-P53 and CDC2-CAV1-RB-P53-PTEN, respectively. Real-time quantitative reverse transcription-PCR analysis revealed CSK21 to be moderately upregulated and PP1A to be overexpressed by 20-fold in GBM tumor samples. Immunohistochemical staining revealed nuclear expression of PP1A only in GBM samples. Thus, CSK21 and PP1A, whose functions are intimately associated with cell cycle regulation, might play key role in gliomagenesis.
A Science for the Art of Consensus
Authors: D L Sackett
Journal: JNCI Journal of the National Cancer Institute (1997)

Editor's note: How is it that different people of good intent can look at the same data and draw opposing conclusions? The recent National Institutes of Health Consensus Development Conference on screening mammography for women ages 40 through 49 is a prime example of this dilemma: The conference was convened to weigh information on the effectiveness of screening this age group and to see if an across-the-board recommendation for mammography was warranted. The panel, composed of non-federal medical and public health experts and patient representatives, concluded that no recommendation should be made that would apply to all women in this age range. A minority report was produced by two panel members who thought otherwise. Several weeks later, on the basis of virtually the same data, the National Cancer Advisory Board, the principal advisory body to the National Cancer Institute, recommended in favor of screening women in their forties. Public reaction was polarized in the ensuing confusion. In this issue, we publish the full text of the consensus statement, as well as the minority report (pages 1015-26). We have also included the following Commentary by Dr. Sackett to illuminate the nature of this kind of dilemma, one bound to arise many times at the interface of scientific inquiry and the formulation of public policy.
Episodic Sexual Transmission of HIV Revealed by Molecular Phylodynamics
Authors: Fraser Lewis, Gareth J Hughes, Andrew Rambaut, Anton Pozniak, Andrew J. Leigh Brown
Journal: PLoS Medicine (2008)

The structure of sexual contact networks plays a key role in the epidemiology of sexually transmitted infections, and their reconstruction from interview data has provided valuable insights into the spread of infection. For HIV, the long period of infectivity has made the interpretation of contact networks more difficult, and major discrepancies have been observed between the contact network and the transmission network revealed by viral phylogenetics. The high rate of HIV evolution in principle allows for detailed reconstruction of links between virus from different individuals, but often sampling has been too sparse to describe the structure of the transmission network. The aim of this study was to analyze a high-density sample of an HIV-infected population using recently developed techniques in phylogenetics to infer the short-term dynamics of the epidemic among men who have sex with men (MSM).Sequences of the protease and reverse transcriptase coding regions from 2,126 patients, predominantly MSM, from London were compared: 402 of these showed a close match to at least one other subtype B sequence. Nine large clusters were identified on the basis of genetic distance; all were confirmed by Bayesian Monte Carlo Markov chain (MCMC) phylogenetic analysis. Overall, 25% of individuals with a close match with one sequence are linked to 10 or more others. Dated phylogenies of the clusters using a relaxed clock indicated that 65% of the transmissions within clusters took place between 1995 and 2000, and 25% occurred within 6 mo after infection. The likelihood that not all members of the clusters have been identified renders the latter observation conservative.Reconstruction of the HIV transmission network using a dated phylogeny approach has revealed the HIV epidemic among MSM in London to have been episodic, with evidence of multiple clusters of transmissions dating to the late 1990s, a period when HIV prevalence is known to have doubled in this population. The quantitative description of the transmission dynamics among MSM will be important for parameterization of epidemiological models and in designing intervention strategies.
Ghrelin and a Novel Preproghrelin Isoform Are Highly Expressed in Prostate Cancer and Ghrelin Activates Mitogen-Activated Protein Kinase in Prostate Cancer
Authors: Anthony H. Yeh, Penelope L. Jeffery, Russell P. Duncan, Adrian C. Herington, Lisa K. Chopin
Journal: Clinical Cancer Research (2005)

Abstract Purpose: There is evidence that the hormone ghrelin stimulates proliferation in the PC3 prostate cancer cell line although the underlying mechanism(s) remain to be determined. A novel, exon 3–deleted preproghrelin isoform has previously been detected in breast and prostate cancer cells; however, its characterization, expression, and potential function in prostate cancer tissues are unknown. Experimental Design: Expression of ghrelin and exon 3–deleted preproghrelin was investigated in prostate cancer cell lines and tissues by reverse transcription-PCR and immunohistochemistry. Proliferation and apoptosis assays were done in the LNCaP prostate cancer cell line to determine if ghrelin stimulates proliferation and/or cell survival. Stimulation of mitogen-activated protein kinase (MAPK) pathway activation by ghrelin was determined in PC3 and LNCaP cells by immunoblotting with antibodies specific for phosphorylated MAPKs. Results: Prostate cancer tissues display greater immunoreactivity for ghrelin and exon 3–deleted preproghrelin than normal prostate tissues, and prostate cancer cell lines secrete mature ghrelin into conditioned medium. Treatment with ghrelin (10 nmol/L), but not the unique COOH-terminal peptide derived from exon 3–deleted preproghrelin, stimulates proliferation in the LNCaP cells (45.0 ± 1.7% above control, P &amp;lt; 0.01) and rapidly activates the extracellular signal-regulated kinase-1/2 MAPK pathway in both PC3 and LNCaP cell lines. Ghrelin, however, does not protect prostate cancer cells from apoptosis induced by actinomycin D (1 μg/mL). The MAPK inhibitors PD98059 and U0126 blocked ghrelin-induced MAPK activation, as well as proliferation, in both cell lines. Conclusions: These data suggest that these components of the ghrelin axis may have potential as novel biomarkers and/or adjunctive therapeutic targets for prostate cancer.
Sulforaphane Inhibits Prostate Carcinogenesis and Pulmonary Metastasis in TRAMP Mice in Association with Increased Cytotoxicity of Natural Killer Cells
Authors: Shivendra V. Singh, Renaud Warin, Dong Xiao, Anna A. Powolny, Silvia D. Stan, Julie A. Arlotti, Yan Zeng, Eun-Ryeong Hahm, Stanley W. Marynowski, Ajay Bommareddy, Dhimant Desai, Shantu Amin, Robert A. Parise, Jan H. Beumer, William H. Chambers
Journal: Cancer Research (2009)

The present study shows that oral gavage of 6 mumol d,l-sulforaphane (SFN), a synthetic analogue of cruciferous vegetable-derived L isomer, thrice per week beginning at 6 weeks of age, significantly inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice without causing any side effects. The incidence of the prostatic intraepithelial neoplasia and well-differentiated (WD) carcinoma were approximately 23% to 28% lower (P < 0.05 compared with control by Mann-Whitney test) in the dorsolateral prostate (DLP) of SFN-treated mice compared with controls, which was not due to the suppression of T-antigen expression. The area occupied by the WD carcinoma was also approximately 44% lower in the DLP of SFN-treated mice relative to that of control mice (P = 0.0011 by Mann Whitney test). Strikingly, the SFN-treated mice exhibited approximately 50% and 63% decrease, respectively, in pulmonary metastasis incidence and multiplicity compared with control mice (P < 0.05 by t test). The DLP from SFN-treated mice showed decreased cellular proliferation and increased apoptosis when compared with that from control mice. Additionally, SFN administration enhanced cytotoxicity of cocultures of natural killer (NK) cells and dendritic cells (DC) against TRAMP-C1 target cells, which correlated with infiltration of T cells in the neoplastic lesions and increased levels of interleukin-12 production by the DC. In conclusion, the results of the present study indicate that SFN administration inhibits prostate cancer progression and pulmonary metastasis in TRAMP mice by reducing cell proliferation and augmenting NK cell lytic activity.