tbuckley/cabot-search huggingface dataset:
Negative inotropic mediators released from the heart after myocardial ischaemia–reperfusion
Authors: Verena Stangl, Gert Baumann, Karl Stangl, Stephan B Felix
Journal: Cardiovascular Research (2002)

The heart responds to ischaemic stimuli with release of negative inotropic mediators such as cytokines, platelet-activating factor, oxygen free radicals, arachidonic acids, nitric oxide, adenosine, and still unidentified “cardiodepressant factors” that modulate myocardial performance via autocrine and paracrine coupling. This review summarises experimental and clinical data on the role of negative inotropic mediators that are released from cardiac cells (including cardiomyocytes, endothelial cells, and resident mast cells) after myocardial ischaemia-reperfusion.
Regulation of mitogen-activated protein kinase cascade in adult rat heart preparations in vitro.
Authors: A Lazou, M A Bogoyevitch, A Clerk, S J Fuller, J Marshall C, P H Sugden
Journal: Circulation Research (1994)

The regulation of mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK) was studied in freshly isolated adult rat heart preparations. In contrast to the situation in ventricular myocytes cultured from neonatal rat hearts, stimulation of MAPK activity by 1 mumol/L phorbol 12-myristate 13-acetate (PMA) was not consistently detectable in crude extracts. After fast protein liquid chromatography, MAPK isoforms p42MAPK and p44MAPK and two peaks of MEK were shown to be activated &gt; 10-fold in perfused hearts or ventricular myocytes exposed to 1 mumol/L PMA for 5 minutes. The identities of MAPK or MEK were confirmed by immunoblotting and, for MAPK, by the "in-gel" myelin basic protein phosphorylation assay. In retrogradely perfused hearts, high coronary perfusion pressure (120 mm Hg for 5 minutes), norepinephrine (50 mumol/L for 5 minutes), or isoproterenol (50 mumol/L for 5 minutes) stimulated MAPK and MEK approximately 2- to 5-fold. In isolated myocytes, endothelin 1 (100 nmol/L for 5 minutes) also stimulated MAPK, but stimulation by norepinephrine or isoproterenol was difficult to detect. Immunoblotting showed that the relative abundances of MAPK and MEK protein in ventricles declined to &lt; 20% of their postpartal abundances after 50 days. This may explain the difficulties encountered in assaying the activity of MAPK in crude extracts from adult hearts. We conclude that potentially hypertrophic agonists and interventions stimulate the MAPK cascade in adult rats and suggest that the MAPK cascade may be an important intracellular signaling pathway in this response.
The Critical Role of the Class III Histone Deacetylase SIRT1 in Cancer
Authors: Tao Liu, Pei Y. Liu, Glenn M. Marshall
Journal: Cancer Research (2009)

Abstract Gene expression and deacetylase activity of the class III histone deacetylase SIRT1 are up-regulated in cancer cells due to oncogene overexpression or loss of function of tumor suppressor genes. SIRT1 induces histone deacetylation and methylation, promoter CpG island methylation, transcriptional repression, and deacetylation of tumor suppressor proteins. SIRT1 may play a critical role in tumor initiation, progression, and drug resistance by blocking senescence and apoptosis, and promoting cell growth and angiogenesis. SIRT1 inhibitors have shown promising anticancer effects in animal models of cancer. Further screening for more potent SIRT1 inhibitors may lead to compounds suitable for clinical trials in patients. [Cancer Res 2009;69(5):1702–5]
Prelamin A Accelerates Vascular Calcification Via Activation of the DNA Damage Response and Senescence-Associated Secretory Phenotype in Vascular Smooth Muscle Cells
Authors: Yiwen Liu, Ignat Drozdov, Rukshana Shroff, Leilani E. Beltran, Catherine M. Shanahan
Journal: Circulation Research (2013)

Vascular calcification is prevalent in the aging population, yet little is known of the mechanisms driving age-associated vascular smooth muscle cell (VSMC) phenotypic change.To investigate the role of nuclear lamina disruption, a specific hallmark of VSMC aging, in driving VSMC osteogenic differentiation.Prelamin A, the unprocessed form of the nuclear lamina protein lamin A, accumulated in calcifying human VSMCs in vitro and in vivo, and its overexpression promoted VSMC osteogenic differentiation and mineralization. During VSMC aging in vitro, prelamin A accumulation occurred concomitantly with increased p16 expression and osteogenic differentiation and was associated with increased levels of DNA damage. Microarray analysis showed that DNA damage repair pathways were significantly impaired in VSMCs expressing prelamin A and that chemical inhibition and siRNA depletion of the DNA damage response kinases ataxia-telangiectasia mutated/ataxia-telangiectasia- and Rad3-related effectively blocked VSMC osteogenic differentiation and mineralization. In coculture experiments, prelamin A-expressing VSMCs induced alkaline phosphatase activity in mesenchymal progenitor cells, and this was abrogated by inhibition of ataxia-telangiectasia-mutated signaling, suggesting that DNA damage induces the secretion of pro-osteogenic factors by VSMCs. Cytokine array analysis identified several ataxia-telangiectasia mutated-dependent senescence-associated secretory phenotype factors/cytokines released by prelamin A-positive VSMCs, including the calcification regulators bone morphogenetic protein 2, osteoprotegerin, and interleukin 6.Prelamin A promotes VSMC calcification and aging by inducing persistent DNA damage signaling, which acts upstream of VSMC osteogenic differentiation and the senescence-associated secretory phenotype. Agents that target the DNA damage response and prelamin A toxicity may be potential therapies for the treatment of vascular calcification.
Tumor-Secreted Vascular Endothelial Growth Factor-C Is Necessary for Prostate Cancer Lymphangiogenesis, but Lymphangiogenesis Is Unnecessary for Lymph Node Metastasis
Authors: Sunny Y. Wong, Herbert Haack, Denise Crowley, Marc Barry, Roderick T. Bronson, Richard O. Hynes
Journal: Cancer Research (2005)

Abstract Dissemination to draining lymph nodes is a frequent first step in prostate cancer metastasis. Although tumors metastasize to lymph nodes via the lymphatics, the importance of lymphangiogenesis in mediating the process remains controversial. Here, we inhibit intratumoral lymphangiogenesis in s.c. and surgical orthotopic implantation mouse models of human prostate cancer using several strategies. Stable expression of small interfering RNAs (siRNA) targeted against human vascular endothelial growth factor-C (VEGF-C) in PC-3 cells reduced intratumoral lymphatics by 99% in s.c. tumors, indicating that tumor-secreted VEGF-C is necessary for lymphangiogenesis. Expression of siRNAs against human VEGF-A somewhat reduced tumor lymphangiogenesis. Secretion of a soluble VEGF receptor-3/Flt4 fusion protein by PC-3 cells reduced intratumoral lymphatics by 100% in s.c. tumors. Combination of soluble Flt4 and VEGF-C siRNA yielded &amp;gt;92% reduction of intratumoral lymphatics in orthotopic prostate tumors. However, metastasis to lymph nodes was not significantly affected regardless of intratumoral lymphatic vessel density. The abundance of marginal lymphatics at the tumor-stromal interface was unchanged in orthotopic tumors whose intratumoral lymphatics were inhibited, suggesting that these marginal vessels could be sufficient for lymph node metastasis. Hematogenous metastasis (blood tumor burden, lung metastasis) correlated with degree of lymph node invasion. We also analyzed the lymphatics in spontaneous transgenic adenocarcinomas of the mouse prostate which metastasize to lymph nodes. Progression from well-differentiated prostate intraepithelial neoplasia to metastatic, undifferentiated adenocarcinoma was accompanied by loss of lymphatics. These results suggest that tumor-secreted VEGF-C and, to a lesser extent, VEGF-A, are important for inducing prostate cancer intratumoral lymphangiogenesis but are unnecessary for lymph node metastasis.
Adenovirus-Mediated Transfer of siRNA against Survivin Induced Apoptosis and Attenuated Tumor Cell Growth in Vitro and in Vivo
Authors: Hiroaki Uchida, Toshihiro Tanaka, Katsunori Sasaki, Kazunori Kato, Hironari Dehari, Yoshinori Ito, Masayoshi Kobune, Makoto Miyagishi, Kazunari Taira, Hideaki Tahara, Hirofumi Hamada
Journal: Molecular Therapy (2004)

Gene targeting using short interfering RNA (siRNA) has become a common strategy to explore gene function because of its prominent efficacy and specificity. For the application of siRNA technology to gene therapy, however, still more efficient transduction of siRNA into target cells is needed. In this study, we developed an adenoviral vector harboring a tandem-type siRNA expression unit, in which sense and antisense strands composing the siRNA duplex were separately transcribed by two human U6 promoters. Targeting survivin, an antiapoptotic molecule widely overexpressed in malignancies but not detected in terminally differentiated adult tissues, this type of adenoviral vector (Adv-siSurv) successfully exerted a gene knockdown effect and induced apoptosis in HeLa, U251, and MCF-7 cells. These cancer cells, once infected with Adv-siSurv, displayed remarkably attenuated growth potential, both in vitro and in vivo. Moreover, intratumoral injection of Adv-siSurv significantly suppressed tumor growth in a xenograft model using U251 glioma cells. This novel modality may be a promising tool for cancer therapy.
A Phase I Clinical Trial of Safingol in Combination with Cisplatin in Advanced Solid Tumors
Authors: Mark A. Dickson, Richard D. Carvajal, Alfred H Merrill, Mithat Gonen, Lauren M. Cane, Gary K. Schwartz
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Sphingosine 1-phosphate (S1P) is an important mediator of cancer cell growth and proliferation. Production of S1P is catalyzed by sphingosine kinase 1 (SphK). Safingol, (l-threo-dihydrosphingosine) is a putative inhibitor of SphK. We conducted a phase I trial of safingol (S) alone and in combination with cisplatin (C). Experimental Design: A 3 + 3 dose escalation was used. For safety, S was given alone 1 week before the combination. S + C were then administered every 3 weeks. S was given over 60 to 120 minutes, depending on dose. Sixty minutes later, C was given over 60 minutes. The C dose of 75 mg/m2 was reduced in cohort 4 to 60 mg/m2 due to excessive fatigue. Results: Forty-three patients were treated, 41 were evaluable for toxicity, and 37 for response. The maximum tolerated dose (MTD) was S 840 mg/m2 over 120 minutes C 60 mg/m2, every 3 weeks. Dose-limiting toxicity (DLT) attributed to cisplatin included fatigue and hyponatremia. DLT from S was hepatic enzyme elevation. S pharmacokinetic parameters were linear throughout the dose range with no significant interaction with C. Patients treated at or near the MTD achieved S levels of more than 20 μmol/L and maintained levels greater than and equal to 5 μmol/L for 4 hours. The best response was stable disease in 6 patients for on average 3.3 months (range 1.8–7.2 m). One patient with adrenal cortical cancer had significant regression of liver and lung metastases and another had prolonged stable disease. S was associated with a dose-dependent reduction in S1P in plasma. Conclusions: Safingol, the first putative SphK inhibitor to enter clinical trials, can be safely administered in combination with cisplatin. Reversible dose-dependent hepatic toxicity was seen, as expected from preclinical data. Target inhibition was achieved with downregulation of S1P. The recommended phase II dose is S 840 mg/m2 and C 60 mg/m2, every 3 weeks. Clin Cancer Res; 17(8); 2484–92. ©2011 AACR.
18F-fluorodeoxyglucose uptake in brown adipose tissue during insulin-induced hypoglycemia and mild cold exposure in non-diabetic adults
Authors: Josefine E Schopman, Wanda M Admiraal, Maarten R Soeters, Mariette T Ackermans, Peter L H T Bisschop, Brian M Frier, Joost B L Hoekstra, Johannes A Romijn, Hein J Verberne, Frits Holleman
Journal: Metabolism (2014)
Adjuvant-Mediated Tumor Regression and Tumor-Specific Cytotoxic Response Are Impaired in MyD88-Deficient Mice
Authors: Takashi Akazawa, Hisayo Masuda, Yoshiko Saeki, Misako Matsumoto, Kiyoshi Takeda, Kunio Tsujimura, Kiyotaka Kuzushima, Toshitada Takahashi, Ichiro Azuma, Shizuo Akira, Kumao Toyoshima, Tsukasa Seya
Journal: Cancer Research (2004)

Abstract The Mycobacterium bovis bacillus Calmette-Guérin cell-wall skeleton (BCG-CWS) activates Toll-like receptor (TLR) 2 and TLR4, but unlike the typical TLR4 agonist bacterial lipopolysaccharide barely induces type 1 IFN. BCG-CWS has been used for adjuvant immunotherapy for patients with cancer. We investigated the adjuvant potential of BCG-CWS for induction of CTLs subsequent to TLR-mediated dendritic cell (DC) maturation, using a syngeneic mouse tumor model (B16 melanoma in C57BL/6). We evaluated the retardation of tumor growth and cytotoxic response in wild-type and MyD88−/− mice immunized with tumor debris and/or BCG-CWS. Delays in tumor growth and cytotoxic response were induced by immunization with a mixture of BCG-CWS emulsion and the tumor. BCG-CWS was capable of activating DCs ex vivo by the criteria of CD80/CD86 up-regulation and cytokine (interleukin-12, tumor necrosis factor-α) induction. Efficient tumor suppression and ex vivo cytokine induction did not occur in MyD88-deficient mice and cells, suggesting that the MyD88 adapter is crucial for induction of tumor cytotoxicity. Because TLR4 is involved in both MyD88-dependent and -independent pathways and the latter affects DC maturation, our findings indicate that both pathways cooperate to induce CTL-based tumor immunity.
Prospective study of cytotoxic T lymphocyte responses to influenza and antibodies to human T lymphotropic virus-III in homosexual men. Selective loss of an influenza-specific, human leukocyte antigen-restricted cytotoxic T lymphocyte response in human T lymphotropic virus-III positive individuals with symptoms of acquired immunodeficiency syndrome and in a patient with acquired immunodeficiency syndrome.
Authors: G M Shearer, S Z Salahuddin, P D Markham, L J Joseph, S M Payne, P Kriebel, D C Bernstein, W E Biddison, M G Sarngadharan, R C Gallo
Journal: Journal of Clinical Investigation (1985)

Peripheral blood leukocytes (PBL) from 18 homosexual men who did not have acquired immunodeficiency syndrome (AIDS) and from 9 heterosexual men were repetitively tested for their ability to generate HLA self-restricted cytotoxic T lymphocyte responses to influenza virus (flu-self) over a 2-yr period. The sera of the same donors were tested for antibodies to human T lymphotropic virus-III (HTLV-III). Six of the homosexual and none of the heterosexual donors consistently generated weak cytotoxic T lymphocyte responses to flu-self. Seven of the homosexual and none of the heterosexual donors were seropositive for antibodies to HTLV-III. No obvious correlation was detected between weak flu-self cytotoxic T lymphocyte responses and antibodies to HTLV-III. However, one homosexual donor generated no detectable cytotoxic T lymphocyte activity to flu-self, although he was a strong responder to HLA-alloantigens. This donor had an OKT4:OKT8 ratio of 0.4 and was seropositive for HTLV-III antigens; HTLV-III virus was identified in his PBL; and he developed AIDS during the course of this study. A second donor with lymphadenopathy and who was seropositive for HTLV-III antigens exhibited marginal cytotoxic T lymphocyte activity to flu-self which he subsequently lost. PBL from two patients, one with Kaposi's sarcoma and one with generalized lymphadenopathy, were also tested for cytotoxic T lymphocyte responses to flu-self and to alloantigens. Both donors failed to generate cytotoxic T lymphocyte to flu-self, but generated strong cytotoxic T lymphocyte responses to alloantigens. The selective loss of an HLA-restricted cytotoxic T lymphocyte response without loss of HLA alloantigenic cytotoxic T lymphocyte activity may be an important functional immunologic characteristic in the development of AIDS.
Principles of applied neurogastroenterology: physiology/motility-sensation
Authors: J E Kellow, M Delvaux, F Azpiroz, M Camilleri, E M M Quigley, D G Thompson
Journal: Gut (1999)

By the genetic selection of mouse cDNAs encoding secreted proteins, a B7-like cDNA clone termed mouse GL50 (mGL50) was isolated encoding a 322-aa polypeptide identical with B7h. Isolation of the human ortholog of this cDNA (hGL50) revealed a coding sequence of 309 aa residues with 42% sequence identity with mGL50. Northern analysis indicated GL50 to be present in many tissues including lymphoid, embryonic yolk sac, and fetal liver samples. Of the CD28, CTLA4, and ICOS fusion constructs tested, flow cytometric analysis demonstrated only mouse ICOS-IgG binding to mGL50 cell transfectants. Subsequent phenotyping demonstrated high levels of ICOS ligand staining on splenic CD19<sup>+</sup> B cells and low levels on CD3<sup>+</sup> T cells. These results indicate that GL50 is a specific ligand for the ICOS receptor and suggest that the GL50-ICOS interaction functions in lymphocyte costimulation.
Expression of the B cell differentiation factor BAFF and chemokine CXCL13 in a murine model of human respiratory syncytial virus infection
Authors: Wael Alturaiki, Amanda McFarlane, Paul Fitch, Joseph Slupsky, Paul McNamara, Jürgen Schwarze, Brian Flanagan
Journal: European Respiratory Journal (2013)

BACKGROUND AND AIMS:   Production of antibody in the lungs is an essential defense mechanism against respiratory pathogens. However, little is known about the mechanisms of local B cell activation in airway mucosa. Previously, we have demonstrated expression of the B cell differentiation factor, BAFF in human RSV infection (McNamara et al 2013 Thorax).  To better understand this process we examined BAFF expression in a murine model of RSV infection and measured expression of the chemokines CXCL13, CCl19 and CCl21 which could influence lymphocyte recruitment.   METHODS:   We measured BAFF, CXCL13, CCL19 and CCL21 expression in homogenised lung tissue from control mice at day 0 and mice challenged with RSV (A2 strain) or control UV-treated RSV at days 1,2,4 or 7 post infection (n=3) by ELISA. Cytokine mRNA and RSV N gene expression were measured by Taqman PCR.   RESULTS:   BAFF was elevated significantly post RSV infection at day1 (mean1092pg/ml, P=0.07), day2 (1157pg/ml, P=0.01) and day 7(2941 pg/ml, P=0.0001) in comparison to UV treated RSV control on day1 (421pg/ml), day2 (370 pg/ml) and day7 (393pg/ml). BAFF mRNA expression was similarly increased on day 1 (fold increase 2, P=0.03) and day 7(1.7, P=0.02).  CXCL13 protein was increased post RSV infection at day 1 (mean762pg/ml, P=0.01), day2 (612pg/ml, P=0.02), and day 7 (388pg/ml, P=0.007) in comparison to control day 1 (374pg/ml), day2 (278pg/ml) and day7 (249pg/ml). CCL19 or CCL21 levels were not increased.   CONCLUSION:   RSV infection results in up-regulated BAFF and CXCl13 expression, consistent with a role for CXCL13 in recruiting B cells and BAFF in promoting airway B cell differentiation.
Direct and Indirect Involvement of MicroRNA-499 in Clinical and Experimental Cardiomyopathy
Authors: Scot J. Matkovich, Yuanxin Hu, William H. Eschenbacher, Lisa E. Dorn, Gerald W. Dorn
Journal: Circulation Research (2012)

MicroRNA-499 and other members of the myomiR family regulate myosin isoforms in pressure-overload hypertrophy. miR-499 expression varies in human disease, but results of mouse cardiac miR-499 overexpression are inconsistent, either protecting against ischemic damage or aggravating cardiomyopathy after pressure overload. Likewise, there is disagreement over direct and indirect cardiac mRNAs targeted in vivo by miR-499.To define the associations between regulated miR-499 level in clinical and experimental heart disease and modulation of its predicted mRNA targets and to determine the consequences of increased cardiac miR-499 on direct mRNA targeting, indirect mRNA modulation, and on myocardial protein content and posttranslational modification.miR-499 levels were increased in failing and hypertrophied human hearts and associated with decreased levels of predicted target mRNAs. Likewise, miR-499 is increased in Gq-mediated murine cardiomyopathy. Forced cardiomyocyte expression of miR-499 at levels comparable to human cardiomyopathy induced progressive murine heart failure and exacerbated cardiac remodeling after pressure overloading. Genome-wide RNA-induced silencing complex and RNA sequencing identified 67 direct, and numerous indirect, cardiac mRNA targets, including Akt and MAPKs. Myocardial proteomics identified alterations in protein phosphorylation linked to the miR-499 cardiomyopathy phenotype, including of heat shock protein 90 and protein serine/threonine phosphatase 1-α.miR-499 is increased in human and murine cardiac hypertrophy and cardiomyopathy, is sufficient to cause murine heart failure, and accelerates maladaptation to pressure overloading. The deleterious effects of miR-499 reflect the cumulative consequences of direct and indirect mRNA regulation, modulation of cardiac kinase and phosphatase pathways, and higher-order effects on posttranslational modification of myocardial proteins.
Multiple Cases of Life-threatening Adenovirus Pneumonia in a Mental Health Care Center
Authors: JAMES R. KLINGER, MARIA PIA SANCHEZ, LINDA A. CURTIN, MARGARET DURKIN, BELA MATYAS
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Eighteen cases of pneumonia developed during an outbreak of adenovirus infection in a chronic psychiatric care facility. The six patients most severely affected were admitted to the intensive care unit (ICU) at our institution. Four of these patients developed septic shock. We report the presentation, disease progression, and response to treatment of these patients. Clinical features consisted of high fever, nonproductive cough, and dense lower lobe infiltrates. Laboratory abnormalities included transient fall in white blood cell and platelet counts, and elevations of transaminases, lactate dehydrogenase (LDH), and creatinine phosphokinase (CPK). Five patients were intubated for hypoxemia and four developed the acute respiratory distress syndrome (ARDS) and septic shock (mean cardiac output, 14.1 ± 1.3 L / min; cardiac index, 6.4 ± 0.4 L / min / min2; systemic vascular resistance, 326 ± 107 dyne cm / s2). All patients recovered and were discharged back to the chronic care facility except for one patient with chronic renal failure who died 2 mo after admission. Adenovirus (serotype 35) was isolated from the respiratory secretions of five patients and antibody titers increased 6-fold in the other. These patients constitute the largest series of patients with ARDS and septic shock caused by adenovirus pneumonia and the first outbreak of multiple cases of adenovirus pneumonia in immunocompetent civilian adults occurring from a single source.