MedWorm: Adenoviruses

Progesterone inhibits glucose uptake by affecting diverse steps of insulin signaling in 3T3-L1 adipocytes

AJP: Endocrinology and Metabolism — Fri, 19 Mar 2010 20:12:53 +0100

Maternal insulin resistance is essential for efficient provision of glucose to the fetus. Although elevation of placental hormones is known to relate to the development of insulin resistance, the precise underlying mechanism of maternal insulin resistance is unknown. Therefore, we examined the molecular mechanisms of progesterone causing insulin resistance in 3T3-L1 adipocytes. Progesterone at 10–4 M, but not 10–5 M, reduced the amount of IRS-1. As a result, insulin-induced phosphorylation of IRS-1, the association of IRS-1 with p85, and subsequent phosphorylation of Akt1 and -2 was decreased moderately by 10–4 M progesterone. Subsequently, insulin-induced translocation of GLUT4 to the plasma membrane evaluated by immunostaining on the plasma membrane sheet by confocal la...

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Adenovirus-mediated gene transfer of hIGF-IB in mouse lungs induced prolonged inflammation but no fibroproliferation

AJP: Lung Cellular and Molecular Physiology — Fri, 19 Mar 2010 17:05:33 +0100

In this study, we investigated whether human IGF-IB (hIGF-IB) expression in the lungs induces PF in a C57BL/6 mouse model. Mice were subjected to adenoviral gene transfer, and the effects of hIGF-IB expression on the lungs were examined 3, 7, 14, 21, and 42 days after gene delivery. hIGF-IB expression induced significant and prolonged inflammatory cell infiltration into the lungs, with an early neutrophil infiltration followed by a late macrophage infiltration. No significant fibroblast or matrix accumulation could be detected in the lungs of these mice. No significant collagen accumulation could be detected in vivo, despite in vitro evidence that hIGF-IB induces collagen mRNA expression in fibroblasts. Therefore, IGF-IB alone is not sufficient to induce fibrosis, and it is possible that a...

Human CD34+ cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand target both tumor cells and tumor vasculature

Blood — Thu, 18 Mar 2010 16:02:03 +0100

Adenovirus-transduced CD34+ cells expressing membrane-bound tumor necrosis factor–related apoptosis-inducing ligand (CD34-TRAIL+ cells) exert potent antitumor activity. To further investigate the mechanism(s) of action of CD34-TRAIL+ cells, we analyzed their homing properties as well as antitumor and antivascular effects using a subcutaneous myeloma model in immunodeficient mice. After intravenous injection, transduced cells homed in the tumor peaking at 48 hours when 188 plus or minus 25 CD45+ cells per 105 tumor cells were detected. Inhibition experiments showed that tumor homing of CD34-TRAIL+ cells was largely mediated by vascular cell adhesion molecule-1 and stromal cell–derived factor-1. Both CD34-TRAIL+ cells and soluble (s)TRAIL significantly reduced tumor volume by 40%...

Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors

Gene Therapy — Thu, 18 Mar 2010 00:00:00 +0100

Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5/3-Cox2L-D24 in patients with metastatic and refractory solid tumors Gene Therapy advance online publication, March 18, 2010. doi:10.1038/gt.2010.17 Authors: S Pesonen, P Nokisalmi, S Escutenaire, M Särkioja, M Raki, V Cerullo, L Kangasniemi, L Laasonen, C Ribacka, K Guse, E Haavisto, M Oksanen, M Rajecki, A Helminen, A Ristimäki, A Karioja-Kallio, E Karli, T Kantola, G Bauerschmitz, A Kanerva, T Joensuu & A Hemminki (Source: Gene Therapy)

Self-complementary AAV-mediated gene therapy restores cone function and prevents cone degeneration in two models of Rpe65 deficiency

Gene Therapy — Thu, 18 Mar 2010 00:00:00 +0100

Authors: J Pang, S E Boye, B Lei, S L Boye, D Everhart, R Ryals, Y Umino, B Rohrer, J Alexander, J Li, X Dai, Q Li, B Chang, R Barlow & W W Hauswirth (Source: Gene Therapy)

A cancer derived mutation in the Retinoblastoma gene with a distinct defect for LXCXE dependent interactions

Cancer Cell International — Thu, 18 Mar 2010 00:00:00 +0100

Conclusions: Our work provides proof of principal that alleles encoding distinct, partial loss of function mutations in the retinoblastoma gene that specifically lose LXCXE dependent interactions, are found in human cancer. (Source: Cancer Cell International)

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Neurologix Receives Notice Of Allowance For Epilepsy Therapeutic Approach

Health News from Medical News Today — Wed, 17 Mar 2010 08:00:00 +0100

Neurologix, Inc. (OTCBB:NRGX) announced that it has received a Notice of Allowance from the U.S. Patent and Trademark Office (US PTO) for intellectual property central to the company's approach to the treatment of epilepsy. The patent allowance specifically refers to Neurologix's patent application, "Methods and Compositions for the Treatment of Neurological Disease," which covers the treatment of seizures associated with temporal lobe epilepsy by direct administration into the brain's temporal lobe of an AAV vector encoding Neuropeptide Y (NPY)... (Source: Health News from Medical News Today)

Immunotherapy Can Reject Intracranial Tumor Cells without Damaging the Brain despite Sharing the Target Antigen.

Journal of Immunology — Wed, 17 Mar 2010 00:00:00 +0100

Authors: Bridle BW, Li J, Jiang S, Chang R, Lichty BD, Bramson JL, Wan Y Although vaccines targeting tissue differentiation Ags represent a promising strategy for cancer immunotherapy, the risk of triggering autoimmune damage to normal tissues remains to be determined. Immunizing against a melanoma-associated Ag, dopachrome tautomerase (DCT), which normal melanocytes and glial cells also express, allowed concurrent analysis of autoimmune consequences in multiple tissues. We show that vaccination with recombinant adenovirus expressing DCT elicited a strong CTL response in C57BL/6 mice, leading to protection against intracranial challenge with B16-F10 melanoma cells. Both histological analysis and behavioral testing indicated that there was no evidence of neuropathology in vaccinated ani...

Apoptosis induction by eIF5A1 involves activation of the intrinsic mitochondrial pathway

Journal of Cellular Physiology — Mon, 15 Mar 2010 00:00:00 +0100

The regulatory role of eukaryotic translation initiation factor 5A1 (eIF5A1) in apoptosis was examined using HT-29 and HeLa S3 cells. eIF5A is the only known protein to contain the unusual amino acid, hypusine, and eIF5A1 is one of two human eIF5A family members. Two observations indicated that eIF5A1 is involved in apoptosis. First, siRNA-mediated suppression of eIF5A1 resulted in inhibition of apoptosis induced by various apoptotic stimuli, and second, adenovirus-mediated over-expression of eIF5A1 strongly induced apoptotic cell death. A mutant of eIF5A1 incapable of being hypusinated also induced apoptosis when over-expressed indicating that unhypusinated eIF5A1 is the pro-apoptotic form of the protein. Over-expression of eIF5A1 or of the mutant resulted in loss of mitochondrial transme...

Observational prospective study of viral infections in children undergoing allogeneic hematopoietic cell transplantation: a 3-year GETMON experience.

Adv Data — Mon, 15 Mar 2010 00:00:00 +0100

Authors: Verdeguer A, de Heredia CD, González M, Martínez AM, Fernández-Navarro JM, Pérez-Hurtado JM, Badell I, Gómez P, González ME, Muñoz A, Díaz MA We studied surveillance, incidence and outcome of viral infections in children undergoing allogeneic hematopoietic cell transplantation (HCT) in the main pediatric transplant units in Spain. We prospectively collected data from first year post-HCT in every consecutive allogeneic HCT performed during 3 years (N=215): first HCT=188 and second HCT=27; median age=6.6 years (0.1-20.7). Most patients had acute leukemia (N=137) and 135 recipients (63%) were CMV seropositive. A total of 46 patients underwent cord blood transplant, 133 patients underwent HCT from alternative donors (62%) and 101 patients re...

Nicotine-induced human breast cancer cell proliferation attenuated by garcinol through down-regulation of the nicotinic receptor and cyclin D3 proteins

Breast Cancer Research and Treatment — Sun, 14 Mar 2010 11:26:12 +0100

Abstract Previous studies have demonstrated that the persistent exposure of human bronchial epithelial cells to nicotine (Nic) through nicotinic acetylcholine receptors increases cyclin D1 promoter activity and protein expression. The main purpose of this study is to elucidate the carcinogenic role of cyclin D3, which is involved in breast tumorigenesis when induced by Nic. Real-time PCR analysis revealed that cyclin D3 is highly expressed at the mRNA level in surgically dissected breast tumor tissue, compared to the surrounding normal tissue (tumor/normal fold ratio = 17.93, n = 74). To test whether Nic/nicotinic acetylcholine receptor (nAChR) binding could affect cyclin D3 expression in human breast cancer cells, the transformed cell line MCF-10A-Nic (...

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beta-catenin regulates melanocyte dendricity through the modulation of PKCzeta and PKCdelta.

Pigment Cell and Melanoma Research — Sat, 13 Mar 2010 00:00:00 +0100

Authors: Kim JH, Sohn KC, Choi TY, Kim MY, Ando H, Yoon J, Choi SJ, Kim S, Lee YH, Lee JH, Kim CD, Yoon TJ Summary The Wnt/beta-catenin signaling pathway is involved in the melanocyte differentiation and melanoma development. However, the effect of beta-catenin for dendrite formation has not been clearly elucidated yet in normal human epidermal melanocytes (NHEM). To investigate the effect of beta-catenin, we transduced NHEM with recombinant adenovirus expressing beta-catenin. Forced expression of beta-catenin led to the dramatic morphological changes of NHEM, including the reduction of dendrite length and enlargement of cell body. Concomitantly with, the protein levels for dendrite formation-related molecules, such as Rac1 and Cdc42, were markedly decreased. In addition, phosphorylati...

Expression of a Homeostatic Regulator, Wip1 (Wild-type p53-induced Phosphatase), Is Temporally Induced by c-Jun and p53 in Response to UV Irradiation [Cell Biology]

Journal of Biological Chemistry — Fri, 12 Mar 2010 14:36:07 +0100

Wild-type p53-induced phosphatase (Wip1) is induced by p53 in response to stress, which results in the dephosphorylation of proteins (i.e. p38 MAPK, p53, and uracil DNA glycosylase) involved in DNA repair and cell cycle checkpoint pathways. p38 MAPK-p53 signaling is a unique way to induce Wip1 in response to stress. Here, we show that c-Jun directly binds to and activates the Wip1 promoter in response to UV irradiation. The binding of p53 to the promoter occurs earlier than that of c-Jun. In experiments, mutation of the p53 response element (p53RE) or c-Jun consensus sites reduced promoter activity in both non-stressed and stressed A549 cells. Overexpression of p53 significantly decreased Wip1 expression in HCT116 p53+/+ cells but increased it in HCT116 p53–/– cells. Adenovirus...

Transdifferentiated circulating monocytes release exosomes containing 14-3-3 proteins with matrix metalloproteinase-1 stimulating effect for dermal fibroblasts

Wound Repair and Regeneration — Fri, 12 Mar 2010 00:00:00 +0100

This study describes exosomes as a major delivery system that keratinocyte-like cells use to release proteins into the conditioned media. The exosomes exhibited distinctive size, density, and saucer-like morphology. Using PKH-26 and GFP-adenovirus infection, we demonstrated that exosomes are able to fuse and then release their protein content into dermal fibroblasts. Mass spectrometry and Western blotting identified five 14-3-3 isoforms ([beta], [gamma], ɛ, [tau], and [zeta]) as MMP-1 stimulating factors for dermal fibroblasts. Immunoprecipation assays confirmed that these 14-3-3 isoforms account for almost the entire MMP-1 up-regulation induced by exosomes. In summary, our results demonstrated that circulating monocytes stimulated to be transformed into "keratinocyte-like cells" co...

15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires Src-mediated Egr-1-dependent rapid induction of FGF-2 expression

Blood — Thu, 11 Mar 2010 17:02:03 +0100

To understand the mechanisms underlying 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE]–induced angiogenesis, we studied the role of Egr-1. 15(S)-HETE induced Egr-1 expression in a time-dependent manner in human dermal microvascular endothelial cells (HDMVECs). Blockade of Egr-1 via forced expression of its dominant-negative mutant attenuated 15(S)-HETE–induced HDMVEC migration and tube formation as well as Matrigel plug angiogenesis. 15(S)-HETE–induced Egr-1 expression requires Src activation. In addition, adenovirus-mediated expression of dominant-negative mutant of Src blocked 15(S)-HETE's effects on migration and tube formation of HDMVECs and Matrigel plug angiogenesis. 15(S)-HETE induced fibroblast growth factor-2 (FGF-2) expression rapidly via Src-mediated productio...

Adenovirus-mediated transfer of siRNA against basic fibroblast growth factor mRNA enhances the sensitivity of glioblastoma cells to chemotherapy

Medical Oncology — Thu, 11 Mar 2010 02:49:32 +0100

In this study, we used an adenovirus(Ad)-mediated transfer of siRNA against bFGF mRNA (Ad-bFGF-siRNA) to study the effect of down-regulating bFGF expression on the sensitivity of glioma cells to chemotherapeutics. An optimal siRNA sequence specific for bFGF mRNA was cloned into an adenoviral vector and transfected into three glioma cell lines: U251, A172, and LN229. Methyl thiazolyl tetrazolium (MTT) assays were used to examine changes in cell proliferation, and changes in bFGF mRNA and protein levels in U251 cells were detected using quantitative RT-PCR and Western blot, respectively. Apoptosis of U251 cells was detected using Hoechst staining and flow cytometry, with expression of apoptosis-related proteins evaluated by Western blot. Following the transfection of a bFGF-specific si...

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Articular cartilage repair by genetically modified bone marrow aspirate in sheep

Gene Therapy — Thu, 11 Mar 2010 00:00:00 +0100

Authors: A Ivkovic, A Pascher, D Hudetz, D Maticic, M Jelic, S Dickinson, M Loparic, M Haspl, R Windhager & M Pecina (Source: Gene Therapy)

An ex vivo loop system models the toxicity and efficacy of PEGylated and unmodified adenovirus serotype 5 in whole human blood

Gene Therapy — Thu, 11 Mar 2010 00:00:00 +0100

Authors: A Danielsson, G Elgue, B M Nilsson, B Nilsson, J D Lambris, T H Tötterman, S Kochanek, F Kreppel & M Essand (Source: Gene Therapy)

Organ-specific shifts in mtDNA heteroplasmy following systemic delivery of a mitochondria-targeted restriction endonuclease

Gene Therapy — Thu, 11 Mar 2010 00:00:00 +0100

Authors: S R Bacman, S L Williams, S Garcia & C T Moraes (Source: Gene Therapy)

Effect of Administration Route on the Biodistribution and Shedding of Replication-Deficient AAV2. A Qualitative Modelling Approach.

Current Gene Therapy — Thu, 11 Mar 2010 00:00:00 +0100

Authors: Brandon EF, Hermsen HP, van Eijkeren JC, Tiesjema B Gene therapy is a rapidly developing field in which recombinant nucleic acid sequences are introduced to individuals to regulate, repair, replace, add or delete a genetic sequence. Recombinant adeno-associated viral (AAV) vectors, especially AAV2, are frequently used in gene therapy. Knowledge on the biodistribution and potential shedding of AAV2 is crucial to evaluate the risks of infection with the viral vector for the patient and the environment. Literature was analysed for biodistribution and shedding data for AAV2. Preclinical and clinical studies were included with a focus on the influence of the administration route on spreading. Based on biodistribution and shedding data, a qualitative model for the biodistribution an...

A Dominant-Negative PPARγ Mutant Promotes Cell Cycle Progression and Cell Growth in Vascular Smooth Muscle Cells

PPAR Research — Wed, 10 Mar 2010 17:48:02 +0100

PPARγ ligands have been shown to have antiproliferative effects on many cell types. We herein report that a synthetic dominant-negative (DN) PPARγ mutant functions like a growth factor to promote cell cycle progression and cell proliferation in human coronary artery smooth muscle cells (CASMCs). In quiescent CASMCs, adenovirus-expressed DN-PPARγ promoted G1→S cell cycle progression, enhanced BrdU incorporation, and increased cell proliferation. DN-PPARγ expression also markedly enhanced positive regulators of the cell cycle, increasing Rb and CDC2 phosphorylation and the expression of cyclin A, B1, D1, and MCM7. Conversely, overexpression of wild-type (WT) or constitutively-active (CA) PPARγ inhibited cell cycle progression and the activity and exp...

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Nitric oxide reduces SLC29A1 promoter activity and adenosine transport involving transcription factor complex hCHOP-C/EBP{alpha} in human umbilical vein endothelial cells from gestational diabetes

Cardiovascular Research — Wed, 10 Mar 2010 16:52:14 +0100

Conclusion The hCHOP–C/EBP complex down-regulates SLC29A1 expression in an NO-dependent manner in HUVECs from gestational diabetes. (Source: Cardiovascular Research)

The efficacy of combination therapy using adeno-associated virus-TRAIL targeting to telomerase activity and cisplatin in a mice model of hepatocellular carcinoma

Journal of Cancer Research and Clinical Oncology — Wed, 10 Mar 2010 16:10:22 +0100

Conclusions AAV-mediated therapeutic gene expression in combination with chemotherapy provides a promising therapeutic strategy for human cancers. These data suggest that combined use of AAV-hTERT-TRAIL and cisplatin may have potential clinical application. Content Type Journal ArticleCategory Original PaperDOI 10.1007/s00432-010-0841-8Authors Yigang Wang, East China University of Science and Technology State Key Laboratory of Bioreactor Engineering Shanghai 200237 ChinaFang Huang, Zhejiang Sci-Tech University Institute of Xinyuan Medicine and Biotechnology, College of Life Science Hangzhou 310018 ChinaHaibo Cai, East China University of Science and Technology State Key Laboratory of Bioreactor Engineering Shanghai 200237 ChinaYumei Wu, Zhejiang Sci-Tech University I...

Overexpression of the orphan receptor Nur77 alters glucose metabolism in rat muscle cells and rat muscle in vivo

Diabetologia — Wed, 10 Mar 2010 15:41:28 +0100

Conclusions/interpretation Our data provide compelling evidence that NUR77 is a functional regulator of glucose metabolism in skeletal muscle in vivo. Importantly, the diminished content in muscle of obese insulin-resistant men suggests that it might be a potential therapeutic target for the treatment of dysregulated glucose metabolism. Content Type Journal ArticleCategory ArticleDOI 10.1007/s00125-010-1703-2Authors T. Kanzleiter, Garvan Institute of Medical Research Diabetes and Obesity Research Program 384 Victoria Street, Darlinghurst Sydney NSW 2010 AustraliaE. Preston, Garvan Institute of Medical Research Diabetes and Obesity Research Program 384 Victoria Street, Darlinghurst Sydney NSW 2010 AustraliaD. Wilks, Garvan Institute of Medical Research Diabetes and O...

Phospholipase D2 Mediates Acute Aldosterone Secretion in Response to Angiotensin II in Adrenal Glomerulosa Cells.

Endocrinology — Wed, 10 Mar 2010 00:00:00 +0100

Authors: Qin H, Frohman MA, Bollag WB In primary bovine adrenal glomerulosa cells, the signaling enzyme phospholipase D (PLD) is suggested to mediate priming, the enhancement of aldosterone secretion after pretreatment with and removal of angiotensin II (AngII), via the formation of persistently elevated diacylglycerol (DAG). To further explore PLD's role in priming, glomerulosa cells were pretreated with an exogenous bacterial PLD. Using this approach, phosphatidic acid (PA) is generated on the outer, rather than the inner, leaflet of the plasma membrane. Although PA is not readily internalized, the PA is nonetheless rapidly hydrolyzed by cell-surface PA phosphatases to DAG, which efficiently flips to the inner leaflet and accesses the cell interior. Pretreatment with bacterial PLD re...

Viral and bacterial aetiologies of male urethritis: findings of a high prevalence of Epstein-Barr virus

International Journal of STD and AIDS — Tue, 09 Mar 2010 21:06:05 +0100

In this study the prevalences of Epstein–Barr virus (EBV), herpes simplex virus type 1 (HSV-1), HSV-2, cytomegalovirus (CMV), adenovirus, Chlamydia trachomatis, Mycoplasma genitalium and Ureaplasma urealyticum (including subtyping) were investigated. Samples from 112 male STI attendants with microscopically verified urethritis and from a control group of 103 men without clinical or microscopic signs of urethritis were analysed. Prevalences in the urethritis group compared with the controls were as follows: EBV 21%, 6% (P < 0.01); C. trachomatis 15%, 3% (P < 0.01); M. genitalium 6%, 1% (P = 0.067) and U. urealyticum 10%, 10% (ns). The results for HSV-1, HSV-2, CMV and adenovirus were negative in patients, and therefore not analysed in the controls. EBV was shown to be an indepen...

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Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cholesterol transport during the acute phase response but not group IIA secretory phospholipase A2 [Research Articles]

The Journal of Lipid Research — Tue, 09 Mar 2010 19:16:08 +0100

In conclusion, our data demonstrate that acute inflammation impairs cholesterol efflux in patients and macrophage-to-feces RCT in vivo in mice. Myeloperoxidase and SAA contribute to a certain extent to reduced RCT during inflammation but not sPLA2. However, reduced bile acid formation and decreased biliary sterol excretion might represent major contributing factors to decreased RCT in inflammation. (Source: The Journal of Lipid Research)

Broad Spectrum Respiratory Pathogen Analysis of Throat Swabs from Military Recruits Reveals Interference Between Rhinoviruses and Adenoviruses.

Microbial Ecology — Tue, 09 Mar 2010 00:00:00 +0100

In this study, we explore the carriage rates and disease associations of adenovirus, enterovirus, rhinovirus, Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis in military recruits using high-density resequencing microarrays. The results showed that rhinoviruses, adenoviruses, S. pneumoniae, H. influenzae, and N. meningitidis were widely distributed in recruits. Of these five agents, only adenovirus showed significant correlation with illness. Among the samples tested, only pathogens associated with FRI, such as adenovirus 4 and enterovirus 68, revealed strong temporal and spatial clustering of specific strains, indicating that they are transmitted primarily within sites. The results showed a strong negative association between adenoviral FRI and the presence of ...

PEA-15 Inhibits Tumorigenesis in an MDA-MB-468 Triple-Negative Breast Cancer Xenograft Model through Increased Cytoplasmic Localization of Activated Extracellular Signal-Regulated Kinase.

Clinical Cancer Research — Tue, 09 Mar 2010 00:00:00 +0100

CONCLUSION: PEA-15 has therapeutic potential in breast cancer. Further preclinical and clinical exploration of PEA-15 as a druggable target is warranted. Clin Cancer Res; 16(6); 1802-11. PMID: 20215547 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

Toward gene therapy of premature ovarian failure: intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR(-/-) FORKO mice

Molecular Human Reproduction — Mon, 08 Mar 2010 15:51:10 +0100

In conclusion, intra-ovarian injection of an adenovirus expressing human FSHR gene is able to restore FSH responsiveness and reinitiate ovarian folliculogenesis as well as resume estrogen production in female FORKO mice. Ad-LacZ injections indicate the absence of systemic viral dissemination or germ line transmission of adenovirus DNA to offspring. (Source: Molecular Human Reproduction)

What Causes Pharyngitis?

PediatricEducation.org — Mon, 08 Mar 2010 00:10:32 +0100

Discussion Sore throat caused by group A, beta-hemolytic streptococcus (GAS) is classically characterized as a patient with a constellation of various symptoms including fever, headache, emesis, sore throat, palatal petechiae, abdominal pain, sand-papery skin rash and often with a history of close contact. The rapidity of onset is relatively short but generally not characterized as rapid. Patients with upper respiratory tract symptoms or allergic symptoms including rhinitis, conjunctivitis, voice changes (e.g. raspy, croupy, laryngitic) tend to have viral etiologies for their sore throat. Differentiating between viral pharyngitis and GAS is a common conundrum. Rapid antigen testing and throat cultures assist in making the proper diagnosis, so that nonsupprative complications such as acute ...

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CD40 ligand induced cytotoxicity in carcinoma cells is enhanced by inhibition of metalloproteinase cleavage and delivery via a conditionally-replicating adenovirus

Molecular Cancer — Mon, 08 Mar 2010 00:00:00 +0100

Conclusions: Combined with numerous studies demonstrating its immunotherapeutic potential, these data provide a strong rationale for the exploitation of the CD40-CD40L pathway for the treatment of solid tumours. (Source: Molecular Cancer)

Efficient transduction of spiral ganglion cells using adenovirus type 5 vector in the rat.

Acta Oto-Laryngologica — Mon, 08 Mar 2010 00:00:00 +0100

Conclusions: The adenovirus-5 vector specifically transduced spiral ganglion cells with high efficiency, suggesting that it is a potential gene therapeutic tool for the survival of spiral ganglion cells with secondary injury. Objectives: This study aimed to find a suitable viral vector allowing efficient transduction to spiral ganglion cells. Methods: Lentivirus, adeno-associated virus-2 and adenovirus-5 constructs habouring green fluorescence protein (GFP) gene were injected into scala tympani via the round window membrane of rat. Distribution and fluorescence intensity of GFP within the cochlea were estimated using a fluorescence microscope. Results: The GFP expressions mediated by all three viral vectors were observed in multiple cell types of the cochlea. Compared with the other two vi...

Pancreatitis-associated chymotrypsinogen C (CTRC) mutant elicits endoplasmic reticulum stress in pancreatic acinar cells

Gut — Fri, 05 Mar 2010 11:12:51 +0100

Conclusions Pancreatitis-associated CTRC mutations can markedly increase the propensity of chymotrypsinogen C to elicit ER stress in pancreatic acinar cells. Thus, carriers of CTRC mutations may be at a higher risk of developing ER stress in the exocrine pancreas, which may contribute to parenchymal damage through acinar cell apoptosis. (Source: Gut)

Long-term impact of respiratory viral infection after pediatric lung transplantation

Pediatric Transplantation — Fri, 05 Mar 2010 00:00:00 +0100

Liu M, Mallory GB, Schecter MG, Worley S, Arrigain S, Robertson J, Elidemir O, Danziger-Isakov LA. Long-term impact of respiratory viral infection after pediatric lung transplantation. Pediatr Transplantation 2010 00: 000[ndash]000. © 2010 John Wiley & Sons A/S.Abstract: To evaluate the epidemiology and to investigate the impact of RVI on chronic allograft rejection after pediatric lung transplantation, a retrospective study of pediatric lung transplant recipients from 2002 to 2007 was conducted. Association between RVI and continuous and categorical risk factors was assessed using Wilcoxon rank-sum tests and Fisher's exact tests, respectively. Association between risk factors and outcomes were assessed using Cox proportional hazards models. Fifty-five subjects were followed for a mean of...

Efficient co-transduction of adenoviral vectors encoding carcinoembryonic antigen and survivin into dendritic cells by the CAR-TAT adaptor molecule enhance antitumor immunity in a murine colorectal cancer model.

Immunology Letters — Fri, 05 Mar 2010 00:00:00 +0100

Authors: Kim HS, Kim CH, Park MY, Park JS, Park HM, Sohn HJ, Kim HJ, Kim SG, Oh ST, Kim TG Because multiple tumor antigens, including carcinoembryonic antigen (CEA) and survivin (SVV), have been frequently observed in human colorectal cancer, we investigated whether the expression of both CEA and SVV by co-transduction of adenovirus vectors into dendritic cells (DC) could improve antitumor immunity in a murine colorectal cancer model. The adaptor fusion protein of Coxsackie and adenovirus receptor and TAT-protein transduction domain (CAR-TAT) enhanced co-transduction of adenovirus vectors encoding CEA (AdCEA) and SVV (AdSVV) into DCs, and increased antitumor immunity. DCs expressing both CEA and SVV in the presence of CAR-TAT (DC-AdCEA/AdSVV+CAR-TAT) induced T-cell responses specific f...

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A new system for regulated functional gene expression for gene therapy applications: Nuclear delivery of a p16INK4A-estrogen receptor carboxy terminal fusion protein only in the presence of estrogen.

International Journal of Oncology — Thu, 04 Mar 2010 22:58:57 +0100

Authors: Tamura T, Kanuma T, Nakazato T, Faried LS, Aoki H, Minegishi T The clinical use of gene therapy requires tight regulation of the gene of interest and functional expression only when it is needed. Thus, it is necessary to develop ways of regulating functional gene expression with exogenous stimuli. Many regulatable systems are currently under development. For example, the tetracycline-dependent transcriptional switch has been successfully employed for in vivo preclinical applications. However, there are no examples of regulatable systems that have been employed in human clinical trials. In the present study, we established an adenovirus-delivered functional gene expression system that is regulated by estrogen. This system uses p16INK4A fused at its C-terminus to the ligand-bind...

The Adenovirus Type 3 Dodecahedron's RGD Loop Comprises an HSPG Binding Site That Influences Integrin Binding

Journal of Biomedicine and Biotechnology — Thu, 04 Mar 2010 18:13:20 +0100

Human type 3 adenovirus dodecahedron (a virus like particle made of twelve penton bases) features the ability to enter cells through Heparan Sulphate Proteoglycans (HSPGs) and integrins interaction and is used as a versatile vector to deliver DNA or proteins. Cryo-EM reconstruction of the pseudoviral particle with Heparan Sulphate (HS) oligosaccharide shows an extradensity on the RGD loop. A set of mutants was designed to study the respective roles of the RGD sequence (RGE mutant) and of a basic sequence located just downstream. Results showed that the RGE mutant binding to the HS deficient CHO-2241 cells was abolished and unexpectedly, mutation of the basic sequence (KQKR to AQAS) dramatically decreased integrin recognition by the viral pseudoparticle. This basic sequence is thus involved...

Adeno-associated virus-mediated delivery of kringle 5 of human plasminogen inhibits orthotopic growth of ovarian cancer

Gene Therapy — Thu, 04 Mar 2010 00:00:00 +0100

Authors: T M B Nguyen, I V Subramanian, X Xiao, P Nguyen & S Ramakrishnan (Source: Gene Therapy)

Continuous supply of TGF[beta]3 via adenoviral vector promotes type I collagen and viability of fibroblasts in alginate hydrogel

Journal of Tissue Engineering and Regenerative Medicine — Thu, 04 Mar 2010 00:00:00 +0100

In recent years, transforming growth factor-[beta]3 (TGF[beta]3) has interested more and more researchers with its competence in engineered histogenesis. In the present study we employed recombinant adenoviral vectors to deliver the constitutively active TGF[beta]3 gene to human dermal fibroblasts, which could maintain the continuous secretion of TGF[beta]3 from the cells. The expression of type I collagen in the Ad-TGF[beta]3 group increased significantly in comparison with other three groups: Neg (cells without treatment of the adenovirus), Ad-null (cells with treatment of the adenovirus, without the inserted gene) and Ad-shRNA (cells with treatment of the adenovirus encoding shRNA specific for type I collagen). Additionally, we demonstrated that TGF[beta]3 enhanced the expression of Sma...

Generation of a Dominant-Negative Glycogen Targeting Subunit for Protein Phosphatase-1.

Obesity — Thu, 04 Mar 2010 00:00:00 +0100

Authors: Jurczak MJ, Zapater JL, Greenberg CC, Brady MJ Modulation of the expression of the protein phosphatase-1 (PP1) glycogen-targeting subunit PTG exerts profound effects on cellular glycogen metabolism in vitro and in vivo. PTG contains three distinct binding domains for glycogen, PP1, and a common site for glycogen synthase and phosphorylase. The impact of disrupting the PP1-binding domain on PTG function was examined in 3T3-L1 adipocytes. A full-length PTG mutant was generated as an adenoviral construct in which the valine and phenylalanine residues in the conserved PP1-binding domain were mutated to alanine (PTG-VF). Infection of fully differentiated 3T3-L1 adipocytes with the PTG-VF adenovirus reduced glycogen stores by over 50%. In vitro, PTG-VF competitively interfered with ...

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Performance of direct fluorescent antibody staining, point-of-care rapid antigen test and virus isolation for the detection of novel 2009 influenza A (H1N1) virus in comparison to RT-PCR in respiratory specimens.

Journal of Medical Microbiology — Thu, 04 Mar 2010 00:00:00 +0100

Authors: Ganzenmueller T, Kluba J, Hilfrich B, Puppe W, Verhagen W, Heim A, Schulz T, Henke-Gendo C Although infections with the novel pandemic 2009 influenza A (H1N1) virus (A(H1N1)2009) appeared relatively mild during the first summer of circulation 'off-season'), there has been significant morbidity, hospitalization, and several fatal cases. Thus, rapid detection of A(H1N1)2009 is crucial for efficient treatment and infection control measures. In contrast to seasonal influenza, where point-of-care (POC) rapid antigen tests and direct fluorescent antibody (DFA) staining ensure rapid detection, diagnosis of A(H1N1)2009 is hitherto based on RT-PCR. We retrospectively analyzed the performance of the Quidel QuickVue POC test, DFA staining and virus isolation for A(H1N1)2009 detection in ...

Keap1-Nrf2 activation in the presence and absence of DJ-1

European Journal of Neuroscience — Wed, 03 Mar 2010 00:00:00 +0100

The molecular mechanisms leading to neurodegeneration in Parkinson's disease remain elusive. Deletion and mutations of DJ-1 (PARK7) have been reported to cause autosomal recessive familial Parkinson's disease. Wildtype DJ-1 scavenges H2O2 by cysteine oxidation in response to oxidative stress, and thus confers neuroprotection. Activation of the transcription factor NF-E2-related factor-2 (Nrf2) has also been shown to be important for protection against oxidative stress in many models of neurodegenerative diseases. Previous data indicate that DJ-1 affects the transcriptional functions and stability of Nrf2. However, this observation has not been confirmed. In the current study, the role of DJ-1 in the regulation of Nrf2 is examined in primary cultured neurons, astrocytes and in vivo. The pro...

PGC-1{alpha} overexpression increases lipid oxidation in myocytes from extremely obese individuals.

Diabetes — Wed, 03 Mar 2010 00:00:00 +0100

Conclusion - Reduced mitochondrial content is related to impaired FAO in HSkMC derived from obese individuals. Increasing PGC-1alpha protein levels did not correct the obesity-related absolute reduction in FAO and mtDNA content, implicating mechanisms other than PGC-1alpha abundance. PMID: 20200320 [PubMed - as supplied by publisher] (Source: Diabetes)

Phosphatidylserine immobilization of lentivirus for localized gene transfer.

Biomaterials — Wed, 03 Mar 2010 00:00:00 +0100

Authors: Shin S, Tuinstra HM, Salvay DM, Shea LD Localized and efficient gene transfer can be promoted by exploiting the interaction between the vector and biomaterial. Regulation of the vector-material interaction was investigated by capitalizing on the binding between lentivirus and phosphatidylserine (PS), a component of the plasma membrane. PS was incorporated into microspheres composed of the copolymers of lactide and glycolide (PLG) using an emulsion process. Increasing the weight ratio of PS to PLG led to a greater incorporation of PS. Lentivirus, but not adenovirus, associated with PS-PLG microspheres, and binding was specific to PS relative to PLG alone or PLG modified with phosphatidylcholine. Immobilized lentivirus produced large numbers of transduced cells, and increased tr...

Regulation of Adrenal Aldosterone Production by Serine Protease Prostasin

Journal of Biomedicine and Biotechnology — Tue, 02 Mar 2010 17:36:59 +0100

A serine protease prostasin has been demonstrated to have a pivotal role in the activation of the epithelial sodium channel. Systemic administration of adenovirus carrying human prostasin gene in rats resulted in an increase in plasma prostasin and aldosterone levels. However, the mechanism by which the elevation of prostasin levels in the systemic circulation stimulated the plasma aldosterone levels remains unknown. Therefore, we examined if prostasin increases the aldosterone synthesis in a human adrenocortical cell line (H295R cells). Luciferase assay using CYP11B2 promoter revealed that prostasin significantly increased the transcriptional activity of CYP11B2. Prostasin significantly increased both CYP11B2 mRNA expression and aldosterone production in a dose-dependent manner. Surprisin...

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AAV-2: how can the capsid be modified to improve the viral vector in gene therapy?

Future Virology — Mon, 01 Mar 2010 15:56:13 +0100

Future Virology , March 2010, Vol. 5, No. 2, Pages 133-135. (Source: Future Virology)

The In Vitro and In Vivo Antitumor Activity of Adenovirus-Mediated Interleukin-24 Expression for Laryngocarcinoma

Cancer Biotherapy and Radiopharmaceuticals — Mon, 01 Mar 2010 04:53:52 +0100

Cancer Biotherapy & Radiopharmaceuticals Feb 2010, Vol. 25, No. 1: 29-38. (Source: Cancer Biotherapy and Radiopharmaceuticals)

Acute idiopathic hemorrhagic pericarditis with cardiac tamponade as the initial presentation of acquired immune deficiency syndrome.

Yonsei Medical Journal — Mon, 01 Mar 2010 00:00:00 +0100

Authors: Park YI, Sir JJ, Park SW, Kim HT, Lee B, Kwak YK, Cho WH, Choi SK This paper presents a case of cardiac tamponade with idiopathic hemorrhagic pericarditis as the initial symptom of human immunodeficiency virus (HIV) infection. A 29-year-old male came to the emergency room with a sudden onset of dizziness. Upon arrival, he was hypotensive although not tachycardic, and his jugular venous pressure was not elevated. His chest X-rays revealed a mild cardiomegaly. Transthoracic echocardiography revealed a large amount of pericardial effusion with a diastolic collapse of the right ventricle, a dilated inferior vena cava with little change in respiration, and exaggerated respiratory variation of mitral inflow velocities, representing echocardiographic evidence of cardiac tamponade. Af...

Targeted retrograde gene delivery of brain-derived neurotrophic factor suppresses apoptosis of neurons and oligodendroglia after spinal cord injury in rats.

Adv Data — Mon, 01 Mar 2010 00:00:00 +0100

CONCLUSION.: Our results suggest that targeted retrograde BDNF gene delivery suppresses apoptosis of neurons and oligodendrocytes in the injured rat spinal cord. PMID: 20190624 [PubMed - in process] (Source: Adv Data)

The DNA damage response to non-replicating adeno-associated virus: Centriole overduplication and mitotic catastrophe independent of the spindle checkpoint.

Virology — Mon, 01 Mar 2010 00:00:00 +0100

Authors: Ingemarsdotter C, Keller D, Beard P Adeno-associated virus (AAV) type 2 or UV-inactivated AAV (UV-AAV2) infection provokes a DNA damage response that leads to cell cycle arrest at the G2/M border. p53-deficient cells cannot sustain the G2 arrest, enter prolonged impaired mitosis, and die. Here, we studied how non-replicating AAV2 kills p53-deficient osteosarcoma cells. We found that the virus uncouples centriole duplication from the cell cycle, inducing centrosome overamplification that is dependent on Chk1, ATR and CDK kinases, and on G2 arrest. Interference with spindle checkpoint components Mad2 and BubR1 revealed unexpectedly that mitotic catastrophe occurs independently of spindle checkpoint function. We conclude that, in the p53-deficient cells, UV-AAV2 triggers mitotic ...

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Therapeutic angiogenesis by transplantation of human embryonic stem cell-derived CD133(+) endothelial progenitor cells for cardiac repair.

Regenerative Medicine — Mon, 01 Mar 2010 00:00:00 +0100

Conclusion: hESC-derived CD133(+) endothelial progenitor cells can be utilized to regenerate the infarcted heart. PMID: 20210583 [PubMed - in process] (Source: Regenerative Medicine)

Maxillary sinus floor elevation using a tissue engineered bone complex with BMP-2 gene modified bMSCs and a novel porous ceramic scaffold in rabbits

Archives of Oral Biology — Mon, 01 Mar 2010 00:00:00 +0100

Abstract: Objectives: To study the effects of maxillary sinus floor elevation by a tissue engineered bone complex with bone morphogenetic protein-2 (BMP-2) gene modified bone marrow stromal cells (bMSCs) and a novel porous ceramic scaffold (OsteoBone™) in rabbits.Materials and methods: bMSCs derived from New Zealand rabbit bone marrow were cultured and transduced with adenovirus AdBMP-2 and with AdEGFP gene (without BMP-2 gene sequence) as a control, respectively, in vitro. These bMSCs were then combined with OsteoBone™ scaffold at a concentration of 2×107cells/ml and used to elevate the maxillary sinus floor in rabbits. Eight rabbits were randomly allocated into groups and sacrificed at weeks 2 and 4. For each time point, 8 maxillary sinus floor elevation surgeries were made bilatera...

Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN

Nature Biotechnology — Sun, 28 Feb 2010 00:00:00 +0100

Authors: Kevin D Foust, Xueyong Wang, Vicki L McGovern, Lyndsey Braun, Adam K Bevan, Amanda M Haidet, Thanh T Le, Pablo R Morales, Mark M Rich, Arthur H M Burghes & Brian K Kaspar Spinal muscular atrophy (SMA), the most common autosomal recessive neurodegenerative disease affecting children, results in impaired motor neuron function. Despite knowledge of the pathogenic role of decreased survival motor neuron (SMN) protein levels, efforts to increase SMN have not resulted in a treatment for patients. We recently demonstrated that self-complementary adeno-associated virus 9 (scAAV9) can infect ∼60% of motor neurons when injected intravenously into neonatal mice. Here we use scAAV9-mediated postnatal day 1 vascular gene delivery to replace SMN in SMA pups and rescue motor function, ...

Ex vivo gene transferring of human dimethylarginine dimethylaminohydrolase-2 improved endothelial dysfunction in diabetic rat aortas and high glucose-treated endothelial cells

Atherosclerosis — Sat, 27 Feb 2010 13:53:26 +0100

Conclusion: These results indicate that suppression of DDAH2 expression contributes to hyperglycemia-induced endothelial dysfunction, which can be improved by DDAH2 overexpression. This study suggests that targeted modulation of DDAH2 gene in vascular endothelium may be a novel approach for the treatment of endothelial dysfunction in diabetes mellitus. (Source: Atherosclerosis)

Mitochondrial content and distribution changes specific to mouse diaphragm after chronic normobaric hypoxia

AJP: Regulatory, Integrative and Comparative Physiology — Fri, 26 Feb 2010 17:04:25 +0100

Chronic hypoxia reduces aerobic capacity (mitochondrial content) in limb skeletal muscles, and one of the causes seems to be decreased physical activity. Diaphragm and other respiratory muscles, however, may have a different pattern of adaptation as hypoxia increases the work of breathing. Thus, we hypothesized that chronic hypoxia would not reduce mitochondrial content in mouse diaphragm. Adult male C57BL/6J mice were kept in normoxia (FiO2 = 21%, control) or normobaric hypoxia (FiO2 = 10%, hypoxia) for 1, 2, and 4 wk. Mice were then killed, and the diaphragm and gastrocnemius muscles collected for analysis. In the diaphragm, cytochrome c oxidase histochemistry showed less intense staining in the hypoxia group. The total content of subunits from the electron transport chain, pyruvate dehy...

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A potential role for hypothalamomedullary POMC projections in leptin-induced suppression of food intake

AJP: Regulatory, Integrative and Comparative Physiology — Fri, 26 Feb 2010 17:04:25 +0100

Melanocortin-3/4 receptor ligands administered to the caudal brain stem potently modulate food intake by changing meal size. The origin of the endogenous ligands is unclear, because the arcuate nucleus of the hypothalamus and the nucleus of the solitary tract (NTS) harbor populations of proopiomelanocortin (POMC)-expressing neurons. Here we demonstrate that activation of hypothalamic POMC neurons leads to suppression of food intake and that this suppression is prevented by administration of a melanocortin-3/4 receptor antagonist to the NTS and its vicinity. Bilateral leptin injections into the rat arcuate nucleus produced long-lasting suppression of meal size and total chow intake. These effects were significantly blunted by injection of SHU-9119 into the fourth ventricle, although SHU-911...

Outbreak of Adenovirus 14 Respiratory Illness -- Prince of Wales Island, Alaska, 2008

Medscape Infectious Diseases Headlines — Fri, 26 Feb 2010 14:27:07 +0100

This report details the first recognized outbreak of adenovirus 14, an emerging serotype in the US that is associated with a higher rate of severe illness compared with other adenoviruses. Morbidity & Mortality Weekly Report (Source: Medscape Infectious Diseases Headlines)

Adeno-associated virus type 5-mediated intraarticular administration of tumor necrosis factor small interfering RNA improves collagen-induced arthritis

Arthritis and Rheumatism — Thu, 25 Feb 2010 00:00:00 +0100

RNA interference (RNAi) is a powerful tool for sequence-specific gene silencing, and interest in its application in human diseases is growing. Given the success of recent strategies for administering gene therapy in rheumatoid arthritis using recombinant vectors such as adeno-associated virus type 5 (rAAV5) for optimized intraarticular gene transfer, we undertook the present study to determine the feasibility of using rAAV5-mediated RNAi-based therapy in arthritis.We developed rAAV5 vectors expressing short hairpin small interfering RNA (shRNA) against tumor necrosis factor [alpha] (TNF[alpha]) under H1 promoter, and carrying the enhanced green fluorescent protein (eGFP) reporter gene under cytomegalovirus promoter (rAAV5-shTNF). TNF[alpha] gene silencing was validated in vitro with mouse ...

Prime and boost immunization with influenza and adenovirus encoding the Toxoplasma gondii surface antigen 2 (SAG2) induces strong protective immunity.

Vaccine — Thu, 25 Feb 2010 00:00:00 +0100

Authors: Machado AV, Caetano BC, Barbosa RP, Salgado AP, Rabelo RH, Garcia CC, Bruna-Romero O, Escriou N, Gazzinelli RT In this work, we explored an original vaccination protocol using recombinant influenza and adenovirus. We constructed recombinant influenza viruses harboring dicistronic NA segments containing the surface antigen 2 (SAG2) from Toxoplasma gondii under control of the duplicated 3' promoter. Recombinant influenza viruses were able to drive the expression of the foreign SAG2 sequence in cell culture and to replicate efficiently both in cell culture and in lungs of infected mice. In addition, mice primed with recombinant influenza virus and boosted with a recombinant adenovirus encoding SAG2 elicited both humoral and cellular immune responses specific for SAG2. Moreover, w...

Soluble Flt-1 gene therapy ameliorates albuminuria but accelerates tubulointerstitial injury in diabetic mice

AJP: Renal Physiology — Wed, 24 Feb 2010 22:28:42 +0100

In conclusion, gene therapy with sFlt-1-AAV1 protects podocytes but accelerates tubulointerstitial injury in diabetic db/db mice. These data suggest systemic overexpression of sFlt-1 will not likely be useful for treating diabetic nephropathy. (Source: AJP: Renal Physiology)

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Ca2+ influx via TRPC channels induces NF-{kappa}B-dependent A20 expression to prevent thrombin-induced apoptosis in endothelial cells

AJP: Cell Physiology — Wed, 24 Feb 2010 22:22:56 +0100

NF-B signaling is known to induce the expression of antiapoptotic and proinflammatory genes in endothelial cells (ECs). We have shown recently that Ca2+ influx through canonical transient receptor potential (TRPC) channels activates NF-B in ECs. Here we show that Ca2+ influx signal prevents thrombin-induced apoptosis by inducing NF-B-dependent A20 expression in ECs. Knockdown of TRPC1 expressed in human umbilical vein ECs with small interfering RNA (siRNA) suppressed thrombin-induced Ca2+ influx and NF-B activation in ECs. Interestingly, we observed that thrombin induced >25% of cell death (apoptosis) in TRPC1-knockdown ECs whereas thrombin had no effect on control or control siRNA-transfected ECs. To understand the basis of EC survival, we performed gene microarray analysis using ECs. ...

Caveolin gene transfer improves glucose metabolism in diabetic mice

AJP: Cell Physiology — Wed, 24 Feb 2010 22:22:55 +0100

In conclusion, our results suggest that caveolin is an important regulator of glucose metabolism that can enhance insulin signals. (Source: AJP: Cell Physiology)

The Role of Adenovirus in Respiratory Tract Infections

Current Infectious Disease Reports — Wed, 24 Feb 2010 06:55:49 +0100

Abstract Adenovirus plays a significant role in respiratory tract disease in pediatric and adult patients. It has been linked to outbreaks and epidemics in various patient populations, resulting in considerable morbidity and mortality. In this article, we discuss the epidemiology, pathogenesis, respiratory tract illnesses and complications, and roles of potential treatment options. The role of the past oral adenovirus vaccine and the military implications of its withdrawal from routine use in military recruits is discussed as well. Content Type Journal ArticleDOI 10.1007/s11908-010-0084-5Authors Anjali N. Kunz, Uniformed Services University of the Health Sciences Department of Pediatrics Bethesda MD 20184 USAMartin Ottolini, Uniformed Services University of the Health...

T-cells in ANCA-associated vasculitis: what can we learn from lesional versus circulating T-cells?

Arthritis Research and Therapy — Wed, 24 Feb 2010 00:00:00 +0100

ANCA-associated vasculitis (AAV) is a life-threatening autoimmune disease characterized by an antibody mediated glomerulonephritis and necrotizing vasculitis. Apart from antibodies, T-cells are also involved in disease pathogenesis. This review stresses the hallmarks of T-cell mediated pathology in AAV and highlights the characteristics of lesional and circulating T-cells in the immune response in AAV. Circulating effector T-cell populations are expanded and are in a persistent state of activation. Circulating regulatory T-cell subsets are less well characterized but seem to be impaired in function. Lesional effector T-cells are present in granulomas, vasculitic lesions and in nephritis. Lesional T-cells usually show pro-inflammatory properties and promote granuloma formation. Apart from T...

Evaluation of Adenovirus and E. coli as indicators for human enteric viruses presence in mussels produced in La Spezia Gulf (Italy)

Letters in Applied Microbiology — Wed, 24 Feb 2010 00:00:00 +0100

Conclusion: This study showed that there was not a direct correlation between the presence of human pathogenic viruses and bacterial indicators.Significance and Impact of the Study: Both E. coli and Adenovirus cannot be considered valid substitutes for the direct research of human pathogenic viruses in mussels. To improve consumer health protection, the European Commission will provide standardized methods for Norovirus and hepatitis A virus detection as soon as possible. (Source: Letters in Applied Microbiology)

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Protection of Nonhuman Primates Against Two Species of Ebola Virus Infection with a Single Complex Adenovirus Vector.

Clinical and Vaccine Immunology — Wed, 24 Feb 2010 00:00:00 +0100

Authors: Pratt WD, Wang D, Nichols DK, Luo M, Woraratanadharm J, Dye JM, Holman DH, Dong JY Ebola viruses are highly pathogenic viruses that cause outbreaks of hemorrhagic fever in humans and other primates. To meet the need for a vaccine against the several types of Ebola viruses that cause human diseases, we developed a multivalent vaccine candidate (EBO7) that expresses the glycoproteins of Zaire ebolavirus (ZEBOV) and Sudan ebolavirus (SEBOV) in a single complex adenovirus-based vector (CAdVax). We evaluated our vaccine in nonhuman primates against the parenteral and aerosol routes of lethal challenge. EBO7 vaccine provided protection against both Ebola viruses by either route of infection. Significantly, protection against SEBOV given by aerosol challenge, which has not previously...

Characterization of a unique proline iminopeptidase from white-rot basidiomycetes Phanerochaete chrysosporium.

Biochimie — Wed, 24 Feb 2010 00:00:00 +0100

Authors: Li N, Wu JM, Zhang LF, Zhang YZ, Feng H A putative gene encoding proline iminopeptidase (PchPiPA) was cloned from Phanerochaete chrysosporium BKM-F-1767 by RT-PCR and expressed successfully in Escherichia coli. The cDNA is 942bp in length and encodes 313 amino acids. The recombinant enzyme was only able to hydrolyze Pro-pNA among the tested synthetic substrates. There is no activity detected toward Leu-pNA, Phe-pNA and Tyr-pNA, as well as GGG-pNA, SGR-pNA, AAV-pNA, AAPL-pNA, AAVA-pNA. And the recombinant enzyme could cleave the peptides derived from enzyme-hydrolytic natural proteins to release free lysine, which was confirmed using synthetic oligopeptides with lysine at N termini as substrate. The optimal pH and temperature for this enzyme were 8.0 and 45 degrees C, respectiv...

Adenovectors induce functional antibodies capable of potent inhibition of blood stage malaria parasite growth.

Vaccine — Wed, 24 Feb 2010 00:00:00 +0100

Authors: Bruder JT, Stefaniak ME, Patterson NB, Chen P, Konovalova S, Limbach K, Campo JJ, Ettyreddy D, Li S, Dubovsky F, Richie TL, King CR, Long CA, Doolan DL An effective malaria vaccine remains a global health priority. Recombinant adenoviruses are a promising vaccine platform, and Plasmodium falciparum apical membrane antigen 1 (AMA1) and merozoite surface protein 1-42 (MSP1(42)) are leading blood stage vaccine candidates. We evaluated the importance of surface antigen localization and glycosylation on the immunogenicity of adenovector delivered AMA1 and MSP1(42) and assessed the ability of these vaccines to induce functional antibody responses capable of inhibiting parasite growth in vitro. Adenovector delivery induced unprecedented levels of biologically active antibodies in rab...

Co-administration of viral vector-based vaccines suppresses antigen-specific effector CD8 T cells.

Vaccine — Wed, 24 Feb 2010 00:00:00 +0100

In this study, we explored immune responses after intramuscular co-administration of the HIV-1 gp160 Env gene-expressing adenovirus (Ad) vector and modified vaccinia virus Ankara (MVA) vector in a mouse model. Surprisingly, the simultaneous vaccination of the two vaccines, either as a mixture or separately, suppressed responses, when compared with the administration of each vaccine separately. Ad vaccine or MVA vaccine, co-administered with a mock MVA or mock Ad vector, also resulted in suppressing HIV-specific effector T-cell responses, and a part of antigen-specific memory T-cell responses. In an in vitro experiment, the two vectors infected individual cells and MVA suppressed the transgene expression produced by the adenovirus vector. This viral interference may involve soluble factor(s...

Crosstalk between desmoglein-2/desmocollin-2/Src kinase and, coxsackie and adenovirus receptor/ZO-1 protein complexes, regulates blood-testis barrier dynamics.

The International Journal of Biochemistry and Cell Biology — Wed, 24 Feb 2010 00:00:00 +0100

This study aims to fill this gap with the functional investigation of two desmosomal cadherins, desmoglein-2 and desmocollin-2, by their specific knockdown in Sertoli cells cultured in vitro. Reminiscent of the blood-testis barrier in vivo, desmosome-like structures were visible by electron microscopy when Sertoli cells were cultured at high density, thereby forming a polarized epithelium with functional cell junctions. At this point, we opted to focus our efforts on desmoglein-2 and desmocollin-2 based on results which illustrated desmosomal mRNAs to be expressed by Sertoli and germ cells, as well as on results which illustrated desmoglein-2 to co-immunoprecipitate with plakoglobin, c-Src and desmocollin-2. Simultaneous knockdown of desmoglein-2 and desmocollin-2 not only led to a reducti...

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Adeno-Associated Virus-Mediated Rhodopsin Replacement Provides Therapeutic Benefit in Mice with a Targeted Disruption of the Rhodopsin Gene

Human Gene Therapy — Tue, 23 Feb 2010 04:06:14 +0100

Human Gene Therapy , Vol. 0, No. 0. (Source: Human Gene Therapy)

Adenovirus-specific human T cells are pervasive, polyfunctional, and cross-reactive.

Vaccine — Tue, 23 Feb 2010 00:00:00 +0100

Authors: Hutnick NA, Carnathan D, Demers K, Makedonas G, Ertl HC, Betts MR Pre-existing immunity to adenovirus (Ad) reduces the efficacy of Ad-based vaccines. The goal of this study was to define the prevalence, magnitude, functionality and phenotype of Ad-specific human T cells directly ex vivo. To study the magnitude of T-cell responses to Ad, we developed a highly reproducible whole Ad vector stimulation assay for use with polychromatic flow cytometry. Ad-specific CD4(+) and CD8(+) T-cells were detected in all 17 human subjects tested and were capable of proliferating upon restimulation. Ad5-specific CD4(+) T cells were primarily monofunctional CD4(+) T cells that produced IL-2, IFN-gamma or TNFalpha and expressed the memory markers CD27 and CD45RO. In contrast, Ad5-specific CD8(+) ...

Hepatocyte nuclear factor 4{alpha} attenuates hepatic fibrosis in rats

Gut — Mon, 22 Feb 2010 10:58:24 +0100

Conclusions Our study suggests that HNF4 is critical for hepatic fibrogenesis and upregulation of HNF4 might present as an ideal option for the treatment of hepatic fibrosis. (Source: Gut)

The role of the estrogen receptor alpha in the medial amygdala and ventromedial nucleus of the hypothalamus in social recognition, anxiety and aggression.

Behavioural Brain Research — Mon, 22 Feb 2010 00:00:00 +0100

In conclusion, social recognition and anxiety in female rats are modulated by the ERalpha in the amygdala. Moreover, aggression against juveniles but not against adults could, at least partly, depend on the ERalpha in the VMN. PMID: 20184922 [PubMed - as supplied by publisher] (Source: Behavioural Brain Research)

Repair of large cranial defects by hBMP-2 expressing bone marrow stromal cells: Comparison between alginate and collagen type I systems.

Biomed Res — Mon, 22 Feb 2010 00:00:00 +0100

We report now the effectiveness of various hydrogels as the scaffold for this type of bone regeneration, comparing specifically alginate with Type I collagen. Cultured MSC of miniature swine were infected with BMP-2 or beta-gal adenovirus 7 days before implantation. These cells were mixed with alginate, ultrapure alginate, alginate-RGD, or type I collagen to fabricate the MSC/biomaterial constructs. The results of cranial bone regeneration were assessed by gross examination, histology, 3D CT, and biomechanical tests at 6 weeks and 3 months after implantation. We found that the BMP-2 MSC/collagen type I construct, but not the beta-gal control, effectively achieved nearly complete repair of the cranial defects. No bone regeneration was observed with the other hydrogels. Biomechanical testing...

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Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys

Nature Medicine — Sun, 21 Feb 2010 00:00:00 +0100

Authors: Dan H Barouch, Kara L O'Brien, Nathaniel L Simmons, Sharon L King, Peter Abbink, Lori F Maxfield, Ying-Hua Sun, Annalena La Porte, Ambryice M Riggs, Diana M Lynch, Sarah L Clark, Katherine Backus, James R Perry, Michael S Seaman, Angela Carville, Keith G Mansfield, James J Szinger, Will Fischer, Mark Muldoon & Bette Korber The worldwide diversity of HIV-1 presents an unprecedented challenge for vaccine development. Antigens derived from natural HIV-1 sequences have elicited only a limited breadth of cellular immune responses in nonhuman primate studies and clinical trials to date. Polyvalent 'mosaic' antigens, in contrast, are designed to optimize cellular immunologic coverage of global HIV-1 sequence diversity. Here we show that mosaic HIV-1 Gag, Pol and Env antigens expresse...

Potent antitumor effects of combined therapy with a telomerase-specific, replication-competent adenovirus (OBP-301) and IL-2 in a mouse model of renal cell carcinoma

Kidney Cancer Association — Sat, 20 Feb 2010 17:02:08 +0100

This study investigated the effectiveness of a combination therapy of OBP-301 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). The cell-killing effect of OBP-301 was confirmed in vitro in the RENCA cancer cells.02/21/2010 (Source: Kidney Cancer Association)

LXR-SREBP-1c-Phospholipid Transfer Protein Axis Controls Very Low Density Lipoprotein (VLDL) Particle Size [Lipids]

Journal of Biological Chemistry — Fri, 19 Feb 2010 14:39:21 +0100

Liver X receptors (LXRs) activate triglyceride synthesis in liver directly and indirectly by inducing sterol regulatory element-binding protein-1c (SREBP-1c). When administered to wild-type mice, the LXR activator T0901317 produces a mild and transient hypertriglyceridemia. Here, we show that T0901317 produces massive hypertriglyceridemia when given to mice lacking low density lipoprotein (LDL) receptors (Ldlr–/– mice). Triglycerides ranged from 4000 to 6000 mg/dl, and the plasma turned milky. The median diameter of VLDL particles, measured by electron microscopy, increased from 43 to 112 nm, 87% exceeding 80 nm, the size of chylomicrons. Hypertriglyceridemia was prevented in Ldlr–/– recipient mice that lacked SREBP-1c (Ldlr–/–;Srebp-1c–/– do...

Map4k4 Negatively Regulates Peroxisome Proliferator-activated Receptor (PPAR) {gamma} Protein Translation by Suppressing the Mammalian Target of Rapamycin (mTOR) Signaling Pathway in Cultured Adipocytes [Signal Transduction]

Journal of Biological Chemistry — Fri, 19 Feb 2010 14:39:19 +0100

The receptor peroxisome proliferator-activated receptor (PPAR) is considered a master regulator of adipocyte differentiation and promotes glucose and lipid metabolism in mature adipocytes. We recently identified the yeast Sterile 20 (Ste20) protein kinase ortholog, Map4k4, in an RNA interference-based screen as an inhibitor of PPAR expression in cultured adipocytes. Here, we show that RNA interference-mediated silencing of Map4k4 elevates the levels of both PPAR1 and PPAR2 proteins in 3T3-L1 adipocytes without affecting PPAR mRNA levels, suggesting that Map4k4 regulates PPAR at a post-transcriptional step. PPAR degradation rates are remarkably rapid as measured in the presence of cycloheximide (t1/2 = 2 h), but silencing Map4k4 had no effect on PPAR degradation. However, depletion of Map4k...

Adiponectin Promotes Macrophage Polarization toward an Anti-inflammatory Phenotype [Signal Transduction]

Journal of Biological Chemistry — Fri, 19 Feb 2010 14:39:16 +0100

It is established that the adipocyte-derived cytokine adiponectin protects against cardiovascular and metabolic diseases, but the effect of this adipokine on macrophage polarization, an important mediator of disease progression, has never been assessed. We hypothesized that adiponectin modulates macrophage polarization from that resembling a classically activated M1 phenotype to that resembling alternatively-activated M2 cells. Peritoneal macrophages and the stromal vascular fraction (SVF) cells of adipose tissue isolated from adiponectin knock-out mice displayed increased M1 markers, including tumor necrosis factor-, interleukin-6, and monocyte chemoattractant protein-1 and decreased M2 markers, including arginase-1, macrophage galactose N-acetyl-galactosamine specific lectin-1, and inter...

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Hepatitis and hydropericardium syndrome associated with adenovirus infection in goslings.

Acta Veterinaria Hungarica — Fri, 19 Feb 2010 11:28:30 +0100

Authors: Ivanics E, Palya V, Markos B, Dán A, Ursu K, Harrach B, Kaján G, Glávits R Two outbreaks of severe acute disease characterised by hepatitis and hydropericardium were observed in young goslings on large-scale farms in Hungary. Histological examination revealed multifocal necrotic areas and two types of intranuclear inclusion bodies adjacent to necrotic areas in the liver. The most prominent type of inclusion bodies showed strong basophilic staining and completely filled the enlarged nucleus. The other type was eosinophilic and occupied the centre of the nucleus, which had margination of chromatin. In the heart, haemorrhage was associated with multifocal necrosis in the myocardium. The presence of fowl adenovirus DNA in different organs of the naturally infected g...

Evaluation of positively charged alumina nanofibre cartridge filters for the primary concentration of noroviruses, adenoviruses and male-specific coliphages from seawater

Journal of Applied Microbiology — Fri, 19 Feb 2010 00:00:00 +0100

Conclusion: The NanoCeram cartridge filter was an effective primary concentration method for the concentration of norovirus and male-specific coliphages from natural seawater, but not for adenovirus, in spite of the high adsorption of adenovirus to the filter.Significance and Impact of the Study: This study demonstrates that NanoCeram cartridge filter is an effective primary method for concentrating noroviruses and male-specific coliphages from seawater, thereby simplifying collection and processing of water samples for virus recovery. (Source: Journal of Applied Microbiology)

A role for caveolin-1 in mechanotransduction of fetal type II epithelial cells.

Am J Physiol Lung Ce... — Fri, 19 Feb 2010 00:00:00 +0100

In conclusion, our data suggest that caveolin-1 is present in E19 fetal type II epithelial cells. Caveolin-1 is translocated from the plasma membrane to the cytoplasm by mechanical stretch and functions as an inhibitory protein in stretch-induced type II cell differentiation via the ERK pathway. Key words: caveolin-1, mechanotransduction, fetal type II epithelial cells, lung development. PMID: 20172952 [PubMed - as supplied by publisher] (Source: Am J Physiol Lung Ce...)

Characterization of transgene expression in adenoviral-vector based HIV-1 vaccine candidates

Virology Journal — Thu, 18 Feb 2010 00:00:00 +0100

Recombinant adenovirus vectors have been extensively used in gene therapy clinical studies. More recently, the capability of inducing potent cell-mediated and humoral immunity has made these vectors equally attractive candidates for prophylactic or therapeutic vaccine applications. Merck developed HIV-1 vaccine candidates based on adenovirus serotype 5 (Ad5) vectors in which the E1 gene, a critical component for adenovirus replication, was replaced by the cytomegalovirus immediate/early promoter, followed by mutated versions of the HIV-1 gag, pol or nef genes (constructs referred to as MRKAd5gag, MRKAd5pol and MRKAd5nef, respectively). Vaccine performance was evaluated in vitro in a novel assay that measures the level of transgene expression in non-permissive A549 cells. Various combinatio...

Cellular toxicity following application of adeno-associated viral vector-mediated RNA interference in the nervous system

BMC Neuroscience - Latest articles — Thu, 18 Feb 2010 00:00:00 +0100

Conclusions: RNAi is a powerful tool to knock down Semaphorin receptor expression in neuronal cells in vitro and in vivo. However, when shRNAs are expressed at high levels in CNS neurons, they trigger an adverse tissue response leading to neuronal degradation. (Source: BMC Neuroscience - Latest articles)

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Induction of SIV p27-Specific Multifunctional T Cells in the Gut Following Prime-Boost Immunization with Clostridium perfringens and Adenovirus Vaccines Expressing SIV p27.

Current HIV Research — Thu, 18 Feb 2010 00:00:00 +0100

Authors: Helmus RA, Poonam P, Caruso L, Gupta P, Chen Y A vaccine-induced cellular immune response to simian immunodeficiency virus (SIV) in the gut mucosal tissue may prevent the establishment or severity of new SIV infection. An oral Clostridium perfringens expressing SIV p27 (Cp-p27) vaccine that delivers SIV p27 to the gut was evaluated for its ability to prime multifunctional cellular immunity in the gut mucosa. Gut Peyer's patches dendritic cells matured in response to in vitro exposure to Cp-p27 and stimulated production of p27-specific IFN-gamma. In mice, the oral vaccination with the Cp-p27 vaccine and systemic immunization with adenovirus expressing SIV p27 (Ad-p27) induced robust systemic and mucosal immune responses. Furthermore, the prime-boost regimen induced p27-specific...

Dichloroacetate (DCA) enhances tumor cell death in combination with oncolytic adenovirus armed with MDA-7/IL-24.

Molecular and Cellular Biochemistry — Thu, 18 Feb 2010 00:00:00 +0100

Authors: Xiao L, Li X, Niu N, Qian J, Xie G, Wang Y Dichloroacetate (DCA) is a metabolic modulator for the treatment of lactic acidosis and inherited mitochondrial diseases. A recent study showed that DCA treatment could induce apoptosis in many kinds of tumor cell lines via mitochondrial apoptotic pathway while sparing normal cells. ONYX-015 (dl 1520) is one of the oncolytic adenoviruses developed by the deletion of E1B-55kD gene of type 5 adenoviral DNA, and it replicates efficiently and selectively in tumor cells. ZD55-IL-24, an E1B-55kD deleted oncolytic adenovirus carrying interleukin-24 (IL-24, also called melanoma differentiation associated gene-7), had showed potent antitumor efficacy in a variety of tumor cells and exerted no apparent toxicity on normal cells. Given both the g...

Adenovirus-mediated stem cell leukemia gene transfer induces rescue of interstitial cells of Cajal in ICC-loss mice

International Journal of Colorectal Disease — Wed, 17 Feb 2010 18:27:49 +0100

Conclusions Ad-SCL was able to enhance c-Kit expression, reactivate the c-Kit/SCF pathway, and rescue ICC in ICC-loss mice. Since loss and defects of ICC are associated with many human gut motility disorders, Ad-SCL may be of potential use in gene therapy of these patients. Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s00384-010-0883-zAuthors Fan Li, Third Military Medical University Department of General Surgery, Institute of Surgery Research, Daping Hospital Chongqing 400042 ChinaLin Zhang, Third Military Medical University Department of General Surgery, Institute of Surgery Research, Daping Hospital Chongqing 400042 ChinaChunxue Li, Third Military Medical University Department of General Surgery, Institute of Surgery Research, Daping Hospital C...

Detection of new respiratory viruses in hospitalized infants with bronchiolitis: a three-year prospective study

Acta Paediatrica — Wed, 17 Feb 2010 00:00:00 +0100

Conclusions: In hospitalized infants, RSV was the most frequent agent in bronchiolitis in winter, but other viruses were present in 47% of the patients. RV, HBoV and hMPV had a significant proportion of single infections. Clinical characteristics were similar amongst them, but seasonality was clearly different. (Source: Acta Paediatrica)

Comprehensive serotyping and epidemiology of human adenovirus isolated from the respiratory tract of Korean children over 17 consecutive years (1991-2007)

Journal of Medical Virology — Wed, 17 Feb 2010 00:00:00 +0100

In conclusion, a total of 13 different serotypes of HAdV were detected among Korean children with respiratory tract infections. HAdV-3 and HAdV-7 were the most common serotypes, and they were associated with HAdV outbreaks. J. Med. Virol. 82:624-631, 2010. © 2010 Wiley-Liss, Inc. (Source: Journal of Medical Virology)

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The Major Locus for Mouse Adenovirus Susceptibility Maps to Genes of the Hematopoietic Cell Surface-Expressed LY6 Family.

Journal of Immunology — Wed, 17 Feb 2010 00:00:00 +0100

Authors: Spindler KR, Welton AR, Lim ES, Duvvuru S, Althaus IW, Imperiale JE, Daoud AI, Chesler EJ Susceptibility to mouse adenovirus type 1 is associated with the major quantitative trait locus Msq1. Msq1 was originally mapped to a 13-Mb region of mouse chromosome (Chr) 15 in crosses between SJL/J and BALB/cJ inbred mice. We have now narrowed Msq1 to a 0.75-Mb interval from 74.68 to 75.43 Mb, defined by two anonymous markers, rs8259436 and D15Spn14, using data from 1396 backcross mice. The critical interval includes 14 Ly6 or Ly6-related genes, including Ly6a (encoding Sca-1/TAP), Ly6e (Sca-2/Tsa1), Ly6g (Gr-1), and gpihbp1 (GPI-anchored high-density lipoprotein-binding protein 1), as well as the gene encoding an aldosterone synthase (Cyp11b2). The Ly6 family members are attractive ca...

Study of the Efficacy, Biodistribution, and Safety Profile of Therapeutic Gutless Adenovirus Vectors as a Prelude to a Phase I Clinical Trial for Glioblastoma.

Clinical Pharmacology and Therapeutics — Wed, 17 Feb 2010 00:00:00 +0100

Authors: Muhammad AK, Puntel M, Candolfi M, Salem A, Yagiz K, Farrokhi C, Kroeger KM, Xiong W, Curtin JF, Liu C, Lawrence K, Bondale NS, Lerner J, Baker GJ, Foulad D, Pechnick RN, Palmer D, Ng P, Lowenstein PR, Castro MG Glioblastoma multiforme (GBM) is the most common and most aggressive primary brain tumor in humans. Systemic immunity against gene therapy vectors has been shown to hamper therapeutic efficacy; however, helper-dependent high-capacity adenovirus (HC-Ad) vectors elicit sustained transgene expression, even in the presence of systemic anti-adenoviral immunity. We engineered HC-Ads encoding the conditional cytotoxic herpes simplex type 1 thymidine kinase (TK) and the immunostimulatory cytokine fms-like tyrosine kinase ligand 3 (Flt3L). Flt3L expression is under the control ...

MyD88-Dependent Silencing of Transgene Expression During the Innate and Adaptive Immune Response to Helper-Dependent Adenovirus

Human Gene Therapy — Tue, 16 Feb 2010 22:24:26 +0100

Human Gene Therapy , Vol. 0, No. 0. (Source: Human Gene Therapy)

Scavenger receptor BI facilitates hepatic very low density lipoprotein production in mice [Research Articles]

The Journal of Lipid Research — Mon, 15 Feb 2010 19:50:12 +0100

Scavenger receptor BI (SR-BI) is a selective uptake receptor for HDL cholesterol but is also involved in the catabolism of apolipoprotein (apo)B-containing lipoproteins. However, plasma levels of apoB-containing lipoproteins increase following hepatic SR-BI overexpression, suggesting that SR-BI not solely mediates their catabolism. We therefore tested the hypothesis that hepatic SR-BI impacts on VLDL production. On day 7 following adenovirus (Ad)-mediated overexpression of SR-BI, VLDL-triglyceride and VLDL-apoB production rates were significantly increased (P < 0.001), whereas VLDL production was significantly lower in SR-BI knockout mice compared with controls (P < 0.05). In mice injected with AdSR-BI, hepatic cholesterol content increased (P < 0.001), microsomal triglyceride tra...

Experimental study of antiangiogenic gene therapy targeting VEGF in oral cancer

Odontology — Mon, 15 Feb 2010 06:40:13 +0100

This study aimed to investigate the effectiveness of systemically available antiangiogenic gene therapy targeting vascular endothelial growth factor (VEGF), which is one of the most important angiogenesis accelerators. We administered a soluble form of VEGF receptor-expressing gene incorporated into adenovirus (AdVEGF-ExR) intraperitoneally to nude mice to which oral cancer cell lines (SAS, HSC-3, and Ca9-22) had been transplanted subcutaneously in vivo to inhibit angiogenesis and tumor proliferation. Then, we measured tumor volumes over time, and tumors were enucleated and examined histopathologically and immunohistologically at 28 days after AdVEGF-ExR administration. Compared to the controls to which we administered AdLacZ or saline, significant antiproliferative effects were obse...

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CFTR trafficking modulates the barrier function of airway epithelial cell monolayers.

The Journal of Physiology — Mon, 15 Feb 2010 00:00:00 +0100

Authors: Lesimple P, Liao J, Robert R, Gruenert DC, Hanrahan JW The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is an integral membrane glycoprotein which functions as an anion channel and influences diverse cellular processes. We studied its role in the development of epithelial tightness by expressing wild-type (WT-CFTR) or mutant (DeltaF508-CFTR) CFTR in human airway epithelial cell monolayers cultured at the air/liquid interface. GFP-tagged WT or DeltaF508 constructs were expressed in the CF bronchial cell line CFBE41o- using adenoviruses, and the results were compared with those obtained using CFBE41o- lines stably complemented with wild-type or mutant CFTR. As predicted, GFP-WT-CFTR reached the apical membrane whereas GFP-DeltaF508-CFTR was only detected intracellu...

Long-term correction of murine phenylketonuria by viral gene transfer: liver versus muscle

Journal of Inherited Metabolic Disease — Fri, 12 Feb 2010 07:14:40 +0100

Abstract Current therapy for phenylketonuria (PKU) consists of life-long dietary restriction of phenylalanine (Phe), which presents problems of adherence for patients. Alternative therapies under investigation include, among others, the use of gene therapy to provide copies of wild-type, non-mutant, phenylalanine hydroxylase (PAH) enzyme. Expression of PAH in both liver (the usual metabolic source of this enzyme) and skeletal muscle is under investigation. Liver gene therapy, using a viral vector based on the adeno-associated viruses (AAVs), provided effective clearance of serum Phe that was sustained for 1 year in some mice. In order for PAH expression to be effective in skeletal muscle, the essential metabolic cofactor, tetrahydrobiopterin (BH4), must also be provide...

Peroxisome proliferator-activated receptors gamma reverses hepatic nutritional fibrosis in mice and suppresses activation of hepatic stellate cells in vitro.

The International Journal of Biochemistry and Cell Biology — Fri, 12 Feb 2010 00:00:00 +0100

In conclusion, the present study shows that MCD diet-induced fibrosing steatohepatitis can be reversed by overexpression of PPARgamma. It is likely that PPARgamma reverses fibrosis by reducing HSCs proliferation, inducing cell cycle arrest and apoptosis. PMID: 20156580 [PubMed - as supplied by publisher] (Source: The International Journal of Biochemistry and Cell Biology)

Ileocecal Intussusception with Histomorphological Features of Inflammatory Neuropathy in Adenovirus Infection

Gastroenterology Research and Practice — Thu, 11 Feb 2010 14:24:37 +0100

The pathophysiological mechanisms for ileocecal intussusception in children with adenovirus infection are not well characterized. Here we demonstrate coincidence of adenovirus infection and inflammatory neuropathy of myenteric plexus in two children with ileocecal intussusception. Inflammatory neuropathy, an unspecific morphological feature which is found in peristalsis disorders, was morphologically characterized by the influx of CD3 positive lymphocytes in nervous plexus. To our knowledge, this is the first report suggesting peristalsis disorders from inflammatory neuropathy as additional mechanism in the pathophysiological concept of adenovirus-associated ileocecal intussusception. (Source: Gastroenterology Research and Practice)

Protection by D609 Through Cell-Cycle Regulation After Stroke

Molecular Neurobiology — Thu, 11 Feb 2010 11:41:18 +0100

Abstract Expressions of cell-cycle regulating proteins are altered after stroke. Cell-cycle inhibition has shown dramatic reduction in infarction after stroke. Ceramide can induce cell-cycle arrest by up-regulation of cyclin-dependent kinase (Cdk) inhibitors p21 and p27 through activation of protein phosphatase 2A (PP2A). Tricyclodecan-9-yl-xanthogenate (D609)-increased ceramide levels after transient middle cerebral artery occlusion (tMCAO) in spontaneously hypertensive rat (SHR) probably by inhibiting sphingomyelin synthase (SMS). D609 significantly reduced cerebral infarction and up-regulated Cdk inhibitor p21 and down-regulated phospho-retinoblastoma (pRb) expression after tMCAO in rat. Others have suggested bFGF-induced astrocyte proliferation is attenuated by D609 du...

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[Consensus conference on acute bronchiolitis (II): epidemiology of acute bronchiolitis. Review of the scientific evidence.]

Anales de Pediatria — Thu, 11 Feb 2010 00:00:00 +0100

Authors: Ochoa Sangrador C, González de Dios J, A review of the evidence on epidemiology, risk factors, etiology and clinical-etiological profile of acute bronchiolitis is presented. The frequency estimates are very heterogeneous; in the population under two years the frequency of admission for bronchiolitis is between 1 and 3.5%, primary care consultations between 4 and 20% and emergency visits between 1 and 2%. The frequency of admissions for respiratory infection by respiratory syncytial virus in the risk population is: in premature infants </=32 weeks of gestation between 4.4 and 18%, in patients with bronchopulmonary dysplasia between 7.3 and 42%, and in infants with congenital heart disease between 1.6 and 9.8%. The main risk factors are: prematurity, chronic lung diseas...

Spred2 is involved in imatinib-induced cytotoxicity in chronic myeloid leukemia cells.

Biochemical and Biophysical Research communications — Thu, 11 Feb 2010 00:00:00 +0100

In this study, we investigated the in vitro effects of Spred2 on chronic myeloid leukemia (CML) cells. In addition to inhibiting the well-established Ras-ERK cascade, adenovirus-mediated Spred2 overexpression inhibits constitutive and stem cell factor (SCF)-stimulated sphingosine kinase-1 (SPHK1) and Mcl-1 expression, as well as inhibiting proliferation and inducing apoptosis in CML cells. In K562 cells and primary CML cells, imatinib induces endogenous Spred2 expression. Spred2 silencing by stable RNA interference partly protects K562 cells against imatinib-induced apoptosis. Together, these data implicate Spred2 in imatinib-induced cytotoxicity in CML cells, possibly by inhibiting the Ras-ERK cascade and the pro-survival signaling molecules SPHK1 and Mcl-1. These findings reveal potentia...

Environmental surveillance and molecular characterization of human enteric viruses in tropical urban wastewaters

Journal of Applied Microbiology — Thu, 11 Feb 2010 00:00:00 +0100

Conclusions: This study showed the widespread occurrence of all tested enteric virus groups in urban wastewaters. Genetic diversity of astroviruses, enteroviruses and noroviruses in the tropical region was observed.Significance and Impact of the Study: The high prevalence and great genetic diversity of human enteric viruses in urban wastewaters strongly supports the need of further comprehensive studies for evaluating the public health risk associated with viral pathogens in water environments. (Source: Journal of Applied Microbiology)

Connexin43 knockdown or overexpression modulates cell coupling in control and failing rabbit left ventricular myocytes

Cardiovascular Research — Wed, 10 Feb 2010 16:28:21 +0100

Conclusion In addition to Cx43 dephosphorylation, downregulation of Cx43 plays an essential role in reduced cell coupling in the failing rabbit heart. Modulation of Cx43 expression could be a novel therapeutic approach to improve conduction and decrease sudden death in HF. (Source: Cardiovascular Research)

A novel multiplex real-time rt-pcr assay with fret hybridization probes for the detection and quantitation of 13 respiratory viruses.

Journal of Virological Methods — Wed, 10 Feb 2010 00:00:00 +0100

A NOVEL MULTIPLEX REAL-TIME RT-PCR ASSAY WITH FRET HYBRIDIZATION PROBES FOR THE DETECTION AND QUANTITATION OF 13 RESPIRATORY VIRUSES. J Virol Methods. 2010 Feb 10; Authors: Lassauniére R, Kresfelder T, Venter M Quantitative multiplex real-time RT-PCR assays utilizing fluorescence resonance energy transfer (FRET) hybridization probes were developed for the detection of 13 respiratory viruses, including well recognized viral causes (respiratory syncytial virus, influenza viruses A and B, parainfluenza viruses types 1, 2, and 3, adenovirus) as well as viruses described recently as causes of acute respiratory tract infections (human coronaviruses NL63, HKU1, 229E, and OC43, human bocavirus, and human metapneumovirus). FRET probes have an improved toleration for single base mis...

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Adenovirus VA RNA-derived miRNAs target cellular genes involved in cell growth, gene expression and DNA repair

Nucleic Acids Research — Mon, 08 Feb 2010 05:44:12 +0100

Adenovirus virus-associated (VA) RNAs are processed to functional viral miRNAs or mivaRNAs. mivaRNAs are important for virus production, suggesting that they may target cellular or viral genes that affect the virus cell cycle. To look for cellular targets of mivaRNAs, we first identified genes downregulated in the presence of VA RNAs by microarray analysis. These genes were then screened for mivaRNA target sites using several bioinformatic tools. The combination of microarray analysis and bioinformatics allowed us to select the splicing and translation regulator TIA-1 as a putative mivaRNA target. We show that TIA-1 is downregulated at mRNA and protein levels in infected cells expressing functional mivaRNAs and in transfected cells that express mivaRNAI-138, one of the most abundant adenov...

Enhanced bone formation in large segmental radial defects by combining adipose-derived stem cells expressing bone morphogenetic protein 2 with nHA/RHLC/PLA scaffold

International Orthopaedics — Sat, 06 Feb 2010 17:59:03 +0100

In this study, rabbit adipose-derived stem cells (rASCs) were isolated, cultured in vitro, and transfected with recombinant adenovirus vector containing human bone morphogenetic protein 2 (Ad-hBMP2). These cells were combined with a nano-hydroxyapatite/recombinant human-like collagen/poly(lactic acid) scaffold (nHA/RHLC/PLA) to fabricate a new biocomposite (hBMP2/rASCs-nHA/RHLC/PLA, group 1) and cultured in osteogenic medium. Non-transfected rASCs mixed with nHA/RHLC/PLA (rASCs-nHA/RHLC/PLA, group 2) and nHA/RHLC/PLA scaffold alone (group 3) served as controls. Scanning electron microscope (SEM) demonstrated integration of rASCs with the nHA/RHLC/PLA scaffold. Quantitative real-time RT-PCR analyses of collagen I, osteonectin, and osteopontin cDNA expression indicated that the osteoge...

Cryptogenic organizing pneumonia after rituximab therapy for presumed post-kidney transplant lymphoproliferative disease

Pediatric Nephrology — Fri, 05 Feb 2010 17:54:13 +0100

We describe an 11-year-old girl with Epstein–Barr virus (EBV) reactivation/presumed post-transplant lymphoproliferative disease (PTLD) 15 months after undergoing a deceased donor kidney transplantation. Treatment with reduced immunosuppression, ganciclovir, and cytomegalovirus immunoglobulin was complicated by severe graft rejection, prompting therapy with methylprednisolone, anti-thymocyte globulin and four weekly doses of rituximab (total 1500 mg/m2). Tacrolimus- and prednisone-based anti-rejection prophylaxis was complemented with low-dose sirolimus. When the lactate dehydrogenase and uric acid levels rose 10 weeks after the first rituximab infusion and bilateral pulmonary nodules were detected by computerized tomography, recurrence of PTLD was suspected. Open lun...

Assessment of the Na/I symporter as a reporter gene to visualize oncolytic adenovirus propagation in peritoneal tumours

European Journal of Nuclear Medicine and Molecular Imaging — Fri, 05 Feb 2010 17:52:58 +0100

Conclusion This study demonstrated that despite the detrimental effect observed in vitro, insertion of the reporter gene NIS in an oncolytic adenovirus did not affect its therapeutic efficacy in vivo. We conclude that NIS is a highly relevant reporter gene to monitor the fate of oncolytic adenovectors in live subjects. Content Type Journal ArticleCategory Original ArticleDOI 10.1007/s00259-009-1379-3Authors Andrew Merron, Queen Mary’s School of Medicine and Dentistry Centre for Molecular Oncology, Institute of Cancer London UKPatrick Baril, CHU Hôtel Dieu INSERM U948 1 place Alexis Ricordeau 44035 Nantes Cedex1 FrancePilar Martin-Duque, Instituto Aragonés de Ciencias de la Salud I+CS/ Araid Fund Zaragoza SpainAntonio de la Vieja, Instituto de Investigaciones Bioméd...

Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 during cardiac remodelling in rats

Acta Physiologica — Fri, 05 Feb 2010 00:00:00 +0100

Conclusions: In conclusion, the cardiac TWEAK/Fn14 pathway is modified in response to myocardial injury, inflammation and pressure overload. Furthermore, our findings underscore the importance of Fn14 as a mediator of TWEAK/Fn14 signalling in the heart and a potential target for therapeutic interventions. (Source: Acta Physiologica)

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Viral transactivator proteins enhance enteric adenovirus cultivation.

Applied and Environmental Microbiology — Fri, 05 Feb 2010 00:00:00 +0100

Authors: Kim M, Lim M, Ko G Human enteric adenoviruses (serotypes 40 and 41; HAdVs) are important waterborne and foodborne pathogens. However, HAdVs are fastidious, are difficult to cultivate, and do not produce a clear cytopathic effect during cell culture within a reasonable time. Thus, we examined whether the viral transactivator proteins CMV IE1 and HBV X promoted the multiplication of HAdVs. Additionally, we constructed a new 293 cell line expressing CMV IE1 protein for cultivation assays. We analyzed the nucleic acid sequences of the promoter regions of both E1A and hexon genes, which are considered to be the most important regions for HAdV replication. Expression of either HBV X or CMV IE1 protein significantly increased the promoter activities of E1A and hexon genes of HAdVs by...

Blockade of the Ras-Extracellular Signal-Regulated Kinase 1/2 Pathway Is Involved in Smooth Muscle 22{alpha}-Mediated Suppression of Vascular Smooth Muscle Cell Proliferation and Neointima Hyperplasia.

Arteriosclerosis, Thrombosis and Vascular Biology — Fri, 05 Feb 2010 00:00:00 +0100

CONCLUSIONS: These findings suggest that high expression of SM22alpha inhibits cell proliferation via reduction of the response to mitogen stimuli in VSMCs and provide a novel mechanism by which VSMCs maintain their contractile phenotype and resist mitogenic stimuli in an SM22alpha-dependent manner. PMID: 20139360 [PubMed - as supplied by publisher] (Source: Arteriosclerosis, Thrombosis and Vascular Biology)

Combination gene therapy of lung cancer with conditionally replicating adenovirus and adenovirus-herpes simplex virus thymidine kinase.

International Journal of Molecular Medicine — Thu, 04 Feb 2010 11:48:41 +0100

Authors: Oh JY, Park MY, Kim DR, Lee JH, Shim SH, Chung JH, Yoon HI, Lee JH, Sung MW, Kim YS, Lee CT A major obstacle to the success of gene therapy strategies that directly target cancer cells is the low gene transfer rate. To address this problem, we had previously proposed a combination adenoviral gene therapy containing a conditionally replicating adenovirus (CRAD) expressing mutant E1 (Delta24RGD), and a replication-defective E1-deleted adenovirus to enhance the efficiency of gene transfer. Suicide/pro-drug gene therapy has an important additional benefit to the therapy of cancer. This relates to the transfer and expression of non-mammalian genes encoding enzymes that convert non-toxic pro-drugs into cellular toxins. We investigated the interaction between CRAD (Delta24RGD) and a ...

Endogenous Angiogenesis Inhibitor Vasohibin1 Exhibits Broad-Spectrum Antilymphangiogenic Activity and Suppresses Lymph Node Metastasis.

The American Journal of Pathology — Thu, 04 Feb 2010 00:00:00 +0100

Authors: Heishi T, Hosaka T, Suzuki Y, Miyashita H, Oike Y, Takahashi T, Nakamura T, Arioka S, Mitsuda Y, Takakura T, Hojo K, Matsumoto M, Yamauchi C, Ohta H, Sonoda H, Sato Y During cancer progression, the angiogenesis that occurs is involved in tumor growth and hematogenous-distant metastasis, whereas lymphangiogenesis is involved in regional lymph node metastasis. Angiogenesis is counterregulated by various endogenous inhibitors; however, little is known about endogenous inhibitors of lymphangiogenesis. We recently isolated vasohibin1 as an angiogenesis inhibitor intrinsic to the endothelium and further demonstrated its anticancer activity through angiogenesis inhibition. Here, we examined the effect of vasohibin1 on lymphangiogenesis. Vasohibin1 exhibited broad-spectrum antilymphan...

Effects of CXCR4 Gene Transfer on Cardiac Function After Ischemia-Reperfusion Injury.

The American Journal of Pathology — Thu, 04 Feb 2010 00:00:00 +0100

Authors: Chen J, Chemaly E, Liang L, Kho C, Lee A, Park J, Altman P, Schecter AD, Hajjar RJ, Tarzami ST Acute coronary occlusion is the leading cause of death in the Western world. There is an unmet need for the development of treatments to limit the extent of myocardial infarction (MI) during the acute phase of occlusion. Recently, investigators have focused on the use of a chemokine, CXCL12, the only identified ligand for CXCR4, as a new therapeutic modality to recruit stem cells to individuals suffering from MI. Here, we examined the effects of overexpression of CXCR4 by gene transfer on MI. Adenoviruses carrying the CXCR4 gene were injected into the rat heart one week before ligation of the left anterior descending coronary artery followed by 24 hours reperfusion. Cardiac function ...

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Prokineticin-1 (PROK1) modulates interleukin (IL)-11 expression via prokineticin receptor 1 (PROKR1) and the calcineurin/NFAT signalling pathway

Molecular Human Reproduction — Wed, 03 Feb 2010 16:40:16 +0100

Prokineticin-1 (PROK1) is a multifunctional secreted protein which signals via the G-protein coupled receptor, PROKR1. Previous data from our laboratory using a human genome survey microarray showed that PROK1–prokineticin receptor 1 (PROKR1) signalling regulates numerous genes important for establishment of early pregnancy, including the cytokine interleukin (IL)-11. Here, we have shown that PROK1–PROKR1 induces the expression of IL-11 in PROKR1 Ishikawa cells and first trimester decidua via the calcium–calcineurin signalling pathway in a guanine nucleotide-binding protein (Gq/11), extracellular signal-regulated kinases, Ca2+ and calcineurin–nuclear factor of activated T cells dependent manner. Conversely, treatment of human decidua with a lentiviral miRNA to aboli...

Construction of NF-kappaB-targeting RNAi adenovirus vector and the effect of NF-kappaB pathway on proliferation and apoptosis of vascular endothelial cells.

Molecular Biology Reports — Wed, 03 Feb 2010 00:00:00 +0100

Authors: Chen G, Qiao Y, Yao J, Jiang Q, Lin X, Chen F, Lin F, Lin M, Lin L, Zhu P To construct a recombinant adenovirus vector expressing a RNAi for the Nuclear Factor kappa B (NF-kappaB)/p65 gene and use it to explore the role of the NF-kappaB pathway on the regulation of proliferation and apoptosis of vascular endothelial cells. A recombinant adenovirus containing a RNAi cassette targeting the p65 gene was constructed, and its silencing effect on p65 was detected by Western blot analysis in ECV304 cells. Expression of the p65 protein in ECV304 cells was efficiently down-regulated by the RNAi adenovirus for more than 6 days. ECV304 cells proliferation and apoptosis were measured using the MTT assay and flow cytometry, respectively. Blocking the NF-kappaB pathway with the RNAi adenovi...

Self-complementary AAV5 Vector Facilitates Quicker Transgene Expression in Photoreceptor and Retinal Pigment Epithelial Cells of Normal Mouse.

Experimental Eye Research — Tue, 02 Feb 2010 00:00:00 +0100

Authors: Kong F, Li W, Li X, Zheng Q, Dai X, Zhou X, Boye SL, Hauswirth WW, Qu J, Pang JJ To clarify whether transduction efficiency and cell type specificity of self-complementary (sc) AAV5 vectors are similar to those of standard, single stranded AAV5 vectors in normal retina, one micro liter of scAAV5-smCBA-GFP vector (1X10(12) genome containing particles/ml) and AAV5-smCBA-GFP vector (1X10(12) genome containing particles/ml) were subretinally or intravitreally (in both cases through the cornea) injected into the right and left eyes of adult C57BL/6J mice, respectively. On post-injection day (PID) 1, 2, 5, 7, 10, 14, 21, 28 and 35, eyes were enucleated; retinal pigment epithelium (RPE) wholemounts, neuroretinal wholemounts and eyecup sections were prepared to evaluate green fluoresc...

Rotavirus genotype G4P[8] and enteric adenovirus in HIV-positive patients with and without diarrhoea in São Paulo State, Brazil

Transactions of the Royal Society of Tropical Medicine and Hygiene — Mon, 01 Feb 2010 00:00:00 +0100

Summary: The present study was carried out in order to identify rotavirus and enteric adenovirus in HIV-positive patients with and without diarrhoea, collected in a pre- and early highly active antiretroviral therapy era. Rotavirus was detected in 2.5% (3/118) and adenovirus in 14.4% (17/118) of the samples from patients without diarrhoea. In the patients with diarrhoea, rotavirus was identified in 1.5% (2/133) and adenovirus in 7.5% (10/133). These findings suggest no increased frequency of virus excretion in HIV-infected patients with diarrhoea. The genotype G4P[8] was characterized in all positive rotavirus samples, and this is the first report of rotavirus molecular characterization in HIV-positive patients in Brazil. (Source: Transactions of the Royal Society of Tropical Medicine and ...

Vasculitis in children

Paediatrics and Child Health — Mon, 01 Feb 2010 00:00:00 +0100

Abstract: The term vasculitis refers to inflammation in the blood vessel walls. The vasculitic conditions which affect children are a varied group of diseases many of which carry a potentially significant morbidity and mortality. This review describes the classification, diagnosis and management of the main primary systemic paediatric vasculitides. The conditions described include Henoch-Schönlein purpura, Kawasaki disease, Takayasu's arteritis, polyarteritis nodosa, and the ANCA associated vasculitic (AAV) conditions Wegener's granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome. (Source: Paediatrics and Child Health)

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The effects of Runx2 immobilization on poly (varepsilon-caprolactone) on osteoblast differentiation of bone marrow stromal cells in vitro.

Biomaterials — Mon, 01 Feb 2010 00:00:00 +0100

Authors: Zhang Y, Deng X, Scheller EL, Kwon TG, Lahann J, Franceschi RT, Krebsbach PH In vivo regenerative gene therapy is a promising approach for bone regeneration and can help to address cell-source limitations through surgical implantation of osteoinductive materials and subsequent recruitment of host-derived cells. Localized viral delivery may reduce the risk of virus dispersion, enhance transduction efficiency, and reduce administration/injection dosing, which subsequently increases patient safety. In this manuscript, we present a custom-tailored strategy to immobilize adenovirus expressing runt-related transcription factor 2 (AdRunx2) by using reactive polymer coatings to enhance in vitro osteoblast differentiation of bone marrow stromal cells (BMSCs). A thin polymer film of pol...

The non-essential left end region of the fowl adenovirus 9 genome is suitable for foreign gene insertion/replacement.

Virus Research — Mon, 01 Feb 2010 00:00:00 +0100

This study demonstrated the suitability of the non-essential region as an insertion/replacement site for foreign genes to generate FAdV-9-based vectors that can be applied as recombinant vaccines for poultry or gene delivery vehicles for mammalian systems. PMID: 20132849 [PubMed - as supplied by publisher] (Source: Virus Research)

[Effect of adenovirus-mediated CD/TK double suicide gene system on colorectal cancer growth and cytokines in the tumor microenvironment in mice.]

Journal of Southern Medical University — Mon, 01 Feb 2010 00:00:00 +0100

CONCLUSION: CD/TK double suicide gene system produces significant tumor inhibition effect and causes obvious cytokine changes in the tumor microenvironment in mice bearing transplanted colorectal cancer. PMID: 20159695 [PubMed - in process] (Source: Journal of Southern Medical University)

[A double suicide gene system driven by KDR promoter selectively kills human colon adneocarcinoma SW480 cells.]

Journal of Southern Medical University — Mon, 01 Feb 2010 00:00:00 +0100

CONCLUSION: CDglyTK fusion gene system driven by the KDR promoter selectively kills and induces the apoptosis of the KDR-CDglyTK SW480 cells. PMID: 20159685 [PubMed - in process] (Source: Journal of Southern Medical University)

[Effect of different doses of recombinant adenovirus mediated hypoxia-inducible factor-1alpha on angiogenesis in ischemic lower hind limb of rabbits.]

Journal of Southern Medical University — Mon, 01 Feb 2010 00:00:00 +0100

CONCLUSION: Ad-HIF-1alpha can dose-dependently promote the angiogenesis in the ischemic limb of rabbits. PMID: 20159682 [PubMed - in process] (Source: Journal of Southern Medical University)

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OSU-03012 enhances Ad.mda-7-induced GBM cell killing via ER stress and autophagy and by decreasing expression of mitochondrial protective proteins.

Cancer Biology and Therapy — Sat, 30 Jan 2010 06:06:09 +0100

Authors: Hamed HA, Yacoub A, Park MA, Eulitt P, Sarkar D, Dimitriev IP, Chen CS, Grant S, Curiel DT, Fisher PB, Dent P The present studies focused on determining whether the autophagy-inducing drug OSU-03012 (AR-12) could enhance the toxicity of recombinant adenoviral delivery of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) in glioblastoma multiforme (GBM) cells. The toxicity of a recombinant adenovirus to express MDA-7/IL-24 (Ad.mda-7) was enhanced by OSU-03012 in a diverse panel of primary human GBM cells. The enhanced toxicity correlated with reduced ERK1/2 phosphorylation and expression of MCL-1 and BCL-X(L), and was blocked by molecular activation of ERK1/2 and by inhibition of the intrinsic, but not the extrinsic, apoptosis pathway. Both OSU-03012 and e...

c-Jun Regulates Shear- and Injury-inducible Egr-1 Expression, Vein Graft Stenosis after Autologous End-to-Side Transplantation in Rabbits, and Intimal Hyperplasia in Human Saphenous Veins [Molecular Basis Of Cell and Developmental Biology]

Journal of Biological Chemistry — Fri, 29 Jan 2010 14:36:37 +0100

Coronary artery bypass graft failure represents an unsolved problem in interventional cardiology and heart surgery. Late occlusion of autologous saphenous vein bypass grafts is a consequence of neointima formation underpinned by smooth muscle cell (SMC) migration and proliferation. Poor long term patency and the lack of pharmacologic agents that prevent graft failure necessitate effective alternative therapies. Our objective here was to evaluate the effect of targeted inhibition of the bZIP transcription factor c-Jun on intimal hyperplasia in human saphenous veins and vein graft stenosis after autologous end-to-side transplantation. DNAzymes targeting c-Jun attenuated intimal hyperplasia in human saphenous vein explants. Adenovirus-forced c-Jun expression stimulated SMC proliferation, prol...

Anti-viral state segregates two molecular phenotypes of pancreatic adenocarcinoma: potential relevance for adenoviral gene therapy

BioMed Central — Fri, 29 Jan 2010 00:00:00 +0100

Conclusion: Our study identified two molecular phenotypes of pancreatic cancer, characterized by a differential expression of interferon-stimulated genes and easily recognized by the expression of the Myxovirus-resistance A protein. We suggest that the detection of these two phenotypes might help the selection of patients enrolled in virally-mediated gene therapy trials. (Source: BioMed Central)

Single-strand conformation polymorphism analysis for the study of adenoviral diversity in urban rivers.

Journal of Virological Methods — Thu, 28 Jan 2010 00:00:00 +0100

Authors: Lee C, Kim SJ The diversity of human adenoviruses (AdVs) in river waters was studied by single-strand conformational polymorphism (SSCP) analysis. Water samples were collected between 2002 and 2003 from 4 rivers in the Gyeonggi Province, South Korea. Forty-six (79.3%) of the 58 samples were positive for AdVs as determined on PCR amplification. Nine different SSCP profiles (profile A to I) were detected in all the AdVs-positive samples by SSCP analysis, and most of the AdVs-positive samples (38 of 46 samples; 82.6%) showed the SSCP profile D. Nine different sequences were obtained in the SSCP profiles; sequence alignments and phylogenetic analysis identified 5 different sequences that were closely related to the human AdV type 41, and the 4 different sequences that were closely...

Emerging Opportunities for Site-Specific Molecular and Cellular Interventions in Autoimmune Hepatitis

Digestive Diseases and Sciences — Wed, 27 Jan 2010 20:03:38 +0100

Abstract Current corticosteroid-based treatments of autoimmune hepatitis frequently have incomplete or unsatisfactory outcomes, side effects, and excessive immune suppression. The goal of this review is to describe the advances in developing animal models of autoimmune hepatitis and in treating diverse immune-mediated diseases that make pursuit of site-specific molecular and cellular inventions in autoimmune hepatitis feasible. Prime source and review articles in English were selected by a Medline search through October 2009. A murine model infected with an adenovirus expressing human CYP2D6 is a resource for evaluating new therapies because of its histological and serological features, persistence, and progressive hepatic fibrosis. Synthetic analog peptides that block aut...

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Rac1 mediates NaCl-induced superoxide generation in the thick ascending limb

AJP: Renal Physiology — Wed, 27 Jan 2010 01:14:33 +0100

Superoxide (O2–) produced by NADPH oxidase regulates Na absorption and renal hemodynamics. Increased NaCl in the thick ascending limb (TAL) stimulates O2– generation. However, we do not know whether physiological changes in NaCl concentration augment O2– generation, nor do we know the mediator(s) involved. In other cells, Rac1, a regulatory subunit of NADPH oxidase, is activated by elevated NaCl. We hypothesized that increasing luminal NaCl within the physiological range activates Rac1 and NADPH oxidase and, thereby, increases O2– production. We increased NaCl from 10 to 57 mM in medullary TAL suspensions and used lucigenin to measure O2– generation and Western blot to measure Rac1 activity. Increasing NaCl stimulated O2– generation from 1.41 ± 0....

Inhibition of transforming growth factor-[beta]/Smad signaling improves regeneration of small-for-size rat liver grafts

Liver Transplantation — Tue, 26 Jan 2010 00:00:00 +0100

This study investigated whether overexpression of Smad7, which blocks TGF-[beta]-induced activation of Smad2/3, could prevent the suppression of regeneration of small-for-size liver grafts. Rats were intravenously given adenoviruses (2 × 1010 pfu/rat) carrying the LacZ gene or the Smad7 gene (Ad-Smad7) 3 days prior to liver harvesting. Half-size livers were implanted into recipients of the same weight or twice the donor weight, and this resulted in half-size or quarter-size liver grafts. Cell proliferation, detected by 5-bromo-2[prime]-deoxyuridine (BrdU) incorporation, increased to 23% in half-size grafts at 38 hours after implantation but was only 4% in quarter-size grafts. Graft weight did not increase after 38 hours in full-size and quarter-size grafts but increased 28% in half-size g...

Evaluation of adenovirus capsid labeling versus transgene expression

Virology Journal — Tue, 26 Jan 2010 00:00:00 +0100

Adenoviral vectors have been utilized for a variety of gene therapy applications. Our group has incorporated bioluminescent, flurographic reporters, and/or suicide genes within the adenovirus genome for analytical and/or therapeutic purposes. These molecules have also been incorporated as capsid components. Recognizing that incorporations at either locale yield potential advantages and disadvantages, our report evaluates the benefits of transgene incorporation versus capsid incorporation. To this end, we have genetically incorporated firefly luciferase within the early region 3 or at minor capsid protein IX and compared vector functionality by means of reporter readout. (Source: Virology Journal)

Inhibition of Met/HGF receptor and angiogenesis by NK4 leads to suppression of tumor growth and migration in malignant pleural mesothelioma

International Journal of Cancer — Tue, 26 Jan 2010 00:00:00 +0100

NK4 exhibits two distinct biological actions: antagonistic inhibition of hepatocyte growth factor (HGF) through binding to the Met/HGF receptor, and antiangiogenic action through binding to perlecan. Here, the anti-tumor effect of NK4 on malignant pleural mesothelioma was investigated. Of the 7 human malignant mesothelioma cell lines (ACC-Meso-1, ACC-Meso-4, EHMES-1, EHMES-10, H28, H2052 and JMN-1B), only EHMES-10 cells formed subcutaneous tumors when implanted into mice. For EHMES-10 cells, HGF facilitated invasion of the cells in collagen gel, whereas NK4 and neutralizing anti-HGF antibody suppressed the HGF-induced invasion. In addition, NK4 but not anti-HGF antibody suppressed proliferation of EHMES-10 cells in collagen, suggesting that the suppression by NK4 was independent of the HGF...

Testing a Tropism-Modified Conditionally Replicative Adenovirus for Breast Cancer in a Tissue Slice Model System

Journal of Surgical Research — Mon, 25 Jan 2010 16:42:25 +0100

Conclusions: We have shown that our tropism modified conditionally replicative oncolytic adenovirus can infect and replicate in breast cancer tissue slices, which may be an important preclinical indicator for its therapeutic utility. (Source: Journal of Surgical Research)

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Protein Kinase-C Delta Mediates Arterial Injury Responses through Regulation of Vascular Smooth Muscle Cell Apoptosis

Journal of Surgical Research — Mon, 25 Jan 2010 16:41:54 +0100

Introduction: Endovascular intervention has been proven to be a cost-effective approach in revascularization of peripheral arterial disease. However, the long-term efficacy of endovascular procedures is often limited by restenosis, which is primarily caused by excessive intimal hyperplasia after vascular injury. Intimal hyperplasia is a complex process involving vascular smooth muscle cell (VSMC) proliferation, migration, apoptosis and extracellular matrix deposition. Apoptosis of VSMC has been shown to influence intimal hyperplasia, presumably through reduction of the lesion cell numbers. However, how apoptosis is regulated after vascular injury is not fully understood. We have previously demonstrated Protein Kinase-C delta (PKCδ) is an integral mediator of VSMC apoptosis in vitro. Here,...

B Cell Transduction of Capsid Mutant (Y730F) Adeno-Associated Virus-2 Vectors with Mage-A3 Gene for Immunotherapy of Colorectal Cancer

Journal of Surgical Research — Mon, 25 Jan 2010 16:39:59 +0100

Conclusions: For the first time we showed an efficient B cell transduction of new generation scAAV-2 MAGE-A3 (Y730F) vectors. Use of B cells as APCs allowed us to expand them in vitro unlike DCs and we further we significantly enhanced the MAGE-A3 trans-gene expression by using Y730F capsid mutant scAAV-2. Gene therapy with novel AAV vector transduced B cells to enhance anti-tumor immunity is a promising new approach to treat CRC. (Source: Journal of Surgical Research)

Genomic characterization of human adenovirus 36, a putative obesity agent.

Virus Research — Mon, 25 Jan 2010 00:00:00 +0100

Authors: Arnold J, Jánoska M, Kajon AE, Metzgar D, Hudson NR, Torres S, Harrach B, Seto D, Chodosh J, Jones MS Increased levels of serum antibody titers against Human adenovirus 36 (HAdV-D36) are associated with human obesity and experimental obesity in laboratory animals. While HAdV-D36 has been studied as an infectious agent implicated in obesity for over a decade, the complete genome sequence and its analysis have yet to be reported. A detailed analysis of the genome sequence of HAdV-D36 may be important to understand its role in obesity. Genomic and bioinformatic comparisons with other HAdVs identified differences that suggested unique functions. Global pairwise genome alignment with all sequenced Human adenovirus D (HAdV-D) genomes revealed areas of nonconserved sequences in ...

Adenovector-mediated hair cell regeneration is affected by promoter type.

Acta Oto-Laryngologica — Sun, 24 Jan 2010 22:26:10 +0100

CONCLUSION: Replacement of vestibular hair cells induced by atoh1 driven by the tissue-specific GFAP promoter was significantly more efficient than use of the cBA or hCMV promoter. OBJECTIVE: To test whether expression level, persistence, or selectivity from adenovirus vectors delivered in the inner ear can be altered by changing the adenovector backbone or by using different cellular and viral promoters. MATERIALS AND METHODS: Adenovector and promoter modifications were tested for differences in transgene expression in adult macular organs. The effect of using an E1/E3 deleted vector was compared to E1/E3/E4 deleted vectors. The effect of using viral and cellular promoters to modify transgene expression was tested in explanted adult mouse macular organs. Based on these results three diffe...

Expression of Wnt5a in tooth germs and the related signal transduction analysis

Archives of Oral Biology — Sun, 24 Jan 2010 13:57:29 +0100

Conclusions: It was concluded that WNT5A is expressed in human tooth development, and that p42/44 MAPK, p38 MAPK, JNK and AKT signal pathways and DLX1, DLX2, LEF1, MSX2, PAX9, RUNX2 could be activated by Wnt5a. (Source: Archives of Oral Biology)

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Adenovirus 5–Fiber 35 Chimeric Vector Mediates Efficient Apical Correction of the Cystic Fibrosis Transmembrane Conductance Regulator Defect in Cystic Fibrosis Primary Airway Epithelia

Human Gene Therapy — Sat, 23 Jan 2010 16:53:13 +0100

Human Gene Therapy , Vol. 0, No. 0. (Source: Human Gene Therapy)

Optimized Adeno-Associated Virus (AAV)–Protein Phosphatase-5 Helper Viruses for Efficient Liver Transduction by Single-Stranded AAV Vectors: Therapeutic Expression of Factor IX at Reduced Vector Doses

Human Gene Therapy — Sat, 23 Jan 2010 16:51:32 +0100

Human Gene Therapy , Vol. 0, No. 0. (Source: Human Gene Therapy)

Elevated mitochondrial superoxide contributes to enhanced chemoreflex in heart failure rabbits

AJP: Regulatory, Integrative and Comparative Physiology — Sat, 23 Jan 2010 00:12:04 +0100

Peripheral chemoreflex sensitivity is enhanced in both clinical and experimental chronic heart failure (CHF). Here we investigated the role of manganese superoxide dismutase (MnSOD), the SOD isoform specially targeted to mitochondria, and mitochondrial superoxide levels in the enhanced chemoreceptor activity and function of the carotid body (CB) in CHF rabbits. CHF suppressed MnSOD protein expression and elevated mitochondrial superoxide levels in CB compared with that in sham CB. Adenovirus (Ad) MnSOD (1 x 108 plaque-forming units/ml) gene transfer selectively to the CBs normalized mitochondrial superoxide levels in glomus cells from CHF CB. In addition, Ad MnSOD reduced the elevation of superoxide level in CB tissue from CHF rabbits. Ad MnSOD significantly increased MnSOD expression in C...

Design of a Miniature Tissue Culture System to Culture Mouse Heart Valves.

Annals of Biomedical Engineering — Sat, 23 Jan 2010 00:00:00 +0100

Authors: Lieber SC, Kruithof BP, Aubry N, Vatner SF, Gaussin V Valvular heart disease is a leading cause of morbidity and mortality in adults but little is known about the underlying etiology. A better understanding of the genetic and hemodynamic mechanisms involved in growth and remodeling of heart valves during physiological and pathological conditions is needed for a better understanding of valvular heart disease. Here, we report the design of a miniature tissue culture system (MTCS) that allows the culture of mitral valves from perinatal to adult mice. The design of the MTCS is novel in that fine positioning and cannulation can be conducted with hearts of different sizes (perinatal to adult). Perfusion of the heart and hence, culture of the mitral valve in its natural position, occ...

Sites in the AAV5 capsid tolerant to deletions and tandem duplications.

Archives of Biochemistry and Biophysics — Sat, 23 Jan 2010 00:00:00 +0100

Authors: Hida K, Won SY, Pasquale GD, Hanes J, Chiorini JA, Ostermeier M Gene therapy vectors based on adeno-associated virus (AAV) have shown much promise in clinical trials for the treatment of a variety of diseases. However, the ability to manipulate and engineer the viral surface for enhanced efficiency is necessary to overcome such barriers as pre-existing immunity and transduction of non-target cells that currently limit AAV applications. Although single amino acid changes and peptide insertions at select sites have been explored previously, the tolerance of AAV to small deletions and tandem duplications of sequence has not been globally addressed. Here, we have generated a large, diverse library of >10(5) members containing deletions and tandem duplications throughout the vir...

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Cyclin D1 Is a Bona Fide Target Gene of NFATc1 and Is Sufficient in the Mediation of Injury-induced Vascular Wall Remodeling [Mechanisms Of Signal Transduction]

Journal of Biological Chemistry — Fri, 22 Jan 2010 14:36:03 +0100

Platelet-derived growth factor BB induced cyclin D1 expression in a time- and nuclear factor of activated T cells (NFAT)-dependent manner in human aortic smooth muscle cells (HASMCs), and blockade of NFATs prevented HASMC DNA synthesis and their cell cycle progression from G1 to S phase. Selective inhibition of NFATc1 by its small interfering RNA also blocked HASMC proliferation and migration. Characterization of the cyclin D1 promoter revealed the presence of several NFAT binding sites, and the site at nucleotide –1333 was found to be sufficient in mediating platelet-derived growth factor BB-induced cyclin D1 promoter-luciferase reporter gene activity. In addition to its role in cell cycle progression, cyclin D1 mediated HASMC migration in an NFATc1-dependent manner. Balloon injury-...

Identification of Novel Pathways That Control Farnesoid X Receptor-mediated Hypocholesterolemia [Metabolism and Bioenergetics]

Journal of Biological Chemistry — Fri, 22 Jan 2010 14:36:01 +0100

Farnesoid X receptor (FXR) plays important regulatory roles in bile acid, lipoprotein, and glucose homeostasis. Here, we have utilized Fxr–/– mice and mice deficient in scavenger receptor class B type I (SR-BI), together with an FXR-specific agonist and adenovirus expressing hepatocyte nuclear factor 4 or constitutively active FXR, to identify the mechanisms by which activation of FXR results in hypocholesterolemia. We identify a novel pathway linking FXR to changes in hepatic p-JNK, hepatocyte nuclear factor 4, and finally SR-BI. Importantly, we demonstrate that the FXR-dependent increase in SR-BI results in both hypocholesterolemia and an increase in reverse cholesterol transport, a process involving the transport of cholesterol from peripheral macrophages to the liver for ex...

Increased expression of MAP2 inhibits melanoma cell proliferation, invasion and tumor growth in vitro and in vivo

Experimental Dermatology — Fri, 22 Jan 2010 00:00:00 +0100

Please cite this paper as: Increased expression of MAP2 inhibits melanoma cell proliferation, invasion and tumor growth in vitro and in vivo. Experimental Dermatology 2010.Abstract: Malignant melanoma (MM) is characterized by aggressive metastasis and high mortality rate. Microtubule-associated proteins 2 (MAP2) is expressed abundantly in majority of melanocytic nevi and primary melanomas, but absent in metastatic melanomas. To determine whether MAP2 correlates with tumor progression of MM, we investigated the effects of MAP2 inhibition on the biological behaviour of metastatic melanoma in vitro and in vivo. Our results demonstrated that adenovirus-mediated MAP2 induced apoptotic cell death and cell cycle arrest in metastatic human and mouse melanoma cell lines in vitro, and substantially ...

Identification of Genes related to Heart Failure Using Global Gene Expression Profiling of Human Failing Myocardium.

Biochemical and Biophysical Research communications — Fri, 22 Jan 2010 00:00:00 +0100

Authors: Min KD, Asakura M, Liao Y, Nakamaru K, Okazaki H, Takahashi T, Fujimoto K, Ito S, Takahashi A, Asanuma H, Yamasaki S, Minamino T, Sanada S, Seguchi O, Nakano A, Ando Y, Otsuka T, Furukawa H, Isomura T, Takashima S, Mochizuki N, Kitakaze M Although various management methods have been developed for heart failure, it is necessary to investigate the diagnostic or therapeutic targets of heart failure. Accordingly, we have developed different approaches for managing heart failure by using conventional microarray analyses. We analyzed gene expression profiles of myocardial samples from 12 patients with heart failure and constructed datasets of heart failure-associated genes using clinical parameters such as pulmonary artery pressure (PAP) and ejection fraction (EF). From these 12 ge...