The prevalence of antibodies to adenovirus serotype 5 in an adult Indian population and implications for adenovirus vector vaccines

In vivo gene delivery using human adenovirus serotype 5 (AdV5) vectors is being explored for vaccination purposes. The presence of anti‐AdV5 antibodies in human serum arising from natural exposure to AdV5 can interfere potentially with and compromise the efficacy of rAdV5‐based vaccine vectors. In this report, a collection of 114 sera from healthy adult Indian blood donors was analyzed for the presence of anti‐AdV5 antibodies, using an AdV5 vector encoding the green fluorescent protein (GFP) to monitor the presence of anti‐AdV5 neutralizing antibodies in human sera based on their ability to block virus entry into HeLa cells which express the Coxsackievirus‐and‐Adenovirus Receptor (CAR). In this assay all samples tested were positive for anti‐AdV5 antibodies, with titers varying over a very wide range. It was also observed that these antibodies facilitated the uptake of the reporter AdV5 vector into the monocytic cell line U937 which does not express CAR, but expresses Fc receptors (FcRs) instead. These observations have implications for rAdV5‐based vaccine development. J. Med. Virol. 82:407–414, 2010. © 2010 Wiley‐Liss, Inc.     

Early treatment with zoledronic acid prevents bone loss at the hip following acute spinal cord injury

Summary  

Osteoporosis after spinal cord injury is common. Reductions in bone density are rapid and fracture rates are higher after injury. Early treatment with 4 mg zoledronic acid significantly reduced bone loss at the hip compared to untreated individuals in the first year. Treatment appeared safe and well tolerated.     

Phenotype‐based selection of bone marrow mesenchymal stem cell‐derived smooth muscle cells for elastic matrix regenerative repair in abdominal aortic aneurysms

Chronic proteolytic disruption of elastic fibres within the abdominal aortic wall results in wall vessel expansion to form rupture‐prone abdominal aortic aneurysms (AAA). Arresting AAA growth is not possible as adult vascular smooth muscle cells (SMCs) poorly auto‐regenerate and repair elastic fibres. Thus, there is a need to identify alternate cell sources capable of robust elastic matrix assembly to overcome elastolysis in the AAA wall. Previously, we demonstrated the superior elastogenic properties of rat bone marrow mesenchymal stem cell (BM‐MSC)‐derived SMCs (BM‐SMCs) relative to aneurysmal and healthy rat aortic SMCs. In the present study, we investigate how phenotypic coordinates of the derived BM‐SMCs, in turn dependent on conditions of BM‐MSC differentiation, impact their elastic matrix synthesis abilities. More specifically, we investigated how glucose content, serum levels and the presence of transforming growth factor (TGF)‐β1 supplements alone or together with platelet‐derived growth factor (PDGF‐BB) in the differentiation medium influence phenotype of, and elastogenesis by derived rat BM‐SMCs. BM‐SMCs generated in low‐glucose and 10% v/v serum conditions in the presence of TGF‐β1 with or without PDGF‐BB exhibited a mature phenotype characterized by contractility and migrative tendencies similar to healthy rat aortic SMCs, and yet capable of robust tropoelastin (precursor) synthesis and assembly of a fibrous, highly crosslinked elastic matrix. Thus, we have identified metrics and conditions for selecting BM‐SMCs with superior elastogenesis for in situ elastic matrix regeneration. Future studies will focus on characterizing these specific BM‐SMC subtypes for their pro‐elastogenic and anti‐proteolytic effects on aneurysmal SMCs to confirm their preferred use for therapy aimed at AAA tissue regenerative repair. Copyright © 2016 John Wiley & Sons, Ltd.     

Motif mimetic of epsin perturbs tumor growth and metastasis

Tumor angiogenesis is critical for cancer progression. In multiple murine models, endothelium-specific epsin deficiency abrogates tumor progression by shifting the balance of VEGFR2 signaling toward uncontrolled tumor angiogenesis, resulting in dysfunctional tumor vasculature. Here, we designed a tumor endothelium–targeting chimeric peptide (UPI) for the purpose of inhibiting endogenous tumor endothelial epsins by competitively binding activated VEGFR2. We determined that the UPI peptide specifically targets tumor endothelial VEGFR2 through an unconventional binding mechanism that is driven by unique residues present only in the epsin ubiquitin–interacting motif (UIM) and the VEGFR2 kinase domain. In murine models of neoangiogenesis, UPI peptide increased VEGF-driven angiogenesis and neovascularization but spared quiescent vascular beds. Further, in tumor-bearing mice, UPI peptide markedly impaired functional tumor angiogenesis, tumor growth, and metastasis, resulting in a notable increase in survival. Coadministration of UPI peptide with cytotoxic chemotherapeutics further sustained tumor inhibition. Equipped with localized tumor endothelium–specific targeting, our UPI peptide provides potential for an effective and alternative cancer therapy.