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A novel single-chain antibody redirects adenovirus to IL13RÎ±2-expressing brain tumors. - Scientific reports
The generation of a targeting agent that strictly binds to IL13RÎ±2 will significantly expand the therapeutic potential for the treatment of IL13RÎ±2-expressing cancers. In order to fulfill this goal, we generated a single-chain antibody (scFv47) from our parental IL13RÎ±2 monoclonal antibody and tested its binding properties. Furthermore, to demonstrate the potential therapeutic applicability of scFv47, we engineered an adenovirus by incorporating scFv47 as the targeting moiety in the viral fiber and characterized its properties in vitro and in vivo. The scFv47 binds to human recombinant IL13RÎ±2, but not to IL13RÎ±1 with a high affinity of 0.9 Â· 10(-9) M, similar to that of the parental antibody. Moreover, the scFv47 successfully redirects adenovirus to IL13RÎ±2 expressing glioma cells both in vitro and in vivo. Our data validate scFv47 as a highly selective IL13RÎ±2 targeting agent and justify further development of scFv47-modified oncolytic adenovirus and other therapeutics for the treatment of IL13RÎ±2-expressing glioma and other malignancies.
A Genetically Modified Adenoviral Vector with a Phage Display-Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma. - Human gene therapy
The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma-specific adenovirus by instituting more advanced genetic modifications that can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptide (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as "GliomaFF." We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. In addition, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restricted in glioma cells by controlling expression of the E1 gene under the activity of the tumor-specific survivin promoter. Using this approach, we were able to explore the combinatorial efficacy of various adenoviral modifications that could amplify the specificity, infectivity, and exclusive replication of this therapeutic adenovirus in glioma. Finally, virotherapy with this modified virus resulted in up to 70% extended survival in an in vivo murine glioma model. These data demonstrate that this novel adenoviral vector is a safe and efficient treatment for this difficult malignancy.
Costs and absence of HCV-infected employees by disease stage. - Journal of medical economics
Quantify the costs and absenteeism associated with stages of the Hepatitis C virus (HCV).Retrospective analysis of the HCMS integrated database from multiple geographically diverse, US-based employers with employee information on medical, prescription, and absenteeism claims.Employee data were extracted from July 2001-March 2013. Employees with HCV were identified by ICD-9-CM codes and classified into disease severity cohorts using diagnosis/procedure codes assigning the first date of most severe claim as the index date. Non-HCV employees (controls) were assigned random index dates. Inclusion required 6-month pre-/post-index eligibility. Medical, prescription, and absenteeism cost and time were analyzed using two-part regression (logistic/generalized linear) models, controlling for potentially confounding factors. Costs were inflation adjusted to September 2013.All direct costs comparisons were statistically significant (pâ€‰â‰¤â€‰0.05) with mean medical costs of $1813 [SEâ€‰=â€‰$3] for controls (nâ€‰=â€‰727,588), $4611 [SEâ€‰=â€‰$211] for non-cirrhotic (nâ€‰=â€‰1007), $4646 [SEâ€‰=â€‰$721] for compensated cirrhosis (CC, nâ€‰=â€‰87), $12,384 [SEâ€‰=â€‰$1122] for decompensated cirrhosis (DCC, nâ€‰=â€‰256), $33,494 [SEâ€‰=â€‰$11,753] for hepatocellular carcinoma (HCC, nâ€‰=â€‰17) and $97,724 [SEâ€‰=â€‰$32,437] for liver transplant (LT, nâ€‰=â€‰19) cohorts. Mean short-term disability days/costs were significantly greater for the non-cirrhotic (daysâ€‰=â€‰2.03 [SEâ€‰=â€‰0.36]; $299 [SEâ€‰=â€‰$53]), DCC (daysâ€‰=â€‰6.20 [SEâ€‰=â€‰1.36]; $763 [SEâ€‰=â€‰$169]), and LT cohorts (daysâ€‰=â€‰21.98 [SEâ€‰=â€‰8.21]; $2537 [SEâ€‰=â€‰$972]) compared to controls (daysâ€‰=â€‰1.19 [SEâ€‰=â€‰0.01]; $155 [SEâ€‰=â€‰$1]). Mean sick leave costs were significantly greater for non-cirrhotic ($373 [SEâ€‰=â€‰$22]) and DCC ($460 [SEâ€‰=â€‰$54]) compared to controls ($327 [SEâ€‰=â€‰$1]).Employees with HCV were shown to have greater direct and indirect costs compared to non-HCV employee controls. Costs progressively increased in the more severe HCV disease categories. Slowing or preventing disease progression may avert the costs of more severe liver disease stages and enable employees with HCV to continue as productive members of the workforce.
Unlocking the promise of oncolytic virotherapy in glioma: combination with chemotherapy to enhance efficacy. - Therapeutic delivery
Malignant glioma is a relentless burden to both patients and clinicians, and calls for innovation to overcome the limitations in current management. Glioma therapy using viruses has been investigated to accentuate the nature of a virus, killing a host tumor cell during its replication. As virus mediated approaches progress with promising therapeutic advantages, combination therapy with chemotherapy and oncolytic viruses has emerged as a more synergistic and possibly efficacious therapy. Here, we will review malignant glioma as well as prior experience with oncolytic viruses, chemotherapy and combination of the two, examining how the combination can be optimized in the future.
Synchrony between sensory and cognitive networks is associated with subclinical variation in autistic traits. - Frontiers in human neuroscience
Individuals with autistic spectrum disorders exhibit distinct personality traits linked to attentional, social, and affective functions, and those traits are expressed with varying levels of severity in the neurotypical and subclinical population. Variation in autistic traits has been linked to reduced functional and structural connectivity (i.e., underconnectivity, or reduced synchrony) with neural networks modulated by attentional, social, and affective functions. Yet, it remains unclear whether reduced synchrony between these neural networks contributes to autistic traits. To investigate this issue, we used functional magnetic resonance imaging to record brain activation while neurotypical participants who varied in their subclinical scores on the Autism-Spectrum Quotient (AQ) viewed alternating blocks of social and nonsocial stimuli (i.e., images of faces and of landscape scenes). We used independent component analysis (ICA) combined with a spatiotemporal regression to quantify synchrony between neural networks. Our results indicated that decreased synchrony between the executive control network (ECN) and a face-scene network (FSN) predicted higher scores on the AQ. This relationship was not explained by individual differences in head motion, preferences for faces, or personality variables related to social cognition. Our findings build on clinical reports by demonstrating that reduced synchrony between distinct neural networks contributes to a range of subclinical autistic traits.
Neural stem cell-mediated delivery of oncolytic adenovirus. - Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.]
The use of stem cells (SCs) as carriers for therapeutic agents has now progressed to early clinical trials. These clinical trials exploring SC-mediated delivery of oncolytic adenoviruses will commence in the near future, hopefully yielding meritorious results that can provoke further scientific inquiry. Preclinical animal studies have demonstrated that SCs can be successfully loaded with conditionally-replicative adenoviruses and delivered to the tumor, whereupon they may evoke pronounced therapeutic efficacy. In this protocol, we describe the maintenance of SCs, provide an analysis of optimal adenoviral titers for SC loading, and evaluate the optimized viral loading on SCs. Â© 2015 by John Wiley & Sons, Inc.Copyright Â© 2015 John Wiley & Sons, Inc.
Sui generis: gene therapy and delivery systems for the treatment of glioblastoma. - Neuro-oncology
Gene therapy offers a multidimensional set of approaches intended to treat and cure glioblastoma (GBM), in combination with the existing standard-of-care treatment (surgery and chemoradiotherapy), by capitalizing on the ability to deliver genes directly to the site of neoplasia to yield antitumoral effects. Four types of gene therapy are currently being investigated for their potential use in treating GBM: (i) suicide gene therapy, which induces the localized generation of cytotoxic compounds; (ii) immunomodulatory gene therapy, which induces or augments an enhanced antitumoral immune response; (iii) tumor-suppressor gene therapy, which induces apoptosis in cancer cells; and (iv) oncolytic virotherapy, which causes the lysis of tumor cells. The delivery of genes to the tumor site is made possible by means of viral and nonviral vectors for direct delivery of therapeutic gene(s), tumor-tropic cell carriers expressing therapeutic gene(s), and "intelligent" carriers designed to increase delivery, specificity, and tumoral toxicity against GBM. These vehicles are used to carry genetic material to the site of pathology, with the expectation that they can provide specific tropism to the desired site while limiting interaction with noncancerous tissue. Encouraging preclinical results using gene therapies for GBM have led to a series of human clinical trials. Although there is limited evidence of a therapeutic benefit to date, a number of clinical trials have convincingly established that different types of gene therapies delivered by various methods appear to be safe. Due to the flexibility of specialized carriers and genetic material, the technology for generating new and more effective therapies already exists.Â© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: email@example.com.
Caudate asymmetry is related to attentional impulsivity and an objective measure of ADHD-like attentional problems in healthy adults. - Brain structure & function
Case-control studies comparing ADHD with typically developing individuals suggest that anatomical asymmetry of the caudate nucleus is a marker of attention deficit hyperactivity disorder (ADHD). However, there is no consensus on whether the asymmetry favors the right or left caudate nucleus in ADHD, or whether the asymmetry is increased or decreased in ADHD. The current study aimed to clarify this relationship by applying a dimensional approach to assessing ADHD symptoms that, instead of relying on clinical classification, utilizes the natural behavioral continuum of traits related to ADHD. Structural T1-weighted MRI was collected from 71 adults between 18 and 35Â years and analyzed for caudate asymmetry. ADHD-like attentional symptoms were assessed with an objective measure of attentional problems, the ADHD score from the Test of Variables of Attention (TOVA). Impulsivity, a core feature in ADHD, was measured using the Barratt Impulsiveness Scale, a self-report measure that assesses attentional, non-planning, and motor features of impulsivity. We found that larger right relative to left caudate volumes correlated with both higher attentional impulsiveness and worse ADHD scores on the TOVA. Higher attentional impulsiveness also correlated with worse ADHD scores, establishing coherence between the objective measure and the self-report measure of attentional problems. These results suggest that a differential passage of information through frontal-striatal networks may produce instability leading to attentional problems. The findings also demonstrate the utility of a dimensional approach to understanding structural correlates of ADHD symptoms.
Advances in stem cells, induced pluripotent stem cells, and engineered cells: delivery vehicles for anti-glioma therapy. - Expert opinion on drug delivery
A limitation of small molecule inhibitors, nanoparticles (NPs) and therapeutic adenoviruses is their incomplete distribution within the entirety of solid tumors such as malignant gliomas. Currently, cell-based carriers are making their way into the clinical setting as they offer the potential to selectively deliver many types of therapies to cancer cells.Here, we review the properties of stem cells, induced pluripotent stem cells and engineered cells that possess the tumor-tropic behavior necessary to serve as cell carriers. We also report on the different types of therapeutic agents that have been delivered to tumors by these cell carriers, including: i) therapeutic genes; ii) oncolytic viruses; iii) NPs; and iv) antibodies. The current challenges and future promises of cell-based drug delivery are also discussed.While the emergence of stem cell-mediated therapy has resulted in promising preclinical results and a human clinical trial utilizing this approach is currently underway, there is still a need to optimize these delivery platforms. By improving the loading of therapeutic agents into stem cells and enhancing their migratory ability and persistence, significant improvements in targeted cancer therapy may be achieved.
Therapeutic cell carriers: a potential road to cure glioma. - Expert review of neurotherapeutics
Many different experimental molecular therapeutic approaches have been evaluated in an attempt to treat brain cancer. However, despite the success of these experimental molecular therapies, research has shown that the specific and efficient delivery of therapeutic agents to tumor cells is a limitation. In this regard, cell carrier systems have garnered significant attraction due to their capacity to be loaded with therapeutic agents and carry them specifically to tumor sites. Furthermore, cell carriers can be genetically modified to express therapeutic agents that can directly eradicate cancerous cells or can modulate tumor microenvironments. This review describes the current state of cell carriers, their use as vehicles for the delivery of therapeutic agents to brain tumors, and future directions that will help overcome the present obstacles to cell carrier mediated therapy for brain cancer.
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