Newly Characterized Murine Undifferentiated Sarcoma Models Sensitive to Virotherapy with Oncolytic HSV-1 M002

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Eric K. Ring

2017-12-01

Full Text Available Despite advances in conventional chemotherapy, surgical techniques, and radiation, outcomes for patients with relapsed, refractory, or metastatic soft tissue sarcomas are dismal. Survivors often suffer from lasting morbidity from current treatments. New targeted therapies with less toxicity, such as those that harness the immune system, and immunocompetent murine sarcoma models to test these therapies are greatly needed. We characterized two new serendipitous murine models of undifferentiated sarcoma (SARC-28 and SARC-45 and tested their sensitivity to virotherapy with oncolytic herpes simplex virus 1 (HSV-1. Both models expressed high levels of the primary HSV entry molecule nectin-1 (CD111 and were susceptible to killing by interleukin-12 (IL-12 producing HSV-1 M002 in vitro and in vivo. M002 resulted in a significant intratumoral increase in effector CD4+ and CD8+ T cells and activated monocytes, and a decrease in myeloid-derived suppressor cells (MDSCs in immunocompetent mice. Compared to parent virus R3659 (no IL-12 production, M002 resulted in higher CD8:MDSC and CD8:T regulatory cell (Treg ratios, suggesting that M002 creates a more favorable immune tumor microenvironment. These data provide support for clinical trials targeting sarcomas with oncolytic HSV-1. These models provide an exciting opportunity to explore combination therapies for soft tissue sarcomas that rely on an intact immune system to reach full therapeutic potential.

Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy In Vitro

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Rodolfo Garza-Morales

2018-05-01

Full Text Available Triple-negative breast cancer (TNBC is one of the most aggressive types of cancer, and treatment is limited to chemotherapy and radiation. Oncolytic virotherapy may be a promising approach to treat TNBC. However, oncolytic adenovirus (OAd-based mono-therapeutic clinical trials have resulted in modest outcomes. The OAd potency could be increased by chemotherapy-induced autophagy, an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. In this study, the ability of alkylating agent temozolomide (TMZ-induced autophagy to increase OAd replication and oncolysis in TNBC cells was evaluated. Human TNBC MDA-MB-231 and HCC1937 cells and mouse 4T1 cells were infected with an OAd expressing the red fluorescent protein mCherry on the virus capsid (OAdmCherry alone or in combination with TMZ. TNBC cells treated with OAdmCherry/TMZ displayed greater mCherry and adenovirus (Ad early region 1A (E1A expression and enhanced cancer-cell killing compared to OAdmCherry or TMZ alone. The combined therapy-mediated cell death was associated with virus replication and accumulation of the autophagy marker light chain 3 (LC3-II. Overall, this study provides experimental evidence of TMZ’s ability to increase oncolytic virotherapy in both human and murine TNBC cells.

Novel therapeutic strategies in human malignancy: combining immunotherapy and oncolytic virotherapy

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Sampath P

2015-06-01

Full Text Available Padma Sampath, Steve H Thorne Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA Abstract: Results from randomized clinical trials over the last several years have finally begun to demonstrate the potential of oncolytic viral therapies to treat a variety of cancers. One reason for these successes has been the realization that this platform is most effective when considered primarily as an immunotherapy. Cancer immunotherapy has also made dramatic strides recently with antibodies capable of blocking immune checkpoint inhibitors and adoptive T-cell therapies, notably CAR T-cells, leading a panel of novel and highly clinically effective therapies. It is clear therefore that an understanding of how and when these complementary approaches can most effectively be combined offers the real hope of moving beyond simply treating the disease and toward starting to talk about curative therapies. In this review we discuss approaches to combining these therapeutic platforms, both through engineering the viral vectors to more beneficially interact with the host immune response during therapy, as well as through the direct combinations of different therapeutics. This primarily, but not exclusively focuses on strains of oncolytic vaccinia virus. Some of the results reported to date, primarily in pre-clinical models but also in early clinical trials, are dramatic and hold great promise for the future development of similar therapies and their translation into cancer therapies. Keywords: oncolytic virus, CAR T-cell, adoptive cell therapy, immune checkpoint inhibitor 

Virotherapy: cancer gene therapy at last? [version 1; referees: 2 approved

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Alan E. Bilsland

2016-08-01

Full Text Available For decades, effective cancer gene therapy has been a tantalising prospect; for a therapeutic modality potentially able to elicit highly effective and selective responses, definitive efficacy outcomes have often seemed out of reach. However, steady progress in vector development and accumulated experience from previous clinical studies has finally led the field to its first licensed therapy. Following a pivotal phase III trial, Imlygic (talimogene laherparepvec/T-Vec received US approval as a treatment for cutaneous and subcutaneous melanoma in October 2015, followed several weeks later by its European authorisation. These represent the first approvals for an oncolytic virotherapy. Imlygic is an advanced-generation herpesvirus-based vector optimised for oncolytic and immunomodulatory activities. Many other oncolytic agents currently remain in development, providing hope that current success will be followed by other diverse vectors that may ultimately come to constitute a new class of clinical anti-cancer agents. In this review, we discuss some of the key oncolytic viral agents developed in the adenovirus and herpesvirus classes, and the prospects for further enhancing their efficacy by combining them with novel immunotherapeutic approaches.

Oncolytic virotherapy in veterinary medicine: current status and future prospects for canine patients

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Patil Sandeep S

2012-01-01

Full Text Available Abstract Oncolytic viruses refer to those that are able to eliminate malignancies by direct targeting and lysis of cancer cells, leaving non-cancerous tissues unharmed. Several oncolytic viruses including adenovirus strains, canine distemper virus and vaccinia virus strains have been used for canine cancer therapy in preclinical studies. However, in contrast to human studies, clinical trials with oncolytic viruses for canine cancer patients have not been reported. An 'ideal' virus has yet to be identified. This review is focused on the prospective use of oncolytic viruses in the treatment of canine tumors - a knowledge that will undoubtedly contribute to the development of oncolytic viral agents for canine cancer therapy in the future.

Immune cells: more than simple carriers for systemic delivery of oncolytic viruses

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Eisenstein S

2014-11-01

Full Text Available Samuel Eisenstein,1 Shu-Hsia Chen,2 Ping-Ying Pan21Department of Surgery, 2Department of Oncological Sciences and Tisch Cancer Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, USAAbstract: Oncolytic virotherapy on its own has numerous drawbacks, including an inability of the virus to actively target tumor cells and systemic toxicities at the high doses necessary to effectively treat tumors. Addition of immune cell-based carriers of oncolytic viruses holds promise as a technique in which oncolytic virus can be delivered directly to tumors in smaller and less toxic doses. Interestingly, the cell carriers themselves have also demonstrated antitumor effects, which can be augmented further by tailoring the appropriate oncolytic virus to the appropriate cell type. This review discusses the multiple factors that go into devising an effective, cell-based delivery system for oncolytic viruses.Keywords: oncolytic virus, cell carrier, immune cells, cancer therapy, myeloid-derived suppressor cells

Treatment of medulloblastoma with oncolytic measles viruses expressing the angiogenesis inhibitors endostatin and angiostatin

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Hutzen, Brian; Bid, Hemant Kumar; Houghton, Peter J; Pierson, Christopher R; Powell, Kimerly; Bratasz, Anna; Raffel, Corey; Studebaker, Adam W

2014-01-01

Medulloblastoma is the most common type of pediatric brain tumor. Although numerous factors influence patient survival rates, more than 30% of all cases will ultimately be refractory to conventional therapies. Current standards of care are also associated with significant morbidities, giving impetus for the development of new treatments. We have previously shown that oncolytic measles virotherapy is effective against medulloblastoma, leading to significant prolongation of survival and even cures in mouse xenograft models of localized and metastatic disease. Because medulloblastomas are known to be highly vascularized tumors, we reasoned that the addition of angiogenesis inhibitors could further enhance the efficacy of oncolytic measles virotherapy. Toward this end, we have engineered an oncolytic measles virus that express a fusion protein of endostatin and angiostatin, two endogenous and potent inhibitors of angiogenesis. Oncolytic measles viruses encoding human and mouse variants of a secretable endostatin/angiostatin fusion protein were designed and rescued according to established protocols. These viruses, known as MV-hE:A and MV-mE:A respectively, were then evaluated for their anti-angiogenic potential and efficacy against medulloblastoma cell lines and orthotopic mouse models of localized disease. Medulloblastoma cells infected by MV-E:A readily secrete endostatin and angiostatin prior to lysis. The inclusion of the endostatin/angiostatin gene did not negatively impact the measles virus’ cytotoxicity against medulloblastoma cells or alter its growth kinetics. Conditioned media obtained from these infected cells was capable of inhibiting multiple angiogenic factors in vitro, significantly reducing endothelial cell tube formation, viability and migration compared to conditioned media derived from cells infected by a control measles virus. Mice that were given a single intratumoral injection of MV-E:A likewise showed reduced numbers of tumor-associated blood

Measles to the Rescue: A Review of Oncolytic Measles Virus

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Sarah Aref

2016-10-01

Full Text Available Oncolytic virotherapeutic agents are likely to become serious contenders in cancer treatment. The vaccine strain of measles virus is an agent with an impressive range of oncolytic activity in pre-clinical trials with increasing evidence of safety and efficacy in early clinical trials. This paramyxovirus vaccine has a proven safety record and is amenable to careful genetic modification in the laboratory. Overexpression of the measles virus (MV receptor CD46 in many tumour cells may direct the virus to preferentially enter transformed cells and there is increasing awareness of the importance of nectin-4 and signaling lymphocytic activation molecule (SLAM in oncolysis. Successful attempts to retarget MV by inserting genes for tumour-specific ligands to antigens such as carcinoembryonic antigen (CEA, CD20, CD38, and by engineering the virus to express synthetic microRNA targeting sequences, and “blinding” the virus to the natural viral receptors are exciting measures to increase viral specificity and enhance the oncolytic effect. Sodium iodine symporter (NIS can also be expressed by MV, which enables in vivo tracking of MV infection. Radiovirotherapy using MV-NIS, chemo-virotherapy to convert prodrugs to their toxic metabolites, and immune-virotherapy including incorporating antibodies against immune checkpoint inhibitors can also increase the oncolytic potential. Anti-viral host immune responses are a recognized barrier to the success of MV, and approaches such as transporting MV to the tumour sites by carrier cells, are showing promise. MV Clinical trials are producing encouraging preliminary results in ovarian cancer, myeloma and cutaneous non-Hodgkin lymphoma, and the outcome of currently open trials in glioblastoma multiforme, mesothelioma and squamous cell carcinoma are eagerly anticipated.

Oncolytic Adenovirus: Strategies and Insights for Vector Design and Immuno-Oncolytic Applications

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Hanni Uusi-Kerttula

2015-11-01

Full Text Available Adenoviruses (Ad are commonly used both experimentally and clinically, including oncolytic virotherapy applications. In the clinical area, efficacy is frequently hampered by the high rates of neutralizing immunity, estimated as high as 90% in some populations that promote vector clearance and limit bioavailability for tumor targeting following systemic delivery. Active tumor targeting is also hampered by the ubiquitous nature of the Ad5 receptor, hCAR, as well as the lack of highly tumor-selective targeting ligands and suitable targeting strategies. Furthermore, significant off-target interactions between the viral vector and cellular and proteinaceous components of the bloodstream have been documented that promote uptake into non-target cells and determine dose-limiting toxicities. Novel strategies are therefore needed to overcome the obstacles that prevent efficacious Ad deployment for wider clinical applications. The use of less seroprevalent Ad serotypes, non-human serotypes, capsid pseudotyping, chemical shielding and genetic masking by heterologous peptide incorporation are all potential strategies to achieve efficient vector escape from humoral immune recognition. Conversely, selective vector arming with immunostimulatory agents can be utilized to enhance their oncolytic potential by activation of cancer-specific immune responses against the malignant tissues. This review presents recent advantages and pitfalls occurring in the field of adenoviral oncolytic therapies.

Oncolytic viral therapy: targeting cancer stem cells

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Smith TT

2014-02-01

Full Text Available Tyrel T Smith,1 Justin C Roth,1 Gregory K Friedman,1 G Yancey Gillespie2 1Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA Abstract: Cancer stem cells (CSCs are defined as rare populations of tumor-initiating cancer cells that are capable of both self-renewal and differentiation. Extensive research is currently underway to develop therapeutics that target CSCs for cancer therapy, due to their critical role in tumorigenesis, as well as their resistance to chemotherapy and radiotherapy. To this end, oncolytic viruses targeting unique CSC markers, signaling pathways, or the pro-tumor CSC niche offer promising potential as CSCs-destroying agents/therapeutics. We provide a summary of existing knowledge on the biology of CSCs, including their markers and their niche thought to comprise the tumor microenvironment, and then we provide a critical analysis of the potential for targeting CSCs with oncolytic viruses, including herpes simplex virus-1, adenovirus, measles virus, reovirus, and vaccinia virus. Specifically, we review current literature regarding first-generation oncolytic viruses with their innate ability to replicate in CSCs, as well as second-generation viruses engineered to enhance the oncolytic effect and CSC-targeting through transgene expression. Keywords: oncolytic virotherapy, cancer stem cell niche

Therapeutic potential of oncolytic Newcastle disease virus: a critical review.

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Tayeb, Shay; Zakay-Rones, Zichria; Panet, Amos

2015-01-01

Newcastle disease virus (NDV) features a natural preference for replication in many tumor cells compared with normal cells. The observed antitumor effect of NDV appears to be a result of both selective killing of tumor cells and induction of immune responses. Genetic manipulations to change viral tropism and arming the virus with genes encoding for cytokines improved the oncolytic capacity of NDV. Several intracellular proteins in tumor cells, including antiapoptotic proteins (Livin) and oncogenic proteins (H-Ras), are relevant for the oncolytic activity of NDV. Defects in the interferon system, found in some tumor cells, also contribute to the oncolytic selectivity of NDV. Notwithstanding, NDV displays effective oncolytic activity in many tumor types, despite having intact interferon signaling. Taken together, several cellular systems appear to dictate the selective oncolytic activity of NDV. Some barriers, such as neutralizing antibodies elicited during NDV treatment and the extracellular matrix in tumor tissue appear to interfere with spread of NDV and reduce oncolysis. To further understand the oncolytic activity of NDV, we compared two NDV strains, ie, an attenuated virus (NDV-HUJ) and a pathogenic virus (NDV-MTH-68/H). Significant differences in amino acid sequence were noted in several viral proteins, including the fusion precursor (F0) glycoprotein, an important determinant of replication and pathogenicity. However, no difference in the oncolytic activity of the two strains was noted using human tumor tissues maintained as organ cultures or in mouse tumor models. To optimize virotherapy in clinical trials, we describe here a unique organ culture methodology, using a biopsy taken from a patient's tumor before treatment for ex vivo infection with NDV to determine the oncolytic potential on an individual basis. In conclusion, oncolytic NDV is an excellent candidate for cancer therapy, but more knowledge is needed to ensure success in clinical trials.

Genetic Modification of Oncolytic Newcastle Disease Virus for Cancer Therapy.

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Cheng, Xing; Wang, Weijia; Xu, Qi; Harper, James; Carroll, Danielle; Galinski, Mark S; Suzich, JoAnn; Jin, Hong

2016-06-01

Clinical development of a mesogenic strain of Newcastle disease virus (NDV) as an oncolytic agent for cancer therapy has been hampered by its select agent status due to its pathogenicity in avian species. Using reverse genetics, we have generated a lead candidate oncolytic NDV based on the mesogenic NDV-73T strain that is no longer classified as a select agent for clinical development. This recombinant NDV has a modification at the fusion protein (F) cleavage site to reduce the efficiency of F protein cleavage and an insertion of a 198-nucleotide sequence into the HN-L intergenic region, resulting in reduced viral gene expression and replication in avian cells but not in mammalian cells. In mammalian cells, except for viral polymerase (L) gene expression, viral gene expression is not negatively impacted or increased by the HN-L intergenic insertion. Furthermore, the virus can be engineered to express a foreign gene while still retaining the ability to grow to high titers in cell culture. The recombinant NDV selectively replicates in and kills tumor cells and is able to drive potent tumor growth inhibition following intratumoral or intravenous administration in a mouse tumor model. The candidate is well positioned for clinical development as an oncolytic virus. Avian paramyxovirus type 1, NDV, has been an attractive oncolytic agent for cancer virotherapy. However, this virus can cause epidemic disease in poultry, and concerns about the potential environmental and economic impact of an NDV outbreak have precluded its clinical development. Here we describe generation and characterization of a highly potent oncolytic NDV variant that is unlikely to cause Newcastle disease in its avian host, representing an essential step toward moving NDV forward as an oncolytic agent. Several attenuation mechanisms have been genetically engineered into the recombinant NDV that reduce chicken pathogenicity to a level that is acceptable worldwide without impacting viral production in

Pediatric glioma stem cells: biologic strategies for oncolytic HSV virotherapy

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Gregory K Friedman

2013-02-01

Full Text Available While glioblastoma multiforme (GBM is the most common adult malignant brain tumor, GBMs in childhood represent less than 10% of pediatric malignant brain tumors and are phenotypically and molecularly distinct from adult GBMs. Similar to adult patients, outcomes for children with high-grade gliomas (HGGs remain poor. Furthermore, the significant morbidity and mortality yielded by pediatric GBM is compounded by neurotoxicity for the developing brain caused by current therapies. Poor outcomes have been attributed to a subpopulation of chemotherapy and radiotherapy resistant cells, termed ‘glioma stem cells’ (GSCs, ‘glioma progenitor cells’, or ‘glioma-initiating cells', which have the ability to initiate and maintain the tumor and to repopulate the recurring tumor after conventional therapy. Future innovative therapies for pediatric HGGs must be able to eradicate these therapy-resistant GSCs. Oncolytic herpes simplex viruses, genetically engineered to be safe for normal cells and to express diverse foreign anti-tumor therapeutic genes, have been demonstrated in preclinical studies to infect and kill GSCs and tumor cells equally while sparing normal brain cells. In this review, we discuss the unique aspects of pediatric GSCs, including markers to identify them, the microenvironment they reside in, signaling pathways that regulate them, mechanisms of cellular resistance, and approaches to target GSCs, with a focus on the promising therapeutic, genetically engineered oncolytic herpes simplex virus (HSV.

Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs

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Braidwood L

2013-12-01

such studies of oncolytic HSV in combination with other drugs, and we review their findings here. Viral interactions with cellular hosts are complex and frequently involve intracellular signaling networks, thus creating diverse opportunities for synergistic or additive combinations with many anticancer drugs. We discuss potential mechanisms that may lead to synergistic interactions.Keywords: combination studies, herpes simplex virus, oncolytic virus, virotherapy

A NOTCH-sensitive uPAR-regulated oncolytic adenovirus effectively suppresses pancreatic tumor growth and triggers synergistic anticancer effects with gemcitabine and nab-paclitaxel.

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Mato-Berciano, Ana; Raimondi, Giulia; Maliandi, Maria Victoria; Alemany, Ramon; Montoliu, Lluis; Fillat, Cristina

2017-04-04

Notch signaling pathway is an embryonic program that becomes reactivated in pancreatic cancer and contributes to cancer stem cell (CSC) maintenance. We explored the concept of oncolytic adenoviral activity in response to Notch activation signaling, in the context of a chimeric promoter with uPAR regulatory sequences, as a strategy to drive its activity in neoplastic and CSC. We explored the advantages of a chemo-virotherapy approach based on synergistic combinations. Regulatory sequences recognized by the transcriptional factor CSL upstream a minimal uPAR promoter were engineered in adenoviral vectors and in the oncolytic adenovirus AdNuPARmE1A. Viral response to Notch signaling, and viral potency in cell lines and pancreatic cancer stem cells (PCSC) was tested. Preclinical toxicity and antitumor efficacy in xenografts and Patient-derived xenografts (PDX) mouse models was evaluated, as unimodal or in combination with gemcitabine+nab-paclitaxel. Mechanistic studies were conducted to explore the synergism of combined therapies.We demonstrate that CSL-binding site optimized-engineered sequences respond to Notch activation in AdNuPARmLuc and AdNuPARmE1A. AdNuPARmE1A showed strong lytic effects in pancreatic cancer cell lines and PCSC. AdNuPARmE1A displayed attenuated activity in normal tissues, but robust antitumor effects in xenograft and PDX models, leading to a reduced capacity of treated tumors to form tumorspheres. Chemo-virotherapy treatment enlarged therapeutic response in both tumor models. Synergistic effects of the combination resulted from viral sensitization of apoptotic cell death triggered by chemotherapy.In summary we present a novel effective oncolytic adenovirus, AdNuPARmE1A that reduces PCSC and presents synergistic effects with gemcitabine and nab-paclitaxel, supporting further clinical development.

Oncolytic adenovirus targeting cyclin E overexpression repressed tumor growth in syngeneic immunocompetent mice

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Cheng, Pei-Hsin; Rao, Xiao-Mei; Wechman, Stephen L.; Li, Xiao-Feng; McMasters, Kelly M.; Zhou, Heshan Sam

2015-01-01

Clinical trials have indicated that preclinical results obtained with human tumor xenografts in mouse models may overstate the potential of adenovirus (Ad)-mediated oncolytic therapies. We have previously demonstrated that the replication of human Ads depends on cyclin E dysregulation or overexpression in cancer cells. ED-1 cell derived from mouse lung adenocarcinomas triggered by transgenic overexpression of human cyclin E may be applied to investigate the antitumor efficacy of oncolytic Ads. Ad-cycE was used to target cyclin E overexpression in ED-1 cells and repress tumor growth in a syngeneic mouse model for investigation of oncolytic virotherapies. Murine ED-1 cells were permissive for human Ad replication and Ad-cycE repressed ED-1 tumor growth in immunocompetent FVB mice. ED-1 cells destroyed by oncolytic Ads in tumors were encircled in capsule-like structures, while cells outside the capsules were not infected and survived the treatment. Ad-cycE can target cyclin E overexpression in cancer cells and repress tumor growth in syngeneic mouse models. The capsule structures formed after Ad intratumoral injection may prevent viral particles from spreading to the entire tumor. The online version of this article (doi:10.1186/s12885-015-1731-x) contains supplementary material, which is available to authorized users

Combining Oncolytic Virotherapy with p53 Tumor Suppressor Gene Therapy

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Christian Bressy

2017-06-01

Full Text Available Oncolytic virus (OV therapy utilizes replication-competent viruses to kill cancer cells, leaving non-malignant cells unharmed. With the first U.S. Food and Drug Administration-approved OV, dozens of clinical trials ongoing, and an abundance of translational research in the field, OV therapy is poised to be one of the leading treatments for cancer. A number of recombinant OVs expressing a transgene for p53 (TP53 or another p53 family member (TP63 or TP73 were engineered with the goal of generating more potent OVs that function synergistically with host immunity and/or other therapies to reduce or eliminate tumor burden. Such transgenes have proven effective at improving OV therapies, and basic research has shown mechanisms of p53-mediated enhancement of OV therapy, provided optimized p53 transgenes, explored drug-OV combinational treatments, and challenged canonical roles for p53 in virus-host interactions and tumor suppression. This review summarizes studies combining p53 gene therapy with replication-competent OV therapy, reviews preclinical and clinical studies with replication-deficient gene therapy vectors expressing p53 transgene, examines how wild-type p53 and p53 modifications affect OV replication and anti-tumor effects of OV therapy, and explores future directions for rational design of OV therapy combined with p53 gene therapy.

Oncolytic viruses: a step into cancer immunotherapy

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Pol JG

2011-12-01

Full Text Available Jonathan G Pol, Julien Rességuier, Brian D LichtyMcMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, CanadaAbstract: Oncolytic virotherapy is currently under investigation in phase I–III clinical trials for approval as a new cancer treatment. Oncolytic viruses (OVs selectively infect, replicate in, and kill tumor cells. For a long time, the therapeutic efficacy was thought to depend on the direct viral oncolysis (virocentric view. The host immune system was considered as a brake that impaired virus delivery and spread. Attention was paid primarily to approaches enhancing virus tumor selectivity and cytotoxicity and/or that limited antiviral responses. Thinking has changed over the past few years with the discovery that OV therapy was also inducing indirect oncolysis mechanisms. Among them, induction of an antitumor immunity following OV injection appeared to be a key factor for an efficient therapeutic activity (immunocentric view. Indeed, tumor-specific immune cells persist post-therapy and can search and destroy any tumor cells that escape the OVs, and thus immune memory may prevent relapse of the disease. Various strategies, which are summarized in this manuscript, have been developed to enhance the efficacy of OV therapy with a focus on its immunotherapeutic aspects. These include genetic engineering and combination with existing cancer treatments. Several are currently being evaluated in human patients and already display promising efficacy.Keywords: oncolytic virus, cancer immunotherapy, tumor antigen, cancer vaccine, combination strategies

Expression of DAI by an oncolytic vaccinia virus boosts the immunogenicity of the virus and enhances antitumor immunity

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Mari Hirvinen

2016-01-01

Full Text Available In oncolytic virotherapy, the ability of the virus to activate the immune system is a key attribute with regard to long-term antitumor effects. Vaccinia viruses bear one of the strongest oncolytic activities among all oncolytic viruses. However, its capacity for stimulation of antitumor immunity is not optimal, mainly due to its immunosuppressive nature. To overcome this problem, we developed an oncolytic VV that expresses intracellular pattern recognition receptor DNA-dependent activator of IFN-regulatory factors (DAI to boost the innate immune system and to activate adaptive immune cells in the tumor. We showed that infection with DAI-expressing VV increases expression of several genes related to important immunological pathways. Treatment with DAI-armed VV resulted in significant reduction in the size of syngeneic melanoma tumors in mice. When the mice were rechallenged with the same tumor, DAI-VV-treated mice completely rejected growth of the new tumor, which indicates immunity established against the tumor. We also showed enhanced control of growth of human melanoma tumors and elevated levels of human T-cells in DAI-VV-treated mice humanized with human peripheral blood mononuclear cells. We conclude that expression of DAI by an oncolytic VV is a promising way to amplify the vaccine potency of an oncolytic vaccinia virus to trigger the innate—and eventually the long-lasting adaptive immunity against cancer.

Pediatric cancer gone viral. Part II: potential clinical application of oncolytic herpes simplex virus-1 in children

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Gregory K Friedman

Full Text Available Oncolytic engineered herpes simplex viruses (HSVs possess many biologic and functional attributes that support their use in clinical trials in children with solid tumors. Tumor cells, in an effort to escape regulatory mechanisms that would impair their growth and progression, have removed many mechanisms that would have protected them from virus infection and eventual virus-mediated destruction. Viruses engineered to exploit this weakness, like mutant HSV, can be safely employed as tumor cell killers, since normal cells retain these antiviral strategies. Many preclinical studies and early phase trials in adults demonstrated that oncolytic HSV can be safely used and are highly effective in killing tumor cells that comprise pediatric malignancies, without generating the toxic side effects of nondiscriminatory chemotherapy or radiation therapy. A variety of engineered viruses have been developed and tested in numerous preclinical models of pediatric cancers and initial trials in patients are underway. In Part II of this review series, we examine the preclinical evidence to support the further advancement of oncolytic HSV in the pediatric population. We discuss clinical advances made to date in this emerging era of oncolytic virotherapy.

Advances in the design and development of oncolytic measles viruses

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Hutzen B

2015-08-01

Full Text Available Brian Hutzen,1 Corey Raffel,2 Adam W Studebaker1 1Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; 2Department of Neurological Surgery and Pediatrics, University of California, San Francisco, San Francisco, CA, USA Abstract: A successful oncolytic virus is one that selectively propagates and destroys cancerous tissue without causing excessive damage to the normal surrounding tissue. Oncolytic measles virus (MV is one such virus that exhibits this characteristic and thus has rapidly emerged as a potentially useful anticancer modality. Derivatives of the Edmonston MV vaccine strain possess a remarkable safety record in humans. Promising results in preclinical animal models and evidence of biological activity in early phase trials contribute to the enthusiasm. Genetic modifications have enabled MV to evolve from a vaccine agent to a potential anticancer therapy. Specifically, alterations of the MV genome have led to improved tumor selectivity and delivery, therapeutic potency, and immune system modulation. In this article, we will review the advancements that have been made in the design and development of MV that have led to its use as a cancer therapy. In addition, we will discuss the evidence supporting its use, as well as the challenges associated with MV as a potential cancer therapeutic. Keywords: virotherapy, measles virus, oncolytic therapy

Oncolytic Viruses-Interaction of Virus and Tumor Cells in the Battle to Eliminate Cancer.

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Howells, Anwen; Marelli, Giulia; Lemoine, Nicholas R; Wang, Yaohe

2017-01-01

Oncolytic viruses (OVs) are an emerging treatment option for many cancer types and have recently been the focus of extensive research aiming to develop their therapeutic potential. The ultimate aim is to design a virus which can effectively replicate within the host, specifically target and lyse tumor cells and induce robust, long lasting tumor-specific immunity. There are a number of viruses which are either naturally tumor-selective or can be modified to specifically target and eliminate tumor cells. This means they are able to infect only tumor cells and healthy tissue remains unharmed. This specificity is imperative in order to reduce the side effects of oncolytic virotherapy. These viruses can also be modified by various methods including insertion and deletion of specific genes with the aim of improving their efficacy and safety profiles. In this review, we have provided an overview of the various virus species currently being investigated for their oncolytic potential and the positive and negative effects of a multitude of modifications used to increase their infectivity, anti-tumor immunity, and treatment safety, in particular focusing on the interaction of tumor cells and OVs.

Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics.

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Cai, Jing; Lin, Yuan; Zhang, Haipeng; Liang, Jiankai; Tan, Yaqian; Cavenee, Webster K; Yan, Guangmei

2017-06-27

Oncolytic virotherapy is a treatment modality that uses native or genetically modified viruses that selectively replicate in and kill tumor cells. Viruses represent a type of pathogen-associated molecular pattern and thereby induce the up-regulation of dozens of cytokines via activating the host innate immune system. Second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs), which antagonize the function of inhibitor of apoptosis proteins (IAPs) and induce apoptosis, sensitize tumor cells to multiple cytokines. Therefore, we sought to determine whether SMCs sensitize tumor cells to cytokines induced by the oncolytic M1 virus, thus enhancing a bystander killing effect. Here, we report that SMCs potentiate the oncolytic effect of M1 in vitro, in vivo, and ex vivo. This strengthened oncolytic efficacy resulted from the enhanced bystander killing effect caused by the M1 virus via cytokine induction. Through a microarray analysis and subsequent validation using recombinant cytokines, we identified IL-8, IL-1A, and TRAIL as the key cytokines in the bystander killing effect. Furthermore, SMCs increased the replication of M1, and the accumulation of virus protein induced irreversible endoplasmic reticulum stress- and c-Jun N-terminal kinase-mediated apoptosis. Nevertheless, the combined treatment with M1 and SMCs had little effect on normal and human primary cells. Because SMCs selectively and significantly enhance the bystander killing effect and the replication of oncolytic virus M1 specifically in cancer cells, this combined treatment may represent a promising therapeutic strategy.

Preclinical evaluation of oncolytic vaccinia virus for therapy of canine soft tissue sarcoma.

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Ivaylo Gentschev

Full Text Available Virotherapy using oncolytic vaccinia virus (VACV strains is one promising new strategy for canine cancer therapy. In this study we describe the establishment of an in vivo model of canine soft tissue sarcoma (CSTS using the new isolated cell line STSA-1 and the analysis of the virus-mediated oncolytic and immunological effects of two different Lister VACV LIVP1.1.1 and GLV-1h68 strains against CSTS. Cell culture data demonstrated that both tested VACV strains efficiently infected and destroyed cells of the canine soft tissue sarcoma line STSA-1. In addition, in our new canine sarcoma tumor xenograft mouse model, systemic administration of LIVP1.1.1 or GLV-1h68 viruses led to significant inhibition of tumor growth compared to control mice. Furthermore, LIVP1.1.1 mediated therapy resulted in almost complete tumor regression and resulted in long-term survival of sarcoma-bearing mice. The replication of the tested VACV strains in tumor tissues led to strong oncolytic effects accompanied by an intense intratumoral infiltration of host immune cells, mainly neutrophils. These findings suggest that the direct viral oncolysis of tumor cells and the virus-dependent activation of tumor-associated host immune cells could be crucial parts of anti-tumor mechanism in STSA-1 xenografts. In summary, the data showed that both tested vaccinia virus strains and especially LIVP1.1.1 have great potential for effective treatment of CSTS.

MicroRNA-mediated suppression of oncolytic adenovirus replication in human liver.

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Erkko Ylösmäki

Full Text Available MicroRNAs (miRNAs are important and ubiquitous regulators of gene expression that can suppress their target genes by translational inhibition as well as mRNA destruction. Cell type-specific miRNA expression patterns have been successfully exploited for targeting the expression of experimental and therapeutic gene constructs, for example to reduce pathogenic effects of cancer virotherapy in normal tissues. In order to avoid liver damage associated with systemic or intrahepatic delivery of oncolytic adenoviruses we have introduced the concept of suppressing adenovirus replication in hepatic cells by inserting target elements for the liver-specific miR122 into the viral genome. Here we show using ex vivo cultured tissue specimens that six perfectly complementary miR122 target sites in the 3' untranslated region of the viral E1A gene are sufficient in the absence of any other genetic modifications to prevent productive replication of serotype 5 adenovirus (Ad5 in normal human liver. This modification did not compromise the replicative capacity of the modified virus in cancer tissue derived from a colon carcinoma liver metastasis or its oncolytic potency in a human lung cancer xenograft mouse model. Unlike wild-type Ad5, the modified virus did not result in increased serum levels of liver enzymes in infected mice. These results provide a strong preclinical proof of concept for the use of miR122 target sites for reducing the risk of liver damage caused by oncolytic adenoviruses, and suggest that ectopic miR122 target elements should be considered as an additional safety measure included in any therapeutic virus or viral vector posing potential hazard to the liver.

Ex Vivo Oncolytic Virotherapy with Myxoma Virus Arms Multiple Allogeneic Bone Marrow Transplant Leukocytes to Enhance Graft versus Tumor

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Lilly, Cameron L.; Villa, Nancy Y.; Lemos de Matos, Ana; Ali, Haider M.; Dhillon, Jess-Karan S.; Hofland, Tom; Rahman, Masmudur M.; Chan, Winnie; Bogen, Bjarne; Cogle, Christopher; McFadden, Grant

2017-01-01

Allogeneic stem cell transplant-derived T cells have the potential to seek and eliminate sites of residual cancer that escaped primary therapy. Oncolytic myxoma virus (MYXV) exhibits potent anti-cancer efficacy against human cancers like multiple myeloma (MM) and can arm transplant-derived T cells

Oncolytic Herpes Virus rRp450 Shows Efficacy in Orthotopic Xenograft Group 3/4 Medulloblastomas and Atypical Teratoid/Rhabdoid Tumors

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Adam W. Studebaker

2017-09-01

Full Text Available Pediatric brain tumors including medulloblastoma and atypical teratoid/rhabdoid tumor are associated with significant mortality and treatment-associated morbidity. While medulloblastoma tumors within molecular subgroups 3 and 4 have a propensity to metastasize, atypical teratoid/rhabdoid tumors frequently afflict a very young patient population. Adjuvant treatment options for children suffering with these tumors are not only sub-optimal but also associated with many neurocognitive obstacles. A potentially novel treatment approach is oncolytic virotherapy, a developing therapeutic platform currently in early-phase clinical trials for pediatric brain tumors and recently US Food and Drug Administration (FDA-approved to treat melanoma in adults. We evaluated the therapeutic potential of the clinically available oncolytic herpes simplex vector rRp450 in cell lines derived from medulloblastoma and atypical teratoid/rhabdoid tumor. Cells of both tumor types were supportive of virus replication and virus-mediated cytotoxicity. Orthotopic xenograft models of medulloblastoma and atypical teratoid/rhabdoid tumors displayed significantly prolonged survival following a single, stereotactic intratumoral injection of rRp450. Furthermore, addition of the chemotherapeutic prodrug cyclophosphamide (CPA enhanced rRp450’s in vivo efficacy. In conclusion, oncolytic herpes viruses with the ability to bioactivate the prodrug CPA within the tumor microenvironment warrant further investigation as a potential therapy for pediatric brain tumors.

Capitalizing on Cancer Specific Replication: Oncolytic Viruses as a Versatile Platform for the Enhancement of Cancer Immunotherapy Strategies

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Donald Bastin

2016-08-01

Full Text Available The past decade has seen considerable excitement in the use of biological therapies in treating neoplastic disease. In particular, cancer immunotherapy and oncolytic virotherapy have emerged as two frontrunners in this regard with the first FDA approvals for agents in both categories being obtained in the last 5 years. It is becoming increasingly apparent that these two approaches are not mutually exclusive and that much of the therapeutic benefit obtained from the use of oncolytic viruses (OVs is in fact the result of their immunotherapeutic function. Indeed, OVs have been shown to recruit and activate an antitumor immune response and much of the current work in this field centers around increasing this activity through strategies such as engineering genes for immunomodulators into OV backbones. Because of their broad immunostimulatory functions, OVs can also be rationally combined with a variety of other immunotherapeutic approaches including cancer vaccination strategies, adoptive cell transfer and checkpoint blockade. Therefore, while they are important therapeutics in their own right, the true power of OVs may lie in their ability to enhance the effectiveness of a wide range of immunotherapies.

Genetically engineered oncolytic Newcastle disease virus mediates cytolysis of prostate cancer stem like cells.

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Raghunath, Shobana; Pudupakam, Raghavendra Sumanth; Allen, Adria; Biswas, Moanaro; Sriranganathan, Nammalwar

2017-10-20

Oncolytic virotherapy is a promising novel approach that overcomes the limitations posed by radiation and chemotherapy. In this study, the oncolytic efficacy of a recombinant Newcastle disease virus (rNDV) BC-KLQL-GFP, against prostate cancer stem-like/tumor initiating cells was evaluated. Xenograft derived prostaspheres (XPS) induced tumor more efficiently than monolayer cell derived prostaspheres (MCPS) in nude mice. Primary and secondary XPS show enhanced self-renewal and clonogenic potential compared to MCPS. XPS also expressed embryonic stem cell markers, such as Nanog, CD44 and Nestin. Further, prostate specific antigen (PSA) activated recombinant Newcastle Disease Virus (rNDV) was selectively cytotoxic to tumor derived DU145 prostaspheres. An effective concentration (EC 50 ) of 0.11-0.14 multiplicity of infection was sufficient to cause prostasphere cell death in serum free culture. DU145 tumor xenograft derived prostaspheres were used as tumor surrogates as they were enriched for a putative tumor initiating cell population. PSA activated rNDV was efficient in inducing cell death of cells and prostaspheres derived from primary xenografts ex-vivo, thus signifying a potential in vivo efficacy. The EC 50 (∼0.1 MOI) for cytolysis of tumor initiating cells was slightly higher than that was required for the parental cell line, but within the therapeutic margin for safety and efficacy. Copyright © 2017 Elsevier B.V. All rights reserved.

Designing herpes viruses as oncolytics

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Peters, Cole; Rabkin, Samuel D

2015-01-01

Oncolytic herpes simplex virus (oHSV) was one of the first genetically-engineered oncolytic viruses. Because HSV is a natural human pathogen that can cause serious disease, it is incumbent that it can be genetically-engineered or significantly attenuated for safety. Here, we present a detailed explanation of the functions of HSV-1 genes frequently mutated to endow oncolytic activity. These genes are nonessential for growth in tissue culture cells but are important for growth in postmitotic cells, interfering with intrinsic antiviral and innate immune responses or causing pathology, functions dispensable for replication in cancer cells. Understanding the function of these genes leads to informed creation of new oHSVs with better therapeutic efficacy. Virus infection and replication can also be directed to cancer cells through tumor-selective receptor binding and transcriptional- or post-transcriptional miRNA-targeting, respectively. In addition to the direct effects of oHSV on infected cancer cells and tumors, oHSV can be “armed” with transgenes that are: reporters, to track virus replication and spread; cytotoxic, to kill uninfected tumor cells; immune modulatory, to stimulate antitumor immunity; or tumor microenvironment altering, to enhance virus spread or to inhibit tumor growth. In addition to HSV-1, other alphaherpesviruses are also discussed for their oncolytic activity. PMID:26462293

The current status of oncolytic viral therapy for head and neck cancer

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Matthew O. Old

2016-06-01

Full Text Available Objective: Cancer affects the head and neck region frequently and leads to significant morbidity and mortality. Oncolytic viral therapy has the potential to make a big impact in cancers that affect the head and neck. We intend to review the current state of oncolytic viruses in the treatment of cancers that affect the head and neck region. Method: Data sources are from National clinical trials database, literature, and current research. Results: There are many past and active trials for oncolytic viruses that show promise for treating cancers of the head and neck. The first oncolytic virus was approved by the FDA October 2015 (T-VEC, Amgen for the treatment of melanoma. Active translational research continues for this and many other oncolytic viruses. Conclusion: The evolving field of oncolytic viruses is impacting the treatment of head and neck cancer and further trials and agents are moving forward in the coming years. Keywords: Head and neck squamous cell carcinoma, Oncolytic viruses, Clinical trials, Novel therapeutics

Designing herpes viruses as oncolytics

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Cole Peters

Full Text Available Oncolytic herpes simplex virus (oHSV was one of the first genetically-engineered oncolytic viruses. Because HSV is a natural human pathogen that can cause serious disease, it is incumbent that it can be genetically-engineered or significantly attenuated for safety. Here, we present a detailed explanation of the functions of HSV-1 genes frequently mutated to endow oncolytic activity. These genes are nonessential for growth in tissue culture cells but are important for growth in postmitotic cells, interfering with intrinsic antiviral and innate immune responses or causing pathology, functions dispensable for replication in cancer cells. Understanding the function of these genes leads to informed creation of new oHSVs with better therapeutic efficacy. Virus infection and replication can also be directed to cancer cells through tumor-selective receptor binding and transcriptional- or post-transcriptional miRNA-targeting, respectively. In addition to the direct effects of oHSV on infected cancer cells and tumors, oHSV can be “armed” with transgenes that are: reporters, to track virus replication and spread; cytotoxic, to kill uninfected tumor cells; immune modulatory, to stimulate antitumor immunity; or tumor microenvironment altering, to enhance virus spread or to inhibit tumor growth. In addition to HSV-1, other alphaherpesviruses are also discussed for their oncolytic activity.

Imaging characteristics, tissue distribution, and spread of a novel oncolytic vaccinia virus carrying the human sodium iodide symporter.

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Dana Haddad

Full Text Available INTRODUCTION: Oncolytic viruses show promise for treating cancer. However, to assess therapy and potential toxicity, a noninvasive imaging modality is needed. This study aims to determine the in vivo biodistribution, and imaging and timing characteristics of a vaccinia virus, GLV-1h153, encoding the human sodium iodide symporter (hNIS. METHODS: GLV-1h153 was modified from GLV-1h68 to encode the hNIS gene. Timing of cellular uptake of radioiodide (131I in human pancreatic carcinoma cells PANC-1 was assessed using radiouptake assays. Viral biodistribution was determined in nude mice bearing PANC-1 xenografts, and infection in tumors confirmed histologically and optically via Green Fluorescent Protein (GFP and bioluminescence. Timing characteristics of enhanced radiouptake in xenografts were assessed via (124I-positron emission tomography (PET. Detection of systemic administration of virus was investigated with both (124I-PET and 99m-technecium gamma-scintigraphy. RESULTS: GLV-1h153 successfully facilitated time-dependent intracellular uptake of (131I in PANC-1 cells with a maximum uptake at 24 hours postinfection (P<0.05. In vivo, biodistribution profiles revealed persistence of virus in tumors 5 weeks postinjection at 10(9 plaque-forming unit (PFU/gm tissue, with the virus mainly cleared from all other major organs. Tumor infection by GLV-1h153 was confirmed via optical imaging and histology. GLV-1h153 facilitated imaging virus replication in tumors via PET even at 8 hours post radiotracer injection, with a mean %ID/gm of 3.82 ± 0.46 (P<0.05 2 days after intratumoral administration of virus, confirmed via tissue radiouptake assays. One week post systemic administration, GLV-1h153-infected tumors were detected via (124I-PET and 99m-technecium-scintigraphy. CONCLUSION: GLV-1h153 is a promising oncolytic agent against pancreatic cancer with a promising biosafety profile. GLV-1h153 facilitated time-dependent hNIS-specific radiouptake in pancreatic

Insertion of the human sodium iodide symporter to facilitate deep tissue imaging does not alter oncolytic or replication capability of a novel vaccinia virus

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Mittra Arjun

2011-03-01

Full Text Available Abstract Introduction Oncolytic viruses show promise for treating cancer. However, to assess therapeutic efficacy and potential toxicity, a noninvasive imaging modality is needed. This study aimed to determine if insertion of the human sodium iodide symporter (hNIS cDNA as a marker for non-invasive imaging of virotherapy alters the replication and oncolytic capability of a novel vaccinia virus, GLV-1h153. Methods GLV-1h153 was modified from parental vaccinia virus GLV-1h68 to carry hNIS via homologous recombination. GLV-1h153 was tested against human pancreatic cancer cell line PANC-1 for replication via viral plaque assays and flow cytometry. Expression and transportation of hNIS in infected cells was evaluated using Westernblot and immunofluorescence. Intracellular uptake of radioiodide was assessed using radiouptake assays. Viral cytotoxicity and tumor regression of treated PANC-1tumor xenografts in nude mice was also determined. Finally, tumor radiouptake in xenografts was assessed via positron emission tomography (PET utilizing carrier-free 124I radiotracer. Results GLV-1h153 infected, replicated within, and killed PANC-1 cells as efficiently as GLV-1h68. GLV-1h153 provided dose-dependent levels of hNIS expression in infected cells. Immunofluorescence detected transport of the protein to the cell membrane prior to cell lysis, enhancing hNIS-specific radiouptake (P In vivo, GLV-1h153 was as safe and effective as GLV-1h68 in regressing pancreatic cancer xenografts (P 124I-PET. Conclusion Insertion of the hNIS gene does not hinder replication or oncolytic capability of GLV-1h153, rendering this novel virus a promising new candidate for the noninvasive imaging and tracking of oncolytic viral therapy.

Oncolysis of malignant human melanoma tumors by Coxsackieviruses A13, A15 and A18

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Barry Richard D

2011-01-01

Full Text Available Abstract Many RNA viruses are displaying great promise in the field of oncolytic virotherapy. Previously, we reported that the picornavirus Coxsackievirus A21 (CVA21 possessed potent oncolytic activity against cultured malignant melanoma cells and melanoma xenografts in mice. In the present study, we demonstrate that three additional Group A Coxsackieviruses; Coxsackievirus A13 (CVA13, Coxsackievirus A15 (CVA15 and Coxsackievirus A18 (CVA18, also have similar oncolytic activity against malignant melanoma. Each of the viruses grew quickly to high titers in cancer cells expressing ICAM-1 and intratumoral injection of preformed subcutaneous SK-Mel-28 xenografts in mice with CVA13, CVA15 and CVA18 resulted in significant tumor volume reduction. As preexisting immunity could potentially hinder oncolytic virotherapy, sera from stage IV melanoma patients and normal controls were tested for levels of protective antibody against the panel of oncolytic Coxsackieviruses. Serum neutralization assays revealed that 3 of 21 subjects possessed low levels of anti-CVA21 antibodies, while protective antibodies for CVA13, CVA15 and CVA18 were not detected in any sample. Serum from individuals who were seropositive for CVA21 failed to exhibit cross-neutralization of CVA13, CVA15 and CVA18. From these studies it can be concluded that the administration of CVA13, CVA15 or CVA18 could be employed as a potential multivalent oncolytic therapy against malignant melanoma.

Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense

International Nuclear Information System (INIS)

Echchgadda, Ibtissam; Chang, Te-Hung; Sabbah, Ahmed; Bakri, Imad; Ikeno, Yuji; Hubbard, Gene B; Chatterjee, Bandana; Bose, Santanu

2011-01-01

Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells. The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further

Immunogenicity of oncolytic vaccinia viruses JX-GFP and TG6002 in a human melanoma in vitro model: studying immunogenic cell death, dendritic cell maturation and interaction with cytotoxic T lymphocytes

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Heinrich B

2017-05-01

Full Text Available B Heinrich,1 J Klein,1 M Delic,1 K Goepfert,1 V Engel,1 L Geberzahn,1 M Lusky,2 P Erbs,2 X Preville,3 M Moehler1 1First Department of Internal Medicine, University Medical Center Mainz, Mainz, Germany; 2Transgene SA, Illkirch-Graffenstaden, 3Amoneta Diagnostics, Huningue, France Abstract: Oncolytic virotherapy is an emerging immunotherapeutic modality for cancer treatment. Oncolytic viruses with genetic modifications can further enhance the oncolytic effects on tumor cells and stimulate antitumor immunity. The oncolytic vaccinia viruses JX-594-GFP+/hGM-CSF (JX-GFP and TG6002 are genetically modified by secreting granulocyte-macrophage colony-stimulating factor (GM-CSF or transforming 5-fluorocytosine (5-FC into 5-fluorouracil (5-FU. We compared their properties to kill tumor cells and induce an immunogenic type of cell death in a human melanoma cell model using SK29-MEL melanoma cells. Their influence on human immune cells, specifically regarding the activation of dendritic cells (DCs and the interaction with the autologous cytotoxic T lymphocyte (CTL clone, was investigated. Melanoma cells were infected with either JX-GFP or TG6002 alone or in combination with 5-FC and 5-FU. The influence of viral infection on cell viability followed a time- and multiplicity of infection dependent manner. Combination of virus treatment with 5-FU resulted in stronger reduction of cell viability. TG6002 in combination with 5-FC did not significantly strengthen the reduction of cell viability in this setting. Expression of calreticulin and high mobility group 1 protein (HMGB1, markers of immunogenic cell death (ICD, could be detected after viral infection. Accordingly, DC maturation was noted after viral oncolysis. DCs presented stronger expression of activation and maturation markers. The autologous CTL clone IVSB expressed the activation marker CD69, but viral treatment failed to enhance cytotoxicity marker. In summary, vaccinia viruses JX-GFP and TG6002 lyse

Oncolytic Immunotherapy: Conceptual Evolution, Current Strategies, and Future Perspectives

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Zong Sheng Guo

2017-05-01

Full Text Available The concept of oncolytic virus (OV-mediated cancer therapy has been shifted from an operational virotherapy paradigm to an immunotherapy. OVs often induce immunogenic cell death (ICD of cancer cells, and they may interact directly with immune cells as well to prime antitumor immunity. We and others have developed a number of strategies to further stimulate antitumor immunity and to productively modulate the tumor microenvironment (TME for potent and sustained antitumor immune cell activity. First, OVs have been engineered or combined with other ICD inducers to promote more effective T cell cross-priming, and in many cases, the breaking of functional immune tolerance. Second, OVs may be armed to express Th1-stimulatory cytokines/chemokines or costimulators to recruit and sustain the potent antitumor immunity into the TME to focus their therapeutic activity within the sites of disease. Third, combinations of OV with immunomodulatory drugs or antibodies that recondition the TME have proven to be highly promising in early studies. Fourth, combinations of OVs with other immunotherapeutic regimens (such as prime-boost cancer vaccines, CAR T cells; armed with bispecific T-cell engagers have also yielded promising preliminary findings. Finally, OVs have been combined with immune checkpoint blockade, with robust antitumor efficacy being observed in pilot evaluations. Despite some expected hurdles for the rapid translation of OV-based state-of-the-art protocols, we believe that a cohort of these novel approaches will join the repertoire of standard cancer treatment options in the near future.

Oncolytic effects of parvovirus H-1 in medulloblastoma are associated with repression of master regulators of early neurogenesis.

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Lacroix, Jeannine; Schlund, Franziska; Leuchs, Barbara; Adolph, Kathrin; Sturm, Dominik; Bender, Sebastian; Hielscher, Thomas; Pfister, Stefan M; Witt, Olaf; Rommelaere, Jean; Schlehofer, Jörg R; Witt, Hendrik

2014-02-01

Based on extensive pre-clinical studies, the oncolytic parvovirus H-1 (H-1PV) is currently applied to patients with recurrent glioblastoma in a phase I/IIa clinical trial (ParvOryx01, NCT01301430). Cure rates of about 40% in pediatric high-risk medulloblastoma (MB) patients also indicate the need of new therapeutic approaches. In order to prepare a future application of oncolytic parvovirotherapy to MB, the present study preclinically evaluates the cytotoxic efficacy of H-1PV on MB cells in vitro and characterizes cellular target genes involved in this effect. Six MB cell lines were analyzed by whole genome oligonucleotide microarrays after treatment and the results were matched to known molecular and cytogenetic risk factors. In contrast to non-transformed infant astrocytes and neurons, in five out of six MB cell lines lytic H-1PV infection and efficient viral replication could be demonstrated. The cytotoxic effects induced by H-1PV were observed at LD50s below 0.05 p. f. u. per cell indicating high susceptibility. Gene expression patterns in the responsive MB cell lines allowed the identification of candidate target genes mediating the cytotoxic effects of H-1PV. H-1PV induced down-regulation of key regulators of early neurogenesis shown to confer poor prognosis in MB such as ZIC1, FOXG1B, MYC, and NFIA. In MB cell lines with genomic amplification of MYC, expression of MYC was the single gene most significantly repressed after H-1PV infection. H-1PV virotherapy may be a promising treatment approach for MB since it targets genes of functional relevance and induces cell death at very low titers of input virus. Copyright © 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

Suppression of Oncolytic Adenovirus-Mediated Hepatotoxicity by Liver-Specific Inhibition of NF-κB

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Mitsuhiro Machitani

2017-12-01

Full Text Available Telomerase-specific replication-competent adenoviruses (Ads, i.e., TRADs, which possess an E1 gene expression cassette driven by the human telomerase reverse transcriptase promoter, are promising agents for cancer treatment. However, even though oncolytic Ads, including TRAD, are intratumorally administered, they are disseminated from the tumor to systemic circulation, causing concern about oncolytic Ad-mediated hepatotoxicity (due mainly to leaky expression of Ad genes in liver. We reported that inhibition of nuclear factor-κB (NF-κB leads to the suppression of replication-incompetent Ad vector-mediated hepatotoxicity via reduction of the leaky expression of Ad genes in liver. Here, to develop a TRAD with an improved safety profile, we designed a TRAD that carries a liver-specific promoter-driven dominant-negative IκBα (DNIκBα expression cassette (TRAD-DNIκBα. Compared with a conventional TRAD, TRAD-DNIκBα showed hepatocyte-specific inhibition of NF-κB signaling and significantly reduced Ad gene expression and replication in the normal human hepatocyte cell line. TRAD-induced hepatotoxicity was largely suppressed in mice following intravenous administration of TRAD-DNIκBα. However, the replication profiles and oncolytic activities of TRAD-DNIκBα were comparable with those of the conventional TRAD in human non-hepatic tumor cells. These results indicate that oncolytic Ads containing the liver-specific DNIκBα expression cassette have improved safety profiles without inhibiting oncolytic activities.

Fighting Cancer with Mathematics and Viruses.

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Santiago, Daniel N; Heidbuechel, Johannes P W; Kandell, Wendy M; Walker, Rachel; Djeu, Julie; Engeland, Christine E; Abate-Daga, Daniel; Enderling, Heiko

2017-08-23

After decades of research, oncolytic virotherapy has recently advanced to clinical application, and currently a multitude of novel agents and combination treatments are being evaluated for cancer therapy. Oncolytic agents preferentially replicate in tumor cells, inducing tumor cell lysis and complex antitumor effects, such as innate and adaptive immune responses and the destruction of tumor vasculature. With the availability of different vector platforms and the potential of both genetic engineering and combination regimens to enhance particular aspects of safety and efficacy, the identification of optimal treatments for patient subpopulations or even individual patients becomes a top priority. Mathematical modeling can provide support in this arena by making use of experimental and clinical data to generate hypotheses about the mechanisms underlying complex biology and, ultimately, predict optimal treatment protocols. Increasingly complex models can be applied to account for therapeutically relevant parameters such as components of the immune system. In this review, we describe current developments in oncolytic virotherapy and mathematical modeling to discuss the benefit of integrating different modeling approaches into biological and clinical experimentation. Conclusively, we propose a mutual combination of these research fields to increase the value of the preclinical development and the therapeutic efficacy of the resulting treatments.

Virotherapy of digestive tumors with rodent parvovirus: overview and perspectives.

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Akladios, Cherif; Aprahamian, Marc

2016-01-01

Toolan's H-1 parvovirus (H-1PV) exerts a cytotoxic/oncolytic effect, predominantly mediated by its non-structural protein (NS1). This rat parvovirus is harmless, unlike other parvoviruses, and its antitumor potential may be useful to clinicians as its oncolytic action appears to be true in numerous non-digestive and digestive cancers. After a brief review of parvovirus genus and biology, we summarize the proposed mechanisms to explain the cytotoxicity of H-1PV to tumors which results in dysregulation of cell transcription, cell-cycle arrest, termination of cell replication, activation of cellular stress response and induction of cell death. Viral oncolysis induces a strong tumor-specific immune response leading to the recognition and elimination of minimal residual disease. As the action of H-1PV is not limited to the digestive tract, we initially analyse studies performed in non-digestive cancers such as glioma (as the virus is able to cross the blood brain barrier), and then focused more particularly on the results in digestive cancers. Based on the results of studies showing little H-1PV toxicity to living bodies, we advocate for the use of the parvovirus in cancers such as melanoma, glioma and pancreatic ductal adenocarcinoma in addition to conventional chemotherapy.

Measles virus: Background and oncolytic virotherapy

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Sankhajit Bhattacharjee; Pramod Kumar Yadava

2018-01-01

Measles is a highly transmissible disease caused by measles virus and remains a major cause of child mortality in developing countries. Measles virus nucleoprotein (N) encapsidates the RNA genome of the virus for providing protection from host cell endonucleases and for specific recognition of viral RNA as template for transcription and replication. This protein is over-expressed at the time of viral replication. The C-terminal of N protein is intrinsically disordered, which enables this prot...

Molecular imaging of oncolytic viral therapy

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Dana Haddad

2014-01-01

Full Text Available Oncolytic viruses have made their mark on the cancer world as a potential therapeutic option, with the possible advantages of reduced side effects and strengthened treatment efficacy due to higher tumor selectivity. Results have been so promising, that oncolytic viral treatments have now been approved for clinical trials in several countries. However, clinical studies may benefit from the ability to noninvasively and serially identify sites of viral targeting via molecular imaging in order to provide safety, efficacy, and toxicity information. Furthermore, molecular imaging of oncolytic viral therapy may provide a more sensitive and specific diagnostic technique to detect tumor origin and, more importantly, presence of metastases. Several strategies have been investigated for molecular imaging of viral replication broadly categorized into optical and deep tissue imaging, utilizing several reporter genes encoding for fluorescence proteins, conditional enzymes, and membrane protein and transporters. Various imaging methods facilitate molecular imaging, including computer tomography, magnetic resonance imaging, positron emission tomography, single photon emission CT, gamma-scintigraphy, and photoacoustic imaging. In addition, several molecular probes are used for medical imaging, which act as targeting moieties or signaling agents. This review will explore the preclinical and clinical use of in vivo molecular imaging of replication-competent oncolytic viral therapy.

Use of an oncolytic virus secreting GM-CSF as combined oncolytic and immunotherapy for treatment of colorectal and hepatic adenocarcinomas.

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Malhotra, Sandeep; Kim, Teresa; Zager, Jonathan; Bennett, Joseph; Ebright, Michael; D'Angelica, Michael; Fong, Yuman

2007-04-01

Oncolytic cancer therapy using herpes simplex viruses (HSV) that have direct tumoricidal effects and cancer immunotherapy using the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) have each been effective in preclinical testing. NV1034 is a multimutated oncolytic HSV carrying the gene for murine GM-CSF that attempts to combine these 2 anticancer strategies. The purpose of this study was to compare NV1034 to NV1023, the parent HSV mutants lacking GM-CSF, to determine if such combined oncolytic and immunotherapy using a single vector has advantages over oncolytic therapy alone. Expression GM-CSF in vitro did not alter the infectivity, cytotoxicity, or replication of NV1034 compared to the noncytokine-secreting control. Tumors infected with NV1034 produced GM-CSF in picogram quantities. In vivo efficacy of the viruses against murine colorectal carcinoma CT26 and murine hepatoma Hepa l-6 was then tested in subcutaneous tumors in syngeneic Balb/c and C57 L/J mice, respectively. In these immune-competent models, NV1034 and NV1023 each demonstrated potent antitumor activity. Treatment with NV1034 had significantly better antitumor effect compared to treatment with NV1023. Furthermore, there was no difference in the antitumor efficacy of these viruses in mice depleted of CD4+ and CD8+ T lymphocytes. Viral vectors combining oncolytic and immunotherapy are promising agents in treatment of colorectal carcinoma and hepatoma.

Oncolytic Adenoviruses in Cancer Treatment

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Ramon Alemany

2014-02-01

Full Text Available The therapeutic use of viruses against cancer has been revived during the last two decades. Oncolytic viruses replicate and spread inside tumors, amplifying their cytotoxicity and simultaneously reversing the tumor immune suppression. Among different viruses, recombinant adenoviruses designed to replicate selectively in tumor cells have been clinically tested by intratumoral or systemic administration. Limited efficacy has been associated to poor tumor targeting, intratumoral spread, and virocentric immune responses. A deeper understanding of these three barriers will be required to design more effective oncolytic adenoviruses that, alone or combined with chemotherapy or immunotherapy, may become tools for oncologists.

Oncolytic Herpes Simplex Viral Therapy: A Stride toward Selective Targeting of Cancer Cells.

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Sanchala, Dhaval S; Bhatt, Lokesh K; Prabhavalkar, Kedar S

2017-01-01

Oncolytic viral therapy, which makes use of replication-competent lytic viruses, has emerged as a promising modality to treat malignancies. It has shown meaningful outcomes in both solid tumor and hematologic malignancies. Advancements during the last decade, mainly genetic engineering of oncolytic viruses have resulted in improved specificity and efficacy of oncolytic viruses in cancer therapeutics. Oncolytic viral therapy for treating cancer with herpes simplex virus-1 has been of particular interest owing to its range of benefits like: (a) large genome and power to infiltrate in the tumor, (b) easy access to manipulation with the flexibility to insert multiple transgenes, (c) infecting majority of the malignant cell types with quick replication in the infected cells and (d) as Anti-HSV agent to terminate HSV replication. This review provides an exhaustive list of oncolytic herpes simplex virus-1 along with their genetic alterations. It also encompasses the major developments in oncolytic herpes simplex-1 viral therapy and outlines the limitations and drawbacks of oncolytic herpes simplex viral therapy.

Myxoma virus expressing interleukin-15 fails to cause lethal myxomatosis in European rabbits.

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Liu, Jia; Wennier, Sonia; Reinhard, Mary; Roy, Edward; MacNeill, Amy; McFadden, Grant

2009-06-01

Myxoma virus (MYXV) is a poxvirus pathogenic only for European rabbits, but its permissiveness in human cancer cells gives it potential as an oncolytic virus. A recombinant MYXV expressing both the tdTomato red fluorescent protein and interleukin-15 (IL-15) (vMyx-IL-15-tdTr) was constructed. Cells infected with vMyx-IL-15-tdTr secreted bioactive IL-15 and had in vitro replication kinetics similar to that of wild-type MYXV. To determine the safety of this virus for future oncolytic studies, we tested its pathogenesis in European rabbits. In vivo, vMyx-IL-15-tdTr no longer causes lethal myxomatosis. Thus, ectopic IL-15 functions as an antiviral cytokine in vivo, and vMyx-IL-15-tdTr is a safe candidate for animal studies of oncolytic virotherapy.

Efficacy of combining ING4 and TRAIL genes in cancer-targeting gene virotherapy strategy: first evidence in preclinical hepatocellular carcinoma.

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Galal El-Shemi, A; Mohammed Ashshi, A; Oh, E; Jung, B-K; Basalamah, M; Alsaegh, A; Yun, C-O

2018-01-01

Current treatments of hepatocellular carcinoma (HCC) are ineffective and unsatisfactory in many aspects. Cancer-targeting gene virotherapy using oncolytic adenoviruses (OAds) armed with anticancer genes has shown efficacy and safety in clinical trials. Nowadays, both inhibitor of growth 4 (ING4), as a multimodal tumor suppressor gene, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as a potent apoptosis-inducing gene, are experiencing a renaissance in cancer gene therapy. Herein we investigated the antitumor activity and safety of mono- and combined therapy with OAds armed with ING4 (Ad-ΔB/ING4) and TRAIL (Ad-ΔB/TRAIL) gene, respectively, on preclinical models of human HCC. OAd-mediated expression of ING4 or TRAIL transgene was confirmed. Ad-ΔB/TRAIL and/or Ad-ΔB/ING4 exhibited potent killing effect on human HCC cells (HuH7 and Hep3B) but not on normal liver cells. Most importantly, systemic therapy with Ad-ΔB/ING4 plus Ad-ΔB/TRAIL elicited more eradicative effect on an orthotopic mouse model of human HCC than their monotherapy, without causing obvious overlapping toxicity. Mechanistically, Ad-ΔB/ING4 and Ad-ΔB/TRAIL were remarkably cooperated to induce antitumor apoptosis and immune response, and to repress tumor angiogenesis. This is the first study showing that concomitant therapy with Ad-ΔB/ING4 and Ad-ΔB/TRAIL may provide a potential strategy for HCC therapy and merits further investigations to realize its possible clinical translation.

Oncolytic Virotherapy Targeting Lung Cancer Drug Resistance

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2013-08-01

Von Hoff DD, Kim DH: ONYX..01S. an E1B gene- attenuated adenovirus , cau888 tumor-specific cytolysis and antitumoral efficacy that can be augmented...ORGANIZATION: Vaccine & Gene Therapy Institute of Florida Port St. Lucie, FL 34987...NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER Vaccine & Gene Therapy Institute of

Spotlight on talimogene laherparepvec for the treatment of melanoma lesions in the skin and lymph nodes

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Orloff M

2016-10-01

Full Text Available Marlana Orloff Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, USA Abstract: On October 27, 2015, talimogene laherparepvec (T-VEC, a first in class intralesional oncolytic virotherapy, was granted the US Food and Drug Administration approval for the treatment of melanoma in the skin and lymph nodes. Its approval has added yet another therapeutic option to the growing list of effective therapies for melanoma. Though the Phase III OPTiM trial has demonstrated its efficacy as a single agent, the target patient population remains narrow. With numerous effective and tolerable treatments available for unresectable and metastatic melanoma, intralesional therapies such as T-VEC are still finding their niche. T-VEC is now widely accepted as option for treatment; however, its combination with various other agents in an effort to expand its use and synergize with other interventions is still being explored. This article will review the pre-clinical and clinical work that eventually led to the Food and Drug Administration approval of this first-in-class agent, as well as address concerns about clinical application and ongoing research. Keywords: T-VEC, talimogene laherparepvec intralesional, melanoma, oncolytic virus, virotherapy, immunotherapy

Myxoma Virus Expressing Interleukin-15 Fails To Cause Lethal Myxomatosis in European Rabbits▿

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Liu, Jia; Wennier, Sonia; Reinhard, Mary; Roy, Edward; MacNeill, Amy; McFadden, Grant

2009-01-01

Myxoma virus (MYXV) is a poxvirus pathogenic only for European rabbits, but its permissiveness in human cancer cells gives it potential as an oncolytic virus. A recombinant MYXV expressing both the tdTomato red fluorescent protein and interleukin-15 (IL-15) (vMyx-IL-15-tdTr) was constructed. Cells infected with vMyx-IL-15-tdTr secreted bioactive IL-15 and had in vitro replication kinetics similar to that of wild-type MYXV. To determine the safety of this virus for future oncolytic studies, we tested its pathogenesis in European rabbits. In vivo, vMyx-IL-15-tdTr no longer causes lethal myxomatosis. Thus, ectopic IL-15 functions as an antiviral cytokine in vivo, and vMyx-IL-15-tdTr is a safe candidate for animal studies of oncolytic virotherapy. PMID:19279088

New frontiers in oncolytic viruses: optimizing and selecting for virus strains with improved efficacy

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Lundstrom K

2018-02-01

Full Text Available Kenneth Lundstrom PanTherapeutics, Lutry, Switzerland Abstract: Oncolytic viruses have demonstrated selective replication and killing of tumor cells. Different types of oncolytic viruses – adenoviruses, alphaviruses, herpes simplex viruses, Newcastle disease viruses, rhabdoviruses, Coxsackie viruses, and vaccinia viruses – have been applied as either naturally occurring or engineered vectors. Numerous studies in animal-tumor models have demonstrated substantial tumor regression and prolonged survival rates. Moreover, clinical trials have confirmed good safety profiles and therapeutic efficacy for oncolytic viruses. Most encouragingly, the first cancer gene-therapy drug – Gendicine, based on oncolytic adenovirus type 5 – was approved in China. Likewise, a second-generation oncolytic herpes simplex virus-based drug for the treatment of melanoma has been registered in the US and Europe as talimogene laherparepvec. Keywords: immunotherapy, viral vectors, clinical trials, drug approval

Application of interferon modulators to overcome partial resistance of human ovarian cancers to VSV-GP oncolytic viral therapy

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Catherine Dold

2016-01-01

Full Text Available Previously, we described an oncolytic vesicular stomatitis virus variant pseudotyped with the nonneurotropic glycoprotein of the lymphocytic choriomeningitis virus, VSV-GP, which was highly effective in glioblastoma. Here, we tested its potency for the treatment of ovarian cancer, a leading cause of death from gynecological malignancies. Effective oncolytic activity of VSV-GP could be demonstrated in ovarian cancer cell lines and xenografts in mice; however, remission was temporary in most mice. Analysis of the innate immune response revealed that ovarian cancer cell lines were able to respond to and produce type I interferon, inducing an antiviral state upon virus infection. This is in stark contrast to published data for other cancer cell lines, which were mostly found to be interferon incompetent. We showed that in vitro this antiviral state could be reverted by combining VSV-GP with the JAK1/2-inhibitor ruxolitinib. In addition, for the first time, we report the in vivo enhancement of oncolytic virus treatment by ruxolitinib, both in subcutaneous as well as in orthotopic xenograft mouse models, without causing significant additional toxicity. In conclusion, VSV-GP has the potential to be a potent and safe oncolytic virus to treat ovarian cancer, especially when combined with an inhibitor of the interferon response.

Myxoma Virus Expressing Human Interleukin-12 Does Not Induce Myxomatosis in European Rabbits▿

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Stanford, Marianne M.; Barrett, John W.; Gilbert, Philippe-Alexandre; Bankert, Richard; McFadden, Grant

2007-01-01

Myxoma virus (MV) is a candidate for oncolytic virotherapy due to its ability to selectively infect and kill tumor cells, yet MV is a species-specific pathogen that causes disease only in European rabbits. To assess the ability of MV to deliver cytokines to tumors, we created an MV (vMyxIL-12) that expresses human interleukin-12 (IL-12). vMyxIL-12 replicates similarly to wild-type MV, and virus-infected cells secrete bioactive IL-12. Yet, vMyxIL-12 does not cause myxomatosis, despite expressing the complete repertoire of MV proteins. Thus, vMyxIL-12 exhibits promise as an oncolytic candidate and is safe in all known vertebrate hosts, including lagomorphs. PMID:17728229

Myxoma virus expressing human interleukin-12 does not induce myxomatosis in European rabbits.

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Stanford, Marianne M; Barrett, John W; Gilbert, Philippe-Alexandre; Bankert, Richard; McFadden, Grant

2007-11-01

Myxoma virus (MV) is a candidate for oncolytic virotherapy due to its ability to selectively infect and kill tumor cells, yet MV is a species-specific pathogen that causes disease only in European rabbits. To assess the ability of MV to deliver cytokines to tumors, we created an MV (vMyxIL-12) that expresses human interleukin-12 (IL-12). vMyxIL-12 replicates similarly to wild-type MV, and virus-infected cells secrete bioactive IL-12. Yet, vMyxIL-12 does not cause myxomatosis, despite expressing the complete repertoire of MV proteins. Thus, vMyxIL-12 exhibits promise as an oncolytic candidate and is safe in all known vertebrate hosts, including lagomorphs.

Oncolytic viruses for cancer therapy II. Cell-internal factors for conditional growth in neoplastic cells.

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Campbell, Stephanie A; Gromeier, Matthias

2005-04-01

Recent advances in our understanding of virus-host interactions have fueled new studies in the field of oncolytic viruses. The first part of this review explained how cell-external factors, such as cellular receptors, influence tumor tropism and specificity of oncolytic virus candidates. In the second part of this review, we focus on cellinternal factors that mediate tumor-specific virus growth. An oncolytic virus must be able to replicate within cancerous cells and kill them without collateral damage to healthy surrounding cells. This desirable property is inherent to some proposed oncolytic viral agents or has been achieved by genetic manipulation in others.

Combinatorial Effects of VEGFR Kinase Inhibitor Axitinib and Oncolytic Virotherapy in Mouse and Human Glioblastoma Stem-Like Cell Models.

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Saha, Dipongkor; Wakimoto, Hiroaki; Peters, Cole W; Antoszczyk, Slawomir J; Rabkin, Samuel D; Martuza, Robert L

2018-03-29

Purpose: Glioblastoma (GBM), a fatal brain cancer, contains a subpopulation of GBM stem-like cells (GSCs) that contribute to resistance to current therapy. Angiogenesis also plays a key role in GBM progression. Therefore, we developed a strategy to target the complex GBM microenvironment, including GSCs and tumor vasculature. Experimental Design: We evaluated the cytotoxic effects of VEFGR tyrosine kinase inhibitor (TKI) axitinib in vitro and then tested antitumor efficacy of axitinib in combination with oncolytic herpes simplex virus (oHSV) expressing antiangiogenic cytokine murine IL12 (G47Δ-mIL12) in two orthotopic GSC-derived GBM models: patient-derived recurrent MGG123 GSCs, forming vascular xenografts in immunodeficient mice; and mouse 005 GSCs, forming syngeneic tumors in immunocompetent mice. Results: GSCs form endothelial-like tubes and were sensitive to axitinib. G47Δ-mIL12 significantly improved survival, as did axitinib, while dual combinations further extended survival significantly compared with single therapies alone in both models. In MGG123 tumors, axitinib was effective only at high doses (50 mg/kg), alone and in combination with G47Δ-mIL12, and this was associated with greatly decreased vascularity, increased macrophage infiltration, extensive tumor necrosis, and PDGFR/ERK pathway inhibition. In the mouse 005 model, antiglioma activity, after single and combination therapy, was only observed in immunocompetent mice and not the T-cell-deficient athymic mice. Interestingly, immune checkpoint inhibition did not improve efficacy. Conclusions: Systemic TKI (axitinib) beneficially combines with G47Δ-mIL12 to enhance antitumor efficacy in both immunodeficient and immunocompetent orthotopic GBM models. Our results support further investigation of TKIs in combination with oHSV for GBM treatment. Clin Cancer Res; 1-14. ©2018 AACR. ©2018 American Association for Cancer Research.

Pediatric medulloblastoma xenografts including molecular subgroup 3 and CD133+ and CD15+ cells are sensitive to killing by oncolytic herpes simplex viruses.

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Friedman, Gregory K; Moore, Blake P; Nan, Li; Kelly, Virginia M; Etminan, Tina; Langford, Catherine P; Xu, Hui; Han, Xiaosi; Markert, James M; Beierle, Elizabeth A; Gillespie, G Yancey

2016-02-01

Childhood medulloblastoma is associated with significant morbidity and mortality that is compounded by neurotoxicity for the developing brain caused by current therapies, including surgery, craniospinal radiation, and chemotherapy. Innate therapeutic resistance of some aggressive pediatric medulloblastoma has been attributed to a subpopulation of cells, termed cancer-initiating cells or cancer stemlike cells (CSCs), marked by the surface protein CD133 or CD15. Brain tumors characteristically contain areas of pathophysiologic hypoxia, which has been shown to drive the CSC phenotype leading to heightened invasiveness, angiogenesis, and metastasis. Novel therapies that target medulloblastoma CSCs are needed to improve outcomes and decrease toxicity. We hypothesized that oncolytic engineered herpes simplex virus (oHSV) therapy could effectively infect and kill pediatric medulloblastoma cells, including CSCs marked by CD133 or CD15. Using 4 human pediatric medulloblastoma xenografts, including 3 molecular subgroup 3 tumors, which portend worse patient outcomes, we determined the expression of CD133, CD15, and the primary HSV-1 entry molecule nectin-1 (CD111) by fluorescence activated cell sorting (FACS) analysis. Infectability and cytotoxicity of clinically relevant oHSVs (G207 and M002) were determined in vitro and in vivo by FACS, immunofluorescent staining, cytotoxicity assays, and murine survival studies. We demonstrate that hypoxia increased the CD133+ cell fraction, while having the opposite effect on CD15 expression. We established that all 4 xenografts, including the CSCs, expressed CD111 and were highly sensitive to killing by G207 or M002. Pediatric medulloblastoma, including Group 3 tumors, may be an excellent target for oHSV virotherapy, and a clinical trial in medulloblastoma is warranted. © 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: journals.permissions@oup.com.

Oncolytic effects of a novel influenza A virus expressing interleukin-15 from the NS reading frame.

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Marijke van Rikxoort

Full Text Available Oncolytic influenza A viruses with deleted NS1 gene (delNS1 replicate selectively in tumour cells with defective interferon response and/or activated Ras/Raf/MEK/ERK signalling pathway. To develop a delNS1 virus with specific immunostimulatory properties, we used an optimised technology to insert the interleukin-15 (IL-15 coding sequence into the viral NS gene segment (delNS1-IL-15. DelNS1 and delNS1-IL-15 exerted similar oncolytic effects. Both viruses replicated and caused caspase-dependent apoptosis in interferon-defective melanoma cells. Virus replication was required for their oncolytic activity. Cisplatin enhanced the oncolytic activity of delNS1 viruses. The cytotoxic drug increased delNS1 replication and delNS1-induced caspase-dependent apoptosis. Interference with MEK/ERK signalling by RNAi-mediated depletion or the MEK inhibitor U0126 did not affect the oncolytic effects of the delNS1 viruses. In oncolysis sensitive melanoma cells, delNS1-IL-15 (but not delNS1 infection resulted in the production of IL-15 levels ranging from 70 to 1140 pg/mL in the cell culture supernatants. The supernatants of delNS1-IL-15-infected (but not of delNS1-infected melanoma cells induced primary human natural killer cell-mediated lysis of non-infected tumour cells. In conclusion, we constructed a novel oncolytic influenza virus that combines the oncolytic activity of delNS1 viruses with immunostimulatory properties through production of functional IL-15. Moreover, we showed that the oncolytic activity of delNS1 viruses can be enhanced in combination with cytotoxic anti-cancer drugs.

IL-12 Expressing oncolytic herpes simplex virus promotes anti-tumor activity and immunologic control of metastatic ovarian cancer in mice.

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Thomas, Eric D; Meza-Perez, Selene; Bevis, Kerri S; Randall, Troy D; Gillespie, G Yancey; Langford, Catherine; Alvarez, Ronald D

2016-10-27

sterile phosphate buffer solution. Our pilot study demonstrates that an interleukin-12-expressing oncolytic herpes simplex virus effectively kills both murine and human ovarian cancer cell lines and promotes tumor antigen-specific CD8 + T-cell responses in the peritoneal cavity and omentum, leading to reduced peritoneal metastasis and improved survival in a mouse model.

Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword Against Cancer.

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Marelli, Giulia; Howells, Anwen; Lemoine, Nicholas R; Wang, Yaohe

2018-01-01

Oncolytic viral therapy is a new promising strategy against cancer. Oncolytic viruses (OVs) can replicate in cancer cells but not in normal cells, leading to lysis of the tumor mass. Beside this primary effect, OVs can also stimulate the immune system. Tumors are an immuno-suppressive environment in which the immune system is silenced in order to avoid the immune response against cancer cells. The delivery of OVs into the tumor wakes up the immune system so that it can facilitate a strong and durable response against the tumor itself. Both innate and adaptive immune responses contribute to this process, producing an immune response against tumor antigens and facilitating immunological memory. However, viruses are recognized by the immune system as pathogens and the consequent anti-viral response could represent a big hurdle for OVs. Finding a balance between anti-tumor and anti-viral immunity is, under this new light, a priority for researchers. In this review, we provide an overview of the various ways in which different components of the immune system can be allied with OVs. We have analyzed the different immune responses in order to highlight the new and promising perspectives leading to increased anti-tumor response and decreased immune reaction to the OVs.

Silk-elastin-like protein polymer matrix for intraoperative delivery of an oncolytic vaccinia virus.

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Price, Daniel L; Li, Pingdong; Chen, Chun-Hao; Wong, Danni; Yu, Zhenkun; Chen, Nanhai G; Yu, Yong A; Szalay, Aladar A; Cappello, Joseph; Fong, Yuman; Wong, Richard J

2016-02-01

Oncolytic viral efficacy may be limited by the penetration of the virus into tumors. This may be enhanced by intraoperative application of virus immediately after surgical resection. Oncolytic vaccinia virus GLV-1h68 was delivered in silk-elastin-like protein polymer (SELP) in vitro and in vivo in anaplastic thyroid carcinoma cell line 8505c in nude mice. GLV-1h68 in SELP infected and lysed anaplastic thyroid cancer cells in vitro equally as effectively as in phosphate-buffered saline (PBS), and at 1 week retains a thousand fold greater infectious plaque-forming units. In surgical resection models of residual tumor, GLV-1h68 in SELP improves tumor control and shows increased viral β-galactosidase expression as compared to PBS. The use of SELP matrix for intraoperative oncolytic viral delivery protects infectious viral particles from degradation, facilitates sustained viral delivery and transgene expression, and improves tumor control. Such optimization of methods of oncolytic viral delivery may enhance therapeutic outcomes. © 2014 Wiley Periodicals, Inc.

Development of new therapy for canine mammary cancer with recombinant measles virus

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Koichiro Shoji

2016-01-01

Full Text Available Oncolytic virotherapy is a promising treatment strategy for cancer. We previously generated a recombinant measles virus (rMV-SLAMblind that selectively uses a poliovirus receptor-related 4 (PVRL4/Nectin4 receptor, but not signaling lymphocyte activation molecule (SLAM. We demonstrated that the virus exerts therapeutic effects against human breast cancer cells. Here, we examined the applicability of rMV-SLAMblind to treating canine mammary cancers (CMCs. We found that the susceptibilities of host cells to rMV-SLAMblind were dependent on canine Nectin-4 expression. Nectin-4 was detected in four of nine CMC cell lines. The rMV-SLAMblind efficiently infected those four Nectin-4-positive cell lines and was cytotoxic for three of them (CF33, CHMm, and CTBm. In vivo experiment showed that the administration of rMV-SLAMblind greatly suppressed the progression of tumors in mice xenografted with a CMC cell line (CF33. Immunohistochemistry revealed that canine Nectin-4 was expressed in 45% of canine mammary tumors, and the tumor cells derived from one clinical specimen were efficiently infected with rMV-SLAMblind. These results suggest that rMV-SLAMblind infects CMC cells and displays antitumor activity in vitro, in xenografts, and ex vivo. Therefore, oncolytic virotherapy with rMV-SLAMblind can be a novel method for treating CMCs.

Myocardial Contractile Dysfunction is Present Without Histopathology in a Mouse Model of Limb-Girdle Muscular Dystrophy-2F and is Prevented after Claudin-5 Virotherapy

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Nima Milani-Nejad

2016-12-01

Full Text Available AbstractMutations in several members of the dystrophin glycoprotein complex lead to skeletal and cardiomyopathies. Cardiac care for these muscular dystrophies consists of management of symptoms with standard heart medications after detection of reduced whole heart function. Recent evidence from both Duchenne muscular dystrophy patients and animal models suggests that myocardial dysfunction is present before myocardial damage or deficiencies in whole heart function, and that treatment prior to heart failure symptoms may be beneficial. To determine whether this same early myocardial dysfunction is present in other muscular dystrophy cardiomyopathies, we conducted a physiological assessment of cardiac function at the tissue level in the δ-sarcoglycan null mouse model (Sgcd-/- of Limb-girdle muscular dystrophy type 2F. Baseline cardiac contractile force measurements using ex vivo intact linear muscle preparations, were severely depressed in these mice without the presence of histopathology. Virotherapy with claudin-5 prevents the onset of cardiomyopathy in another muscular dystrophy model. After virotherapy with claudin-5, the cardiac contractile force deficits in Sgcd-/- mice are no longer significant. These studies suggest that screening Limb-girdle muscular dystrophy patients using methods that detect earlier functional changes may provide a longer therapeutic window for cardiac care.

Comparison of Liver Detargeting Strategies for Systemic Therapy with Oncolytic Adenovirus Serotype 5

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Tien V. Nguyen

2017-08-01

Full Text Available Oncolytic viruses would ideally be of use for systemic therapy to treat disseminated cancer. To do this safely, this may require multiple layers of cancer specificity. The pharmacology and specificity of oncolytic adenoviruses can be modified by (1 physical retargeting, (2 physical detargeting, (3 chemical shielding, or (4 by modifying the ability of viral early gene products to selectively activate in cancer versus normal cells. We explored the utility of these approaches with oncolytic adenovirus serotype 5 (Ad5 in immunocompetent Syrian hamsters bearing subcutaneous HaK tumors. After a single intravenous injection to reach the distant tumors, the physically hepatocyte-detargeted virus Ad5-hexon-BAP was more effective than conditionally replicating Ad5-dl1101/07 with mutations in its E1A protein. When these control or Ad5 treated animals were treated a second time by intratumoral injection, prior exposure to Ad5 did not affect tumor growth, suggesting that anti-Ad immunity neither prevented treatment nor amplified anti-tumor immune responses. Ad5-dl1101/07 was next chemically shielded with polyethylene glycol (PEG. While 5 kDa of PEG blunted pro-inflammatory IL-6 production induced by Ad5-dl1101/07, this shielding reduced Ad oncolytic activity.

The combination of i-leader truncation and gemcitabine improves oncolytic adenovirus efficacy in an immunocompetent model.

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Puig-Saus, C; Laborda, E; Rodríguez-García, A; Cascalló, M; Moreno, R; Alemany, R

2014-02-01

Adenovirus (Ad) i-leader protein is a small protein of unknown function. The C-terminus truncation of the i-leader protein increases Ad release from infected cells and cytotoxicity. In the current study, we use the i-leader truncation to enhance the potency of an oncolytic Ad. In vitro, an i-leader truncated oncolytic Ad is released faster to the supernatant of infected cells, generates larger plaques, and is more cytotoxic in both human and Syrian hamster cell lines. In mice bearing human tumor xenografts, the i-leader truncation enhances oncolytic efficacy. However, in a Syrian hamster pancreatic tumor model, which is immunocompetent and less permissive to human Ad, antitumor efficacy is only observed when the i-leader truncated oncolytic Ad, but not the non-truncated version, is combined with gemcitabine. This synergistic effect observed in the Syrian hamster model was not seen in vitro or in immunodeficient mice bearing the same pancreatic hamster tumors, suggesting a role of the immune system in this synergism. These results highlight the interest of the i-leader C-terminus truncation because it enhances the antitumor potency of an oncolytic Ad and provides synergistic effects with gemcitabine in the presence of an immune competent system.

A novel oncolytic adenovirus targeting Wnt signaling effectively inhibits cancer-stem like cell growth via metastasis, apoptosis and autophagy in HCC models.

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Zhang, Jian; Lai, Weijie; Li, Qiang; Yu, Yang; Jin, Jin; Guo, Wan; Zhou, Xiumei; Liu, Xinyuan; Wang, Yigang

2017-09-16

Cancer stem cells (CSCs), which are highly differentiated and self-renewing, play an important role in the occurrence, therapeutic resistant and metastasis of hepatacellular carcinoma (HCC). Oncolytic adenoviruses have targeted killing effect on tumor cells, and are invoked as candidate drugs for cancer treatment. We designed a dual-regulated oncolytic adenovirus Ad.wnt-E1A(△24bp)-TSLC1 that targets Wnt and Rb signaling pathways respectively, and carries the tumor suppressor gene, TSLC1. Previous studies have demonstrated that oncolytic adenovirus mediated TSLC1can target liver cancer and exhibit significant cytotoxicity. However, whether Ad.wnt-E1A(△24bp)-TSLC1 can effectively eliminate liver CSCs remains to be explored. We first used the spheroid culture to enrich the liver CSCs-like cells, and detected the self-renewal capacity, differentiation, drug resistance and tumorigenicity. The results showed that Ad-wnt-E1A(△24bp)-TSLC1 could effectively lead to autophagic death. In addition, recombinant adenovirus effectively induced the apoptosis, inhibit metastasis of hepatic CSCs-like cells in vivo. Further animal experiments indicated that Ad-wnt-E1A(△24bp)-TSLC1could effectively inhibit the growth of transplanted tumor of hepatic CSCs and prolong the survival time of mice. Therefore, the novel oncolytic adenovirus Ad.wnt-E1A(△24bp)-TSLC1 has potential application as a therapeutic target for HCC stem cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Chimeric HCMV/HSV-1 and Δγ134.5 oncolytic herpes simplex virus elicit immune mediated antigliomal effect and antitumor memory

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Mohammed G. Ghonime

2018-02-01

Full Text Available Malignant gliomas are the most common primary brain tumor and are characterized by rapid and highly invasive growth. Because of their poor prognosis, new therapeutic strategies are needed. Oncolytic virotherapy (OV is a promising strategy for treating cancer that incorporates both direct viral replication mediated and immune mediated mechanisms to kill tumor cells. C134 is a next generation Δγ134.5 oHSV-1 with improved intratumoral viral replication. It remains safe in the CNS environment by inducing early IFN signaling which restricts its replication in non-malignant cells. We sought to identify how C134 performed in an immunocompetent tumor model that restricts its replication advantage over first generation viruses. To achieve this we identified tumors that have intact IFN signaling responses that restrict C134 and first generation virus replication similarly. Our results show that both viruses elicit a T cell mediated anti-tumor effect and improved animal survival but that subtle difference exist between the viruses effect on median survival despite equivalent in vivo viral replication. To further investigate this we examined the anti-tumor activity in immunodeficient mice and in syngeneic models with re-challenge. These studies show that the T cell response is integral to C134 replication independent anti-tumor response and that OV therapy elicits a durable and circulating anti-tumor memory. The studies also show that repeated intratumoral administration can extend both OV anti-tumor effects and induce durable anti-tumor memory that is superior to tumor antigen exposure alone.

Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy.

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Allan, Kristina J; Mahoney, Douglas J; Baird, Stephen D; Lefebvre, Charles A; Stojdl, David F

2018-04-03

High-throughput genome-wide RNAi (RNA interference) screening technology has been widely used for discovering host factors that impact virus replication. Here we present the application of this technology to uncovering host targets that specifically modulate the replication of Maraba virus, an oncolytic rhabdovirus, and vaccinia virus with the goal of enhancing therapy. While the protocol has been tested for use with oncolytic Maraba virus and oncolytic vaccinia virus, this approach is applicable to other oncolytic viruses and can also be utilized for identifying host targets that modulate virus replication in mammalian cells in general. This protocol describes the development and validation of an assay for high-throughput RNAi screening in mammalian cells, the key considerations and preparation steps important for conducting a primary high-throughput RNAi screen, and a step-by-step guide for conducting a primary high-throughput RNAi screen; in addition, it broadly outlines the methods for conducting secondary screen validation and tertiary validation studies. The benefit of high-throughput RNAi screening is that it allows one to catalogue, in an extensive and unbiased fashion, host factors that modulate any aspect of virus replication for which one can develop an in vitro assay such as infectivity, burst size, and cytotoxicity. It has the power to uncover biotherapeutic targets unforeseen based on current knowledge.

Immunostimulatory Gene Therapy Using Oncolytic Viruses as Vehicles

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Angelica Loskog

2015-11-01

Full Text Available Immunostimulatory gene therapy has been developed during the past twenty years. The aim of immunostimulatory gene therapy is to tilt the suppressive tumor microenvironment to promote anti-tumor immunity. Hence, like a Trojan horse, the gene vehicle can carry warriors and weapons into enemy territory to combat the tumor from within. The most promising immune stimulators are those activating and sustaining Th1 responses, but even if potent effects were seen in preclinical models, many clinical trials failed to show objective responses in cancer patients. However, with new tools to control ongoing immunosuppression in cancer patients, immunostimulatory gene therapy is now emerging as an interesting option. In parallel, oncolytic viruses have been shown to be safe in patients. To prolong immune stimulation and to increase efficacy, these two fields are now merging and oncolytic viruses are armed with immunostimulatory transgenes. These novel agents are racing towards approval as established cancer immunotherapeutics.

Rapid Generation of Multiple Loci-Engineered Marker-free Poxvirus and Characterization of a Clinical-Grade Oncolytic Vaccinia Virus

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Zong Sheng Guo

2017-12-01

Full Text Available Recombinant poxviruses, utilized as vaccine vectors and oncolytic viruses, often require manipulation at multiple genetic loci in the viral genome. It is essential for viral vectors to possess no adventitious mutations and no (antibiotic selection marker in the final product for human patients in order to comply with the guidance from the regulatory agencies. Rintoul et al. have previously developed a selectable and excisable marker (SEM system for the rapid generation of recombinant vaccinia virus. In the current study, we describe an improved methodology for rapid creation and selection of recombinant poxviruses with multiple genetic manipulations solely based on expression of a fluorescent protein and with no requirement for drug selection that can lead to cellular stress and the risk of adventitious mutations throughout the viral genome. Using this improved procedure combined with the SEM system, we have constructed multiple marker-free oncolytic poxviruses expressing different cytokines and other therapeutic genes. The high fidelity of inserted DNA sequences validates the utility of this improved procedure for generation of therapeutic viruses for human patients. We have created an oncolytic poxvirus expressing human chemokine CCL5, designated as vvDD-A34R-hCCL5, with manipulations at two genetic loci in a single virus. Finally, we have produced and purified this virus in clinical grade for its use in a phase I clinical trial and presented data on initial in vitro characterization of the virus.

Effect of ultrasound on herpes simplex virus infection in cell culture

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Iwai Soichi

2011-09-01

Full Text Available Abstract Background Ultrasound has been shown to increase the efficiency of gene expression from retroviruses, adenoviruses and adeno-associated viruses. The effect of ultrasound to stimulate cell membrane permeabilization on infection with an oncolytic herpes simplex virus type 1 (HSV-1 was examined. Results Vero monkey kidney cells were infected with HSV-1 and exposed to 1 MHz ultrasound after an adsorption period. The number of plaques was significantly greater than that of the untreated control. A combination of ultrasound and microbubbles further increased the plaque number. Similar results were obtained using a different type of HSV-1 and oral squamous cell carcinoma (SCC cells. The appropriate intensity, duty cycle and time of ultrasound to increase the plaque number were 0.5 W/cm2, 20% duty cycle and 10 sec, respectively. Ultrasound with microbubbles at an intensity of 2.0 W/cm2, at 50% duty cycle, or for 40 sec reduced cell viability. Conclusion These results indicate that ultrasound promotes the entry of oncolytic HSV-1 into cells. It may be useful to enhance the efficiency of HSV-1 infection in oncolytic virotherapy.

Targeting an Oncolytic Influenza A Virus to Tumor Tissue by Elastase

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Irina Kuznetsova

2017-12-01

Full Text Available Oncolytic viruses are currently established as a novel type of immunotherapy. The challenge is to safely target oncolytic viruses to tumors. Previously, we have generated influenza A viruses (IAVs containing deletions in the viral interferon antagonist. Those deletions have attenuated the virus in normal tissue but allowed replication in tumor cells. IAV entry is mediated by hemagglutinin (HA, which needs to be activated by a serine protease, for example, through trypsin. To further target the IAV to tumors, we have changed the trypsin cleavage site to an elastase cleavage site. We chose this cleavage site because elastase is expressed in the tumor microenvironment. Moreover, the exchange of the cleavage site previously has been shown to attenuate viral growth in lungs. Newly generated elastase-activated influenza viruses (AE viruses grew to similar titers in tumor cells as the trypsin-activated counterparts (AT viruses. Intratumoral injection of AE viruses into syngeneic B16f1 melanoma-derived tumors in mice reduced tumor growth similar to AT viruses and had a better therapeutic effect in heterologous human PANC-1-derived tumors. Therefore, the introduction of the attenuation marker “elastase cleavage site” in viral HA allows for safe, effective oncolytic virus therapy.

Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in children

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Timothy P Cripe

Full Text Available Progress for improving outcomes in pediatric patients with solid tumors remains slow. In addition, currently available therapies are fraught with numerous side effects, often causing significant life-long morbidity for long-term survivors. The use of viruses to kill tumor cells based on their increased vulnerability to infection is gaining traction, with several viruses moving through early and advanced phase clinical testing. The prospect of increased efficacy and decreased toxicity with these agents is thus attractive for pediatric cancer. In part I of this two-part review, we focus on strategies for utilizing oncolytic engineered herpes simplex virus (HSV to target pediatric malignancies. We discuss mechanisms of action, routes of delivery, and the role of preexisting immunity on antitumor efficacy. Challenges to maximizing oncolytic HSV in children are examined, and we highlight how these may be overcome through various arming strategies. We review the preclinical and clinical evidence demonstrating safety of a variety of oncolytic HSVs. In Part II, we focus on the antitumor efficacy of oncolytic HSV in pediatric tumor types, pediatric clinical advances made to date, and future prospects for utilizing HSV in pediatric patients with solid tumors.

Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in children

Science.gov (United States)

Cripe, Timothy P; Chen, Chun-Yu; Denton, Nicholas L; Haworth, Kellie B; Hutzen, Brian; Leddon, Jennifer L; Streby, Keri A; Wang, Pin-Yi; Markert, James M; Waters, Alicia M; Gillespie, George Yancey; Beierle, Elizabeth A; Friedman, Gregory K

2015-01-01

Progress for improving outcomes in pediatric patients with solid tumors remains slow. In addition, currently available therapies are fraught with numerous side effects, often causing significant life-long morbidity for long-term survivors. The use of viruses to kill tumor cells based on their increased vulnerability to infection is gaining traction, with several viruses moving through early and advanced phase clinical testing. The prospect of increased efficacy and decreased toxicity with these agents is thus attractive for pediatric cancer. In part I of this two-part review, we focus on strategies for utilizing oncolytic engineered herpes simplex virus (HSV) to target pediatric malignancies. We discuss mechanisms of action, routes of delivery, and the role of preexisting immunity on antitumor efficacy. Challenges to maximizing oncolytic HSV in children are examined, and we highlight how these may be overcome through various arming strategies. We review the preclinical and clinical evidence demonstrating safety of a variety of oncolytic HSVs. In Part II, we focus on the antitumor efficacy of oncolytic HSV in pediatric tumor types, pediatric clinical advances made to date, and future prospects for utilizing HSV in pediatric patients with solid tumors. PMID:26436135

E4orf1 Limits the Oncolytic Potential of the E1B-55K Deletion Mutant Adenovirus▿

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Thomas, Michael A.; Broughton, Robin S.; Goodrum, Felicia D.; Ornelles, David A.

2009-01-01

Clinical trials have shown oncolytic adenoviruses to be tumor selective with minimal toxicity toward normal tissue. The virus ONYX-015, in which the gene encoding the early region 1B 55-kDa (E1B-55K) protein is deleted, has been most effective when used in combination with either chemotherapy or radiation therapy. Therefore, improving the oncolytic nature of tumor-selective adenoviruses remains an important objective for improving this form of cancer therapy. Cells infected during the G1 phase of the cell cycle with the E1B-55K deletion mutant virus exhibit a reduced rate of viral late protein synthesis, produce fewer viral progeny, and are less efficiently killed than cells infected during the S phase. Here we demonstrate that the G1 restriction imposed on the E1B-55K deletion mutant virus is due to the viral oncogene encoded by open reading frame 1 of early region 4 (E4orf1). E4orf1 has been reported to signal through the phosphatidylinositol 3′-kinase pathway leading to the activation of Akt, mTOR, and p70 S6K. Evidence presented here shows that E4orf1 may also induce the phosphorylation of Akt and p70 S6K in a manner that depends on Rac1 and its guanine nucleotide exchange factor Tiam1. Accordingly, agents that have been reported to disrupt the Tiam1-Rac1 interaction or to prevent phosphorylation of the ribosomal S6 kinase partially alleviated the E4orf1 restriction to late viral protein synthesis and enhanced tumor cell killing by the E1B-55K mutant virus. These results demonstrate that E4orf1 limits the oncolytic nature of a conditionally replicating adenovirus such as ONYX-015. The therapeutic value of similar oncolytic adenoviruses may be improved by abrogating E4orf1 function. PMID:19129452

E4orf1 limits the oncolytic potential of the E1B-55K deletion mutant adenovirus.

Science.gov (United States)

Thomas, Michael A; Broughton, Robin S; Goodrum, Felicia D; Ornelles, David A

2009-03-01

Clinical trials have shown oncolytic adenoviruses to be tumor selective with minimal toxicity toward normal tissue. The virus ONYX-015, in which the gene encoding the early region 1B 55-kDa (E1B-55K) protein is deleted, has been most effective when used in combination with either chemotherapy or radiation therapy. Therefore, improving the oncolytic nature of tumor-selective adenoviruses remains an important objective for improving this form of cancer therapy. Cells infected during the G(1) phase of the cell cycle with the E1B-55K deletion mutant virus exhibit a reduced rate of viral late protein synthesis, produce fewer viral progeny, and are less efficiently killed than cells infected during the S phase. Here we demonstrate that the G(1) restriction imposed on the E1B-55K deletion mutant virus is due to the viral oncogene encoded by open reading frame 1 of early region 4 (E4orf1). E4orf1 has been reported to signal through the phosphatidylinositol 3'-kinase pathway leading to the activation of Akt, mTOR, and p70 S6K. Evidence presented here shows that E4orf1 may also induce the phosphorylation of Akt and p70 S6K in a manner that depends on Rac1 and its guanine nucleotide exchange factor Tiam1. Accordingly, agents that have been reported to disrupt the Tiam1-Rac1 interaction or to prevent phosphorylation of the ribosomal S6 kinase partially alleviated the E4orf1 restriction to late viral protein synthesis and enhanced tumor cell killing by the E1B-55K mutant virus. These results demonstrate that E4orf1 limits the oncolytic nature of a conditionally replicating adenovirus such as ONYX-015. The therapeutic value of similar oncolytic adenoviruses may be improved by abrogating E4orf1 function.

Using Targeted Virotherapy to Treat a Resistant Ewing Sarcoma Model: From the Bedside to the Bench and Back

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Hesham Abdelbary

2014-01-01

Full Text Available Metastatic Ewing sarcoma (EWS is often resistant to current multimodal chemotherapeutic regimens. Oncolytic virus therapy (OV is a novel therapeutic platform whereby viruses can selectively infect as well as replicate in and kill tumor cells, while sparing normal tissues. The purpose of this study is to investigate the efficacy of the biotherapeutic oncolytic agent, vesicular stomatitis virus (VSVΔM51, to kill EWS cells that are resistant to conventional therapy. Our hypothesis is that systemic delivery of VSVΔM51 can demonstrate tumor-specific killing of resistant EWS cells, as well as a significant decrease of tumor burden in EWS bearing mice. Methods. A biopsy sample was obtained from a patient with metastatic EWS and was used to establish a novel EWS cell line. In vitro assays evaluated the oncolytic effect of vesicular stomatitis virus (VSVΔM51 on this cell line. EWS xenograft mice model bearing either lung or subcutaneous tumors was established to evaluate the antitumor specific oncolytic effect of VSVΔM51 after local and systemic delivery. Results. The established EWS cell line shared similar molecular and genetic traits to the patient’s original tumor specimen. VSVΔM51 effectively infected and killed EWS cells in vitro. In vivo, VSVΔM51 selectively infected and killed EWS and led to significant delay in tumor growth. Conclusion. This study has been designed to implement a translational link between the bedside and the bench, where a specific challenging clinical scenario guided this basic science research. This research demonstrated that a sarcoma, which is resistant to current conventional standard therapies, is still susceptible to an alternative therapeutic platform, such as OV. Adding OV to the armamentarium of sarcoma treatment can enhance the future therapeutic approach towards these cancer patients.

Showing the Way: Oncolytic Adenoviruses as Chaperones of Immunostimulatory Adjuncts

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Jing Li Huang

2016-09-01

Full Text Available Oncolytic adenoviruses (OAds are increasingly recognized as vectors for immunotherapy in the treatment of various solid tumors. The myriads of advantages of using adenovirus include targeted specificity upon infection and selective replication, which lead to localized viral burst, exponential spread of OAds, and antitumor effect. OAds can also induce a strong immune reaction due to the massive release of tumor antigens upon cytolysis and the presence of viral antigens. This review will highlight recent advances in adenoviral vectors expressing immunostimulatory effectors, such as GM-CSF (granulocyte macrophage colony-stimulating factor, interferon-α, interleukin-12, and CD40L. We will also discuss the combination of OAds with other immunotherapeutic strategies and describe the current understanding of how adenoviral vectors interact with the immune system to eliminate cancer cells.

Showing the Way: Oncolytic Adenoviruses as Chaperones of Immunostimulatory Adjuncts.

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Huang, Jing Li; LaRocca, Christopher J; Yamamoto, Masato

2016-09-19

Oncolytic adenoviruses (OAds) are increasingly recognized as vectors for immunotherapy in the treatment of various solid tumors. The myriads of advantages of using adenovirus include targeted specificity upon infection and selective replication, which lead to localized viral burst, exponential spread of OAds, and antitumor effect. OAds can also induce a strong immune reaction due to the massive release of tumor antigens upon cytolysis and the presence of viral antigens. This review will highlight recent advances in adenoviral vectors expressing immunostimulatory effectors, such as GM-CSF (granulocyte macrophage colony-stimulating factor), interferon-α, interleukin-12, and CD40L. We will also discuss the combination of OAds with other immunotherapeutic strategies and describe the current understanding of how adenoviral vectors interact with the immune system to eliminate cancer cells.

Improvement of oncolytic adenovirus vectors through genetic capsid modifications

NARCIS (Netherlands)

Vrij, Jeroen de

2012-01-01

Recombinant viral vectors hold great promise in the field of cancer gene therapy. While a plethora of viruses is being evaluated as oncolytic agents, human adenoviruses of serotype 5 (HAdV-5) are among the most popular of viruses to be developed. Although clinical studies have demonstrated safety of

Recent advances in genetic modification of adenovirus vectors for cancer treatment.

Science.gov (United States)

Yamamoto, Yuki; Nagasato, Masaki; Yoshida, Teruhiko; Aoki, Kazunori

2017-05-01

Adenoviruses are widely used to deliver genes to a variety of cell types and have been used in a number of clinical trials for gene therapy and oncolytic virotherapy. However, several concerns must be addressed for the clinical use of adenovirus vectors. Selective delivery of a therapeutic gene by adenovirus vectors to target cancer is precluded by the widespread distribution of the primary cellular receptors. The systemic administration of adenoviruses results in hepatic tropism independent of the primary receptors. Adenoviruses induce strong innate and acquired immunity in vivo. Furthermore, several modifications to these vectors are necessary to enhance their oncolytic activity and ensure patient safety. As such, the adenovirus genome has been engineered to overcome these problems. The first part of the present review outlines recent progress in the genetic modification of adenovirus vectors for cancer treatment. In addition, several groups have recently developed cancer-targeting adenovirus vectors by using libraries that display random peptides on a fiber knob. Pancreatic cancer-targeting sequences have been isolated, and these oncolytic vectors have been shown by our group to be associated with a higher gene transduction efficiency and more potent oncolytic activity in cell lines, murine models, and surgical specimens of pancreatic cancer. In the second part of this review, we explain that combining cancer-targeting strategies can be a promising approach to increase the clinical usefulness of oncolytic adenovirus vectors. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Safety studies on intravenous administration of oncolytic recombinant vesicular stomatitis virus in purpose-bred beagle dogs.

Science.gov (United States)

LeBlanc, Amy K; Naik, Shruthi; Galyon, Gina D; Jenks, Nathan; Steele, Mike; Peng, Kah-Whye; Federspiel, Mark J; Donnell, Robert; Russell, Stephen J

2013-12-01

VSV-IFNβ-NIS is a novel recombinant oncolytic vesicular stomatitis virus (VSV) with documented efficacy and safety in preclinical murine models of cancer. To facilitate clinical translation of this promising oncolytic therapy in patients with disseminated cancer, we are utilizing a comparative oncology approach to gather data describing the safety and efficacy of systemic VSV-IFNβ-NIS administration in dogs with naturally occurring cancer. In support of this, we executed a dose-escalation study in purpose-bred dogs to determine the maximum tolerated dose (MTD) of systemic VSV-hIFNβ-NIS, characterize the adverse event profile, and describe routes and duration of viral shedding in healthy, immune-competent dogs. The data indicate that an intravenous dose of 10(10) TCID50 is well tolerated in dogs. Expected adverse events were mild to moderate fever, self-limiting nausea and vomiting, lymphopenia, and oral mucosal lesions. Unexpected adverse events included prolongation of partial thromboplastin time, development of bacterial urinary tract infection, and scrotal dermatitis, and in one dog receiving 10(11) TCID50 (10 × the MTD), the development of severe hepatotoxicity and symptoms of shock leading to euthanasia. Viral shedding data indicate that detectable viral genome in blood diminishes rapidly with anti-VSV neutralizing antibodies detectable in blood as early as day 5 postintravenous virus administration. While low levels of viral genome copies were detectable in plasma, urine, and buccal swabs of dogs treated at the MTD, no infectious virus was detectable in plasma, urine, or buccal swabs at any of the doses tested. These studies confirm that VSV can be safely administered systemically in dogs, justifying the use of oncolytic VSV as a novel therapy for the treatment of canine cancer.

Differential biodistribution of oncolytic poxvirus administered systemically in an autochthonous model of hepatocellular carcinoma.

Science.gov (United States)

Baril, Patrick; Touchefeu, Yann; Cany, Jeannette; Cherel, Yan; Thorne, Steve H; Tran, Lucile; Conchon, Sophie; Vassaux, Georges

2011-12-01

Preclinical studies have demonstrated that, unlike oncolytic adenoviruses, oncolytic vaccinia viruses can reach implanted tumors upon systemic injection. However, the biodistribution of this oncolytic agent in in situ autochthonous tumor models remains poorly characterized. In the present study, we assessed this biodistribution in a model of mouse hepatocellular carcinoma (HCC) obtained after injection of the carcinogen diethylnitrosamine (DEN). Twelve months after DEN administration, histology, quantitative reverse transcription-polymerase chain reaction, in situ hybridization and viral titration were used to characterize tumors, as well as to assess the viral load of the livers upon either intravenous or intraperitoineal injection. The results obtained showed that the architecture of the liver was lost, with a noticeable absence of sinusoids, as well as the presence of steatosis and α-fetoprotein-positive HCC tumor nodules. Bioluminescence imaging and measures of the infective virus load demonstrated that intravenous injection of 10(8)  plaque-forming units of the recombinant vaccinia virus led to a predominant transduction of the liver, whereas intraperitoneal injection resulted in a lower level of liver transduction accompanied by an increased infection of the lungs, spleen, kidneys and bowels. Immunohistochemical analysis of liver sections of animals injected intravenously with the virus revealed a preferential localization of vaccinia-specific immunoreactivity in the tumors. The findings of the present study emphasize the importance of the route of administration of the vector and highlight the relevance of systemic injection of oncolytic vaccinia virus in the context of hepatocellular carcinoma. Copyright © 2011 John Wiley & Sons, Ltd.

Oncorine, the World First Oncolytic Virus Medicine and its Update in China.

Science.gov (United States)

Liang, Min

2018-01-01

The oncolytic viruses now hold a promise of new therapeutic strategy for cancer. Its concept has inspired a wave of commercial research and development activities for the products of this category in China since 1998. The first commercialized oncolytic virus product in the world, Oncorine (H101), developed by Shanghai Sunway Biotech Co., Ltd since 1999, was approved by Chinese SFDA in November, 2005 for nasopharyngeal carcinoma in combination with chemotherapy after the phase III clinical trial, and finally acquired GMP certificate in August, 2006. This review introduces how Oncorine was successfully developed in China, and how the Chinese market responded after it was launched into the market in 2006. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

ONCOLYTIC VIRUS-MEDIATED REVERSAL OF IMPAIRED TUMOR ANTIGEN PRESENTATION

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Shashi Ashok Gujar

2014-04-01

Full Text Available Anti-tumor immunity can eliminate existing cancer cells and also maintain a constant surveillance against possible relapse. Such an antigen-specific adaptive response begins when tumor-specific T cells become activated. T cell activation requires two signals on antigen presenting cells (APCs: antigen presentation through MHC molecules and co-stimulation. In the absence of one or both of these signals, T cells remain inactivated or can even become tolerized. Cancer cells and their associated microenvironment strategically hinder the processing and presentation of tumor antigens and consequently prevent the development of anti-tumor immunity. Many studies, however, demonstrate that interventions that overturn tumor-associated immune evasion mechanisms can establish anti-tumor immune responses of therapeutic potential. One such intervention is oncolytic virus (OV-based anti-cancer therapy. Here we discuss how OV-induced immunological events override tumor-associated antigen presentation impairment and promote appropriate T cell:APC interaction. Detailed understanding of this phenomenon is pivotal for devising the strategies that will enhance the efficacy of OV-based anti-cancer therapy by complementing its inherent oncolytic

Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus.

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Yonatan Y Mahller

Full Text Available Although disease remission can frequently be achieved for patients with neuroblastoma, relapse is common. The cancer stem cell theory suggests that rare tumorigenic cells, resistant to conventional therapy, are responsible for relapse. If true for neuroblastoma, improved cure rates may only be achieved via identification and therapeutic targeting of the neuroblastoma tumor initiating cell. Based on cues from normal stem cells, evidence for tumor populating progenitor cells has been found in a variety of cancers.Four of eight human neuroblastoma cell lines formed tumorspheres in neural stem cell media, and all contained some cells that expressed neurogenic stem cell markers including CD133, ABCG2, and nestin. Three lines tested could be induced into multi-lineage differentiation. LA-N-5 spheres were further studied and showed a verapamil-sensitive side population, relative resistance to doxorubicin, and CD133+ cells showed increased sphere formation and tumorigenicity. Oncolytic viruses, engineered to be clinically safe by genetic mutation, are emerging as next generation anticancer therapeutics. Because oncolytic viruses circumvent typical drug-resistance mechanisms, they may represent an effective therapy for chemotherapy-resistant tumor initiating cells. A Nestin-targeted oncolytic herpes simplex virus efficiently replicated within and killed neuroblastoma tumor initiating cells preventing their ability to form tumors in athymic nude mice.These results suggest that human neuroblastoma contains tumor initiating cells that may be effectively targeted by an oncolytic virus.

Expression of RNA interference triggers from an oncolytic herpes simplex virus results in specific silencing in tumour cells in vitro and tumours in vivo

International Nuclear Information System (INIS)

Anesti, Anna-Maria; Simpson, Guy R; Price, Toby; Pandha, Hardev S; Coffin, Robert S

2010-01-01

Delivery of small interfering RNA (siRNA) to tumours remains a major obstacle for the development of RNA interference (RNAi)-based therapeutics. Following the promising pre-clinical and clinical results with the oncolytic herpes simplex virus (HSV) OncoVEX GM-CSF , we aimed to express RNAi triggers from oncolytic HSV, which although has the potential to improve treatment by silencing tumour-related genes, was not considered possible due to the highly oncolytic properties of HSV. To evaluate RNAi-mediated silencing from an oncolytic HSV backbone, we developed novel replicating HSV vectors expressing short-hairpin RNA (shRNA) or artificial microRNA (miRNA) against the reporter genes green fluorescent protein (eGFP) and β-galactosidase (lacZ). These vectors were tested in non-tumour cell lines in vitro and tumour cells that are moderately susceptible to HSV infection both in vitro and in mice xenografts in vivo. Silencing was assessed at the protein level by fluorescent microscopy, x-gal staining, enzyme activity assay, and western blotting. Our results demonstrate that it is possible to express shRNA and artificial miRNA from an oncolytic HSV backbone, which had not been previously investigated. Furthermore, oncolytic HSV-mediated delivery of RNAi triggers resulted in effective and specific silencing of targeted genes in tumour cells in vitro and tumours in vivo, with the viruses expressing artificial miRNA being comprehensibly more effective. This preliminary data provide the first demonstration of oncolytic HSV-mediated expression of shRNA or artificial miRNA and silencing of targeted genes in tumour cells in vitro and in vivo. The vectors developed in this study are being adapted to silence tumour-related genes in an ongoing study that aims to improve the effectiveness of oncolytic HSV treatment in tumours that are moderately susceptible to HSV infection and thus, potentially improve response rates seen in human clinical trials

A Potent Oncolytic Herpes Simplex Virus for Therapy of Advanced Prostate Cancer

National Research Council Canada - National Science Library

Zhang, Xiaoliu

2005-01-01

... only. Therefore fusogenic oncolytic HSV should be no more toxic than its parental construct. Nonetheless, we proposed in the year 2 of this funded project to conduct extensive studies in animal models...

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

Energy Technology Data Exchange (ETDEWEB)

Merron, Andrew; McNeish, Iain A. [Queen Mary' s School of Medicine and Dentistry, Centre for Molecular Oncology, Institute of Cancer, London (United Kingdom); Baril, Patrick; Tran, Lucile; Vassaux, Georges [CHU Hotel Dieu, INSERM, Nantes (France); CHU de Nantes, Institut des Maladies de l' Appareil Digestif, Nantes (France); Martin-Duque, Pilar [Instituto Aragones de Ciencias de la Salud, Zaragoza (Spain); Vieja, Antonio de la [Instituto de Investigaciones Biomedicas, Madrid (Spain); Briat, Arnaud [INSERM U877, Grenoble (France); Harrington, Kevin J. [Chester Beatty Laboratories, Institute of Cancer Research, London (United Kingdom)

2010-07-15

In vivo imaging of the spread of oncolytic viruses using the Na/I symporter (NIS) has been proposed. Here, we assessed whether the presence of NIS in the viral genome affects the therapeutic efficacy of the oncolytic adenovirus dl922-947 following intraperitoneal administration, in a mouse model of peritoneal ovarian carcinoma. We generated AdAM7, a dl922-947 oncolytic adenovirus encoding the NIS coding sequence. Iodide uptake, NIS expression, infectivity and cell-killing activity of AdAM7, as well as that of relevant controls, were determined in vitro. In vivo, the propagation of this virus in the peritoneal cavity of tumour-bearing mice was determined using SPECT/CT imaging and its therapeutic efficacy was evaluated. In vitro infection of ovarian carcinoma IGROV-1 cells with ADAM7 led to functional expression of NIS. However, the insertion of NIS into the viral genome resulted in a loss of efficacy of the virus in terms of replication and cytotoxicity. In vivo, on SPECT/CT imaging AdAM7 was only detectable in the peritoneal cavity of animals bearing peritoneal ovarian tumours for up to 5 days after intraperitoneal administration. Therapeutic experiments in vivo demonstrated that AdAM7 is as potent as its NIS-negative counterpart. 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. (orig.)

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

International Nuclear Information System (INIS)

Merron, Andrew; McNeish, Iain A.; Baril, Patrick; Tran, Lucile; Vassaux, Georges; Martin-Duque, Pilar; Vieja, Antonio de la; Briat, Arnaud; Harrington, Kevin J.

2010-01-01

In vivo imaging of the spread of oncolytic viruses using the Na/I symporter (NIS) has been proposed. Here, we assessed whether the presence of NIS in the viral genome affects the therapeutic efficacy of the oncolytic adenovirus dl922-947 following intraperitoneal administration, in a mouse model of peritoneal ovarian carcinoma. We generated AdAM7, a dl922-947 oncolytic adenovirus encoding the NIS coding sequence. Iodide uptake, NIS expression, infectivity and cell-killing activity of AdAM7, as well as that of relevant controls, were determined in vitro. In vivo, the propagation of this virus in the peritoneal cavity of tumour-bearing mice was determined using SPECT/CT imaging and its therapeutic efficacy was evaluated. In vitro infection of ovarian carcinoma IGROV-1 cells with ADAM7 led to functional expression of NIS. However, the insertion of NIS into the viral genome resulted in a loss of efficacy of the virus in terms of replication and cytotoxicity. In vivo, on SPECT/CT imaging AdAM7 was only detectable in the peritoneal cavity of animals bearing peritoneal ovarian tumours for up to 5 days after intraperitoneal administration. Therapeutic experiments in vivo demonstrated that AdAM7 is as potent as its NIS-negative counterpart. 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. (orig.)

A Fusogenic Oncolytic Herpes Simplex Virus for Therapy of Advanced Ovarian Cancer

National Research Council Canada - National Science Library

Zhang, Xiaoliu

2004-01-01

The tasks that were originally planned for the first year of this 3 year project are to demonstrate that the fusogenic oncolytic herpes simplex viruses are potent anti-tumor agents for advanced ovarian cancer...

High titer oncolytic measles virus production process by integration of dielectric spectroscopy as online monitoring system.

Science.gov (United States)

Grein, Tanja A; Loewe, Daniel; Dieken, Hauke; Salzig, Denise; Weidner, Tobias; Czermak, Peter

2018-05-01

Oncolytic viruses offer new hope to millions of patients with incurable cancer. One promising class of oncolytic viruses is Measles virus, but its broad administration to cancer patients is currently hampered by the inability to produce the large amounts of virus needed for treatment (10 10 -10 12 virus particles per dose). Measles virus is unstable, leading to very low virus titers during production. The time of infection and time of harvest are therefore critical parameters in a Measles virus production process, and their optimization requires an accurate online monitoring system. We integrated a probe based on dielectric spectroscopy (DS) into a stirred tank reactor to characterize the Measles virus production process in adherent growing Vero cells. We found that DS could be used to monitor cell adhesion on the microcarrier and that the optimal virus harvest time correlated with the global maximum permittivity signal. In 16 independent bioreactor runs, the maximum Measles virus titer was achieved approximately 40 hr after the permittivity maximum. Compared to an uncontrolled Measles virus production process, the integration of DS increased the maximum virus concentration by more than three orders of magnitude. This was sufficient to achieve an active Measles virus concentration of > 10 10 TCID 50 ml -1 . © 2017 Wiley Periodicals, Inc.

A Potent Oncolytic Herpes Simplex Virus for the Therapy of Advanced Prostate

National Research Council Canada - National Science Library

Zhang, Xiaoliu

2006-01-01

.... WE PROPOSED IN THE AIM 3 OF THIS FUNDED PROJECT TO ADDRESS THIS ISSUE WITH TWO STRATEGIES: 1) TO DELIVER ONCOLYTIC HSVS THROUGH LIPOSOME-FORMULATED VIRAL DNA INSTEAD OF THE TRADITIONAL VIRAL PARTICLES AND 2...

uPAR-controlled oncolytic adenoviruses eliminate cancer stem cells in human pancreatic tumors.

Science.gov (United States)

Sobrevals, Luciano; Mato-Berciano, Ana; Urtasun, Nerea; Mazo, Adela; Fillat, Cristina

2014-01-01

Pancreatic tumors contain cancer stem cells highly resistant to chemotherapy. The identification of therapies that can eliminate this population of cells might provide with more effective treatments. In the current work we evaluated the potential of oncolytic adenoviruses to act against pancreatic cancer stem cells (PCSC). PCSC from two patient-derived xenograft models were isolated from orthotopic pancreatic tumors treated with saline, or with the chemotherapeutic agent gemcitabine. An enrichment in the number of PCSC expressing the cell surface marker CD133 and a marked enhancement on tumorsphere formation was observed in gemcitabine treated tumors. No significant increase in the CD44, CD24, and epithelial-specific antigen (ESA) positive cells was observed. Neoplastic sphere-forming cells were susceptible to adenoviral infection and exposure to oncolytic adenoviruses resulted in elevated cytotoxicity with both Adwt and the tumor specific AduPARE1A adenovirus. In vivo, intravenous administration of a single dose of AduPARE1A in human-derived pancreatic xenografts led to a remarkable anti-tumor effect. In contrast to gemcitabine AduPARE1A treatment did not result in PCSC enrichment. No enrichment on tumorspheres neither on the CD133(+) population was detected. Therefore our data provide evidences of the relevance of uPAR-controlled oncolytic adenoviruses for the elimination of pancreatic cancer stem cells. © 2013.

Targeting Poxvirus Decapping Enzymes and mRNA Decay to Generate an Effective Oncolytic Virus

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Hannah Burgess

2018-03-01

Full Text Available Through the action of two virus-encoded decapping enzymes (D9 and D10 that remove protective caps from mRNA 5′-termini, Vaccinia virus (VACV accelerates mRNA decay and limits activation of host defenses. D9- or D10-deficient VACV are markedly attenuated in mice and fail to counter cellular double-stranded RNA-responsive innate immune effectors, including PKR. Here, we capitalize upon this phenotype and demonstrate that VACV deficient in either decapping enzyme are effective oncolytic viruses. Significantly, D9- or D10-deficient VACV displayed anti-tumor activity against syngeneic mouse tumors of different genetic backgrounds and human hepatocellular carcinoma xenografts. Furthermore, D9- and D10-deficient VACV hyperactivated the host anti-viral enzyme PKR in non-tumorigenic cells compared to wild-type virus. This establishes a new genetic platform for oncolytic VACV development that is deficient for a major pathogenesis determinant while retaining viral genes that support robust productive replication like those required for nucleotide metabolism. It further demonstrates how VACV mutants unable to execute a fundamental step in virus-induced mRNA decay can be unexpectedly translated into a powerful anti-tumor therapy. Keywords: oncolytic virus, mRNA decay, decapping

Tumour necrosis factor-alpha-induced protein 8 (TNFAIP8) expression associated with cell survival and death in cancer cell lines infected with canine distemper virus.

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Garcia, J A; Ferreira, H L; Vieira, F V; Gameiro, R; Andrade, A L; Eugênio, F R; Flores, E F; Cardoso, T C

2017-06-01

Oncolytic virotherapy is a novel strategy for treatment of cancer in humans and companion animals as well. Canine distemper virus (CDV), a paramyxovirus, has proven to be oncolytic through induction of apoptosis in canine-derived tumour cells, yet the mechanism behind this inhibitory action is poorly understood. In this study, three human mammary tumour cell lines and one canine-derived adenofibrosarcoma cell line were tested regarding to their susceptibility to CDV infection, cell proliferation, apoptosis, mitochondrial membrane potential and expression of tumour necrosis factor-alpha-induced protein 8 (TNFAIP8). CDV replication-induced cytopathic effect, decrease of cell proliferation rates, and >45% of infected cells were considered death and/or under late apoptosis/necrosis. TNFAIP8 and CDVM gene expression were positively correlated in all cell lines. In addition, mitochondrial membrane depolarization was associated with increase in virus titres (p < 0.005). Thus, these results strongly suggest that both human and canine mammary tumour cells are potential candidates for studies concerning CDV-induced cancer therapy. © 2015 John Wiley & Sons Ltd.

A double-regulated oncolytic adenovirus with improved safety for adenocarcinoma therapy

International Nuclear Information System (INIS)

Wei, Na; Fan, Jun Kai; Gu, Jin Fa; He, Ling Feng; Tang, Wen Hao; Cao, Xin; Liu, Xin Yuan

2009-01-01

Safety and efficiency are equally important to be considered in developing oncolytic adenovirus. Previously, we have reported that ZD55, an oncolytic adenovirus with the deletion of E1B-55K gene, exhibited potent antitumor activity. In this study, to improve the safety of ZD55, we utilized MUC1 promoter to replace the native promoter of E1A on the basis of ZD55, and generated a double-regulated adenovirus, named MUD55. Our data demonstrated that the expression of early and late genes of MUD55 was both reduced in MUC1-negative cells, resulting in its stricter glandular-tumor selective progeny production. The cytopathic effect of MUD55 was about 10-fold lower than mono-regulated adenovirus ZD55 or Ad.MUC1 in normal cells and not obviously attenuated in glandular tumor cells. Moreover, MUD55 showed the least liver toxicity when administrated by intravenous injection in nude mice. These results indicate that MUD55 could be a promising candidate for the treatment of adenocarcinoma.

Mechanisms of cell death in canine parvovirus-infected cells provide intuitive insights to developing nanotools for medicine

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Jonna Nykky

2010-06-01

Full Text Available Jonna Nykky, Jenni E Tuusa, Sanna Kirjavainen, Matti Vuento, Leona GilbertNanoscience Center and Department of Biological and Environmental Science, University of Jyväskylä, FinlandAbstract: Viruses have great potential as nanotools in medicine for gene transfer, targeted gene delivery, and oncolytic cancer virotherapy. Here we have studied cell death mechanisms of canine parvovirus (CPV to increase the knowledge on the CPV life cycle in order to facilitate the development of better parvovirus vectors. Morphological studies of CPV-infected Norden laboratory feline kidney (NLFK cells and canine fibroma cells (A72 displayed characteristic apoptotic events. Apoptosis was further confirmed by activation of caspases and cellular DNA damage. However, results from annexin V-propidium iodide (PI labeling and membrane polarization assays indicated disruption of the plasma membrane uncommon to apoptosis. These results provide evidence that secondary necrosis followed apoptosis. In addition, two human cancer cell lines were found to be infected by CPV. This necrotic event over apoptotic cell death and infection in human cells provide insightful information when developing CPV as a nanotool for cancer treatments.Keywords: canine parvovirus, apoptosis, necrosis, nanoparticle, virotherapy

Oncolytic vaccinia therapy of squamous cell carcinoma

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Yu Yong A

2009-07-01

Full Text Available Abstract Background Novel therapies are necessary to improve outcomes for patients with squamous cell carcinomas (SCC of the head and neck. Historically, vaccinia virus was administered widely to humans as a vaccine and led to the eradication of smallpox. We examined the therapeutic effects of an attenuated, replication-competent vaccinia virus (GLV-1h68 as an oncolytic agent against a panel of six human head and neck SCC cell lines. Results All six cell lines supported viral transgene expression (β-galactosidase, green fluorescent protein, and luciferase as early as 6 hours after viral exposure. Efficient transgene expression and viral replication (>150-fold titer increase over 72 hrs were observed in four of the cell lines. At a multiplicity of infection (MOI of 1, GLV-1h68 was highly cytotoxic to the four cell lines, resulting in ≥ 90% cytotoxicity over 6 days, and the remaining two cell lines exhibited >45% cytotoxicity. Even at a very low MOI of 0.01, three cell lines still demonstrated >60% cell death over 6 days. A single injection of GLV-1h68 (5 × 106 pfu intratumorally into MSKQLL2 xenografts in mice exhibited localized intratumoral luciferase activity peaking at days 2–4, with gradual resolution over 10 days and no evidence of spread to normal organs. Treated animals exhibited near-complete tumor regression over a 24-day period without any observed toxicity, while control animals demonstrated rapid tumor progression. Conclusion These results demonstrate significant oncolytic efficacy by an attenuated vaccinia virus for infecting and lysing head and neck SCC both in vitro and in vivo, and support its continued investigation in future clinical trials.

Oncolytic Vesicular Stomatitis Virus as a Viro-Immunotherapy: Defeating Cancer with a “Hammer” and “Anvil”

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Michael Karl Melzer

2017-02-01

Full Text Available Oncolytic viruses have gained much attention in recent years, due, not only to their ability to selectively replicate in and lyse tumor cells, but to their potential to stimulate antitumor immune responses directed against the tumor. Vesicular stomatitis virus (VSV, a negative-strand RNA virus, is under intense development as an oncolytic virus due to a variety of favorable properties, including its rapid replication kinetics, inherent tumor specificity, and its potential to elicit a broad range of immunomodulatory responses to break immune tolerance in the tumor microenvironment. Based on this powerful platform, a multitude of strategies have been applied to further improve the immune-stimulating potential of VSV and synergize these responses with the direct oncolytic effect. These strategies include: 1. modification of endogenous virus genes to stimulate interferon induction; 2. virus-mediated expression of cytokines or immune-stimulatory molecules to enhance anti-tumor immune responses; 3. vaccination approaches to stimulate adaptive immune responses against a tumor antigen; 4. combination with adoptive immune cell therapy for potentially synergistic therapeutic responses. A summary of these approaches will be presented in this review.

Generation of an adenovirus-parvovirus chimera with enhanced oncolytic potential.

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El-Andaloussi, Nazim; Bonifati, Serena; Kaufmann, Johanna K; Mailly, Laurent; Daeffler, Laurent; Deryckère, François; Nettelbeck, Dirk M; Rommelaere, Jean; Marchini, Antonio

2012-10-01

In this study, our goal was to generate a chimeric adenovirus-parvovirus (Ad-PV) vector that combines the high-titer and efficient gene transfer of adenovirus with the anticancer potential of rodent parvovirus. To this end, the entire oncolytic PV genome was inserted into a replication-defective E1- and E3-deleted Ad5 vector genome. As we found that parvoviral NS expression inhibited Ad-PV chimera production, we engineered the parvoviral P4 early promoter, which governs NS expression, by inserting into its sequence tetracycline operator elements. As a result of these modifications, P4-driven expression was blocked in the packaging T-REx-293 cells, which constitutively express the tetracycline repressor, allowing high-yield chimera production. The chimera effectively delivered the PV genome into cancer cells, from which fully infectious replication-competent parvovirus particles were generated. Remarkably, the Ad-PV chimera exerted stronger cytotoxic activities against various cancer cell lines, compared with the PV and Ad parental viruses, while being still innocuous to a panel of tested healthy primary human cells. This Ad-PV chimera represents a novel versatile anticancer agent which can be subjected to further genetic manipulations in order to reinforce its enhanced oncolytic capacity through arming with transgenes or retargeting into tumor cells.

77 FR 22333 - Prospective Grant of Exclusive License: Development of Oncolytic Viral Cancer Therapies

Science.gov (United States)

2012-04-13

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Prospective Grant of Exclusive License: Development of Oncolytic Viral Cancer Therapies AGENCY: National Institutes of Health... administration of the recombinant virus to a human or animal subject, the foreign gene is expressed in vivo to...

Attenuated, oncolytic, but not wild-type measles virus infection has pleiotropic effects on human neutrophil function.

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Zhang, Yu; Patel, Bella; Dey, Aditi; Ghorani, Ehsan; Rai, Lena; Elham, Mohammed; Castleton, Anna Z; Fielding, Adele K

2012-02-01

We previously showed that neutrophils play a role in regression of human tumor xenografts in immunodeficient mice following oncolytic vaccine measles virus (MV-Vac) treatment. In this study, we sought, using normal human neutrophils, to identify potential neutrophil-mediated mechanisms for the attenuated MV-Vac induced effects seen in vivo, by comparison with those consequent on wild-type (WT-MV) infection. Both MV-Vac and WT-MV infected and replicated within neutrophils, despite lack of SLAM expression. In both cases, neutrophils survived longer ex vivo postinfection. Furthermore, MV-Vac (but not WT-MV) infection activated neutrophils and stimulated secretion of several specific antitumor cytokines (IL-8, TNF-α, MCP-1, and IFN-α) via induction of de novo RNA and protein synthesis. In addition, MV-Vac (but not WT-MV) infection caused TRAIL secretion in the absence of de novo synthesis by triggering release of prefabricated TRAIL, via a direct effect upon degranulation. The differences between the outcome of infection by MV-Vac and WT-MV were not entirely explained by differential infection and replication of the viruses within neutrophils. To our knowledge, this is the first demonstration of potential mechanisms of oncolytic activity of an attenuated MV as compared with its WT parent. Furthermore, our study suggests that neutrophils have an important role to play in the antitumor effects of oncolytic MV.

Oncolytic Maraba Virus MG1 as a Treatment for Sarcoma.

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Le Boeuf, Fabrice; Selman, Mohammed; Son, Hwan Hee; Bergeron, Anabel; Chen, Andrew; Tsang, Jovian; Butterwick, Derek; Arulanandam, Rozanne; Forbes, Nicole E; Tzelepis, Fanny; Bell, John C; Werier, Joel; Abdelbary, Hesham; Diallo, Jean-Simon

2017-09-15

The poor prognosis of patients with advanced bone and soft-tissue sarcoma has not changed in the past several decades, highlighting the necessity for new therapeutic approaches. Immunotherapies, including oncolytic viral (OV) therapy, have shown great promise in a number of clinical trials for a variety of tumor types. However, the effective application of OV in treating sarcoma still remains to be demonstrated. Although few pre-clinical studies using distinct OVs have been performed and demonstrated therapeutic benefit in sarcoma models, a side-by-side comparison of clinically relevant OV platforms has not been performed. Four clinically relevant OV platforms (Reovirus, Vaccinia virus, Herpes-simplex virus and Rhabdovirus) were screened for their ability to infect and kill human and canine sarcoma cell lines in vitro, and human sarcoma specimens ex vivo. In vivo treatment efficacy was tested in a murine model. The rhabdovirus MG1 demonstrated the highest potency in vitro. Ex vivo, MG1 productively infected more than 80% of human sarcoma tissues tested, and treatment in vivo led to a significant increase in long-lasting cures in sarcoma-bearing mice. Importantly, MG1 treatment induced the generation of memory immune response that provided protection against a subsequent tumor challenge. This study opens the door for the use of MG1-based oncolytic immunotherapy strategies as treatment for sarcoma or as a component of a combined therapy. © 2017 UICC.

Oncolytic viruses in head and neck cancer: a new ray of hope in the ...

African Journals Online (AJOL)

This paper intends to highlight the different types of oncolytic viruses (OVs), mechanism of tumor specificity, its safety, and various obstacles in the design of treatment and combination therapy utilizing oncotherapy. Search was conducted using the internet‑based search engines and scholarly bibliographic databases with ...

High-throughput screening to enhance oncolytic virus immunotherapy

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Allan KJ

2016-04-01

Full Text Available KJ Allan,1,2 David F Stojdl,1–3 SL Swift1 1Children’s Hospital of Eastern Ontario (CHEO Research Institute, 2Department of Biology, Microbiology and Immunology, 3Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada Abstract: High-throughput screens can rapidly scan and capture large amounts of information across multiple biological parameters. Although many screens have been designed to uncover potential new therapeutic targets capable of crippling viruses that cause disease, there have been relatively few directed at improving the efficacy of viruses that are used to treat disease. Oncolytic viruses (OVs are biotherapeutic agents with an inherent specificity for treating malignant disease. Certain OV platforms – including those based on herpes simplex virus, reovirus, and vaccinia virus – have shown success against solid tumors in advanced clinical trials. Yet, many of these OVs have only undergone minimal engineering to solidify tumor specificity, with few extra modifications to manipulate additional factors. Several aspects of the interaction between an OV and a tumor-bearing host have clear value as targets to improve therapeutic outcomes. At the virus level, these include delivery to the tumor, infectivity, productivity, oncolysis, bystander killing, spread, and persistence. At the host level, these include engaging the immune system and manipulating the tumor microenvironment. Here, we review the chemical- and genome-based high-throughput screens that have been performed to manipulate such parameters during OV infection and analyze their impact on therapeutic efficacy. We further explore emerging themes that represent key areas of focus for future research. Keywords: oncolytic, virus, screen, high-throughput, cancer, chemical, genomic, immunotherapy

Improving CART-Cell Therapy of Solid Tumors with Oncolytic Virus-Driven Production of a Bispecific T-cell Engager.

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Wing, Anna; Fajardo, Carlos Alberto; Posey, Avery D; Shaw, Carolyn; Da, Tong; Young, Regina M; Alemany, Ramon; June, Carl H; Guedan, Sonia

2018-05-01

T cells expressing chimeric antigen receptors (CART) have shown significant promise in clinical trials to treat hematologic malignancies, but their efficacy in solid tumors has been limited. Oncolytic viruses have the potential to act in synergy with immunotherapies due to their immunogenic oncolytic properties and the opportunity of incorporating therapeutic transgenes in their genomes. Here, we hypothesized that an oncolytic adenovirus armed with an EGFR-targeting, bispecific T-cell engager (OAd-BiTE) would improve the outcome of CART-cell therapy in solid tumors. We report that CART cells targeting the folate receptor alpha (FR-α) successfully infiltrated preestablished xenograft tumors but failed to induce complete responses, presumably due to the presence of antigen-negative cancer cells. We demonstrated that OAd-BiTE-mediated oncolysis significantly improved CART-cell activation and proliferation, while increasing cytokine production and cytotoxicity, and showed an in vitro favorable safety profile compared with EGFR-targeting CARTs. BiTEs secreted from infected cells redirected CART cells toward EGFR in the absence of FR-α, thereby addressing tumor heterogeneity. BiTE secretion also redirected CAR-negative, nonspecific T cells found in CART-cell preparations toward tumor cells. The combinatorial approach improved antitumor efficacy and prolonged survival in mouse models of cancer when compared with the monotherapies, and this was the result of an increased BiTE-mediated T-cell activation in tumors. Overall, these results demonstrated that the combination of a BiTE-expressing oncolytic virus with adoptive CART-cell therapy overcomes key limitations of CART cells and BiTEs as monotherapies in solid tumors and encourage its further evaluation in human trials. Cancer Immunol Res; 6(5); 605-16. ©2018 AACR . ©2018 American Association for Cancer Research.

Treatment of colon cancer with oncolytic herpes simplex virus in preclinical models.

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Yang, H; Peng, T; Li, J; Wang, Y; Zhang, W; Zhang, P; Peng, S; Du, T; Li, Y; Yan, Q; Liu, B

2016-05-01

Cancer stem cells (CSCs), which are a rare population in any type of cancer, including colon cancer, are tumorigenic and responsible for cancer recurrence and metastasis. CSCs have been isolated from a number of different solid tumors recently, although the isolation of CSCs in colon cancer is still challenging. We cultured colon cancer cells in stem cell medium to obtain colonosphere cells. These cells possessed the characteristics of CSCs, with a high capacity of tumorigenicity, migration and invasion in vitro and in vivo. The isolation and identification of CSCs have provided new targets for the therapeutics. Oncolytic herpes simplex viruses (oHSV) are an effective strategy for killing colon cancer cells in preclinical models. Here, we examined the efficacy of an oncolytic herpes simplex virus type 2 (oHSV2) in killing colon cancer cells and colon cancer stem-like cells (CSLCs). oHSV2 was found to be highly cytotoxic to the adherent and sphere cells in vitro, and oHSV2 treatment in vivo significantly inhibited tumor growth. This study demonstrates that oHSV2 is effective against colon cancer cells and colon CSLCs and could be a promising strategy for treating colon cancer patients.

Cap-dependent translational control of oncolytic measles virus infection in malignant mesothelioma.

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Jacobson, Blake A; Sadiq, Ahad A; Tang, Shaogeng; Jay-Dixon, Joe; Patel, Manish R; Drees, Jeremy; Sorenson, Brent S; Russell, Stephen J; Kratzke, Robert A

2017-09-08

Malignant mesothelioma has a poor prognosis for which there remains an urgent need for successful treatment approaches. Infection with the Edmonston vaccine strain (MV-Edm) derivative of measles virus results in lysis of cancer cells and has been tested in clinical trials for numerous tumor types including mesothelioma. Many factors play a role in MV-Edm tumor cell selectivity and cytopathic activity while also sparing non-cancerous cells. The MV-Edm receptor CD46 (cluster of differentiation 46) was demonstrated to be significantly higher in mesothelioma cells than in control cells. In contrast, mesothelioma cells are not reliant upon the alternative MV-Edm receptor nectin-4 for entry. MV-Edm treatment of mesothelioma reduced cell viability and also invoked apoptotic cell death. Forced expression of eIF4E or translation stimulation following IGF-I (insulin-like growth factor 1) exposure strengthened the potency of measles virus oncolytic activity. It was also shown that repression of cap-dependent translation by treatment with agents [4EASO, 4EGI-1] that suppress host cell translation or by forcing cells to produce an activated repressor protein diminishes the strength of oncolytic viral efficacy.

Inhibitory effect of Survivin promoter-regulated oncolytic adenovirus carrying P53 gene against gallbladder cancer.

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Liu, Chen; Sun, Bin; An, Ni; Tan, Weifeng; Cao, Lu; Luo, Xiangji; Yu, Yong; Feng, Feiling; Li, Bin; Wu, Mengchao; Su, Changqing; Jiang, Xiaoqing

2011-12-01

Gene therapy has become an important strategy for treatment of malignancies, but problems remains concerning the low gene transferring efficiency, poor transgene expression and limited targeting specific tumors, which have greatly hampered the clinical application of tumor gene therapy. Gallbladder cancer is characterized by rapid progress, poor prognosis, and aberrantly high expression of Survivin. In the present study, we used a human tumor-specific Survivin promoter-regulated oncolytic adenovirus vector carrying P53 gene, whose anti-cancer effect has been widely confirmed, to construct a wide spectrum, specific, safe, effective gene-viral therapy system, AdSurp-P53. Examining expression of enhanced green fluorecent protein (EGFP), E1A and the target gene P53 in the oncolytic adenovirus system validated that Survivin promoter-regulated oncolytic adenovirus had high proliferation activity and high P53 expression in Survivin-positive gallbladder cancer cells. Our in vitro cytotoxicity experiment demonstrated that AdSurp-P53 possessed a stronger cytotoxic effect against gallbladder cancer cells and hepatic cancer cells. The survival rate of EH-GB1 cells was lower than 40% after infection of AdSurp-P53 at multiplicity of infection (MOI) = 1 pfu/cell, while the rate was higher than 90% after infection of Ad-P53 at the same MOI, demonstrating that AdSurp-P53 has a potent cytotoxicity against EH-GB1 cells. The tumor growth was greatly inhibited in nude mice bearing EH-GB1 xenografts when the total dose of AdSurp-P53 was 1 × 10(9) pfu, and terminal dUTP nick end-labeling (TUNEL) revealed that the apoptotic rate of cancer cells was (33.4 ± 8.4)%. This oncolytic adenovirus system overcomes the long-standing shortcomings of gene therapy: poor transgene expression and targeting of only specific tumors, with its therapeutic effect better than the traditional Ad-P53 therapy regimen already on market; our system might be used for patients with advanced gallbladder cancer and

Enhanced lysis by bispecific oncolytic measles viruses simultaneously using HER2/neu or EpCAM as target receptors

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Jan RH Hanauer

2016-01-01

Full Text Available To target oncolytic measles viruses (MV to tumors, we exploit the binding specificity of designed ankyrin repeat proteins (DARPins. These DARPin-MVs have high tumor selectivity while maintaining excellent oncolytic potency. Stability, small size, and efficacy of DARPins allowed the generation of MVs simultaneously targeted to tumor marker HER2/neu and cancer stem cell (CSC marker EpCAM. For optimization, the linker connecting both DARPins was varied in flexibility and length. Flexibility had no impact on fusion helper activity whereas length had. MVs with bispecific MV-H are genetically stable and revealed the desired double-target specificity. In vitro, the cytolytic activity of bispecific MVs was superior or comparable to mono-targeted viruses depending on the target cells. In vivo, therapeutic efficacy of the bispecific viruses was validated in an orthotopic ovarian carcinoma model revealing an effective reduction of tumor mass. Finally, the power of bispecific targeting was demonstrated on cocultures of different tumor cells thereby mimicking tumor heterogeneity in vitro, more closely reflecting real tumors. Here, bispecific excelled monospecific viruses in efficacy. DARPin-based targeting domains thus allow the generation of efficacious oncolytic viruses with double specificity, with the potential to handle intratumoral variation of antigen expression and to simultaneously target CSCs and the bulk tumor mass.

The oncolytic peptide LTX-315 induces cell death and DAMP release by mitochondria distortion in human melanoma cells

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Eike, Liv-Marie; Yang, Nannan; Rekdal, Øystein; Sveinbjørnsson, Baldur

2015-01-01

Host defense peptides (HDPs) are naturally occurring molecules found in most species, in which they play a significant role in the first line defense against intruding pathogens, and several HDPs have been shown to possess anticancer activity. Structure-activity relationship studies on the HDP bovine lactoferricin revealed a de novo design of a nonamer peptide LTX-315, with oncolytic properties. In the present study, we investigated the oncolytic activity of LTX-315 in human melanoma cells (A375). LTX-315 induced a rapid plasma membrane disruption and cell death within 2 hours. At a low concentration, fluorescence-labeled LTX-315 was internalized and accumulated in cytoplasmic vacuoles in close proximity to the mitochondria. The mitochondrial membrane potential was shown to depolarize as a consequence of LTX-315 treatment and at ultrastructural level, the mitochondria morphology was significantly altered. Release of danger signals (DAMPs) such as ATP, Cytochrome C and HMGB1 into the cell supernatant of cultured cells was evident minutes after peptide treatment. The oncolytic effect of LTX-315 involving perturbation of both the cell membrane and the mitochondria with subsequent release of DAMPs may highlight the ability of LTX-315 to induce complete regression and long-term protective immune responses as previously reported in experimental animal models. PMID:26472184

Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer

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Prestwich Robin

2011-06-01

Full Text Available Abstract Background Reovirus type 3 Dearing (T3D has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication. Methods The effects of reovirus and chemotherapy on in vitro cytotoxicity were investigated in PC3 and Du 145 cells and the interactions between agents were assessed by combination index analysis. An Annexin V/propidium iodide fluorescence-activated cell sorting-based assay was used to determine mode of cell death. The effects of reovirus and docetaxel administered as single agent or combination therapy were tested in vivo in a murine model. The effects of docetaxel and reovirus, alone and together, on microtubule stabilisation were investigated by Western blot analysis. Results Variable degrees of synergistic cytotoxicity were observed in PC3 and Du 145 cells exposed to live reovirus and several chemotherapy agents. Combination of reovirus infection with docetaxel exposure led to increased late apoptotic/necrotic cell populations. Reovirus/docetaxel combined therapy led to reduced tumour growth and increased survival in a PC3 tumour bearing mouse model. Microtubule stabilization was enhanced in PC3 cells treated with reovirus/docetaxel combined therapy compared to other reovirus/chemotherapy combinations. Conclusions The co

Cancer-Targeted Oncolytic Adenoviruses for Modulation of the Immune System.

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Cerullo, Vincenzo; Capasso, Cristian; Vaha-Koskela, Markus; Hemminki, Otto; Hemminki, Akseli

2018-01-01

Adenovirus is one of the most commonly used vectors for gene therapy and it is the first approved virus-derived drug for treatment of cancer. As an oncolytic agent, it can induce lysis of infected cells, but it can also engage the immune system, promoting activation and maturation of antigen- presenting cells (APCs). In essence, oncolysis combined with the associated immunostimulatory actions result in a "personalized in situ vaccine" for each patient. In order to take full advantage of these features, we should try to understand how adenovirus interacts with the immune system, what are the receptors involved in triggering subsequent signals and which kind of responses they elicit. Tackling these questions will give us further insight in how to manipulate adenovirus-mediated immune responses for enhancement of anti-tumor efficacy. In this review, we first highlight how oncolytic adenovirus interacts with the innate immune system and its receptors such as Toll-like receptors, nucleotide-binding and oligomerization domain (NOD)- like receptors and other immune sensors. Then we describe the effect of these interactions on the adaptive immune system and its cells, especially B and T lymphocytes. Finally, we summarize the most significant preclinical and clinical results in the field of gene therapy where researchers have engineered adenovirus to manipulate the host immune system by expressing cytokines and signalingmediators. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The in vivo therapeutic efficacy of the oncolytic adenovirus Delta24-RGD is mediated by tumor-specific immunity.

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Anne Kleijn

Full Text Available The oncolytic adenovirus Delta24-RGD represents a new promising therapeutic agent for patients with a malignant glioma and is currently under investigation in clinical phase I/II trials. Earlier preclinical studies showed that Delta24-RGD is able to effectively lyse tumor cells, yielding promising results in various immune-deficient glioma models. However, the role of the immune response in oncolytic adenovirus therapy for glioma has never been explored. To this end, we assessed Delta24-RGD treatment in an immune-competent orthotopic mouse model for glioma and evaluated immune responses against tumor and virus. Delta24-RGD treatment led to long-term survival in 50% of mice and this effect was completely lost upon administration of the immunosuppressive agent dexamethasone. Delta24-RGD enhanced intra-tumoral infiltration of F4/80+ macrophages, CD4+ and CD8+ T-cells, and increased the local production of pro-inflammatory cytokines and chemokines. In treated mice, T cell responses were directed to the virus as well as to the tumor cells, which was reflected in the presence of protective immunological memory in mice that underwent tumor rechallenge. Together, these data provide evidence that the immune system plays a vital role in the therapeutic efficacy of oncolytic adenovirus therapy of glioma, and may provide angles to future improvements on Delta24-RGD therapy.

Complementary induction of immunogenic cell death by oncolytic parvovirus H-1PV and gemcitabine in pancreatic cancer.

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Angelova, Assia L; Grekova, Svitlana P; Heller, Anette; Kuhlmann, Olga; Soyka, Esther; Giese, Thomas; Aprahamian, Marc; Bour, Gaétan; Rüffer, Sven; Cziepluch, Celina; Daeffler, Laurent; Rommelaere, Jean; Werner, Jens; Raykov, Zahari; Giese, Nathalia A

2014-05-01

Novel therapies employing oncolytic viruses have emerged as promising anticancer modalities. The cure of particularly aggressive malignancies requires induction of immunogenic cell death (ICD), coupling oncolysis with immune responses via calreticulin, ATP, and high-mobility group box protein B1 (HMGB1) release from dying tumor cells. The present study shows that in human pancreatic cancer cells (pancreatic ductal adenocarcinoma [PDAC] cells n=4), oncolytic parvovirus H-1 (H-1PV) activated multiple interconnected death pathways but failed to induce calreticulin exposure or ATP release. In contrast, H-1PV elevated extracellular HMGB1 levels by 4.0±0.5 times (58%±9% of total content; up to 100 ng/ml) in all infected cultures, whether nondying, necrotic, or apoptotic. An alternative secretory route allowed H-1PV to overcome the failure of gemcitabine to trigger HMGB1 release, without impeding cytotoxicity or other ICD activities of the standard PDAC medication. Such broad resistance of H-1PV-induced HMGB1 release to apoptotic blockage coincided with but was uncoupled from an autocrine interleukin-1β (IL-1β) loop. That and the pattern of viral determinants maintained in gemcitabine-treated cells suggested the activation of an inflammasome/caspase 1 (CASP1) platform alongside DNA detachment and/or nuclear exclusion of HMGB1 during early stages of the viral life cycle. We concluded that H-1PV infection of PDAC cells is signaled through secretion of the alarmin HMGB1 and, besides its own oncolytic effect, might convert drug-induced apoptosis into an ICD process. A transient arrest of cells in the cyclin A1-rich S phase would suffice to support compatibility of proliferation-dependent H-1PV with cytotoxic regimens. These properties warrant incorporation of the oncolytic virus H-1PV, which is not pathogenic in humans, into multimodal anticancer treatments. The current therapeutic concepts targeting aggressive malignancies require an induction of immunogenic cell death

Current good manufacturing practice production of an oncolytic recombinant vesicular stomatitis viral vector for cancer treatment.

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Ausubel, L J; Meseck, M; Derecho, I; Lopez, P; Knoblauch, C; McMahon, R; Anderson, J; Dunphy, N; Quezada, V; Khan, R; Huang, P; Dang, W; Luo, M; Hsu, D; Woo, S L C; Couture, L

2011-04-01

Vesicular stomatitis virus (VSV) is an oncolytic virus currently being investigated as a promising tool to treat cancer because of its ability to selectively replicate in cancer cells. To enhance the oncolytic property of the nonpathologic laboratory strain of VSV, we generated a recombinant vector [rVSV(MΔ51)-M3] expressing murine gammaherpesvirus M3, a secreted viral chemokine-binding protein that binds to a broad range of mammalian chemokines with high affinity. As previously reported, when rVSV(MΔ51)-M3 was used in an orthotopic model of hepatocellular carcinoma (HCC) in rats, it suppressed inflammatory cell migration to the virus-infected tumor site, which allowed for enhanced intratumoral virus replication leading to increased tumor necrosis and substantially prolonged survival. These encouraging results led to the development of this vector for clinical translation in patients with HCC. However, a scalable current Good Manufacturing Practice (cGMP)-compliant manufacturing process has not been described for this vector. To produce the quantities of high-titer virus required for clinical trials, a process that is amenable to GMP manufacturing and scale-up was developed. We describe here a large-scale (50-liter) vector production process capable of achieving crude titers on the order of 10(9) plaque-forming units (PFU)/ml under cGMP. This process was used to generate a master virus seed stock and a clinical lot of the clinical trial agent under cGMP with an infectious viral titer of approximately 2 × 10(10) PFU/ml (total yield, 1 × 10(13) PFU). The lot has passed all U.S. Food and Drug Administration-mandated release testing and will be used in a phase 1 clinical translational trial in patients with advanced HCC.

An oncolytic adenovirus regulated by a radiation-inducible promoter selectively mediates hSulf-1 gene expression and mutually reinforces antitumor activity of I131-metuximab in hepatocellular carcinoma.

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Zhang, Yan; Fang, Lin; Zhang, Quan'an; Zheng, Qin; Tong, Jinlong; Fu, Xiaohui; Jiang, Xiaoqing; Su, Changqing; Zheng, Junnian

2013-06-01

Gene therapy and antibody approaches are crucial auxiliary strategies for hepatocellular carcinoma (HCC) treatment. Previously, we established a survivin promoter-regulated oncolytic adenovirus that has inhibitory effect on HCC growth. The human sulfatase-1 (hSulf-1) gene can suppress the growth factor signaling pathways, then inhibit the proliferation of cancer cells and enhance cellular sensitivity to radiotherapy and chemotherapy. I(131)-metuximab (I(131)-mab) is a monoclonal anti-HCC antibody that conjugated to I(131) and specifically recognizes the HAb18G/CD147 antigen on HCC cells. To integrate the oncolytic adenovirus-based gene therapy and the I(131)-mab-based radioimmunotherapy, this study combined the CArG element of early growth response-l (Egr-l) gene with the survivin promoter to construct a radiation-inducible enhanced promoter, which was used to recombine a radiation-inducible oncolytic adenovirus as hSulf-1 gene vector. When I(131)-mab was incorporated into the treatment regimen, not only could the antibody produce radioimmunotherapeutic effect, but the I(131) radiation was able to further boost adenoviral proliferation. We demonstrated that the CArG-enhanced survivin promoter markedly improved the proliferative activity of the oncolytic adenovirus in HCC cells, thereby augmenting hSulf-1 expression and inducing cancer cell apoptosis. This novel strategy that involved multiple, synergistic mechanisms, including oncolytic therapy, gene therapy and radioimmunotherapy, was demonstrated to exert an excellent anti-cancer outcome, which will be a promising approach in HCC treatment. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Cyclophosphamide increases transgene expression mediated by an oncolytic adenovirus in glioma-bearing mice monitored by bioluminescence imaging

NARCIS (Netherlands)

Lamfers, Martine L. M.; Fulci, Giulia; Gianni, Davide; Tang, Yi; Kurozumi, Kazuhiko; Kaur, Balveen; Moeniralm, Sharif; Saeki, Yoshinaga; Carette, Jan E.; Weissleder, Ralph; Vandertop, W. Peter; van Beusechem, Victor W.; Dirven, Clemens M. F.; Chiocca, E. Antonio

2006-01-01

Approaches to improve the oncolytic potency of replication-competent adenoviruses include the insertion of therapeutic transgenes into the viral genome. Little is known about the levels and duration of in vivo transgene expression by cells infected with such "armed" viruses. Using a tumor-selective

Sensitivity of C6 Glioma Cells Carrying the Human Poliovirus Receptor to Oncolytic Polioviruses.

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Sosnovtseva, A O; Lipatova, A V; Grinenko, N F; Baklaushev, V P; Chumakov, P M; Chekhonin, V P

2016-10-01

A humanized line of rat C6 glioma cells expressing human poliovirus receptor was obtained and tested for the sensitivity to oncolytic effects of vaccine strains of type 1, 2, and 3 polioviruses. Presentation of the poliovirus receptor on the surface of C6 glioma cells was shown to be a necessary condition for the interaction of cells with polioviruses, but insufficient for complete poliovirus oncolysis.

A hypoxia- and {alpha}-fetoprotein-dependent oncolytic adenovirus exhibits specific killing of hepatocellular carcinomas.

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Kwon, Oh-Joon; Kim, Pyung-Hwan; Huyn, Steven; Wu, Lily; Kim, Minjung; Yun, Chae-Ok

2010-12-15

Oncolytic adenoviruses (Ad) constitute a new promising modality of cancer gene therapy that displays improved efficacy over nonreplicating Ads. We have previously shown that an E1B 19-kDa-deleted oncolytic Ad exhibits a strong cell-killing effect but lacks tumor selectivity. To achieve hepatoma-restricted cytotoxicity and enhance replication of Ad within the context of tumor microenvironment, we used a modified human α-fetoprotein (hAFP) promoter to control the replication of Ad with a hypoxia response element (HRE). We constructed Ad-HRE(6)/hAFPΔ19 and Ad-HRE(12)/hAFPΔ19 that incorporated either 6 or 12 copies of HRE upstream of promoter. The promoter activity and specificity to hepatoma were examined by luciferase assay and fluorescence-activated cell sorting analysis. In addition, the AFP expression- and hypoxia-dependent in vitro cytotoxicity of Ad-HRE(6)/hAFPΔ19 and Ad-HRE(12)/hAFPΔ19 was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and cytopathic effect assay. In vivo tumoricidal activity on subcutaneous and liver orthotopic model was monitored by noninvasive molecular imaging. Ad-HRE(12)/hAFPΔ19 exhibited enhanced tumor selectivity and cell-killing activity when compared with Ad-hAFPΔ19. The tumoricidal activity of Ad-HRE(12)/hAFPΔ19 resulted in significant inhibition of tumor growth in both subcutaneous and orthotopic models. Histologic examination of the primary tumor after treatment confirmed accumulation of viral particles near hypoxic areas. Furthermore, Ad-HRE(12)/hAFPΔ19 did not cause severe inflammatory immune response and toxicity after systemic injection. The results presented here show the advantages of incorporating HREs into a hAFP promoter-driven oncolytic virus. This system is unique in that it acts in both a tissue-specific and tumor environment-selective manner. The greatly enhanced selectivity and tumoricidal activity of Ad-HRE(12)/hAFPΔ19 make it a promising therapeutic agent in the treatment

Attacking Postoperative Metastases using Perioperative Oncolytic Viruses and Viral Vaccines

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Tai, Lee-Hwa; Auer, Rebecca

2014-01-01

Surgical resection of solid primary malignancies is a mainstay of therapy for cancer patients. Despite being the most effective treatment for these tumors, cancer surgery has been associated with impaired metastatic clearance due to immunosuppression. In preclinical surgery models and human cancer patients, we and others have demonstrated a profound suppression of both natural killer (NK) and T cell function in the postoperative period and this plays a major role in the enhanced development of metastases following surgery. Oncolytic viruses (OV) were originally designed to selectively infect and replicate in tumors, with the primary objective of directly lysing cancer cells. It is becoming increasingly clear, however, that OV infection results in a profound inflammatory reaction within the tumor, initiating innate and adaptive immune responses against it that is critical for its therapeutic benefit. This anti-tumor immunity appears to be mediated predominantly by NK and cytotoxic T cells. In preclinical models, we found that preoperative OV prevents postoperative NK cell dysfunction and attenuates tumor dissemination. Due to theoretical safety concerns of administering live virus prior to surgery in cancer patients, we characterized safe, attenuated versions of OV, and viral vaccines that could stimulate NK cells and reduce metastases when administered in the perioperative period. In cancer patients, we observed that in vivo infusion with oncolytic vaccinia virus and ex vivo stimulation with viral vaccines promote NK cell activation. These preclinical studies provide a novel and clinically relevant setting for OV therapy. Our challenge is to identify safe and promising OV therapies that will activate NK and T cells in the perioperative period preventing the establishment of micrometastatic disease in cancer patients. PMID:25161958

Proof-of-principle that a decoy virus protects oncolytic measles virus against neutralizing antibodies

OpenAIRE

Xu C; Goß AV; Dorneburg C; Debatin KM; Wei J; Beltinger C

2018-01-01

Chun Xu,1,2,* Annika Verena Goß,1,* Carmen Dorneburg,1 Klaus-Michael Debatin,1 Jiwu Wei,2 Christian Beltinger1 1Department of Pediatrics and Adolescent Medicine, Section of Experimental Pediatric Oncology, University Medical Center Ulm, Ulm, Germany; 2Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, China *These authors contributed equally to this work Background: Attenuated oncolytic measles virus (OMV) is a promising antitumor agent in early-phase cl...

Oncolytic Viruses: Therapeutics With an Identity Crisis

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Caroline J. Breitbach

2016-07-01

Full Text Available Oncolytic viruses (OV are replicating viral therapeutics for the treatment of cancer and have been in laboratory development for about twenty years. Recently, the FDA approved Imlygic, a herpes virus based therapeutic for the treatment of melanoma and thus OVs have entered a new era where they are a weapon in the armament of the oncologist. OVs are unique therapeutics with multiple mechanisms of therapeutic activity. The exact path for their development and eventual uptake by pharmaceutical companies is somewhat clouded by an uncertain identity. Are they vaccines, tumour lysing therapeutics, inducers of innate immunity, gene therapy vectors, anti-vascular agents or all of the above? Should they be developed as stand-alone loco-regional therapeutics, systemically delivered tumour hunters or immune modulators best tested as combination therapeutics? We summarize data here supporting the idea, depending upon the virus, that OVs can be any or all of these things. Pursuing a “one-size fits all” approach is counter-productive to their clinical development and instead as a field we should build on the strengths of individual virus platforms.

Moving oncolytic viruses into the clinic: clinical-grade production, purification, and characterization of diverse oncolytic viruses

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Guy Ungerechts

2016-01-01

Full Text Available Oncolytic viruses (OVs are unique anticancer agents based on their pleotropic modes of action, which include, besides viral tumor cell lysis, activation of antitumor immunity. A panel of diverse viruses, often genetically engineered, has advanced to clinical investigation, including phase 3 studies. This diversity of virotherapeutics not only offers interesting opportunities for the implementation of different therapeutic regimens but also poses challenges for clinical translation. Thus, manufacturing processes and regulatory approval paths need to be established for each OV individually. This review provides an overview of clinical-grade manufacturing procedures for OVs using six virus families as examples, and key challenges are discussed individually. For example, different virus features with respect to particle size, presence/absence of an envelope, and host species imply specific requirements for measures to ensure sterility, for handling, and for determination of appropriate animal models for toxicity testing, respectively. On the other hand, optimization of serum-free culture conditions, increasing virus yields, development of scalable purification strategies, and formulations guaranteeing long-term stability are challenges common to several if not all OVs. In light of the recent marketing approval of the first OV in the Western world, strategies for further upscaling OV manufacturing and optimizing product characterization will receive increasing attention.

Moving oncolytic viruses into the clinic: clinical-grade production, purification, and characterization of diverse oncolytic viruses.

Science.gov (United States)

Ungerechts, Guy; Bossow, Sascha; Leuchs, Barbara; Holm, Per S; Rommelaere, Jean; Coffey, Matt; Coffin, Rob; Bell, John; Nettelbeck, Dirk M

2016-01-01

Oncolytic viruses (OVs) are unique anticancer agents based on their pleotropic modes of action, which include, besides viral tumor cell lysis, activation of antitumor immunity. A panel of diverse viruses, often genetically engineered, has advanced to clinical investigation, including phase 3 studies. This diversity of virotherapeutics not only offers interesting opportunities for the implementation of different therapeutic regimens but also poses challenges for clinical translation. Thus, manufacturing processes and regulatory approval paths need to be established for each OV individually. This review provides an overview of clinical-grade manufacturing procedures for OVs using six virus families as examples, and key challenges are discussed individually. For example, different virus features with respect to particle size, presence/absence of an envelope, and host species imply specific requirements for measures to ensure sterility, for handling, and for determination of appropriate animal models for toxicity testing, respectively. On the other hand, optimization of serum-free culture conditions, increasing virus yields, development of scalable purification strategies, and formulations guaranteeing long-term stability are challenges common to several if not all OVs. In light of the recent marketing approval of the first OV in the Western world, strategies for further upscaling OV manufacturing and optimizing product characterization will receive increasing attention.

Pediatric and Adult High-Grade Glioma Stem Cell Culture Models Are Permissive to Lytic Infection with Parvovirus H-1.

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Josupeit, Rafael; Bender, Sebastian; Kern, Sonja; Leuchs, Barbara; Hielscher, Thomas; Herold-Mende, Christel; Schlehofer, Jörg R; Dinsart, Christiane; Witt, Olaf; Rommelaere, Jean; Lacroix, Jeannine

2016-05-19

Combining virus-induced cytotoxic and immunotherapeutic effects, oncolytic virotherapy represents a promising therapeutic approach for high-grade glioma (HGG). A clinical trial has recently provided evidence for the clinical safety of the oncolytic parvovirus H-1 (H-1PV) in adult glioblastoma relapse patients. The present study assesses the efficacy of H-1PV in eliminating HGG initiating cells. H-1PV was able to enter and to transduce all HGG neurosphere culture models (n = 6), including cultures derived from adult glioblastoma, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Cytotoxic effects induced by the virus have been observed in all HGG neurospheres at half maximal inhibitory concentration (IC50) doses of input virus between 1 and 10 plaque forming units per cell. H-1PV infection at this dose range was able to prevent tumorigenicity of NCH421k glioblastoma multiforme (GBM) "stem-like" cells in NOD/SCID mice. Interestingly NCH421R, an isogenic subclone with equal capacity of xenograft formation, but resistant to H-1PV infection could be isolated from the parental NCH421k culture. To reveal changes in gene expression associated with H-1PV resistance we performed a comparative gene expression analysis in these subclones. Several dysregulated genes encoding receptor proteins, endocytosis factors or regulators innate antiviral responses were identified and represent intriguing candidates for to further study molecular mechanisms of H-1PV resistance.

Oncotargeting by Vesicular Stomatitis Virus (VSV: Advances in Cancer Therapy

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Suman Bishnoi

2018-02-01

Full Text Available Modern oncotherapy approaches are based on inducing controlled apoptosis in tumor cells. Although a number of apoptosis-induction approaches are available, site-specific delivery of therapeutic agents still remain the biggest hurdle in achieving the desired cancer treatment benefit. Additionally, systemic treatment-induced toxicity remains a major limiting factor in chemotherapy. To specifically address drug-accessibility and chemotherapy side effects, oncolytic virotherapy (OV has emerged as a novel cancer treatment alternative. In OV, recombinant viruses with higher replication capacity and stronger lytic properties are being considered for tumor cell-targeting and subsequent cell lysing. Successful application of OVs lies in achieving strict tumor-specific tropism called oncotropism, which is contingent upon the biophysical interactions of tumor cell surface receptors with viral receptors and subsequent replication of oncolytic viruses in cancer cells. In this direction, few viral vector platforms have been developed and some of these have entered pre-clinical/clinical trials. Among these, the Vesicular stomatitis virus (VSV-based platform shows high promise, as it is not pathogenic to humans. Further, modern molecular biology techniques such as reverse genetics tools have favorably advanced this field by creating efficient recombinant VSVs for OV; some have entered into clinical trials. In this review, we discuss the current status of VSV based oncotherapy, challenges, and future perspectives regarding its therapeutic applications in the cancer treatment.

Oncotargeting by Vesicular Stomatitis Virus (VSV): Advances in Cancer Therapy.

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Bishnoi, Suman; Tiwari, Ritudhwaj; Gupta, Sharad; Byrareddy, Siddappa N; Nayak, Debasis

2018-02-23

Modern oncotherapy approaches are based on inducing controlled apoptosis in tumor cells. Although a number of apoptosis-induction approaches are available, site-specific delivery of therapeutic agents still remain the biggest hurdle in achieving the desired cancer treatment benefit. Additionally, systemic treatment-induced toxicity remains a major limiting factor in chemotherapy. To specifically address drug-accessibility and chemotherapy side effects, oncolytic virotherapy (OV) has emerged as a novel cancer treatment alternative. In OV, recombinant viruses with higher replication capacity and stronger lytic properties are being considered for tumor cell-targeting and subsequent cell lysing. Successful application of OVs lies in achieving strict tumor-specific tropism called oncotropism, which is contingent upon the biophysical interactions of tumor cell surface receptors with viral receptors and subsequent replication of oncolytic viruses in cancer cells. In this direction, few viral vector platforms have been developed and some of these have entered pre-clinical/clinical trials. Among these, the Vesicular stomatitis virus (VSV)-based platform shows high promise, as it is not pathogenic to humans. Further, modern molecular biology techniques such as reverse genetics tools have favorably advanced this field by creating efficient recombinant VSVs for OV; some have entered into clinical trials. In this review, we discuss the current status of VSV based oncotherapy, challenges, and future perspectives regarding its therapeutic applications in the cancer treatment.

A novel combination treatment of armed oncolytic adenovirus expressing IL-12 and GM-CSF with radiotherapy in murine hepatocarcinoma

International Nuclear Information System (INIS)

Kim, Wonwoo; Seong, Jinsil; Oh, Hae-Jin; Koom, Woong-Sub; Choi, Kyung-Joo; Yun, Chae-Ok

2011-01-01

In this study, a novel combination treatment of armed oncolytic adenovirus expressing interleukin 12 (IL-12) and granulocyte-macrophage colony-stimulating factor (GM-CSF) with radiation was investigated for antitumor and antimetastatic effect in a murine hepatic cancer (HCa-I) model. Tumor bearing syngeneic mice were treated with radiation, armed oncolytic virus Ad-ΔE1Bmt7 (dB7) expressing both IL-12 and GM-CSF (armed dB7), or a combination of both. The adenovirus was administered by intratumoral injection 1 x 10 8 plaque forming units (PFU) per tumor in 50 μl of phosphate buffered saline (PBS) four times every other day. Tumor response to treatment was determined by a tumor growth delay assay. Metastatic potential was evaluated by a lung metastasis model. To understand the underlying mechanism, the level of apoptosis was examined as well as the change in microvessel density and expression of immunological markers: CD4+, CD8+ and Cd11c. The combination of armed dB7 and radiation resulted in significant growth delay of murine hepatic cancer, HCa-1, with an enhancement factor of 4.3. The combination treatment also resulted in significant suppression of lung metastasis. Increase of apoptosis level as well as decrease of microvessel density was shown in the combination treatment, suggesting an underlying mechanism for the enhancement of antitumor effect. Expression of immunological markers: CD4+, CD8+ and Cd11c also increased in the combination treatment. This study showed that a novel combination treatment of radiotherapy with armed oncolytic adenovirus expressing IL-12 and GM-CSF was effective in suppressing primary tumor growth. (author)

Characterization of the Antiglioma Effect of the Oncolytic Adenovirus VCN-01.

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Beatriz Vera

Full Text Available Despite the recent advances in the development of antitumor therapies, the prognosis for patients with malignant gliomas remains dismal. Therapy with tumor-selective viruses is emerging as a treatment option for this devastating disease. In this study we characterize the anti-glioma effect of VCN-01, an improved hyaluronidase-armed pRB-pathway-selective oncolytic adenovirus that has proven safe and effective in the treatment of several solid tumors. VCN-01 displayed a significant cytotoxic effect on glioma cells in vitro. In vivo, in two different orthotopic glioma models, a single intra-tumoral administration of VCN-01 increased overall survival significantly and led to long-term survivors free of disease.

Pancreatic adenocarcinoma upregulated factor (PAUF) confers resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNA receptor-mediated signaling

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Kaowinn, Sirichat; Cho, Il-Rae; Moon, Jeong; Jun, Seung Won; Kim, Chang Seok [BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736 (Korea, Republic of); Kang, Ho Young [Department of Microbiology, Pusan National University, Busan 609-736 (Korea, Republic of); Kim, Manbok [Department of Medical Science, Dankook University College of Medicine, Cheonan 330-714 (Korea, Republic of); Koh, Sang Seok [Department of Biological Sciences, Dong-A University, Busan 604-714 (Korea, Republic of); Chung, Young-Hwa, E-mail: younghc@pusan.ac.kr [BK21+, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-736 (Korea, Republic of)

2015-04-03

Pancreatic adenocarcinoma upregulated factor (PAUF), a novel oncogene, plays a crucial role in the development of pancreatic cancer, including its metastasis and proliferation. Therefore, PAUF-expressing pancreatic cancer cells could be important targets for oncolytic virus-mediated treatment. Panc-1 cells expressing PAUF (Panc-PAUF) showed relative resistance to parvovirus H-1 infection compared with Panc-1 cells expressing an empty vector (Panc-Vec). Of interest, expression of type I IFN-α receptor (IFNAR) was higher in Panc-PAUF cells than in Panc-Vec cells. Increased expression of IFNAR in turn increased the activation of Stat1 and Tyk2 in Panc-PAUF cells compared with that in Panc-Vec cells. Suppression of Tyk2 and Stat1, which are important downstream molecules for IFN-α signaling, sensitized pancreatic cancer cells to parvovirus H-1-mediated apoptosis. Further, constitutive suppression of PAUF sensitized Bxpc3 pancreatic cancer cells to parvovirus H-1 infection. Taken together, these results suggested that PAUF conferred resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNAR-mediated signaling. - Highlights: • PAUF confers resistance against oncolytic parvovirus H-1 infection. • PAUF enhances the expression of IFNAR in Panc-1 cells. • Increased activation of Tyk2 or Stat1 by PAUF provides resistance to parvovirus H-1-mediated apoptosis. • Constitutive inhibition of PAUF enhances parvovirus H-1-mediated oncolysis of Bxpc3 pancreatic cancer cells.

Pancreatic adenocarcinoma upregulated factor (PAUF) confers resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNA receptor-mediated signaling

International Nuclear Information System (INIS)

Kaowinn, Sirichat; Cho, Il-Rae; Moon, Jeong; Jun, Seung Won; Kim, Chang Seok; Kang, Ho Young; Kim, Manbok; Koh, Sang Seok; Chung, Young-Hwa

2015-01-01

Pancreatic adenocarcinoma upregulated factor (PAUF), a novel oncogene, plays a crucial role in the development of pancreatic cancer, including its metastasis and proliferation. Therefore, PAUF-expressing pancreatic cancer cells could be important targets for oncolytic virus-mediated treatment. Panc-1 cells expressing PAUF (Panc-PAUF) showed relative resistance to parvovirus H-1 infection compared with Panc-1 cells expressing an empty vector (Panc-Vec). Of interest, expression of type I IFN-α receptor (IFNAR) was higher in Panc-PAUF cells than in Panc-Vec cells. Increased expression of IFNAR in turn increased the activation of Stat1 and Tyk2 in Panc-PAUF cells compared with that in Panc-Vec cells. Suppression of Tyk2 and Stat1, which are important downstream molecules for IFN-α signaling, sensitized pancreatic cancer cells to parvovirus H-1-mediated apoptosis. Further, constitutive suppression of PAUF sensitized Bxpc3 pancreatic cancer cells to parvovirus H-1 infection. Taken together, these results suggested that PAUF conferred resistance to pancreatic cancer cells against oncolytic parvovirus H-1 infection through IFNAR-mediated signaling. - Highlights: • PAUF confers resistance against oncolytic parvovirus H-1 infection. • PAUF enhances the expression of IFNAR in Panc-1 cells. • Increased activation of Tyk2 or Stat1 by PAUF provides resistance to parvovirus H-1-mediated apoptosis. • Constitutive inhibition of PAUF enhances parvovirus H-1-mediated oncolysis of Bxpc3 pancreatic cancer cells

Parainfluenza Virus Infection Sensitizes Cancer Cells to DNA-Damaging Agents: Implications for Oncolytic Virus Therapy.

Science.gov (United States)

Fox, Candace R; Parks, Griffith D

2018-04-01

A parainfluenza virus 5 (PIV5) with mutations in the P/V gene (P/V-CPI - ) is restricted for spread in normal cells but not in cancer cells in vitro and is effective at reducing tumor burdens in mouse model systems. Here we show that P/V-CPI - infection of HEp-2 human laryngeal cancer cells results in the majority of the cells dying, but unexpectedly, over time, there is an emergence of a population of cells that survive as P/V-CPI - persistently infected (PI) cells. P/V-CPI - PI cells had elevated levels of basal caspase activation, and viability was highly dependent on the activity of cellular inhibitor-of-apoptosis proteins (IAPs) such as Survivin and XIAP. In challenge experiments with external inducers of apoptosis, PI cells were more sensitive to cisplatin-induced DNA damage and cell death. This increased cisplatin sensitivity correlated with defects in DNA damage signaling pathways such as phosphorylation of Chk1 and translocation of damage-specific DNA binding protein 1 (DDB1) to the nucleus. Cisplatin-induced killing of PI cells was sensitive to the inhibition of wild-type (WT) p53-inducible protein 1 (WIP1), a phosphatase which acts to terminate DNA damage signaling pathways. A similar sensitivity to cisplatin was seen with cells during acute infection with P/V-CPI - as well as during acute infections with WT PIV5 and the related virus human parainfluenza virus type 2 (hPIV2). Our results have general implications for the design of safer paramyxovirus-based vectors that cannot establish PI as well as the potential for combining chemotherapy with oncolytic RNA virus vectors. IMPORTANCE There is intense interest in developing oncolytic viral vectors with increased potency against cancer cells, particularly those cancer cells that have gained resistance to chemotherapies. We have found that infection with cytoplasmically replicating parainfluenza virus can result in increases in the killing of cancer cells by agents that induce DNA damage, and this is linked

Permissivity of the NCI-60 cancer cell lines to oncolytic Vaccinia Virus GLV-1h68

International Nuclear Information System (INIS)

Ascierto, Maria Libera; Bedognetti, Davide; Uccellini, Lorenzo; Rossano, Fabio; Ascierto, Paolo A; Stroncek, David F; Restifo, Nicholas P; Wang, Ena; Szalay, Aladar A; Marincola, Francesco M; Worschech, Andrea; Yu, Zhiya; Adams, Sharon; Reinboth, Jennifer; Chen, Nanhai G; Pos, Zoltan; Roychoudhuri, Rahul; Di Pasquale, Giovanni

2011-01-01

Oncolytic viral therapy represents an alternative therapeutic strategy for the treatment of cancer. We previously described GLV-1h68, a modified Vaccinia Virus with exclusive tropism for tumor cells, and we observed a cell line-specific relationship between the ability of GLV-1h68 to replicate in vitro and its ability to colonize and eliminate tumor in vivo. In the current study we surveyed the in vitro permissivity to GLV-1h68 replication of the NCI-60 panel of cell lines. Selected cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain. In order to identify correlates of permissity to viral infection, we measured transcriptional profiles of the cell lines prior infection. We observed highly heterogeneous permissivity to VACV infection amongst the cell lines. The heterogeneity of permissivity was independent of tissue with the exception of B cell derivation. Cell lines were also tested for permissivity to another Vaccinia Virus and a vesicular stomatitis virus (VSV) strain and a significant correlation was found suggesting a common permissive phenotype. While no clear transcriptional pattern could be identified as predictor of permissivity to infection, some associations were observed suggesting multifactorial basis permissivity to viral infection. Our findings have implications for the design of oncolytic therapies for cancer and offer insights into the nature of permissivity of tumor cells to viral infection

p21 promotes oncolytic adenoviral activity in ovarian cancer and is a potential biomarker

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Lockley Michelle

2010-07-01

Full Text Available Abstract The oncolytic adenovirus dl922-947 replicates selectively within and lyses cells with a dysregulated Rb pathway, a finding seen in > 90% human cancers. dl922-947 is more potent than wild type adenovirus and the E1B-deletion mutant dl1520 (Onyx-015. We wished to determine which host cell factors influence cytotoxicity. SV40 large T-transformed MRC5-VA cells are 3-logs more sensitive to dl922-947 than isogenic parental MRC5 cells, confirming that an abnormal G1/S checkpoint increases viral efficacy. The sensitivity of ovarian cancer cells to dl922-947 varied widely: IC50 values ranged from 51 (SKOV3ip1 to 0.03 pfu/cell (TOV21G. Cells sensitive to dl922-947 had higher S phase populations and supported earlier E1A expression. Cytotoxicity correlated poorly with both infectivity and replication, but well with expression of p21 by microarray and western blot analyses. Matched p21+/+ and -/- Hct116 cells confirmed that p21 influences dl922-947 activity in vitro and in vivo. siRNA-mediated p21 knockdown in sensitive TOV21G cells decreases E1A expression and viral cytotoxicity, whilst expression of p21 in resistant A2780CP cells increases virus activity in vitro and in intraperitoneal xenografts. These results highlight that host cell factors beyond simple infectivity can influence the efficacy of oncolytic adenoviruses. p21 expression may be an important biomarker of response in clinical trials.

The potential application of a transcriptionally regulated oncolytic herpes simplex virus for human cancer therapy

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Miao, L; Fraefel, C; Sia, K C; Newman, J P; Mohamed-Bashir, S A; Ng, W H; Lam, P Y P

2014-01-01

Background: Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer therapy. Methods: Using bacterial artificial chromosome (BAC) recombineering, a cell cycle-regulatable luciferase transgene cassette was replaced with the infected cell protein 6 (ICP6) coding region (encoded for UL39 or large subunit of ribonucleotide reductase) of the HSV-1 genome. These recombinant viruses, YE-PC8, were further tested for its proliferation-dependent luciferase gene expression. Results: The ability of YE-PC8 to confer proliferation-dependent transgene expression was demonstrated by injecting similar amount of viruses into the tumour-bearing region of the brain and the contralateral normal brain parenchyma of the same mouse. The results showed enhanced levels of luciferase activities in the tumour region but not in the normal brain parenchyma. Similar findings were observed in YE-PC8-infected short-term human brain patient-derived glioma cells compared with normal human astrocytes. intratumoural injection of YE-PC8 viruses resulted in 77% and 80% of tumour regression in human glioma and human hepatocellular carcinoma xenografts, respectively. Conclusion: YE-PC8 viruses confer tumour selectivity in proliferating cells and may be developed further as a feasible approach to treat human cancers. PMID:24196790

ATN-224 enhances antitumor efficacy of oncolytic herpes virus against both local and metastatic head and neck squamous cell carcinoma

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Ji Young Yoo

Full Text Available Head and neck squamous cell carcinoma (HNSCC is the sixth most frequent cancer worldwide, and the 5-year survival rates are among the worst of the major cancers. Oncolytic herpes simplex viruses (oHSV have the potential to make a significant impact in the targeted treatment of these patients. Here, we tested antitumor efficacy of RAMBO, an oHSV armed with the antiangiogenic Vstat120, alone and in conjunction with ATN-224, a copper chelator against HNSCC in vitro and in vivo animal models. We found that all tested HNSCC cells responded well to virus treatment and were sensitive to RAMBO-mediated oncolytic destruction. In vivo, RAMBO had a significant antiangiogenic and antitumorigenic effect. Physiologic levels of copper inhibited viral replication and HNSCC cell killing. Chelation of copper using ATN-224 treatment significantly improved serum stability of RAMBO and permitted systemic delivery in HNSCC tumor xenografts models. Furthermore, our results show that the combination of ATN-224 and RAMBO strongly inhibits lung metastases in a mouse model of HNSCC. These findings suggest that combining ATN-224 with RAMBO has potential for clinical trials in both early and advanced HNSCC patients.

Complex spatial dynamics of oncolytic viruses in vitro: mathematical and experimental approaches.

Directory of Open Access Journals (Sweden)

Dominik Wodarz

Full Text Available Oncolytic viruses replicate selectively in tumor cells and can serve as targeted treatment agents. While promising results have been observed in clinical trials, consistent success of therapy remains elusive. The dynamics of virus spread through tumor cell populations has been studied both experimentally and computationally. However, a basic understanding of the principles underlying virus spread in spatially structured target cell populations has yet to be obtained. This paper studies such dynamics, using a newly constructed recombinant adenovirus type-5 (Ad5 that expresses enhanced jellyfish green fluorescent protein (EGFP, AdEGFPuci, and grows on human 293 embryonic kidney epithelial cells, allowing us to track cell numbers and spatial patterns over time. The cells are arranged in a two-dimensional setting and allow virus spread to occur only to target cells within the local neighborhood. Despite the simplicity of the setup, complex dynamics are observed. Experiments gave rise to three spatial patterns that we call "hollow ring structure", "filled ring structure", and "disperse pattern". An agent-based, stochastic computational model is used to simulate and interpret the experiments. The model can reproduce the experimentally observed patterns, and identifies key parameters that determine which pattern of virus growth arises. The model is further used to study the long-term outcome of the dynamics for the different growth patterns, and to investigate conditions under which the virus population eliminates the target cells. We find that both the filled ring structure and disperse pattern of initial expansion are indicative of treatment failure, where target cells persist in the long run. The hollow ring structure is associated with either target cell extinction or low-level persistence, both of which can be viewed as treatment success. Interestingly, it is found that equilibrium properties of ordinary differential equations describing the

Selectivity and Efficiency of Late Transgene Expression by Transcriptionally Targeted Oncolytic Adenoviruses Are Dependent on the Transgene Insertion Strategy

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Quirin, Christina; Rohmer, Stanimira; Fernández-Ulibarri, Inés; Behr, Michael; Hesse, Andrea; Engelhardt, Sarah; Erbs, Philippe; Enk, Alexander H.; Nettelbeck, Dirk M.

2010-01-01

Key challenges facing cancer therapy are the development of tumor-specific drugs and potent multimodal regimens. Oncolytic adenoviruses possess the potential to realize both aims by restricting virus replication to tumors and inserting therapeutic genes into the virus genome, respectively. A major effort in this regard is to express transgenes in a tumor-specific manner without affecting virus replication. Using both luciferase as a sensitive reporter and genetic prodrug activation, we show t...

A dynamical systems model for combinatorial cancer therapy enhances oncolytic adenovirus efficacy by MEK-inhibition.

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Bagheri, Neda; Shiina, Marisa; Lauffenburger, Douglas A; Korn, W Michael

2011-02-01

Oncolytic adenoviruses, such as ONYX-015, have been tested in clinical trials for currently untreatable tumors, but have yet to demonstrate adequate therapeutic efficacy. The extent to which viruses infect targeted cells determines the efficacy of this approach but many tumors down-regulate the Coxsackievirus and Adenovirus Receptor (CAR), rendering them less susceptible to infection. Disrupting MAPK pathway signaling by pharmacological inhibition of MEK up-regulates CAR expression, offering possible enhanced adenovirus infection. MEK inhibition, however, interferes with adenovirus replication due to resulting G1-phase cell cycle arrest. Therefore, enhanced efficacy will depend on treatment protocols that productively balance these competing effects. Predictive understanding of how to attain and enhance therapeutic efficacy of combinatorial treatment is difficult since the effects of MEK inhibitors, in conjunction with adenovirus/cell interactions, are complex nonlinear dynamic processes. We investigated combinatorial treatment strategies using a mathematical model that predicts the impact of MEK inhibition on tumor cell proliferation, ONYX-015 infection, and oncolysis. Specifically, we fit a nonlinear differential equation system to dedicated experimental data and analyzed the resulting simulations for favorable treatment strategies. Simulations predicted enhanced combinatorial therapy when both treatments were applied simultaneously; we successfully validated these predictions in an ensuing explicit test study. Further analysis revealed that a CAR-independent mechanism may be responsible for amplified virus production and cell death. We conclude that integrated computational and experimental analysis of combinatorial therapy provides a useful means to identify treatment/infection protocols that yield clinically significant oncolysis. Enhanced oncolytic therapy has the potential to dramatically improve non-surgical cancer treatment, especially in locally advanced

Preclinical Testing of an Oncolytic Parvovirus: Standard Protoparvovirus H-1PV Efficiently Induces Osteosarcoma Cell Lysis In Vitro

OpenAIRE

Carsten Geiss; Zoltán Kis; Barbara Leuchs; Monika Frank-Stöhr; Jörg R. Schlehofer; Jean Rommelaere; Christiane Dinsart; Jeannine Lacroix

2017-01-01

Osteosarcoma is the most frequent malignant disease of the bone. On the basis of early clinical experience in the 1960s with H-1 protoparvovirus (H-1PV) in osteosarcoma patients, this effective oncolytic virus was selected for systematic preclinical testing on various osteosarcoma cell cultures. A panel of five human osteosarcoma cell lines (CAL 72, H-OS, MG-63, SaOS-2, U-2OS) was tested. Virus oncoselectivity was confirmed by infecting non-malignant human neonatal fibroblasts and osteoblasts...

Mode of transgene expression after fusion to early or late viral genes of a conditionally replicating adenovirus via an optimized internal ribosome entry site in vitro and in vivo

International Nuclear Information System (INIS)

Rivera, Angel A.; Wang Minghui; Suzuki, Kaori; Uil, Taco G.; Krasnykh, Victor; Curiel, David T.; Nettelbeck, Dirk M.

2004-01-01

The expression of therapeutic genes by oncolytic viruses is a promising strategy to improve viral oncolysis, to augment gene transfer compared with a nonreplicating adenoviral vector, or to combine virotherapy and gene therapy. Both the mode of transgene expression and the locale of transgene insertion into the virus genome critically determine the efficacy of this approach. We report here on the properties of oncolytic adenoviruses which contain the luciferase cDNA fused via an optimized internal ribosome entry site (IRES) to the immediate early adenoviral gene E1A (AdΔE1AIL), the early gene E2B (AdΔE2BIL), or the late fiber gene (AdΔfiberIL). These viruses showed distinct kinetics of transgene expression and luciferase activity. Early after infection, luciferase activities were lower for these viruses, especially for AdΔE2BIL, compared with nonreplicating AdTL, which contained the luciferase gene expressed from the strong CMV promoter. However, 6 days after infection, luciferase activities were approximately four (AdΔE1AIL) to six (AdΔfiberIL) orders of magnitude higher than for AdTL, reflecting virus replication and efficient transgene expression. Similar results were obtained in vivo after intratumoral injection of AdΔE2BIL, AdΔfiberIL, and AdTL. AdΔfiberIL and the parental virus, Ad5-Δ24, resulted in similar cytotoxicity, but AdΔE2BIL and AdΔE1AIL were slightly attenuated. Disruption of the expression of neighboring viral genes by insertion of the transgene was minimal for AdΔE2BIL and AdΔfiberIL, but substantial for AdΔE1AIL. Our observations suggest that insertion of IRES-transgene cassettes into viral transcription units is an attractive strategy for the development of armed oncolytic adenoviruses with defined kinetics and strength of transgene expression

Use of tissue-specific microRNA to control pathology of wild-type adenovirus without attenuation of its ability to kill cancer cells.

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Cawood, Ryan; Chen, Hannah H; Carroll, Fionnadh; Bazan-Peregrino, Miriam; van Rooijen, Nico; Seymour, Leonard W

2009-05-01

Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines; however, uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective microRNA expression now affords the possibility of engineering replicating viruses that are attenuated at the RNA level in sites of potential pathology, but retain wild-type replication activity at sites not expressing the relevant microRNA. To assess the usefulness of this approach for the DNA virus adenovirus, we have engineered a hepatocyte-safe wild-type adenovirus 5 (Ad5), which normally mediates significant toxicity and is potentially lethal in mice. To do this, we have included binding sites for hepatocyte-selective microRNA mir-122 within the 3' UTR of the E1A transcription cassette. Imaging versions of these viruses, produced by fusing E1A with luciferase, showed that inclusion of mir-122 binding sites caused up to 80-fold decreased hepatic expression of E1A following intravenous delivery to mice. Animals administered a ten-times lethal dose of wild-type Ad5 (5x10(10) viral particles/mouse) showed substantial hepatic genome replication and extensive liver pathology, while inclusion of 4 microRNA binding sites decreased replication 50-fold and virtually abrogated liver toxicity. This modified wild-type virus retained full activity within cancer cells and provided a potent, liver-safe oncolytic virus. In addition to providing many potent new viruses for cancer virotherapy, microRNA control of virus replication should provide a new strategy for designing safe attenuated vaccines applied across a broad range of viral diseases.

Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

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Kim, Manbok, E-mail: manbok66@dankook.ac.kr [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Rahman, Masmudur M. [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Cogle, Christopher R. [Department of Hematology/Oncology, University of Florida, Gainesville, FL 32610 (United States); McFadden, Grant [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States)

2015-07-10

Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases.

Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

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Kim, Manbok; Rahman, Masmudur M.; Cogle, Christopher R.; McFadden, Grant

2015-01-01

Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases

Oncolytic Immunotherapy: Dying the Right Way is a Key to Eliciting Potent Antitumor Immunity

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Zong Sheng eGuo

2014-04-01

Full Text Available Oncolytic viruses (OVs are novel immunotherapeutic agents whose anticancer effects come from both oncolysis and elicited antitumor immunity. OVs induce mostly immunogenic cancer cell death (ICD, including immunogenic apoptosis, necrosis/necroptosis, pyroptosis and autophagic cell death, leading to exposure of calreticulin and heat-shock proteins to the cell surface, and/or released ATP, high mobility group box-1 [HMGB1], uric acid, and other DAMPs as well as PAMPs as danger signals, along with tumor-associated antigens, to activate dendritic cells (DCs and elicit adaptive antitumor immunity. Dying the right way may greatly potentiate adaptive antitumor immunity. The mode of cancer cell death may be modulated by individual OVs and cancer cells as they often encode and express genes that inhibit/promote apoptosis, necroptosis or autophagic cell death. We can genetically engineer OVs with death-pathway-modulating genes and thus skew the infected cancer cells towards certain death pathways for the enhanced immunogenicity. Strategies combining with some standard therapeutic regimens may also change the immunological consequence of cancer cell death. In this review, we discuss recent advances in our understanding of danger signals, modes of cancer cell death induced by OVs, the induced danger signals and functions in eliciting subsequent antitumor immunity. We also discuss potential combination strategies to target cells into specific modes of ICD and enhance cancer immunogenicity, including blockade of immune checkpoints, in order to break immune tolerance, improve antitumor immunity and thus the overall therapeutic efficacy.

Adaptive T cell responses induced by oncolytic Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor therapy expanded by dendritic cell and cytokine-induced killer cell adoptive therapy.

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Ren, Jun; Gwin, William R; Zhou, Xinna; Wang, Xiaoli; Huang, Hongyan; Jiang, Ni; Zhou, Lei; Agarwal, Pankaj; Hobeika, Amy; Crosby, Erika; Hartman, Zachary C; Morse, Michael A; H Eng, Kevin; Lyerly, H Kim

2017-01-01

Purpose : Although local oncolytic viral therapy (OVT) may enhance tumor lysis, antigen release, and adaptive immune responses, systemic antitumor responses post-therapy are limited. Adoptive immunotherapy with autologous dendritic cells (DC) and cytokine-induced killer cells (DC-CIK) synergizes with systemic therapies. We hypothesized that OVT with Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor (HSV-GM-CSF) would induce adaptive T cell responses that could be expanded systemically with sequential DC-CIK therapy. Patients and Methods : We performed a pilot study of intratumoral HSV-GM-CSF OVT followed by autologous DC-CIK cell therapy. In addition to safety and clinical endpoints, we monitored adaptive T cell responses by quantifying T cell receptor (TCR) populations in pre-oncolytic therapy, post-oncolytic therapy, and after DC-CIK therapy. Results : Nine patients with advanced malignancy were treated with OVT (OrienX010), of whom seven experienced stable disease (SD). Five of the OVT treated patients underwent leukapheresis, generation, and delivery of DC-CIKs, and two had SD, whereas three progressed. T cell receptor sequencing of TCR β sequences one month after OVT therapy demonstrates a dynamic TCR repertoire in response to OVT therapy in the majority of patients with the systematic expansion of multiple T cell clone populations following DC-CIK therapy. This treatment was well tolerated and long-term event free and overall survival was observed in six of the nine patients. Conclusions : Strategies inducing the local activation of tumor-specific immune responses can be combined with adoptive cellular therapies to expand the adaptive T cell responses systemically and further studies are warranted.

Hepatoma targeting peptide conjugated bio-reducible polymer complexed with oncolytic adenovirus for cancer gene therapy.

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Choi, Joung-Woo; Kim, Hyun Ah; Nam, Kihoon; Na, Youjin; Yun, Chae-Ok; Kim, SungWan

2015-12-28

Despite adenovirus (Ad) vector's numerous advantages for cancer gene therapy, such as high ability of endosomal escape, efficient nuclear entry mechanism, and high transduction, and therapeutic efficacy, tumor specific targeting and antiviral immune response still remain as a critical challenge in clinical setting. To overcome these obstacles and achieve cancer-specific targeting, we constructed tumor targeting bioreducible polymer, an arginine grafted bio-reducible polymer (ABP)-PEG-HCBP1, by conjugating PEGylated ABP with HCBP1 peptides which has high affinity and selectivity towards hepatoma. The ABP-PEG-HCBP1-conjugated replication incompetent GFP-expressing ad, (Ad/GFP)-ABP-PEG-HCBP1, showed a hepatoma cancer specific uptake and transduction compared to either naked Ad/GFP or Ad/GFP-ABP. Competition assays demonstrated that Ad/GFP-ABP-PEG-HCBP1-mediated transduction was specifically inhibited by HCBP1 peptide rather than coxsackie and adenovirus receptor specific antibody. In addition, ABP-PEG-HCBP1 can protect biological activity of Ad against serum, and considerably reduced both innate and adaptive immune response against Ad. shMet-expressing oncolytic Ad (oAd; RdB/shMet) complexed with ABP-PEG-HCBP1 delivered oAd efficiently into hepatoma cancer cells. The oAd/ABP-PEG-HCBP1 demonstrated enhanced cancer cell killing efficacy in comparison to oAd/ABP complex. Furthermore, Huh7 and HT1080 cancer cells treated with oAd/shMet-ABP-PEG-HCBP1 complex had significantly decreased Met and VEGF expression in hepatoma cancer, but not in non-hepatoma cancer. In sum, these results suggest that HCBP1-conjugated bioreducible polymer could be used to deliver oncolytic Ad safely and efficiently to treat hepatoma. Copyright © 2015 Elsevier B.V. All rights reserved.

Combination of Vaccine-Strain Measles and Mumps Viruses Enhances Oncolytic Activity against Human Solid Malignancies.

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Son, Ho Anh; Zhang, LiFeng; Cuong, Bui Khac; Van Tong, Hoang; Cuong, Le Duy; Hang, Ngo Thu; Nhung, Hoang Thi My; Yamamoto, Naoki; Toan, Nguyen Linh

2018-02-07

Oncolytic measles and mumps viruses (MeV, MuV) have a potential for anti-cancer treatment. We examined the anti-tumor activity of MeV, MuV, and MeV-MuV combination (MM) against human solid malignancies (HSM). MeV, MuV, and MM targeted and significantly killed various cancer cell lines of HSM but not normal cells. MM demonstrated a greater anti-tumor effect and prolonged survival in a human prostate cancer xenograft tumor model compared to MeV and MuV. MeV, MuV, and MM significantly induced the expression of immunogenic cell death markers and enhanced spleen-infiltrating immune cells. In conclusion, MM combination significantly improves the treatment of human solid malignancies.

Intraventricular Delivery of Engineered Oncolytic Herpes Simplex Virotherapy to Treat Localized and Metastatic Pediatric Brain Tumors

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2016-08-01

improving my grant writing skills and navigating an NIH grant application. I plan to apply for a laboratory based R01 or R21 during the time period...enable us to further pinpoint what role the influx of immune effector cells (cytotoxic T cells, T helper cells and B cells) has on the toxicity. We...opportunity to enhance my skills as a developing mentor, and these meetings provided them with an opportunity to learn how to prepare an abstract and a poster

Therapeutic Use of Native and Recombinant Enteroviruses

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Jani Ylä-Pelto

2016-02-01

Full Text Available Research on human enteroviruses has resulted in the identification of more than 100 enterovirus types, which use more than 10 protein receptors and/or attachment factors required in cell binding and initiation of the replication cycle. Many of these “viral” receptors are overexpressed in cancer cells. Receptor binding and the ability to replicate in specific target cells define the tropism and pathogenesis of enterovirus types, because cellular infection often results in cytolytic response, i.e., disruption of the cells. Viral tropism and cytolytic properties thus make native enteroviruses prime candidates for oncolytic virotherapy. Copy DNA cloning and modification of enterovirus genomes have resulted in the generation of enterovirus vectors with properties that are useful in therapy or in vaccine trials where foreign antigenic epitopes are expressed from or on the surface of the vector virus. The small genome size and compact particle structure, however, set limits to enterovirus genome modifications. This review focuses on the therapeutic use of native and recombinant enteroviruses and the methods that have been applied to modify enterovirus genomes for therapy.

Increased suppression of oncolytic adenovirus carrying mutant k5 on colorectal tumor

International Nuclear Information System (INIS)

Fan Junkai; Xiao Tian; Gu Jinfa; Wei Na; He Lingfeng; Ding Miao; Liu Xinyuan

2008-01-01

Angiogenesis plays a key role in the development of a wide variety of malignant tumors. The approach of targeting antiangiogenesis has become an important field of cancer gene therapy. In this study, the antiangiogenesis protein K5 (the kringle 5 of human plasminogen) has been mutated by changing leucine71 to arginine to form mK5. Then the ZD55-mK5, which is an oncolytic adenovirus expressing mK5, was constructed. It showed stronger inhibition on proliferation of human umbilical vein endothelial cell. Moreover, in tube formation and embryonic chorioallantoic membrane assay, ZD55-mK5 exhibited more effective antiangiogenesis than ZD55-K5. In addition, ZD55-mK5 generated obvious suppression on the growth of colorectal tumor xenografts and prolonged the life span of nude mice. These results indicate that ZD55-mK5 is a potent agent for inhibiting the tumor angiogenesis and tumor growth

The hTERT promoter enhances the antitumor activity of an oncolytic adenovirus under a hypoxic microenvironment.

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Yuuri Hashimoto

Full Text Available Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor-specific replication-competent oncolytic adenovirus (OBP-301: Telomelysin, in which the human telomerase reverse transcriptase (hTERT promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild-type adenovirus 5 (Ad5. In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen or a hypoxic (1% oxygen condition. Hypoxic condition induced nuclear accumulation of the hypoxia-inducible factor-1α and upregulation of hTERT promoter activity in human cancer cells. The cytopathic activity of OBP-301 was significantly higher than that of Ad5 under hypoxic condition. Consistent with their cytopathic activity, the replication of OBP-301 was significantly higher than that of Ad5 under the hypoxic condition. OBP-301-mediated E1A was expressed within hypoxic areas of human xenograft tumors in mice. These results suggest that the cytopathic activity of OBP-301 against hypoxic tumor cells is mediated through hypoxia-mediated activation of the hTERT promoter. Regulation of oncolytic adenoviruses by the hTERT promoter is a promising antitumor strategy, not only for induction of tumor-specific oncolysis, but also for efficient elimination of hypoxic tumor cells.

Preclinical Testing of an Oncolytic Parvovirus in Ewing Sarcoma: Protoparvovirus H-1 Induces Apoptosis and Lytic Infection In Vitro but Fails to Improve Survival In Vivo.

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Lacroix, Jeannine; Kis, Zoltán; Josupeit, Rafael; Schlund, Franziska; Stroh-Dege, Alexandra; Frank-Stöhr, Monika; Leuchs, Barbara; Schlehofer, Jörg R; Rommelaere, Jean; Dinsart, Christiane

2018-06-03

About 70% of all Ewing sarcoma (EWS) patients are diagnosed under the age of 20 years. Over the last decades little progress has been made towards finding effective treatment approaches for primarily metastasized or refractory Ewing sarcoma in young patients. Here, in the context of the search for novel therapeutic options, the potential of oncolytic protoparvovirus H-1 (H-1PV) to treat Ewing sarcoma was evaluated, its safety having been proven previously tested in adult cancer patients and its oncolytic efficacy demonstrated on osteosarcoma cell cultures. The effects of viral infection were tested in vitro on four human Ewing sarcoma cell lines. Notably evaluated were effects of the virus on the cell cycle and its replication efficiency. Within 24 h after infection, the synthesis of viral proteins was induced. Efficient H-1PV replication was confirmed in all four Ewing sarcoma cell lines. The cytotoxicity of the virus was determined on the basis of cytopathic effects, cell viability, and cell lysis. These in vitro experiments revealed efficient killing of Ewing sarcoma cells by H-1PV at a multiplicity of infection between 0.1 and 5 plaque forming units (PFU)/cell. In two of the four tested cell lines, significant induction of apoptosis by H-1PV was observed. H-1PV thus meets all the in vitro criteria for a virus to be oncolytic towards Ewing sarcoma. In the first xenograft experiments, however, although an antiproliferative effect of intratumoral H-1PV injection was observed, no significant improvement of animal survival was noted. Future projects aiming to validate parvovirotherapy for the treatment of pediatric Ewing sarcoma should focus on combinatorial treatments and will require the use of patient-derived xenografts and immunocompetent syngeneic animal models.

Preclinical Testing of an Oncolytic Parvovirus in Ewing Sarcoma: Protoparvovirus H-1 Induces Apoptosis and Lytic Infection In Vitro but Fails to Improve Survival In Vivo

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Jeannine Lacroix

2018-06-01

Full Text Available About 70% of all Ewing sarcoma (EWS patients are diagnosed under the age of 20 years. Over the last decades little progress has been made towards finding effective treatment approaches for primarily metastasized or refractory Ewing sarcoma in young patients. Here, in the context of the search for novel therapeutic options, the potential of oncolytic protoparvovirus H-1 (H-1PV to treat Ewing sarcoma was evaluated, its safety having been proven previously tested in adult cancer patients and its oncolytic efficacy demonstrated on osteosarcoma cell cultures. The effects of viral infection were tested in vitro on four human Ewing sarcoma cell lines. Notably evaluated were effects of the virus on the cell cycle and its replication efficiency. Within 24 h after infection, the synthesis of viral proteins was induced. Efficient H-1PV replication was confirmed in all four Ewing sarcoma cell lines. The cytotoxicity of the virus was determined on the basis of cytopathic effects, cell viability, and cell lysis. These in vitro experiments revealed efficient killing of Ewing sarcoma cells by H-1PV at a multiplicity of infection between 0.1 and 5 plaque forming units (PFU/cell. In two of the four tested cell lines, significant induction of apoptosis by H-1PV was observed. H-1PV thus meets all the in vitro criteria for a virus to be oncolytic towards Ewing sarcoma. In the first xenograft experiments, however, although an antiproliferative effect of intratumoral H-1PV injection was observed, no significant improvement of animal survival was noted. Future projects aiming to validate parvovirotherapy for the treatment of pediatric Ewing sarcoma should focus on combinatorial treatments and will require the use of patient-derived xenografts and immunocompetent syngeneic animal models.

Potent efficacy signals from systemically administered oncolytic herpes simplex virus (HSV1716 in hepatocellular carcinoma xenograft models

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Braidwood L

2014-10-01

Full Text Available Lynne Braidwood, Kirsty Learmonth, Alex Graham, Joe Conner Virttu Biologics Ltd, Department of Neurology, Southern General Hospital, Glasgow, UK Abstract: Oncolytic herpes simplex virus (HSV1716, lacking the neurovirulence factor ICP34.5, has highly selective replication competence for cancer cells and has been used in clinical studies of glioma, melanoma, head and neck squamous cell carcinoma, pediatric non-central nervous system solid tumors, and malignant pleural mesothelioma. To date, 88 patients have received HSV1716 and the virus is well tolerated, with selective replication in tumor cells and no spread to surrounding normal tissue. We assessed the potential value of HSV1716 in preclinical studies with two human hepatocellular carcinoma cell lines, HuH7 and HepG2-luc. HSV1716 displayed excellent replication kinetics in vitro in HepG2-luc cells, a cell line engineered to express luciferase, and virus-mediated cell killing correlated with loss of light emissions from the cells. In vivo, the HepG2-luc cells readily formed light-emitting xenografts that were easily visualized by an in vivo imaging system and efficiently eliminated by HSV1716 oncolysis after intratumoral injection. HSV1716 also demonstrated strong efficacy signals in subcutaneous HuH7 xenografts in nude mice after intravenous administration of virus. In the HuH7 model, the intravenously injected virus replicated prolifically immediately after efficient tumor localization, resulting in highly significant reductions in tumor growth and enhanced survival. Our preclinical results demonstrate excellent tumor uptake of HSV1716, with prolific replication and potent oncolysis. These observations warrant a clinical study of HSV1716 in hepatocellular carcinoma. Keywords: oncolytic herpes simplex virus, HSV1716, hepatocellular carcinoma, xenografts, efficacy 

Chemovirotherapy for head and neck squamous cell carcinoma with EGFR-targeted and CD/UPRT-armed oncolytic measles virus.

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Zaoui, K; Bossow, S; Grossardt, C; Leber, M F; Springfeld, C; Plinkert, P K; Kalle, C von; Ungerechts, G

2012-03-01

First-line treatment of recurrent and/or refractory head and neck squamous cell carcinoma (HNSCC) is based on platinum, 5-fluorouracil (5-FU) and the monoclonal antiEGFR antibody cetuximab. However, in most cases this chemoimmunotherapy does not cure the disease, and more than 50% of HNSCC patients are dying because of local recurrence of the tumors. In the majority of cases, HNSCC overexpress the epidermal growth factor receptor (EGFR), and its presence is associated with a poor outcome. In this study, we engineered an EGFR-targeted oncolytic measles virus (MV), armed with the bifunctional enzyme cytosine deaminase/uracil phosphoribosyltransferase (CD/UPRT). CD/UPRT converts 5-fluorocytosine (5-FC) into the chemotherapeutic 5-FU, a mainstay of HNSCC chemotherapy. This virus efficiently replicates in and lyses primary HNSCC cells in vitro. Arming with CD/UPRT mediates efficient prodrug activation with high bystander killing of non-infected tumor cells. In mice bearing primary HNSCC xenografts, intratumoral administration of MV-antiEGFR resulted in statistically significant tumor growth delay and prolongation of survival. Importantly, combination with 5-FC is superior to virus-only treatment leading to significant tumor growth inhibition. Thus, chemovirotherapy with EGFR-targeted and CD/UPRT-armed MV is highly efficacious in preclinical settings with direct translational implications for a planned Phase I clinical trial of MV for locoregional treatment of HNSCC.

Tropism ablation and stealthing of oncolytic adenovirus enhances systemic delivery to tumors and improves virotherapy of cancer

Czech Academy of Sciences Publication Activity Database

Green, N. K.; Hale, A.; Cawood, R.; Illingworth, S.; Herbert, C.; Hermiston, T.; Šubr, Vladimír; Ulbrich, Karel; van Rooijen, N.; Seymour, L. W.; Fisher, K. D.

2012-01-01

Roč. 7, č. 11 (2012), s. 1683-1695 ISSN 1743-5889 R&D Projects: GA AV ČR IAAX00500803 Institutional research plan: CEZ:AV0Z40500505 Institutional support: RVO:61389013 Keywords : clodronate liposomes * polymer-coated adenovirus * predosing strategy Subject RIV: CD - Macromolecular Chemistry Impact factor: 5.260, year: 2012

Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells

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Coffey Matthew C

2009-07-01

Full Text Available Abstract Background Reovirus type 3 Dearing strain (ReoT3D has an inherent propensity to preferentially infect and destroy cancer cells. The oncolytic activity of ReoT3D as a single agent has been demonstrated in vitro and in vivo against various cancers, including colon, pancreatic, ovarian and breast cancers. Its human safety and potential efficacy are currently being investigated in early clinical trials. In this study, we investigated the in vitro combination effects of ReoT3D and chemotherapeutic agents against human non-small cell lung cancer (NSCLC. Results ReoT3D alone exerted significant cytolytic activity in 7 of 9 NSCLC cell lines examined, with the 50% effective dose, defined as the initial virus dose to achieve 50% cell killing after 48 hours of infection, ranging from 1.46 ± 0.12 ~2.68 ± 0.25 (mean ± SD log10 pfu/cell. Chou-Talalay analysis of the combination of ReoT3D with cisplatin, gemcitabine, or vinblastine demonstrated strong synergistic effects on cell killing, but only in cell lines that were sensitive to these compounds. In contrast, the combination of ReoT3D and paclitaxel was invariably synergistic in all cell lines tested, regardless of their levels of sensitivity to either agent. Treatment of NSCLC cell lines with the ReoT3D-paclitaxel combination resulted in increased poly (ADP-ribose polymerase cleavage and caspase activity compared to single therapy, indicating enhanced apoptosis induction in dually treated NSCLC cells. NSCLC cells treated with the ReoT3D-paclitaxel combination showed increased proportions of mitotic and apoptotic cells, and a more pronounced level of caspase-3 activation was demonstrated in mitotically arrested cells. Conclusion These data suggest that the oncolytic activity of ReoT3D can be potentiated by taxanes and other chemotherapeutic agents, and that the ReoT3D-taxane combination most effectively achieves synergy through accelerated apoptosis triggered by prolonged mitotic arrest.

Selectivity and Efficiency of Late Transgene Expression by Transcriptionally Targeted Oncolytic Adenoviruses Are Dependent on the Transgene Insertion Strategy

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Quirin, Christina; Rohmer, Stanimira; Fernández-Ulibarri, Inés; Behr, Michael; Hesse, Andrea; Engelhardt, Sarah; Erbs, Philippe; Enk, Alexander H.

2011-01-01

Abstract Key challenges facing cancer therapy are the development of tumor-specific drugs and potent multimodal regimens. Oncolytic adenoviruses possess the potential to realize both aims by restricting virus replication to tumors and inserting therapeutic genes into the virus genome, respectively. A major effort in this regard is to express transgenes in a tumor-specific manner without affecting virus replication. Using both luciferase as a sensitive reporter and genetic prodrug activation, we show that promoter control of E1A facilitates highly selective expression of transgenes inserted into the late transcription unit. This, however, required multistep optimization of late transgene expression. Transgene insertion via internal ribosome entry site (IRES), splice acceptor (SA), or viral 2A sequences resulted in replication-dependent expression. Unexpectedly, analyses in appropriate substrates and with matching control viruses revealed that IRES and SA, but not 2A, facilitated indirect transgene targeting via tyrosinase promoter control of E1A. Transgene expression via SA was more selective (up to 1,500-fold) but less effective than via IRES. Notably, we also revealed transgene-dependent interference with splicing. Hence, the prodrug convertase FCU1 (a cytosine deaminase–uracil phosphoribosyltransferase fusion protein) was expressed only after optimizing the sequence surrounding the SA site and mutating a cryptic splice site within the transgene. The resulting tyrosinase promoter-regulated and FCU1-encoding adenovirus combined effective oncolysis with targeted prodrug activation therapy of melanoma. Thus, prodrug activation showed potent bystander killing and increased cytotoxicity of the virus up to 10-fold. We conclude that armed oncolytic viruses can be improved substantially by comparing and optimizing strategies for targeted transgene expression, thereby implementing selective and multimodal cancer therapies. PMID:20939692

Cell-based delivery of oncolytic viruses: a new strategic alliance for a biological strike against cancer.

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Power, Anthony T; Bell, John C

2007-04-01

Recent years have seen tremendous advances in the development of exquisitely targeted replicating virotherapeutics that can safely destroy malignant cells. Despite this promise, clinical advancement of this powerful and unique approach has been hindered by vulnerability to host defenses and inefficient systemic delivery. However, it now appears that delivery of oncolytic viruses within carrier cells may offer one solution to this critical problem. In this review, we compare the advantages and limitations of the numerous cell lineages that have been investigated as delivery platforms for viral therapeutics, and discuss examples showing how combined cell-virus biotherapeutics can be used to achieve synergistic gains in antitumor activity. Finally, we highlight avenues for future preclinical research that might be taken in order to refine cell-virus biotherapeutics in preparation for human trials.

Antitumour effects of combined radio- and parvovirotherapy in N-Ras-positive tumour cells

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Angelova, A.; Galabov, A.; Rommelaere, J.; Raykov, Z.

2007-01-01

Many innovative approaches have attempted to challenge the dominant position of surgery, chemotherapy and radiotherapy as the major therapeutic modalities to treat cancer. However, only recently some new agents have appeared that achieve effects comparable to the ones of these established treatments. A novel class of such therapeutics consists of oncolytic viruses with several main representatives, namely adeno-, herpes, reo- and parvovirus. The latter class of anticancer agents has proven to be quite effective in many preclinical models and is now considered for a phase I clinical trial in patients with glioma and pancreatic cancer. An important question to be answered is whether virotherapy can be combined with standard treatments to achieve an enhanced antitumor effect still at a low level of toxicity. Here we present data concerning the application of irradiation together with H-1PV parvovirus infection comparing their toxic effects on normal and Ras -transformed fibroblasts. This proved to be a potent combination achieving high level of synergistic toxicity on transformed cells at doses, which did not affect the viability of normal human fibroblasts. This strategy holds promise to become a part of the clinical treatment of radioresistant tumours. (authors)

Novel therapies for high-grade gliomas: A vision for future

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Vivek Tandon

2012-01-01

Full Text Available The treatment for high-grade glioma remains an enigma. The standard treatment using surgery, radiation therapy and chemotherapy for such highly malignant lesions has only yielded modest results, in terms of survival and improving the quality of life of patients. Less than 10% of such patients survive beyond two years. All conventional therapies have failed to increase the survival beyond this extent. There has been a growing interest in the molecular approaches for the treatment of high-grade gliomas which include gene therapy, oncolytic virotherapy, and immunotherapy. These new therapies are in preclinical and investigational stages. They may not substitute the conventional therapies; they may not be the ultimate elixir for this deadly disease. However, in the coming years, they are likely to have synergistic and complimentary roles alongside conventional therapies. Through this paper, we have attempted to highlight the rationale behind gene therapy which can be used for cytotoxic approaches, immunomodulation strategy, and targeted toxin delivery in the tumor cell. We have reviewed current available literature and through this paper focus on reporting such therapeutic options, their potential usage, benefits and limitations.

Seneca Valley Virus 3Cpro Substrate Optimization Yields Efficient Substrates for Use in Peptide-Prodrug Therapy.

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Linde A Miles

Full Text Available The oncolytic picornavirus Seneca Valley Virus (SVV-001 demonstrates anti-tumor activity in models of small cell lung cancer (SCLC, but may ultimately need to be combined with cytotoxic therapies to improve responses observed in patients. Combining SVV-001 virotherapy with a peptide prodrug activated by the viral protease 3Cpro is a novel strategy that may increase the therapeutic potential of SVV-001. Using recombinant SVV-001 3Cpro, we measured cleavage kinetics of predicted SVV-001 3Cpro substrates. An efficient substrate, L/VP4 (kcat/KM = 1932 ± 183 M(-1s(-1, was further optimized by a P2' N→P substitution yielding L/VP4.1 (kcat/KM = 17446 ± 2203 M(-1s(-1. We also determined essential substrate amino acids by sequential N-terminal deletion and substitution of amino acids found in other picornavirus genera. A peptide corresponding to the L/VP4.1 substrate was selectively cleaved by SVV-001 3Cpro in vitro and was stable in human plasma. These data define an optimized peptide substrate for SVV-001 3Cpro, with direct implications for anti-cancer therapeutic development.

Combination of the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus as a new option for epi-virotherapeutic treatment of hepatocellular carcinoma

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Benjamin Ruf

Full Text Available Epigenetic therapies such as histone deacetylase inhibitors (HDACi not only have the capability to decrease tumor cell proliferation and to induce tumor cell death but also to silence antiviral response genes. Here, we investigated whether the combination of an oncolytic measles vaccine virus (MeV with the novel oral HDACi resminostat (Res, being in clinical testing in patients with hepatocellular carcinoma (HCC, results in an enhanced efficacy of this epi-virotherapeutic approach compared to any of the two corresponding monotherapies. When testing a panel of human hepatoma cell lines, we found (i a significantly improved rate of primary infections when using oncolytic MeV under concurrent treatment with resminostat, (ii a boosted cytotoxic effect of the epi-virotherapeutic combination (Res + MeV with enhanced induction of apoptosis, and, quite importantly, (iii an absence of any resminostat-induced impairment of MeV replication and spread. Beyond that, we could also show that (iv resminostat, after hepatoma cell stimulation with exogenous human interferon (IFN-β, is able to prevent the induction of IFN-stimulated genes, such as IFIT-1. This finding outlines the possible impact of resminostat on cellular innate immunity, being instrumental in overcoming resistances to MeV-mediated viral oncolysis. Thus, our results support the onset of epi-virotherapeutic clinical trials in patients exhibiting advanced stages of HCC.

Construction of Various γ34.5 Deleted Fluorescent-Expressing Oncolytic herpes Simplex type 1 (oHSV) for Generation and Isolation of HSV-Based Vectors

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Abdoli, Shahriyar; Roohvand, Farzin; Teimoori-Toolabi, Ladan; Shokrgozar, Mohammad Ali; Bahrololoumi, Mina; Azadmanesh, Kayhan

2017-07-01

Oncolytic herpes simplex virus (oHSV)-based vectors lacking γ34.5 gene, are considered as ideal templates to construct efficient vectors for (targeted) cancer gene therapy. Herein, we reported the construction of three single/dually-flourescence labeled and γ34.5-deleted, recombinant HSV-1 vectors for rapid generation and easy selection/isolation of different HSV-Based vectors. Generation of recombinant viruses was performed with conventional homologous recombination methods using green fluorescent protein (GFP) and BleCherry harboring shuttle vectors. Viruses were isolated by direct fluorescence observation and standard plaque purifying methods and confirmed by PCR and sequencing and flow cytometry. XTT and plaque assay titration were performed on Vero, U87MG, and T98 GBM cell lines. We generated three recombinant viruses, HSV-GFP, HSV-GR (Green-Red), and HSV-Red. The HSV-GFP showed two log higher titer (1010 PFU) than wild type (108 PFU). In contrast, HSV-GR and HSV-Red showed one log lower titer (107 PFU) than parental HSV. Cytotoxicity analysis showed that HSV-GR and HSV-Red can lyse target tumor cells at multiplicity of infection of 10 and 1 (Pidentification via fluorescence activated cell sorting. These vectors can also be used for tracing the efficacy of therapeutic agents on target cells, imaging of neural or tumoral cells in vitro/in vivo and as oncolytic agents in cancer therapy.

Cavitation-enhanced delivery of a replicating oncolytic adenovirus to tumors using focused ultrasound.

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Bazan-Peregrino, Miriam; Rifai, Bassel; Carlisle, Robert C; Choi, James; Arvanitis, Costas D; Seymour, Leonard W; Coussios, Constantin C

2013-07-10

Oncolytic viruses (OV) and ultrasound-enhanced drug delivery are powerful novel technologies. OV selectively self-amplify and kill cancer cells but their clinical use has been restricted by limited delivery from the bloodstream into the tumor. Ultrasound has been previously exploited for targeted release of OV in vivo, but its use to induce cavitation, microbubble oscillations, for enhanced OV tumor extravasation and delivery has not been previously reported. By identifying and optimizing the underlying physical mechanism, this work demonstrates that focused ultrasound significantly enhances the delivery and biodistribution of systemically administered OV co-injected with microbubbles. Up to a fiftyfold increase in tumor transgene expression was achieved, without any observable tissue damage. Ultrasound exposure parameters were optimized as a function of tumor reperfusion time to sustain inertial cavitation, a type of microbubble activity, throughout the exposure. Passive detection of acoustic emissions during treatment confirmed inertial cavitation as the mechanism responsible for enhanced delivery and enabled real-time monitoring of successful viral delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

Treatment of medulloblastoma using an oncolytic measles virus encoding the thyroidal sodium iodide symporter shows enhanced efficacy with radioiodine

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Hutzen, Brian; Pierson, Christopher R; Russell, Stephen J; Galanis, Evanthia; Raffel, Corey; Studebaker, Adam W

2012-01-01

Medulloblastoma is the most common malignant brain tumor of childhood. Although the clinical outcome for medulloblastoma patients has improved significantly, children afflicted with the disease frequently suffer from debilitating side effects related to the aggressive nature of currently available therapy. Alternative means for treating medulloblastoma are desperately needed. We have previously shown that oncolytic measles virus (MV) can selectively target and destroy medulloblastoma tumor cells in localized and disseminated models of the disease. MV-NIS, an oncolytic measles virus that encodes the human thyroidal sodium iodide symporter (NIS), has the potential to deliver targeted radiotherapy to the tumor site and promote a localized bystander effect above and beyond that achieved by MV alone. We evaluated the efficacy of MV-NIS against medulloblastoma cells in vitro and examined their ability to incorporate radioiodine at various timepoints, finding peak uptake at 48 hours post infection. The effects of MV-NIS were also evaluated in mouse xenograft models of localized and disseminated medulloblastoma. Athymic nude mice were injected with D283med-Luc medulloblastoma cells in the caudate putamen (localized disease) or right lateral ventricle (disseminated disease) and subsequently treated with MV-NIS. Subsets of these mice were given a dose of 131 I at 24, 48 or 72 hours later. MV-NIS treatment, both by itself and in combination with 131 I, elicited tumor stabilization and regression in the treated mice and significantly extended their survival times. Mice given 131 I were found to concentrate radioiodine at the site of their tumor implantations. In addition, mice with localized tumors that were given 131 I either 24 or 48 hours after MV-NIS treatment exhibited a significant survival advantage over mice given MV-NIS alone. These data suggest MV-NIS plus radioiodine may be a potentially useful therapy for the treatment of medulloblastoma

Treatment of medulloblastoma using an oncolytic measles virus encoding the thyroidal sodium iodide symporter shows enhanced efficacy with radioiodine

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Hutzen Brian

2012-11-01

Full Text Available Abstract Background Medulloblastoma is the most common malignant brain tumor of childhood. Although the clinical outcome for medulloblastoma patients has improved significantly, children afflicted with the disease frequently suffer from debilitating side effects related to the aggressive nature of currently available therapy. Alternative means for treating medulloblastoma are desperately needed. We have previously shown that oncolytic measles virus (MV can selectively target and destroy medulloblastoma tumor cells in localized and disseminated models of the disease. MV-NIS, an oncolytic measles virus that encodes the human thyroidal sodium iodide symporter (NIS, has the potential to deliver targeted radiotherapy to the tumor site and promote a localized bystander effect above and beyond that achieved by MV alone. Methods We evaluated the efficacy of MV-NIS against medulloblastoma cells in vitro and examined their ability to incorporate radioiodine at various timepoints, finding peak uptake at 48 hours post infection. The effects of MV-NIS were also evaluated in mouse xenograft models of localized and disseminated medulloblastoma. Athymic nude mice were injected with D283med-Luc medulloblastoma cells in the caudate putamen (localized disease or right lateral ventricle (disseminated disease and subsequently treated with MV-NIS. Subsets of these mice were given a dose of 131I at 24, 48 or 72 hours later. Results MV-NIS treatment, both by itself and in combination with 131I, elicited tumor stabilization and regression in the treated mice and significantly extended their survival times. Mice given 131I were found to concentrate radioiodine at the site of their tumor implantations. In addition, mice with localized tumors that were given 131I either 24 or 48 hours after MV-NIS treatment exhibited a significant survival advantage over mice given MV-NIS alone. Conclusions These data suggest MV-NIS plus radioiodine may be a potentially useful therapy for

Autonomous parvoviruses neither stimulate nor are inhibited by the type I interferon response in human normal or cancer cells.

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Paglino, Justin C; Andres, Wells; van den Pol, Anthony N

2014-05-01

Members of the genus Parvovirus are small, nonenveloped single-stranded DNA viruses that are nonpathogenic in humans but have potential utility as cancer therapeutics. Because the innate immune response to parvoviruses has received relatively little attention, we compared the response to parvoviruses to that of several other types of viruses in human cells. In normal human glia, fibroblasts, or melanocytes, vesicular stomatitis virus evoked robust beta interferon (IFN-β) responses. Cytomegalovirus, pseudorabies virus, and Sindbis virus all evoked a 2-log-unit or greater upregulation of IFN-β in glia; in contrast, LuIII and MVMp parvoviruses did not evoke a detectable IFN-β or interferon-stimulated gene (ISG; MX1, oligoadenylate synthetase [OAS], IFIT-1) response in the same cell types. The lack of response raised the question of whether parvoviral infection can be attenuated by IFN; interestingly, we found that IFN did not decrease parvovirus (MVMp, LuIII, and H-1) infectivity in normal human glia, fibroblasts, or melanocytes. The same was true in human cancers, including glioma, sarcoma, and melanoma. Similarly, IFN failed to attenuate transduction by the dependovirus vector adeno-associated virus type 2. Progeny production of parvoviruses was also unimpaired by IFN in both glioma and melanoma, whereas vesicular stomatitis virus replication was blocked. Sarcoma cells with upregulated IFN signaling that show high levels of resistance to other viruses showed strong infection by LuIII. Unlike many other oncolytic viruses, we found no evidence that impairment of innate immunity in cancer cells plays a role in the oncoselectivity of parvoviruses in human cells. Parvoviral resistance to the effects of IFN in cancer cells may constitute an advantage in the virotherapy of some tumors. Understanding the interactions between oncolytic viruses and the innate immune system will facilitate employing these viruses as therapeutic agents in cancer patients. The cancer

An oncolytic adenovirus enhances antiangiogenic and antitumoral effects of a replication-deficient adenovirus encoding endostatin by rescuing its selective replication in nasopharyngeal carcinoma cells

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Liu, Ran-yi; Zhou, Ling; Zhang, Yan-ling; Huang, Bi-jun; Ke, Miao-la; Chen, Jie-min; Li, Li-xia; Fu, Xiang; Wu, Jiang-xue; Huang, Wenlin

2013-01-01

Highlights: •H101 promotes endostatin expression by Ad-Endo via rescuing Ad-Endo replication. •H101 rescued Ad-Endo replication by supplying E1A and E1B19k proteins. •Ad-Endo enhanced the cytotoxicity of H101 in NPC cells. •Ad-Endo and oncolytic Ad H101 have synergistic antitumor effects on NPC. -- Abstract: A replication-deficient adenovirus (Ad) encoding secreted human endostatin (Ad-Endo) has been demonstrated to have promising antiangiogenic and antitumoral effects. The E1B55k-deleted Ad H101 can selectively lyse cancer cells. In this study, we explored the antitumor effects and cross-interactions of Ad-Endo and H101 on nasopharyngeal carcinoma (NPC). The results showed that H101 dramatically promoted endostatin expression by Ad-Endo via rescuing Ad-Endo replication in NPC cells, and the expressed endostatin proteins significantly inhibited the proliferation of human umbilical vein endothelial cells. E1A and E1B19k products are required for the rescuing of H101 to Ad-Endo replication in CNE-1 and CNE-2 cells, but not in C666-1 cells. On the other hand, Ad-Endo enhanced the cytotoxicity of H101 by enhancing Ad replication in NPC cells. The combination of H101 and Ad-Endo significantly inhibited CNE-2 xenografts growth through the increased endostatin expression and Ad replication. These findings indicate that the combination of Ad-Endo gene therapy and oncolytic Ad therapeutics could be promising in comprehensive treatment of NPC

An oncolytic adenovirus enhances antiangiogenic and antitumoral effects of a replication-deficient adenovirus encoding endostatin by rescuing its selective replication in nasopharyngeal carcinoma cells

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Liu, Ran-yi, E-mail: liuranyi@mail.sysu.edu.cn [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Zhou, Ling [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Zhang, Yan-ling [School of Biotechnology, Southern Medical University, Guangzhou 510515 (China); Huang, Bi-jun; Ke, Miao-la; Chen, Jie-min [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Li, Li-xia [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); General Hospital of Guangzhou Military Command of PLA, Guangzhou 510010 (China); Fu, Xiang; Wu, Jiang-xue [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Huang, Wenlin, E-mail: hwenl@mail.sysu.edu.cn [Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060 (China); Guangdong Provincial Key Laboratory of Tumor-Targeted Drug, Doublle Bioproducts Inc., Guangzhou 510663 (China)

2013-12-13

Highlights: •H101 promotes endostatin expression by Ad-Endo via rescuing Ad-Endo replication. •H101 rescued Ad-Endo replication by supplying E1A and E1B19k proteins. •Ad-Endo enhanced the cytotoxicity of H101 in NPC cells. •Ad-Endo and oncolytic Ad H101 have synergistic antitumor effects on NPC. -- Abstract: A replication-deficient adenovirus (Ad) encoding secreted human endostatin (Ad-Endo) has been demonstrated to have promising antiangiogenic and antitumoral effects. The E1B55k-deleted Ad H101 can selectively lyse cancer cells. In this study, we explored the antitumor effects and cross-interactions of Ad-Endo and H101 on nasopharyngeal carcinoma (NPC). The results showed that H101 dramatically promoted endostatin expression by Ad-Endo via rescuing Ad-Endo replication in NPC cells, and the expressed endostatin proteins significantly inhibited the proliferation of human umbilical vein endothelial cells. E1A and E1B19k products are required for the rescuing of H101 to Ad-Endo replication in CNE-1 and CNE-2 cells, but not in C666-1 cells. On the other hand, Ad-Endo enhanced the cytotoxicity of H101 by enhancing Ad replication in NPC cells. The combination of H101 and Ad-Endo significantly inhibited CNE-2 xenografts growth through the increased endostatin expression and Ad replication. These findings indicate that the combination of Ad-Endo gene therapy and oncolytic Ad therapeutics could be promising in comprehensive treatment of NPC.

Lister vaccine strain of vaccinia virus armed with the endostatin-angiostatin fusion gene: an oncolytic virus superior to dl1520 (ONYX-015) for human head and neck cancer.

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Tysome, James R; Wang, Pengju; Alusi, Ghassan; Briat, Arnaud; Gangeswaran, Rathi; Wang, Jiwei; Bhakta, Vipul; Fodor, Istvan; Lemoine, Nick R; Wang, Yaohe

2011-09-01

Oncolytic viral therapy represents a promising strategy for the treatment of head and neck squamous cell carcinoma (HNSCC), with dl1520 (ONYX-015) the most widely used oncolytic adenovirus in clinical trials. This study aimed to determine the effectiveness of the Lister vaccine strain of vaccinia virus as well as a vaccinia virus armed with the endostatin-angiostatin fusion gene (VVhEA) as a novel therapy for HNSCC and to compare them with dl1520. The potency and replication of the Lister strain and VVhEA and the expression and function of the fusion protein were determined in human HNSCC cells in vitro and in vivo. Finally, the efficacy of VVhEA was compared with dl1520 in vivo in a human HNSCC model. The Lister vaccine strain of vaccinia virus was more effective than the adenovirus against all HNSCC cell lines tested in vitro. Although the potency of VVhEA was attenuated in vitro, the expression and function of the endostatin-angiostatin fusion protein was confirmed in HNSCC models both in vitro and in vivo. This novel vaccinia virus (VVhEA) demonstrated superior antitumor potency in vivo compared with both dl1520 and the control vaccinia virus. This study suggests that the Lister strain vaccinia virus armed with an endostatin-angiostatin fusion gene may be a potential therapeutic agent for HNSCC.

Preclinical Safety Studies of Enadenotucirev, a Chimeric Group B Human-Specific Oncolytic Adenovirus

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Sam Illingworth

2017-06-01

Full Text Available Enadenotucirev is an oncolytic group B adenovirus identified by a process of bio-selection for the ability to selectively propagate in and rapidly kill carcinoma cells. It is resistant to inactivation by human blood components, potentially enabling intravenous dosing in patients with metastatic cancer. However, there are no known permissive animal models described for group B adenoviruses that could facilitate a conventional approach to preclinical safety studies. In this manuscript, we describe our tailored preclinical strategy designed to evaluate the key biological properties of enadenotucirev. As enadenotucirev does not replicate in animal cells, a panel of primary human cells was used to evaluate enadenotucirev replication selectivity in vitro, demonstrating that virus genome levels were >100-fold lower in normal cells relative to tumor cells. Acute intravenous tolerability in mice was used to assess virus particle-mediated toxicology and effects on innate immunity. These studies showed that particle toxicity could be ameliorated by dose fractionation, using an initial dose of virus to condition the host such that cytokine responses to subsequent doses were significantly attenuated. This, in turn, supported the initiation of a phase I intravenous clinical trial with a starting dose of 1 × 1010 virus particles given on days 1, 3, and 5.

Activation of the human immune system by chemotherapeutic or targeted agents combined with the oncolytic parvovirus H-1

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Moehler, Markus; Sieben, Maike; Roth, Susanne; Springsguth, Franziska; Leuchs, Barbara; Zeidler, Maja; Dinsart, Christiane; Rommelaere, Jean; Galle, Peter R

2011-01-01

Parvovirus H-1 (H-1PV) infects and lyses human tumor cells including melanoma, hepatoma, gastric, colorectal, cervix and pancreatic cancers. We assessed whether the beneficial effects of chemotherapeutic agents or targeted agents could be combined with the oncolytic and immunostimmulatory properties of H-1PV. Using human ex vivo models we evaluated the biological and immunological effects of H-1PV-induced tumor cell lysis alone or in combination with chemotherapeutic or targeted agents in human melanoma cells +/- characterized human cytotoxic T-cells (CTL) and HLA-A2-restricted dendritic cells (DC). H-1PV-infected MZ7-Mel cells showed a clear reduction in cell viability of >50%, which appeared to occur primarily through apoptosis. This correlated with viral NS1 expression levels and was enhanced by combination with chemotherapeutic agents or sunitinib. Tumor cell preparations were phagocytosed by DC whose maturation was measured according to the treatment administered. Immature DC incubated with H-1PV-induced MZ7-Mel lysates significantly increased DC maturation compared with non-infected or necrotic MZ7-Mel cells. Tumor necrosis factor-α and interleukin-6 release was clearly increased by DC incubated with H-1PV-induced SK29-Mel tumor cell lysates (TCL) and was also high with DC-CTL co-cultures incubated with H-1PV-induced TCL. Similarly, DC co-cultures with TCL incubated with H-1PV combined with cytotoxic agents or sunitinib enhanced DC maturation to a greater extent than cytotoxic agents or sunitinib alone. Again, these combinations increased pro-inflammatory responses in DC-CTL co-cultures compared with chemotherapy or sunitinib alone. In our human models, chemotherapeutic or targeted agents did not only interfere with the pronounced immunomodulatory properties of H-1PV, but also reinforced drug-induced tumor cell killing. H-1PV combined with cisplatin, vincristine or sunitinib induced effective immunostimulation via a pronounced DC maturation, better cytokine

Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication.

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Passer, Brent J; Cheema, Tooba; Zhou, Bingsen; Wakimoto, Hiroaki; Zaupa, Cecile; Razmjoo, Mani; Sarte, Jason; Wu, Shulin; Wu, Chin-lee; Noah, James W; Li, Qianjun; Buolamwini, John K; Yen, Yun; Rabkin, Samuel D; Martuza, Robert L

2010-05-15

Oncolytic herpes simplex virus-1 (oHSV) vectors selectively replicate in tumor cells, where they kill through oncolysis while sparing normal cells. One of the drawbacks of oHSV vectors is their limited replication and spread to neighboring cancer cells. Here, we report the outcome of a high-throughput chemical library screen to identify small-molecule compounds that augment the replication of oHSV G47Delta. Of the 2,640-screened bioactives, 6 compounds were identified and subsequently validated for enhanced G47Delta replication. Two of these compounds, dipyridamole and dilazep, interfered with nucleotide metabolism by potently and directly inhibiting the equilibrative nucleoside transporter-1 (ENT1). Replicative amplification promoted by dipyridamole and dilazep were dependent on HSV mutations in ICP6, the large subunit of ribonucleotide reductase. Our results indicate that ENT1 antagonists augment oHSV replication in tumor cells by increasing cellular ribonucleoside activity. (c)2010 AACR.

Molecular network, pathway, and functional analysis of time-dependent gene changes associated with pancreatic cancer susceptibility to oncolytic vaccinia virotherapy

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Dana Haddad

2016-01-01

Conclusions: Our study reveals the ability to assess time-dependent changes in gene expression patterns in pancreatic cancer cells associated with infection and susceptibility to vaccinia viruses. This suggests that molecular assays may be useful to develop safer and more efficacious oncolyticvirotherapies and support the idea that these treatments may target pathways implicated in pancreatic cancer resistance to conventional therapies.

Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity.

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Angelova, Assia L; Barf, Milena; Geletneky, Karsten; Unterberg, Andreas; Rommelaere, Jean

2017-12-15

Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and clinical investigation. Oncolytic viruses, including the autonomous protoparvovirus H-1 (H-1PV), show great promise as novel immunotherapeutic tools. In a first phase I/IIa clinical trial (ParvOryx01), H-1PV was safe and well tolerated when locally or systemically administered to recurrent glioblastoma patients. The virus was able to cross the blood-brain (tumor) barrier after intravenous infusion. Importantly, H-1PV treatment of glioblastoma patients was associated with immunogenic changes in the tumor microenvironment. Tumor infiltration with activated cytotoxic T cells, induction of cathepsin B and inducible nitric oxide (NO) synthase (iNOS) expression in tumor-associated microglia/macrophages (TAM), and accumulation of activated TAM in cluster of differentiation (CD) 40 ligand (CD40L)-positive glioblastoma regions was detected. These are the first-in-human observations of H-1PV capacity to switch the immunosuppressed tumor microenvironment towards immunogenicity. Based on this pilot study, we present a tentative model of H-1PV-mediated modulation of glioblastoma microenvironment and propose a combinatorial therapeutic approach taking advantage of H-1PV-induced microglia/macrophage activation for further (pre)clinical testing.

Probing the Oncolytic and Chemosensitizing Effects of Dihydrotanshinone in an In Vitro Glioblastoma Model.

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Kumar, Varun; Radin, Daniel; Leonardi, Donna

2017-11-01

Temozolomide is the primary chemotherapeutic agent used to treat glioblastoma. However, many tumors are initially resistant to or develop resistance to temozolomide, mainly due to high levels of O 6 -methylguanine DNA transferase (MGMT) which repairs DNA damage traditionally caused by temozolomide. Dihydrotanshinone (DHT) is extracted from Salvia miltiorrhiza, a Chinese medicinal plant, and has also been shown to have antiproliferative effects on various cancer cell lines. DHT has been to shown to induce apoptosis via induction endoplasmic reticulum stress, that can reportedly sensitize cells to temozolomide. MTS cellular proliferation assays or trypan blue viability assays were used to determine the effects of DHT/temozolomide combinatorial treatment. Enzyme-linked immunosorbent assay (ELISA) was used to determine effects on MGMT and P-glycoprotein levels after singular and combinatorial treatment. DHT had a synergistic oncolytic effect in a MGMT-deficient cell line and a sensitizing effect in a MGMT-expressing cell line. Cytotoxicity due to DHT was shown to be reactive oxygen species-dependent, while the combinatorial effect of DHT and temozolomide synergistically reduced MGMT and P-glycoprotein levels. DHT was shown to augment temozolomide efficacy, indicating that, since DHT can penetrate the blood-brain barrier, temozolomide in combination with DHT may represent a promising therapeutic option for glioblastoma. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Maraba MG1 Virus Enhances Natural Killer Cell Function via Conventional Dendritic Cells to Reduce Postoperative Metastatic Disease

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Zhang, Jiqing; Tai, Lee-Hwa; Ilkow, Carolina S; Alkayyal, Almohanad A; Ananth, Abhirami A; de Souza, Christiano Tanese; Wang, Jiahu; Sahi, Shalini; Ly, Lundi; Lefebvre, Charles; Falls, Theresa J; Stephenson, Kyle B; Mahmoud, Ahmad B; Makrigiannis, Andrew P; Lichty, Brian D; Bell, John C; Stojdl, David F; Auer, Rebecca C

2014-01-01

This study characterizes the ability of novel oncolytic rhabdoviruses (Maraba MG1) to boost natural killer (NK) cell activity. Our results demonstrate that MG1 activates NK cells via direct infection and maturation of conventional dendritic cells. Using NK depletion and conventional dendritic cells ablation studies in vivo, we established that both are required for MG1 efficacy. We further explored the efficacy of attenuated MG1 (nonreplicating MG1-UV2min and single-cycle replicating MG1-Gless) and demonstrated that these viruses activate conventional dendritic cells, although to a lesser extent than live MG1. This translates to equivalent abilities to remove tumor metastases only at the highest viral doses of attenuated MG1. In tandem, we characterized the antitumor ability of NK cells following preoperative administration of live and attenuated MG1. Our results demonstrates that a similar level of NK activation and reduction in postoperative tumor metastases was achieved with equivalent high viral doses concluding that viral replication is important, but not necessary for NK activation. Biochemical characterization of a panel of UV-inactivated MG1 (2–120 minutes) revealed that intact viral particle and target cell recognition are essential for NK cell–mediated antitumor responses. These findings provide mechanistic insight and preclinical rationale for safe perioperative virotherapy to effectively reduce metastatic disease following cancer surgery. PMID:24695102

Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway

International Nuclear Information System (INIS)

Twigger, Katie; Coffey, Matt; Thompson, Brad; Jebar, Adel; Errington, Fiona; Melcher, Alan A; Vile, Richard G; Pandha, Hardev S; Harrington, Kevin J; Roulstone, Victoria; Kyula, Joan; Karapanagiotou, Eleni M; Syrigos, Konstantinos N; Morgan, Richard; White, Christine; Bhide, Shreerang; Nuovo, Gerard

2012-01-01

Reovirus exploits aberrant signalling downstream of Ras to mediate tumor-specific oncolysis. Since ~90% squamous cell carcinomas of the head and neck (SCCHN) over-express EGFR and SCCHN cell lines are sensitive to oncolytic reovirus, we conducted a detailed analysis of the effects of reovirus in 15 head and neck cancer cell lines. Both pre- and post-entry events were studied in an attempt to define biomarkers predictive of sensitivity/resistance to reovirus. In particular, we analysed the role of EGFR/Ras signalling in determining virus-mediated cytotoxicity in SCCHN. To test whether EGFR pathway activity was predictive of increased sensitivity to reovirus, correlative analyses between reoviral IC50 by MTT assay and EGFR levels by western blot and FACS were conducted. Inhibition or stimulation of EGFR signalling were analysed for their effect on reoviral oncolysis by MTT assay, and viral growth by TCID50 assay. We next analysed the effects of inhibiting signalling downstream of Ras, by specific inhibitors of p38MAPK, PI3-K or MEK, on reoviral killing examined by MTT assay. The role of PKR in reoviral killing was also determined by blockade of PKR using 2-aminopurine and assaying for cell survival by MTT assay. The apoptotic response of SCCHN to reovirus was examined by western blot analysis of caspase 3 cleavage. Correlative analyses between reoviral sensitivity and EGFR levels revealed no association. Intermediate sub-viral and core particles showed the same infectivity/cytotoxicity as intact reovirus. Therefore, sensitivity was not determined by cell entry. In 4 cell lines, oncolysis and viral growth were both unaffected by inhibition or stimulation of EGFR signalling. Inhibition of signalling downstream of Ras did not abrogate reoviral oncolysis and, in addition, modulation of PKR using 2-aminopurine did not alter reovirus sensitivity in resistant cell lines. Caspase 3 cleavage was not detected in infected cells and oncolysis was observed in pan

Histone deacetylase inhibitors improve the replication of oncolytic herpes simplex virus in breast cancer cells.

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James J Cody

Full Text Available New therapies are needed for metastatic breast cancer patients. Oncolytic herpes simplex virus (oHSV is an exciting therapy being developed for use against aggressive tumors and established metastases. Although oHSV have been demonstrated safe in clinical trials, a lack of sufficient potency has slowed the clinical application of this approach. We utilized histone deacetylase (HDAC inhibitors, which have been noted to impair the innate antiviral response and improve gene transcription from viral vectors, to enhance the replication of oHSV in breast cancer cells. A panel of chemically diverse HDAC inhibitors were tested at three different doses (LD50 for their ability to modulate the replication of oHSV in breast cancer cells. Several of the tested HDAC inhibitors enhanced oHSV replication at low multiplicity of infection (MOI following pre-treatment of the metastatic breast cancer cell line MDA-MB-231 and the oHSV-resistant cell line 4T1, but not in the normal breast epithelial cell line MCF10A. Inhibitors of class I HDACs, including pan-selective compounds, were more effective for increasing oHSV replication compared to inhibitors that selectively target class II HDACs. These studies demonstrate that select HDAC inhibitors increase oHSV replication in breast cancer cells and provides support for pre-clinical evaluation of this combination strategy.

Reduction of virion-associated σ1 fibers on oncolytic reovirus variants promotes adaptation toward tumorigenic cells.

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Mohamed, Adil; Teicher, Carmit; Haefliger, Sarah; Shmulevitz, Maya

2015-04-01

Wild-type mammalian orthoreovirus serotype 3 Dearing (T3wt) is nonpathogenic in humans but preferentially infects and kills cancer cells in culture and demonstrates promising antitumor activity in vivo. Using forward genetics, we previously isolated two variants of reovirus, T3v1 and T3v2, with increased infectivity toward a panel of cancer cell lines and improved in vivo oncolysis in a murine melanoma model relative to that of T3wt. Our current study explored how mutations in T3v1 and T3v2 promote infectivity. Reovirions contain trimers of σ1, the reovirus cell attachment protein, at icosahedral capsid vertices. Quantitative Western blot analysis showed that purified T3v1 and T3v2 virions had ∼ 2- and 4-fold-lower levels of σ1 fiber than did T3wt virions. Importantly, using RNA interference to reduce σ1 levels during T3wt production, we were able to generate wild-type reovirus with reduced levels of σ1 per virion. As σ1 levels were reduced, virion infectivity increased by 2- to 5-fold per cell-bound particle, demonstrating a causal relationship between virion σ1 levels and the infectivity of incoming virions. During infection of tumorigenic L929 cells, T3wt, T3v1, and T3v2 uncoated the outer capsid proteins σ3 and μ1C at similar rates. However, having started with fewer σ1 molecules, a complete loss of σ1 was achieved sooner for T3v1 and T3v2. Distinct from intracellular uncoating, chymotrypsin digestion, as a mimic of natural enteric infection, resulted in more rapid σ3 and μ1C removal, unique disassembly intermediates, and a rapid loss of infectivity for T3v1 and T3v2 compared to T3wt. Optimal infectivity toward natural versus therapeutic niches may therefore require distinct reovirus structures and σ1 levels. Wild-type reovirus is currently in clinical trials as a potential cancer therapy. Our molecular studies on variants of reovirus with enhanced oncolytic activity in vitro and in vivo now show that distinct reovirus structures promote

Safety and biodistribution of a double-deleted oncolytic vaccinia virus encoding CD40 ligand in laboratory Beagles

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Karoliina Autio

2014-01-01

Full Text Available We evaluated adverse events, biodistribution and shedding of oncolytic vaccinia virus encoding CD40 ligand in two Beagles, in preparation for a phase 1 trial in canine cancer patients. Dog 1 received one dose of vaccinia virus and was euthanized 24 hours afterwards, while dog 2 received virus four times once weekly and was euthanized 7 days after that. Dogs were monitored for adverse events and underwent a detailed postmortem examination. Blood, saliva, urine, feces, and organs were collected for virus detection. Dog 1 had mild fever and lethargy while dog 2 experienced a possible seizure 5.5 hours after first virus administration. Viral DNA declined quickly in the blood after virus administration in both dogs but was still detectable 1 week later by quantitative polymerase chain reaction. Only samples taken directly after virus infusion contained infectious virus. Small amounts of viral DNA, but no infectious virus, were detected in a few saliva and urine samples. Necropsies did not reveal any relevant pathological changes and virus DNA was detected mainly in the spleen. The dogs in the study did not have cancer, and thus adverse events could be more common and viral load higher in dogs with tumors which allow viral amplification.

Anti-cancer effect of oncolytic adenovirus-armed shRNA targeting MYCN gene on doxorubicin-resistant neuroblastoma cells.

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Li, Yuan; Zhuo, Baobiao; Yin, Yiyu; Han, Tao; Li, Shixian; Li, Zhengwei; Wang, Jian

2017-09-09

Chemotherapy is one of the few effective choices for patients with neuroblastoma. However, the development of muti-drug resistance (MDR) to chemotherapy is a major obstacle to the effective treatment of advanced or recurrent neuroblastoma. The muti-drug resistance-associated protein (MRP), which encodes a transmembrane glycoprotein, is a key regulator of MDR. The expression of MRP is a close correlation with MYCN oncogene in neuroblastoma. We have recently shown ZD55-shMYCN (oncolytic virus armed with shRNA against MYCN) can down-regulate MYCN to inhibit tumor cells proliferation and induce apoptosis in neuroblastoma. Here we further report ZD55-shMYCN re-sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis, and inhibited cell migration), and reduced the in vivo growth rate of neuroblastoma xenografts by down-regulation of MRP expression. Sequential therapy with doxorubicin did not affect the replication of ZD55-shMYCN in doxorubicin-resistant neuroblastoma cells, but decreased the expression of Bcl-2, Bcl-X L , MMP-1. Thus, this synergistic effect of ZD55-shMYCN in combination with doxorubicin provides a novel therapy strategy for doxorubicin-resistant neuroblastoma, and is a promising approach for further clinical development. Copyright © 2017 Elsevier Inc. All rights reserved.

Dynamics of melanoma tumor therapy with vesicular stomatitis virus: explaining the variability in outcomes using mathematical modeling.

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Rommelfanger, D M; Offord, C P; Dev, J; Bajzer, Z; Vile, R G; Dingli, D

2012-05-01

Tumor selective, replication competent viruses are being tested for cancer gene therapy. This approach introduces a new therapeutic paradigm due to potential replication of the therapeutic agent and induction of a tumor-specific immune response. However, the experimental outcomes are quite variable, even when studies utilize highly inbred strains of mice and the same cell line and virus. Recognizing that virotherapy is an exercise in population dynamics, we utilize mathematical modeling to understand the variable outcomes observed when B16ova malignant melanoma tumors are treated with vesicular stomatitis virus in syngeneic, fully immunocompetent mice. We show how variability in the initial tumor size and the actual amount of virus delivered to the tumor have critical roles on the outcome of therapy. Virotherapy works best when tumors are small, and a robust innate immune response can lead to superior tumor control. Strategies that reduce tumor burden without suppressing the immune response and methods that maximize the amount of virus delivered to the tumor should optimize tumor control in this model system.

The Oncolytic Virus MG1 Targets and Eliminates Cells Latently Infected With HIV-1: Implications for an HIV Cure.

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Ranganath, Nischal; Sandstrom, Teslin S; Burke Schinkel, Stephanie C; Côté, Sandra C; Angel, Jonathan B

2018-02-14

Cells latently infected with human immunodeficiency virus (HIV) evade immune- and drug-mediated clearance. These cells harbor intracellular signaling defects, including impairment of the antiviral type I interferon response. Such defects have also been observed in several cancers and have been exploited for the development of therapeutic oncolytic viruses, including the recombinant Maraba virus (MG1). We therefore hypothesized that MG1 would infect and eliminate cells latently infected with HIV-1, while sparing healthy uninfected cells. Preferential infection and elimination by MG1 was first demonstrated in cell lines latently infected with HIV-1. Following this, a reduction in HIV-1 DNA and inducible HIV-1 replication was observed following MG1 infection of latently infected, resting CD4+ T cells generated using an in vitro model of latency. Last, MG1 infection resulted in a reduction in HIV-1 DNA and inducible HIV-1 replication in memory CD4+ T cells isolated from effectively treated, HIV-1-infected individuals. Our results therefore highlight a novel approach to eliminate the latent HIV-1 reservoir. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas.

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Li, Junwei; Bonifati, Serena; Hristov, Georgi; Marttila, Tiina; Valmary-Degano, Séverine; Stanzel, Sven; Schnölzer, Martina; Mougin, Christiane; Aprahamian, Marc; Grekova, Svitlana P; Raykov, Zahari; Rommelaere, Jean; Marchini, Antonio

2013-10-01

The rat parvovirus H-1PV has oncolytic and tumour-suppressive properties potentially exploitable in cancer therapy. This possibility is being explored and results are encouraging, but it is necessary to improve the oncotoxicity of the virus. Here we show that this can be achieved by co-treating cancer cells with H-1PV and histone deacetylase inhibitors (HDACIs) such as valproic acid (VPA). We demonstrate that these agents act synergistically to kill a range of human cervical carcinoma and pancreatic carcinoma cell lines by inducing oxidative stress, DNA damage and apoptosis. Strikingly, in rat and mouse xenograft models, H-1PV/VPA co-treatment strongly inhibits tumour growth promoting complete tumour remission in all co-treated animals. At the molecular level, we found acetylation of the parvovirus nonstructural protein NS1 at residues K85 and K257 to modulate NS1-mediated transcription and cytotoxicity, both of which are enhanced by VPA treatment. These results warrant clinical evaluation of H-1PV/VPA co-treatment against cervical and pancreatic ductal carcinomas. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allows their intratumoral delivery and an improved tumor-growth inhibition.

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Kleinpeter, Patricia; Fend, Laetitia; Thioudellet, Christine; Geist, Michel; Sfrontato, Nathalie; Koerper, Véronique; Fahrner, Catherine; Schmitt, Doris; Gantzer, Murielle; Remy-Ziller, Christelle; Brandely, Renée; Villeval, Dominique; Rittner, Karola; Silvestre, Nathalie; Erbs, Philippe; Zitvogel, Laurence; Quéméneur, Eric; Préville, Xavier; Marchand, Jean-Baptiste

2016-01-01

We report here the successful vectorization of a hamster monoclonal IgG (namely J43) recognizing the murine Programmed cell death-1 (mPD-1) in Western Reserve (WR) oncolytic vaccinia virus. Three forms of mPD-1 binders have been inserted into the virus: whole antibody (mAb), Fragment antigen-binding (Fab) or single-chain variable fragment (scFv). MAb, Fab and scFv were produced and assembled with the expected patterns in supernatants of cells infected by the recombinant viruses. The three purified mPD-1 binders were able to block the binding of mPD-1 ligand to mPD-1 in vitro . Moreover, mAb was detected in tumor and in serum of C57BL/6 mice when the recombinant WR-mAb was injected intratumorally (IT) in B16F10 and MCA 205 tumors. The concentration of circulating mAb detected after IT injection was up to 1,900-fold higher than the level obtained after a subcutaneous (SC) injection (i.e., without tumor) confirming the virus tropism for tumoral cells and/or microenvironment. Moreover, the overall tumoral accumulation of the mAb was higher and lasted longer after IT injection of WR-mAb1, than after IT administration of 10 µg of J43. The IT injection of viruses induced a massive infiltration of immune cells including activated lymphocytes (CD8 + and CD4 + ). Interestingly, in the MCA 205 tumor model, WR-mAb1 and WR-scFv induced a therapeutic control of tumor growth similar to unarmed WR combined to systemically administered J43 and superior to that obtained with an unarmed WR. These results pave the way for next generation of oncolytic vaccinia armed with immunomodulatory therapeutic proteins such as mAbs.

Targeting human breast cancer cells by an oncolytic adenovirus using microRNA-targeting strategy.

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Shayestehpour, Mohammad; Moghim, Sharareh; Salimi, Vahid; Jalilvand, Somayeh; Yavarian, Jila; Romani, Bizhan; Mokhtari-Azad, Talat

2017-08-15

MicroRNA-targeting strategy is a promising approach that enables oncolytic viruses to replicate in tumor cells but not in normal cells. In this study, we targeted adenoviral replication toward breast cancer cells by inserting ten complementary binding sites for miR-145-5p downstream of E1A gene. In addition, we evaluated the effect of increasing miR-145 binding sites on inhibition of virus replication. Ad5-control and adenoviruses carrying five or ten copies of miR145-5p target sites (Ad5-5miR145T, Ad5-10miR145T) were generated and inoculated into MDA-MB-453, BT-20, MCF-7 breast cancer cell lines and human mammary epithelial cells (HMEpC). Titer of Ad5-10miR145T in HMEpC was significantly lower than Ad5-control titer. Difference between the titer of these two viruses at 12, 24, 36, and 48h after infection was 1.25, 2.96, 3.06, and 3.77 log TCID 50 . No significant difference was observed between the titer of both adenoviruses in MDA-MB-453, BT-20 and MCF-7 cells. The infectious titer of adenovirus containing 10 miR-145 binding sites in HMEpC cells at 24, 36, and 48h post-infection was 1.7, 2.08, and 4-fold, respectively, lower than the titer of adenovirus carrying 5 miR-145 targets. Our results suggest that miR-145-targeting strategy provides selectivity for adenovirus replication in breast cancer cells. Increasing the number of miRNA binding sites within the adenoviral genome confers more selectivity for viral replication in cancer cells. Copyright © 2017. Published by Elsevier B.V.

Oncolytic measles virus enhances antitumour responses of adoptive CD8+NKG2D+ cells in hepatocellular carcinoma treatment.

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Chen, Aiping; Zhang, Yonghui; Meng, Gang; Jiang, Dengxu; Zhang, Hailin; Zheng, Meihong; Xia, Mao; Jiang, Aiqin; Wu, Junhua; Beltinger, Christian; Wei, Jiwu

2017-07-12

There is an urgent need for novel effective treatment for hepatocellular carcinoma (HCC). Oncolytic viruses (OVs) not only directly lyse malignant cells, but also induce potent antitumour immune responses. The potency and precise mechanisms of antitumour immune activation by attenuated measles virus remain unclear. In this study, we investigated the potency of the measles virus vaccine strain Edmonston (MV-Edm) in improving adoptive CD8 + NKG2D + cells for HCC treatment. We show that MV-Edm-infected HCC enhanced the antitumour activity of CD8 + NKG2D + cells, mediated by at least three distinct mechanisms. First, MV-Edm infection compelled HCC cells to express the specific NKG2D ligands MICA/B, which may contribute to the activation of CD8 + NKG2D + cells. Second, MV-Edm-infected HCC cells stimulated CD8 + NKG2D + cells to express high level of FasL resulting in enhanced induction of apoptosis. Third, intratumoural administration of MV-Edm enhanced infiltration of intravenously injected CD8 + NKG2D + cells. Moreover, we found that MV-Edm and adoptive CD8 + NKG2D + cells, either administered alone or combined, upregulated the immune suppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in HCC. Elimination of IDO1 by fludarabine enhanced antitumour responses. Taken together, our data provide a novel and clinically relevant strategy for treatment of HCC.

Fusion of the BCL9 HD2 domain to E1A increases the cytopathic effect of an oncolytic adenovirus that targets colon cancer cells

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Pittet Anne-Laure

2006-10-01

Full Text Available Abstract Background The Wnt signaling pathway is activated by mutations in the APC and β-catenin genes in many types of human cancer. β-catenin is stabilized by these mutations and activates transcription in part by acting as a bridge between Tcf/LEF proteins and the HD2 domain of the BCL9 coactivator. We have previously described oncolytic adenoviruses with binding sites for Tcf/LEF transcription factors inserted into the early viral promoters. These viruses replicate selectively in cells with activation of the Wnt pathway. To increase the activity of these viruses we have fused the viral transactivator E1A to the BCL9 HD2 domain. Methods Luciferase assays, co-immunoprecipitation and Western blotting, immunofluorescent cell staining and cytopathic effect assays were used to characterize the E1A-HD2 fusion protein and virus in vitro. Growth curves of subcutaneous SW620 colon cancer xenografts were used to characterize the virus in vivo. Results The E1A-HD2 fusion protein binds to β-catenin in vivo and activates a Tcf-regulated luciferase reporter better than wild-type E1A in cells with activated Wnt signaling. Expression of the E1A-HD2 protein promotes nuclear import of β-catenin, mediated by the strong nuclear localization signal in E1A. Tcf-regulated viruses expressing the fusion protein show increased expression of viral proteins and a five-fold increase in cytopathic effect (CPE in colorectal cancer cell lines. There was no change in viral protein expression or CPE in HeLa cells, indicating that E1A-HD2 viruses retain selectivity for cells with activation of the Wnt signaling pathway. Despite increasing the cytopathic effect of the virus in vitro, fusion of the HD2 domain to E1A did not increase the burst size of the virus in vitro or the anti-tumor effect of the virus in an SW620 xenograft model in vivo. Conclusion Despite an increase in the nuclear pool of β-catenin, the effects on viral activity in colon cancer cells were small

Ultrasound-induced cavitation enhances the delivery and therapeutic efficacy of an oncolytic virus in an in vitro model.

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Bazan-Peregrino, Miriam; Arvanitis, Costas D; Rifai, Bassel; Seymour, Leonard W; Coussios, Constantin-C

2012-01-30

We investigated whether ultrasound-induced cavitation at 0.5 MHz could improve the extravasation and distribution of a potent breast cancer-selective oncolytic adenovirus, AdEHE2F-Luc, to tumour regions that are remote from blood vessels. We developed a novel tumour-mimicking model consisting of a gel matrix containing human breast cancer cells traversed by a fluid channel simulating a tumour blood vessel, through which the virus and microbubbles could be made to flow. Ultrasonic pressures were chosen to maximize either broadband emissions, associated with inertial cavitation, or ultraharmonic emissions, associated with stable cavitation, while varying duty cycle to keep the total acoustic energy delivered constant for comparison across exposures. None of the exposure conditions tested affected cell viability in the absence of the adenovirus. When AdEHE2F-Luc was delivered via the vessel, inertial cavitation increased transgene expression in tumour cells by up to 200 times. This increase was not observed in the absence of Coxsackie and Adenovirus Receptor cell expression, discounting sonoporation as the mechanism of action. In the presence of inertial cavitation, AdEHE2F-Luc distribution was greatly improved in the matrix surrounding the vessel, particularly in the direction of the ultrasound beam; this enabled AdEHE2F-Luc to kill up to 80% of cancer cells within the ultrasound focal volume in the gel 24 hours after delivery, compared to 0% in the absence of cavitation. Copyright © 2011 Elsevier B.V. All rights reserved.

Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs

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Kazue Kasai

2013-01-01

Full Text Available MGH2.1 is a herpes simplex virus type 1 (HSV1 oncolytic virus that expresses two prodrug-activating transgenes: the cyclophosphamide (CPA-activating cytochrome P4502B1 (CYP2B1 and the CPT11-activating secreted human intestinal carboxylesterase (shiCE. Toxicology and biodistribution of MGH2.1 in the presence/absence of prodrugs was evaluated in mice. MGH2.1 ± prodrugs was cytotoxic to human glioma cells, but not to normal cells. Pharmacokinetically, intracranial MGH2.1 did not significantly alter the metabolism of intraperitoneally (i.p. administered prodrugs in mouse plasma, brain, or liver. MGH2.1 did not induce an acute inflammatory reaction. MGH2.1 DNA was detected in brains of mice inoculated with 108 pfus for up to 60 days. However, only one animal showed evidence of viral gene expression at this time. Expression of virally encoded genes was restricted to brain. Intracranial inoculation of MGH2.1 did not induce lethality at 108 pfus in the absence of prodrugs and at 106 pfus in the presence of prodrugs. This study provides safety and toxicology data justifying a possible clinical trial of intratumoral injection of MGH2.1 with peripheral administration of CPA and/or CPT11 prodrugs in humans with malignant gliomas.

Preclinical Testing of an Oncolytic Parvovirus: Standard Protoparvovirus H-1PV Efficiently Induces Osteosarcoma Cell Lysis In Vitro.

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Geiss, Carsten; Kis, Zoltán; Leuchs, Barbara; Frank-Stöhr, Monika; Schlehofer, Jörg R; Rommelaere, Jean; Dinsart, Christiane; Lacroix, Jeannine

2017-10-17

Osteosarcoma is the most frequent malignant disease of the bone. On the basis of early clinical experience in the 1960s with H-1 protoparvovirus (H-1PV) in osteosarcoma patients, this effective oncolytic virus was selected for systematic preclinical testing on various osteosarcoma cell cultures. A panel of five human osteosarcoma cell lines (CAL 72, H-OS, MG-63, SaOS-2, U-2OS) was tested. Virus oncoselectivity was confirmed by infecting non-malignant human neonatal fibroblasts and osteoblasts used as culture models of non-transformed mesenchymal cells. H-1PV was found to enter osteosarcoma cells and to induce viral DNA replication, transcription of viral genes, and translation to viral proteins. After H-1PV infection, release of infectious viral particles from osteosarcoma cells into the supernatant indicated successful viral assembly and egress. Crystal violet staining revealed progressive cytomorphological changes in all osteosarcoma cell lines. Infection of osteosarcoma cell lines with the standard H-1PV caused an arrest of the cell cycle in the G2 phase, and these lines had a limited capacity for standard H-1PV virus replication. The cytotoxicity of wild-type H-1PV virus towards osteosarcoma cells was compared in vitro with that of two variants, Del H-1PV and DM H-1PV, previously described as fitness variants displaying higher infectivity and spreading in human transformed cell lines of different origins. Surprisingly, wild-type H-1PV displayed the strongest cytostatic and cytotoxic effects in this analysis and thus seems the most promising for the next preclinical validation steps in vivo.

Preclinical Testing of an Oncolytic Parvovirus: Standard Protoparvovirus H-1PV Efficiently Induces Osteosarcoma Cell Lysis In Vitro

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Carsten Geiss

2017-10-01

Full Text Available Osteosarcoma is the most frequent malignant disease of the bone. On the basis of early clinical experience in the 1960s with H-1 protoparvovirus (H-1PV in osteosarcoma patients, this effective oncolytic virus was selected for systematic preclinical testing on various osteosarcoma cell cultures. A panel of five human osteosarcoma cell lines (CAL 72, H-OS, MG-63, SaOS-2, U-2OS was tested. Virus oncoselectivity was confirmed by infecting non-malignant human neonatal fibroblasts and osteoblasts used as culture models of non-transformed mesenchymal cells. H-1PV was found to enter osteosarcoma cells and to induce viral DNA replication, transcription of viral genes, and translation to viral proteins. After H-1PV infection, release of infectious viral particles from osteosarcoma cells into the supernatant indicated successful viral assembly and egress. Crystal violet staining revealed progressive cytomorphological changes in all osteosarcoma cell lines. Infection of osteosarcoma cell lines with the standard H-1PV caused an arrest of the cell cycle in the G2 phase, and these lines had a limited capacity for standard H-1PV virus replication. The cytotoxicity of wild-type H-1PV virus towards osteosarcoma cells was compared in vitro with that of two variants, Del H-1PV and DM H-1PV, previously described as fitness variants displaying higher infectivity and spreading in human transformed cell lines of different origins. Surprisingly, wild-type H-1PV displayed the strongest cytostatic and cytotoxic effects in this analysis and thus seems the most promising for the next preclinical validation steps in vivo.

Glioma stem cells targeted by oncolytic virus carrying endostatin-angiostatin fusion gene and the expression of its exogenous gene in vitro.

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Zhu, Guidong; Su, Wei; Jin, Guishan; Xu, Fujian; Hao, Shuyu; Guan, Fangxia; Jia, William; Liu, Fusheng

2011-05-16

The development of the cancer stem cell (CSCs) niche theory has provided a new target for the treatment of gliomas. Gene therapy using oncolytic viral vectors has shown great potential for the therapeutic targeting of CSCs. To explore whether a viral vector carrying an exogenous Endo-Angio fusion gene (VAE) can infect and kill glioma stem cells (GSCs), as well as inhibit their vascular niche in vitro, we have collected surgical specimens of human high-grade glioma (world health organization, WHO Classes III-VI) from which we isolated and cultured GSCs under conditions originally designed for the selective expansion of neural stem cells. Our results demonstrate the following: (1) Four lines of GSCs (isolated from 20 surgical specimens) could grow in suspension, were multipotent, had the ability to self-renew and expressed the neural stem cell markers, CD133 and nestin. (2) VAE could infect GSCs and significantly inhibit their viability. (3) The Endo-Angio fusion gene was expressed in GSCs 48 h after VAE infection and could inhibit the proliferation of human brain microvascular endothelial cells (HBMEC). (4) Residual viable cells lose the ability of self-renewal and adherent differentiation. In conclusion, VAE can significantly inhibit the activity of GSCs in vitro and the expression of exogenous Endo-Angio fusion gene can inhibit HBMEC proliferation. VAE can be used as a novel virus-gene therapy strategy for glioma. Copyright © 2011 Elsevier B.V. All rights reserved.

Inventory of oral anticancer agents : Pharmaceutical formulation aspects with focus on the solid dispersion technique

NARCIS (Netherlands)

Sawicki, E.; Schellens, J. H M; Beijnen, J. H.; Nuijen, B.

2016-01-01

Dissolution from the pharmaceutical formulation is a prerequisite for complete and consistent absorption of any orally administered drug, including anticancer agents (oncolytics). Poor dissolution of an oncolytic can result in low oral bioavailability, high variability in blood concentrations and

Phase I/IIa study of intratumoral/intracerebral or intravenous/intracerebral administration of Parvovirus H-1 (ParvOryx) in patients with progressive primary or recurrent glioblastoma multiforme: ParvOryx01 protocol

International Nuclear Information System (INIS)

Geletneky, Karsten; Hajda, Jacek; Huesing, Johannes; Rommelaere, Jean; Schlehofer, Joerg R; Leuchs, Barbara; Dahm, Michael; Krebs, Ottheinz; Knebel Doeberitz, Magnus von; Huber, Bernard

2012-01-01

The treatment of patients with malignant brain tumors remains a major oncological problem. The median survival of patients with glioblastoma multiforme (GBM), the most malignant type, is only 15 months after initial diagnosis and even less after tumor recurrence. Improvements of standard treatment including surgery and radio-chemotherapy have not lead to major improvements. Therefore, alternative therapeutics such as oncolytic viruses that specifically target and destroy cancer cells are under investigation. Preclinical data of oncolytic parvovirus H-1 (H-1PV) infection of glioma cells demonstrated strong cytotoxic and oncosuppressing effects, leading to a phase I/IIa trial of H-1PV in patients with recurrent GBM (ParvOryx01). ParvOryx01 is the first trial with a replication competent oncolytic virus in Germany. ParvOryx01 is an open, non-controlled, two groups, intra-group dose escalation, single center, phase I/IIa trial. 18 patients with recurrent GBM will be treated in 2 groups of 9 patients each. Treatment group 1 will first receive H-1PV by intratumoral injection and second by administration into the walls of the tumor cavity during tumor resection. In treatment group 2 the virus will initially be injected intravenously and afterwards, identical to group 1, into the surrounding brain tissue during tumor removal. Main eligibility criteria are: age of 18 years, unifocal recurrent GBM, amenable to complete or subtotal resection. Dose escalation will be based on the Continual Reassessment Method. The primary objective of the trial is local and systemic safety and tolerability and to determine the maximum tolerated dose (MTD). Secondary objectives are proof of concept (PoC) and Progression-free Survival (PFS) up to 6 months. This is the first trial with H-1PV in patients with recurrent GBM. The risks for the participants appear well predictable and justified. Furthermore, ParvOryx01 will be the first assessment of combined intratumoral and intravenous application

Use of Tissue-Specific MicroRNA to Control Pathology of Wild-Type Adenovirus without Attenuation of Its Ability to Kill Cancer Cells

NARCIS (Netherlands)

Cawood, R.; Chen, H.H.; Carroll, F.; Bazan-Peregrino, M.; Rooijen, van N.; Seymour, L.W.

2009-01-01

Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines; however, uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective

Overcoming tumor resistance by heterologous adeno-poxvirus combination therapy

Directory of Open Access Journals (Sweden)

Markus Vähä-Koskela

2014-01-01

Full Text Available Successful cancer control relies on overcoming resistance to cell death and on activation of host antitumor immunity. Oncolytic viruses are particularly attractive in this regard, as they lyse infected tumor cells and trigger robust immune responses during the infection. However, repeated injections of the same virus promote antiviral rather than antitumor immunity and tumors may mount innate antiviral defenses to restrict oncolytic virus replication. In this article, we have explored if alternating the therapy virus could circumvent these problems. We demonstrate in two virus-resistant animal models a substantial delay in antiviral immune- and innate cellular response induction by alternating injections of two immunologically distinct oncolytic viruses, adenovirus, and vaccinia virus. Our results are in support of clinical development of heterologous adeno-/vaccinia virus therapy of cancer.

Characterization of infectivity of knob-modified adenoviral vectors in glioma

NARCIS (Netherlands)

C.P.L. Paul (C. P L); M. Everts (M.); J.N. Glasgow (J.); P. Dent (P.); P.B. Fisher (P.); I.V. Ulasov (I.); M.S. Lesniak (M.); M.A. Stoff-Khalili (M.); J.C. Roth (J.); M. Preuss (Michael); C.M.F. Dirven (Clemens); M.L.M. Lamfers (Martine); T. Siegal (Tali); Z.B. Zhu (Z.); R.E. Curiel (Rafael E.)

2008-01-01

textabstractMalignant glioma continues to be a major target for gene therapy and virotherapy due to its aggressive growth and the current lack of effective treatment. However, these approaches have been hampered by inefficient infection of glioma cells by viral vectors, particularly vectors derived

Prospective Randomized Phase 2 Trial of Intensity Modulated Radiation Therapy With or Without Oncolytic Adenovirus-Mediated Cytotoxic Gene Therapy in Intermediate-Risk Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Freytag, Svend O., E-mail: sfreyta1@hfhs.org [Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan (United States); Stricker, Hans [Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan (United States); Lu, Mei [Public Health Sciences, Henry Ford Health System, Detroit, Michigan (United States); Elshaikh, Mohamed; Aref, Ibrahim; Pradhan, Deepak; Levin, Kenneth; Kim, Jae Ho [Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan (United States); Peabody, James [Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan (United States); Siddiqui, Farzan; Barton, Kenneth; Pegg, Jan; Zhang, Yingshu; Cheng, Jingfang [Department of Radiation Oncology, Henry Ford Health System, Detroit, Michigan (United States); Oja-Tebbe, Nancy; Bourgeois, Renee [Public Health Sciences, Henry Ford Health System, Detroit, Michigan (United States); Gupta, Nilesh; Lane, Zhaoli [Pathology, Henry Ford Health System, Detroit, Michigan (United States); Rodriguez, Ron [Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); DeWeese, Theodore [Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); and others

2014-06-01

Purpose: To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. Methods and Materials: Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. Results: Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the 2 arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. Conclusions: Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer.

Prospective Randomized Phase 2 Trial of Intensity Modulated Radiation Therapy With or Without Oncolytic Adenovirus-Mediated Cytotoxic Gene Therapy in Intermediate-Risk Prostate Cancer

International Nuclear Information System (INIS)

Freytag, Svend O.; Stricker, Hans; Lu, Mei; Elshaikh, Mohamed; Aref, Ibrahim; Pradhan, Deepak; Levin, Kenneth; Kim, Jae Ho; Peabody, James; Siddiqui, Farzan; Barton, Kenneth; Pegg, Jan; Zhang, Yingshu; Cheng, Jingfang; Oja-Tebbe, Nancy; Bourgeois, Renee; Gupta, Nilesh; Lane, Zhaoli; Rodriguez, Ron; DeWeese, Theodore

2014-01-01

Purpose: To assess the safety and efficacy of combining oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) with intensity modulated radiation therapy (IMRT) in intermediate-risk prostate cancer. Methods and Materials: Forty-four men with intermediate-risk prostate cancer were randomly assigned to receive either OAMCGT plus IMRT (arm 1; n=21) or IMRT only (arm 2; n=23). The primary phase 2 endpoint was acute (≤90 days) toxicity. Secondary endpoints included quality of life (QOL), prostate biopsy (12-core) positivity at 2 years, freedom from biochemical/clinical failure (FFF), freedom from metastases, and survival. Results: Men in arm 1 exhibited a greater incidence of low-grade influenza-like symptoms, transaminitis, neutropenia, and thrombocytopenia than men in arm 2. There were no significant differences in gastrointestinal or genitourinary events or QOL between the 2 arms. Two-year prostate biopsies were obtained from 37 men (84%). Thirty-three percent of men in arm 1 were biopsy-positive versus 58% in arm 2, representing a 42% relative reduction in biopsy positivity in the investigational arm (P=.13). There was a 60% relative reduction in biopsy positivity in the investigational arm in men with <50% positive biopsy cores at baseline (P=.07). To date, 1 patient in each arm exhibited biochemical failure (arm 1, 4.8%; arm 2, 4.3%). No patient developed hormone-refractory or metastatic disease, and none has died from prostate cancer. Conclusions: Combining OAMCGT with IMRT does not exacerbate the most common side effects of prostate radiation therapy and suggests a clinically meaningful reduction in positive biopsy results at 2 years in men with intermediate-risk prostate cancer

E1B-attenuated onco lytic adenovirus enhances antitumor effect of radionuclide therapy by P53-independent way: cellular basic for radionuclide-viral therapy

Energy Technology Data Exchange (ETDEWEB)

Zhenwei, Zhang [Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Hua, Wu; Xuemei, Zhang [Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Xinyuan, Liu [Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai (China)

2004-07-01

Purpose: Chemotherapy or external radiation therapy can potentiate the therapeutic effect of E1 B-attenuated oncolytic adenovirus. In this study, the antitumor efficacy of oncolytic adenovirus combined with internal radionuclide therapy was evaluated. Methods: Firstly, viral replication was examined by plaque assay and Southern blotting, after oncolytic adenovirus, ZD55, was exposed to iodine-131. Cell viability was evaluated qualitatively by crystal violet staining and quantitatively by MTT assay. FACS analysis was performed to determine the synergic proapoptotic effect of iodine-131 combined with ZD55. Results: Irradiation of iodine-131 does not influence ZD55 viral DNA replication. In combination with ZD55, iodine-131 can efficiently kill tumor cells in a p53-independent model. ZD55 augments the proapoptotic effect of iodine-131. Conclusion: Radionuclide-viral therapy might be a novel tool for treatment of hepatocarcinoma. (authors)

Immunovirotherapy with measles virus strains in combination with anti-PD-1 antibody blockade enhances antitumor activity in glioblastoma treatment.

Science.gov (United States)

Hardcastle, Jayson; Mills, Lisa; Malo, Courtney S; Jin, Fang; Kurokawa, Cheyne; Geekiyanage, Hirosha; Schroeder, Mark; Sarkaria, Jann; Johnson, Aaron J; Galanis, Evanthia

2017-04-01

Glioblastoma (GBM) is the most common primary malignant brain tumor and has a dismal prognosis. Measles virus (MV) therapy of GBM is a promising strategy due to preclinical efficacy, excellent clinical safety, and its ability to evoke antitumor pro-inflammatory responses. We hypothesized that combining anti- programmed cell death protein 1 (anti-PD-1) blockade and MV therapy can overcome immunosuppression and enhance immune effector cell responses against GBM, thus improving therapeutic outcome. In vitro assays of MV infection of glioma cells and infected glioma cells with mouse microglia ± aPD-1 blockade were established to assess damage associated molecular pattern (DAMP) molecule production, migration, and pro-inflammatory effects. C57BL/6 or athymic mice bearing syngeneic orthotopic GL261 gliomas were treated with MV, aPD-1, and combination treatment. T2* weighted immune cell-specific MRI and fluorescence activated cell sorting (FACS) analysis of treated mouse brains was used to examine adaptive immune responses following therapy. In vitro, MV infection induced human GBM cell secretion of DAMP (high-mobility group protein 1, heat shock protein 90) and upregulated programmed cell death ligand 1 (PD-L1). MV infection of GL261 murine glioma cells resulted in a pro-inflammatory response and increased migration of BV2 microglia. In vivo, MV+aPD-1 therapy synergistically enhanced survival of C57BL/6 mice bearing syngeneic orthotopic GL261 gliomas. MRI showed increased inflammatory cell influx into the brains of mice treated with MV+aPD-1; FACS analysis confirmed increased T-cell influx predominantly consisting of activated CD8+ T cells. This report demonstrates that oncolytic measles virotherapy in combination with aPD-1 blockade significantly improves survival outcome in a syngeneic GBM model and supports the potential of clinical/translational strategies combining MV with αPD-1 therapy in GBM treatment. © The Author(s) 2016. Published by Oxford University Press

Factors Associated with Adherence to and Treatment Duration of Erlotinib Among Patients with Non-Small Cell Lung Cancer.

Science.gov (United States)

Hess, Lisa M; Louder, Anthony; Winfree, Katherine; Zhu, Yajun E; Oton, Ana B; Nair, Radhika

2017-06-01

In lung cancer, there is an increasing number of oral agents available for patients; however, little is known about the factors associated with adherence to and treatment duration on oral medications in non-small cell lung cancer (NSCLC). To evaluate the clinical and demographic factors associated with adherence and treatment discontinuation, respectively, to oral oncolytics among patients with NSCLC. A retrospective, claims-based analysis of the Humana Research Database supplemented with medical chart review was conducted among patients with NSCLC who started an oral oncolytic between January 1, 2008, and June 30, 2013. Patients were required to be enrolled at least 1 year before the start of oral oncolytics and have no evidence of any oral oncolytic use during this period. Logistic regression models and Cox proportional hazard models were used to identify predictors associated with medication adherence and treatment duration, respectively. Among all oral oncolytics, only the cohort starting on erlotinib had sufficient sample size (n = 1,452). A wide variety of factors were found to be associated with adherence. Low-income subsidy status, previous use of intravenous chemotherapy, and lower total baseline health care costs were significantly related to decreasing adherence (each P cost was associated with decreasing adherence to erlotinib (P costs (P Company to Comprehensive Health Insights, a Humana company, as a collaborative research project involving employees of both companies. Hess, Winfree, Zhu, and Oton are employees of Eli Lilly and Company. Louder and Nair are employees of Comprehensive Health Insights, which received funding to complete this research. Study concept and design were contributed by Hess, Zhu, Winfree, and Oton. Nair and Louder collected the data, and data interpretation was performed by all the authors. The manuscript was written primarily by Hess, along with Nair, and revised by Hess, Nair, Louder, and Winfree, with assistance from Zhu and

Live attenuated measles virus vaccine therapy for locally established malignant glioblastoma tumor cells

Directory of Open Access Journals (Sweden)

Al-Shammari AM

2014-05-01

, and 120 hours of infection compared with control cells. This study concludes that live attenuated MV Schwarz vaccine induces the oncolytic effect in Iraqi tumor cell line ANGM5 and in the rhabdomyosarcoma cell line through syncytia in tumor cells, which is one of the causes of cell death. The MV vaccine strain has the ability to insert its hemagglutinin protein into the tumor cell surface, leading to modification of the antigenic surface of tumor cells that may induce an antitumor immune response, MV vaccine strain induced cell killing by direct cytolysis and apoptosis induction. These antitumor features may indicate the use of MV in the treatment of glioblastoma.Keywords: virotherapy, glioblastoma multiforme

Changing costs of metastatic non small cell lung cancer in the Netherlands.

Science.gov (United States)

Keusters, W R; de Weger, V A; Hövels, A; Schellens, J H M; Frederix, G W J

2017-12-01

The primary objective of this study was to identify the total intramural cost of illness of metastatic non-small cell lung cancer (NSCLC) in the Netherlands between 2006-2012. Secondary objective was to identify whether changes in cost patterns of metastatic NSCLC have occurred over the last years. Patients diagnosed with metastatic NSCLC between 1-1-2006 and 31-12-2012, who had follow-up to death or the date of data cut-off and no trial participation were included. A structured chart review was performed using a case report form. Data collection started after diagnosis of metastatic NSCLC and ended at death or April first, 2015. Data regarding outpatient visits, clinical attendance, oncolytic drug use, imaging, lab tests, radiotherapy and surgery were collected. Sixty-seven patients were included with a median age of 67 years. The median follow-up was 234days. On average patients had 28 outpatient visits and 11 inpatient days. Oncolytic drugs were administered to 76% of the patients. Mean per patient expenditures amounted up to €17,463, with oncolytic drugs (€6,390) as the main cost driver. In comparison with the time-period of 2003-2005 total per patient per year expenses decreased by 44%. The contribution to total yearly costs of oncolytic drugs increased from 18% to 35%, while costs for inpatient stay decreased from 52% to 28% of total expenditures. Outcomes in this study demonstrate that average treatment costs for metastatic NSCLC in the Netherlands Cancer Institute amount to €17,463. Compared to a prior study the average cost for metastatic NSCLC over time in the Netherlands has decreased. A shift of main cost drivers seems to have occurred from inpatient stay, to oncolytic drugs as main contributor. The shift towards treatment cost might become more visible with the introduction of immunotherapy. These results mark the importance of up-to-date cost of illness studies. Copyright © 2017 Elsevier B.V. All rights reserved.

In vivo x-ray fluorescence of bone lead in the study of human lead metabolism: Serum lead, whole blood lead, bone lead, and cumulative exposure

International Nuclear Information System (INIS)

Cake, K.M.; Chettle, D.R.; Webber, C.E.; Gordon, C.L.

1995-01-01

Traditionally, clinical studies of lead's effect on health have relied on blood lead levels to indicate lead exposure. However, this is unsatisfactory because blood lead levels have a half-life of approximately 5 weeks, and thus reflect recent exposure. Over 90% of the lead body burden is in bone, and it is thought to have a long residence time, thus implying that measurements of bone lead reflect cumulative exposure. So, measurements of bone lead are useful in understanding the long-term health effects of lead. Ahlgren reported the first noninvasive measurements of bone lead in humans, where γ-rays from 57 Co were used to excite the K series x-rays of lead. The lead detection system at McMaster University uses a 109 Cd source which is positioned at the center of the detector face (HPGe) and a near backscatter (∼160 degrees) geometry. This arrangement allows great flexibility, since one can sample lead in a range of different bone sites due to a robust normalization technique which eliminates the need to correct for bone geometry, thickness of overlying tissue, and other related factors. The effective radiation dose to an adult during an x-ray fluorescence bone lead measurement is extremely low, being 35 nSv. This paper addresses the issue of how bone, whole blood, and serum lead concentrations can be related in order to understand a person's lead exposure history

Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus

International Nuclear Information System (INIS)

Qi, Yanxin; Guo, Huanhuan; Hu, Ningning; He, Dongyun; Zhang, Shi; Chu, Yunjie; Huang, Yubin; Li, Xiao; Sun, LiLi; Jin, Ningyi

2014-01-01

Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0 × 10 8 , 2.5 × 10 9 , and 1.25 × 10 10 viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0 × 10 8 , 2.5 × 10 9 , and 1.25 × 10 10 VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose > 5 × 10 10 VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25 × 10 10 VP/kg) and beagles (2.5 × 10 9 VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35 × 10 10 VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67 × 10 8 VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. - Highlights: • We use the rodents and non-rodents animal models to evaluation Ad-hTERT-E1a-Apoptin. • Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. • Demonstrate the safety and feasibility dose of injected Ad-hTERT-E1a-Apoptin

Production of bioactive soluble interleukin-15 in complex with interleukin-15 receptor alpha from a conditionally-replicating oncolytic HSV-1.

Directory of Open Access Journals (Sweden)

David C Gaston

Full Text Available Oncolytic type-1 herpes simplex viruses (oHSVs lacking the γ134.5 neurovirulence gene are being evaluated for treatment of a variety of malignancies. oHSVs replicate within and directly kill permissive cancer cells. To augment their anti-tumor activity, oHSVs have been engineered to express immunostimulatory molecules, including cytokines, to elicit tumor-specific immune responses. Interleukin-15 (IL-15 holds potential as an immunotherapeutic cytokine because it has been demonstrated to promote both natural killer (NK cell-mediated and CD8(+ T cell-mediated cytotoxicity against cancer cells. The purpose of these studies was to engineer an oHSV producing bioactive IL-15. Two oHSVs were constructed encoding murine (mIL-15 alone (J100 or with the mIL-15 receptor α (mIL-15Rα, J100D to determine whether co-expression of these proteins is required for production of bioactive mIL-15 from oHSV. The following were demonstrated: i both oHSVs retain replication competence and cytotoxicity in permissive tumor cell lines. ii Enhanced production of mIL-15 was detected in cell lysates of neuro-2a cells following J100D infection as compared to J100 infection, suggesting that mIL-15Rα improved mIL-15 production. iii Soluble mIL-15 in complex with mIL-15Rα was detected in supernates from J100D-infected, but not J100-infected, neuro-2a, GL261, and CT-2A cells. These cell lines vary in permissiveness to oHSV replication and cytotoxicity, demonstrating soluble mIL-15/IL-15Rα complex production from J100D was independent of direct oHSV effects. iv The soluble mIL-15/IL-15Rα complex produced by J100D was bioactive, stimulating NK cells to proliferate and reduce the viability of syngeneic GL261 and CT-2A cells. v J100 and J100D were aneurovirulent inasmuch as no neuropathologic effects were documented following direct inoculation into brains of CBA/J mice at up to 1x10(7 plaque forming units. The production of mIL-15/mIL-15Rα from multiple tumor lines, as well

Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus

Energy Technology Data Exchange (ETDEWEB)

Qi, Yanxin [State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022 (China); Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); Guo, Huanhuan [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); Changchun Brother Biotech Co., Ltd., Changchun, 130000 (China); Hu, Ningning; He, Dongyun [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122 (China); Zhang, Shi [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); School of Clinical Medicine, Jilin University, Changchun 130001 (China); Chu, Yunjie [Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun 130021 (China); Huang, Yubin [State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022 (China); Li, Xiao, E-mail: lixiao06@mails.jlu.edu.cn [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122 (China); Sun, LiLi, E-mail: linjiaxiaoya@163.com [Department of Head and Neck Surgery, Tumor Hospital of Jilin Province, Changchun 130012 (China); Jin, Ningyi, E-mail: ningyij@126.com [Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122 (China); The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122 (China)

2014-10-15

Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0 × 10{sup 8}, 2.5 × 10{sup 9}, and 1.25 × 10{sup 10} VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose > 5 × 10{sup 10} VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25 × 10{sup 10} VP/kg) and beagles (2.5 × 10{sup 9} VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35 × 10{sup 10} VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67 × 10{sup 8} VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. - Highlights: • We use the rodents and non-rodents animal models to evaluation Ad-hTERT-E1a-Apoptin. • Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent. • Demonstrate the safety and feasibility dose of injected Ad

Total contribution of airborne lead to blood lead.

OpenAIRE

Manton, W I

1985-01-01

A nine year study of blood lead concentrations and isotope ratios carried out on a married couple shows that pulmonary deposition cannot account for all the airborne lead in blood; that lead from bone may comprise 70% of blood lead; and that during pregnancy blood lead may double due to mobilisation of lead from bone.

Total contribution of airborne lead to blood lead.

Science.gov (United States)

Manton, W I

1985-01-01

A nine year study of blood lead concentrations and isotope ratios carried out on a married couple shows that pulmonary deposition cannot account for all the airborne lead in blood; that lead from bone may comprise 70% of blood lead; and that during pregnancy blood lead may double due to mobilisation of lead from bone. PMID:3970881

Lead- or Lead-bismuth-cooled fast reactors

International Nuclear Information System (INIS)

Bouchter, J.C.; Courouau, J.L.; Dufour, P.; Guidez, J.; Latge, C.; Martinelli, L.; Renault, C.; Rimpault, G.

2014-01-01

Lead-cooled fast reactors are one of the 6 concepts retained for the 4. generation of nuclear reactors. So far no lead-cooled reactors have existed in the world except lead-bismuth-cooled reactors in soviet submarines. Some problems linked to the use of the lead-bismuth eutectic appeared but were satisfactorily solved by a more rigorous monitoring of the chemistry of the lead-bismuth coolant. Lead presents various advantages as a coolant: no reactivity with water and the air,a high boiling temperature and low contamination when irradiated. The main asset of the lead-bismuth alloy is the drop of the fusion temperature from 327 C degrees to 125 C degrees. The main drawback of using lead (or lead-bismuth) is its high corrosiveness with metals like iron, chromium and nickel. The high corrosiveness of the coolant implies low flow velocities which means a bigger core and consequently a bigger reactor containment. Different research programs in the world (in Europe, Russia and the USA) are reviewed in the article but it appears that the development of this type of reactor requires technological breakthroughs concerning materials and the resistance to corrosion. Furthermore the concept of lead-cooled reactors seems to be associated to a range of low output power because of the compromise between the size of the reactor and its resistance to earthquakes. (A.C.)

Lead in teeth from lead-dosed goats: Microdistribution and relationship to the cumulative lead dose

International Nuclear Information System (INIS)

Bellis, David J.; Hetter, Katherine M.; Jones, Joseph; Amarasiriwardena, Dula; Parsons, Patrick J.

2008-01-01

Teeth are commonly used as a biomarker of long-term lead exposure. There appear to be few data, however, on the content or distribution of lead in teeth where data on specific lead intake (dose) are also available. This study describes the analysis of a convenience sample of teeth from animals that were dosed with lead for other purposes, i.e., a proficiency testing program for blood lead. Lead concentration of whole teeth obtained from 23 animals, as determined by atomic absorption spectrometry, varied from 0.6 to 80 μg g -1 . Linear regression of whole tooth lead (μg g -1 ) on the cumulative lead dose received by the animal (g) yielded a slope of 1.2, with r 2 =0.647 (p -1 , were found in circumpulpal dentine. Linear regression of circumpulpal lead (μg g -1 ) on cumulative lead dose (g) yielded a slope of 23 with r 2 =0.961 (p=0.0001). The data indicated that whole tooth lead, and especially circumpulpal lead, of dosed goats increased linearly with cumulative lead exposure. These data suggest that circumpulpal dentine is a better biomarker of cumulative lead exposure than is whole tooth lead, at least for lead-dosed goats

A strategy for genetic modification of the spike-encoding segment of human reovirus T3D for reovirus targeting.

Science.gov (United States)

van den Wollenberg, D J M; van den Hengel, S K; Dautzenberg, I J C; Cramer, S J; Kranenburg, O; Hoeben, R C

2008-12-01

Human Orthoreovirus Type 3 Dearing is not pathogenic to humans and has been evaluated clinically as an oncolytic agent. Its transduction efficiency and the tumor cell selectivity may be enhanced by incorporating ligands for alternative receptors. However, the genetic modification of reoviruses has been difficult, and genetic targeting of reoviruses has not been reported so far. Here we describe a technique for generating genetically targeted reoviruses. The propagation of wild-type reoviruses on cells expressing a modified sigma 1-encoding segment embedded in a conventional RNA polymerase II transcript leads to substitution of the wild-type genome segment by the modified version. This technique was used for generating reoviruses that are genetically targeted to an artificial receptor expressed on U118MG cells. These cells lack the junction adhesion molecule-1 and therefore resist infection by wild-type reoviruses. The targeted reoviruses were engineered to carry the ligand for this receptor at the C terminus of the sigma 1 spike protein. This demonstrates that the C terminus of the sigma 1 protein is a suitable locale for the insertion of oligopeptide ligands and that targeting of reoviruses is feasible. The genetically targeted viruses can be propagated using the modified U118MG cells as helper cells. This technique may be applicable for the improvement of human reoviruses as oncolytic agents.

The optimum lead thickness for lead-activation detectors

International Nuclear Information System (INIS)

Si Fenni; Hu Qingyuan

2009-01-01

The optimum lead thickness for lead-activation detectors has been studied in this paper. First existence of the optimum lead thickness is explained theoretically. Then the optimum lead thickness is obtained by two methods, MCNP5 calculation and mathematical estimation. At last factors which affect the optimum lead thickness are discussed. It turns out that the optimum lead thickness is irrelevant to incident neutron energies. It is recommended 2.5 cm generally.

[The therapeutic effect of HSV1-hGM-CSF combined with doxorubicin on the mouse breast cancer model].

Science.gov (United States)

Zhuang, X F; Zhang, S R; Liu, B L; Wu, J L; Li, X Q; Gu, H G; Shu, Y

2018-03-23

Objective: To evaluate the oncolytic effect of herpes simplex virus type 1 which carried recombined human granulocyte-macrophage colony-stimulating factor (HSV1-hGM-CSF) on the mouse breast cancer cell line 4T1 and compare the anticancer effects of HSV1-hGM-CSF, doxorubicin alone or combination on the breast cancer in mice. Methods: We investigated the cytotoxic effect on 4T1 cells in vitro, the cell growth, cell apoptosis and cell cycle of 4T1 cells treated with oncolytic HSV1-hGM-CSF at different MOIs (0, 0.5, 1 and 2) and doxorubicin at different concentrations (0, 2, 4 and 8 μg/ml). The effects of oncolytic HSV1-hGM-CSF and doxorubicin on the tumor growth, survival time and their side effects on the mouse breast cancer model were observed. Results: Both oncolytic HSV1-hGM-CSF and doxorubicin significantly inhibited the proliferation of 4T1 cells in vitro . Doxorubicin induced the G(2)/M phase arrest of 4T1 cells, while the cytotoxicity of oncolytic HSV1-hGM-CSF was no cell cycle-dependent.At day 16 after treatment with doxorubicin and HSV1-hGM-CSF, the tumor volume of 4T1 tumor bearing mice were (144.40±27.68)mm(3,) (216.80±57.18)mm(3,) (246.10±21.90)mm(3,) (327.50±44.24)mm(3,) (213.30±32.31)mm(3) and (495.80±75.87)mm(3) in the groups of doxorubicin combined with high dose HSV1-hGM-CSF, doxorubicin combined with low dose HSV1-hGM-CSF, doxorubicin alone, high dose HSV1-hGM-CSF alone, low dose HSV1-hGM-CSF alone and control, respectively.Compared with the control group, both doxorubicin and HSV1-hGM-CSF treatment exhibited significant reduction of primary tumor volume in vivo ( P CSF alone and low dose HSV1-hGM-CSF alone were significantly longer than that of control ( P CSF is observed in 4T1 mouse breast cancer.

Insulated hsp70B' promoter: stringent heat-inducible activity in replication-deficient, but not replication-competent adenoviruses.

Science.gov (United States)

Rohmer, Stanimira; Mainka, Astrid; Knippertz, Ilka; Hesse, Andrea; Nettelbeck, Dirk M

2008-04-01

Key to the realization of gene therapy is the development of efficient and targeted gene transfer vectors. Therapeutic gene transfer by replication-deficient or more recently by conditionally replication-competent/oncolytic adenoviruses has shown much promise. For specific applications, however, it will be advantageous to provide vectors that allow for external control of gene expression. The efficient cellular heat shock system in combination with available technology for focused and controlled hyperthermia suggests heat-regulated transcription control as a promising tool for this purpose. We investigated the feasibility of a short fragment of the human hsp70B' promoter, with and without upstream insulator elements, for the regulation of transgene expression by replication-deficient or oncolytic adenoviruses. Two novel adenoviral vectors with an insulated hsp70B' promoter were developed and showed stringent heat-inducible gene expression with induction ratios up to 8000-fold. In contrast, regulation of gene expression from the hsp70B' promoter without insulation was suboptimal. In replication-competent/oncolytic adenoviruses regulation of the hsp70B' promoter was lost specifically during late replication in permissive cells and could not be restored by the insulators. We developed novel adenovirus gene transfer vectors that feature improved and stringent regulation of transgene expression from the hsp70B' promoter using promoter insulation. These vectors have potential for gene therapy applications that benefit from external modulation of therapeutic gene expression or for combination therapy with hyperthermia. Furthermore, our study reveals that vector replication can deregulate inserted cellular promoters, an observation which is of relevance for the development of replication-competent/oncolytic gene transfer vectors. (c) 2008 John Wiley & Sons, Ltd.

Lead poisoning

Energy Technology Data Exchange (ETDEWEB)

Beijers, J A

1952-01-01

Three cases of acute lead poisoning of cattle herds via ingestion are reported, and reference is made to several other incidents of lead in both humans and animals. The quantity of lead which was found in the livers of the dead cows varied from 6.5 to 19 mg/kg, while 1160 mg/kg of lead in the liver was found for a young cow which was poisoned experimentally with 5 gms of lead acetate per day; hence, there appears to be great variability in the amounts deposited that can lead to intoxication and death. No evidence was found for a lead seam around the teeth, prophyrinuria, or basophil granules in the erythrocytes during acute or chronic lead poisoning of cattle or horses examined. Reference is made to attempts of finding the boundary line between increased lead absorption and lead intoxication in humans, and an examination of 60 laborers in an offset-printing office containing a great deal of inhalable lead (0.16 to 1.9 mg/cu m air) is reviewed. Physical deviation, basophylic granulation of erythrocytes, increased lead content of the urine, and porphyrinuria only indicate an increased absorption of lead; the use of the term intoxication is justified if, in addition, there are complaints of lack of appetite, constipation, fatigue, abdominal pain, and emaciation.

Biosorption of lead phosphates by lead-tolerant bacteria as a mechanism for lead immobilization.

Science.gov (United States)

Rodríguez-Sánchez, Viridiana; Guzmán-Moreno, Jesús; Rodríguez-González, Vicente; Flores-de la Torre, Juan Armando; Ramírez-Santoyo, Rosa María; Vidales-Rodríguez, Luz Elena

2017-08-01

The study of metal-tolerant bacteria is important for bioremediation of contaminated environments and development of green technologies for material synthesis due to their potential to transform toxic metal ions into less toxic compounds by mechanisms such as reduction, oxidation and/or sequestration. In this study, we report the isolation of seven lead-tolerant bacteria from a metal-contaminated site at Zacatecas, México. The bacteria were identified as members of the Staphylococcus and Bacillus genera by microscopic, biochemical and 16S rDNA analyses. Minimal inhibitory concentration of these isolates was established between 4.5 and 7.0 mM of Pb(NO 3 ) 2 in solid and 1.0-4.0 mM of Pb(NO 3 ) 2 in liquid media. A quantitative analysis of the lead associated to bacterial biomass in growing cultures, revealed that the percentage of lead associated to biomass was between 1 and 37% in the PbT isolates. A mechanism of complexation/biosorption of lead ions as inorganic phosphates (lead hydroxyapatite and pyromorphite) in bacterial biomass, was determined by Fourier transform infrared spectroscopy and X-ray diffraction analyses. Thus, the ability of the lead-tolerant isolates to transform lead ions into stable and highly insoluble lead minerals make them potentially useful for immobilization of lead in mining waste.

SHORT OVERVIEW OF CLINICAL TRIALS WITH CURRENT IMMUNOTHERAPEUTIC TOOLS FOR CANCER TREATMENT

Directory of Open Access Journals (Sweden)

T. S. Nepomnyashchikh

2017-01-01

Full Text Available Over last decade, a substantial progress has been made, with respect to understanding of cancer biology and its interplay with the host immune system. Different immunotherapeutic drugs based on recombinant cytokines and monoclonal antibodies are widely used in cancer therapy, and a large number of experimental cancer treatments have been developed, many of which are currently undergoing various stages of clinical trials. Recent endorsement of a recombinant oncolytic herpesvirus T-VEC for the treatment of melanoma was an important step towards a more safe and efficient anticancer therapeutics. In this review, we shall mention only some of the most promising cancer immunotherapy strategies, namely, immune checkpoint inhibitors, cellular therapy and oncolytic viruses. 

Lead and lead-based alloys as waste matrix materials

International Nuclear Information System (INIS)

Arustamov, A.E.; Ojovan, M.I.; Kachalov, M.B.

1999-01-01

Metals and alloys with relatively low melting temperatures such as lead and lead-based alloys are considered in Russia as prospective matrices for encapsulation of spent nuclear fuel in containers in preparation for final disposal in underground repositories. Now lead and lead-based alloys are being used for conditioning spent sealed radioactive sources at radioactive waste disposal facilities

Lead poisoning

Science.gov (United States)

... drinking water in homes containing pipes that were connected with lead solder . Although new building codes require ... lead in their bodies when they put lead objects in their mouths, especially if they swallow those ...

The HDAC Inhibitors Scriptaid and LBH589 Combined with the Oncolytic Virus Delta24-RGD Exert Enhanced Anti-Tumor Efficacy in Patient-Derived Glioblastoma Cells.

Directory of Open Access Journals (Sweden)

Lotte M E Berghauser Pont

Full Text Available A phase I/II trial for glioblastoma with the oncolytic adenovirus Delta24-RGD was recently completed. Delta24-RGD conditionally replicates in cells with a disrupted retinoblastoma-pathway and enters cells via αvβ3/5 integrins. Glioblastomas are differentially sensitive to Delta24-RGD. HDAC inhibitors (HDACi affect integrins and share common cell death pathways with Delta24-RGD. We studied the combination treatment effects of HDACi and Delta24-RGD in patient-derived glioblastoma stem-like cells (GSC, and we determined the most effective HDACi.SAHA, Valproic Acid, Scriptaid, MS275 and LBH589 were combined with Delta24-RGD in fourteen distinct GSCs. Synergy was determined by Chou Talalay method. Viral infection and replication were assessed using luciferase and GFP encoding vectors and hexon-titration assays. Coxsackie adenovirus receptor and αvβ3 integrin levels were determined by flow cytometry. Oncolysis and mechanisms of cell death were studied by viability, caspase-3/7, LDH and LC3B/p62, phospho-p70S6K. Toxicity was studied on normal human astrocytes. MGMT promotor methylation status, TCGA classification, Rb-pathway and integrin gene expression levels were assessed as markers of responsiveness.Scriptaid and LBH589 acted synergistically with Delta24-RGD in approximately 50% of the GSCs. Both drugs moderately increased αvβ3 integrin levels and viral infection in responding but not in non-responding GSCs. LBH589 moderately increased late viral gene expression, however, virus titration revealed diminished viral progeny production by both HDACi, Scriptaid augmented caspase-3/7 activity, LC3B conversion, p62 and phospho-p70S6K consumption, as well as LDH levels. LBH589 increased LDH and phospho-p70S6K consumption. Responsiveness correlated with expression of various Rb-pathway genes and integrins. Combination treatments induced limited toxicity to human astrocytes.LBH589 and Scriptaid combined with Delta24-RGD revealed synergistic anti

Lead Poisoning

Science.gov (United States)

Lead is a metal that occurs naturally in the earth's crust. Lead can be found in all parts of our ... from human activities such as mining and manufacturing. Lead used to be in paint; older houses may ...

Lead Test

Science.gov (United States)

... to do renovation and repair projects using lead-safe work practices to avoid creating more lead dust or ... in a dangerous area? Yes. If you are working in a potentially harmful environment with exposure to lead dust or fumes: Wash ...

Bulk diffusion and solubility of silver and nickel in lead, lead-silver and lead-nickel solid solutions

International Nuclear Information System (INIS)

Amenzou-Badrour, H.; Moya, G.; Bernardini, J.

1988-01-01

The results of a study of solubility and bulk diffusion of /sup 110/Ag and /sup 63/Ni in lead, lead-silver and lead-nickel solid solutions in the temperature range 220 to 88 0 C are reported. Owing to the low solubility of silver and nickel in lead, Fick's solution corresponding to the boundary condition of a constant concentration of solute at the surface has been used. Depth profile concentration analysis suggests a fundamental difference between the diffusion mechanisms of silver and nickel. Since silver penetration profiles in pure lead give diffusion coefficients independent of the penetration depth and silver concentration, it is suggested that slight decreases of silver diffusivity in lead-silver solid solutions have no significance. This implies that the interstitial silver atoms do not associate significantly with each other to form Ag-Ag dimers. In contrast, different behaviors of /sup 63/Ni depth profile concentration in pure lead and saturated PbNi solid solutions agree with a Ni-Ni interaction leading to the formation of less mobile dimers near the surface in pure lead

Electrical properties of a novel lead alkoxide precursor: Lead glycolate

International Nuclear Information System (INIS)

Tangboriboon, Nuchnapa; Pakdeewanishsukho, Kittikhun; Jamieson, Alexander; Sirivat, Anuvat; Wongkasemjit, Sujitra

2006-01-01

The reaction of lead acetate trihydrate Pb(CH 3 COO) 2 .3H 2 O and ethylene glycol, using triethylenetetramine (TETA) as a catalyst, provides in one step access to a polymer-like precursor of lead glycolate [-PbOCH 2 CH 2 O-]. On the basis of high-resolution mass spectroscopy, chemical analysis composition, FTIR, 13 C-solid state NMR and TGA, the lead glycolate precursor can be identified as a trimer structure. The FTIR spectrum demonstrates the characteristics of lead glycolate; the peaks at 1086 and 1042 cm -1 can be assigned to the C-O-Pb stretchings. The 13 C-solid state NMR spectrum gives notably only one peak at 68.639 ppm belonging to the ethylene glycol ligand. The phase transformations of lead glycolate and lead acetate trihydrate to lead oxide, their microstructures, and electrical properties were found to vary with increasing temperature. The lead glycolate precursor has superior electrical properties relative to those of lead acetate trihydrate, suggesting that the lead glycolate precursor can possibly be used as a starting material for producing electrical and semiconducting ceramics, viz. ferroelectric, anti-ferroelectric, and piezoelectric materials

Relational Leading

DEFF Research Database (Denmark)

Larsen, Mette Vinther; Rasmussen, Jørgen Gulddahl

2015-01-01

This first chapter presents the exploratory and curious approach to leading as relational processes – an approach that pervades the entire book. We explore leading from a perspective that emphasises the unpredictable challenges and triviality of everyday life, which we consider an interesting......, relevant and realistic way to examine leading. The chapter brings up a number of concepts and contexts as formulated by researchers within the field, and in this way seeks to construct a first understanding of relational leading....

Correlation between some parameters of lead absorption and lead intoxication

Science.gov (United States)

Waldron, H. A.

1971-01-01

Waldron, H. A. (1971).Brit. J. industr. Med.,28, 195-199. Correlation between some parameters of lead absorption and lead intoxication. Use has been made of data collected over a number of years from workers exposed to a lead hazard in a motor-car factory. The correlations between various parameters of lead absorption and lead intoxication were computed, including blood and urine lead concentrations, urinary coproporphyrin, ALA and PBG concentrations, and haemoglobin concentration. In all, 15 correlation coefficients were calculated, of which only six showed a statistically significant result (i.e., Plead and urine lead (r = 0·38, Plead and coproporphyrin (r = 0·42, Plead and ALA (r = 0·43, Plead and PBG (r = 0·19, P<0·05). PMID:5572689

The identification of lead ammunition as a source of lead exposure in First Nations: The use of lead isotope ratios

International Nuclear Information System (INIS)

Tsuji, Leonard J.S.; Wainman, Bruce C.; Martin, Ian D.; Sutherland, Celine; Weber, Jean-Philippe; Dumas, Pierre; Nieboer, Evert

2008-01-01

The use of lead shotshell to hunt water birds has been associated with lead-contamination in game meat. However, evidence illustrating that lead shotshell is a source of lead exposure in subsistence hunting groups cannot be deemed definitive. This study seeks to determine whether lead shotshell constitutes a source of lead exposure using lead isotope ratios. We examined stable lead isotope ratios for lichens, lead shotshell and bullets, and blood from residents of Fort Albany and Kashechewan First Nations, and the City of Hamilton, Ontario, Canada. Data were analyzed using ANOVA and regression analyses. ANOVA of isotope ratios for blood revealed significant differences with respect to location, but not sex. Hamilton differed from both Kashechewan and Fort Albany; however, the First Nations did not differ from each other. ANOVA of the isotope ratios for lead ammunition and lichens revealed no significant differences between lichen groups (north and south) and for the lead ammunition sources (pellets and bullets). A plot of 206 Pb/ 204 Pb and 206 Pb/ 207 Pb values illustrated that lichens and lead ammunition were distinct groupings and only the 95% confidence ellipse of the First Nations group overlapped that of lead ammunition. In addition, partial correlations between blood-lead levels (adjusted for age) and isotope ratios revealed significant (p 206 Pb/ 204 Pb and 206 Pb/ 207 Pb, and a significant negative correlation for 208 Pb/ 206 Pb, as predicted if leaded ammunition were the source of lead exposure. In conclusion, lead ammunition was identified as a source of lead exposure for First Nations people; however, the isotope ratios for lead shotshell pellets and bullets were indistinguishable. Thus, lead-contaminated meat from game harvested with lead bullets may also be contributing to the lead body burden

Effect on blood lead of airborne lead particles characterized by size.

Science.gov (United States)

Park, Dong-Uk; Paik, Nam-Won

2002-03-01

Worker exposure to airborne lead particles was evaluated for a total of 117 workers in 12 work-places of four different industrial types in Korea. The particle sizes were measured using 8-stage cascade impactors worn by the workers. Mass median aerodynamic diameters (MMAD) were determined by type of industry and percentage of lead particles as a fraction of airborne lead (PbA) concentration was determined by particle size. Blood lead (PbB) levels of workers who matched airborne lead samples were also examined. A Scheffé's pairwise comparison test showed that MMAD and the fractions of each of respirable particles and lead particles lead particles lead particles (r = 0.82) than that between concentrations of small particles and PbA (r = 0.61). A simple linear regression indicated that PbB correlated better with respirable lead concentration (r2 = 0.35, P = 0.0001) than with PbA concentration and had a higher slope coefficient. Controlling for respirable lead concentration reduced the partial correlation coefficient between PbA concentration and PbB level from 0.56 to 0.20 (P = 0.053). The results indicate that the contribution of respirable lead particles to lead absorption would be greater than that of PbA. This study concludes that the measurement of PbA only may not properly reflect a worker's exposure to lead particles with diverse characteristics. For the evaluation of a worker's exposure to various types of lead particles, it is recommended that respirable lead particles as well as PbA be measured.

Common ECG Lead Placement Errors. Part I: Limb Lead Reversals

Directory of Open Access Journals (Sweden)

Allison V. Rosen

2015-10-01

Full Text Available Background: Electrocardiography (ECG is a very useful diagnostic tool. However, errors in placement of ECG leads can create artifacts, mimic pathologies, and hinder proper ECG interpretation. It is important for members of the health care team to be able to recognize the common patterns resulting from lead placement errors. Methods: 12-lead ECGs were recorded in a single male healthy subject in his mid 20s. Six different limb lead reversals were compared to ECG recordings from correct lead placement. Results: Classic ECG patterns were observed when leads were reversed. Methods of discriminating these ECG patterns from true pathologic findings were described. Conclusion: Correct recording and interpretation of ECGs is key to providing optimal patient care. It is therefore crucial to be able to recognize common ECG patterns that are indicative of lead reversals.

LEADING WITH LEADING INDICATORS

International Nuclear Information System (INIS)

PREVETTE, S.S.

2005-01-01

This paper documents Fluor Hanford's use of Leading Indicators, management leadership, and statistical methodology in order to improve safe performance of work. By applying these methods, Fluor Hanford achieved a significant reduction in injury rates in 2003 and 2004, and the improvement continues today. The integration of data, leadership, and teamwork pays off with improved safety performance and credibility with the customer. The use of Statistical Process Control, Pareto Charts, and Systems Thinking and their effect on management decisions and employee involvement are discussed. Included are practical examples of choosing leading indicators. A statistically based color coded dashboard presentation system methodology is provided. These tools, management theories and methods, coupled with involved leadership and employee efforts, directly led to significant improvements in worker safety and health, and environmental protection and restoration at one of the nation's largest nuclear cleanup sites

Vesicular stomatitis virus expressing a chimeric Sindbis glycoprotein containing an Fc antibody binding domain targets to Her2/neu overexpressing breast cancer cells

International Nuclear Information System (INIS)

Bergman, Ira; Whitaker-Dowling, Patricia; Gao Yanhua; Griffin, Judith A.; Watkins, Simon C.

2003-01-01

Vesicular stomatitis virus (VSV) is a candidate for development for cancer therapy. It is an oncolytic virus that is safe in humans. Recombinant virus can be made directly from plasmid components. We attempted to create a virus that targeted specifically to breast cancer cells. Nonreplicating and replicating pseudotype VSV were created whose only surface glycoprotein (gp) was a Sindbis gp, called Sindbis-ZZ, modified to severely reduce its native binding function and to contain the Fc-binding domain of Staphylococcus aureus protein A. When titered on Her2/neu overexpressing SKBR3 human breast cancer cells, pseudotype VSV coated with Sindbis-ZZ had 5 /ml. This work demonstrates the ability to easily create, directly from plasmid components, an oncolytic replicating VSV with a restricted host cell range

Secondary lead production

Energy Technology Data Exchange (ETDEWEB)

Hollis, R.G.

1990-10-16

This invention is concerned with the efficient recovery of soft lead from the paste component of used automobile lead-acid storage batteries. According to the invention, a scrap which contains lead oxide, lead sulfate, and antimony in an oxidized state is processed in the following steps to recover lead. A refractory lined reaction vessel is continuously charged with the scrap, along with a reductant effective for reducing lead oxide. The charged material is melted and agitated by means of a submerged lance at 900-1150{degree}C whereby some of the lead oxide of the scrap is reduced to form molten lead. A slag layer is then formed above the molten lead, and an amount of lead oxide is maintained in the slag layer. The molten lead, now containing under 0.5 wt % of antimony, is removed, and the antimony oxide in the scrap is concentrated as oxide in the slag layer. Preferred embodiments of the invention result in the production, in a single step, of a soft lead substantially free of antimony. The slag may be subsequently treated to reduce the antimony oxide and produce a valuable antimony-lead product. Further advantages of the process are that a wet battery paste may be used as the feed without prior drying, and the process can be conducted at a temperature 100-150{degree}C lower than in previously known methods. In addition, a smaller reactor can be employed which reduces both capital cost and fuel costs. The process of the invention is illustrated by descriptions of pilot plant tests. 1 fig.

Kinetics of oil saponification by lead salts in ancient preparations of pharmaceutical lead plasters and painting lead mediums.

Science.gov (United States)

Cotte, M; Checroun, E; Susini, J; Dumas, P; Tchoreloff, P; Besnard, M; Walter, Ph

2006-12-15

Lead soaps can be found in archaeological cosmetics as well as in oil paintings, as product of interactions of lead salts with oil. In this context, a better understanding of the formation of lead soaps allows a follow-up of the historical evolution of preparation recipes and provides new insights into conservation conditions. First, ancient recipes of both pharmaceutical lead plasters and painting lead mediums, mixtures of oil and lead salts, were reconstructed. The ester saponification by lead salts is determined by the preparation parameters which were quantified by FT-IR spectrometry. In particular, ATR/FT-IR spectrometer was calibrated by the standard addition method to quantitatively follow the kinetics of this reaction. The influence of different parameters such as temperature, presence of water and choice of lead salts was assessed: the saponification is clearly accelerated by water and heating. This analysis provides chemical explanations to the historical evolution of cosmetic and painting preparation recipes.

Lead levels - blood

Science.gov (United States)

Blood lead levels ... is used to screen people at risk for lead poisoning. This may include industrial workers and children ... also used to measure how well treatment for lead poisoning is working. Lead is common in the ...

Lead and osteoporosis: Mobilization of lead from bone in postmenopausal women

Energy Technology Data Exchange (ETDEWEB)

Silbergeld, E.K. (Environmental Defense Fund, WA (USA)); Schwartz, J. (Environmental Protection Agency, Washington, DC (USA)); Mahaffey, K. (National Institute of Environmental Health Sciences, Research Triangle Park, NC (USA))

1988-10-01

Although it has been known that humans accumulate lead in bone, mineralized tissue has been considered primarily as a sequestering compartment and not as a site of toxic action for lead. However, experimental data indicate that bone lead can be released during conditions of demineralization, such as pregnancy and lactation. We have examined lead status in women, before and after menopause, using the NHANES II dataset compiled between 1976 and 1980. In 2981 black and white women there was a highly significant increase in both whole blood and calculated plasma lead concentrations after menopause. The results indicate that bone lead is not an inert storage site for absorbed lead. Moreover, lead may interact with other factors in the course of postmenopausal osteoporosis, to aggravate the course of the disease, since lead is known to inhibit activation of vitamin D, uptake of dietary calcium, and several regulatory aspects of bone cell function. The consequences of this mobilization may also be of importance in assessing the risks of maternal lead exposure to fetal and infant health.

Safe leads and lead changes in competitive team sports

Science.gov (United States)

Clauset, A.; Kogan, M.; Redner, S.

2015-06-01

We investigate the time evolution of lead changes within individual games of competitive team sports. Exploiting ideas from the theory of random walks, the number of lead changes within a single game follows a Gaussian distribution. We show that the probability that the last lead change and the time of the largest lead size are governed by the same arcsine law, a bimodal distribution that diverges at the start and at the end of the game. We also determine the probability that a given lead is "safe" as a function of its size L and game time t . Our predictions generally agree with comprehensive data on more than 1.25 million scoring events in roughly 40 000 games across four professional or semiprofessional team sports, and are more accurate than popular heuristics currently used in sports analytics.

Molecular Characterization of Prostate Cancer Cell Oncolysis by Herpes Simplex Virus ICP0 Mutants

National Research Council Canada - National Science Library

Mossman, Karen

2005-01-01

.... Briefly, the goals of the proposal were to characterize the oncolytic capacity of Herpes simplex virus type 1 ICPO mutants in prostate cancer cells given the relationship between ICPO and two tumor...

[Environmental lead poisoning from lead-glazed earthenware used for storing drinks].

Science.gov (United States)

Sabouraud, S; Coppéré, B; Rousseau, C; Testud, F; Pulce, C; Tholly, F; Blanc, M; Culoma, F; Facchin, A; Ninet, J; Chambon, P; Medina, B; Descotes, J

2009-12-01

Current unusual environmental sources of lead exposure mainly include traditional medicines, either ayurvedic remedies or others, traditional cosmetics (kohl, surma), and the use of traditional earthenware, for storage or cooking. We report two cases of lead poisoning in adults initially identified by paroxysmal abdominal pain or anemia. In both cases, the environmental investigation evidenced one main source of lead exposure, namely a lead-glazed earthenware jug in which a drink was stored, "kefir" in the first case, and "kombucha" tea in the second one. It is recommended to search for lead intoxication in patients with unexplained anemia. Environmental sources of lead can be multiple. Their relative importance has to be ranked during the environmental investigation and among these, lead-glazed earthenware must be considered as a source of high lead exposure when drinks are stored inside and thus can soak.

Lead pollution: lead content in milk from cows fed on contaminated forages

Energy Technology Data Exchange (ETDEWEB)

Sapetti, C; Arduino, E; Durio, P

1973-01-01

Lead toxicity is reviewed, and the history of the lead poisoning is described. Much of the lead pollution in soil is due to automobile exhaust. Two milk cows were fed forage with added lead acetate. The 20 kg of lead corresponded to 50 ppm, a level that is often found in hays near major highways. The cows milk was then analyzed for lead content. During the first and second phase of administration of lead salts, the milk cows did not show any evident symptoms of intoxication. The lead in the milk did have a marked correlation with the administered lead. The lead doses did not last long enough for chronic symptoms to begin. The dosage of lead in milk, due to the facility of drawing samples and the relevant levels of response, could represent a valid method for diagnosing incipient chronic intoxications.

Effect measure modification of blood lead-air lead slope factors.

Science.gov (United States)

Richmond-Bryant, Jennifer; Meng, Qingyu; Cohen, Jonathan; Davis, J Allen; Svendsgaard, David; Brown, James S; Tuttle, Lauren; Hubbard, Heidi; Rice, Joann; Kirrane, Ellen; Vinikoor-Imler, Lisa; Kotchmar, Dennis; Hines, Erin; Ross, Mary

2015-01-01

There is abundant literature finding that susceptibility factors, including race and ethnicity, age, and housing, directly influence blood lead levels. No study has explored how susceptibility factors influence the blood lead-air lead relationship nationally. The objective is to evaluate whether susceptibility factors act as effect measure modifiers on the blood lead-air lead relationship. Participant level blood lead data from the 1999 to 2008 National Health and Nutrition Examination Survey were merged with air lead data from the US Environmental Protection Agency. Linear mixed effects models were run with and without an air lead interaction term for age group, sex, housing age, or race/ethnicity to determine whether these factors are effect measure modifiers for all ages combined and for five age brackets. Age group and race/ethnicity were determined to be effect measure modifiers in the all-age model and for some age groups. Being a child (1-5, 6-11, and 12-19 years) or of Mexican-American ethnicity increased the effect estimate. Living in older housing (built before 1950) decreased the effect estimate for all models except for the 1-5-year group, where older housing was an effect measure modifier. These results are consistent with the peer-reviewed literature of time-activity patterns, ventilation, and toxicokinetics.

Lead - nutritional considerations

Science.gov (United States)

... billion people had toxic (poisonous) blood lead levels. Food Sources Lead can be found in canned goods if there is lead solder in the ... to bottled water for drinking and cooking. Avoid canned goods from foreign ... cans goes into effect. If imported wine containers have a lead foil ...

The refining of secondary lead for use in advanced lead-acid batteries

International Nuclear Information System (INIS)

Ellis, Timothy W.; Mirza, Abbas H.

2010-01-01

Secondary lead, i.e. material produced by the recycling of lead-acid batteries has become the primary source of lead in much of the world. This has been important to the secondary lead industry as other uses have dwindled, e.g. lead based pigments, chemicals, fuel additives, solders and CRT glasses. Presently, battery manufacturing accounts for greater than 80% of lead consumption while recycled lead accounts for approximately the same market share of lead supply. These two facts strongly demonstrate the battery manufacturing and recycled lead are intimately coupled in everyday life. In this paper we will explore how recycled lead has become the material of choice for battery construction through the development of a recovery and refining process that exceeds the industries requirements. Particular focus will be on addressing the results presented by Prengaman on the effects of contaminant or tramp elements on gassing in lead-acid batteries. (author)

The effect of lead-based paint hazard remediation on blood lead levels of lead poisoned children in New York City.

Science.gov (United States)

Leighton, Jessica; Klitzman, Susan; Sedlar, Slavenka; Matte, Thomas; Cohen, Neal L

2003-07-01

Despite the widespread use of lead paint hazard control for children with lead poisoning, few controlled studies that estimate the effect of such control on children's blood lead levels have been published. This retrospective follow-up study examined the effects of lead hazard remediation and its timing on the blood lead levels of lead-poisoned children. From the New York City child blood lead registry, 221 children were selected who had an initial blood lead level of 20-44 micro g/dL between 1 July 1994 and 31 December 1996; were 6 months to 6 years of age; had a report of a follow-up blood lead test between 10 and 14 months after the initial test; had a lead-based paint hazard identified in the primary dwelling unit prior to the 10- to 14-month follow-up blood lead test; had resided or spent time at only one address with an identified lead-based paint hazard; and were not chelated. The decline in geometric mean blood lead levels from baseline to 10-14 months later was compared for children whose homes were remediated and whose homes were not remediated during the follow-up period. Regardless of remediation, geometric mean blood lead levels declined significantly from 24.3 micro g/dL at the initial diagnosis to 12.3 micro g/dL at the 10- to 14-month follow-up blood lead test (Premediated the geometric mean blood lead levels declined 53% compared to 41% among the 75 children whose homes were not remediated by the follow-up blood lead test, a remediation effect of approximately 20% (Premediation effect was 11%, although it was no longer significant. Race was the only factor that appeared to confound the relationship: Black children had higher follow-up blood lead levels even after controlling for other factors, including the natural logarithm of the initial blood lead level. The effect of remediation appeared to be stronger for younger (10 to remediation (within less than 3 months) appeared to have greater declines in blood lead levels at the follow-up test than

Melatonin reduces lead levels in blood, brain and bone and increases lead excretion in rats subjected to subacute lead treatment.

Science.gov (United States)

Hernández-Plata, Everardo; Quiroz-Compeán, Fátima; Ramírez-Garcia, Gonzalo; Barrientos, Eunice Yáñez; Rodríguez-Morales, Nadia M; Flores, Alberto; Wrobel, Katarzina; Wrobel, Kazimierz; Méndez, Isabel; Díaz-Muñoz, Mauricio; Robles, Juvencio; Martínez-Alfaro, Minerva

2015-03-04

Melatonin, a hormone known for its effects on free radical scavenging and antioxidant activity, can reduce lead toxicity in vivo and in vitro.We examined the effects of melatonin on lead bio-distribution. Rats were intraperitoneally injected with lead acetate (10, 15 or 20mg/kg/day) with or without melatonin (10mg/kg/day) daily for 10 days. In rats intoxicated with the highest lead doses, those treated with melatonin had lower lead levels in blood and higher levels in urine and feces than those treated with lead alone, suggesting that melatonin increases lead excretion. To explore the mechanism underlying this effect, we first assessed whether lead/melatonin complexes were formed directly. Electronic density functional (DFT) calculations showed that a lead/melatonin complex is energetically feasible; however, UV spectroscopy and NMR analysis showed no evidence of such complexes. Next, we examined the liver mRNA levels of metallothioneins (MT) 1 and 2. Melatonin cotreatment increased the MT2 mRNA expression in the liver of rats that received the highest doses of lead. The potential effects of MTs on the tissue distribution and excretion of lead are not well understood. This is the first report to suggest that melatonin directly affects lead levels in organisms exposed to subacute lead intoxication. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Lead elimination by ICRF 158 in rats after chronic lead exposure

Energy Technology Data Exchange (ETDEWEB)

Witting, U; Hultsch, E

1981-02-01

Lead elimination by ICRF 158, a lipophilic derivative of ethylene-diaminetetra-acetate (EDTA), was investigated in rats after chronic lead exposure. The animals had received a lead concentration of 550 ppm in their drinking water for 140 days. Subsequent treatment with ICRF 158 for 30 days led to increased mobilization and elimination of incorporated lead, and the lead-induced inhibition of hemosynthesis was removed. ICR 158 produced no renal damage in excess to lead-induced tubular nephrosis. Separate toxicity tests in mice demonstrated that is less toxic than CaNa/sub 2/EDTA. ICRF 158 does not form stable complexes with lead ions in vitro. The mechanism of action of this lipophilic EDTA derivative is compared to that of its hydrophilic correspondent, the chelating agent CaNa/sub 2/EDTA.

Cryogenic current leads

Energy Technology Data Exchange (ETDEWEB)

Zizek, F.

1982-01-01

Theoretical, technical and design questions are examined of cryogenic current leads for SP of magnetic systems. Simplified mathematical models are presented for the current leads. To illustrate modeling, the calculation is made of the real current leads for 500 A and three variants of current leads for 1500 A for the enterprise ''Shkoda.''

The effect of lead-based paint hazard remediation on blood lead levels of lead poisoned children in New York City

International Nuclear Information System (INIS)

Leighton, Jessica; Klitzman, Susan; Sedlar, Slavenka; Matte, Thomas; Cohen, Neal L.

2003-01-01

Despite the widespread use of lead paint hazard control for children with lead poisoning, few controlled studies that estimate the effect of such control on children's blood lead levels have been published. This retrospective follow-up study examined the effects of lead hazard remediation and its timing on the blood lead levels of lead-poisoned children. From the New York City child blood lead registry, 221 children were selected who had an initial blood lead level of 20-44 μg/dL between 1 July 1994 and 31 December 1996; were 6 months to 6 years of age; had a report of a follow-up blood lead test between 10 and 14 months after the initial test; had a lead-based paint hazard identified in the primary dwelling unit prior to the 10- to 14-month follow-up blood lead test; had resided or spent time at only one address with an identified lead-based paint hazard; and were not chelated. The decline in geometric mean blood lead levels from baseline to 10-14 months later was compared for children whose homes were remediated and whose homes were not remediated during the follow-up period. Regardless of remediation, geometric mean blood lead levels declined significantly from 24.3 μg/dL at the initial diagnosis to 12.3 μg/dL at the 10- to 14-month follow-up blood lead test (P<0.01). Among the 146 children whose homes were remediated the geometric mean blood lead levels declined 53% compared to 41% among the 75 children whose homes were not remediated by the follow-up blood lead test, a remediation effect of approximately 20% (P<0.01). After adjusting for potential confounders, the remediation effect was 11%, although it was no longer significant. Race was the only factor that appeared to confound the relationship: Black children had higher follow-up blood lead levels even after controlling for other factors, including the natural logarithm of the initial blood lead level. The effect of remediation appeared to be stronger for younger (10 to <36 months old) than for older (36

Replication and virus-induced transcriptome of HAdV-5 in normal host cells versus cancer cells--differences of relevance for adenoviral oncolysis.

Directory of Open Access Journals (Sweden)

Dominik E Dorer

Full Text Available Adenoviruses (Ads, especially HAdV-5, have been genetically equipped with tumor-restricted replication potential to enable applications in oncolytic cancer therapy. Such oncolytic adenoviruses have been well tolerated in cancer patients, but their anti-tumor efficacy needs to be enhanced. In this regard, it should be considered that cancer cells, dependent on their tissue of origin, can differ substantially from the normal host cells to which Ads are adapted by complex virus-host interactions. Consequently, viral replication efficiency, a key determinant of oncolytic activity, might be suboptimal in cancer cells. Therefore, we have analyzed both the replication kinetics of HAdV-5 and the virus-induced transcriptome in human bronchial epithelial cells (HBEC in comparison to cancer cells. This is the first report on genome-wide expression profiling of Ads in their native host cells. We found that E1A expression and onset of viral genome replication are most rapid in HBEC and considerably delayed in melanoma cells. In squamous cell lung carcinoma cells, we observed intermediate HAdV-5 replication kinetics. Infectious particle production, viral spread and lytic activity of HAdV-5 were attenuated in melanoma cells versus HBEC. Expression profiling at the onset of viral genome replication revealed that HAdV-5 induced the strongest changes in the cellular transcriptome in HBEC, followed by lung cancer and melanoma cells. We identified prominent regulation of genes involved in cell cycle and DNA metabolism, replication and packaging in HBEC, which is in accord with the necessity to induce S phase for viral replication. Strikingly, in melanoma cells HAdV-5 triggered opposing regulation of said genes and, in contrast to lung cancer cells, no weak S phase induction was detected when using the E2F promoter as reporter. Our results provide a rationale for improving oncolytic adenoviruses either by adaptation of viral infection to target tumor cells or by

A Genetically Modified Adenoviral Vector with a Phage Display-Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma.

Science.gov (United States)

Kim, Julius W; Kane, J Robert; Young, Jacob S; Chang, Alan L; Kanojia, Deepak; Morshed, Ramin A; Miska, Jason; Ahmed, Atique U; Balyasnikova, Irina V; Han, Yu; Zhang, Lingjiao; Curiel, David T; Lesniak, Maciej S

2015-09-01

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.

Work function of oxygen exposed lead and lead/indium alloy films

International Nuclear Information System (INIS)

Gundlach, K.H.; Hellemann, H.P.; Hoelzl, J.

1982-01-01

The effect of indium in superconducting tunnel junctions with lead/indium alloy base electrodes is investigated by measuring the vacuum work function of lead, indium, and lead/indium alloy films. It is found that the anomalous decrease of the work function of lead upon exposure to oxygen, explained by the penetration of oxygen into the inner surface of the lead film, is reversed into a slight increase in work function when some indium is added to the lead. This result indicates that the addition of indium provides a protection by suppressing the penetration of oxygen (and probably other gases) into the interior of the thin film

Blood lead and lead-210 origins in residents of Toulouse

International Nuclear Information System (INIS)

Servant, J.; Delapart, M.

1981-01-01

Blood lead and lead-210 analyses were performed on blood samples from non-smoking residents of Toulouse (city of 400,000 inhabitants). Simultaneous surface soil lead content determinations were carried out by the same procedure on rural zone samples of southwestern France. The observed isotopic ratios were compared in order to evaluate food chain contamination. For an average of 19.7 +- 5.8 μg 100 cc -1 of lead in blood, atmospheric contamination amounts to 20%, estimated as follows: 6% from direct inhalation and 14% from dry deposits on vegetation absorbed as food. The natural levels carried over by the food chain reach 14.9 μg 100 cc -1 and have a 210 Pb/Pb concentration ratio of 0.055 dpmμg -1 . These results lead to a maximum value of 15 μg 100 cc -1 for natural lead in human blood according to the ICRP model. (author)

Molecular Characterization of Prostate Cancer Cell Oncolysis by Herpes Simplex Virus ICP0 Mutants

National Research Council Canada - National Science Library

Mossman, Karen

2006-01-01

.... Briefly, the goals of the proposal were to characterize the oncolytic capacity of Herpes simplex virus type 1 ICP0 mutants in prostate cancer cells given the relationship between ICP0 and two tumor...

Lead-Free Piezoelectrics

CERN Document Server

Nahm, Sahn

2012-01-01

Ecological restrictions in many parts of the world are demanding the elimination of Pb from all consumer items. At this moment in the piezoelectric ceramics industry, there is no issue of more importance than the transition to lead-free materials. The goal of Lead-Free Piezoelectrics is to provide a comprehensive overview of the fundamentals and developments in the field of lead-free materials and products to leading researchers in the world. The text presents chapters on demonstrated applications of the lead-free materials, which will allow readers to conceptualize the present possibilities and will be useful for both students and professionals conducting research on ferroelectrics, piezoelectrics, smart materials, lead-free materials, and a variety of applications including sensors, actuators, ultrasonic transducers and energy harvesters.

Lead Toxicity

Science.gov (United States)

... o Do not use glazed ceramics, home remedies, cosmetics, or leaded-crystal glassware unless you know that they are lead safe. o If you live near an industry, mine, or waste site that may have contaminated ...

The lead and lead-acid battery industries during 2002 and 2007 in China

Energy Technology Data Exchange (ETDEWEB)

Chen, H.Y.; Li, A.J.; Finlow, D.E. [Key Lab of Electrochemical Technology on Energy Storage and Power Generation in Guangdong Universities, School of Chemistry and Environment, South China Normal University, Guangzhou 510006 (China)

2009-06-01

In the past 15 years, the center of the international lead market has shifted to China. China has become the largest producer of raw and refined lead, plus the largest consumer. This paper reviews the status of the lead and lead-acid battery industries in China, including lead mining, lead refining, secondary lead production, the lead-acid battery industry, new opportunities for lead-acid batteries, and the environmental problems associated with lead and lead-acid batteries. The output of raw and refined lead has increased annually in China, and now accounts for more than 30% of the world total. As a result of a change in the Chinese government's policy regarding the export of lead, plus an increase in the price of lead, the profits of Chinese lead manufacturers were significantly reduced, the trade deficit of the Chinese lead industry increased, the operating rates of lead smelter enterprises greatly reduced, and some small enterprises were forced to shut down. At the present time, an increasing number of enterprises have begun to produce secondary lead, and the scale of production has expanded from tens of tons to tens of thousands of tons. In 2006, the output of secondary lead in China reached 700,000 tons, but outdated technology and equipment limited development of the secondary lead industry. Because of serious pollution problems, raw material shortages, and fierce price competition in the battery market, changes in the development of the lead-acid battery industry have been dramatic; approximately one thousand medium-sized and small lead-acid battery producers have been closed in the past 3 years. The output of large lead-acid battery enterprises has not been reduced, however, as a result of their manufacturing technology and equipment being comparable to those in other advanced industrial countries. In China, the flourishing development of electric bicycles, electric tricycles, and photovoltaic energy systems should provide ongoing opportunities for

The lead and lead-acid battery industries during 2002 and 2007 in China

International Nuclear Information System (INIS)

Chen, H.Y.; Li, A.J.; Finlow, D.E.

2009-01-01

In the past 15 years, the center of the international lead market has shifted to China. China has become the largest producer of raw and refined lead, plus the largest consumer. This paper reviews the status of the lead and lead-acid battery industries in China, including lead mining, lead refining, secondary lead production, the lead-acid battery industry, new opportunities for lead-acid batteries, and the environmental problems associated with lead and lead-acid batteries. The output of raw and refined lead has increased annually in China, and now accounts for more than 30% of the world total. As a result of a change in the Chinese government's policy regarding the export of lead, plus an increase in the price of lead, the profits of Chinese lead manufacturers were significantly reduced, the trade deficit of the Chinese lead industry increased, the operating rates of lead smelter enterprises greatly reduced, and some small enterprises were forced to shut down. At the present time, an increasing number of enterprises have begun to produce secondary lead, and the scale of production has expanded from tens of tons to tens of thousands of tons. In 2006, the output of secondary lead in China reached 700,000 tons, but outdated technology and equipment limited development of the secondary lead industry. Because of serious pollution problems, raw material shortages, and fierce price competition in the battery market, changes in the development of the lead-acid battery industry have been dramatic; approximately one thousand medium-sized and small lead-acid battery producers have been closed in the past 3 years. The output of large lead-acid battery enterprises has not been reduced, however, as a result of their manufacturing technology and equipment being comparable to those in other advanced industrial countries. In China, the flourishing development of electric bicycles, electric tricycles, and photovoltaic energy systems should provide ongoing opportunities for the

A green lead hydrometallurgical process based on a hydrogen-lead oxide fuel cell.

Science.gov (United States)

Pan, Junqing; Sun, Yanzhi; Li, Wei; Knight, James; Manthiram, Arumugam

2013-01-01

The automobile industry consumed 9 million metric tons of lead in 2012 for lead-acid batteries. Recycling lead from spent lead-acid batteries is not only related to the sustainable development of the lead industry, but also to the reduction of lead pollution in the environment. The existing lead pyrometallurgical processes have two main issues, toxic lead emission into the environment and high energy consumption; the developing hydrometallurgical processes have the disadvantages of high electricity consumption, use of toxic chemicals and severe corrosion of metallic components. Here we demonstrate a new green hydrometallurgical process to recover lead based on a hydrogen-lead oxide fuel cell. High-purity lead, along with electricity, is produced with only water as the by-product. It has a >99.5% lead yield, which is higher than that of the existing pyrometallurgical processes (95-97%). This greatly reduces lead pollution to the environment.

Lead Contamination and Microbial Lead Tolerance in Soils at Major ...

African Journals Online (AJOL)

Devika

ABSTRACT: Lead pollution and lead tolerance levels of microbes in soil at major road junctions in Benin. City were investigated. Results revealed that distance from the road junctions affected the concentrations of lead in soil, as well as the microbial population density and types of microbes present in the soil. The highest ...

Lead Contamination and Microbial Lead Tolerance in Soils at Major ...

African Journals Online (AJOL)

Lead pollution and lead tolerance levels of microbes in soil at major road junctions in Benin City were investigated. Results revealed that distance from the road junctions affected the concentrations of lead in soil, as well as the microbial population density and types of microbes present in the soil. The highest concentrations ...

The effects of thiamin on lead metabolism: organ distribution of lead 203.

Science.gov (United States)

Kim, J S; Hamilton, D L; Blakley, B R; Rousseaux, C G

1992-01-01

The effect of thiamin on the organ distribution of lead was evaluated in CD-1 mice exposed intragastrically or intraperitoneally to a single dose of lead acetate (100 micrograms) containing 100 microCi lead 203. They were treated with either thiamin (25 or 50 mg/kg body weight), calcium ethylenediaminetetraacetic acid (CaEDTA) (50 mg/kg body weight), or combinations of thiamin and CaEDTA. The whole body retention and the organ distribution of lead 203 varied depending upon the route of lead administration, dose of thiamin and the specific treatment combination. Thiamin (25 or 50 mg/kg) treatment increased the whole body retention of both intragastric and intraperitoneal lead by approximately 10% in each instance. Calcium ethylenediaminetetraacetic acid, either alone or in combination with thiamin (50 mg/kg) reduced the whole body retention of lead by as much as 14% regardless of route of lead exposure. The relative retention of lead by the liver, kidney and spleen was greater in mice exposed to lead by the intragastric route. Regardless of route, CaEDTA in the combined treatment reduced the relative retention of lead in both the liver and kidney, whereas thiamin alone only reduced the retention of lead in the kidney. The results of this study indicate that thiamin in combination with CaEDTA alters the distribution and retention of lead in a manner which may have therapeutic application as it relates to chelation therapy. PMID:1423063

Lead shot from hunting as a source of lead in human blood

International Nuclear Information System (INIS)

Johansen, Poul; Pedersen, Henning Sloth; Asmund, Gert; Riget, Frank

2006-01-01

This study investigates the relationship between the intake of birds hunted with lead shot and the lead concentration in human blood. Fifty adult men from Nuuk, Greenland took part in the study. From September 2003 to June 2004 they regularly gave blood samples and recorded how many birds they ate. We found a clear relationship between the number of bird meals and blood lead and also a clear seasonal variation. The concentration was highest in mid-winter when bird consumption is at its highest. Blood lead was low (15 μg/L, mean concentration) among the participants reporting not eating birds. Among those reporting to eat birds regularly, blood lead was significantly higher, up to 128 μg/L (mean concentration). Concentrations depended on the frequency of bird meals: the more the bird meals, the higher the resulting blood lead. This clear relationship points to lead shot as the dominating lead source to people in Greenland. - Birds hunted with lead shot and consumed are a source of lead in human blood

Lead shot from hunting as a source of lead in human blood

Energy Technology Data Exchange (ETDEWEB)

Johansen, Poul [National Environmental Research Institute, Frederiksborgvej 399, DK-4000 Roskilde (Denmark)]. E-mail: poj@dmu.dk; Pedersen, Henning Sloth [Primary Health Care Center, DK-3900 Nuuk (Greenland); Asmund, Gert [National Environmental Research Institute, Frederiksborgvej 399, DK-4000 Roskilde (Denmark); Riget, Frank [National Environmental Research Institute, Frederiksborgvej 399, DK-4000 Roskilde (Denmark)

2006-07-15

This study investigates the relationship between the intake of birds hunted with lead shot and the lead concentration in human blood. Fifty adult men from Nuuk, Greenland took part in the study. From September 2003 to June 2004 they regularly gave blood samples and recorded how many birds they ate. We found a clear relationship between the number of bird meals and blood lead and also a clear seasonal variation. The concentration was highest in mid-winter when bird consumption is at its highest. Blood lead was low (15 {mu}g/L, mean concentration) among the participants reporting not eating birds. Among those reporting to eat birds regularly, blood lead was significantly higher, up to 128 {mu}g/L (mean concentration). Concentrations depended on the frequency of bird meals: the more the bird meals, the higher the resulting blood lead. This clear relationship points to lead shot as the dominating lead source to people in Greenland. - Birds hunted with lead shot and consumed are a source of lead in human blood.

The leaching of lead from lead-based paint in landfill environments.

Science.gov (United States)

Wadanambi, Lakmini; Dubey, Brajesh; Townsend, Timothy

2008-08-30

Lead leaching from lead-based paint (LBP) was examined using standardized laboratory protocols and tests with leachate from actual and simulated landfill environments. Two different LBP samples were tested; leaching solutions included leachates from three municipal solid waste (MSW) landfills and three construction and demolition (C&D) debris landfills. The toxicity characteristic leaching procedure (TCLP) and the synthetic precipitation leaching procedure (SPLP) were also performed. Lead concentrations were many times higher using the TCLP compared to the SPLP and the landfill leachates. No significant difference (alpha=0.05) was observed in leached lead concentrations from the MSW landfill and C&D debris landfill leachates. The impact of other building materials present in LBP debris on lead leaching was examined by testing mixtures of LBP (2%) and different building materials (98%; steel, wood, drywall, concrete). The type of substrate present impacted lead leaching results, with concrete demonstrating the most dramatic impact; the lowest lead concentrations were measured in the presence of concrete under both TCLP and SPLP extractions.

Relationship between soil lead and airborne lead concentrations at Springfield, Missouri, USA

Energy Technology Data Exchange (ETDEWEB)

Sheets, R W; Kyger, J R; Biagioni, R N; Probst, S [Department of Chemistry, Southwest Missouri State University, 65804 Springfield, MO (United States); Boyer, R; Barke, K [Greene County Health Department, 65802 Springfield, MO (United States)

2001-04-23

This study tests whether lead deposited to soil from automobiles during past years in a medium-sized US city (population 150000) may present a current health risk. It examines the relationship between current soil lead concentrations at nine locations within the city of Springfield, Missouri, and airborne lead levels measured at the same locations during years (1975-1981) when lead emissions from automobiles were much greater than at present. A strong, significant correlation is found between soil and airborne lead levels at eight of the sites (r=0.91, P<0.005 for soil lead vs. 1979 airborne lead), in low-traffic areas as well as in areas adjacent to heavy traffic flow. Residual lead concentrations in these soils are relatively low, even for the high-traffic sites, as expected for a medium sized city.

Corrosion by liquid lead and lead-bismuth: experimental results review and analysis

Energy Technology Data Exchange (ETDEWEB)

Zhang, Jinsuo [Los Alamos National Laboratory

2008-01-01

Liquid metal technologies for liquid lead and lead-bismuth alloy are under wide investigation and development for advanced nuclear energy systems and waste transmutation systems. Material corrosion is one of the main issues studied a lot recently in the development of the liquid metal technology. This study reviews corrosion by liquid lead and lead bismuth, including the corrosion mechanisms, corrosion inhibitor and the formation of the protective oxide layer. The available experimental data are analyzed by using a corrosion model in which the oxidation and scale removal are coupled. Based on the model, long-term behaviors of steels in liquid lead and lead-bismuth are predictable. This report provides information for the selection of structural materials for typical nuclear reactor coolant systems when selecting liquid lead or lead bismuth as heat transfer media.

Relationship between soil lead and airborne lead concentrations at Springfield, Missouri, USA.

Science.gov (United States)

Sheets, R W; Kyger, J R; Biagioni, R N; Probst, S; Boyer, R; Barke, K

2001-04-23

This study tests whether lead deposited to soil from automobiles during past years in a medium-sized US city (population 150,000) may present a current health risk. It examines the relationship between current soil lead concentrations at nine locations within the city of Springfield, Missouri, and airborne lead levels measured at the same locations during years (1975-1981) when lead emissions from automobiles were much greater than at present. A strong, significant correlation is found between soil and airborne lead levels at eight of the sites (r = 0.91, P lead vs. 1979 airborne lead), in low-traffic areas as well as in areas adjacent to heavy traffic flow. Residual lead concentrations in these soils are relatively low, even for the high-traffic sites, as expected for a medium sized city.

Uranium-lead systematics

International Nuclear Information System (INIS)

Wickman, F.E.

1983-01-01

The method of Levchenkov and Shukolyukov for calculating age and time disturbance of minerals without correction for original lead is generalized to include the cases when (1) original lead and radiogenic lead leach differently, and (2) the crystals studied consist of a core and a mantle. It is also shown that a straight line obtained from the solution of the equations is the locus of the isotopic composition of original lead. (Auth.)

Lead dust in Broken Hill homes: effect of remediation on indoor lead levels.

Science.gov (United States)

Boreland, F; Lyle, D M

2006-02-01

This study was undertaken to determine whether home remediation effectively reduced indoor lead levels in Broken Hill, a long-established silver-lead-zinc mining town in outback Australia. A before-after study of the effect of home remediation on indoor lead levels was embedded into a randomized controlled trial of the effectiveness of remediation for reducing elevated blood lead levels in young children. Moist towelettes were used to measure lead loading (microg/m2) on internal windowsills and internal and entry floors of 98 homes; samples were collected before, immediately after, and 2, 4, 6, 8, and 10 months after remediation. Data were log(10) transformed for the analysis. Remediation reduced average indoor lead levels by approximately 50%, and lead levels remained low for the duration of the follow-up period (10 months). The greatest gains were made in homes with the highest initial lead levels; homes with low preremediation lead levels showed little or no benefit. Before remediation, homes located in areas with high soil lead levels or with "poor" dust proofing had higher lead levels than those in areas with lower soil lead levels or with "medium" or "good" dust proofing; these relative differences remained after remediation. There was no evidence that lead loading was reduced by an increased opportunity to become aware of lead issues. We conclude that remediation is an effective strategy for reducing the lead exposure of children living in homes with high indoor lead levels.

High human exposure to lead through consumption of birds hunted with lead shot

International Nuclear Information System (INIS)

Johansen, P.; Asmund, G.; Riget, F.

2004-01-01

Lead shot contaminates the edible parts of birds so that tolerable human lead intake is exceeded. - We assess lead contamination of Greenland seabirds killed with lead shot having studied thick-billed murre and common eider, the two most important species in the diet. The lead concentration is very high in meat of eiders killed with lead shot (mean 6.1 μg/g-wet wt, 95% CL 2.1-12). This level is about 44 times higher than in drowned eiders and eight times higher than in shot murres. Analyzing whole breasts instead of sub-samples reveals about seven times higher lead levels in birds' meat. We conclude that in some cases the lead intake by Greenland bird eaters will largely exceed the FAO/WHO tolerable lead intake guideline and that lead shot is a more important source of lead in the diet than previously estimated

Lead in the environment

Science.gov (United States)

Pattee, Oliver H.; Pain, Deborah J.; Hoffman, David J.; Rattner, Barnett A.; Burton, G. Allen; Cairns, John

2003-01-01

Anthropogenic uses of lead have probably altered its availability and environmental distribution more than any other toxic element. Consequently, lead concentrations in many living organisms may be approaching thresholds of toxicity for the adverse effects of lead. Such thresholds are difficult to define, as they vary with the chemical and physical form of lead, exposure regime, other elements present and also vary both within and between species. The technological capability to accurately quantify low lead concentrations has increased over the last decade, and physiological and behavioral effects have been measured in wildlife with tissue lead concentrations below those previously considered safe for humans.s.236 Consequently. lead criteria for the protection of wildlife and human health are frequently under review, and 'thresholds' of lead toxicity are being reconsidered. Proposed lead criteria for the protection of natural resources have been reviewed by Eisler. Uptake of lead by plants is limited by its generally low availability in soils and sediments, and toxicity may be limited by storage mechanisms and its apparently limited translocation within most plants. Lead does not generally accumulate within the foliar parts of plants, which limits its transfer to higher trophic levels. Although lead may concentrate in plant and animal tissues, no evidence of biomagnification exists. Acid deposition onto surface waters and soils with low buffering capacity may influence the availability of lead for uptake by plants and animals, and this may merit investigation at susceptible sites. The biological significance of chronic low-level lead exposure to wildlife is sometimes difficult to quantify. Animals living in urban environments or near point sources of lead emission are inevitably subject to greater exposure to lead and enhanced risk of lead poisoning. Increasingly strict controls on lead emissions in many countries have reduced exposure to lead from some sources

Anemia risk in relation to lead exposure in lead-related manufacturing

Directory of Open Access Journals (Sweden)

Nan-Hung Hsieh

2017-05-01

Full Text Available Abstract Background Lead-exposed workers may suffer adverse health effects under the currently regulated blood lead (BPb levels. However, a probabilistic assessment about lead exposure-associated anemia risk is lacking. The goal of this study was to examine the association between lead exposure and anemia risk among factory workers in Taiwan. Methods We first collated BPb and indicators of hematopoietic function data via health examination records that included 533 male and 218 female lead-exposed workers between 2012 and 2014. We used benchmark dose (BMD modeling to estimate the critical effect doses for detection of abnormal indicators. A risk-based probabilistic model was used to characterize the potential hazard of lead poisoning for job-specific workers by hazard index (HI. We applied Bayesian decision analysis to determine whether BMD could be implicated as a suitable BPb standard. Results Our results indicated that HI for total lead-exposed workers was 0.78 (95% confidence interval: 0.50–1.26 with risk occurrence probability of 11.1%. The abnormal risk of anemia indicators for male and female workers could be reduced, respectively, by 67–77% and 86–95% by adopting the suggested BPb standards of 25 and 15 μg/dL. Conclusions We conclude that cumulative exposure to lead in the workplace was significantly associated with anemia risk. This study suggests that current BPb standard needs to be better understood for the application of lead-exposed population protection in different scenarios to provide a novel standard for health management. Low-level lead exposure risk is an occupational and public health problem that should be paid more attention.

Lead exposure from lead pellets: age-related accumulation in mute swans

Energy Technology Data Exchange (ETDEWEB)

Eskildsen, J.; Grandjean, P.

1984-05-01

In a cross-sectional study of adult swans and their successfully fledged young in Ringkobing Fjord, West Jutland, Denmark, 128 venous blood samples were taken during the moulting period and analyzed for lead. While the juveniles generally showed blood lead levels below 15 micrograms/100 ml (median, 11 micrograms/100 ml), the values were significantly higher in adults (median, 25 micrograms/100 ml). Adult females showed slightly higher levels than did adult males. None of the birds examined showed signs of acute lead toxicity, and increased blood levels in adults may reflect increased lead body burdens from previous ingestion of lead shot as gizzard stones.

Lead-free piezoceramics.

Science.gov (United States)

Saito, Yasuyoshi; Takao, Hisaaki; Tani, Toshihiko; Nonoyama, Tatsuhiko; Takatori, Kazumasa; Homma, Takahiko; Nagaya, Toshiatsu; Nakamura, Masaya

2004-11-04

Lead has recently been expelled from many commercial applications and materials (for example, from solder, glass and pottery glaze) owing to concerns regarding its toxicity. Lead zirconium titanate (PZT) ceramics are high-performance piezoelectric materials, which are widely used in sensors, actuators and other electronic devices; they contain more than 60 weight per cent lead. Although there has been a concerted effort to develop lead-free piezoelectric ceramics, no effective alternative to PZT has yet been found. Here we report a lead-free piezoelectric ceramic with an electric-field-induced strain comparable to typical actuator-grade PZT. We achieved this through the combination of the discovery of a morphotropic phase boundary in an alkaline niobate-based perovskite solid solution, and the development of a processing route leading to highly textured polycrystals. The ceramic exhibits a piezoelectric constant d33 (the induced charge per unit force applied in the same direction) of above 300 picocoulombs per newton (pC N(-1)), and texturing the material leads to a peak d33 of 416 pC N(-1). The textured material also exhibits temperature-independent field-induced strain characteristics.

Specificities of reactor coolant pumps units with lead and lead-bismuth coolant

International Nuclear Information System (INIS)

Beznosov, A.V.; Anotonenkov, M.A.; Bokov, P.A.; Baranova, V.S.; Kustov, M.S.

2009-01-01

The analysis results of impact of lead and lead-bismuth coolants specific properties on the coolants flow features in flow channels of the main and auxiliary circulating pumps are presented. Impossibility of cavitation initiation in flow channels of vane pumps pumping lead and lead-bismuth coolants was demonstrated. The experimental research results of discontinuity of heavy liquid metal coolant column were presented and conditions of gas cavitation initiation in coolant flow were discussed. Invalidity of traditional calculation methods of water and sodium coolants circulation pumps calculations for lead and lead-bismuth coolants circulation pumps was substantiated [ru

Photocatalyzed removal of lead ion from lead-chelator solution

Energy Technology Data Exchange (ETDEWEB)

Cho, Young Hyun; Na, Jung Won; Sung, Ki Woung [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

1994-07-01

The present study was undertaken to examine the influence of such chelating agents on the ease and speed of photocatalyzed metal removal and deposition. With excess EDTA, the free EDTA competes with Pb for oxidation, and at a ten fold excess, no lead oxidation (hence removal) occurs. With insufficient EDTA, the corresponding initial concentration of Pb-EDTA is decreased; after its destruction, the remaining Pb{sup 2+} is removed more slowly, at rates found with lead nitrate solution. The net result is that the maximum rate of lead deposition occurs at the stoichiometric ratio of 1:1 EDTA : Pb{sup 2+}.

Vector boson and Charmonium production in proton-lead and lead-lead collisions with ATLAS at the LHC

CERN Document Server

AUTHOR|(INSPIRE)INSPIRE-00241320; The ATLAS collaboration

2016-01-01

Electroweak bosons do not interact strongly with the dense and hot medium formed in nuclear collisions, and thus should be sensitive to the nuclear modification of parton distribution functions (nPDFs). The in-medium modification of heavy charmonium states plays an important role in studying the hot and dense medium. The ATLAS detector, optimized to search for new physics in proton-proton collisions, is well equipped to measure Z and W bosons as well as quarkonium in the high occupancy environment produced in heavy ion collisions. Results from the ATLAS experiment on W and Z boson yields as a function of centrality, transverse momentum and rapidity, in lead-lead and proton-lead collisions are presented. Quarkonium results from proton-lead collisions are also presented.

Lead-elevated activity of xanthine oxidase in lead-exposed workers

Directory of Open Access Journals (Sweden)

Sławomir Kasperczyk

2013-04-01

Full Text Available Background: The aim of the present study was to explore the connection between lead toxicity and the activity of xanthine oxidase (XO. In addition, we indicated the uric acid (UA and creatinine levels and concentration of erythrocyte malondialdehyde (MDA to estimate oxidative stress intensity. Materials and Methods: The examined group consisted of 125 healthy male employees of zinc and lead works. The examined group was divided into tertiles according to blood lead levels. In the collected blood samples, concentrations of lead-exposure indices, UA, creatinine, and MDA as well as activity of XO were measured concomitantly. The control group consisted of 32 healthy male administrative workers who were exposed to lead only environmentally. Results: XO activity and MDA level were significantly elevated in all tertiles compared to the control group. Creatinine level was significantly elevated in the medium and high tertiles. However, the level of UA was significantly elevated in the high tertile, while in the low and medium tertile only a tendency toward higher values was observed. Conclusions: Occupational exposure to lead induces activity of XO. This induction may contribute to the observed simultaneously increased oxidative stress, measured as MDA level, and the increased level of UA. Med Pr 2013;64(2:175–180

Role of Airborne Lead in Increased Body Burden of Lead in Hartford Children*

Science.gov (United States)

Lepow, Martha L.; Bruckman, Leonard; Rubino, Robert A.; Markowitz, Steven; Gillette, Marybeth; Kapish, Janet

1974-01-01

The ingestion of airborne lead fallout is the mechanism responsible for increased lead body burdens found in 10 urban Connecticut children. The mean indoor lead levels found in housedust was 11,000 μg/g; highest concentrations occurred on windowsills and in floor dust. The mean lead content of Hartford street dirt was 1,200 μg/g; levels were highest near the street and next to the buildings. The mean lead concentration of hand samples taken from the subject children was 2,400 μg/g; the mean weight of hand samples was 11 mg. The concentration of lead in dirt and househould dust was high enough to theoretically result in excessive lead accumulation in young children who are putting their dusty, dirty hands in their mouths during play. While we believe that lead emitted from automobiles contributes significantly to air, dirt and dust lead levels the environmental impact of reducing or eliminating lead from gasoline is not yet completely understood. PMID:4133903

Lead Poisoning Prevention Tips

Science.gov (United States)

... or removed safely. How are children exposed to lead? Lead-based paint and lead contaminated dust are ... What can be done to prevent exposure to lead? It is important to determine the construction year ...

The effects of thiamin on lead metabolism: organ distribution of lead 203.

OpenAIRE

Kim, J S; Hamilton, D L; Blakley, B R; Rousseaux, C G

1992-01-01

The effect of thiamin on the organ distribution of lead was evaluated in CD-1 mice exposed intragastrically or intraperitoneally to a single dose of lead acetate (100 micrograms) containing 100 microCi lead 203. They were treated with either thiamin (25 or 50 mg/kg body weight), calcium ethylenediaminetetraacetic acid (CaEDTA) (50 mg/kg body weight), or combinations of thiamin and CaEDTA. The whole body retention and the organ distribution of lead 203 varied depending upon the route of lead a...

Method of handling of scrap lead from lead-acid batteries

Energy Technology Data Exchange (ETDEWEB)

Sytschev, A P; Kim, G V; Larin, V F; Sidorova, G D; Vicharev, I G; Kuur, V P; Achmetov, R S; Moiseev, G L; Maslov, V I; Kabatschek, V G

1979-12-13

Scrap lead and the casings of accumulators are mined and molten together in oxidixing atmosphere at a temperature of 1300 to 1500/sup 0/C. The lead oxide contained in the melt is then reduced to blue lead. Due to the combustion of the accumulator casings consisting of organic substances the fuel consumption in the melting process is reduced in accordance. The oxidizing atmosphere in the melting process is produced by use of air or oxygen.

Lead isotope ratios in artists' lead white: a progress report

Energy Technology Data Exchange (ETDEWEB)

Keisch, B; Callahan, R C [Carnegie-Mellon Univ., Pittsburgh, Pa. (USA)

1976-07-01

The lead isotope ratios in over four hundred samples of lead white have been determined. The samples represent various geographical sources and dates from the thirteenth century to the present. A new method for organizing this large volume of data is described which helps with the visualization of temporal and geographic patterns. A number of interesting relationships between lead isotope ratio and date or source are shown to exist. Some examples of successful applications of this methodology are described.

Activity of lead deposited in the tissues in conditions of occupational lead exposure

Energy Technology Data Exchange (ETDEWEB)

1974-01-01

The author measured urinary excretion of delta-aminolevulinic acid (ALA), coproporphyrins and lead, before and after administration of chelating agents (CaEDTA and D-penicillamine) to subjects presenting clinical symptoms of lead poisoning and workers occupationally exposed to lead. He found a great increase in lead following its mobilization in subjects with lead poisoning who had previously shown a high level of haemoglobin precursors and a low urinary lead level. In these subjects ALA excretion was proportional to the duration of exposure. A correlation was found between urinary ALA and coproporphyrins, on the one hand, and lead excretion after provocation, on the other. This suggests that the lead deposited in the tissues, as well as that in circulation, retains all its activity.

Health care of people at work. Workers exposed to lead. I. Inorganic lead

Energy Technology Data Exchange (ETDEWEB)

Waldron, H.A.

1978-01-01

The risks associated with exposure to inorganic lead and the means by which these risks can be minimized are outlined. Lead is used to make a variety of metal products, the grids and oxides in storage batteries, pigments, chemicals, and also for lead plating. In the United States about 70% of the total lead consumption is related to transportation. Uptake of inorganic lead is by ingestion and inhalation. About 90% of the total body burden of lead is contained within the skeletal tissues. Lead is excreted in the kidney, in sweat, and in milk. Toxic effects are directed against the blood, the nervous system, and the kidney. Symptoms of lead poisoning are abdominal pain, constipation, vomiting, asthenia, paresthesia, psychological symptoms, and diarrhea. Physical and biological monitoring can serve to protect workers. Diagnosis of lead poisoning is not easy. Treatment involves removal from exposure and/or treatment with a chelating agent.

Leading Democratically

Science.gov (United States)

Brookfield, Stephen

2010-01-01

Democracy is the most venerated of American ideas, the one for which wars are fought and people die. So most people would probably agree that leaders should be able to lead well in a democratic society. Yet, genuinely democratic leadership is a relative rarity. Leading democratically means viewing leadership as a function or process, rather than…

Who Leads China's Leading Universities?

Science.gov (United States)

Huang, Futao

2017-01-01

This study attempts to identify the major characteristics of two different groups of institutional leaders in China's leading universities. The study begins with a review of relevant literature and theory. Then, there is a brief introduction to the selection of party secretaries, deputy secretaries, presidents and vice presidents in leading…

Remediation of lead contaminated soil

International Nuclear Information System (INIS)

Urban, W.; Krishnamurthy, S.

1992-01-01

Lead contaminated soil in urban area is of major concern because of the potential health risk to children. Many studies have established a direct correlation between lead in soil and elevated blood lead levels in children. In Minneapolis, Minnesota, Mielke et al. (1983) reported that 50% of the Hmong children with lead poisioning were in areas where soil lead levels were between 500 and 1000 micrograms per gram (ug/g), and 40% of the children suffering from lead poisioning lived in areas where soil lead levels exceeded 1000 ug/g. In urban areas, lead pollution in soil has come from many different sources. The sources include lead paint, lead batteries and automobile exhaust. Olson and Skogerbee (1975) found the following lead compounds in soils where the primary source of pollution was from automobiles: lead sulfate, lead oxide, lead dioxide, lead sulfide, and metallic lead. The primary form of lead found was lead sulfate. Lead sulfate, lead tetraoxide, white lead, and other forms of lead have been used in the manufacture of paints for houses. At present, two remediation techniques, solidification and Bureau of Mines fluosilicic acid leaching, are available for lead-contaminated sites. The objective of the present investigation at the Risk Reduction Engineering Laboratory (RREL), Edison, was to try to solubilize the lead species by appropriate reagents and then recover the contaminants by precipitation as lead sulfate, using environmentally acceptable methods. The apparatus used for mixing was a LabMaster mixer, with variable speed and high-shear impeller. Previous work had used nitric acid for dissolving metallic lead. Owing to the environmental concerns, it was decided to use acetic acid in the presence of oxygen. The theoretical justification for this approach is the favorable redox potential for the reaction between metallic lead, acetic acid, and gaseous oxygen

Lead theft--a study of the "uniqueness" of lead from church roofs.

Science.gov (United States)

Bond, John W; Hainsworth, Sarah V; Lau, Tien L

2013-07-01

In the United Kingdom, theft of lead is common, particularly from churches and other public buildings with lead roofs. To assess the potential to distinguish lead from different sources, 41 samples of lead from 24 church roofs in Northamptonshire, U.K, have been analyzed for relative abundance of trace elements and isotopes of lead using X-ray fluorescence (XRF) and inductively coupled plasma mass spectrometry, respectively. XRF revealed the overall presence of 12 trace elements with the four most abundant, calcium, phosphorus, silicon, and sulfur, showing a large weight percentage standard error of the mean of all samples suggesting variation in the weight percentage of these elements between different church roofs. Multiple samples from the same roofs, but different lead sheets, showed much lower weight percentage standard errors of the mean suggesting similar trace element concentrations. Lead isotope ratios were similar for all samples. Factors likely to affect the occurrence of these trace elements are discussed. © 2013 American Academy of Forensic Sciences.

Lead isotope ratios in artists' lead white: a progress report

International Nuclear Information System (INIS)

Keisch, B.; Callahan, R.C.

1976-01-01

The lead isotope ratios in over four hundred samples of lead white have been determined. The samples represent various geographical sources and dates from the thirteenth century to the present. A new method for organizing this large volume of data is described which helps with the visualization of temporal and geographic patterns. A number of interesting relationships between lead isotope ratio and date or source are shown to exist. Some examples of successful applications of this methodology are described. (author)

Quantification of atmospheric lead emissions from 70 years of leaded petrol consumption in Australia

Science.gov (United States)

Kristensen, Louise Jane

2015-06-01

Lead is a persistent pollutant and the subject of many environmental studies, yet, in Australia, the extent of atmospheric lead emissions from the use of leaded petrol is unquantified. This paper details the first comprehensive account of leaded petrol sales and its lead concentrations over the 70 years of use in Australia. The resulting atmospheric lead emissions are calculated to provide the most complete understanding of the volume of lead released to the Australian continent from the consumption of leaded petrol. Atmospheric emissions of lead to the entire Australian continent from leaded petrol are calculated to total 240,510 tonnes over seven decades of use, peaking at 7869 tonnes in 1974. Total emissions for individual states and territories range from 1745 to 67,893 tonnes, with New South Wales responsible for the largest emissions. The effect of regulations on allowable concentrations of tetraethyl-lead additives are observed in the reduction of lead emissions in New South Wales and Victoria. The consequences to human health and the environment of leaded petrol consumption in Australia's populous cities are examined against historical air quality data and blood lead levels.

Large-capacity current leads

International Nuclear Information System (INIS)

Ballarino, A.

2008-01-01

Feeding superconducting magnets with reliable low-loss devices is a key issue for any cryo-electrical system. Conventional or HTS current leads can be used, and cooling methods, materials, and geometries can be chosen to optimize the thermo-electrical performance of the system. The LHC magnets are powered via more than 3000 current leads transporting altogether about 3 MA of current. With thousands of leads, the LHC lead project represents today the largest project of its kind ever undertaken. Following a review of the LHC lead project, an overview of the choices that can be made for the optimization of large capacity current leads is presented. Examples are given of other leads for large scale magnet systems for which the use of HTS is being envisaged

Performance of Lead-Free versus Lead-Based Hunting Ammunition in Ballistic Soap

Science.gov (United States)

Gremse, Felix; Krone, Oliver; Thamm, Mirko; Kiessling, Fabian; Tolba, René Hany; Rieger, Siegfried; Gremse, Carl

2014-01-01

Background Lead-free hunting bullets are an alternative to lead-containing bullets which cause health risks for humans and endangered scavenging raptors through lead ingestion. However, doubts concerning the effectiveness of lead-free hunting bullets hinder the wide-spread acceptance in the hunting and wildlife management community. Methods We performed terminal ballistic experiments under standardized conditions with ballistic soap as surrogate for game animal tissue to characterize dimensionally stable, partially fragmenting, and deforming lead-free bullets and one commonly used lead-containing bullet. The permanent cavities created in soap blocks are used as a measure for the potential wound damage. The soap blocks were imaged using computed tomography to assess the volume and shape of the cavity and the number of fragments. Shots were performed at different impact speeds, covering a realistic shooting range. Using 3D image segmentation, cavity volume, metal fragment count, deflection angle, and depth of maximum damage were determined. Shots were repeated to investigate the reproducibility of ballistic soap experiments. Results All bullets showed an increasing cavity volume with increasing deposited energy. The dimensionally stable and fragmenting lead-free bullets achieved a constant conversion ratio while the deforming copper and lead-containing bullets showed a ratio, which increases linearly with the total deposited energy. The lead-containing bullet created hundreds of fragments and significantly more fragments than the lead-free bullets. The deflection angle was significantly higher for the dimensionally stable bullet due to its tumbling behavior and was similarly low for the other bullets. The deforming bullets achieved higher reproducibility than the fragmenting and dimensionally stable bullets. Conclusion The deforming lead-free bullet closely resembled the deforming lead-containing bullet in terms of energy conversion, deflection angle, cavity shape

Performance of lead-free versus lead-based hunting ammunition in ballistic soap.

Directory of Open Access Journals (Sweden)

Felix Gremse

Full Text Available BACKGROUND: Lead-free hunting bullets are an alternative to lead-containing bullets which cause health risks for humans and endangered scavenging raptors through lead ingestion. However, doubts concerning the effectiveness of lead-free hunting bullets hinder the wide-spread acceptance in the hunting and wildlife management community. METHODS: We performed terminal ballistic experiments under standardized conditions with ballistic soap as surrogate for game animal tissue to characterize dimensionally stable, partially fragmenting, and deforming lead-free bullets and one commonly used lead-containing bullet. The permanent cavities created in soap blocks are used as a measure for the potential wound damage. The soap blocks were imaged using computed tomography to assess the volume and shape of the cavity and the number of fragments. Shots were performed at different impact speeds, covering a realistic shooting range. Using 3D image segmentation, cavity volume, metal fragment count, deflection angle, and depth of maximum damage were determined. Shots were repeated to investigate the reproducibility of ballistic soap experiments. RESULTS: All bullets showed an increasing cavity volume with increasing deposited energy. The dimensionally stable and fragmenting lead-free bullets achieved a constant conversion ratio while the deforming copper and lead-containing bullets showed a ratio, which increases linearly with the total deposited energy. The lead-containing bullet created hundreds of fragments and significantly more fragments than the lead-free bullets. The deflection angle was significantly higher for the dimensionally stable bullet due to its tumbling behavior and was similarly low for the other bullets. The deforming bullets achieved higher reproducibility than the fragmenting and dimensionally stable bullets. CONCLUSION: The deforming lead-free bullet closely resembled the deforming lead-containing bullet in terms of energy conversion

Penetration of a magnetic field into superconducting lead and lead-indium alloys

International Nuclear Information System (INIS)

Egloff, C.; Raychaudhuri, A.K.; Rinderer, L.

1983-01-01

The temperature dependence of the magnetic field penetration depth of superconducting lead and lead-indium alloys has been studied over the temperature range between about 2 K and T/sub c/. Data are analyzed in terms of the microscopic theory. The difficulties of a unique analysis of the penetration data are pointed out and a strategy for the analysis is discussed. The penetration depth at T = 0K for pure lead is determined as 522 A. This value, though higher than the previously accepted value for lead, is nevertheless consistent with the strong coupling character of lead

Lead inclusions in aluminium

International Nuclear Information System (INIS)

Johnson, E.; Johansen, A.; Sarholt-Kristensen, L.; Andersen, H.H.; Grabaek, L.; Bohr, J.

1990-01-01

Ion implantation at room temperature of lead into aluminum leads to spontaneous phase separation and formation of lead precipitates growing topotactically with the matrix. Unlike the highly pressurized (∼ 1-5 GPa) solid inclusions formed after noble gas implantations, the pressure in the lead precipitates is found to be less than 0.12 GPa. Recently the authors have observed the result that the lead inclusions in aluminum exhibit both superheating and supercooling. In this paper they review and elaborate on these results. Small implantation-induced lead precipitates embedded in an aluminum matrix were studied by x-ray diffraction

EP toxicity testing of lead to resolve disposition of radioactively contaminated lead

International Nuclear Information System (INIS)

Larsen, M.M.; Boehmer, A.M.

1986-03-01

The Department of Energy (DOE), in its efforts to comply with the requirements of the Resource Conservation and Recovery Act (RCRA) of 1976, is concerned with hazardous waste which is also radioactively contaminated. There are no existing facilities to treat or dispose of these wastes. One such waste is lead, which is extensively used in the nuclear industry as shielding. This paper reports the results of leach testing of lead (both solid lead samples and lead shot) to resolve questions as to whether or not radioactively contaminated waste lead must be treated as a hazardous waste. The results of these tests showed that: some samples passed the leach test. Results of development efforts performed to date to recycle lead and those planned for the future are included in this report

Elution of lead from lead zirconate titanate ceramics to acid rain

Science.gov (United States)

Tsurumi, Takaaki; Takezawa, Shuhei; Hoshina, Takuya; Takeda, Hiroaki

2017-10-01

The amount of lead that eluted from lead zirconate titanate (PZT) ceramics to artificial acid rain was evaluated. Four kinds of PZT ceramics, namely, pure PZT at MPB composition, CuO-added PZT, PZT with 10 mol % substitution of Ba for Pb, and CuO-added PZT with 10 mol % substitution of Ba for Pb, were used as samples of the elution test. These PZT ceramics of 8 mm2 and 1.1-1.2 mm thickness were suspended in 300 ml of H2SO4 solution of pH 4.0. The concentration of lead eluted from PZT was in the range from 0.2 to 0.8 ppm. It was found that both liquid phase formation by the addition of CuO and the substitution of Ba for Pb were effective to reduce the amount of lead that eluted. By fitting the leaching out curve with a classical equation, a master curve assuming no sampling effect was obtained. The lead concentration evaluated from the amount of lead that eluted from a commercial PZT plate to H2SO4 solution of pH 5.3 was almost the same as the limit in city water. It is concluded that PZT is not harmful to health and the environment and the amount of lead that eluted from PZT can be controlled by modifying PZT composition.

Production of oncolytic adenovirus and human mesenchymal stem cells in a single-use, Vertical-Wheel bioreactor system: Impact of bioreactor design on performance of microcarrier-based cell culture processes.

Science.gov (United States)

Sousa, Marcos F Q; Silva, Marta M; Giroux, Daniel; Hashimura, Yas; Wesselschmidt, Robin; Lee, Brian; Roldão, António; Carrondo, Manuel J T; Alves, Paula M; Serra, Margarida

2015-01-01

Anchorage-dependent cell cultures are used for the production of viruses, viral vectors, and vaccines, as well as for various cell therapies and tissue engineering applications. Most of these applications currently rely on planar technologies for the generation of biological products. However, as new cell therapy product candidates move from clinical trials towards potential commercialization, planar platforms have proven to be inadequate to meet large-scale manufacturing demand. Therefore, a new scalable platform for culturing anchorage-dependent cells at high cell volumetric concentrations is urgently needed. One promising solution is to grow cells on microcarriers suspended in single-use bioreactors. Toward this goal, a novel bioreactor system utilizing an innovative Vertical-Wheel™ technology was evaluated for its potential to support scalable cell culture process development. Two anchorage-dependent human cell types were used: human lung carcinoma cells (A549 cell line) and human bone marrow-derived mesenchymal stem cells (hMSC). Key hydrodynamic parameters such as power input, mixing time, Kolmogorov length scale, and shear stress were estimated. The performance of Vertical-Wheel bioreactors (PBS-VW) was then evaluated for A549 cell growth and oncolytic adenovirus type 5 production as well as for hMSC expansion. Regarding the first cell model, higher cell growth and number of infectious viruses per cell were achieved when compared with stirred tank (ST) bioreactors. For the hMSC model, although higher percentages of proliferative cells could be reached in the PBS-VW compared with ST bioreactors, no significant differences in the cell volumetric concentration and expansion factor were observed. Noteworthy, the hMSC population generated in the PBS-VW showed a significantly lower percentage of apoptotic cells as well as reduced levels of HLA-DR positive cells. Overall, these results showed that process transfer from ST bioreactor to PBS-VW, and scale-up was

Long range correlations, leading particle spectrum and correlations with leading particles

International Nuclear Information System (INIS)

Ilgenfritz, E.M.

1976-05-01

The unitary cluster emission model by de Groot and Ruijgrok is discussed as an approach to understand the leading particle behaviour. Consequences of the model concerning co--rrelations between leading particles and produced particles in the central region are considered. No satisfactory agreement was found. Production of leading clusters is argued for being an essential feature of these correlations. (author)

Comparative toxicity of tetra ethyl lead and lead oxide to earthworms, Eisenia fetida (Savigny)

International Nuclear Information System (INIS)

Venkateswara Rao, J.; Kavitha, P.; Padmanabha Rao, A.

2003-01-01

Leaded gasoline contains tetra ethyl lead (TEL) as an antiknocking agent, which produces major amounts of lead oxide in automobile exhaust along with traces of TEL. To minimize the lead contamination, methyl tertiary butyl ether (MTBE) is used as a substitute for producing unleaded gasoline. It has become increasingly apparent that young children are highly susceptible to the harmful effects of lead. Hence, a study was carried out to monitor lead toxicity in soil, using adult earthworms (Eisenia fetida, Savigny). Leaded gasoline (TEL) and lead oxide are 383- and 211-fold more toxic than unleaded gasoline (MTBE) in 7 days of exposure and 627- and 290-fold more toxic in 14 days, respectively. Results indicate that the presence of TEL in leaded gasoline and lead oxide has a significant effect on behavior, morphology, and histopathology of earthworms. Absorption of TEL into the tissues is comparatively less than that of lead oxide but toxic effects were severe. Rupture of the cuticle, extrusion of coelomic fluid and inflexible metameric segmentation were observed, causing desensitization of the posterior region leading to fragmentation in earthworms

Lead-resistant Providencia alcalifaciens strain 2EA bioprecipitates Pb+2 as lead phosphate.

Science.gov (United States)

Naik, M M; Khanolkar, D; Dubey, S K

2013-02-01

A lead-resistant bacteria isolated from soil contaminated with car battery waste were identified as Providencia alcalifaciens based on biochemical characteristics, FAME profile and 16S rRNA sequencing and designated as strain 2EA. It resists lead nitrate up to 0·0014 mol l(-1) by precipitating soluble lead as insoluble light brown solid. Scanning electron microscopy coupled with energy-dispersive X-ray spectrometric analysis (SEM-EDX) and X-ray diffraction spectroscopy (XRD) revealed extracellular light brown precipitate as lead orthophosphate mineral, that is, Pb(9) (PO(4))(6) catalysed by phosphatase enzyme. This lead-resistant bacterial strain also demonstrated tolerance to high levels of cadmium and mercury along with multiple antibiotic resistance. Providencia alcalifaciens strain 2EA could be used for bioremediation of lead-contaminated environmental sites, as it can efficiently precipitate lead as lead phosphate. © 2012 The Society for Applied Microbiology.

Lead isotopes in soils near five historic American lead smelters and refineries

International Nuclear Information System (INIS)

Rabinowitz, Michael B.

2005-01-01

This survey of soil lead in the vicinity of old industrial sites examines how the stable isotope patterns vary among the sites according to the sources of the lead ore processed at each site. Lead smelters and refineries, which closed down decades ago, are the basis of this investigation. Samples were taken from near five old factory sites in Collinsville and Alton (Illinois), Ponderay (Idaho), East Chicago (Indiana) and Omaha (Nebraska). Historical records were searched for accounts of the sources of the lead. Lead concentrations were measured by atomic absorption flame spectrophotometry, and stable isotopic analysis was done by plasma ionization mass spectrometry. At every site visited, remnants of the old factories, in terms of soil lead pollution, could be found. In spite of potential complications of varying smelter feedstock sourced from mines of different geological age, it was possible to match the isotopic patterns in the soils with the documented sources of the ores. The Collinsville and Alton sites resembled Missouri lead. The Ponderay value was higher than major Bunker Hill, Idaho deposits, but closer to the minor, nearby Oreille County, Washington ores. Mostly Utah ore was used in East Chicago. The Omaha soil reflects lead from Mexico, Colorado and Montana

The void nucleation mechanism within lead phase during spallation of leaded brass

Science.gov (United States)

Yang, Yang; Wang, Can; Chen, Xingzhi; Chen, Kaiguo; Hu, Haibo; Fu, Yanan

2018-07-01

The incipient spall behaviours of Cu-34%Zn-3%Pb leaded brass samples with annealed and cryogenic-treated conditions were loaded using one-stage light gas gun experiments. The effect of Pb-phase on dynamic damage nucleation in leaded brass specimens was investigated by means of optical microscopy, scanning electron microscopy and x-ray computer tomography. It was found that the voids of incipient spall were mainly nucleated in the interior of the lead (no tensile stress would be produced within lead according to the impact theory) instead of nucleated at the phase interface as expected by quasi-static damage fracture theory. A nucleation model is proposed in the present work that is the asymmetry high compression zones in the centre of the lead-phase were formed by the rarefaction wave convergence effects of matrix/quasi-spherical lead interface, which caused adiabatic temperature rise that exceeded melting point of lead due to severe plastic deformation, finally led to local melting and void nucleation. In addition, the spall strength and damage rate increased with the increase in the Pb-phase number.

Lead toxicity on hematological parameters in workers with occupational exposure to lead

International Nuclear Information System (INIS)

Dursun, N.; Koese, K.

1998-01-01

The effects of lead on hematological parameters were studied in lead exposed male workers occupied for 17.84+-4.22 years in a metal powder producing factory in Kayseri, Turkey and control male workers in same city. Blood lead and plasma zinc levels were measured by Atomic Absorption Spectrophotometry (AAS) and hematological parameters by Culture Counter S. The lead exposure workers had higher lead levels (13.81+- 9.21 mug/dl) as compared to control subjects (2.37+-0.10 mug/dl). No difference was observed in the plasma zinc levels of both groups. As indices of lead exposure, red blood cell (RBC) counts, hemoglobin (Hb), and hematocrit (Hct) values significantly decreased. Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular haemoglobin concentration (MCHC) significantly increased except MCV. There was also an increase in MCV, but it was not significant. (author)

Monetary benefits of preventing childhood lead poisoning with lead-safe window replacement

OpenAIRE

Nevin, Rick; Jacobs, David / E.; Berg, Michael; Cohen, Jonathan

2007-01-01

Previous estimates of childhood lead poisoning prevention benefits have quantified the present value of some health benefits, but not the costs of lead paint hazard control or the benefits associated with housing and energy markets. Because older housing with lead paint constitutes the main exposure source today in the U.S., we quantify health benefits, costs, market value benefits, energy savings, and net economic benefits of lead-safe window replacement (which includes paint stabilization ...

Pacemaker lead fracture without an increase in lead impedance caused by cardiac fibroma

Directory of Open Access Journals (Sweden)

Daisuke Sato

2013-12-01

Full Text Available We report the case of a 64-year-old man who had a permanent pacemaker with a unipolar silicone electrode positioned in the right ventricle in 1989 for sinus node dysfunction. On a routine checkup in June 2011, a 28-mm-diameter mass was discovered, which appeared to adhere to the tricuspid valve and the ventricular lead. The size of the mass did not change for the next 6 months, and the lead impedance was maintained at around 500–600 Ω. Because pacing failure was observed in January 2012, he underwent an urgent pacemaker check; however, the lead impedance was found not to have increased greatly (689 Ω. Nevertheless, the pacemaker lead was noted to be fractured at the tricuspid level. His echocardiogram showed new severe tricuspid regurgitation and a floating mass around the lead. We extracted the fractured lead, enucleated the tumor, replaced the tricuspid valve, and placed an epicardial lead. Macroscopic examination revealed that the tumor surrounded the fractured lead and covered the stump. Pathological examination revealed that the tumor was composed of fibrous connective tissue. We presumed that electric current continued to flow through the stump of the fractured unipolar lead to the generator, and this might have caused the limited increase in lead impedance.

Highly reversible lead-carbon battery anode with lead grafting on the carbon surface

KAUST Repository

Yin, Jian; Lin, Nan; Zhang, Wenli; Lin, Zheqi; Zhang, Ziqing; Wang, Yue; Shi, Jun; Bao, Jinpeng; Lin, Haibo

2018-01-01

A novel C/Pb composite has been successfully prepared by electroless plating to reduce the hydrogen evolution and achieve the high reversibility of the anode of lead-carbon battery (LCB). The deposited lead on the surface of C/Pb composite was found to be uniform and adherent to carbon surface. Because lead has been stuck on the surface of C/Pb composite, the embedded structure suppresses the hydrogen evolution of lead-carbon anode and strengthens the connection between carbon additive and sponge lead. Compared with the blank anode, the lead-carbon anode with C/Pb composite displays excellent charge–discharge reversibility, which is attributed to the good connection between carbon additives and lead that has been stuck on the surface of C/Pb composite during the preparation process. The addition of C/Pb composite maintains a solid anode structure with high specific surface area and power volume, and thereby, it plays a significant role in the highly reversible lead-carbon anode.

Highly reversible lead-carbon battery anode with lead grafting on the carbon surface

KAUST Repository

Yin, Jian

2018-03-27

A novel C/Pb composite has been successfully prepared by electroless plating to reduce the hydrogen evolution and achieve the high reversibility of the anode of lead-carbon battery (LCB). The deposited lead on the surface of C/Pb composite was found to be uniform and adherent to carbon surface. Because lead has been stuck on the surface of C/Pb composite, the embedded structure suppresses the hydrogen evolution of lead-carbon anode and strengthens the connection between carbon additive and sponge lead. Compared with the blank anode, the lead-carbon anode with C/Pb composite displays excellent charge–discharge reversibility, which is attributed to the good connection between carbon additives and lead that has been stuck on the surface of C/Pb composite during the preparation process. The addition of C/Pb composite maintains a solid anode structure with high specific surface area and power volume, and thereby, it plays a significant role in the highly reversible lead-carbon anode.

Impact of lead tolerant plant growth promoting rhizobacteria on growth, physiology, antioxidant activities, yield and lead content in sunflower in lead contaminated soil.

Science.gov (United States)

Saleem, Muhammad; Asghar, Hafiz Naeem; Zahir, Zahir Ahmad; Shahid, Muhammad

2018-03-01

Present study was conducted to evaluate the effect of lead tolerant plant growth promoting rhizobacteria (LTPGPR) on growth, physiology, yield, antioxidant activities and lead uptake in sunflower in soil contaminated with lead under pot conditions. Three pre-characterized LTPGP strains (S2 (Pseudomonas gessardii strain BLP141), S5 (Pseudomonas fluorescens A506) and S10 (Pseudomonas fluorescens strain LMG 2189)) were used to inoculate sunflower growing in soil contaminated with different levels (300, 600 and 900 mg kg -1 ) of lead by using lead nitrate salt as source of lead. Treatments were arranged according to completely randomized design with factorial arrangements. At harvesting, data regarding growth attributes (root shoot length, root shoot fresh and dry weights), yield per plant, physiological attributes (Chlorophyll 'a', 'b' and carotenoids content), antioxidant activities (Ascorbate peroxidase, catalase, superoxide dismutase and glutathione reductase), proline and malanodialdehyde content, and lead content in root, shoot and achenes of sunflower were recorded. Data were analysed by standard statistical procedures. Results showed that lead contamination reduced the plants growth, physiology and yield at all levels of lead stress. But application of LTPGPR in soil contaminated with lead improved plant growth, physiology, yield, and antioxidant activities, proline, and reduced the malanodialdehyde content (that is reduced by the application of different strains in lead contamination) of sunflower as compared to plants grown in soil without inoculation. Inoculation also promoted the uptake of lead in root, shoots and reduced the uptake of lead in achenes of plants as compared to plants in lead contamination without inoculation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Temporal stability of blood lead concentrations in adults exposed only to environmental lead

Energy Technology Data Exchange (ETDEWEB)

Delves, H T; Sherlock, J C; Quinn, M J

1984-08-01

The temporal stability of blood lead concentrations of 21 health adults (14 men and 7 women) exposed only to environmental lead was assessed by analysis of 253 blood specimens collected serially over periods from 7 to 11 months. The women had lower blood lead concentrations (mean 8.5, range 7.4-10.8 micrograms/100 ml) than did the men (mean 12.2, range 8.6-15.8 micrograms/100 ml). These are within the expected ranges for non-occupationally exposed persons. Blood lead concentrations in the serial specimens from both men and women changed very little over the study period, with standard deviations of less than 0.5 micrograms/100 ml for the majority of individual mean concentrations: for all except low subjects the standard deviations were less than 0.8 micrograms/100 ml. Two subjects showed significant changes in blood lead concentrations during the study. A temporary increase in oral lead intake was identified for one of these subjects. In the absence of substantial changes in lead exposure blood lead levels in adults are remarkably stable and for their environmental monitoring a single blood lead concentration is an excellent biological indicator.

Correlations in particle production in proton-lead and lead-lead collisions at the LHC

CERN Document Server

AUTHOR|(INSPIRE)INSPIRE-00361447

In high-energy heavy-ion collisions at the Large Hadron Collider (LHC), a hot and dense state of matter called the Quark-Gluon Plasma (QGP) is formed. The initial collision geometry and the subsequent expansion during the QGP stage result in the correlations of produced particles, through which the properties of the QGP can be investigated. Two analyses based on the geometrical correlations of produced particles, one in proton-lead (p–Pb) collisions and the other in lead-lead (Pb–Pb) collisions, are presented in this thesis. The data analyzed in this thesis were collected with the ALICE detector at the LHC in p– Pb collisions at a nucleon–nucleon center-of-mass energy of 5.02 TeV, and Pb–Pb collisions at a nucleon–nucleon center-of-mass energy of 2.76 TeV. In the forward-central two-particle correlation analysis in p–Pb collisions, two-particle an- gular correlations between trigger particles in the forward pseudorapidity range (2.5 < |η| < 4.0) and associated particles in the central ran...

Levels and source apportionment of children's lead exposure: could urinary lead be used to identify the levels and sources of children's lead pollution?

Science.gov (United States)

Cao, Suzhen; Duan, Xiaoli; Zhao, Xiuge; Wang, Beibei; Ma, Jin; Fan, Delong; Sun, Chengye; He, Bin; Wei, Fusheng; Jiang, Guibin

2015-04-01

As a highly toxic heavy metal, the pollution and exposure risks of lead are of widespread concern for human health. However, the collection of blood samples for use as an indicator of lead pollution is not always feasible in most cohort or longitudinal studies, especially those involving children health. To evaluate the potential use of urinary lead as an indicator of exposure levels and source apportionment, accompanying with environmental media samples, lead concentrations and isotopic measurements (expressed as (207)Pb/(206)Pb, (208)Pb/(206)Pb and (204)Pb/(206)Pb) were investigated and compared between blood and urine from children living in the vicinities of a typical coking plant and lead-acid battery factory. The results showed urinary lead might not be a preferable proxy for estimating blood lead levels. Fortunately, urinary lead isotopic measurements could be used as an alternative for identifying the sources of children's lead exposure, which coincided well with the blood lead isotope ratio analysis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Determining tissue-lead levels in large game mammals harvested with lead bullets: human health concerns.

Science.gov (United States)

Tsuji, L J S; Wainman, B C; Jayasinghe, R K; VanSpronsen, E P; Liberda, E N

2009-04-01

Recently, the use of lead isotope ratios has definitively identified lead ammunition as a source of lead exposure for First Nations people, but the isotope ratios for lead pellets and bullets were indistinguishable. Thus, lead-contaminated meat from game harvested with lead bullets may also be contributing to the lead body burden; however, few studies have determined if lead bullet fragments are present in big game carcasses. We found elevated tissue-lead concentrations (up to 5,726.0 microg/g ww) in liver (5/9) and muscle (6/7) samples of big game harvested with lead bullets and radiographic evidence of lead fragments. Thus, we would advise that the tissue surrounding the wound channel be removed and discarded, as this tissue may be contaminated by lead bullet fragments.

Lead intoxication in dogs: risk assessment of feeding dogs trimmings of lead-shot game.

Science.gov (United States)

Høgåsen, Helga R; Ørnsrud, Robin; Knutsen, Helle K; Bernhoft, Aksel

2016-07-25

Expanding lead-based bullets, commonly used for hunting of big game, produce a scattering of lead particles in the carcass around the wound channel. Trimmings around this channel, which are sometimes fed to dogs, may contain lead particles. The aim of this study was to assess potential health effects of feeding dogs such trimmings. Lead ingestion most commonly causes gastrointestinal and neurological clinical signs, although renal, skeletal, haematological, cardiovascular and biochemical effects have also been reported. Experimental data indicate that a daily dose of around 1 mg lead as lead acetate/kg body weight for ten days may be considered as a Lowest Observed Effect Level in dogs. Acute toxicity documentation from the Centers for Disease Control and Prevention indicates 300 mg/kg body weight as the lowest dose of lead acetate causing death in dogs after oral ingestion. Our assessment suggests that dogs fed trimmings of lead-shot game may be affected by the amounts of lead present, and that even deadly exposure could occasionally occur. The intestinal absorption of lead from bullets was assumed to be 10-80 % of that of lead acetate, reflecting both the variability in particle size and uncertainty about the bioavailability of metallic lead in dogs. Despite data gaps, this study indicates that feeding dogs trimmings of lead-shot game may represent a risk of lead intoxication. More research is needed to assess the exact consequences, if lead-based bullets are still to be used. Meanwhile, we recommend that trimmings close to the wound channel should be made inaccessible to dogs, as well as to other domestic or wild animals.

NA49: lead-lead collision

CERN Multimedia

1996-01-01

This is an image of an actual lead ion collision taken from tracking detectors on the NA49 experiment, part of the heavy ion project at CERN. These collisions produce a very complicated array of hadrons as the heavy ions break up. It is hoped that one of these collisions will eventually create a new state of matter known as quark-gluon plasma.

Seneca Valley Virus Suppresses Host Type I Interferon Production by Targeting Adaptor Proteins MAVS, TRIF, and TANK for Cleavage.

Science.gov (United States)

Qian, Suhong; Fan, Wenchun; Liu, Tingting; Wu, Mengge; Zhang, Huawei; Cui, Xiaofang; Zhou, Yun; Hu, Junjie; Wei, Shaozhong; Chen, Huanchun; Li, Xiangmin; Qian, Ping

2017-08-15

Seneca Valley virus (SVV) is an oncolytic RNA virus belonging to the Picornaviridae family. Its nucleotide sequence is highly similar to those of members of the Cardiovirus genus. SVV is also a neuroendocrine cancer-selective oncolytic picornavirus that can be used for anticancer therapy. However, the interaction between SVV and its host is yet to be fully characterized. In this study, SVV inhibited antiviral type I interferon (IFN) responses by targeting different host adaptors, including mitochondrial antiviral signaling (MAVS), Toll/interleukin 1 (IL-1) receptor domain-containing adaptor inducing IFN-β (TRIF), and TRAF family member-associated NF-κB activator (TANK), via viral 3C protease (3C pro ). SVV 3C pro mediated the cleavage of MAVS, TRIF, and TANK at specific sites, which required its protease activity. The cleaved MAVS, TRIF, and TANK lost the ability to regulate pattern recognition receptor (PRR)-mediated IFN production. The cleavage of TANK also facilitated TRAF6-induced NF-κB activation. SVV was also found to be sensitive to IFN-β. Therefore, SVV suppressed antiviral IFN production to escape host antiviral innate immune responses by cleaving host adaptor molecules. IMPORTANCE Host cells have developed various defenses against microbial pathogen infection. The production of IFN is the first line of defense against microbial infection. However, viruses have evolved many strategies to disrupt this host defense. SVV, a member of the Picornavirus genus, is an oncolytic virus that shows potential functions in anticancer therapy. It has been demonstrated that IFN can be used in anticancer therapy for certain tumors. However, the relationship between oncolytic virus and innate immune response in anticancer therapy is still not well known. In this study, we showed that SVV has evolved as an effective mechanism to inhibit host type I IFN production by using its 3C pro to cleave the molecules MAVS, TRIF, and TANK directly. These molecules are crucial for

Eryptosis in lead-exposed workers

International Nuclear Information System (INIS)

Aguilar-Dorado, Itzel-Citlalli; Hernández, Gerardo; Quintanar-Escorza, Martha-Angelica; Maldonado-Vega, María; Rosas-Flores, Margarita; Calderón-Salinas, José-Víctor

2014-01-01

Eryptosis is a physiological phenomenon in which old and damaged erythrocytes are removed from circulation. Erythrocytes incubated with lead have exhibited major eryptosis. In the present work we found evidence of high levels of eryptosis in lead exposed workers possibly via oxidation. Blood samples were taken from 40 male workers exposed to lead (mean blood lead concentration 64.8 μg/dl) and non-exposed workers (4.2 μg/dl). The exposure to lead produced an intoxication characterized by 88.3% less δ-aminolevulinic acid dehydratase (δALAD) activity in lead exposed workers with respect to non-lead exposed workers. An increment of oxidation in lead exposed workers was characterized by 2.4 times higher thiobarbituric acid-reactive substance (TBARS) concentration and 32.8% lower reduced/oxidized glutathione (GSH/GSSG) ratio. Oxidative stress in erythrocytes of lead exposed workers is expressed in 192% higher free calcium concentration [Ca 2+ ] i and 1.6 times higher μ-calpain activity with respect to non-lead exposed workers. The adenosine triphosphate (ATP) concentration was not significantly different between the two worker groups. No externalization of phosphatidylserine (PS) was found in non-lead exposed workers (< 0.1%), but lead exposed workers showed 2.82% externalization. Lead intoxication induces eryptosis possibly through a molecular pathway that includes oxidation, depletion of reduced glutathione (GSH), increment of [Ca 2+ ], μ-calpain activation and externalization of PS in erythrocytes. Identifying molecular signals that induce eryptosis in lead intoxication is necessary to understand its physiopathology and chronic complications. - Graphical abstract: Fig. 1. (A) Blood lead concentration (PbB) and (B) phosphatidylserine externalization on erythrocyte membranes of non-lead exposed (□) and lead exposed workers (■). Values are mean ± SD. *Significantly different (P < 0.001). - Highlights: • Erythrocytes of lead exposed workers showed higher PS

Eryptosis in lead-exposed workers

Energy Technology Data Exchange (ETDEWEB)

Aguilar-Dorado, Itzel-Citlalli [Biochemistry Department, Centro de Investigación y Estudios Avanzados IPN, México, DF (Mexico); Hernández, Gerardo [Section of Methodology of Science, Centro de Investigación y Estudios Avanzados IPN, México, DF (Mexico); Quintanar-Escorza, Martha-Angelica [Faculty of Medicine, UJED, Durango, DGO (Mexico); Maldonado-Vega, María [CIATEC, León, GTO (Mexico); Rosas-Flores, Margarita [Biochemistry Department, Centro de Investigación y Estudios Avanzados IPN, México, DF (Mexico); Calderón-Salinas, José-Víctor, E-mail: jcalder@cinvestav.mx [Biochemistry Department, Centro de Investigación y Estudios Avanzados IPN, México, DF (Mexico)

2014-12-01

Eryptosis is a physiological phenomenon in which old and damaged erythrocytes are removed from circulation. Erythrocytes incubated with lead have exhibited major eryptosis. In the present work we found evidence of high levels of eryptosis in lead exposed workers possibly via oxidation. Blood samples were taken from 40 male workers exposed to lead (mean blood lead concentration 64.8 μg/dl) and non-exposed workers (4.2 μg/dl). The exposure to lead produced an intoxication characterized by 88.3% less δ-aminolevulinic acid dehydratase (δALAD) activity in lead exposed workers with respect to non-lead exposed workers. An increment of oxidation in lead exposed workers was characterized by 2.4 times higher thiobarbituric acid-reactive substance (TBARS) concentration and 32.8% lower reduced/oxidized glutathione (GSH/GSSG) ratio. Oxidative stress in erythrocytes of lead exposed workers is expressed in 192% higher free calcium concentration [Ca{sup 2+}]{sub i} and 1.6 times higher μ-calpain activity with respect to non-lead exposed workers. The adenosine triphosphate (ATP) concentration was not significantly different between the two worker groups. No externalization of phosphatidylserine (PS) was found in non-lead exposed workers (< 0.1%), but lead exposed workers showed 2.82% externalization. Lead intoxication induces eryptosis possibly through a molecular pathway that includes oxidation, depletion of reduced glutathione (GSH), increment of [Ca{sup 2+}], μ-calpain activation and externalization of PS in erythrocytes. Identifying molecular signals that induce eryptosis in lead intoxication is necessary to understand its physiopathology and chronic complications. - Graphical abstract: Fig. 1. (A) Blood lead concentration (PbB) and (B) phosphatidylserine externalization on erythrocyte membranes of non-lead exposed (□) and lead exposed workers (■). Values are mean ± SD. *Significantly different (P < 0.001). - Highlights: • Erythrocytes of lead exposed workers

“Lead Leached into Water from Select Plumbing Fixtures” Could Lead to Health Hazard

Directory of Open Access Journals (Sweden)

Ramsey Coles

2014-01-01

Full Text Available Background: Lead is an inert metal and is resistant to corrosion. It also increases tensile strength of many common materials in daily use. Lead was used during the Roman period to transport water (hence the name plumbing/plumber is common terminology even in the present day. Lead enters the biological system through the air, water, and dust. Fine particles of lead, having diameter less than 5 nm are directly absorbed by lungs. Inorganic lead is absorbed by the gastrointestinal tract, and organic lead is absorbed by the skin. Lead has long been known to be a toxic heavy metal and exposure is associated with many deleterious health effects. Still, lead remains a popular ingredient in products ranging from paint to batteries. The lead content in any given material is estimated using various methods. The least cumbersome method is found to be X-Ray Fluorescence technique (XRF. A portable XRF device was used in the present study. Aim: The main aim of this study to investigate whether lead is present in various commonly used plumbing materials. Material and Methods: All types of branded and commonly used pipes were gathered from a market in Bangalore and tested using the XRF machine. In order to evaluate to what extent lead from the pipes could leach into water, seven pipes were randomly selected and filled with Aquafina water (having undetectable level of lead for a 24 hour period. This water was tested at an NABL accredited laboratory in Bangalore, India for lead content. Result: It was determined that lead was present in many of the samples, at an unacceptable levels ranging from, well above the globally accepted level of 0.01 mg/L proof that lead was able to leach from the samples into water. Conclusions: As lead in drinking water represents a direct pathway for human exposure, the authors recommend that significant measures be taken to prevent use of lead in the plumbing industry for prevention of it’s deleterious effects. Authors have also

Lead Poison Detection

Science.gov (United States)

1976-01-01

With NASA contracts, Whittaker Corporations Space Science division has developed an electro-optical instrument to mass screen for lead poisoning. Device is portable and detects protoporphyrin in whole blood. Free corpuscular porphyrins occur as an early effect of lead ingestion. Also detects lead in urine used to confirm blood tests. Test is inexpensive and can be applied by relatively unskilled personnel. Similar Whittaker fluorometry device called "drug screen" can measure morphine and quinine in urine much faster and cheaper than other methods.

Comparative proteomics as a tool for identifying specific alterations within interferon response pathways in human glioblastoma multiforme cells

DEFF Research Database (Denmark)

Tarasova, Irina A; Tereshkova, Alesya V; Lobas, Anna A

2018-01-01

An acquisition of increased sensitivity of cancer cells to viruses is a common outcome of malignant progression that justifies the development of oncolytic viruses as anticancer therapeutics. Studying molecular changes that underlie the sensitivity to viruses would help to identify cases where on...

Lead remediation and changes in human lead exposure: some physiological and biokinetic dimensions.

Science.gov (United States)

Mushak, Paul

2003-02-15

This paper presents a qualitative and quantitative analysis of the various aspects of lead remediation effectiveness with particular reference to human health risk assessment. One of the key elements of lead remediation efforts at such sites as those under the Superfund program deals with populations at elevated exposure and toxicity risk in the proximity of, or at, the site of remediation, especially remediation workers, workers at other tasks on sites that were remediated down to some action level of lead concentration in soils, and groups at risk in nearby communities. A second element has to do with how one measures or models lead exposure changes with special reference to baseline and post-remediation conditions. Various biomarkers of lead exposure can be employed, but their use requires detailed knowledge of what results using each means. The most commonly used approach is measurement of blood lead (Pb-B). Recognized limitations in the use of Pb-B has led to the use of predictive Pb exposure models, which are less vulnerable to the many behavioral, physiological, and environmental parameters that can distort isolated or 'single shot' Pb-B testings. A third aspect covered in this paper presents various physiological factors that affect the methods by which one evaluates Pb remediation effectiveness. Finally, this article offers an integrated look at how lead remediation actions directed at one lead source or pathway affect the total lead exposure picture for human populations at elevated lead exposure and toxicity risk.

Superconductivity in nanostructured lead

Science.gov (United States)

Lungu, Anca; Bleiweiss, Michael; Amirzadeh, Jafar; Saygi, Salih; Dimofte, Andreea; Yin, Ming; Iqbal, Zafar; Datta, Timir

2001-01-01

Three-dimensional nanoscale structures of lead were fabricated by electrodeposition of pure lead into artificial porous opal. The size of the metallic regions was comparable to the superconducting coherence length of bulk lead. Tc as high as 7.36 K was observed, also d Tc/d H was 2.7 times smaller than in bulk lead. Many of the characteristics of these differ from bulk lead, a type I superconductor. Irreversibility line and magnetic relaxation rates ( S) were also studied. S( T) displayed two maxima, with a peak value about 10 times smaller than that of typical high- Tc superconductors.

Efficacy of reovirus against breast cancer

International Nuclear Information System (INIS)

Zhu Jingzhi; Chen Jue; Dong Shengxiang; Yan Weili; Wu Zhiyong

2011-01-01

To investigate the role of oncolytic reovirus in breast cancer, a tumor xenograft model of NOD/SCID mice was established using a biopsy sample of a primary infiltrating ductal carcinoma obtained from a breast cancer patient. The result of HE and TUNEL was analyzed after injecting the reovirus peritoneally for 3 days. The results showed that estrogen supplementation was required to establish appropriate human breast cancer xenograft model of NOD/SCID mice. 29.6% of these transplanted tumors grew with supplementation of Estrogen. Otherwise none grew (P<0.01). ER of the xenograft model was positive.After treatment with reovirus for 3 days, breast cancer cells were disrupted and disappeared which induced tissue looseness. The rate of apoptosis increased double than before. The biological characteristics of tumor xenograft model confirm with the primary breast cancer. The oncolytic reovirus can kill breast cancer in short time. (authors)

Lead (Pb) Air Pollution

Science.gov (United States)

... Regional Offices Labs and Research Centers Lead (Pb) Air Pollution Contact Us Share As a result of EPA's ... and protect aquatic and terrestrial ecosystems. Lead (Pb) Air Pollution Basic Information How does lead get in the ...

Lead poisoning: The invisible disease

Science.gov (United States)

Friend, Milton

1989-01-01

Lead poisoning is an intoxication resulting from absorption of hazardous levels of lead into body tissues. Lead pellets from shot shells, when ingested, are the most common source of lead poisoning in migratory birds. Other far less common sources include lead fishing sinkers, mine wastes, paint pigments, bullets, and other lead objects that are swallowed.

Taking the Lead : Gender, Social Context and Preference to Lead

NARCIS (Netherlands)

Hong, A.P.C.I.; Schaafsma, J.; van der Wijst, P.J.

2014-01-01

Previous research has demonstrated that women tend to emerge as leaders less often than men. In the present study, we examined to what extent women's and men's preference to lead is influenced by social context. It was hypothesized that women have a less strong preference to lead than men in a

Biological fractionation of lead isotopes in Sprague-Dawley rats lead poisoned via the respiratory tract.

Directory of Open Access Journals (Sweden)

Jing Wu

Full Text Available It was considered that lead isotope ratios did not change during physical, chemical, or biological processes. Thus, lead isotope ratios have been used as fingerprints to identify possible lead sources. However, recent evidence has shown that the lead isotope ratios among different biological samples in human are not always identical from its lead origins in vitro. An animal experiment was conducted to explore the biological fractionation of lead isotopes in biological systems.24 male Sprague-Dawley (SD rats were divided into groups that received acute lead exposure (0, 0.02, 0.2, or 2 mg/kg body weight of lead acetate via the respiratory route every day for 5 days. Biological samples (i.e., blood, urine, and feces were collected for comparison with the lead acetate (test substance and the low-lead animal feed (diet administered to the rats. The lead isotope ratios were determined by inductively coupled plasma mass spectrometry (ICP-MS.There are significant differences (p<0.05 in lead isotope ratios between blood, urine, and feces. Moreover, a nonlinear relationship between the blood lead concentration and the blood lead isotope ratios was observed. There is also a threshold effect to the fractionation function. Only the blood isotope ratio of (204Pb/(206Pb matches the test substance well. As for feces, when (204Pb/(206Pb ratio is considered, there is no significant difference between feces-test substance pairs in medium and high dose group.The biological fractionation of lead isotopes in SD rats was observed. Moreover, there might be a threshold for the biological fractionation of lead isotopes which is depending on whole blood lead level. It is considered to be more reliable that we compared the isotope ratios of potential lead hazards with both blood and feces lead fingerprints especially for (204Pb/(206Pb ratio under high-dose exposure.

Preventive maintenance basis: Volume 24 -- Battery -- flooded lead-acid (lead-calcium, lead antimony, plante). Final report

International Nuclear Information System (INIS)

Worledge, D.; Hinchcliffe, G.

1997-12-01

US nuclear power plants are implementing preventive maintenance (PM) tasks with little documented basis beyond fundamental vendor information to support the tasks or their intervals. The Preventive Maintenance Basis project provides utilities with the technical basis for PM tasks and task intervals associated with 40 specific components such as valves, electric motors, pumps, and HVAC equipment. This document provides a program of preventive maintenance tasks suitable for application to flooded lead-acid batteries. The PM tasks that are recommended provide a cost-effective way to intercept the causes and mechanisms that lead to degradation and failure. They can be used in conjunction with material from other sources, to develop a complete PM program or to improve an existing program. This document provides a program of preventive maintenance (PM) tasks suitable for application to flooded lead-acid batteries. The PM tasks that are recommended provide a cost-effective way to intercept the causes and mechanisms that lead to degradation and failure. They can be used, in conjunction with material from other sources, to develop a complete PM program or to improve an existing program. Users of this information will be utility managers, supervisors, system engineers, craft technicians, and training instructors responsible for developing, optimizing, or fine-tuning PM programs

Lead-Binding Proteins: A Review

Directory of Open Access Journals (Sweden)

Harvey C. Gonick

2011-01-01

Full Text Available Lead-binding proteins are a series of low molecular weight proteins, analogous to metallothionein, which segregate lead in a nontoxic form in several organs (kidney, brain, lung, liver, erythrocyte. Whether the lead-binding proteins in every organ are identical or different remains to be determined. In the erythrocyte, delta-aminolevulinic acid dehydratase (ALAD isoforms have commanded the greatest attention as proteins and enzymes that are both inhibitable and inducible by lead. ALAD-2, although it binds lead to a greater degree than ALAD-1, appears to bind lead in a less toxic form. What may be of greater significance is that a low molecular weight lead-binding protein, approximately 10 kDa, appears in the erythrocyte once blood lead exceeds 39 μg/dL and eventually surpasses the lead-binding capacity of ALAD. In brain and kidney of environmentally exposed humans and animals, a cytoplasmic lead-binding protein has been identified as thymosin β4, a 5 kDa protein. In kidney, but not brain, another lead-binding protein has been identified as acyl-CoA binding protein, a 9 kDa protein. Each of these proteins, when coincubated with liver ALAD and titrated with lead, diminishes the inhibition of ALAD by lead, verifying their ability to segregate lead in a nontoxic form.

Gas cooled leads

International Nuclear Information System (INIS)

Shutt, R.P.; Rehak, M.L.; Hornik, K.E.

1993-01-01

The intent of this paper is to cover as completely as possible and in sufficient detail the topics relevant to lead design. The first part identifies the problems associated with lead design, states the mathematical formulation, and shows the results of numerical and analytical solutions. The second part presents the results of a parametric study whose object is to determine the best choice for cooling method, material, and geometry. These findings axe applied in a third part to the design of high-current leads whose end temperatures are determined from the surrounding equipment. It is found that cooling method or improved heat transfer are not critical once good heat exchange is established. The range 5 5 but extends over a large of values. Mass flow needed to prevent thermal runaway varies linearly with current above a given threshold. Below that value, the mass flow is constant with current. Transient analysis shows no evidence of hysteresis. If cooling is interrupted, the mass flow needed to restore the lead to its initially cooled state grows exponentially with the time that the lead was left without cooling

EPA Leads the Way on Lead Exposure Science and Risk Management

Science.gov (United States)

EPA researchers have developed a modeling approach that improves our understanding of the relationship between lead concentrations of various sources (drinking water, soil and dust, food, and air) and children’s blood-lead levels.

Lead Poisoning (For Parents)

Science.gov (United States)

... Staying Safe Videos for Educators Search English Español Lead Poisoning KidsHealth / For Parents / Lead Poisoning What's in ... Print en español La intoxicación por plomo About Lead Poisoning If you have young kids, it's important ...

VOLUMETRIC LEAD ASSAY

International Nuclear Information System (INIS)

Ebadian, M.A.; Dua, S.K.; Roelant, David; Kumar, Sachin

2001-01-01

This report describes a system for handling and radioassay of lead, consisting of a robot, a conveyor, and a gamma spectrometer. The report also presents a cost-benefit analysis of options: radioassay and recycling lead vs. disposal as waste

EMERGING TECHNOLOGY BULLETIN: RECLAMATION OF LEAD FROM SUPERFUND WASTE MATERIAL USING SECONDARY LEAD SMELTERS

Science.gov (United States)

This process involves incorporating lead-contaminated Superfund waste with the regular feed to a secondary lead smelter. Since secondary lead smelters already recover lead from recycled automobile batteries, it seems likely that this technology could be used to treat waste from ...

Biological fractionation of lead isotopes in Sprague-Dawley rats lead poisoned via the respiratory tract.

Science.gov (United States)

Wu, Jing; Liu, Duojian; Xie, Qing; Wang, Jingyu

2012-01-01

It was considered that lead isotope ratios did not change during physical, chemical, or biological processes. Thus, lead isotope ratios have been used as fingerprints to identify possible lead sources. However, recent evidence has shown that the lead isotope ratios among different biological samples in human are not always identical from its lead origins in vitro. An animal experiment was conducted to explore the biological fractionation of lead isotopes in biological systems. 24 male Sprague-Dawley (SD) rats were divided into groups that received acute lead exposure (0, 0.02, 0.2, or 2 mg/kg body weight of lead acetate) via the respiratory route every day for 5 days. Biological samples (i.e., blood, urine, and feces) were collected for comparison with the lead acetate (test substance) and the low-lead animal feed (diet) administered to the rats. The lead isotope ratios were determined by inductively coupled plasma mass spectrometry (ICP-MS). There are significant differences (pblood, urine, and feces. Moreover, a nonlinear relationship between the blood lead concentration and the blood lead isotope ratios was observed. There is also a threshold effect to the fractionation function. Only the blood isotope ratio of (204)Pb/(206)Pb matches the test substance well. As for feces, when (204)Pb/(206)Pb ratio is considered, there is no significant difference between feces-test substance pairs in medium and high dose group. The biological fractionation of lead isotopes in SD rats was observed. Moreover, there might be a threshold for the biological fractionation of lead isotopes which is depending on whole blood lead level. It is considered to be more reliable that we compared the isotope ratios of potential lead hazards with both blood and feces lead fingerprints especially for (204)Pb/(206)Pb ratio under high-dose exposure.

Two cases of acute lead poisoning due to occupational exposure to lead.

Science.gov (United States)

Ogawa, Masanori; Nakajima, Yoshiaki; Kubota, Ryuichi; Endo, Yoko

2008-04-01

We experienced two cases of acute lead poisoning due to occupational exposure to lead. The patients were engaged in stripping off antirust compounds including Pb from a bridge and re-painting it at the same work place. Both patients exhibited colic, arthralgia, and anemia. Blood lead levels were 73.1 microg/dl and 96.3 microg/dl. Intravenous CaEDTA chelation therapy was therefore performed. After chelation, blood lead levels decreased and symptoms gradually disappeared. Although the patients were working with protective equipment, the workplace was in the mountains and there was no water for washing. The patients were thus unable to washing their hands and faces. We assume that they swallowed lead dust left on their hands and faces when they removed their clothing, and believe that this poisoning occurred due to lack of knowledge sufficient for protection.

Arkansas People Participating in Lead Education (APPLE): results of a lead-safe training program.

Science.gov (United States)

Ferguson, Alesia; Bursac, Zoran; Kern, David F

2011-06-01

Lead is still seen as one of the most harmful environmental toxins for young children, with the predominant source being deteriorating lead-based paint. Those at continued risk include those living in homes built before 1978, renovators and remodelers, and especially those with limited access to proper healthcare and diets. Proper training on lead-safe work practices focused on preventing and reducing the spread of lead dust can help reduce lead exposure. Presented in this paper are experiences in delivering lead-safe work practices training in six Arkansas cities, and results from pre- and post- surveys delivered before and immediately after the training. Pre- and post-surveys assess strong and weak areas of training. Participants demonstrated positive shifts in attitude and behavior towards lead-safe work practices following training. However, our research found that more emphasis should be focused on clarifying current lead exposure sources and routes for children.

Lead contamination and transfer in urban environmental compartments analyzed by lead levels and isotopic compositions

International Nuclear Information System (INIS)

Hu, Xin; Sun, Yuanyuan; Ding, Zhuhong; Zhang, Yun; Wu, Jichun; Lian, Hongzhen; Wang, Tijian

2014-01-01

Lead levels and isotopic compositions in atmospheric particles (TSP and PM 2.5 ), street dust and surface soil collected from Nanjing, a mega city in China, were analyzed to investigate the contamination and the transfer of lead in urban environmental compartments. The lead contents in TSP and PM 2.5 are significantly higher than them in the surface soil and street dust (p  206 Pb/ 207 Pb vs. 208 Pb/ 206 Pb and 206 Pb/ 207 Pb vs. 1/Pb imply that the street dust and atmospheric particles (TSP and PM 2.5 ) have very similar lead sources. Coal emissions and smelting activities may be the important lead sources for street dust and atmospheric particles (TSP and PM 2.5 ), while the deposition of airborne lead is an important lead source for urban surface soil. - Highlights: • Lead levels and isotope ratios in atmospheric particles, street dust and surface soil. • Significant enrichment of lead in atmospheric particles was observed. • Street dust and atmospheric particles have similar lead sources. • Endmembers of soil lead differ from street dust and atmospheric particles. • Airborne lead poses the main risks to unban environmental quality. - Transfer of airborne particle bound lead into street dust and surface soil in unban environmental based on lead levels and isotopic compositions

Vesicular Stomatitis Virus Infection Promotes Immune Evasion by Preventing NKG2D-Ligand Surface Expression

DEFF Research Database (Denmark)

Jensen, Helle; Andresen, Lars; Nielsen, Jens

2011-01-01

Vesicular stomatitis virus (VSV) has recently gained attention for its oncolytic ability in cancer treatment. Initially, we hypothesized that VSV infection could increase immune recognition of cancer cells through induction of the immune stimulatory NKG2D-ligands. Here we show that VSV infection ...

Lead pollution sources and Impacts

International Nuclear Information System (INIS)

El-Haggar, S.M.; Saad, S.G.; Saleh, S.K.; El-Kady, M.A.

1996-01-01

Despite the medical awareness of lead toxicity, and despite legislation designed to reduce environmental contamination, lead is one of the most widely used heavy metals. Significant human exposure occurs from automobile exhaust fumes, cigarette smoking, lead-based paints and plumbing systems lead spread in the environment can take place in several ways, the most important of which is through the lead compounds released in automobile exhaust as a direct result of the addition of tetraethyl or tetraethyl lead to gasoline as octane boosting agents. Of special is the effect of lead pollution on children, which affects their behavioral and educational attributes considerably. The major channel through through which lead is absorbed is through inhalation of lead compounds in the atmosphere. Lead is a heavy metal characterized its malleability, ductility and poor conduction of electricity. So, it has a wide range of applications ranging from battery manufacturing to glazing ceramics. It is rarely found free in nature but is present in several minerals and compounds. The aim of this paper is to discuss natural and anthropogenic sources of lead together with its distribution and trends with emphasis on egypt. The effects of lead pollution on human health, vegetation and welfare are also presented. It could be concluded that, the excessive release of lead into the environment, especially through the atmosphere, can produce many detrimental and sometimes fatal effects on human, agriculture and zoological life. Besides, it is very plain that there is a serious problem of pollution lead in egypt and specially in cairo. 7 figs

Eryptosis in lead-exposed workers.

Science.gov (United States)

Aguilar-Dorado, Itzel-Citlalli; Hernández, Gerardo; Quintanar-Escorza, Martha-Angelica; Maldonado-Vega, María; Rosas-Flores, Margarita; Calderón-Salinas, José-Víctor

2014-12-01

Eryptosis is a physiological phenomenon in which old and damaged erythrocytes are removed from circulation. Erythrocytes incubated with lead have exhibited major eryptosis. In the present work we found evidence of high levels of eryptosis in lead exposed workers possibly via oxidation. Blood samples were taken from 40 male workers exposed to lead (mean blood lead concentration 64.8μg/dl) and non-exposed workers (4.2μg/dl). The exposure to lead produced an intoxication characterized by 88.3% less δ-aminolevulinic acid dehydratase (δALAD) activity in lead exposed workers with respect to non-lead exposed workers. An increment of oxidation in lead exposed workers was characterized by 2.4 times higher thiobarbituric acid-reactive substance (TBARS) concentration and 32.8% lower reduced/oxidized glutathione (GSH/GSSG) ratio. Oxidative stress in erythrocytes of lead exposed workers is expressed in 192% higher free calcium concentration [Ca(2+)]i and 1.6 times higher μ-calpain activity with respect to non-lead exposed workers. The adenosine triphosphate (ATP) concentration was not significantly different between the two worker groups. No externalization of phosphatidylserine (PS) was found in non-lead exposed workers (lead exposed workers showed 2.82% externalization. Lead intoxication induces eryptosis possibly through a molecular pathway that includes oxidation, depletion of reduced glutathione (GSH), increment of [Ca(2+)], μ-calpain activation and externalization of PS in erythrocytes. Identifying molecular signals that induce eryptosis in lead intoxication is necessary to understand its physiopathology and chronic complications. Copyright © 2014 Elsevier Inc. All rights reserved.

What is lead-based paint?

International Nuclear Information System (INIS)

Vernon, L.S.

1994-01-01

The number of variety of lead-abatement regulations and requirements make it difficult and confusing to identify and properly respond to dangerous levels of lead in every situation. Definitions of ''lead-based paint'' and three test methods for lead detection are described to help determine when and how to test for the presence of lead

Lead identification in soil surrounding a used lead acid battery smelter area in Banten, Indonesia

International Nuclear Information System (INIS)

Adventini, N; Santoso, M; Lestiani, D D; Syahfitri, W Y N; Rixson, L

2017-01-01

A used lead acid battery smelter generates particulates containing lead that can contaminate the surrounding environment area. Lead is a heavy metal which is harmful to health if it enters the human body through soil, air, or water. An identification of lead in soil samples surrounding formal and informal used lead acid battery smelters area in Banten, Indonesia using EDXRF has been carried out. The EDXRF accuracy and precision evaluated from marine sediment IAEA 457 gave a good agreement to the certified value. A number of 16 soil samples from formal and informal areas and 2 soil samples from control area were taken from surface and subsurface soils. The highest lead concentrations from both lead smelter were approximately 9 folds and 11 folds higher than the reference and control samples. The assessment of lead contamination in soils described in C f index was in category: moderately and strongly polluted by lead for formal and informal lead smelter. Daily lead intake of children in this study from all sites had exceeded the recommended dietary allowance. The HI values for adults and children living near both lead smelter areas were greater than the value of safety threshold 1. This study finding confirmed that there is a potential health risk for inhabitants surrounding the used lead acid battery smelter areas in Banten, Indonesia. (paper)

Stable lead isotopic analyses of historic and contemporary lead contamination of San Francisco Bay estuary

Science.gov (United States)

Ritson, P.I.; Bouse, R.M.; Flegal, A.R.; Luoma, S.N.

1999-01-01

Variations in stable lead isotopic composition (240Pb, 206Pb, 207Pb, 208Pb) in three sediment cores from the San Francisco Bay estuary document temporal changes in sources of lead during the past two centuries. Sediment, with lead from natural geologic sources, and relatively homogeneous lead isotopic compositions are overlain by sediments whose isotopic compositions indicate change in the sources of lead associated with anthropogenic modification of the estuary. The first perturbations of lead isotopic composition in the cores occur in the late 1800s concordant with the beginning of industrialization around the estuary. Large isotopic shifts, toward lower 206Pb/207Pb, occur after the turn of the century in both Richardson and San Pablo Bays. A similar relationship among lead isotopic compositions and lead concentrations in both Bays suggest contamination from the same source (a lead smelter). The uppermost sediments (post 1980) of all cores also have a relatively homogenous lead isotopic composition distinct from pre-anthropogenic and recent aerosol signatures. Lead isotopic compositions of leachates from fourteen surface sediments and five marsh samples from the estuary were also analyzed. These analyses suggest that the lead isotopic signature identified in the upper horizons of the cores is spatially homogeneous among recently deposited sediments throughout the estuary. Current aerosol lead isotopic compositions [Smith, D.R., Niemeyer, S., Flegal, A.R., 1992. Lead sources to California sea otters: industrial inputs circumvent natural lead biodepletion mechanisms. Environmental Research 57, 163-175] are distinct from the isotopic compositions of the surface sediments, suggesting that the major source of lead is cycling of historically contaminated sediments back through the water column. Both the upper core sediments and surface sediments apparently derive their lead predominantly from sources internal to the estuary. These results support the idea that

Heavy flavour production in proton-lead and lead-lead collisions with LHCb

Science.gov (United States)

Winn, Michael

2017-11-01

The LHCb experiment offers the unique opportunity to study heavy-ion interactions in the forward region (2 kinematic domain complementary to the other 3 large experiments at the LHC. The detector has excellent capabilities for reconstructing quarkonia and open charm states, including baryons, down to zero pT. It can separate the prompt and displaced charm components. In pPb collisions, both forward and backward rapidities are covered thanks to the possibility of beam reversal. Results include measurements of the nuclear modification factor and forward-backward ratio for charmonium, open charm and bottomonium states. These quantities are sensitive probes for nuclear effects in heavy flavour production. Perspectives are given with the large accumulated luminosity during the 2016 pPb run at the LHC. In 2015, LHCb participated successfully for the first time in the PbPb data-taking. The status of the forward prompt J/ψ nuclear modification factor measurement in lead-lead collisions is discussed.

Ecotoxicology: Lead

Science.gov (United States)

Scheuhammer, A.M.; Beyer, W.N.; Schmitt, C.J.; Jorgensen, Sven Erik; Fath, Brian D.

2008-01-01

Lead (Pb) is a naturally occurring metallic element; trace concentrations are found in all environmental media and in all living things. However, certain human activities, especially base metal mining and smelting; combustion of leaded gasoline; the use of Pb in hunting, target shooting, and recreational angling; the use of Pb-based paints; and the uncontrolled disposal of Pb-containing products such as old vehicle batteries and electronic devices have resulted in increased environmental levels of Pb, and have created risks for Pb exposure and toxicity in invertebrates, fish, and wildlife in some ecosystems.

Developmental immunotoxicology of lead

International Nuclear Information System (INIS)

Dietert, Rodney R.; Lee, Ji-Eun; Hussain, Irshad; Piepenbrink, Michael

2004-01-01

The heavy metal, lead, is a known developmental immunotoxicant that has been shown to produce immune alterations in humans as well as other species. Unlike many compounds that exert adverse immune effects, lead exposure at low to moderate levels does not produce widespread loss of immune cells. In contrast, changes resulting from lead exposure are subtle at the immune cell population level but, nevertheless, can be functionally dramatic. A hallmark of lead-induced immunotoxicity is a pronounced shift in the balance in T helper cell function toward T helper 2 responses at the expense of T helper 1 functions. This bias alters the nature and range of immune responses that can be produced thereby influencing host susceptibility to various diseases. Immunotoxic responses to lead appear to differ across life stages not only quantitatively with regard to dose response, but also qualitatively in terms of the spectrum of immune alterations. Experimental studies in several lab animal species suggest the latter stages of gestation are a period of considerable sensitivity for lead-induced immunotoxicity. This review describes the basic characteristics of lead-induced immunotoxicity emphasizing experimental animal results. It also provides a framework for the consideration of toxicant exposure effects across life stages. The existence of and probable basis for developmental windows of immune hyper-susceptibility are presented. Finally, the potential for lead to serve as a perinatal risk factor for childhood asthma as well as other diseases is considered

High Burden of Subclinical Lead Toxicity after Phase Out of Lead from Petroleum in Pakistan.

Science.gov (United States)

Majid, Hafsa; Khan, Aysha Habib; Khan, Nadeem Ullah; Siddiqui, Imran; Ghani, Farooq; Jafri, Lena

2017-12-01

To evaluate the frequency of subclinical lead toxicity. Cross-sectional study. Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, from January 2011 to December 2014. Analysis of laboratory data for blood lead levels (BLL) was performed. Lead was tested by atomic absorption spectrometer. For all subjects, only initial test results were included while the results of repeated testing were excluded. Exemption was sought from institutional ethical review committee. BLL of 2-10 ug/dl and 10-70 ug/dl in children and adults, respectively were taken as subclinical lead toxicity. Amongst the total number of subjects tested (n=524), 26.5% (n=139) were children (lead level 16.9 ug/dl (36.1-4)] and lower level [4.2 ug/dl (6.8-2.6)] in children with lead levels while most had either subclinical (76%, n=106) or toxic lead levels (8%, n=11). In adults, (55%, n=212) subjects had desired lead levels, and 40% (n=154) and 4.99% (n=19) had subclinical and toxic lead levels. Presence of subclinical lead poisoning even after phasing out of lead petroleum in Pakistanis is alarming, especially in children. A national population-based study to determine the lead status and targeted intervention to identify potential sources is need of the time.

Lead isotopes reveal different sources of lead in balsamic and other vinegars

International Nuclear Information System (INIS)

Ndung'u, Kuria; Hibdon, Sharon; Veron, Alain; Flegal, A. Russell

2011-01-01

Fifty-eight brands of balsamic vinegars were analyzed for lead concentrations and isotopic compositions ( 204 Pb, 206 Pb, 207 Pb, and 208 Pb) to test the findings of a previous study indicating relatively high levels of lead contamination in some of those vinegars - more than two thirds (70%) of them exceeded California's State Maximum Level (34 μg/L) based on consumption rates ≥ 0.5 μg Pb per day. The Lead isotopic fingerprints of all those vinegars with high lead concentrations were then found to be primarily anthropogenic. This isotopic analysis unquestionably reveals multiple contamination sources including atmospheric pollutant Pb and an unidentified contamination source, likely occurring after grape harvest. Organically grown grape vinegars display the same Pb content and isotopic signatures as other vinegars. This implies that pesticides might not be a significant source of pollutant Pb in vinegars. A significant post-harvest contamination would be inherited from chemicals added during production and/or material used during transport, processing or storage of these vinegars. This is consistent with the highest Pb levels being found in aged vinegars (112 ± 112 μg/L) in contrast to other vinegars (41.6 ± 28.9 μg/L) suggesting contamination during storage. It is, therefore, projected that lead levels in most vinegars, especially aged balsamic and wine vinegars, will decrease with improvements in their manufacture and storage processes consequential to recent concerns of elevated levels of lead in some vinegars. - Highlights: → First extensive study on content and possible sources of lead in balsamic vinegars. → Half of the vinegars exceed California's State Maximum Level for human consumption. → Lead content in vinegars seems to be mainly post-harvest from industrial processes.

Safety and Health Topics: Lead

Science.gov (United States)

... ammunition, pipes, cable covering, building material, solder, radiation shielding, collapsible tubes, and fishing weights. Lead is also ... lead linings in tanks and radiation protection, leaded glass, work involving soldering, and other work involving lead ...

Leading by example to protect the environment : Do the costs of leading matter?

NARCIS (Netherlands)

van der Heijden, E.C.M.; Moxnes, E.

2013-01-01

Environmentalists often urge their home countries to take a leading role in reducing global environmental problems like climate change. A pertinent question is, Will examples set by leading nations influence others to follow suit, and if so, do the costs of leading matter? For instance, will costly

Leading by Example to Protect the Environment; Do the Costs of Leading Matter?

NARCIS (Netherlands)

van der Heijden, E.C.M.; Moxnes, E.

2011-01-01

Environmentalists often urge their home countries to take a leading role in reducing global environmental problems like climate change. A pertinent question is: will examples set by leading nations influence others to follow suit, and if so, do the costs of leading matter? For instance, will costly

Decontaminating lead bricks and shielding

International Nuclear Information System (INIS)

Lussiez, G.

1994-01-01

Lead used for shielding is often surface contaminated with radioisotopes and is therefore a RCRA D008 mixed waste. The technology-based standard for treatment is macroencapsulation. However, decontaminating and recycling the clean lead is a more attractive solution. Los Alamos National Laboratory decontaminates material and equipment contaminated with radioisotopes. Decontaminating lead poses special problems because of the RCRA hazard classification and the size of the inventory, now about 50 tons and likely to grow substantially of planned decommissioning operations. Thus lead, in the form of bricks and other shield shapes, is surface contaminated with fission products. One of the best methods for contaminated lead is removing the superficial layer of contamination with an abrasive medium under pressure. For lead, a mixture of alumina with water and air at about 40 psig rapidly and effectively decontaminates the lead. The abrasive medium is sprayed onto the lead in a scaled-off area. The slurry of abrasive and particles of lead falls through a floor and is collected in a sump. A pump sends the slurry mixture back to the spray gun, creating a continuous process. The process generates small volumes of lead slurry that can be solidified and, because it passes the TCLP, is not a mixed waste. The decontaminated lead can be released for recycling

High-temperature superconducting current leads

Science.gov (United States)

Hull, J. R.

1992-07-01

The use of high-temperature superconductors (HTSs) for current leads to deliver power to devices at liquid helium temperature is near commercial realization. The use of HTSs in this application has the potential to reduce refrigeration requirements and helium boiloff to values significantly lower than the theoretical best achievable with conventional leads. Considerable advantage is achieved by operating these leads with an intermediate temperature heat sink. The HTS part of the lead can be made from pressed and sintered powder. Powder-in-tube fabrication is also possible, however, the normal metal part of the lead acts as a thermal short and cannot provide much stabilization without increasing the refrigeration required. Lead stability favors designs with low current density. Such leads can be manufactured with today's technology, and lower refrigeration results from the same allowable burnout time. Higher current densities result in lower boiloff for the same lead length, but bumout times can be very short. In comparing experiment to theory, the density of helium vapor needs to be accounted for in calculating the expected boiloff. For very low-loss leads, two-dimensional heat transfer and the state of the dewar near the leads may play a dominant role in lead performance.

Lead, arsenic, and copper content of crops grown on lead arsenate-treated and untreated soils

Energy Technology Data Exchange (ETDEWEB)

Chisholm, D

1972-01-01

Increased lead and arsenic concentrations in the surface soil (0-15 cm), resulting from applications of lead arsenate (PbHAs0/sub 1/), increased both lead and arsenic levels in crops grown on treated plots. The lead levels in some crops approached or exceeded the Canadian residue tolerance of 2.0 ppM. Lead arsenate soil treatments did not affect copper absorption by crops. On areas such as old orchard land contaminated with lead arsenate residues it may be advisable to ascertain crops, and also to determine the lead affinity and arsenic sensitivity of the plants to be grown.

Lead poisoning in dogs

International Nuclear Information System (INIS)

Zook, B.C.; Carpenter, J.L.; Leeds, E.B.

1969-01-01

Lead poisoning was diagnosed and studied in 60 dogs. It was found that lead poisoning is a common disease of young dogs, especially in the summer and fall, and is related to their chewing and eating habits resulting in the ingestion of paint, linoleum, or other lead-containing materials. The signs were characterized by gastrointestinal dysfunction (colic, vomiting, and diarrhea) and nervous disorders (convulsions, hysteria, nervousness, behavioral changes). The blood findings, which the authors consider nearly pathognomonic, consisted of numerous stippled and immature (especially nucleated) erythrocytes in the absence of severe anemia. Protein and casts were frequently found in the urine. Radiography sometimes revealed lead-containing particles in the gastro-intestinal tract, and lead lines were occasionally detected in the metaphysis of long bones in immature dogs. Treatment with calcium ethylenediamine-tetraacetic acid resulted in rapid and often dramatic recoveries in nearly all instances. Removal of lead from the gastrointestinal tract and treatment to relieve pronounced central nervous disorders was sometimes necessary. 40 references, 6 figures, 7 tables

ALICE: Simulated lead-lead collision

CERN Multimedia

2003-01-01

This track is an example of simulated data modelled for the ALICE detector on the Large Hadron Collider (LHC) at CERN, which will begin taking data in 2008. ALICE will focus on the study of collisions between nuclei of lead, a heavy element that produces many different particles when collided. It is hoped that these collisions will produce a new state of matter known as the quark-gluon plasma, which existed billionths of a second after the Big Bang.

Experimental lead poisoning in chickens

Energy Technology Data Exchange (ETDEWEB)

Silven, L.

1967-01-01

Poisoning of water fowl due to the intake of lead shot is not rare in the USA. In order to study this kind of poisoning more closely domestic fowl were given varying amounts of lead shot and lead powder. This treatment did not provoke any symptoms of poisoning. Chemical analyses of different organs, muscles, skeleton and eggs yielded low lead values. It is concluded that the low toxicity of lead administered as lead shot to the domestic fowl is due to a low absorption rate from the gastro-intestinal tract.

Bone lead levels and lead isotope ratios in red grouse from Scottish and Yorkshire moors

Energy Technology Data Exchange (ETDEWEB)

Thomas, Vernon G., E-mail: vthomas@uoguelph.ca [Department of Integrative Biology, College of Biological Science, University of Guelph, Guelph, Ontario, N1G 2W1 (Canada); Scheuhammer, Anton M.; Bond, Della E. [Metals Toxicology Laboratory, National Wildlife Research Centre, Carleton University, Ottawa, Ontario, K1A 0H3 (Canada)

2009-05-15

Leg and foot bones of adult and juvenile red grouse (Lagopus lagopus scoticus) were collected from hunter-shot birds on two Scottish estates (Glendye and Invermark) and one Yorkshire estate in September, 2003. The lead content of bones was measured by atomic absorption spectrophotometry, and corresponding stable lead isotopes (Pb204, 206, 207, 208) by inductively coupled plasma mass spectrometry. At the Glendye (N = 111) and Invermark (N = 85) estates, relatively few birds (5.4% and 3.5%, respectively) had highly elevated bone lead concentrations (> 20 mug/g dry weight). In bones of these highly exposed birds, a combination of Pb206:Pb207 and Pb208:Pb207ratios was consistent with ingestion of lead gunshot available in Europe. By contrast, Yorkshire grouse experienced a high incidence (65.8%) of bone lead > 20 mug/g. The Pb206:Pb207 and Pb208:Pb207ratios in bones of these highly exposed birds were consistent with a combined exposure to ingested lead gunshot and lead from galena mining in the region. Lead isotope ratios also indicated that lead from UK gasoline combustion and fallout from atmospheric particles was not a likely source of elevated lead in bones of either Scottish or Yorkshire grouse. Suggested management options for the three moors include adopting nontoxic shot for all game shooting on the estates, allowing heather (Calluna vulgaris) vegetation to grow tall in lead shot fall-out zones to reduce physical access to high densities of lead shot already present, and provision of calcareous grit across moors to reduce lead assimilation from all ingested sources of lead.

The effect of interior lead hazard controls on children's blood lead concentrations: a systematic evaluation.

Science.gov (United States)

Haynes, Erin; Lanphear, Bruce P; Tohn, Ellen; Farr, Nick; Rhoads, George G

2002-01-01

Dust control is often recommended to prevent children's exposure to residential lead hazards, but the effect of these controls on children's blood lead concentrations is uncertain. We conducted a systematic review of randomized, controlled trials of low-cost, lead hazard control interventions to determine the effect of lead hazard control on children's blood lead concentration. Four trials met the inclusion criteria. We examined mean blood lead concentration and elevated blood lead concentrations (> or = 10 microg/dL, > or = 15 microg/dL, and > or = 20 microg/dL) and found no significant differences in mean change in blood lead concentration for children by random group assignment (children assigned to the intervention group compared with those assigned to the control group). We found no significant difference between the intervention and control groups in the percentage of children with blood lead > or = 10 microg/dL, 29% versus 32% [odds ratio (OR), 0.85; 95% confidence interval (CI), 0.56-1.3], but there was a significant difference in the percentage of children with blood lead > or = 15 microg/dL between the intervention and control groups, 6% versus 14% (OR, 0.40; 95% CI, 0.21-0.80) and in the percentage of children with blood lead > or = 20 microg/dL between the intervention and control groups, 2% versus 6% (OR, 0.29; 95% CI, 0.10-0.85). We conclude that although low-cost, interior lead hazard control was associated with 50% or greater reduction in the proportion of children who had blood lead concentrations exceeding 15 microg/dL and > or = 20 microg/dL, there was no substantial effect on mean blood lead concentration.

Bone lead levels and lead isotope ratios in red grouse from Scottish and Yorkshire moors

International Nuclear Information System (INIS)

Thomas, Vernon G.; Scheuhammer, Anton M.; Bond, Della E.

2009-01-01

Leg and foot bones of adult and juvenile red grouse (Lagopus lagopus scoticus) were collected from hunter-shot birds on two Scottish estates (Glendye and Invermark) and one Yorkshire estate in September, 2003. The lead content of bones was measured by atomic absorption spectrophotometry, and corresponding stable lead isotopes (Pb204, 206, 207, 208) by inductively coupled plasma mass spectrometry. At the Glendye (N = 111) and Invermark (N = 85) estates, relatively few birds (5.4% and 3.5%, respectively) had highly elevated bone lead concentrations (> 20 mug/g dry weight). In bones of these highly exposed birds, a combination of Pb206:Pb207 and Pb208:Pb207ratios was consistent with ingestion of lead gunshot available in Europe. By contrast, Yorkshire grouse experienced a high incidence (65.8%) of bone lead > 20 mug/g. The Pb206:Pb207 and Pb208:Pb207ratios in bones of these highly exposed birds were consistent with a combined exposure to ingested lead gunshot and lead from galena mining in the region. Lead isotope ratios also indicated that lead from UK gasoline combustion and fallout from atmospheric particles was not a likely source of elevated lead in bones of either Scottish or Yorkshire grouse. Suggested management options for the three moors include adopting nontoxic shot for all game shooting on the estates, allowing heather (Calluna vulgaris) vegetation to grow tall in lead shot fall-out zones to reduce physical access to high densities of lead shot already present, and provision of calcareous grit across moors to reduce lead assimilation from all ingested sources of lead.

Decontaminating lead bricks and shielding

International Nuclear Information System (INIS)

Lussiez, G.W.

1993-01-01

Lead used for shielding is often surface contaminated with radioisotopes and is therefore a RCRA D008 mixed waste. The technology-based standard for treatment is macroencapsulation. However, decontaminating and recycling the clean lead is a more attractive solution. Los Alamos National Laboratory decontaminates material and equipment contaminated with radioisotopes. Decontaminating lead poses special problems because of the RCRA hazard classification and the size of the inventory, now about 50 tons and likely to grow substantially because of planned decommissioning operations. This lead, in the form of bricks and other shield shapes, is surface contaminated with fission products. One of the best methods for decontaminating lead is removing the thin superficial layer of contamination with an abrasive medium trader pressure. For lead, a mixture of alumina with water and air at about 40 psig rapidly and effectively decontaminates the lead. The abrasive medium is sprayed onto the lead in a sealed-off area. The slurry of abrasive and particles of lead falls through a floor grating and is collected in a sump. A pump sends the slurry mixture back to the spray gun, creating a continuous process. The process generates small volumes of contaminated lead slurry that can be solidified and, because it passes the TCLP, is not a mixed waste. The decontaminated lead can be released for recycling

Lead contamination and transfer in urban environmental compartments analyzed by lead levels and isotopic compositions.

Science.gov (United States)

Hu, Xin; Sun, Yuanyuan; Ding, Zhuhong; Zhang, Yun; Wu, Jichun; Lian, Hongzhen; Wang, Tijian

2014-04-01

Lead levels and isotopic compositions in atmospheric particles (TSP and PM2.5), street dust and surface soil collected from Nanjing, a mega city in China, were analyzed to investigate the contamination and the transfer of lead in urban environmental compartments. The lead contents in TSP and PM2.5 are significantly higher than them in the surface soil and street dust (p lead to the major crustal elements (Al, Sr, Ti and Fe) indicates significant lead enrichment in atmospheric particles. The plots of (206)Pb/(207)Pb vs.(208)Pb/(206)Pb and (206)Pb/(207)Pb vs. 1/Pb imply that the street dust and atmospheric particles (TSP and PM2.5) have very similar lead sources. Coal emissions and smelting activities may be the important lead sources for street dust and atmospheric particles (TSP and PM2.5), while the deposition of airborne lead is an important lead source for urban surface soil. Copyright © 2013 Elsevier Ltd. All rights reserved.

Genetically engineered Newcastle disease virus expressing interleukin-2 and TNF-related apoptosis-inducing ligand for cancer therapy

Science.gov (United States)

Recombinant Newcastle disease virus (rNDV) has shown oncolytic therapeutic efficacy in preclinical studies and are currently in clinical trials. In this study, we have evaluated the possibility to enhance the cancer therapeutic potential of NDV by means of inserting both interleukin-2 (IL-2) and tu...

Epidermal growth factor receptor targeting of replication competent adenovirus enhances cytotoxicity in bladder cancer

NARCIS (Netherlands)

van der Poel, HG; Molenaar, B; van Beusechem, VW; Haisma, HJ; Rodriguez, R; Curiel, DT; Gerritsen, WR

Purpose: We evaluated the delivery and oncolytic potential of targeted replication competent adenoviruses in bladder cancer lines. Materials and Methods: Seven established human bladder cancer tumor lines (5637, SW800, TCCsup, J82, Scaber, T24 and 253J) were studied for the expression of integrins

INAA, AAS, and lead isotope analysis of ancient lead anchors from the black SEA

International Nuclear Information System (INIS)

Kuleff, I.; Djingova, R.; Alexandrova, A.

1995-01-01

Lead stock of wooden-lead anchors found along the Bulgarian Black Sea coast and typo logically dated VI c. B.C. - III c. A.D. have been analyzed for chemical composition and lead isotope ratios by INAA, AAS and mass spectrometry. Using multivariate methods for analysis as well as simple bi variate plots the lead for production of the stocks was localized as originating from Laurion, Thassos, Troas, Chalkidike and the Rhodopes. In general, the chemical composition is not recommended to be used for provenance study of lead artefacts. Combining the results from this study with the existing typo logical classification certain conclusion about the production and distribution of lead anchors in the Aegean region are made. (author). 22 refs., 3 figs., 4 tabs

Antibody neutralization of retargeted measles viruses

Science.gov (United States)

Lech, Patrycja J.; Pappoe, Roland; Nakamura, Takafumi; Tobin, Gregory J.; Nara, Peter L.; Russell, Stephen J.

2014-01-01

The measles virus (MV) vaccine lineage is a promising oncolytic but prior exposure to the measles vaccine or wild-type MV strains limits treatment utility due to the presence of anti-measles antibodies. MV entry can be redirected by displaying a polypeptide ligand on the Hemagglutinin (H) C-terminus. We hypothesized that retargeted MV would escape neutralization by monoclonal antibodies (mAbs) recognizing the H receptor-binding surface and be less susceptible to neutralization by human antisera. Using chimeric H proteins, with and without mutations that ablate MV receptor binding, we show that retargeted MVs escape mAbs that target the H receptor-binding surface by virtue of mutations that ablate infection via SLAM and CD46. However, C-terminally displayed domains do not mediate virus entry in the presence of human antibodies that bind to the underlying H domain. In conclusion, utility of retargeted oncolytic measles viruses does not extend to evasion of human serum neutralization. PMID:24725950

Atrioventricular Pacemaker Lead Reversal

Directory of Open Access Journals (Sweden)

Mehmet K Aktas, MD

2007-01-01

Full Text Available During cardiac surgery temporary epicardial atrial and ventricular leads are placed in case cardiac pacing is required postoperatively. We present the first reported series of patients with reversal of atrioventricular electrodes in the temporary pacemaker without any consequent deleterious hemodynamic effect. We review the electrocardiographic findings and discuss the findings that lead to the discovery of atrioventricular lead reversal.

Lead accumulation in the straw mushroom, Volvariella volvacea, from lead contaminated rice straw and stubble.

Science.gov (United States)

Kumhomkul, Thapakorn; Panich-pat, Thanawan

2013-08-01

Straw mushrooms were grown on lead contaminated rice straw and stubble. Study materials were dried, acid digested, and analyzed for lead using flame atomic absorption spectrophotometry. The results showed the highest lead concentration in substrate was 445.350 mg kg⁻¹ in Treatment 3 (T3) and the lowest was BD (below detection) in Treatment 1 (T1). The maximum lead content in straw mushrooms was 5.072 mg kg⁻¹ dw in pileus of T3 and the minimum lead content in straw mushrooms was BD in egg and mature (stalk and pileus) stage of T1. The lead concentration in straw mushrooms was affected by the age of the mycelium and the morphology of mushrooms. Mushrooms' lead uptake produced the highest accumulation in the cell wall. Some lead concentrations in straw mushrooms exceeded the EU standard (>3 mg kg⁻¹ dw).

Basic principles of lead and lead-bismuth eutectic application in blanket of fusion reactors

International Nuclear Information System (INIS)

Beznosov, A.V.; Pinaev, S.S.; Muraviev, E.V.; Romanov, P.V.

2005-01-01

High magnetohydrodynamic pressure drop is an important issue for liquid metal blanket concepts. To decrease magnetohydrodynamic resistance authors propose to form insulating coatings on internal surface of blanket ducts at any moment of fusion reactor exploitation. It may be achieved easily if lead or lead-bismuth eutectic is used and technology of oxidative potential handling is applied. A number of experiments carried out in NNSTU show the availability of the proposed technology. It bases on formation of the insulating coatings that consist of the oxides of components of the structural materials and of the coolant components. In-situ value of the insulating coatings characteristics ρδ is ∼ 10 -5 Ohm·m 2 for steels and 5,0x10 -6 - 5,0x10 -5 Ohm·m 2 for vanadium alloys. Thermal cycling is possible during exploitation of a blanket. The experimental research of the insulating coatings properties during thermal cycling have shown that the coatings formed into the lead and lead-bismuth coolants save there insulating properties. Experience of many years is an undoubted advantage of the lead-bismuth coolant and less of the lead coolant in comparison with lithium. Russian Federation possesses of experience of exploitation of the research and industrial facilities, of experience of creation of the pumps, steamgenerators and equipment with heavy liquid metal coolants. The unique experience of designing, assembling and exploitation of the fission reactors with lead-bismuth coolant is also available. The problem of technology of lead and lead-bismuth coolants for power high temperature radioactive facilities has been solved. Accidents, emergency situations such as leakage of steamgenerators or depressurization of gas system in facilities with lead and lead-bismuth coolants have been explored and suppressed. (author)

Manurial properties of lead nitrate

Energy Technology Data Exchange (ETDEWEB)

Berry, R A

1924-01-01

Water culture, pot and field experiments were conducted in order to determine the toxic and stimulating limit of lead nitrate in solution. Oats and rye grass were evaluated for evidence of lead poisoning. Results indicate that except in solutions of fairly high concentration, soil adsorbs the lead and destroys the toxicity of soluble lead salts. There was evidence to show that the addition of lead salts increased the rate of nitrification in soil.

Children’s Blood Lead Seasonality in Flint, Michigan (USA), and Soil-Sourced Lead Hazard Risks

Science.gov (United States)

Laidlaw, Mark A.S.; Filippelli, Gabriel M.; Sadler, Richard C.; Gonzales, Christopher R.; Ball, Andrew S.; Mielke, Howard W.

2016-01-01

In Flint; MI; USA; a public health crisis resulted from the switching of the water supply from Lake Huron to a more corrosive source from the Flint River in April 2014; which caused lead to leach from water lines. Between 2010 and 2015; Flint area children’s average blood lead patterns display consistent peaks in the third quarter of the year. The third quarter blood lead peaks displayed a declining trend between 2010 and 2013; then rose abruptly between the third quarters of 2013 from 3.6% blood lead levels ≥5 µg/dL to a peak of about 7% in the third quarter of 2014; an increase of approximately 50%. The percentage of blood lead level ≥5 µg/dL in the first quarter of 2015 then dropped to 2.3%; which was the same percentage as the first quarter of 2014 (prior to the Flint River water source change). The Flint quarterly blood lead level peak then rose to about 6% blood lead levels ≥ 5 µg/dL in the third quarter of 2015; and then declined to about 2.5% in the fourth quarter of 2015. Soil lead data collected by Edible Flint food collaborative reveal generally higher soil lead values in the metropolitan center for Flint; with lower values in the outskirts of the city. The questions that are not being asked is why did children’s blood lead levels display a seasonal blood lead pattern before the introduction of the new water supply in Flint; and what are the implications of these seasonal blood lead patterns? Based upon previous findings in Detroit and other North American cities we infer that resuspension to the air of lead in the form of dust from lead contaminated soils in Flint appears to be a persistent contribution to lead exposure of Flint children even before the change in the water supply from Lake Huron to the Flint River. PMID:27023578

Magnesium Diboride Current Leads

Science.gov (United States)

Panek, John

2010-01-01

A recently discovered superconductor, magnesium diboride (MgB2), can be used to fabricate conducting leads used in cryogenic applications. Dis covered to be superconducting in 2001, MgB2 has the advantage of remaining superconducting at higher temperatures than the previously used material, NbTi. The purpose of these leads is to provide 2 A of electricity to motors located in a 1.3 K environment. The providing environment is a relatively warm 17 K. Requirements for these leads are to survive temperature fluctuations in the 5 K and 11 K heat sinks, and not conduct excessive heat into the 1.3 K environment. Test data showed that each lead in the assembly could conduct 5 A at 4 K, which, when scaled to 17 K, still provided more than the required 2 A. The lead assembly consists of 12 steelclad MgB2 wires, a tensioned Kevlar support, a thermal heat sink interface at 4 K, and base plates. The wires are soldered to heavy copper leads at the 17 K end, and to thin copper-clad NbTi leads at the 1.3 K end. The leads were designed, fabricated, and tested at the Forschungszentrum Karlsruhe - Institut foer Technische Physik before inclusion in Goddard's XRS (X-Ray Spectrometer) instrument onboard the Astro-E2 spacecraft. A key factor is that MgB2 remains superconducting up to 30 K, which means that it does not introduce joule heating as a resistive wire would. Because the required temperature ranges are 1.3-17 K, this provides a large margin of safety. Previous designs lost superconductivity at around 8 K. The disadvantage to MgB2 is that it is a brittle ceramic, and making thin wires from it is challenging. The solution was to encase the leads in thin steel tubes for strength. Previous designs were so brittle as to risk instrument survival. MgB2 leads can be used in any cryogenic application where small currents need to be conducted at below 30 K. Because previous designs would superconduct only at up to 8 K, this new design would be ideal for the 8-30 K range.

Determination of lead in whole blood: Comparison of the LeadCare blood lead testing system with zeeman longitudinal electrothermal atomic absorption spectrometry

International Nuclear Information System (INIS)

Pineau, A.; Viallefont, A.; Fauconneau, B.; Rafael, M.; Guillard, O.

2002-01-01

This study compares the efficiency of blood lead level analysis by graphite furnace atomic absorption spectrometry (GFAAS) and the portable LeadCare Blood lead testing system (LCS). Recoveries of two added lead concentrations of 22 and 42 μg/dL ranged from 102.4 to 105.5% for LCS and from 96.3 to 97.2% for GFAAS. Measurement of a certified sample (Certified Danish Whole Blood) at a blood lead concentration of 26.2 μg/dL gave within- and between-run coefficients of variation which were both approximately 8% by LCS and 2% by GFAAS. Comparison of the tested method (LCS) versus GFAAS from analysis of 76 samples of blood lead collected from workers in different industrial sectors showed imperfect overall correlation (r = 0.95). The LCS is quite suitable for screening purposes, but requires the use of non-frozen blood collected less than 24 h before. Conservative threshold values should be applied when using the LCS for initial screening in the field. (orig.)

Archives of Atmospheric Lead Pollution

Science.gov (United States)

Weiss, Dominik; Shotyk, William; Kempf, Oliver

Environmental archives such as peat bogs, sediments, corals, trees, polar ice, plant material from herbarium collections, and human tissue material have greatly helped to assess both ancient and recent atmospheric lead deposition and its sources on a regional and global scale. In Europe detectable atmospheric lead pollution began as early as 6000years ago due to enhanced soil dust and agricultural activities, as studies of peat bogs reveal. Increased lead emissions during ancient Greek and Roman times have been recorded and identified in many long-term archives such as lake sediments in Sweden, ice cores in Greenland, and peat bogs in Spain, Switzerland, the United Kingdom, and the Netherlands. For the period since the Industrial Revolution, other archives such as corals, trees, and herbarium collections provide similar chronologies of atmospheric lead pollution, with periods of enhanced lead deposition occurring at the turn of the century and since 1950. The main sources have been industry, including coal burning, ferrous and nonferrous smelting, and open waste incineration until c.1950 and leaded gasoline use since 1950. The greatest lead emissions to the atmosphere all over Europe occurred between 1950 and 1980 due to traffic exhaust. A marked drop in atmospheric lead fluxes found in most archives since the 1980s has been attributed to the phasing out of leaded gasoline. The isotope ratios of lead in the various archives show qualitatively similar temporal changes, for example, the immediate response to the introduction and phasing out of leaded gasoline. Isotope studies largely confirm source assessments based on lead emission inventories and allow the contributions of various anthropogenic sources to be calculated.

Decontaminating lead bricks and shielding

International Nuclear Information System (INIS)

Lussiez, G.W.

1993-01-01

Lead used for shielding is often surface contaminated with radionuclides and is therefore a Resource Conservation and Recovery Act (RCRA) D008 mixed waste. The technology-based standard for treatment is macroencapsulation. However, decontaminating and recycling the clean lead is a more attractive solution. Los Alamos National Lab. decontaminates material and equipment contaminated with radioisotopes. Decontaminating lead poses special problems because of the RCRA hazard classification and the size of the inventory, now about 100 metric tons and likely to grow substantially because of planned decommissioning operations. This lead, in the form of bricks and other shield shapes, is surface contaminated with fission products. One of the best methods for decontaminating lead is removing the thin superficial layer of contamination with an abrasive medium under pressure. For lead, a mixture of alumina with water and air at about 280 kPa (40 psig) rapidly and effectively decontaminates the lead. The abrasive medium is sprayed onto the lead in a sealed-off area. The slurry of abrasive and particles of lead falls through a floor grating and is collected in a pump. A pump sends the slurry mixture back to the spray gun, creating a continuous process

Erythrocyte fluorescence and lead intoxication.

Science.gov (United States)

Clark, K G

1976-01-01

Blood samples from people exposed to inorganic lead were examined by fluorescence microscopy for excess erythrocyte porphyrin. With continued lead absorption, fluorescent erythrocytes appeared in the circulation of workers handling this metal or its compounds, and they progressively increased in number and brilliance. These changes ensued if the blood lead concentration was maintained above 2-42 mumol/l (50 mug/100 ml), and preceded any material fall in the haemoglobin value. At one factory, 62-5% of 81 symptomless workers showed erythrocyte fluorescence attributable to the toxic effects of lead. Excess fluorocytes were found in blood samples from a child with pica and three of her eight siblings. These four were subsequently shown to have slightly increased blood lead concentrations (2-03 to 2-32 mumol/l). Fluorescence microscopy for excess erythrocyte porphyrin is a sensitive method for the detection of chronic lead intoxication. A relatively slight increase in the blood lead is associated with demonstrabel changes in erythrocyte porphyrin content. The procedure requires little blood, and may be performed upon stored samples collected for lead estimation. The results are not readily influenced by contamination, and provide good confirmatory evidence for the absorption of biochemically active lead. PMID:963005

Leaded gasoline - an environmental problem

International Nuclear Information System (INIS)

Petrushevska, Ljubica

2001-01-01

In the European countries it is a clear trend towards the increasing consumption of unleaded gasolines. Driving force of this trend is, on the one hand the high toxicity of lead compounds and on the other, the necessity of purification of exhaust gases by catalytic converters, for which the lead represent a catalyst poison. In Macedonia, the limit lead content in the leaded gasolines is relatively high (0,6 g/l), as well as the consumption of the leaded gasolines. Rapid and complete transition to unleaded gasolines can be realized by the concept of step by step reduction of lead in our gasolines. (Original)

Decontamination and coating of lead

International Nuclear Information System (INIS)

Rankin, W.N.; Bush, S.P.; Lyon, C.E.; Walker, V.

1988-01-01

Technology is being developed to decontaminate lead used in shielding applications in contaminated environments for recycle as shieldings. Technology is also being developed to coat either decontaminated lead or new lead before it is used in contaminated environments. The surface of the coating is expected to be much easier to decontaminate than the original lead surface. If contamination becomes severely embedded in the coating and cannot be removed, it can be easily cut with a knife and removed from the lead. The used coating can be disposed of as radioactive (hot hazardous) waste. The lead can then be recoated for further use as a shielding material

PUMA and NF-kB Are Cell Signaling Predictors of Reovirus Oncolysis of Breast Cancer.

Science.gov (United States)

Thirukkumaran, Chandini; Shi, Zhong-Qiao; Thirukkumaran, Ponnampalam; Luider, Joanne; Kopciuk, Karen; Spurrell, Jason; Elzinga, Kate; Morris, Don

2017-01-01

Reovirus is a ubiquitous RNA virus that exploits aberrant signaling pathways for its replication. The oncolytic potential of reovirus against numerous cancers under pre-clinical/clinical conditions has been documented by us and others. Despite its proven clinical activity, the underlying mechanisms of reovirus oncolysis is still not well elucidated. If reovirus therapy is to be optimized for cancer, including breast cancer patients, it is imperative to understand the mechanisms of reovirus oncolysis, especially in treatment of resistant tumour. In the present study global gene expression profiling was utilized as a preliminary roadmap to tease-out pivotal molecules involved in reovirus induced apoptosis in breast cancer. Reovirus treated HTB133 and MCF7 breast cancer cells revealed transcriptional alteration of a defined subset of apoptotic genes and members of the nuclear factor-kappa B (NF-kB) family and p53 upregulated modulator of apoptosis (PUMA) were prominent. Since NF-kB can paradoxically suppress or promote apoptosis in cancer, the significance of NF-kB in reovirus oncolysis of breast cancer was investigated. Real time PCR analysis indicated a 2.9-4.3 fold increase in NF-kB p65 message levels following reovirus infection of MCF7 and HTB133, respectively. Nuclear translocation of NF-kB p65 protein was also dramatically augmented post reovirus treatment and correlated with enhanced DNA binding. Pharmacologic inhibition of NF-kB lead to oncolytic protection and significant down regulation of PUMA message levels. PUMA down regulation using siRNA suppressed reovirus oncolysis via significantly repressed apoptosis in p53 mutant HTB133 cells. This study demonstrates for the first time that a prominent pathway of reovirus oncolysis of breast cancer is mediated through NF-kB and that PUMA upregulation is dependent on NF-kB activation. These findings represent potential therapeutic indicators of reovirus treatment in future clinical trials.

Consumption of lead-shot cervid meat and blood lead concentrations in a group of adult Norwegians.

Science.gov (United States)

Meltzer, H M; Dahl, H; Brantsæter, A L; Birgisdottir, B E; Knutsen, H K; Bernhoft, A; Oftedal, B; Lande, U S; Alexander, J; Haugen, M; Ydersbond, T A

2013-11-01

Several recent investigations have reported high concentrations of lead in samples of minced cervid meat. This paper describes findings from a Norwegian study performed in 2012 among 147 adults with a wide range of cervid game consumption. The main aim was to assess whether high consumption of lead-shot cervid meat is associated with increased concentration of lead in blood. A second aim was to investigate to what extent factors apart from game consumption explain observed variability in blood lead levels. Median (5 and 95 percentile) blood concentration of lead was 16.6 µg/L (7.5 and 39 µg/L). An optimal multivariate linear regression model for log-transformed blood lead indicated that cervid game meat consumption once a month or more was associated with approximately 31% increase in blood lead concentrations. The increase seemed to be mostly associated with consumption of minced cervid meat, particularly purchased minced meat. However, many participants with high and long-lasting game meat intake had low blood lead concentrations. Cervid meat together with number of bullet shots per year, years with game consumption, self-assembly of bullets, wine consumption and smoking jointly accounted for approximately 25% of the variation in blood lead concentrations, while age and sex accounted for 27% of the variance. Blood lead concentrations increased approximately 18% per decade of age, and men had on average 30% higher blood lead concentrations than women. Hunters who assembled their own ammunition had 52% higher blood lead concentrations than persons not making ammunition. In conjunction with minced cervid meat, wine intake was significantly associated with increased blood lead. Our results indicate that hunting practices such as use of lead-based ammunition, self-assembling of lead containing bullets and inclusion of lead-contaminated meat for mincing to a large extent determine the exposure to lead from cervid game consumption. © 2013 Elsevier Inc. All rights

Occupational exposure to lead--granulometric distribution of airborne lead in relation to risk assessment.

Science.gov (United States)

Carelli, G; Masci, O; Altieri, A; Castellino, N

1999-07-01

The amount of airborne lead absorbed by the body during occupational exposure depends not only on lead concentration in workplace air, but also on the granulometric distribution of the aerosol. The Occupational Safety and Health Administration (OSHA) set the lead Permissible Exposure Limit (PEL) at 50 micrograms/m3 on the basis of Bernard's model and a number of assumptions, including assumption "C", which predicts that the first 12.5 micrograms/m3 are made up of fine particles (aerodynamic diameter 1 micron. Occupational exposure to airborne lead at a concentration of 50 micrograms/m3 and a granulometric distribution calculated according to the above mentioned assumption, leads, in the model, to a mean blood level of 40 micrograms/dl. In the present study, we tested the validity of assumption "C" in the environmental air of a factory that manufactured crystal glassware containing 24% lead oxide. An 8-stage impactor was used to measure the particle size of airborne dust collected from personal and area samplings. Results indicate that, on the whole, assumption "C" cannot be considered valid in the work environment investigated in this study. As a result, lead absorption levels in exposed workers may be noticeably different from those predicted by the OSHA model. We therefore suggest that in order to make a correct evaluation of the risk of occupational exposure to lead, it is essential to integrate total airborne lead concentration with a measurement of the granulometric distribution of the aerosol.

Lead-210, polonium-210, and stable lead in the food-chain lichen, reindeer and man

International Nuclear Information System (INIS)

Persson, B.R.

1972-01-01

The measurements of stable lead and the natural fallout radionuclides lead-210 and polonium-210 in communities of lichen (Cladonia alpestris) in central Sweden from 1961 to 1970 indicate a quite constant level. The average lead-210 content per unit area in lichen carpets was found to be 15 +- 2 nCi m -2 , the average lead-210 activity concentration 6.7 +- 0.9 nCi per kg dry weight and the lead-210 specific activity 630 +- 60 nCi per g of stable lead. The polonium-210/lead-210 activity ratio was about 0.9 +- 0.1. The vertical distribution of lead-210 in the lichen carpet showed a maximum concentration in the top layer. The distribution was similar during 1967 and 1968 but the low amount of precipitation during 1968 and 1969 disturbed the distribution pattern in 1969 and 1970. The transfer of lead-210, polonium-210 and stable lead through the food chain: lichen, reindeer, and man was characterized. The absorbed dose rate in Lapps due to polonium-210 was estimated to be about 6 to 8 mrad per year in gonads and 8 to 20 mrad per year in bone tissues. This is about ten percent of their entire absorbed dose contribution from all natural radiation sources. (U.S.)

Involving Lead Users in Innovation

DEFF Research Database (Denmark)

Brem, Alexander; Bilgram, Volker; Gutstein, Adele

2018-01-01

Research on the lead user method has been conducted for more than thirty years and has shown that the method is more likely to generate breakthrough innovation than traditional market research tools. Based on a systematic literature review, this paper shows a detailed view on the broad variety...... of research on lead user characteristics, lead user processes, lead user identification and application, and success factors. The main challenge of the lead user method as identified in literature is the resource issue regarding time, manpower, and costs. Also, internal acceptance and the processing...... of the method have been spotted in literature, as well as the intellectual property protection issue. From the starting point of the initial lead user method process introduced by Lüthje and Herstatt (2004), results are integrated into a revisited view on the lead user method process. In addition, concrete...

The relationship between environmental lead and blood lead in children : a study in environmental epidemiology

NARCIS (Netherlands)

Brunekreef, B.

1985-01-01

This study deals with the relationship between environmental lead and blood lead in children.
Chapter 1 provides a summary of the environmental health aspects of lead. The occurrence of lead in the environment and in man is described; children are discussed as a population at

Lead: Aspects of its ecology and environmental toxicity. [physiological effects of lead compound contamination of environment

Science.gov (United States)

Siegel, S. M.

1973-01-01

An analysis of lead toxicity in the Hawaiian environment was conducted. It was determined that lead enters the environment as an industrial contaminant resulting from the combustion of leaded gasoline. The amount of lead absorbed by the plants in various parts of the Hawaiian Islands is reported. The disposition of lead in the sediments of canals and yacht basins was investigated. The methods for conducting the surveys of lead content are described. Possible consequences of continued environmental pollution by burning leaded gasoline are discussed.

Investigations on organolead compounds V. Lead---lead bond cleavage reactions of hexaphenyldilead

NARCIS (Netherlands)

Willemsens, L.C.; Kerk, G.J.M. van der

1968-01-01

It has been shown that a number of nucleophilic and weakly electrophilic reagents (organolithium and organomagnesium compounds, metallic lithium, potassium permanganate, sodium ethoxide, diaryl disulphides, sulphur, ozone, hypochlorous acid and iodine/iodide) selectively cleave the lead---lead bond

The organotypic multicellular spheroid is a relevant three-dimensional model to study adenovirus replication and penetration in human tumors in vitro

NARCIS (Netherlands)

Grill, Jacques; Lamfers, Martine L. M.; van Beusechem, Victor W.; Dirven, Clemens M.; Pherai, D. Shareen; Kater, Mathijs; van der Valk, Paul; Vogels, Ronald; Vandertop, W. Peter; Pinedo, Herbert M.; Curiel, David T.; Gerritsen, Winald R.

2002-01-01

The use of adenoviruses for gene transfer and as oncolytic agents is currently receiving widespread attention. As specific constraints to adenovirus distribution and spread cannot be studied in cell cultures, there is a need for an in vitro three-dimensional (3D) model mimicking the in vivo biology

A138

Directory of Open Access Journals (Sweden)

K. Yurchenko

2015-11-01

Thus, results suggest that vascular disruption in the NDV-treated group indicates the virus ability to directly or indirectly affect tumor angiogenesis and regulate tissue trophism in that way. Understanding how and in which step this effect occurs may provide capacity to use oncolytic NDV strains for therapeutic benefit.

Childhood lead poisoning investigations: evaluating a portable instrument for testing soil lead.

Science.gov (United States)

Reames, Ginger; Lance, Larrie L

2002-04-01

The Childhood Lead Poisoning Prevention Branch of the California Department of Health Services evaluated a portable X-ray fluorescence (XRF) instrument for use as a soil lead-testing tool during environmental investigations of lead-poisoned children's homes. A Niton XRF was used to test soil at 119 sampling locations in the yards of 11 San Francisco Bay Area houses. Niton XRF readings were highly correlated with laboratory results and met the study criteria for an acceptable screening method. The data suggest that the most health-protective and time-efficient approach to testing for soil lead above regulatory levels is to take either surface readings or readings of a test cup of soil prepared by grinding with a mortar and pestle. The advantage of the test cup method is that the test cup with soil may be submitted to a laboratory for confirmatory analysis.

Lead Poisoning in Wild Birds

Science.gov (United States)

Lahner, Lesanna L.; Franson, J. Christian

2009-01-01

Lead in its various forms has been used for thousands of years, originally in cooking utensils and glazes and more recently in many industrial and commercial applications. However, lead is a potent, potentially deadly toxin that damages many organs in the body and can affect all animals, including humans. By the mid 1990s, lead had been removed from many products in the United States, such as paint and fuel, but it is still commonly used in ammunition for hunting upland game birds, small mammals, and large game animals, as well as in fishing tackle. Wild birds, such as mourning doves, bald eagles, California condors, and loons, can die from the ingestion of one lead shot, bullet fragment, or sinker. According to a recent study on loon mortality, nearly half of adult loons found sick or dead during the breeding season in New England were diagnosed with confirmed or suspected lead poisoning from ingestion of lead fishing weights. Recent regulations in some states have restricted the use of lead ammunition on certain upland game hunting areas, as well as lead fishing tackle in areas frequented by common loons and trumpeter swans. A variety of alternatives to lead are available for use in hunting, shooting sports, and fishing activities.

Blood Lead Levels in Children and Environmental Lead Contamination in Miami Inner City, Florida

Directory of Open Access Journals (Sweden)

Theophile Niyonsenga

2006-09-01

Full Text Available Studies have shown that the environmental conditions of the home are important predictors of health, especially in low-income communities. Understanding the relationship between the environment and health is crucial in the management of certain diseases. One health outcome related to the home environment among urban, minority, and low-income children is childhood lead poisoning. The most common sources of lead exposure for children are lead paint in older, dilapidated housing and contaminated dust and soil produced by accumulated residue of leaded gasoline. Blood lead levels (BLL as low as 10 μg/dL in children are associated with impaired cognitive function, behavior difficulties, and reduced intelligence. Recently, it is suggested that the standard for intervention be lowered to BLL of 5 μg /dl. The objectives of our report were to assess the prevalence of lead poisoning among children under six years of age and to quantify and test the correlations between BLL in children and lead exposure levels in their environment. This cross-sectional analysis was restricted to 75 children under six years of age who lived in 6 zip code areas of inner city Miami. These locations exhibited unacceptably high levels of lead dust and soil in areas where children live and play. Using the 5 μg/dL as the cutoff point, the prevalence of lead poisoning among the study sample was 13.33%. The study revealed that lead levels in floor dust and window sill samples were positively and significantly correlated with BLL among children (p < 0.05. However, the correlations between BLL and the soil, air, and water samples were not significant. Based on this pilot study, a more comprehensive environmental study in surrounding inner city areas is warranted. Parental education on proper housecleaning techniques may also benefit those living in the high lead-exposed communities of inner city Miami.

Neurophysiological effects of lead exposure

Energy Technology Data Exchange (ETDEWEB)

Rosen, I.; Wildt, K.; Gullberg, B.; Berlin, M.

1983-10-01

A series of neurophysiological variables was measured for men occupationally exposed to lead. The results were related to the degree of lead exposure and to the concentrations of lead and zinc protoporphyrin in blood. A small but significant correlation was observed between lead exposure and motor and sensory conduction velocities in the lower limbs, the conduction velocities of slow motor fibers in the upper limbs, and also sensory nerve action potentials. It is suggested that a neurophysiological examination should be considered in the surveillance of the health of lead workers.

Environmental lead exposure among preschool children in Shanghai, China: blood lead levels and risk factors.

Directory of Open Access Journals (Sweden)

Jia Cao

Full Text Available OBJECTIVE: To determine blood lead levels and to identify related risk factors among children in Shanghai; to explore the lead change trend of children after industrial transformation and to provide data for policy development to control environmental lead pollution in Shanghai. METHODS: A stratified-clustered-random sampling method was used. A tungsten atomizer absorption spectrophotometer was employed to determine blood lead levels. RESULTS: The arithmetic mean, geometric mean and median of blood lead levels of 0- to 6-year-old children from Shanghai were 22.49 µg/L, 19.65 µg/L and 19.5 µg/L, including 0.26% (6/2291 with concentrations ≥100 µg/L and 2.7% (61/2291 with concentrations ≥50 µg/L. Boys' levels (23.57 µg/L were greater than those of girls (21.2 µg/L. The blood lead levels increased with age. This survey showed that the Chongming district was the highest and Yangpu district was the lowest, this result is completely opposite with the earlier survey in Shanghai. Risk factors for lead contamination included housing environment, parents' education levels, social status, hobbies, and children's nutritional status. CONCLUSIONS: The blood lead levels of children in Shanghai were lower than the earlier data of Shanghai and those of published studies in China, but higher than the blood lead levels of developed countries. The blood lead levels of urban districts are higher than the central districts with the industrial transformation. Society and the government should take an active interest in childhood lead poisoning of urban areas.

Behavior of active deposit of lead (Teisinger) in the Japanese free from occupational exposure to lead

Energy Technology Data Exchange (ETDEWEB)

Araki, S

1973-12-01

Intravenous infusion of calcium disodium ethylenediamine tetraacetate (CaEDTA) was given to 45 Japanese adults without occupational exposure to lead for 1 hr at a dosage of 20 mg/kg body weight in 250 ml of 5 percent glucose solution. The urinary excretion of lead was estimated for 24 hr before, and for 2 hr and 24 hr after the administration. The least variation of the lead content was recognized in the 24-hour urinary excretion after the injection of CaEDTA. No sexual difference was noted in the creatinine-corrected lead concentration. By multiple linear regression and correlation analyses, age was found to be significant in determining positively the lead level mobilized in 24-hour urine samples. Height was significant in determining positively the spontaneous 24-hour urinary lead excretion. Certain significant correlations existed among lead in blood, delta-aminolevulinic acid dehydratase in erythrocytes, delta-aminolevulinic acid in urine, coproporphyrin in urine, lead in urine, and lead mobilized by CaEDTA. The existence of active body burden of lead was suggested in human subjects under usual urban conditions where the total ambient lead concentration averaged 1.7 micrograms/cm m of air. Based on a few assumptions, it was calculated that about 3 micrograms of lead was retained on the average per day by a Japanese adult. Daily retention of lead by Japanese adults was formularized as lead in micrograms equals a constant (K) times daily creatinine excretion in grams, where K is 1.77 in men and 2.73 in women. (Air Pollut. Abstr.)

Environmental lead hazard to children.

Science.gov (United States)

Mittal, S K

1992-01-01

Clinically evident lead poisoning is rare in Indian children but is more common than in adults. In children, lead poisoning may appear as fever, seizures, anemia, or abdominal pain, while in adults it is more likely to manifest as chronic minor peripheral neuropathy or gum pigmentation. Children with acute lead poisoning can be treated with chelators such as EDTA and BAL, but many are left with permanent brain damage. The most common sources of acute lead poisoning in Indian children are inhalation of fumes from burned car batteries, ingestion of flaking paint, consuming food cooked in cheap aluminum or brass utensils, and eating contaminated soil. The sources of chronic lead poisoning are water from lead pipes and fumes from industrial or automotive exhaust. Another common source in India is application of "kajjal" to children's eyes. Sources of lead in Western countries, such as drinking water, canned food, residential paint, automotive fuel, and ambient air quality, are regulated by law. None of these are regulated in India.

Levels and source apportionment of children's lead exposure: Could urinary lead be used to identify the levels and sources of children's lead pollution?

International Nuclear Information System (INIS)

Cao, Suzhen; Duan, Xiaoli; Zhao, Xiuge; Wang, Beibei; Ma, Jin; Fan, Delong; Sun, Chengye; He, Bin; Wei, Fusheng; Jiang, Guibin

2015-01-01

As a highly toxic heavy metal, the pollution and exposure risks of lead are of widespread concern for human health. However, the collection of blood samples for use as an indicator of lead pollution is not always feasible in most cohort or longitudinal studies, especially those involving children health. To evaluate the potential use of urinary lead as an indicator of exposure levels and source apportionment, accompanying with environmental media samples, lead concentrations and isotopic measurements (expressed as 207 Pb/ 206 Pb, 208 Pb/ 206 Pb and 204 Pb/ 206 Pb) were investigated and compared between blood and urine from children living in the vicinities of a typical coking plant and lead-acid battery factory. The results showed urinary lead might not be a preferable proxy for estimating blood lead levels. Fortunately, urinary lead isotopic measurements could be used as an alternative for identifying the sources of children's lead exposure, which coincided well with the blood lead isotope ratio analysis. - Highlights: • Pb isotopes of environmental media and children's blood and urine were analyzed. • Pb exposure and pollution source were studied in lead-acid battery and coking areas. • Pb isotope ratios in blood and urine were similar to those of food, water and PM. • Urine Pb level may not be used as a proxy for indicating the lead levels in blood. • Urine Pb isotope ratios is an alternative to identify source and exposure pathways. - Urinary lead is not a preferable proxy to estimate blood lead level, but urinary lead isotope ratios could be an alternative for identifying the sources of lead exposure in children

Neurological aspects of lead intoxication

Energy Technology Data Exchange (ETDEWEB)

Lehner, H

1980-05-08

This study gives a survey over the medical and scientific literature on lead intoxications, which were published until 1979. Neurologic aspects are of particular interest. At present dramatic cases of lead intoxications occur only rarely. However, there are numerous studies about cases of chronical, partly subclinical intoxications. This chronical type of lead intoxication can become manifest clinically as relatively vague symptoms, for example vertigos, insomnia, headaches and weakness. Contrary to this, serious encephalopathies, even with fatal outcome, and polyneuropathies with typical paresis of the radial nerve are preferably observed in acute lead intoxications. Besides the numerous sources of intoxication, also the different opinions found in literature are discussed, concerning the effects of lead on the human body. The fact that there are differing opinions about the limiting value of the blood-lead level at which intoxication symptoms have to be expected, becomes apparent when the determined blood-lead level values are compared and evaluated. Besides the description of general intoxication effects, the discussion of the neurologic aspects found in literature - not only those concerning the central, but also the peripheral system - are preferably concerned. Reports about neuropsychical alterations due to lead exposure, which are mainly found in children, supplement the numerous descriptions of the macroscopic and microscopic alterations of the nervous system provoked by lead. Finally the therapeutic and prophylactic measures given in the literature are discussed.

Monetary benefits of preventing childhood lead poisoning with lead-safe window replacement.

Science.gov (United States)

Nevin, Rick; Jacobs, David E; Berg, Michael; Cohen, Jonathan

2008-03-01

Previous estimates of childhood lead poisoning prevention benefits have quantified the present value of some health benefits, but not the costs of lead paint hazard control or the benefits associated with housing and energy markets. Because older housing with lead paint constitutes the main exposure source today in the US, we quantify health benefits, costs, market value benefits, energy savings, and net economic benefits of lead-safe window replacement (which includes paint stabilization and other measures). The benefit per resident child from improved lifetime earnings alone is $21,195 in pre-1940 housing and $8685 in 1940-59 housing (in 2005 dollars). Annual energy savings are $130-486 per housing unit, with or without young resident children, with an associated increase in housing market value of $5900-14,300 per housing unit, depending on home size and number of windows replaced. Net benefits are $4490-5,629 for each housing unit built before 1940, and $491-1629 for each unit built from 1940-1959, depending on home size and number of windows replaced. Lead-safe window replacement in all pre-1960 US housing would yield net benefits of at least $67 billion, which does not include many other benefits. These other benefits, which are shown in this paper, include avoided Attention Deficit Hyperactivity Disorder, other medical costs of childhood lead exposure, avoided special education, and reduced crime and juvenile delinquency in later life. In addition, such a window replacement effort would reduce peak demand for electricity, carbon emissions from power plants, and associated long-term costs of climate change.

Characterization of sources of lead in the urban air of Asia using ratios of stable lead isotopes

Energy Technology Data Exchange (ETDEWEB)

Mukai, H.; Furuta, N.; Fujii, T.; Ambe, Y.; Sakamoto, K.; Hashimoto, Y. (National Institute of Environmental Studies, Tsukuba (Japan). Environmental Chemistry Division)

1993-07-01

Airborne particulate matter was collected at urban sites in six Asian countries (Japan, South Korea, China, Thailand, Sri Lanka, and Indonesia), and the stable lead isotope ratios were measured. Some source-related materials, such as coal and leaded gasoline, were also analyzed and compared to the ratios observed in airborne lead. Airborne lead isotope ratios differed considerably from each other, and these differences corresponded to differences in the regional source of lead. Leaded gasoline was still the primary source of lead in some cities in Asia, and the lead isotope ratios were strongly influenced by those of leaded gasoline. In Chinese and Korean cities, however, the considerable effect from coal combustion and industrial activity was also observed in their isotope ratios, despite leaded gasoline use. On the other hand, only refuse incineration was a possible single source of lead in Japanese air from the view of lead isotope ratios. 49 refs., 13 figs., 3 tabs.

Australian atmospheric lead deposition reconstructed using lead concentrations and isotopic compositions of archival lichen and fungi

International Nuclear Information System (INIS)

Wu, Liqin; Taylor, Mark Patrick; Handley, Heather K.; Wu, Michael

2016-01-01

Lead concentrations and their isotopic compositions were measured in lichen genera Cladonia and Usnea and fungi genus Trametes from the Greater Sydney region (New South Wales, Australia) that had been collected and archived over the past 120 years. The median lead concentrations were elevated in lichens and fungi prior to the introduction of leaded petrol (Cladonia 12.5 mg/kg; Usnea 15.6 mg/kg; Trametes 1.85 mg/kg) corresponding to early industrial development. During the period of leaded petrol use in Australian automobiles from 1932 to 2002, total median lead concentrations rose: Cladonia 18.8 mg/kg; Usnea 21.5 mg/kg; Trametes 4.3 mg/kg. Following the cessation of leaded petrol use, median total lead concentrations decreased sharply in the 2000s: Cladonia 4.8 mg/kg; Usnea 1.7 mg/kg. The lichen and fungi isotopic compositions reveal a significant decrease in "2"0"6Pb/"2"0"7Pb ratios from the end of 19th century to the 1970s. The following decades were characterised by lower allowable levels of lead additive in fuel and the introduction of unleaded petrol in 1985. The environmental response to these regulatory changes was that lichen and fungi "2"0"6Pb/"2"0"7Pb ratios increased, particularly from 1995 onwards. Although the lead isotope ratios of lichens continued to increase in the 2000s they do not return to pre-leaded petrol values. This demonstrates that historic leaded petrol emissions, inter alia other sources, remain a persistent source of anthropogenic contamination in the Greater Sydney region. - Highlights: • Total lead and isotopic composition can be measured in historic lichen and fungi. • Historic lichen and fungi samples can distinguish polluted and unpolluted areas. • Former leaded petrol depositions remain a significant environmental contaminant. - Analysis of a 120-year record of lichens and fungi from the Greater Sydney basin reveal marked shifts in total lead concentrations and lead isotope ratios in response to geogenic inputs

Current leads for superconducting magnets

International Nuclear Information System (INIS)

Ishibashi, Kenji

1989-01-01

Current leads for superconducting magnets have been studied since 1960's. The technology of current leads may seem to have been established both in theory and experiment before the middle of 1970's. Nevertheless, a wide variety of superconducting magnets have been introduced in the last 15 years, and the demands for special current leads have increased in accordance to the variety. A steady advance has been made in the design theory and fabrication of current leads. This paper describes the recent current lead technology regarding the design theory, safety in accidents, and high current capability. (author)

Assessment of the body burden of chelatable lead: a model and its application to lead workers

Energy Technology Data Exchange (ETDEWEB)

Araki, S.; Ushio, K.

1982-05-01

A hypothetical model was introduced to estimate the body burden of chelatable lead from the mobilisation yield of lead by calcium disodium ethylenediamine tetra-acetate. It was estimated that, on average, 14 and 19% of the body burden was mobilized into the urine during the 24 hours after an injection of 53.4 mumol and 107 mumol CaEDTA per kg bodyweight, respectively. The body burden of chelatable lead ranged from 4 mumol to 120 mumol in lead workers with blood lead concentrations of 0.3-2.9 mumol/kg. There were linear relationships between blood lead concentrations and body burden of chelatable lead on a log scale.

Lead contamination of inexpensive plastic jewelry

Energy Technology Data Exchange (ETDEWEB)

Yost, Jamie L. [Department of Chemistry, Ashland University, Ashland, Ohio (United States); Weidenhamer, Jeffrey D. [Department of Chemistry, Ashland University, Ashland, Ohio (United States)], E-mail: jweiden@ashland.edu

2008-04-15

The neurological hazards of lead to children are well-known. As a result of recent documented cases of lead poisoning, regulatory attention in the United States has focused on the lead content of children's metal jewelry. By contrast, little is known about the possible hazards of plastic jewelry items. The objective of this study was to determine whether inexpensive plastic jewelry is a possible source of toxic lead for children. Samples of more than 100 inexpensive plastic jewelry items were analyzed for lead content. Beads were screened by soaking in 1 M nitric acid. Nine items found to release more than 30 {mu}g of lead per bead were further tested for accessible lead, and scrapings of the bead coatings were analyzed for total lead content. The maximum accessible lead found was 49 {mu}g per bead, which is below the current US Consumer Product Safety Commission limit of 175 {mu}g. However, when the number of beads in each item was taken into account, six of the nine leaded samples contained more than 175 {mu}g accessible lead per item. The lead in these items appears to be associated with lead-based paints used to produce glossy coatings on imitation pearls and similar items. Coatings obtained by scraping individual beads contained 3.5-23% lead, which far exceeds the US regulatory limit of 0.06% lead in paints on items intended for children. Our results demonstrate that plastic jewelry items merit the attention of public health and consumer protection agencies seeking to limit the exposure of children to lead.

Lead contamination of inexpensive plastic jewelry

International Nuclear Information System (INIS)

Yost, Jamie L.; Weidenhamer, Jeffrey D.

2008-01-01

The neurological hazards of lead to children are well-known. As a result of recent documented cases of lead poisoning, regulatory attention in the United States has focused on the lead content of children's metal jewelry. By contrast, little is known about the possible hazards of plastic jewelry items. The objective of this study was to determine whether inexpensive plastic jewelry is a possible source of toxic lead for children. Samples of more than 100 inexpensive plastic jewelry items were analyzed for lead content. Beads were screened by soaking in 1 M nitric acid. Nine items found to release more than 30 μg of lead per bead were further tested for accessible lead, and scrapings of the bead coatings were analyzed for total lead content. The maximum accessible lead found was 49 μg per bead, which is below the current US Consumer Product Safety Commission limit of 175 μg. However, when the number of beads in each item was taken into account, six of the nine leaded samples contained more than 175 μg accessible lead per item. The lead in these items appears to be associated with lead-based paints used to produce glossy coatings on imitation pearls and similar items. Coatings obtained by scraping individual beads contained 3.5-23% lead, which far exceeds the US regulatory limit of 0.06% lead in paints on items intended for children. Our results demonstrate that plastic jewelry items merit the attention of public health and consumer protection agencies seeking to limit the exposure of children to lead

Lead transfer in maternal milk, and the absorption, retention, distribution and excretion of lead in suckling mice

Energy Technology Data Exchange (ETDEWEB)

Keller, Charles Arthur [Univ. of Rochester, NY (United States). Dept. of Radiation Biology and Biophysics

1980-01-01

Suckling mice were found to absorb and retain a greater fraction of an oral lead dose than did adult mice. Pinocytotic activity and lead uptake (in vivo) were found to be greatest in the distal small intestinal tissue. Cortisone pretreatment results in precocious cessation of pinocytotic activity in the intestine of suckling mice. Cortisone pretreatment of adult mice had no effect on whole body lead retention or intestinal tissue content of lead following an oral dose. The data indicate that the distal small intestine is the site of active pinocytosis of lead, and that pinocytosis is the major mechanism involved in lead absorption in suckling mice. Developmental differences were also observed in the percentage of lead retained in the whole body. Both groups exhibited dose-independent lead retention, indicating a first-order absorption process for each age group. Lead distribution and elimination from organs also differed between suckling and adult mice. Developmental differences were observed in organ lead concentration for kidneys and brain following oral doses. Relative distribution of lead to the brains of suckling mice were greater than to adult brains. Whole body and bone lead elimination rates were reduced in suckling compared to adult mice. Brain lead elimination rates did not differ in suckling and adult mice. A lactating mouse model was developed to study lead transfer to suckling offspring. Lead was transferred in milk to suckling offspring from mothers which had previously ingested lead in the drinking water. Relative lead transfer to suckled offspring during lactation greatly exceeded transfer to fetuses during gestation. Lactation resulted in an increased rate of maternal lead elimination. Lead concentration in milk exceeded plasma concentration by a factor of approximately 25. (ERB)

Blood lead levels among rural Thai children exposed to lead-acid batteries from solar energy conversion systems.

Science.gov (United States)

Swaddiwudhipong, Witaya; Tontiwattanasap, Worawit; Khunyotying, Wanlee; Sanreun, Cherd

2013-11-01

We evaluate blood lead levels among Thai children to determine if exposure to lead-acid batteries is associated with elevated blood lead levels (EBLL). We screened 254 children aged 1-14 years old from 2 rural Thai villages for blood lead levels. We also screened 18 of 92 houses in these 2 villages for the presence of environmental lead. The overall prevalence of EBLL (> or = 10 microg/dl) was 43.3% and the mean lead level among study subjects was 9.8 +/- 5.1 microg/dl. The blood lead levels significantly decreased with increasing age. Fifty point eight percent of children who lived in a house with vented lead-acid batteries had EBLL while 23.3% of children who lived in a house without vented lead-acid batteries had EBLL. Multiple logistic regression analysis revealed a significant positive association between the presence of vented lead-acid batteries and EBLL, after adjusting for other variables. Forty-two point nine percent of house floor dust samples collected near the batteries had elevated lead levels, 7.1% of house floor dust samples collected from other areas in the house had elevated lead levels and 0% of the house floor dust samples collected in houses without vented lead-acid batteries had elevated lead levels. In the sampled houses with vented lead-acid batteries, lead contamination was found in the drinking-water kept in household containers, but not in the tap water or other village sources of water. Improper care and placement of vented lead-acid batteries can result in lead contamination in the home environment causing EBLL in exposed children.

MicroRNA-Attenuated Clone of Virulent Semliki Forest Virus Overcomes Antiviral Type I Interferon in Resistant Mouse CT-2A Glioma.

Science.gov (United States)

Martikainen, Miika; Niittykoski, Minna; von und zu Fraunberg, Mikael; Immonen, Arto; Koponen, Susanna; van Geenen, Maartje; Vähä-Koskela, Markus; Ylösmäki, Erkko; Jääskeläinen, Juha E; Saksela, Kalle; Hinkkanen, Ari

2015-10-01

Glioblastoma is a terminal disease with no effective treatment currently available. Among the new therapy candidates are oncolytic viruses capable of selectively replicating in cancer cells, causing tumor lysis and inducing adaptive immune responses against the tumor. However, tumor antiviral responses, primarily mediated by type I interferon (IFN-I), remain a key problem that severely restricts viral replication and oncolysis. We show here that the Semliki Forest virus (SFV) strain SFV4, which causes lethal encephalitis in mice, is able to infect and replicate independent of the IFN-I defense in mouse glioblastoma cells and cell lines originating from primary human glioblastoma patient samples. The ability to tolerate IFN-I was retained in SFV4-miRT124 cells, a derivative cell line of strain SFV4 with a restricted capacity to replicate in neurons due to insertion of target sites for neuronal microRNA 124. The IFN-I tolerance was associated with the viral nsp3-nsp4 gene region and distinct from the genetic loci responsible for SFV neurovirulence. In contrast to the naturally attenuated strain SFV A7(74) and its derivatives, SFV4-miRT124 displayed increased oncolytic potency in CT-2A murine astrocytoma cells and in the human glioblastoma cell lines pretreated with IFN-I. Following a single intraperitoneal injection of SFV4-miRT124 into C57BL/6 mice bearing CT-2A orthotopic gliomas, the virus homed to the brain and was amplified in the tumor, resulting in significant tumor growth inhibition and improved survival. Although progress has been made in development of replicative oncolytic viruses, information regarding their overall therapeutic potency in a clinical setting is still lacking. This could be at least partially dependent on the IFN-I sensitivity of the viruses used. Here, we show that the conditionally replicating SFV4-miRT124 virus shares the IFN-I tolerance of the pathogenic wild-type SFV, thereby allowing efficient targeting of a glioma that is refractory

Spent lead-acid battery recycling in China - A review and sustainable analyses on mass flow of lead.

Science.gov (United States)

Sun, Zhi; Cao, Hongbin; Zhang, Xihua; Lin, Xiao; Zheng, Wenwen; Cao, Guoqing; Sun, Yong; Zhang, Yi

2017-06-01

Lead is classified to be one of the top heavy metal pollutants in China. The corresponding environmental issues especially during the management of spent lead-acid battery have already caused significant public awareness and concern. This research gives a brief overview on the recycling situation based on an investigation of the lead industry in China and also the development of technologies for spent lead-acid batteries. The main principles and research focuses of different technologies including pyrometallurgy, hydrometallurgy and greener technologies are summarized and compared. Subsequently, the circulability of lead based on the entire life cycle analyses of lead-acid battery is calculated. By considering different recycling schemes, the recycling situation of spent lead-acid battery in China can be understood semi-quantitatively. According to this research, 30% of the primary lead production can be shut down that the lead production can still ensure consecutive life cycle operation of lead-acid battery, if proper management of the spent lead-acid battery is implemented according to current lead industry situation in China. This research provides a methodology on the view of lead circulability in the whole life cycle of a specific product and is aiming to contribute more quantitative guidelines for efficient organization of lead industry in China. Copyright © 2017 Elsevier Ltd. All rights reserved.

Childhood lead exposure and uptake in teeth in the Cleveland area during the era of leaded gasoline

International Nuclear Information System (INIS)

Robbins, Norman; Zhang, Zhong-Fa; Sun, Jiayang; Ketterer, Michael E.; Lalumandier, James A.; Shulze, Richard A.

2010-01-01

Childhood uptake of lead from exposure to atmospheric leaded gasoline in the United States has been studied using mainly blood lead levels. Since reliable blood lead techniques were used only after the peak use of leaded gasoline, the prior exposure history is unclear. The well-documented decline in blood lead levels after the mid-1970s could represent the continuation of a historic steady decline in exposure from many sources. Alternatively, the post-1970s decline might represent the declining phase of a unimodal rise and fall corresponding closely to usage of leaded gasoline. To assess these possibilities, lead concentration and 207Pb/206Pb isotope ratios were measured in the enamel of permanent molar teeth formed between 1936 and 1993 in mainly African-American donors who grew up in the Cleveland area. Tooth enamel preserves the lead concentration and isotope ratio that prevails during tooth formation. Historical trends in enamel lead concentration were significantly correlated with surrogates of atmospheric lead exposure: lead in sediments of two dated Lake Erie cores, and lead consumed in gasoline. About two-thirds of the total lead uptake into enamel in this period was attributable to leaded gasoline, and the remainder to other sources (e.g. paint). Enamel 207Pb/206Pb isotope ratios were similar to those of one lake sediment. Multivariate analysis revealed significant correlation in neighborhoods with higher levels of traffic, and including lake sediment data, accounted for 53% of the variation in enamel lead levels. Enamel lead concentration was highly correlated with reported African-American childhood blood levels. The extrapolated peak level of 48 μg/dL (range 40 to 63) is associated with clinical and behavioral impairments, which may have implications for adults who were children during the peak gasoline lead exposure. In sum, leaded gasoline emission was the predominant source of lead exposure of African-American Cleveland children during the latter

Ingestion of lead from ammunition and lead concentrations in white-tailed sea eagles (Haliaeetus albicilla) in Sweden

Energy Technology Data Exchange (ETDEWEB)

Helander, B., E-mail: bjorn.helander@nrm.se [Department of Contaminant Research, Swedish Museum of Natural History, Box 50007, SE-104 05 Stockholm (Sweden); Axelsson, J., E-mail: jeanette.axelsson@hgen.slu.se [Department of Environmental Toxicology, Evolutionary Biology Centre, Uppsala University, SE-752 36 Uppsala (Sweden); Borg, H., E-mail: hans.borg@itm.su.se [Department of Applied Environmental Science/ITM, Stockholm University, SE-106 91 Stockholm (Sweden); Holm, K. [Department of Applied Environmental Science/ITM, Stockholm University, SE-106 91 Stockholm (Sweden); Bignert, A., E-mail: anders.bignert@nrm.se [Department of Contaminant Research, Swedish Museum of Natural History, Box 50007, SE-104 05 Stockholm (Sweden)

2009-10-15

In this study we show for the first time that lead poisoning from ammunition is a significant mortality factor for white-tailed sea eagle (WSE) (Haliaeetus albicilla) in Sweden. We analyzed 118 WSEs collected between 1981 and 2004 from which both liver and kidney samples could be taken. A total of 22% of all eagles examined had elevated (> 6 {mu}g/g d.w.) lead concentrations, indicating exposure to leaded ammunition, and 14% of the individuals had either liver or kidney lead concentrations diagnostic of lethal lead poisoning (> 20 {mu}g/g d.w.). Lead concentrations in liver and kidney were significantly correlated. In individuals with lead levels < 6 {mu}g/g, concentrations were significantly higher in kidney than in liver; in individuals with lead levels > 20 {mu}g/g, concentrations were significantly higher in liver. The lead isotope ratios indicate that the source of lead in individuals with lethal concentrations is different from that of individuals exhibiting background concentrations of lead (< 6 {mu}g/g d.w.) There were no significant sex or age differences in lead concentrations. A study from the Baltic reported in principle no biomagnification of lead, but background lead concentrations in WSE liver in this study were still four to > 10 times higher than concentrations reported for Baltic fish from the same time period. In contrast to other biota there was no decrease in lead concentrations in WSE over the study period. The proportion of lead poisoned WSE remained unchanged over the study period, including two years after a partial ban of lead shot was enforced in 2002 for shallow wetlands. The use of lead in ammunition poses a threat to all raptors potentially feeding on shot game or offal. The removal of offal from shot game and alternatives to leaded ammunition needs to be implemented in order to prevent mortality from lead in raptors and scavengers.

Blood lead levels and risk factors for lead poisoning among children in Jakarta, Indonesia

Energy Technology Data Exchange (ETDEWEB)

Albalak, Rachel; Noonan, Gary; Buchanan, Sharunda; Flanders, W. Dana; Gotway-Crawford, Carol; Blumenthal, Wendy; Curtis, Gerald; McGeehin, Michael A. [Division of Environmental Hazards and Health Effects, National Center for Environmental Health, Centers for Disease Control and Prevention, 1600 Clifton Rd. Mailstop E-19, Atlanta, GA 30333 (United States); Kim, Dennis; Tan, Regina [Epidemic Intelligence Service, Epidemiology Program Office, Centers for Disease Control and Prevention, 1600 Clifton Rd. Mailstop D-18, Atlanta, GA 30333 (United States); Jones, Robert L. [Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, 1600 Clifton Rd. Mailstop F-18, Atlanta, GA 30333 (United States); Sulaiman, Rini [Swisscontact, Jl. Wijaya XII No. 44, Jakarta (Indonesia) 12160

2003-01-01

The phase-out of leaded gasoline began in Jakarta, Indonesia on July 1, 2001. We evaluated mean blood lead levels (BLLs) and the prevalence of elevated BLLs of Jakarta school children and assessed risk factors for lead exposure in these children before the beginning of the phase-out activities. The study involved a population-based, cross-sectional blood lead survey that included capillary blood lead sampling and a brief questionnaire on risk factors for lead poisoning. A cluster survey design was used. Forty clusters, defined as primary schools in Jakarta, and 15 2nd- and 3rd-grade children in each cluster were randomly selected for participation in the study. The average age of children in this study was 8.6 years (range 6-12) and the geometric mean BLL of the children was 8.6 {mu}g/dl (median: 8.6 {mu}g/dl; range: 2.6-24.1 {mu}g/dl) (n=397). Thirty-five percent of children had BLLs {>=}10 {mu}g/dl and 2.4% had BLLs {>=}20 {mu}g/dl. Approximately one-fourth of children had BLLs 10-14.9 {mu}g/dl. In multivariate models, level of education of the child's primary caregiver, water collection method, home varnishing and occupational recycling of metals, other than lead, by a family member were predictors of log BLLs after adjustment for age and sex. BLLs of children who lived near a highway or major intersection were significantly higher than those of children who lived near a street with little or no traffic when level of education was not included in the model. Water collection method was a significant predictor of BLLs {>=}10 {mu}g/dl after adjustment for age and sex. BLLs in children in this study were moderately high and consistent with BLLs of children in other countries where leaded gasoline is used. With the phase-out of leaded gasoline, BLLs of children in Jakarta are expected to rapidly decline as they have in other countries that have phased lead out of gasoline.

Some Interesting Events from Lead-Lead Collisions in ATLAS at the LHC (individual captions in abstract)

CERN Multimedia

The ATLAS Experiment, ATLAS, First collisions, Splash events

2010-01-01

Image Captions CERN-EX-1011310 01 -- Event display of a highly asymmetric dijet event, with one jet with ET > 100 GeV and no evident recoiling jet, recorded by ATLAS in LHC lead-lead collisions. CERN-EX-1011310 02 -- Event display of a highly asymmetric dijet event, with one jet with ET > 100 GeV and no evident recoiling jet, recorded by ATLAS in LHC lead-lead collisions. CERN-EX-1011310 03 -- Event display of a highly asymmetric dijet event, with one jet with ET > 100 GeV and no evident recoiling jet, recorded by ATLAS in LHC lead-lead collisions. CERN-EX-1011310 04 -- LHC lead-lead collisions recorded by ATLAS with a candidate Z to μ+μ- decay. The two muons shown in purple are the candidates to originate from the Z decay. The transverse momenta of these two muons are 44 and 45 GeV, and the invariant mass of the dimuon system is 93 GeV. CERN-EX-1011310 05 -- LHC lead-lead collisions recorded by ATLAS with a candidate Z to μ+μ- decay. The two muons shown in red are the candidates to originate from the...

Lead Thickness Measurements

International Nuclear Information System (INIS)

Rucinski, R.

1998-01-01

The preshower lead thickness applied to the outside of D-Zero's superconducting solenoid vacuum shell was measured at the time of application. This engineering documents those thickness measurements. The lead was ordered in sheets 0.09375-inch and 0.0625-inch thick. The tolerance on thickness was specified to be +/- 0.003-inch. The sheets all were within that thickness tolerance. The nomenclature for each sheet was designated 1T, 1B, 2T, 2B where the numeral designates it's location in the wrap and 'T' or 'B' is short for 'top' or 'bottom' half of the solenoid. Micrometer measurements were taken at six locations around the perimeter of each sheet. The width,length, and weight of each piece was then measured. Using an assumed pure lead density of 0.40974 lb/in 3 , an average sheet thickness was calculated and compared to the perimeter thickness measurements. In every case, the calculated average thickness was a few mils thinner than the perimeter measurements. The ratio was constant, 0.98. This discrepancy is likely due to the assumed pure lead density. It is not felt that the perimeter is thicker than the center regions. The data suggests that the physical thickness of the sheets is uniform to +/- 0.0015-inch.

Radiation shielding lead shield

International Nuclear Information System (INIS)

Dei, Shoichi.

1991-01-01

The present invention concerns lead shields for radiation shielding. Shield boxes are disposed so as to surround a pipeline through which radioactive liquids, mists or like other objects are passed. Flanges are formed to each of the end edges of the shield boxes and the shield boxes are connected to each other by the flanges. Upon installation, empty shield boxes not charged with lead particles and iron plate shields are secured at first at the periphery of the pipeline. Then, lead particles are charged into the shield boxes. This attains a state as if lead plate corresponding to the depth of the box is disposed. Accordingly, operations for installation, dismantling and restoration can be conducted in an empty state with reduced weight to facilitate the operations. (I.S.)

Presence of lead in opium.

Science.gov (United States)

Aghaee-Afshar, Mahmoud; Khazaeli, Payam; Behnam, Behzad; Rezazadehkermani, Mohammad; Ashraf-Ganjooei, Narges

2008-09-01

Opium addiction is a common form of addiction in Middle East countries such as Iran. Recently several reports suggested some kinds of pathologic findings such as abdominal pain, nephropathy, and anemia in opium addict patients. Such pathologic findings suggest lead poisoning in the patients. In this study, the concentration of lead in 10 opium samples was evaluated. The mean concentration of lead in the opium samples was 1.88 ppm. This may explain some of the pathologic findings found in addict patients. The authors would suggest further investigations to evaluate the lead concentration in opium addicts' sera and also routine screening for lead poisoning in opium addict patients.

Ingestion of lead from ammunition and lead concentrations in white-tailed sea eagles (Haliaeetus albicilla) in Sweden

International Nuclear Information System (INIS)

Helander, B.; Axelsson, J.; Borg, H.; Holm, K.; Bignert, A.

2009-01-01

In this study we show for the first time that lead poisoning from ammunition is a significant mortality factor for white-tailed sea eagle (WSE) (Haliaeetus albicilla) in Sweden. We analyzed 118 WSEs collected between 1981 and 2004 from which both liver and kidney samples could be taken. A total of 22% of all eagles examined had elevated (> 6 μg/g d.w.) lead concentrations, indicating exposure to leaded ammunition, and 14% of the individuals had either liver or kidney lead concentrations diagnostic of lethal lead poisoning (> 20 μg/g d.w.). Lead concentrations in liver and kidney were significantly correlated. In individuals with lead levels 20 μg/g, concentrations were significantly higher in liver. The lead isotope ratios indicate that the source of lead in individuals with lethal concentrations is different from that of individuals exhibiting background concentrations of lead ( 10 times higher than concentrations reported for Baltic fish from the same time period. In contrast to other biota there was no decrease in lead concentrations in WSE over the study period. The proportion of lead poisoned WSE remained unchanged over the study period, including two years after a partial ban of lead shot was enforced in 2002 for shallow wetlands. The use of lead in ammunition poses a threat to all raptors potentially feeding on shot game or offal. The removal of offal from shot game and alternatives to leaded ammunition needs to be implemented in order to prevent mortality from lead in raptors and scavengers.

Lead-contaminated health food. Association with lead poisoning and leukemia

Energy Technology Data Exchange (ETDEWEB)

Crosby, W.H.

1977-06-13

A doctor prescribed a dietary supplement prepared from powdered animal bone for a young woman with dysmenorrhea. Severe lead poisoning developed while she was taking the powder, which was shown to be contaminated with lead. The diagnosis eluded more than 20 physicians and was finally made by the patient herself. The Food and Drug Administration, informed of the contamination, declined to take action, stating that a food supplement is neither a food nor a drug and, besides, there are no maximal limits for heavy-metal contamination of foods and drugs.

Lead poisoning in dogs

Energy Technology Data Exchange (ETDEWEB)

Wilson, M R; Lewis, G

1963-08-03

Within a short period, 14 cases of lead poisoning in the dogs have been encountered. A detailed record appears justified as no published reference can be found to this condition occurring in Britain and because reports from other countries stress the similarity of the clinical manifestations of lead poisoning to those of the common infections of the dog. Five of the 14 clinical cases of lead poisoning are described. The available literature is reviewed and the diagnosis and significance of the condition discussed. 19 references, 2 tables.

Mass lead intoxication from informal used lead-acid battery recycling in dakar, senegal.

Science.gov (United States)

Haefliger, Pascal; Mathieu-Nolf, Monique; Lociciro, Stephanie; Ndiaye, Cheikh; Coly, Malang; Diouf, Amadou; Faye, Absa Lam; Sow, Aminata; Tempowski, Joanna; Pronczuk, Jenny; Filipe Junior, Antonio Pedro; Bertollini, Roberto; Neira, Maria

2009-10-01

Between November 2007 and March 2008, 18 children died from a rapidly progressive central nervous system disease of unexplained origin in a community involved in the recycling of used lead-acid batteries (ULAB) in the suburbs of Dakar, Senegal. We investigated the cause of these deaths. Because autopsies were not possible, the investigation centered on clinical and laboratory assessments performed on 32 siblings of deceased children and 23 mothers and on 18 children and 8 adults living in the same area, complemented by environmental health investigations. All 81 individuals investigated were poisoned with lead, some of them severely. The blood lead level of the 50 children tested ranged from 39.8 to 613.9 microg/dL with a mean of 129.5 microg/dL. Seventeen children showed severe neurologic features of toxicity. Homes and soil in surrounding areas were heavily contaminated with lead (indoors, up to 14,000 mg/kg; outdoors, up to 302,000 mg/kg) as a result of informal ULAB recycling. Our investigations revealed a mass lead intoxication that occurred through inhalation and ingestion of soil and dust heavily contaminated with lead as a result of informal and unsafe ULAB recycling. Circumstantial evidence suggested that most or all of the 18 deaths were due to encephalopathy resulting from severe lead intoxication. Findings also suggest that most habitants of the contaminated area, estimated at 950, are also likely to be poisoned. This highlights the severe health risks posed by informal ULAB recycling, in particular in developing countries, and emphasizes the need to strengthen national and international efforts to address this global public health problem.

A study on lead equivalent

International Nuclear Information System (INIS)

Lin Guanxin