Publications by authors named "Luke Russell"

24 Publications

  • Page 1 of 1

Characteristics and comparative clinical outcomes of prisoner versus non-prisoner populations hospitalized with COVID-19.

Sci Rep 2021 03 22;11(1):6488. Epub 2021 Mar 22.

Department of Internal Medicine, Henry Ford Allegiance Hospital, Henry Ford Health System, 205 N East Ave, Jackson, MI, 49201, USA.

Prisons in the United States have become a hotbed for spreading COVID-19 among incarcerated individuals. COVID-19 cases among prisoners are on the rise, with more than 143,000 confirmed cases to date. However, there is paucity of data addressing clinical outcomes and mortality in prisoners hospitalized with COVID-19. An observational study of all patients hospitalized with COVID-19 between March 10 and May 10, 2020 at two Henry Ford Health System hospitals in Michigan. Clinical outcomes were compared amongst hospitalized prisoners and non-prisoner patients. The primary outcomes were intubation rates, in-hospital mortality, and 30-day mortality. Multivariable logistic regression and Cox-regression models were used to investigate primary outcomes. Of the 706 hospitalized COVID-19 patients (mean age 66.7 ± 16.1 years, 57% males, and 44% black), 108 were prisoners and 598 were non-prisoners. Compared to non-prisoners, prisoners were more likely to present with fever, tachypnea, hypoxemia, and markedly elevated inflammatory markers. Prisoners were more commonly admitted to the intensive care unit (ICU) (26.9% vs. 18.7%), required vasopressors (24.1% vs. 9.9%), and intubated (25.0% vs. 15.2%). Prisoners had higher unadjusted inpatient mortality (29.6% vs. 20.1%) and 30-day mortality (34.3% vs. 24.6%). In the adjusted models, prisoner status was associated with higher in-hospital death (odds ratio, 2.32; 95% confidence interval (CI), 1.33 to 4.05) and 30-day mortality (hazard ratio, 2.00; 95% CI, 1.33 to 3.00). In this cohort of hospitalized COVID-19 patients, prisoner status was associated with more severe clinical presentation, higher rates of ICU admissions, vasopressors requirement, intubation, in-hospital mortality, and 30-day mortality.
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http://dx.doi.org/10.1038/s41598-021-85916-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985211PMC
March 2021

Oncolytic herpes simplex virus infects myeloma cells and .

Mol Ther Oncolytics 2021 Mar 18;20:519-531. Epub 2021 Feb 18.

Department of Hematology and Hematopoietic Cell Transplantation, Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Monrovia, CA 91016, USA.

Because most patients with multiple myeloma (MM) develop resistance to current regimens, novel approaches are needed. Genetically modified, replication-competent oncolytic viruses exhibit high tropism for tumor cells regardless of cancer stage and prior treatment. Receptors of oncolytic herpes simplex virus 1 (oHSV-1), NECTIN-1, and HVEM are expressed on MM cells, prompting us to investigate the use of oHSV-1 against MM. Using oHSV-1-expressing GFP, we found a dose-dependent increase in the GFP signal in MM cell lines and primary MM cells. Whereas NECTIN-1 expression is variable among MM cells, we discovered that HVEM is ubiquitously and highly expressed on all samples tested. Expression of HVEM was consistently higher on CD138/CD38 plasma cells than in non-plasma cells. HVEM blocking demonstrated the requirement of this receptor for infection. However, we observed that, although oHSV-1 could efficiently infect and kill all MM cell lines tested, no viral replication occurred. Instead, we identified that oHSV-1 induced MM cell apoptosis via caspase-3 cleavage. We further noted that oHSV-1 yielded a significant decrease in tumor volume in two mouse xenograft models. Therefore, oHSV-1 warrants exploration as a novel potentially effective treatment option in MM, and HVEM should be investigated as a possible therapeutic target.
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http://dx.doi.org/10.1016/j.omto.2021.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940704PMC
March 2021

College students' intentions to assist peers with chronic medical conditions.

J Am Coll Health 2020 Apr 28:1-8. Epub 2020 Apr 28.

Family and Consumer Sciences, Illinois State University, Normal, Illinois, USA.

This study identified influences on college students' intentions to assist peers with chronic medical conditions. A panel of 293 U.S. full-time college students completed online surveys in July, 2017. Participants reported the number of people they knew with chronic medical conditions, and completed measures of general empathy, stigma toward chronic conditions, self-efficacy to provide support, and expected likelihood of assisting a peer with a chronic medical condition. Path Analysis and mediation tests were performed. Low stigma, and high confidence in providing support were directly associated with intentions to assist student peers if needed. Empathy and number of people known with chronic conditions were additional indirect predictors. Peer support is important for students with chronic medical conditions. Intention to provide assistance if needed is partially explained by holding low stigma and high confidence in providing support, both of which may be enhanced through education and intervention.
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http://dx.doi.org/10.1080/07448481.2020.1751170DOI Listing
April 2020

Stromal Platelet-Derived Growth Factor Receptor-β Signaling Promotes Breast Cancer Metastasis in the Brain.

Cancer Res 2021 02 23;81(3):606-618. Epub 2020 Apr 23.

The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβ) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβ also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβ was observed within a subset of astrocytes, and aged mice expressing PDGFRβ exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβ in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRβ paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581545PMC
February 2021

Cellular models for discovering prion disease therapeutics: Progress and challenges.

J Neurochem 2020 04 3;153(2):150-172. Epub 2020 Feb 3.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.

Prions, which cause fatal neurodegenerative disorders such as Creutzfeldt-Jakob disease, are misfolded and infectious protein aggregates. Currently, there are no treatments available to halt or even delay the progression of prion disease in the brain. The infectious nature of prions has resulted in animal paradigms that accurately recapitulate all aspects of prion disease, and these have proven to be instrumental for testing the efficacy of candidate therapeutics. Nonetheless, infection of cultured cells with prions provides a much more powerful system for identifying molecules capable of interfering with prion propagation. Certain lines of cultured cells can be chronically infected with various types of mouse prions, and these models have been used to unearth candidate anti-prion drugs that are at least partially efficacious when administered to prion-infected rodents. However, these studies have also revealed that not all types of prions are equal, and that drugs active against mouse prions are not necessarily effective against prions from other species. Despite some recent progress, the number of cellular models available for studying non-mouse prions remains limited. In particular, human prions have proven to be particularly challenging to propagate in cultured cells, which has severely hindered the discovery of drugs for Creutzfeldt-Jakob disease. In this review, we summarize the cellular models that are presently available for discovering and testing drugs capable of blocking the propagation of prions and highlight challenges that remain on the path towards developing therapies for prion disease.
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http://dx.doi.org/10.1111/jnc.14956DOI Listing
April 2020

Oncolytic Viruses: Priming Time for Cancer Immunotherapy.

BioDrugs 2019 Oct;33(5):485-501

Vyriad Inc., 3605 US Highway 52 N, Building 110, Rochester, MN, 55901, USA.

New immuno-oncology therapies are improving cancer treatments beyond the former standard of care, as evidenced by the recent and continuing clinical approvals for immunotherapies in a broad range of indications. However, a majority of patients (particularly those with immunologically cold tumors) still do not benefit, highlighting the need for rational combination approaches. Oncolytic viruses (OV) both directly kill tumor cells and inflame the tumor microenvironment. While OV spread can be limited by the generation of antiviral immune responses, the initial local tumor cell killing can reverse the immunosuppressive tumor microenvironment, resulting in more effective release of tumor-associated antigens (TAAs), cross-presentation, and antitumoral effector T cell recruitment. Moreover, many OVs can be engineered to express immunomodulatory genes. Rational combination approaches to cancer immunotherapy include the use of OVs in combination with immune checkpoint inhibitors (ICIs) or adoptive T cell therapy (ACT) to promote sustained antitumoral immune responses. OV combinations have additive or synergistic efficacy in preclinical tumor models with ICIs or ACT. Several preclinical studies have confirmed systemic reactivation and proliferation of adoptively transferred antitumoral T cells in conjunction with oncolytic OVs (expressing cytokines or TAAs) resulting from the specific tumor cell killing and immunostimulation of the tumor microenvironment which leads to increased tumor trafficking, activity, and survival. Recent clinical trials combining OVs with ICIs have shown additive effects in melanoma. Additional clinical data in an expanded range of patient indications are eagerly awaited. The relative timings of OV and ICI combination remains under-studied and is an area for continued exploration. Studies systematically exploring the effects of systemic ICIs prior to, concomitantly with, or following OV therapy will aid in the future design of clinical trials to enhance efficacy and increase patient response rates.
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http://dx.doi.org/10.1007/s40259-019-00367-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790338PMC
October 2019

Stepfathers' affinity-seeking with stepchildren, stepfather-stepchild relationship quality, marital quality, and stepfamily cohesion among stepfathers and mothers.

J Fam Psychol 2019 Aug 14;33(5):521-531. Epub 2019 Mar 14.

Department of Human Development and Family Science.

Because of the potential stepparent-stepchild relationships have for tension and conflict, clinicians have identified the development of a positive stepparent-stepchild connection as one of the major tasks of stepfamily life. Stepparents often are advised to focus initially on developing friendships with stepchildren, or seeking affinity with them, particularly early in the life of the relationship. Both family systems theory and evolutionary theory suggest that stepparents' affinity-seeking behaviors are related to the quality and functioning of other stepfamily dyads, such as couple relationships, and the whole stepfamily. We extend prior work on stepparents' affinity seeking by including perceptions of both members of the stepcouple about affinity seeking, stepfather-stepchild conflicts, couple relationship quality, and stepfamily cohesion. Stepfathers and mothers from 234 stepcouples independently completed online surveys. After accounting for covariates (i.e., duration of mothers' previous relationships, duration of the stepcouple relationship, focal child's biological sex and age, number of children in the household, and mothers' report of household income), stepfathers' perceptions of affinity-seeking with the focal child significantly predicted both partners' perceptions of stepfather-stepchild conflict, marital quality, marital confidence, and stepfamily cohesion. Mothers' perceptions of stepfathers' affinity-seeking were significantly related to her marital confidence and perceptions of stepfamily cohesion. Stepfathers' perceptions of their affinity-seeking explained more variance in stepfathers' and mothers' outcomes than did mothers' perceptions. The results suggest benefits associated with stepfather affinity-seeking-less conflict with stepchildren, better couple relationships, and closer stepfamily ties. Our findings provide evidence for encouraging stepparents to focus on building affinity with stepchildren. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
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http://dx.doi.org/10.1037/fam0000518DOI Listing
August 2019

Suppression of HMGB1 Released in the Glioblastoma Tumor Microenvironment Reduces Tumoral Edema.

Mol Ther Oncolytics 2019 Mar 6;12:93-102. Epub 2018 Dec 6.

Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA.

HMGB1 is a ubiquitously expressed intracellular protein that binds DNA and transcription factors and regulates chromosomal structure and function. Under conditions of cell death or stress, it is actively or passively released by cells into the extracellular environment, where it functions as damage-associated molecular pattern (DAMP) that orchestrates pro-inflammatory cytokine release and inflammation. Our results demonstrate that HMGB1 is secreted in the tumor microenvironment after oncolytic HSV (oHSV) infection and . The impact of secreted HMGB1 on tumor growth and response to oncolytic viral therapy was evaluated by using HMGB1-blocking antibodies and in mice bearing intracranial tumors. IVIS and MRI imaging was utilized to visualize in real time virus spread, tumor growth, and changes in edema in mice. Our data showed that HMGB1 released in tumor microenvironment orchestrated increased vascular leakiness and edema. Further HMGB1 blocking antibodies rescued vascular leakiness and enhanced survival of intracranial glioma-bearing mice treated with oHSV.
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http://dx.doi.org/10.1016/j.omto.2018.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350213PMC
March 2019

PTEN expression by an oncolytic herpesvirus directs T-cell mediated tumor clearance.

Nat Commun 2018 11 27;9(1):5006. Epub 2018 Nov 27.

Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, 77030, TX, USA.

Engineered oncolytic viruses are used clinically to destroy cancer cells and have the ability to boost anticancer immunity. Phosphatase and tensin homolog deleted on chromosome 10 loss is common across a broad range of malignancies, and is implicated in immune escape. The N-terminally extended isoform, phosphatase and tensin homolog deleted on chromosome 10 alpha (PTENα), regulates cellular functions including protein kinase B signaling and mitochondrial adenosine triphosphate production. Here we constructed HSV-P10, a replicating, PTENα expressing oncolytic herpesvirus, and demonstrate that it inhibits PI3K/AKT signaling, increases cellular adenosine triphosphate secretion, and reduces programmed death-ligand 1 expression in infected tumor cells, thus priming an adaptive immune response and overcoming tumor immune escape. A single dose of HSV-P10 resulted in long term survivors in mice bearing intracranial tumors, priming anticancer T-cell immunity leading to tumor rejection. This implicates HSV-P10 as an oncolytic and immune stimulating therapeutic for anticancer therapy.
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http://dx.doi.org/10.1038/s41467-018-07344-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258708PMC
November 2018

An oncolytic herpesvirus expressing E-cadherin improves survival in mouse models of glioblastoma.

Nat Biotechnol 2018 Nov 26. Epub 2018 Nov 26.

Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA.

The efficacy of oncolytic herpes simplex virus (oHSV) is limited by rapid viral clearance by innate immune effector cells and poor intratumoral viral spread. We combine two approaches to overcome these barriers: inhibition of natural killer (NK) cells and enhancement of intratumoral viral spread. We engineered an oHSV to express CDH1, encoding E-cadherin, an adherent molecule and a ligand for KLRG1, an inhibitory receptor expressed on NK cells. In vitro, infection with this engineered virus, named OV-CDH1, induced high surface E-cadherin expression on infected glioblastoma (GBM) cells, which typically lack endogenous E-cadherin. Ectopically expressed E-cadherin enhanced the spread of OV-CDH1 by facilitating cell-to-cell infection and viral entry and reduced viral clearance by selectively protecting OV-CDH1-infected cells from KLRG1 NK cell killing. In vivo, OV-CDH1 treatment substantially prolonged the survival in GBM-bearing mouse models, primarily because of improved viral spread rather than inhibition of NK cell activity. Thus, virus-induced overexpression of E-cadherin may be a generalizable strategy for improving cancer virotherapy.
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http://dx.doi.org/10.1038/nbt.4302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535376PMC
November 2018

The emerging role of oncolytic virus therapy against cancer.

Chin Clin Oncol 2018 Apr;7(2):16

Mayo Clinic, Rochester, MN, USA.

This review discusses current clinical advancements in oncolytic viral therapy, with a focus on the viral platforms approved for clinical use and highlights the benefits each platform provides. Three oncolytic viruses (OVs), an echovirus, an adenovirus, and a herpes simplex-1 virus, have passed governmental regulatory approval in Latvia, China, and the USA and EU. Numerous other recombinant viruses from diverse families are in clinical testing in cancer patients and we highlight the design features of selected examples, including adenovirus, herpes simplex virus, measles virus, retrovirus, reovirus, vaccinia virus, vesicular stomatitis virus. Lastly, we provide thoughts on the path forward for this rapidly expanding field especially in combination with immune modulating drugs.
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http://dx.doi.org/10.21037/cco.2018.04.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557159PMC
April 2018

Family-Centered Care and Positive Developmental Outcomes for Youth With Special Health Care Needs: Variations Across Family Structures.

J Fam Nurs 2018 02 10;24(1):29-59. Epub 2018 Jan 10.

1 University of Missouri, Columbia, USA.

Drawing on a social determinants of health framework, we evaluated associations between perceived family-centered care (FCC) and positive developmental outcomes for youth with special health care needs across six different family structures (married biological families, cohabiting biological families, married stepfamilies, cohabiting stepfamilies, divorced/separated single-mother families, and never-married single-mother families). Using data from the 2011-2012 National Survey of Children's Health, we found that married biological families perceive greater FCC than do other family structures. Perceived FCC was positively associated with all three positive youth outcomes evaluated (children's health, participation in extracurricular activities, and flourishing) in married biological families, and two of the three outcomes (children's health and flourishing) in married stepfamilies and divorced/separated single-mother families. Implications for health care provision and future research with structurally diverse families are discussed.
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http://dx.doi.org/10.1177/1074840717745520DOI Listing
February 2018

Sex as a biological variable in response to temozolomide.

Neuro Oncol 2017 06;19(6):873-874

Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

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http://dx.doi.org/10.1093/neuonc/nox040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464457PMC
June 2017

Managing chronic conditions in college: Findings from prompted health incidents diaries.

J Am Coll Health 2017 Apr 2;65(3):217-222. Epub 2016 Dec 2.

a Department of Human Development and Family Science , University of Missouri , Columbia , Missouri , USA.

Objective: This pilot study assessed an electronic health diary method designed to collect data about critical health incidents experienced by college students who have chronic health conditions.

Participants: Nine university students with chronic medical conditions were recruited to complete a series of e-mail-based surveys, sent once every 3 days across the fall 2014 semester.

Methods: In each survey, participants described a health-related incident that occurred within the past day and cited resources that helped or could have helped in that situation. They completed follow-up interviews and ranked the importance of cited resources.

Results: The diary completion rate was 78.3% (141/180). Most frequently affected management areas were activities (61.3%), monitoring (34.9%), and problem-solving (34.3%). Resources considered helpful included situational knowledge, campus health professionals, peer support, and relaxation opportunities.

Conclusions: Prompted health incidents diary method achieved a high completion rate and provided data that could be useful for college health researchers and practitioners.
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http://dx.doi.org/10.1080/07448481.2016.1266640DOI Listing
April 2017

Negotiating a Place in the Family-A Grounded Theory Exploration of Stepgrandmothers' Enactment of Roles.

Gerontologist 2017 11;57(6):1148-1157

Department of Human Development and Family Science, University of Missouri, Columbia.

Purpose: Stepgrandparents are becoming more common, and they can, and often do, provide affective and instrumental support to families. Little is known, however, about how they negotiate and enact their roles within families, especially with stepgrandchildren. Stepgrandmothers warrant special attention because researchers have found that women experience more challenges than men in stepfamilies. Guided by symbolic interactionism, the purposes of our study were: (a) to explore stepgrandmothers' role enactment and (b) to explore the intrapersonal, interpersonal, and contextual factors that contribute to role enactment in intergenerational steprelationships.

Design And Methods: Eighteen stepgrandmothers participated in semi-structured interviews, discussing their relationships with 94 stepgrandchildren. Consistent with grounded theory methods, data collection and analysis occurred simultaneously.

Results: Interviews with stepgrandmothers revealed that they spend considerable time and energy defining their roles with stepgrandchildren. Stepgrandmothers' role enactment is a complex, reflexive process. A few perceived that their roles were shaped by their own dispositions, desires, and expectations (evidence for role-making), but most stepgrandmothers described their roles as reflecting the dispositions, desires, and expectations of others (evidence for role-taking). Stepgrandmothers reflected on their roles as a delicate balance of intra- and inter-personal negotiations, operating within cultural expectations.

Implications: Findings draw attention to the complex nature of role-taking, role-making, and gendered, relational processes in multigenerational stepfamilies. We discuss implications for research and theory related to stepgrandmotherhood as an incomplete institution.
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http://dx.doi.org/10.1093/geront/gnw112DOI Listing
November 2017

Divorce and Childhood Chronic Illness: A Grounded Theory of Trust, Gender, and Third-Party Care Providers.

J Fam Nurs 2016 05 27;22(2):252-78. Epub 2016 Mar 27.

University of Missouri, Columbia, USA.

Divorced parents face distinct challenges in providing care for chronically ill children. Children's residence in two households necessitates the development of family-specific strategies to ensure coparents' supervision of regimen adherence and the management of children's health care. Utilizing a risk and resilience perspective, a grounded theory study was conducted with 14 divorced parents of children with chronic illnesses. The importance of trust, gender, and relationships with third-party care providers emerged as key themes related to the development of effective coparenting relationships for maintaining children's health. Divorced parents were best able to support the management of their children's chronic conditions when care providers operated as neutral third parties and intermediaries. Collaborative family care may require health care practitioners to avoid being drawn into contentious inter-parental conflicts.
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http://dx.doi.org/10.1177/1074840716639909DOI Listing
May 2016

The Impact of Macrophage- and Microglia-Secreted TNFα on Oncolytic HSV-1 Therapy in the Glioblastoma Tumor Microenvironment.

Clin Cancer Res 2015 Jul 31;21(14):3274-85. Epub 2015 Mar 31.

Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio.

Purpose: Oncolytic herpes simplex viruses (oHSV) represent a promising therapy for glioblastoma (GBM), but their clinical success has been limited. Early innate immune responses to viral infection reduce oHSV replication, tumor destruction, and efficacy. Here, we characterized the antiviral effects of macrophages and microglia on viral therapy for GBM.

Experimental Design: Quantitative flow cytometry of mice with intracranial gliomas (±oHSV) was used to examine macrophage/microglia infiltration and activation. In vitro coculture assays of infected glioma cells with microglia/macrophages were used to test their impact on oHSV replication. Macrophages from TNFα-knockout mice and blocking antibodies were used to evaluate the biologic effects of TNFα on virus replication. TNFα blocking antibodies were used to evaluate the impact of TNFα on oHSV therapy in vivo.

Results: Flow-cytometry analysis revealed a 7.9-fold increase in macrophage infiltration after virus treatment. Tumor-infiltrating macrophages/microglia were polarized toward a M1, proinflammatory phenotype, and they expressed high levels of CD86, MHCII, and Ly6C. Macrophages/microglia produced significant amounts of TNFα in response to infected glioma cells in vitro and in vivo. Using TNFα-blocking antibodies and macrophages derived from TNFα-knockout mice, we discovered TNFα-induced apoptosis in infected tumor cells and inhibited virus replication. Finally, we demonstrated the transient blockade of TNFα from the tumor microenvironment with TNFα-blocking antibodies significantly enhanced virus replication and survival in GBM intracranial tumors.

Conclusions: The results of these studies suggest that FDA approved TNFα inhibitors may significantly improve the efficacy of oncolytic virus therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-3118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780415PMC
July 2015

Effects of CCN1 and Macrophage Content on Glioma Virotherapy: A Mathematical Model.

Bull Math Biol 2015 Jun 11;77(6):984-1012. Epub 2015 Mar 11.

Mathematical Biosciences Institute, The Ohio State University, Columbus, OH, 43210, USA,

Oncolytic virus (OV) is a genetically engineered virus that can selectively replicate in and kill tumor cells while not harming normal cells. OV therapy has been explored as a treatment for numerous cancers including glioblastoma, an aggressive and devastating brain tumor. Experiments show that extracellular matrix protein CCN1 limits OV therapy of glioma by orchestrating an antiviral response and enhancing the proinflammatory activation and migration of macrophages. Neutralizing CCN1 by antibody has been demonstrated to improve OV spread and tends to increase the time to disease progression. In this paper, we develop a mathematical model to investigate the effects of CCN1 on the treatment of glioma with oncolytic herpes simplex virus. We show that numerical simulations of the model are in agreement with the experimental results and then use the model to explore the anti-tumor effects of combining antibodies with OV therapy. Model simulations suggest that the macrophage content of the tumor is a critical factor to the success of OV therapy and to the reduction in tumor volume gained with the CCN1 antibody.
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http://dx.doi.org/10.1007/s11538-015-0074-8DOI Listing
June 2015

Role of cysteine-rich 61 protein (CCN1) in macrophage-mediated oncolytic herpes simplex virus clearance.

Mol Ther 2014 Sep 4;22(9):1678-87. Epub 2014 Jun 4.

Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Glioblastoma is a devastating disease, and there is an urgent need to develop novel therapies, such as oncolytic HSV1 (OV) to effectively target tumor cells. OV therapy depends on tumor-specific replication leading to destruction of neoplastic tissues. Host responses that curtail virus replication limit its efficacy in vivo. We have previously shown that cysteine-rich 61 protein (CCN1) activates a type 1 IFN antiviral defense response in glioblastoma cells. Incorporating TCGA data, we found CCN1 expression to be a negative prognostic factor for glioblastoma patients. Based on this, we used neutralizing antibodies against CCN1 to investigate its effect on OV therapy. Use of an anti-CCN1 antibody in mice bearing glioblastomas treated with OV led to enhanced virus expression along with reduced immune cell infiltration. OV-induced CCN1 increases macrophage migration toward infected glioblastoma cells by directly binding macrophages and also by enhancing the proinflammatory activation of macrophages inducing MCP-1 expression in glioblastoma cells. Activation of macrophages by CCN1 also increases viral clearance. Neutralization of integrin αMβ2 reversed CCN1-induced macrophage activation and migration, and reduced MCP-1 expression by glioblastoma cells. Our findings reveal that CCN1 plays a novel role in pathogen clearance; increasing macrophage infiltration and activation resulting in increased virus clearance in tumors.
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http://dx.doi.org/10.1038/mt.2014.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435480PMC
September 2014

Faster replication and higher expression levels of viral glycoproteins give the vesicular stomatitis virus/measles virus hybrid VSV-FH a growth advantage over measles virus.

J Virol 2014 Aug 14;88(15):8332-9. Epub 2014 May 14.

Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA Department of Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota, USA

Unlabelled: VSV-FH is a hybrid vesicular stomatitis virus (VSV) with a deletion of its G glycoprotein and encoding the measles virus (MV) fusion (F) and hemagglutinin (H) envelope glycoproteins. VSV-FH infects cells expressing MV receptors and is fusogenic and effective against myeloma xenografts in mice. We evaluated the fusogenic activities of MV and VSV-FH in relationship to the density of receptor on the target cell surface and the kinetics of F and H expression in infected cells. Using a panel of cells expressing increasing numbers of the MV receptor CD46, we evaluated syncytium size in MV- or VSV-FH-infected cells. VSV-FH is not fusogenic at low CD46 density but requires less CD46 for syncytium formation than MV. The size of each syncytium is larger in VSV-FH-infected cells at a specific CD46 density. While syncytium size reached a plateau and did not increase further in MV-infected CHO cells expressing ≥4,620 CD46 copies/cell, there was a corresponding increase in syncytium size with increases in CD46 levels in VSV-FH-infected CD46-expressing CHO (CHO-CD46) cells. Further analysis in VSV-FH-infected cell lines shows earlier and higher expression of F and H mRNAs and protein. However, VSV-FH cytotoxic activity was reduced by pretreatment of the cells with type I interferon. In contrast, the cytopathic effects are not affected in MV-infected cells. In summary, VSV-FH has significant advantages over MV as an oncolytic virus due to its higher viral yield, faster replication kinetics, and larger fusogenic capabilities but should be used in cancer types with defective interferon signaling pathways.

Importance: We studied the cytotoxic activity of a vesicular stomatitis/measles hybrid virus (VSV-FH), which is superior to that of measles virus (MV), in different cancer cell lines. We determined that viral RNA and protein were produced faster and in higher quantities in VSV-FH-infected cells. This resulted in the formation of larger syncytia, higher production of infectious particles, and a more potent cytopathic effect in permissive cells. Importantly, VSV-FH, similar to MV, can discriminate between low- and high-expressing CD46 cells, a phenotype important for cancer therapy as the virus will be able to preferentially infect cancer cells that overexpress CD46 over low-CD46-expressing normal cells.
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http://dx.doi.org/10.1128/JVI.03823-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135973PMC
August 2014

Hybrid projection-reflection method for phase retrieval.

J Opt Soc Am A Opt Image Sci Vis 2003 Jun;20(6):1025-34

Department of Mathematics and Statistics, University of Guelph, Guelph, Ontario N1G 2W1, Canada.

The phase-retrieval problem, fundamental in applied physics and engineering, addresses the question of how to determine the phase of a complex-valued function from modulus data and additional a priori information. Recently we identified two important methods for phase retrieval, namely, Fienup's basic input-output and hybrid input-output (HIO) algorithms, with classical convex projection methods and suggested that further connections between convex optimization and phase retrieval should be explored. Following up on this work, we introduce a new projection-based method, termed the hybrid projection-reflection (HPR) algorithm, for solving phase-retrieval problems featuring nonnegativity constraints in the object domain. Motivated by properties of the HPR algorithm for convex constraints, we recommend an error measure studied by Fienup more than 20 years ago. This error measure, which has received little attention in the literature, lends itself to an easily implementable stopping criterion. In numerical experiments we found the HPR algorithm to be a competitive alternative to the HIO algorithm and the stopping criterion to be reliable and robust.
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http://dx.doi.org/10.1364/josaa.20.001025DOI Listing
June 2003

Phase retrieval, error reduction algorithm, and Fienup variants: a view from convex optimization.

J Opt Soc Am A Opt Image Sci Vis 2002 Jul;19(7):1334-45

Department of Mathematics and Statistics, University of Guelph, Ontario, Canada.

The phase retrieval problem is of paramount importance in various areas of applied physics and engineering. The state of the art for solving this problem in two dimensions relies heavily on the pioneering work of Gerchberg, Saxton, and Fienup. Despite the widespread use of the algorithms proposed by these three researchers, current mathematical theory cannot explain their remarkable success. Nevertheless, great insight can be gained into the behavior, the shortcomings, and the performance of these algorithms from their possible counterparts in convex optimization theory. An important step in this direction was made two decades ago when the error reduction algorithm was identified as a nonconvex alternating projection algorithm. Our purpose is to formulate the phase retrieval problem with mathematical care and to establish new connections between well-established numerical phase retrieval schemes and classical convex optimization methods. Specifically, it is shown that Fienup's basic input-output algorithm corresponds to Dykstra's algorithm and that Fienup's hybrid input-output algorithm can be viewed as an instance of the Douglas-Rachford algorithm. We provide a theoretical framework to better understand and, potentially, to improve existing phase recovery algorithms.
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http://dx.doi.org/10.1364/josaa.19.001334DOI Listing
July 2002