1,720,990 research outputs found
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Targeting Tumor-Resident Myeloid Cells Via BTK Inhibition to Enhance Oncolytic Viroimmunotherapy
Full text linkPediatric sarcomas are highly aggressive cancers that metastasize quickly and can return after treatment. Despite the use of harsh treatments, survival rates for older children and those with metastatic disease remain low. Oncolytic virotherapy is a promising treatment option for pediatric sarcomas that aims to destroy cancer cells and induce antitumor immunity using live, attenuated viruses such as herpes simplex-1 viruses (oHSV). Virotherapy, however, also stimulates the recruitment of tumor-associated immunosuppressive cells, like myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), to the tumor microenvironment. Such immunosuppressive cells limit the ability of the virus to replicate and spread. We hypothesize that this recruitment results in reduced therapeutic efficacy. Previous studies show that trabectedin, a chemotherapeutic, in combination with oHSV treatment enhances the efficacy of virotherapy in A673 Ewing sarcoma models. This is likely due to trabectedin's ability to suppress TAM and MDSC recruitment to the tumor microenvironment. We termed this combination "myelolytic-virotherapy." Though trabectedin was able to enhance oHSV virotherapy through the reduction of immunosuppressive cell recruitment, this mechanism is not well understood. Thus, there is a need to understand if solely targeting tumor-resident MDSC enhances virotherapy. By determining if targeting MDSC improves the efficacy of oncolytic virotherapy, we can develop novel myelolytic-virotherapies that have increased therapeutic efficacy in multiple tumor models. This could have great potential for pediatric cancer patients. Previous studies have also shown that the efficacy of oHSV virotherapy may be dependent on virus-induced antitumor T cell responses. Treatment with oHSV enhanced overall survival and induced T cell recruitment to the tumor microenvironment in M3-9-M rhabdomyosarcoma models. Therefore, there is an additional need to investigate whether antitumor T cell responses are necessary to enhance the efficacy of oncolytic virotherapy, or if solely suppressing MDSC is enough. A study conducted by Dr. William Carson found that ibrutinib, an irreversible Bruton's tyrosine kinase (BTK) inhibitor, selectively reduces MDSC recruitment to tumors and limits their ability to suppress T cell proliferation. Ibrutinib also improved the efficacy of immune based cancer therapies. We hypothesize that ibrutinib enhances oncolytic virotherapy in Ewing sarcoma and rhabdomyosarcoma models by inhibiting tumor-associated MDSC recruitment and enhancing viral replication. In this study, we performed cellular infiltrate and viral replication studies in A673 Ewing sarcoma models to evaluate the effect of ibrutinib on MDSC recruitment and oHSV replication in vivo. We also performed survival studies in A673 and M3-9-M tumor-bearing mice to determine the effect of ibrutinib on tumor growth and survival. The results indicate that while ibrutinib does reduce MDSC recruitment to the microenvironment, it does not enhance oHSV replication or improve the efficacy of oHSV virotherapy.This project was supported by a 2020-21 Undergraduate Research Scholarship from the Ohio State College of Arts and Sciences.No embargoAcademic Major: Molecular Genetic
Star-crossed Side Effects: Evaluating the Interplay between Toxicity and Efficacy in the Combination Treatment of Trabectedin with HSV1716 in Murine Osteosarcoma
Full text linkPediatric patients with solid tumors have unacceptably low cure rates, and immunotherapy, such as oncolytic virotherapy, provides great promise for treatment. However, there is a lack of knowledge regarding the immunosuppressive microenvironment of solid tumors, and how this microenvironment affects the efficacy of virotherapy and other cancer immunotherapies. Tumor-Associated Macrophages, TAMs, specifically, M-2 like macrophages, and Myeloid Derived Suppressor Cells, MDSCs, are two key targets for improving the efficacy of immunotherapies as both play roles in immunosuppression. As such, it is suspected that a combined treatment that both reduces myelolytic cells in the microenvironment while stimulating a pro-inflammatory response will increase cytotoxic immune infiltration in the tumor microenvironment. We have previously demonstrated that trabectedin, an FDA-approved chemotherapy drug, in combination with oncolytic HSV, oHSV, has shown to stimulate tumor regression in two Ewing sarcoma Patient Derived Xenograft, PDX, models10. Our proposed mechanism suggests that trabectedin targets tumor-associated M2-like macrophages, and both depletes their levels while also polarizing remaining macrophages to an M1-like macrophage, which can perform phagocytosis against the tumor. While two Ewing sarcoma PDX models have demonstrated tumor regression in response to this combined myelolytic-virotherapy, it is unknown if these effects are generalizable to other non-Ewing sarcoma pediatric models or syngeneic models. This thesis explores the use of a combination treatment of the oncolytic virus, HSV1716, with the chemotherapy agent, trabectedin, in murine osteosarcoma. Specifically, this thesis focuses on the interplay between the toxicity and efficacy of the combination therapy of HSV1716 and trabectedin.PelotoniaBeau Biden Moonshot AwardNo embargoAcademic Major: Microbiolog
Tumor Associated Macrophages Mitigate Oncolytic Herpes Simplex Virus Anti-Tumor Efficacy in Ewings Sarcoma
Full text linkProfessional Biological Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)Introduction: Ewing sarcoma is a highly aggressive bone tumor that is often lethal following recurrence or metastasis. Oncolytic viruses (OVs), such as the rRp450 herpes simplex virus, are promising anticancer therapeutics designed to selectively replicate in cancer cells. While OV anti-tumor efficacy is partially caused by direct infection and lysis of cancer cells, stimulation of an anti-cancer immune response also contributes to virus-mediated efficacy. Immunologic responses to infections are known to be modulated by macrophages via various cytokines and chemokines and it is now appreciated that tumors are replete with tumor associated macrophages (TAMs). M2 alternatively activated macrophages in particular express pro-tumor immunosuppressive cytokines, such as IL-10 and TGF-β. We hypothesize that TAMs reduce therapeutic efficacy by producing an immunosuppressive tumor microenvironment via IL-10 and TGF-β signaling.
Research methods: Human Ewing sarcoma xenografts were implanted into athymic nude mice and macrophages were depleted using liposomal clodronate prior to intratumoral injection of rRp450 oncolytic HSV. Tumors were allowed to grow for tumor progression. In vitro cytotoxicity was determined using MTS assay. In vitro and in vivo virus replication was determined through plaque assay. Bone marrow derived macrophages were cocultured with Ewing sarcoma cell lines and harvested for flow cytometry and PCR analysis of tumor inflammatory signaling and M1/M2 macrophage gene profiles. F4/80+ tumor associated macrophages were extracted from tumors using magnetic bead separation. TGF-β cytokine superfamily receptor signaling was inhibited with A83-01 (Sigma-Aldrich) small molecule treatment prior to intratumoral injection of rRp450.
Results: Macrophage depletion significantly inhibited tumorigenesis and enhanced rRp450 anti-tumor efficacy in A673, but not 5838 Ewing sarcoma xenografts. No change in virus titer was observed in the macrophage depleted tumors, suggesting the effect isn’t due to enhanced virus replication. Macrophages cocultured with A673 cells had higher expression of M2 pro-tumor macrophage genes than macrophages cocultured with 5838 cells. Macrophages in A673 tumors also demonstrated higher expression of IL-10 and TGF-β than 5838 tumor associated macrophages. Inhibition of TGF-β signaling enhanced rRp450 oncolytic virus anti-tumor efficacy in A673 tumors.
Conclusions: Macrophages play a significant role in mitigating OV anti-tumor efficacy. Specifically, our tumor models that promote M2 macrophage polarization are significantly more resistant to oncolytic virus therapy, in part due to TGF-β signaling. Our results suggest that the combination of oncolytic virus therapy with a macrophage modulatory therapy will improve OV anti-tumor efficacy in patients with highly immunosuppressive tumors.A three-year embargo was granted for this item
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Oncolytic Viroradiotherapy for Neuroblastoma
Full text linkCollege of Education and Human Ecology Undergraduate Research ScholarshipNeuroblastoma is the most common extra-cranial solid tumor in childhood and the leading cause of childhood cancer mortality. MIBG (meta-iodobenzylguanidine), an analogue of noradrenaline, is a form of targeted radiation therapy for high-risk neuroblastoma when bound to 131Iodine. MIBG enters cells through the norepinephrine transporter (NET), a protein expressed on the surface of neuroendocrine cells, including most neuroblastoma cells. 131I-MIBG then radiates the cells it enters and induces cytotoxicity in surrounding cells. However, 131I-MIBG is not always effective, likely in part due to low NET expression in high-risk neuroblastomas. Oncolytic virotherapy is a promising therapeutic approach currently in clinical trials. Previously, our lab has shown that preclinical models of neuroblastoma are sensitive to oncolytic herpes simplex virus (oHSV) therapy. oHSV can also be used to deliver the NET transgene to tumor cells to increase susceptibility to 131I-MIBG. In the present study, we are investigating the efficacy of HSV1716/NET in increasing NET expression and thereby increasing the efficacy of 131I-MIBG. We will also evaluate if 131I-MIBG enhances viral replication. The results to date indicate that neuroblastoma cell lines are susceptible to HSV1716/NET, and upon viral infection, there is effective transfer of the NET gene resulting in an increase in 131I-MIBG uptake.No embargoAcademic Major: Human Development and Family Scienc
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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