Oncolytic HSV-mediated Regulation of the Host Hypoxia Response

Biological Sciences: 2nd Place (The Ohio State University Denman Undergraduate Research Forum)Glioblastoma (GBM) is the most common and deadly primary brain tumor, accounting for over 10,000 new cancer diagnoses in the United States each year. The poor prognosis for GBM patients necessitates novel biological treatments. One such approach is the use of oncolytic herpes simplex virus 1 (oHSV). Like many novel treatments, oHSV therapy causes side effects that are not yet well understood. Our lab has demonstrated that oHSV treatment increases the vascularity of brain tumors. The goal of this study is to determine the mechanism by which oHSV treatment increases the vascularity of brain tumors. We have determined that the hypoxia inducible factor-1 alpha (HIF1α) is activated in cells infected with oHSV, even in normal oxygen conditions. HIF1α is a transcription factor which activates a variety of genes in response to a lack of oxygen. We believe that HIF1α activation may be responsible for the increased vascularity of oHSV treated brain tumors. A screen of targetscan.org for herpes simplex virus 1 (HSV-1) miRNAs and their predicted target genes revealed multiple miRNAs predicted to target a protein called, factor inhibiting HIF1α (FIH). This protein functionally inhibits HIF1α activation by preventing the binding of HIF1α to DNA. We hypothesized that FIH would be negatively regulated in GBM cells infected with oHSV, thus allowing HIF1α activation. In this study, we demonstrate that HSV-1 expresses two miRNA molecules, which target and down regulate FIH. Transfection of miRNA inhibitors (antagomirs) was able to successfully abrogate the virus' ability to downregulate FIH as demonstrated by quantitative PCR and western blot. Moreover, transfection of HSV-1 miRNA mimics in the absence of virus was able to downregulate FIH protein levels (western blot) and activate the expression of a variety of HIF1α driven genes, including VEGF and CCN1 (quantitative PCR). Our future aim is to determine if HSV-1 encodes for miRNA capable of binding to the 3' untranslated region (3' UTR) of FIH. For this study we will employ an FIH-3' UTR luciferase reporter vector. This experiment will demonstrate if the miRNA expressed by oHSV directly binds to the 3' UTR of FIH, thus inhibiting FIH gene expression, and activating HIF1α.Pelotonia Undergraduate FellowshipAcademic Major: Biomedical Scienc

Comparison Of Interpolation Technique For Rain Gauge Data Through The Distributed Rainfall-Runoff Model

Precipitation estimated from different measuring techniques such as rain gauge, radar and satellite have some similarities, but there are also differences among them. For example, techniques based on radar and satellite data underestimate rainfall than those using rain gauge data. In addition, many different interpolation techniques have been used to measure spatial pattern of precipitation but it is still difficult to have an accurate pattern by any one of them. The differences between the rainfall estimates from different techniques vary seasonally as well as regionally so that the radar or satellites are not directly applied into hydrologic analysis. In this regard, a main objective of this study is to develop a systematic way to interpolate ground rain gauge using discharge data from distributed rainfall-runoff model The spatial rainfall patterns estimated from the interpolation methods will be evaluated with the object function to minimize the difference between observed and estimated discharge. In other words, this study seeks to identify the optimal spatial pattern in rain field that can generate a similar pattern of observed discharge through the distributed rainfall-runoff model. This study will compare the spatial pattern from different types of climate systems and different seasons derived from different interpolation methods may help to validate the proposed algorithms

Markedly enhanced intratumoral spread and antitumor effect of oncolytic adenovirus expressing decorin

With the aim of improving viral distribution and tumor penetration, we have engineered decorin expressing replication-incompetent (dl-LacZ-DCNG) and -competent (Ad-[DELTA]E1B-DCNG) adenoviruses. In both tumor spheroids and established solid tumors in vivo, administration of dl-LacZ-DCNG resulted in greater transduction efficiency and viral spread throughout the tumor mass. Ad-[DELTA]E1B-DCNG also enhanced viral distribution and tumor spread, leading to an increased anti-tumor effect and survival advantage. Upon histological analysis, Ad-[DELTA]E1B-DCNG also elicited greater percentage of apoptotic cells and extensive necrosis compared to those from untreated or control virus-treated tumors. Furthermore, Ad-[DELTA]E1B-DCNG substantially decreased extracellular matrix components within the tumor tissue, while normal tissue adjacent to the tumor was not affected. Finally, intratumoral administration of Ad-[DELTA]E1B-DCNG did not enhance but inhibited the formation of pulmonary metastases of B16BL6 melanoma cells in mice. Taken together, these data demonstrate the utility of decorin as a dispersion agent and suggest its utility and potential in improving the efficacy of replicating adenovirus-mediated cancer gene therapy

Application of Copula-Based Markov Model to Generate Monthly Precipitation

Source: ICHE Conference Archive - https://mdi-de.baw.de/icheArchiv

The uncalibrated pulse contour cardiac output during off-pump coronary bypass surgery: performance in patients with a low cardiac output status and a reduced left ventricular function

BACKGROUND: We compared the continuous cardiac index measured by the FloTrac/Vigileo™ system (FCI) to that measured by a pulmonary artery catheter (CCI) with emphasis on the accuracy of the FCI in patients with a decreased left ventricular ejection fraction (LVEF) and a low cardiac output status during off-pump coronary bypass surgery (OPCAB). We also assessed the influence of several factors affecting the pulse contour, such as the mean arterial pressure (MAP), the systemic vascular resistance index (SVRI) and the use of norepinephrine. METHODS: Fifty patients who were undergoing OPCAB (30 patients with a LVEF ≥ 40%, 20 patients with a LVEF < 40%) were enrolled. The FCI and CCI were measured and we performed a Bland-Altman analysis. Subgroup analyses were done according to the LVEF (< 40%), the CCI (≤ 2.4 L/min/m), the MAP (60-80 mmHg), the SVRI (1,600-2,600 dyne/s/cm(5)/m(2)) and the use of norepinephrine. RESULTS: The FCI was reliable at all the time points of measurement with an overall bias and limit of agreement of -0.07 and 0.67 L/min/m(2), respectively, resulting in a percentage error of 26.9%. The percentage errors in the patients with a decreased LVEF and in a low cardiac output status were 28.2% and 22.3%, respectively. However, the percentage error in the 91 data pairs outside the normal range of the SVRI was 40.2%. CONCLUSIONS: The cardiac output measured by the FloTrac/Vigileo™ system was reliable even in patients with a decreased LVEF and in a low cardiac output status during OPCAB. Acceptable agreement was also noted during the period of heart displacement and grafting of the obtuse marginalis branch.ope

Stratifying the early radiologic trajectory in dyspneic patients with COVID-19 pneumonia

OBJECTIVE: This study aimed to stratify the early pneumonia trajectory on chest radiographs and compare patient characteristics in dyspneic patients with coronavirus disease 2019 (COVID-19). MATERIALS AND METHODS: We retrospectively included 139 COVID-19 patients with dyspnea (87 men, 62.7+/-16.3 years) and serial chest radiographs from January to September 2020. Radiographic pneumonia extent was quantified as a percentage using a previously-developed deep learning algorithm. A group-based trajectory model was used to categorize the pneumonia trajectory after symptom onset during hospitalization. Clinical findings, and outcomes were compared, and Cox regression was performed for survival analysis. RESULTS: Radiographic pneumonia trajectories were categorized into four groups. Group 1 (n = 83, 59.7%) had negligible pneumonia, and group 2 (n = 29, 20.9%) had mild pneumonia. Group 3 (n = 13, 9.4%) and group 4 (n = 14, 10.1%) showed similar considerable pneumonia extents at baseline, but group 3 had decreasing pneumonia extent at 1-2 weeks, while group 4 had increasing pneumonia extent. Intensive care unit admission and mortality were significantly more frequent in groups 3 and 4 than in groups 1 and 2 (P \u3c .05). Groups 3 and 4 shared similar clinical and laboratory findings, but thrombocytopenia ( \u3c 150x103/muL) was exclusively observed in group 4 (P = .016). When compared to groups 1 and 2, group 4 (hazard ratio, 63.3; 95% confidence interval, 7.9-504.9) had a two-fold higher risk for mortality than group 3 (hazard ratio, 31.2; 95% confidence interval, 3.5-280.2), and this elevated risk was maintained after adjusting confounders. CONCLUSION: Monitoring the early radiologic trajectory beyond baseline further prognosticated at-risk COVID-19 patients, who potentially had thrombo-inflammatory responses

Pulmonary Venous Malformation in a 4-Year-Old Boy: a Case Report

We report a case of a pulmonary venous malformation in a 4-year-old boy who presented with recurrent pneumonia. A radiograph revealed a right infrahilar mass and a hyperlucent right lung. Computed tomography (CT) demonstrated a mass containing intensely enhancing areas and multiple phleboliths located in the right lower lobe and encasing the right bronchus and right inferior pulmonary vein. Magnetic resonance imaging (MRI) precisely revealed the mass demarcation. A right lower lobectomy was performed and a pathological examination confirmed the diagnosis of a venous malformation. To the best of our knowledge, a venous malformation in pulmonary tissue has not been reported in the English literature. Herein, we report a case of a pulmonary venous malformation, with the radiograph, CT, MRI, and blood pool scan findings, along with its pathologic correlation

Production of Transgenic Cloned Miniature Pigs with Membrane-bound Human Fas Ligand (FasL) by Somatic Cell Nuclear Transfer

Cell-mediated xenograft rejection, including NK cells and CD8+ CTL, is a major obstacle in successful pig-to-human xenotransplantation. Human CD8+ CTL and NK cells display high cytotoxicity for pig cells, mediated at least in part by the Fas/FasL pathway. To prevent cell-mediated xenocytotoxicity, a membrane-bound form of human FasL (mFasL) was generated as an inhibitor for CTL and NK cell cytotoxicity that could not be cleaved by metalloproteinase to produce putative soluble FasL. We produced two healthy transgenic pigs harboring the mFasL gene via somatic cell nuclear transfer (SCNT). In a cytotoxicity assay using transgenic clonal cell lines and transgenic pig ear cells, the rate of CD8+ CTL-mediated cytotoxicity was significantly reduced in transgenic pig&#x27;s ear cells compared with that in normal minipig fetal fibroblasts. Our data indicate that grafts of transgenic pigs expressing membrane-bound human FasL control the cellular immune response to xenografts, creating a window of opportunity to facilitate xenograft survival