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Glioblastoma (GB) patients often present with either radiation-induced necrosis (RN) or develop tumor recurrence (TR). Radiologically, differentiating between these two disease states is particularly difficult, especially utilizing traditional MRI techniques. Accurately distinguishing these separate states is important, as failure to do so can ultimately lead to unnecessary surgical intervention or early cessation of appropriate radiation therapy. Currently, distinction between these pathologies is made using best clinical judgement by the neuro-oncology team. Therefore, there is a need for developing novel non-invasive techniques that can reliably distinguish between radiation necrosis and tumor recurrence. Primary data was collected utilizing orthotopically transplanted GL261 mouse GB cells in a C57BL/6 mouse. Tumor induction was verified by MRI after two weeks. RN and TR were initiated using an aggressive radiation dose fractionation (12 Gy or 60 Gy). This was completed using a 4 mm radiation cone such that one portion of the tumor received 100% dose of 12 Gy or 60 Gy fraction which is sufficient to cause RN, whereas the tumor edge received only 50% of the dose, allowing for tumor recurrence. Our data demonstrated mice tumor recurrence and radiation necrosis on MRI imaging. Axial T2-weighted MRI and DKI sequence at 2 weeks following implantation demonstrated edema compatible with tumor recurrence. One week later, the T2-weighted MRI and DKI sequences demonstrated continued tumor progression. In a separate mouse with orthotopic glioblastoma implantation with high dose (60 Gy) radiation treatment, T2 imaging and DKI demonstrated areas of tumor and suspected central radiation necrosis. DKI imaging biomarkers was compared by liquid biopsy, H&E staining, and Immunohistochemistry (IHC) analysis of sacrificed mice. Our H&E staining results showed typical pathological features of GB and RN, and TR in each case. This result demonstrated that our proposed model for radiation induction was effective at achieving its goal.

Atypical and anaplastic meningiomas (WHO Grade 2 and WHO Grade 3 respectively) represent a subgroup of meningiomas that tend to have higher rates of recurrence with associated’s higher morbidity and mortality than the more common WHO Grade 1 meningiomas. Our laboratory data demonstrated that galectin-3 (Gal-3), a multifunctional β-galactoside-binding protein, is highly expressed in these meningioma subtypes as compared to normal brain tissue. However, the root of the profoundly immunosuppressive tumor microenvironment in meningioma cells is not fully understood. To address this, we used a Gal-3 inhibitor TD 139 paired with low-intensity non-invasive transcranial direct current stimulation (tDCS) to suppress tumor growth and enhance the immune response in the preclinical model. Treatment of tDCS (50 mV/mm for 30 min) followed by 1 mM of TD139 induced cell death in anaplastic meningioma in vitro human triple co-culture model but has no effect on mouse cortical neurons. Furthermore, we demonstrated that inhibiting of Gal-3 expression significantly decreased the protein levels of urokinase-type plasminogen activator receptor as well as phosphorylation of Akt and upregulates Bax expression. Treatment with TD139 (1mg/kg per day for 14 days) with tDCS [350 μA (1 x 30 min/day) for 7 times (within 14 Days) showed a significantly (∼60%) decrease in MGS2 atypical meningioma tumor growth in orthotopic allograft model (at Day 41). The percent survival of tumor-bearing mice treated with TD139 and tDCS was significantly higher than an untreated tumor or single treatment. Following TD139 plus tDCS treatment, our results demonstrated significant meningioma cell death via a decrease in NDRG4 (Meningioma marker) and were associated with downregulation of Ki-67 in treated tumors. Based on our substantial preliminary data, we believe that this proposed translational work has the potential to be an effective combinational modality form of treatment for atypical and malignant meningiomas.

Glioblastoma (GB) is an aggressive tumor showing extensive intertumoral and intratumoral heterogeneity. While preserving as much surrounding normal brain tissue as possible, neurosurgeons must aim to harvest maximal tumor tissue from a variety of tumor locations in an effort to capture heterogenic samples in high volume for molecular and pathologic diagnosis and translational research. A key challenge is the ability to consistently procure high-quality biologically active specimens. In this investigation, we implemented an automated intraoperative system to eliminate inconsistencies in the methodology of tissue collection, handling, and biological preservation immediately in the OR suite to establish a repeatable, standardized practice for obtaining high-quality tissue samples without the need for additional staff. Through this process, we were able to characterize matched specimens from GB patients or GB tumors from corresponding GB-allograft mice and compare the quality of traditional handling and collection processes of intraoperative tissue used in most neurosurgical operating rooms versus an automated resection, collection, and biological preservation system (APS) that captures, preserves, and biologically maintains tissue in a prescribed and controlled microenvironment. Matched specimens/or tissues were then processed in parallel at various time points and temperatures, evaluating viability, RNA and protein concentrations, and isolation of GB cell lines. We found that APS-derived GB slices stored in an APS modified medium remained viable and maintained high-quality RNA and protein concentration for up to 24 hours. Our results showed that primary GB cell cultures derived in this manner had improved growth over the widely used collection and preservation methods. Currently, we are continuing the investigation of collected samples in brain tumor animal models to further understand potential differences within the tumor region harvested and the cellular changes that occur over time. Our hope is this research will lead to new discoveries in the diagnosis and treatment of brain tumors.

Purpose/Objective(s) Breast cancer patients receiving postmastectomy radiotherapy (PMRT) often present with temporary tissue expanders. These expanders aid in postmastectomy breast reconstruction, but cause challenges for radiation treatment planning. The metallic injection port within the tissue expander can lead to dosimetric uncertainty due to generation of metal artifact on CT imaging, and the potential for incorrect contouring and density assignment of the port. In this study, the dosimetric uncertainty resulting from variation of the port definition method was investigated when computing dose with a material-based calculation algorithm, AcurosXB (AXB). Materials/Methods 10 anonymized CT-datasets for breast patients were used for this study. Iterative metal artifact reduction (iMAR) was utilized to minimize artifact. The metallic port consists of a magnetic disc (density = 7.4 g/cm3) and a titanium shell (density = 4.2 g/cm3). Thus, an extended CT Hounsfield Unit (HU) table up to maximum value as 3071 in a TPS was used to more accurately delineate metals within the port. The port was contoured using three methods. # 1: the port was contoured using the bone automatic CT window/level setting. # 2: HU thresholding with tight and high HU range (3000-Max.) was used to contour the port automatically. # 3: The same method as # 2 but the wider and medium HU range (1000-Max.) was changed to be used to identify the magnetic disk within the port, and a contour matching the reported physical dimensions of the port was created. A suitable density was then assigned to the contoured port structures (stainless steel with mass density range 6.2-8 g/cm3). A representative plan was created consisting of opposed tangential fields prescribed to 50Gy in 25 fractions. Finally, dose was computed using each of the three port contours with the AXB algorithm within the TPS. DVHs and two dose points near the skin and on the chest wall were calculated for each port contour and compared. The contour generated using # 3 was considered most accurate, and served as a baseline for comparison. Results Maximum dose differences of > 10% in the PTV and chest wall and > 20% in skin were recorded when comparing the three port contouring methods. Contouring the port using only the bone window/level setting (# 1) produced the greatest difference from # 3. The # 2 is closer to # 3 (approximately 3%-5%) which is acceptance model in clinics. The dose differences in PTV, skin and chest wall were increased with energy increased. Conclusion The AXB algorithm, iMAR, and extended HU table were shown to provide more accurate dose calculation in the presence of metal in a previous study. This study has shown that the method used to contour the metal port is a critical aspect of this calculation. TPS calculations based on the ideal model of the metallic port could improve the accuracy of dose calculations for PMRT patients who have temporary tissue expanders implanted during radiotherapy and could potentially reduce the risk of radiation complications.

This study investigates how audience members relate to and vicariously interact with multiple characters while viewing a narrative. Under the framework of the theory of situation models, we applied...

Meningiomas are common brain tumors, the majority of which are considered benign. Despite surgery and/or radiation therapy, recurrence rates are approximately 8–10%. One likely cause is the dysregulation of cyclin d-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway, which controls the cell cycle restriction point. This pathway is commonly dysregulated in anaplastic meningioma cell lines (AM) and radiation-induced meningioma cells (RIM), making it a rational target for anti-meningioma therapy. In this study, we investigate the effect of a CDK4/6 inhibitor, palbociclib, with radiation in relevant pre-clinical models. In vitro cell culture, ex vivo slice culture and in vivo cell line-derived orthotopic xenograft animal models of AM/RIM were utilized to assess treatment efficacy with palbociclib plus radiation. Treatment effects were examined by immunoblot, cell viability, apoptosis, and cell cycle progression. The in vitro and ex vivo studies demonstrate that palbociclib plus radiation treatment reduced proliferation and has additional effects on cell cycling, including induction of an RB-associated G (1) arrest in Rb+ AM and RIM cells, but not in Rb− cells. Our results also demonstrated reduced CDK4 and CDK6 expression as well as reduced E2F target gene expression (CCNA2 and CCNE2) with the combination therapy. MRI results in vivo demonstrated reduced tumor size at 5 weeks when treated with 14 days palbociclib (10 mg/kg) plus 6 Gy radiation compared to saline-treated tumors. Finally, no hepatic toxicity was found after treatments. A pre-clinical murine model provides preclinical evidence for use of palbociclib plus radiation as a therapeutic agent for Rb+ meningiomas.

Radioresistance remains a major clinical challenge in glioblastoma (GB) therapy. However, the mechanism for the development of radioresistance in GB is unclear. Mounting evidence suggests that Galectin-1 (Gal1: a carbohydrate-binding protein galectin-1) contributes to the radioresistance of GB tumors. Recently, several Gal1-targeting compounds have emerged. OTX008 is a calixarene derivative designed to bind the Gal1 amphipathic β-sheet conformation. Our study aimed to reduce galectin-1 expression using OTX008 in a human GB pre-clinical model. For these studies an in vivo GL261 murine models of GB were utilized to assess efficacy of treatment with radiation plus OTX008. Our results demonstrated that inhibition of Gal-1 with OTX008 plus radiation showed significantly decrease in GB growth rate and improved survival in in vivo. OTX008 treatment plus radiation was associated with downregulation of Gal1 and Ki67 in treated tumors, as well as decreased microvessel density and VEGFR2 expression. Finally, combination studies showed OTX008 synergy with radiation therapies, principally when OTX008 was administered first. This study provides insights of Gal-1inhibitory effects of OTX008 and its enhancement of the efficacy of radiotherapy in mouse models of GB suggest that further studies are warranted.

Chase Burton,1,* Arabinda Das,2,* Daniel McDonald,3 William A Vandergrift III,2 Sunil J Patel,2 David Cachia,2 Eric Bartee1 1Department of Microbiology and Immunology, Medical University of South Carolina, SC, USA; 2Department of Neurosurgery, Medical University of South Carolina, SC, USA; 3Department of Radiation Oncology, Medical University of South Carolina, SC, USA *These authors contributed equally to this work Background: Glioblastoma multiforme (GBM) is an aggressive form of brain cancer which is associated with poor prognosis. A variety of oncolytic viruses have previously shown positive efficacy against GBM, potentially offering new treatment options for patients. One such oncolytic virus is Myxoma virus (MYXV), a rabbit-specific poxvirus that has been shown to be efficacious against a variety of tumor models including GBM. Purpose: The purpose of this study was to test the efficacy of MYXV combined with current treatment regimens for GBM in both established cell lines as well as patient biopsy samples. Materials and methods: U118 gliobastoma cell lines were treated under various standard of care combinations (untreated, radiation and chemotherapeutic) prior to infection with MYXV. Infection was then monitored for differences in rate of infection, titer and rate of spread. Cellular death was measured by MTT assay and Caspase-3 colorimetric assay. Patient biopsies were harvested and treated under similar treatment conditions. Results: The addition of GBM standard of care to MYXV infection resulted in an increased rate of spread compared to single treatment with either radiation or chemotherapeutic alone. SOC did not alter viral replication or infection rates. Similar effects were seen in ex vivo patient biopsies. Cellular viability was significantly decreased with the combination therapy of SOC and MYXV infection compared to any other treatment outcome. Caspase-3 activity was also significantly increased in samples treated with combination therapy when compared to any other treatment combination. Conclusion: Our results show that the combination of MYXV with current SOC results in both increased killing of GBM cells compared to either treatment regime alone as well as increased spread of MYXV infection. These findings lay the foundation for future in vivo studies on combining MYXV with GBM SOC. Keywords: myxoma virus, glioblastoma multiforme, standard of care, oncolytic virotherapy

Meningiomas are common intracranial brain tumors. Despite surgery and/or radiation therapy, recurrence rates occur in approximately 8–10 % of tumors. This may be due to the dysregulation of the cyclin D and cyclin-dependent kinase (CDK) pathway in malignant meningioma cells and radiation-resistant meningioma cells. The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway controls the cell cycle restriction point, and is commonly dysregulated in meningioma; making it a rational target for antimeningioma therapy. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function against Rb+ meningiomas cells in vitro, ex vivo and in vivo xenograft model. Meningioma tumors in SCID mice treated daily with intraperitoneal injections of palbociclib for 14 days dose dependly with X ray irradiation. Treatment effects were examined by immunoblot, cell viability, apoptosis, and cell cycle progression. Radiation resistance BENMEN1 cells were developed after exposure to repeated 320 kV X ray irradiation. Since CDK4 and CDK6 are proteins that are major part of a cell cycle regulatory pathway in meningioma that also includes p16, cyclin D, and the retinoblastoma (Rb) protein, we analyzed those parameters. Our both in vitro and in vivo data clearly demonstrate that pallbociclib (CDK 4/6 inhibitor) treatment reduced proliferation and has additional effects on cell cycling, including induction of an RB-associated G(1) arrest against Rb+ malignant meningioma cells and radiation-resistant meningioma cells. We did not see any significant effect of palbociclib on Rb – meningima cells. Our results also demonstrated that palbociclib treatment inhibits CDK4 and CDK6 expression and also decreases E2F target gene expression (CCNA2 and CCNE2). All together, our results provide strong evidence that palbociclib can be applied to Rb+ meningiomas as a therapeutic agent.

BACKGROUND: External beam irradiation is an accepted treatment for skeletal malignancies. Radiation acts on both cancerous and normal cells and, depending on the balance of these effects, may promote or impair bone healing after pathologic fracture. Previous studies suggest an adverse effect of radiation on endochondral ossification, but the existence of differential effects of radiation on the two distinct bone healing pathways is unknown. QUESTIONS/PURPOSES: The purpose of this study was to investigate the differential effects of external beam irradiation on endochondral compared with intramembranous ossification with intramedullary nail and plate fixation of fractures inducing the two respective osseous healing pathways through assessment of (1) bone biology by histomorphometric analysis of cartilage area and micro-CT volumetric assessment of the calcified callus; and (2) mechanical properties of the healing fracture by four-point bending failure analysis of bending stiffness and strength. METHODS: Thirty-six male Sprague-Dawley rats underwent bilateral iatrogenic femur fracture: one side was repaired with an intramedullary nail and the other with compression plating. Three days postoperatively, half (n = 18) received 8-Gray external beam irradiation to each fracture. Rodents were euthanized at 1, 2, and 4 weeks postoperatively (n = 3/group) for quantitative histomorphometry of cartilage area and micro-CT assessment of callus volume. The remaining rodents were euthanized at 3 months (n = 9/group) and subjected to four-point bending tests to assess stiffness and maximum strength. RESULTS: Nailed femurs that were irradiated exhibited a reduction in cartilage area at both 2 weeks (1.08 ± 1.13 mm(2) versus 37.32 ± 19.88 mm(2); 95% confidence interval [CI] of the difference, 4.32-68.16 mm(2); p = 0.034) and 4 weeks (4.60 ± 3.97 mm(2) versus 39.10 ± 16.28 mm(2); 95% CI of the difference, 7.64-61.36 mm(2); p = 0.023) compared with nonirradiated fractures. There was also a decrease in the volume ratio of calcified callus at 4 weeks (0.35 ± 0.08 versus 0.51 ± 0.05; 95% CI of the difference, 0.01-0.31; p = 0.042) compared with nonirradiated fractures. By contrast, there was no difference in cartilage area or calcified callus between irradiated and nonirradiated plated femurs. The stiffness (128.84 ± 76.60 N/mm versus 26.99 ± 26.07 N/mm; 95% CI of the difference, 44.67-159.03 N/mm; p = 0.012) and maximum strength (41.44 ± 22.06 N versus 23.75 ± 11.00 N; 95% CI of the difference, 0.27-35.11 N; p = 0.047) of irradiated plated femurs was greater than the irradiated nailed femurs. However, for nonirradiated femurs, the maximum strength of nailed fractures (36.05 ± 17.34 N versus 15.63 ± 5.19 N; 95% CI of the difference, 3.96-36.88 N; p = 0.022) was greater than plated fractures, and there was no difference in stiffness between the nailed and plated fractures. CONCLUSIONS: In this model, external beam irradiation was found to preferentially inhibit endochondral over intramembranous ossification with the greatest impairment in healing of radiated fractures repaired with intramedullary nails compared with those fixed with plates. Future work with larger sample sizes might focus on further elucidating the observed differences in mechanical properties. CLINICAL RELEVANCE: This work suggests that there may be a rationale for compression plating rather than intramedullary nailing of long bone fractures in select circumstances where bony union is desirable, adjunctive radiation treatment is required, and bone stock is sufficient for plate and screw fixation.

Beam scanning data collected on the tomotherapy linear accelerator using the TomoScanner water scanning system is primarily used to verify the golden beam profiles included in all Helical TomoTherapy treatment planning systems (TOMO TPSs). The user is not allowed to modify the beam profiles/parameters for beam modeling within the TOMO TPSs. The authors report the first feasibility study using the Blue Phantom Helix (BPH) as an alternative to the TomoScanner (TS) system. This work establishes a benchmark dataset using BPH for target commissioning and quality assurance (QA), and quantifies systematic uncertainties between TS and BPH. Reproducibility of scanning with BPH was tested by three experienced physicists taking five sets of measurements over a six-month period. BPH provides several enhancements over TS, including a 3D scanning arm, which is able to acquire necessary beam-data with one tank setup, a universal chamber mount, and the OmniPro software, which allows online data collection and analysis. Discrepancies between BPH and TS were estimated by acquiring datasets with each tank. In addition, data measured with BPH and TS was compared to the golden TOMO TPS beam data. The total systematic uncertainty, defined as the combination of scanning system and beam modeling uncertainties, was determined through numerical analysis and tabulated. OmniPro was used for all analysis to eliminate uncertainty due to different data processing algorithms. The setup reproducibility of BPH remained within 0.5 mm/0.5%. Comparing BPH, TS, and Golden TPS for PDDs beyond maximum depth, the total systematic uncertainties were within 1.4mm/2.1%. Between BPH and TPS golden data, maximum differences in the field width and penumbra of in-plane profiles were within 0.8 and 1.1 mm, respectively. Furthermore, in cross-plane profiles, the field width differences increased at depth greater than 10 cm up to 2.5 mm, and maximum penumbra uncertainties were 5.6mm and 4.6 mm from TS scanning system and TPS modeling, respectively. Use of BPH reduced measurement time by 1-2 hrs per session. The BPH has been assessed as an efficient, reproducible, and accurate scanning system capable of providing a reliable benchmark beam data. With this data, a physicist can utilize the BPH in a clinical setting with an understanding of the scan discrepancy that may be encountered while validating the TPS or during routine machine QA. Without the flexibility of modifying the TPS and without a golden beam dataset from the vendor or a TPS model generated from data collected with the BPH, this represents the best solution for current clinical use of the BPH.

T-bet is a master regulator for IFN-γ production and Th1 differentiation. We evaluated the roles of T-bet and IFN-γ in T cell responses in acute graft-versus-host disease (GVHD) and found that T-bet−/− T cells induced significantly less GVHD compared with wild-type or IFN-γ−/− counterparts in both MHC-mismatched and MHC-matched but minor histocompatibility Ag–mismatched models driven by CD4 T cells. T-bet−/−, but not IFN-γ−/−, CD4 T cells had a markedly reduced ability to cause tissue damage in liver and gut. This distinct outcome is reflected by the differential gene expression on donor CD4 T cells deficient for T-bet or IFN-γ. At mRNA and protein levels, we defined several T-bet–dependent molecules that may account for the impaired ability of T-bet−/− T cells to migrate into target organs and to produce Th1-related cytokines. Moreover, these molecules were independent of either endogenous IFN-γ, such as CXCR3 and programmed death-1, or systematic IFN-γ, such as NKG2D, I-Ab, and granzyme B. Although both T-bet−/− and IFN-γ−/− CD4 T cells are prone to differentiate into Th17 cells, polarized Th17 cells deficient for T-bet but not for IFN-γ had a significantly reduced ability to cause GVHD. Finally, T-bet−/− T cells had a compromised graft-versus-leukemia effect, which could be essentially reversed by neutralization of IL-17 in the recipients. We conclude that T-bet is required for Th1 differentiation and migration, as well as for optimal function of Th17 cells. Thus, targeting T-bet or regulating its downstream effectors independent of IFN-γ may be a promising strategy to control GVHD in the clinic.

As chemokines are important mediators of cell–cell communication, we sought to identify commonly expressed chemokines in mouse and human medulloblastoma (MB) lines as surrogates to microglia/MB tumor cell interactions. We found CCL2 (chemokine (C-C motif) ligand 2) messenger RNA to be expressed by medulloblastoma lines. However, these lines did not express the CCL2 receptor, CCR2, which was found on microglia. The MP-1 medulloblastoma cell line is known to have low basal levels of CCL2. Hence, we overexpressed CCL2 plasmid with GFP tagging in the MP-1 medulloblastoma line to investigate the hypothesis that medulloblastoma-secreted CCL2 interacts with microglia to affect medulloblastoma growth and invasion. In medulloblastoma–microglia co-culture models, we observed an increase in the proliferation of CCL2-overexpressing clones. ELISA protein analyses revealed that interleukin-6 (IL-6) was consistently increased in the co-culture. Recombinant IL-6 enhanced the invasion of medulloblastoma cells when these were cultured alone, whereas a neutralizing antibody to IL-6 attenuated the microglia-stimulated invasion. This study has uncovered a mechanism by which medulloblastoma cells exploit microglia (M2-phenotype) for increased invasion. Specifically, medulloblastoma-derived CCL2 acts upon CCR2-bearing tumor-associated microglias (TAMs), which produce IL-6 to stimulate medulloblastoma cells, in a CCL2/CCR2/IL-6 loop. We targeted this loop by combining radiation therapy with 4-1BB (CD-137) monoclonal antibody (mAb), as CD-137 is involved in regulation of immune cell proliferation and survival. We re-educated microglia cells toward a cytotoxic M1-like phenotype and amplified effective anti-tumor immune responses in in vitro co-culture models. ELISA spot shows treatment with 50 ng of 4-1BB (CD137) + 1Gy X-ray radiation converted the microglia from M2 to M1 phenotype via a decrease in CCR2. This treatment induces the M1 phenotype microglia to induce MP-1 cell death. Based on our results, the use of 4-1BB mAb plus low-dose single fraction radiation may prove to be beneficial for the treatment of medulloblastoma.

Glioblastoma (GB) is the most common and highly aggressive adult brain cancer. Dysfunction of receptor tyrosine kinases, such as ALK, c-Met and VEGF have all been implicated in the progression of this malignancy and resistance to therapy. Traditional therapeutic strategies targeting ALK/c-Met or VEGF have not yet given satisfactory outcomes. Myxoma virus (MYXV) is a novel oncolytic virus that has been shown to replicate in GB models. Here, we investigated the efficacy of MYXV as monotherapy, or in combination with 1 Gy radiation plus c-Met/ALK inhibitor crizotinib and VEGF inhibitor bevacizumab in different cell lines (GL261, T9, and U118) surgically obtained from GB patients. We investigated the molecular mechanisms of apoptotic death by Western blots. Colorimetric assay demonstrated that treatment with MYXV plus radiation with crizotinib or bevacizumab caused apoptosis due to an increase in activation of caspase-3 and decrease in expression of Bcl-2 proteins in GB cells and tissues. Most importantly, MYXV plus radiation significantly enhanced the anti-cancer effect of crizotinib, bevacizumab and temozolomide, in GB cell lines as well as in fresh tumor biopsies from GB patients. Our studies also suggest that induction of apoptosis by MYXV does not depend on the functional status of the GB cell lines or in the GB tissues. Further studies in different animal models of GB are warranted in the future to determine whether MYXV in combination with radiation, crizotinib or bevacizumab may be useful as anti-cancer agent for the management of human GBs in vivo.

Medulloblastoma cells in situ are surrounded by microglia, suggesting medulloblastoma–microglia interactions to produce various outcomes. As chemokines are important mediators of cell–cell communication, we sought to identify common chemokines in mouse and human medulloblastoma lines. We found CCL2 (chemokine (C-C motif) ligand 2) messenger RNA was expressed by Group 3 and 4 medulloblastoma lines. However, these lines did not express the CCL2 receptor, CCR2, which was found on microglia. The MP-1 medulloblastoma cell line expresses low basal levels of CCL2. Hence, we overexpressed CCL2 plasmid with GFP tagging in MP-1 medulloblastoma cells to investigate the hypothesis that medulloblastoma-secreted CCL2 interacts with microglia to affect medulloblastoma growth and invasion. In medulloblastoma–microglia co-culture models, we observed increased proliferation of CCL2-overexpressing clones. ELISA protein analyses revealed that interleukin-6 (IL-6) was consistently increased in the co-culture. Recombinant IL-6 enhanced the invasion of medulloblastoma cells when these were cultured alone, whereas a neutralizing antibody to IL-6 attenuated the microglia-stimulated medulloblastoma invasion. This study reveals a mechanism by which medulloblastoma cells exploit microglia (M2-phenotype) for increased invasion. Specifically, medulloblastoma-derived CCL2 acts upon CCR2-bearing tumor associated microglias (TAMs), which produce IL-6 to stimulate medulloblastoma cells, in a CCL2/CCR2/IL-6 loop. We targeted this loop by combining radiation therapy with a 4-1BB (CD-137) monoclonal antibody (mAb), as CD-137 is involved in regulation of immune cell proliferation and survival. We re-educated microglia cells toward a cytotoxic M1-like phenotype and amplified effective anti-tumor immune responses in co-culture models. ELISA spot shows treatment with 50 ng of 4-1BB + 1Gy X-ray radiation converted the microglia from M2 to M1 phenotype via a decrease in CCR2. This treatment induces the M1 phenotype microglia to induce MP-1 cell death. Based on our results, the use of 4-1BB mAb plus radiation may prove to be beneficial for the treatment of medulloblastoma by targeting CCL2/CCR2/IL-6 loop.

Atypical and malignant meningiomas are rare tumors that unlike WHO I meningiomas are characteristically more aggressive in nature and are associated with higher recurrence risks of recurrence. In fact despite aggressive treatment of malignant meningiomas, the average 5-year survival rates are in the range of 30% to 60%. Still the standard of care for atypical and malignant meningiomas (AM and MM) has yet to be established. Our laboratory data demonstrated that galectin-3 (Gal-3), a multifunctional β-galactoside-binding protein, is highly expressed in AM and MM as compared to normal tissue. However, the biological functions of Gal-3 in meningioma cells are not fully understood. To address this, we used either small interfering RNA (siRNA) to knock down Gal-3 expression or Gal-3 inhibitor, TD139 to suppress Gal-3 expression in in vitro cell culture model. Silencing or inhibiting of Gal-3 expression significantly decreased the protein levels of urokinase-type plasminogen activator receptor (uPAR) as well as uPAR’s downstream signaling transduction pathway, including phosphorylation of AKT. In both cases, we found that silencing of Gal-3 or inhibiting Gal-3 expression decreased the proliferative activity, and migratory potential of AM and MM cells. Furthermore, we demonstrated that TD139 inhibits MM growth in an in vivo xenograft MM model. Taken together, our results suggest that Gal-3 modulates uPAR expression and that Gal-3 may be a potential therapeutic target for the treatment of atypical and malignant meningiomas.

// Xiaoyuan He 1, * , Aimin Yang 1, * , Daniel G. McDonald 2 , Ellen C. Riemer 1 , Kenneth N. Vanek 2 , Bradley A. Schulte 1 and Gavin Y. Wang 1, 3 1 Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA 2 Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA 3 Cancer Genes and Molecular Regulation Program of Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA * These authors have contributed equally to this work Correspondence to: Gavin Y. Wang, email: wangy@musc.edu Keywords: microRNA-34a (miR-34a), ionizing radiation, non-small cell lung cancer, cellular senescence, c-Myc Received: February 28, 2017 Accepted: June 09, 2017 Published: July 15, 2017 ABSTRACT MicroRNAs (miRNAs) are a new class of gene expression regulators that have been implicated in tumorigenesis and modulation of the responses to cancer treatment including that of human non-small cell lung cancer (NSCLC). However, the role of miR-34a in ionizing radiation (IR)-induced senescence in NSCLC cells remains poorly understood. Here we report that IR-induced premature senescence correlates with upregulation of miR-34a expression in NSCLC cells. Ectopic overexpression of miR-34a by transfection with synthetic miR-34a mimics markedly enhances IR-induced senescence, whereas inhibition of miR-34a by transfection with a synthetic miR-34a inhibitor attenuates IR-induced senescence. Clonogenic assays reveal that treatment with miR-34a mimics augments IR-induced cell killing in human NSCLC cells. Mechanistically, we found that the senescence-promoting effect of miR-34a is associated with a dramatic down-regulation of c-Myc (Myc) expression, suggesting that miR-34a may promote IR-induced senescence via targeting Myc. In agreement with this suggestion, knockdown of Myc expression by RNAi recapitulates the senescence-promoting effect of miR-34a and enhances IR-induced cell killing in NSCLC cells. Collectively, these results demonstrate a previously unrecognized role for miR-34a in modulating IR-induced senescence in human NSCLC cells and suggest that pharmacological intervention of miR-34a expression may represent a new therapeutic strategy for improving the efficacy of lung cancer radiotherapy.

Immunotherapy can be an effective treatment for pediatric medulloblastoma (MB) patients. However, major subpopulations do not respond to immunotherapy, due to the lack of antigenic mutations or the immune-evasive properties of MB cells. Clinical observations suggest that radiation therapy (RT) may expand the therapeutic reach of immunotherapy. The aim of the present investigation is to study the effect of low-dose X-ray radiation (LDXR, 1 Gy) on the functional immunological responses of MB cells (DAOY, D283, and D341). Induction of MB cell death was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Production of reactive oxygen species (ROS) was measured by fluorescent probes. Changes in the expression of human leukocyte antigen (HLA) molecules and caspase-3 activities during treatment were analyzed using Western blotting and caspase-3 assay. Western blot analysis demonstrated that LDXR upregulated the expression of HLA class I and HLA II molecules by more than 20% compared with control and high-dose (12 Gy) groups in vitro. Several of these HLA subtypes, such as MAGE C1, CD137, and ICAM-1, have demonstrated upregulation. In addition, LDXR increases ROS production in association with phosphorylation of NF-κB and cell surface expression of mAb target molecules (HER2 and VEGF). These data suggest that a combined LDXR and mAb therapy can create a synergistic effect in vitro. These results suggest that LDXR modulates HLA molecules, leading to alterations in T-cell/tumor-cell interaction and enhancement of T-cell-mediated MB cell death. Also, low-dose radiotherapy combined with monoclonal antibody therapy may one day augment the standard treatment for MB, but more investigation is needed to prove its utility as a new therapeutic combination for MB patients.

Purpose To evaluate the Mobius second‐check dosimetry system by comparing it to ionization‐chamber dose measurements collected in the recently released Mobius Verification Phantom™ (MVP). For reference, a comparison of these measurements to dose calculated in the primary treatment planning system (TPS), Varian Eclipse with the AcurosXB dose algorithm, is also provided. Finally, patient dose calculated in Mobius is compared directly to Eclipse to demonstrate typical expected results during clinical use of the Mobius system. Methods Seventeen anonymized intensity‐modulated clinical treatment plans were selected for analysis. Dose was recalculated on the MVP in both Eclipse and Mobius. These calculated doses were compared to doses measured using an A1SL ionization‐chamber in the MVP. Dose was measured and analyzed at two different chamber positions for each treatment plan. Mobius calculated dose was then compared directly to Eclipse using the following metrics; target mean dose, target D95%, global 3D gamma pass rate, and target gamma pass rate. Finally, these same metrics were used to analyze the first 36 intensity modulated cases, following clinical implementation of the Mobius system. Results The average difference between Mobius and measurement was 0.3 ± 1.3%. Differences ranged from −3.3 to + 2.2%. The average difference between Eclipse and measurement was −1.2 ± 0.7%. Eclipse vs. measurement differences ranged from −3.0 to −0.1%. For the 17 anonymized pre‐clinical cases, the average target mean dose difference between Mobius and Eclipse was 1.0 ± 1.1%. Average target D95% difference was ‐0.9 ± 2.0%. Average global gamma pass rate, using a criteria of 3%, 2 mm, was 94.4 ± 3.3%, and average gamma pass rate for the target volume only was 80.2 ± 12.3%. Results of the first 36 intensity‐modulated cases, post‐clinical implementation of Mobius, were similar to those seen for the 17 pre‐clinical test cases. Conclusion Mobius correctly calculated dose for each tested intensity modulated treatment plan, agreeing with measurement to within 3.5% for all cases analyzed. The dose calculation accuracy and independence of the Mobius system is sufficient to provide a rigorous second‐check of a modern TPS.

Introduction: Intensity-modulated radiotherapy (IMRT) has been shown to reduce dose to organs at risk (OAR) while adequately treating tumour volume. This study quantitatively compares the dosimetric differences from step-and-shoot IMRT compared with helical tomotherapy (HT) for pancreatic head cancer. Methods: Twelve consecutive patients with non-metastatic, stage T3 or T4, unresectable pancreatic head cancer were planned for step-and-shoot IMRT as well as HT. Radiotherapy was planned to deliver 45.9 Gy to the clinical target volume in 30 fractions with an integrated boost to 54 Gy to the gross tumour volume (planning target volume 5400 including a 1-cm set-up margin). The uniformity index (UI) and conformity index (CI) were used to compare the quality of target coverage, while the quality index (QI) compared the dosimetric performance for OAR. Results: Both methods were effective at covering the tumour with no significant difference in UI or CI. However, HT dosimetry exhibited superior sparing of OAR with significantly less stomach (mean QIStomV30 = 0.84, P = 0.006) and small bowel dosing (mean small bowel QISBV30 = 0.84, P = 0.005). HT reduced dose to the kidney receiving the highest dose but the overall volume of kidney receiving 18 Gy was not significantly different between the two systems, indicating that HT spread the dose more uniformly through the kidneys. Conclusions: Target coverage is equivalent between the two systems; however, HT shows significantly better sparing of the stomach and small bowel. The decreased dose to OAR with HT is likely to improve the therapeutic ratio in the radiotherapy of pancreatic head cancers.

Meningiomas are the most common primary brain tumor reported in the United States each year and account for approximately 30% of primary neoplasms. Though in most cases the etiology of meningiomas is unclear, prior exposure to radiation is responsible for a subset of meningiomas. Some have speculated that there may be a relationship between pretreatment characteristics and radiotherapy parameters in the development of radiation-induced meningiomas (RIM). Compared with their sporadic counterparts, currently, the clinical treatment involves is similar with radiation used as a first line therapy. Novel therapeutic agents being investigated in the treatment of these tumors, rely on the direct or cell cycle-mediated induction of DNA damage to promote cellular apoptosis. Our pre-clinical data showed that disruption of p16INK4a-Cdk4-Rb (retinoblastoma) pathways plays a significant role in the development of RIM in Rb+ low-gradelow-grade meningioma cells. These observations highlight the critical role of the p16INK4a-Cdk4-Rb pathway in RIM and suggest that targeting this pathway might be a promising strategy to improve the therapeutic efficacy among RIM patients. Pretreatment characteristics and radiotherapy parameters which may influence the time interval for development of radiation-induced Rb+ meningiomas (RIM) were identified. Our results also demonstrated that CDK 4/6 Inhibitor, significantly suppresses radiation induced malignant transformation and prolonged survival in a cell-free, slice culture model and xenograft model of meningioma. Success of the proposed therapeutic strategies in both in vitro and in vivo models may form the basis for future research.

Purpose: To calibrate a Gamma Knife (GK) Perfexion using TG-21 with updated chamber-dependent values for modern microionization chambers in the new solid water Leksell dosimetry phantom. This work illustrates a calibration method using commercially available equipment, instruments, and an established dosimetry protocol that may be adopted at any GK center, thus reducing the interinstitutional variation in GK calibration. The calibration was verified by three third-party dosimetry checks. In addition, measurements of the relative output factors are presented and compared to available data and the new manufacturer-provided relative output factors yet to be released. Methods: An absolute dosecalibration based on the TG-21 formalism, utilizing recently reported phantom material and chamber-dependent factors, was performed using a microionization chamber in a spherical solid water phantom. The result was compared to other calibration protocols based on TG-51. Independent verification of the machine output was conducted through M.D. Anderson Dosimetry Services (MDADS), using thermoluminescent dosimeters(TLDs) in an anthropomorphic head phantom; the Radiological Physics Center (RPC), using TLDs in the standard Elekta ABS plastic calibration phantom (gray phantom), included with the GK; and through a collaborative international calibration survey by the University of Pittsburgh Medical Center (UPMC) using alanine dosimeters, also in the gray phantom. The alanine dosimeters were read by the National Institute of Standards and Technology. Finally, Gafchromic EBT film was used to measure relative output factors and these factors were compared to values reported in the literature as well as new values announced for release by Elekta. The films were exposed in the solid water phantom using an included film insert accessory. Results: Compared to the TG-21 protocol in the solid water phantom, the modified and unmodified TG-51 calibrations resulted in dose rates which were 1.8% and 1.3% lower, respectively. Ratios of the doses measured by third parties to the dose reported showed excellent agreement. MDADS returned ratios of 1.00 and 0.98 for the two TLDs irradiated. The RPC returned a mean ratio of 0.98 of the dose reported and the UPMC alanine study returned a mean ratio of 1.008. Relative output factors were found to be 0.817 ± 0.009 and 0.897 ± 0.008 for the 4 and 8 mm collimators, respectively, which are in excellent agreement with revised Monte Carlo-derived relative output factors Elekta is expected to recommend with the next version of the GK treatment planning software (GAMMAPLAN version 10). Conclusions: The TG-21 dosimetry protocol, performed in a solid water phantom in conjunction with modern dosimeters and phantom material and chamber-dependent factors, can yield an accurate dose measurement in the unique GK treatment geometry. The technique described here can be easily adopted by institutions worldwide since all equipment and instruments used are commercially available, thus reducing the existing interinstitutional variation in GK calibration techniques. Relative output factor measurements made in this same solid water phantom were used to verify the relative output factors provided by Elekta and agreed excellently with output factors expected to be released in conjunction withGAMMAPLAN version 10.

Medulloblastoma (MB) is the most common malignant brain tumor in children, and has been historically classified based on clinical markers (patient age, presence of metastases at diagnosis, extent of resection) and histopathological characteristics (classic, desmoplastic/nodular, and large cell/anaplastic). However, the recent gene expression profiling of a large number of tumors across multiple studies has provided evidence of four distinct medulloblastoma molecular subgroups (Wnt, Shh, Group 3, and Group 4), associated with remarkably different prognoses. While current therapies for medulloblastoma are often toxic, and not always effective, immunotherapy, designed to target these subgroups, may offer therapeutic improvement. Although monoclonal antibody (mAb) therapy has not yet been shown to be effective for the treatment of brain tumors, recent data indicate that radiation therapy can induce immunogenic modulation characterized by cell-surface phenotypic changes leading to augmented tumour cell/cytotoxic T-cell interaction. We examined the ability of radiation to upregulate mAb therapy targets. Our data showed that low dose radiation significantly increased cell-surface and total protein expression of mAb targets CD137 (a member of the TNF receptor superfamily), FGF, CD20, HER2, Major Histocompatability Complex (MHC) class I and intercellular adhesion molecule-1 (ICAM-I) in 3 out of 3 medulloblastoma cell lines. These findings highlight a mechanism for combining radiation with immunotherapy, to potentially expand the effect of targeted therapy in brain tumor treatment.

(2004). The Effect of New Networks on U.S. Television Diversity. Journal of Media Economics: Vol. 17, No. 2, pp. 105-121.

Purpose: Manual catheter recognition remains a time-consuming aspect of high-dose-rate brachytherapy (HDR) treatment planning. In this work, a novel catheter lumen recognition algorithm was created for accurate and rapid digitization. Methods: MatLab v8.5 was used to create the catheter recognition algorithm. Initially, the algorithm searches the patient CT dataset using an intensity based k-means filter designed to locate catheters. Once the catheters have been located, seed points are manually selected to initialize digitization of each catheter. From each seed point, the algorithm searches locally in order to automatically digitize the remaining catheter. This digitization is accomplished by finding pixels with similar image curvature and divergence parameters compared to the seed pixel. Newly digitized pixels are treated as new seed positions, and hessian image analysis is used to direct the algorithm toward neighboring catheter pixels, and to make the algorithm insensitive to adjacent catheters that are unresolvable on CT, air pockets, and high Z artifacts. The algorithm was tested using 11 HDR treatment plans, including the Syed template, tandem and ovoid applicator, and multi-catheter lung brachytherapy. Digitization error was calculated by comparing manually determined catheter positions to those determined by the algorithm. Results: he digitization error was 0.23 mm ± 0.14 mm axially and 0.62 mm ± 0.13 mm longitudinally at the tip. The time of digitization, following initial seed placement was less than 1 second per catheter. The maximum total time required to digitize all tested applicators was 4 minutes (Syed template with 15 needles). Conclusion: This algorithm successfully digitizes HDR catheters for a variety of applicators with or without CT markers. The minimal axial error demonstrates the accuracy of the algorithm, and its insensitivity to image artifacts and challenging catheter positioning. Future work to automatically place initial seed positions would improve the algorithm speed.

Bruton’s Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically.

ObjectThe objective of this study was to examine radiation dose distributions created by 2 competing radiosurgery modalities for treating multiple brain metastases: single-isocenter volumetric modulated arc radiosurgery (VMAS) and Gamma Knife Perfexion (GKP). In addition, the effectiveness of multiple radiosurgery quality metrics was evaluated and compared between these advanced treatment modalities.MethodsSeven anonymized MRI data sets, each showing 2–5 metastases, were used to create plans on each system. The GammaPlan (version 10.1) program was used for planning of GKP. A neurosurgeon contoured the volumes to be treated, and no planning target volume expansion was used. A prescription dose coverage of ≥ 99% was achieved for each tumor volume. The Philips Pinnacle (version 9.2) program was used for planning of VMAS, using the SmartArc optimization algorithm for delivery on a Varian iX linear accelerator. Contours were transferred from GammaPlan, and again no planning target volume expansion was used. Between 2 and 5 arcs with table angles of 90°–270° were used. Again, a V100% of ≥ 99% was achieved for each tumor volume. After planning, the MRI scans, tumor volumes, and dose information from each plan were exported according to the Digital Imaging and Communications in Medicine standard to the VelocityAI program for analysis. Brain dose-volume histograms (DVHs) for normal brain tissues were generated, and the volume of these tissues receiving 20%–90% of the prescription dose was tabulated. Finally, the prescription isodose to tumor volume ratio (PITV; Shaw et al., 1993), conformity index (CI; Paddick, 2000), gradient index (GI, Paddick and Lippitz, 2006), and conformity/gradient index (CGI, Wagner et al. 2003) were calculated for each plan. Both the PITV and CI have ideal values of 1, while the GI and CGI have ideal values of lowest and highest achievable, respectively.ResultsThe DVHs consistently showed that with VMAS a higher amount of normal brain tissues received each dose level than with GKP. These increases were largest for lower isodose levels, with the volumes of normal brain that received 20%–50% and 60%–90% of the prescription dose showing average increases of 403% and 227%, respectively. Prescription isodose conformality showed only minor differences between the 2 modalities. Radiosurgery quality metrics including measures of the dose gradient (GI and CGI) indicated that the GKP plan was superior in each case, with respective average GI and CGI values of 3.04 and 57.75 for GKP and of 10.22 and 10.85 for VMAS. Metrics evaluating prescription isodose conformality alone differed only slightly between the modalities. Average respective PITV and CI values were 2.13 and 0.53 for GKP and 2.27 and 0.51 for VMAS.ConclusionsStereotactic radiosurgery plans for the treatment of multiple metastases with VMAS delivered significantly more dose to the normal brain tissues than plans for GKP. Radiosurgery quality metrics including a measure of the dose gradient are better suited to providing contrast between modern radiosurgery treatment platforms.

This article explores children's use of mediated characters as role models for development of their self-concept and personality. Using the perspective of the "social self," we examine data on children's perceptions of electronic game characters as comparisons to their own personality and other developing characteristics. The evidence suggests that children identify quite closely with electronic characters and that these identifications have implications for children's emotional well being and the development of their personality.

Many people today are voicing concerns about the potentially deleterious social effects of media such as television and the Internet. The turn of the twenty-first century provides an interesting vantage point from which to look back one hundred years and examine people's concerns about the impacts of an earlier communication technology - silent film. This kind of historical exercise reminds us, first, that each major communication technology has had its proponents and its critics, and second, that the social influences of communication technologies are more profound than their developers could have anticipated. The turn from the nineteenth to the twentieth century marked the beginning of a communications revolution that was to have a major impact in defining social life in the United States during the twentieth century. That move first began to take shape in devices developed in the late nineteenth century but not finding a strong social place until the twentieth; audio recordings, radio broadcasting, and motion pictures were some of the technologies developed during the last decades of the nineteenth century that were to be characteristic of the twentieth. In addition to changes in communication technology, vast social changes were occurring as a result of urbanization and immigration. The rise of the large American city and its attendant social problems became a major concern of social workers and social commentators. Increasing immigration became a national issue during the 1890s and early 1900s. Millions of people, primarily those from European countries, poured into New York City and settled in areas that seemed most familiar and affordable to them-those made up of other recent immigrants-- forming ghettos and neighborhoods defined by country of origin. This article traces the early development of motion picture technology and examines the roles that motion pictures and the moviegoing experience played in communicating "American" values, sensibilities, and emotions to immigrant populations. The silent motion picture provided an inexpensive and accessible form of entertainment for America's new immigrants. The lack of spoken language was an advantage in that actors in the early cinema used body language and facial expression to their full impact. Unhindered by the complex plots and characters that were to appear with sound films, silent films, as well as the moviegoing experience, provided immigrants with a glimpse of this new country, including what to expect, how to behave, and what to feel. As a new medium at the turn of the twentieth century, silent film helped transform individuals, institutions, and the relationships among people and between social groups. U.S. Immigration in the Nineteenth and Twentieth Centuries United States immigration history is often divided into waves-the "Old Migration" from approximately 1820-1880, the "New Immigration" from approximately 1885-1930, and the modern era, which began around 1930. The Old Migration period was stimulated by steamship and railroad transportation and encouraged by the midwest states, where local governments were attempting to build a larger population base. The Old Migration consisted primarily of Europeans during the early stages and Chinese and Japanese later in the century. Economic difficulties in their home countries and the promise of a new start in the United States was the impetus for many to leave their homes and head for America. The immigrants of the Old Migration were primarily from rural areas; many had lost their place in their newly-industrialized homeland. Many were farmers or artisans who came to this land and found work in large coastal cities or along the rapidly developing highways of westward expansion (Handlin; Morris and Morris). Immigrants of the second wave, the New Immigration period, were also primarily of European origin, with many from eastern and southern Europe. Around the turn of the twentieth century there was a heavy influx from Russia, Poland, and Austria-- Hungary. …

Purpose: To examine the feasibility of using Varian’s EPID-based Machine Performance Check (MPC) system to track daily machine output through comparison with Sun Nuclear’s DailyQA3 (DQA) device. Methods: Daily machine outputs for two photon energies (6 and 16MV) and five electron energies (6, 9, 12, 16, 20MeV) were measured for one month using both MPC and DQA. Baselines measurements for MPC were taken at the start of the measurement series, while DQA baselines were set at an earlier date. In order to make absolute comparisons with MPC, all DQA readings were referenced to the average of the first three DQA readings in that series, minimizing systematic differences between the measurement techniques due to baseline differences. In addition to daily output measurements, weekly averages were also calculated and compared. Finally, the electron energy dependence of each measurement technique was examined by comparing energy-specific measurements to the average electron output of all energies each day. Results: For 6 and 16MV photons, the largest absolute percent differences between MPC and DQA were 0.60% and 0.73%, respectively. Weekly averages were within 0.17% and 0.23%, respectively. For all five electron energies, the greatest absolute percent differences between MPC and DQA for each energy ranged from 0.49%–0.83%. Weekly averages ranged from 0.07%–0.28%. DQA energy-specific electron readings matched the average electron output within 0.29% for all days and all energies. MPC energy-specific readings matched the average within 0.21% for 9–20MeV. However, 6MeV showed a larger distribution about the average with four days showing a difference greater than 0.30% and a maximum difference of 0.51%. Conclusion: MPC output measurements correlated well with the widely-used DQA3 for most beam energies, making it a reliable back up technique for daily output monitoring. However, MPC may display an energy dependence for lower electrons energies, requiring additional investigation.

Purpose: This study explores novel methods to address two significant challenges affecting measurement of patient-specific quality assurance (QA) with IBA’s Matrixx Evolution™ ionization chamber array. First, dose calculation algorithms often struggle to accurately determine dose to the chamber array due to CT artifact and algorithm limitations. Second, finite chamber size and volume averaging effects cause additional deviation from the calculated dose. Methods: QA measurements were taken with the Matrixx positioned on the treatment table in a solid-water Multi-Cube™ phantom. To reduce the effect of CT artifact, the Matrixx CT image set was masked with appropriate materials and densities. Individual ionization chambers were masked as air, while the high-z electronic backplane and remaining solid-water material were masked as aluminum and water, respectively. Dose calculation was done using Varian’s Acuros XB™ (V11) algorithm, which is capable of predicting dose more accurately in non-biologic materials due to its consideration of each material’s atomic properties. Finally, the exported TPS dose was processed using an in-house algorithm (MATLAB) to assign the volume averaged TPS dose to each element of a corresponding 2-D matrix. This matrix was used for comparison with the measured dose. Square fields at regularly-spaced gantry angles, as well as selected patient plansmore » were analyzed. Results: Analyzed plans showed improved agreement, with the average gamma passing rate increasing from 94 to 98%. Correction factors necessary for chamber angular dependence were reduced by 67% compared to factors measured previously, indicating that previously measured factors corrected for dose calculation errors in addition to true chamber angular dependence. Conclusion: By comparing volume averaged dose, calculated with a capable dose engine, on a phantom masked with correct materials and densities, QA results obtained with the Matrixx Evolution™ can be significantly improved. In addition, necessary correction factors are reduced, allowing for more reliable and meaningful patient-specific QA measurements.« less

A great deal of recent research on communication has been developed in the general area of narrative or narrative effects. The majority of this work has brought in older communication concepts without reconciling those concepts with what has been learned about narrative in other social sciences. This review covers some of the major points from research on narrative to help expand the knowledge base and suggest directions for additional work in the field of communication.

This research asked if growers who participated in demonstrations were different from non-participants, and whether any such differences make an impact on demonstration results. We included a non-participant group as a comparison to our demonstration participants, and use a pretest/post-test comparison to assess change which may occur as a result of the demonstration program in contrast to any pre-existing differences which might exist. The results suggest growers' attitude toward and adoption IPM prior to participating in the demonstration have impacts on demonstration results. These results highlight the importance of considering growers' prior attitudes toward the innovation in interpreting the results of research which is designed to show the effectiveness of the innovation.

Recent years have seen changing and shifting technologies as well as an uncertain economic climate. This research focuses on how audiences have reacted to these shifts, using a number of different sources of data to test hypotheses related to spending time and money on media. We suggest that previous studies examining audience expenditures and diffusion of new technologies may have overlooked the stressful economic conditions surrounding diffusion of some of those technologies. We find an increase in entertainment technology purchases as well as time spent with new and traditional media during recession years, beyond that indicated by the longer term trends. While there is a general decrease in coviewing behavior in recent years, the recession years reversed the trend. Results are discussed in terms of the constancy hypothesis and our hypothesis that the media provide outlets for reducing stress during difficult economic times. © 2013 Taylor and Francis Group, LLC.