Citations

Abstract 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. Clin Cancer Res; 21(14); 3274–85. ©2015 AACR.

A two microphone adaptive digital noise cancellation technique was used to improve word-recognition ability of normally hearing and hearing-impaired subjects in the presence of varying amounts of multitalker speech babble noise and speech spectrum noise. Signal-to-noise ratios varied from -8 dB to + 12 dB in 4 dB increments. The adaptive noise cancellation technique resulted in reducing both the speech babble and speech spectrum noises 18 to 22 dB. This reduction in noise resulted in average improvements in word recognition, at the poorest signal-to-noise ratios, ranging from 37% to 50% for the normally hearing subjects and 27% to 40% for the hearing-impaired subjects. Improvements in word recognition in the presence of speech babble noise as a result of adaptive filtering were just as large or larger than improvements found in the presence of speech spectrum noise. The amount of improvement of word-recognition scores was most pronounced at the least favorable signal-to-noise ratios.

A nonlinear model of the human aural system is proposed. Utilizing a homomorphic transformation, the model is implemented in a digital computer and accounts for the Fletcher critical bands in hearing, the nonlinear relationship between input sound intensity and perceived loudness known as recruitment, as well as the thresholds of audibility and the maximum tolerance threshold. The transformed or output signal domain is identified as a perceptual space. It is shown that the model can be used to reproduce the Fletcher Munson equal loudness contours for normal hearing populations. Modification of easily measured parameters results in the generation of equal loudness contours for hearing impaired individuals. Through a combination of the forward homomorphic transformation for normal hearing to the perceptual domain and the inverse mapping utilizing parameters of a hearing impaired individual, it is shown that hearing intelligibility is dramatically improved. It is postulated that signal processing performed in the perceptual domain will produce results more pleasing and intelligible to the listener. Results of auditory testing utilizing the proposed model for both normal and hearing impaired populations are presented. Speech intelligibility scores are shown to increase by more than 40% (i.e., from 40% to over 80%) over preprocessed scores under headphones for hearing impaired subjects used in these tests.

Abstract Background Primary sarcomas of the liver are extremely rare in adults. Optimal therapeutic approaches remain unclear. Methods Twenty consecutive adult patients who had surgical treatment for primary hepatic sarcomas were reviewed. Patient age ranged from 23 to 80 years. Other than one patient with primary hepatic angiosarcoma who had a history of thorium dioxide colloid (Thorotrast) exposure 23 years before diagnosis, no predisposing causes were apparent. Nineteen patients had hepatic resection and one patient had an orthotopic liver transplant. No patient received neoadjuvant chemotherapy or radiotherapy but radiotherapy was delivered intraoperatively in one patient. Results Leiomyosarcoma was the most common histological type of sarcoma diagnosed (five of 20 patients), followed by malignant solitary fibrous tumour (four) and epithelioid haemangioendothelioma (three). Fourteen tumours were high-grade sarcomas and six were low grade malignancies. Thirteen patients developed a recurrence. Distant metastases (ten patients) and intrahepatic recurrence (six) were the predominant sites of initial treatment failure. Six patients received salvage chemotherapy. Histological grade was the only factor significantly associated with overall patient survival (P = 0·03). With complete resection, patients with high-grade tumours had a 5-year survival rate of 18 (95 per cent confidence interval 5–62) per cent compared with 80 (52–100) per cent for patients with low-grade tumours. The 5-year survival rate for all 20 patients was 37 (20–60) per cent. Conclusion Surgical resection is the only effective therapy for primary hepatic sarcomas at present. Better adjuvant therapy is necessary, especially for high-grade malignancies, owing to the high failure rate with operation alone.