The E1B19K-deleted oncolytic adenovirus mutant Ad Delta 19K sensitizes pancreatic cancer cells to drug-induced DNA-damage by down-regulating Claspin and Mre11

This study was supported by a generous grant from the UK charity Pancreatic Cancer Research Fund (PCRF) and by the BCI CRUK Centre Grant [grant number C16420/A18066]

The adenoviral AdDD mutant enhances mitoxantrone-induced cell death by promoting apoptosis and attenuating autophagy in prostate cancer cells.

Meeting Abstrac

Experimental analysis of a window air conditioner with R-22 and zeotropic mixture of R-32/125/134a

This study is the result of the cooperative research and development agreement (CRADA) between Oak Ridge National Laboratory and E.I. Du Pont De Nemours and Company, Inc., (CRADA No. 92-0161) for testing the use of heat exchangers as the evaporator and condenser in an air-conditioning rig. Heat exchangers at typical realistic operating conditions were tested with R-22 and with its potential replacement, a ternary mixture of R-32(30%)/R-125(10%)/R-134a(60%). A test rig was built that provided for operation of the low-temperature exchanger (evaporator) with flooded coils. The test results indicated that the performance of the evaporator heat exchanger using ternary mixture, in terms of cooling capacity, would be around 7.4% less than the performance using R-22. The cooling capacity for both refrigerants improved with flooded evaporator operation by 8.6% for R-22 and by 15% for ternary mixture. Compared with R-22 operation, operation with ternary mixture results in slightly higher compressor discharge pressure, lower compressor discharge temperature, slightly lower compressor power consumption, and a higher compressor high-low pressure ratio. Temperature glide for ternary mixture, for both evaporator and condenser, was clearly evident, but not as pronounced as expected because of the pressure drop (and thus the temperature drop) along the coils. Further improvement of the performance of ternary mixture is possible if the evaporator is arranged in a counter-cross-flow configuration to take advantage of the temperature glide. Current evaporator designs are mostly concurrent-cross-flow, which is more appropriate for single-component refrigerants or azeotropic refrigerant mixtures

Purification of the pancreatic cholecystokinin receptor

We have previously shown that the pancreatic cholecystokinin (CCK) receptor can be solubilized in 1% digitonin. In this study, digitonin-solubilized CCK receptors from rat pancreas were purified using sequential affinity chromatography on ricin-II agarose and on AffiGel-CCK. Electrophoresis of the radioiodinated purified receptors on SDS-polyacrylamide gels followed by autoradiography revealed two proteins: a major band of Mr = 80,000-90,000, and a minor band of Mr = 55,000. Through the purification procedure, the receptors preserved their agonist specificity (CCK-8 Kd = 9.4 nM. The estimated purification was about 80,000 fold and consistent with the expected Bmax for a pure Mr = 80,000 protein binding one CCK molecule. This two-step purification procedure opens the possibility for molecular studies of the CCK receptor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28032/1/0000471.pd

Summary of Gummed Film Results Through December 1959

The data for gummed-film fall-out measurements through Dec. 1959 are reported. While the initial purpose of the gummed-film network was to determine the geographic distribution and time of arrival of fall-out, considerable effort has been devoted to computation of Sr/sup 90/ deposition and infinity gamma dose. These latter computations have been satisfactory for the period of observation and furnish data for locations not covered by other types of measurement. Detailed comparisons are made between Sr/sup 90/ estimates from gummed film and analyses made on pot and soil samples. Comparable tests of the gamma-dose estimate are not possible. Summary tables are given for each gummed-film station listing the monthly estimates of Sr/sup 90/ deposition and infinity gamma dose. (auth

A role for macrophages under cytokine control in mediating resistance to ADI-PEG20 (pegargiminase) in ASS1-deficient mesothelioma

Background Pegylated arginine deiminase (ADI-PEG20; pegargiminase) depletes arginine and improves survival outcomes for patients with argininosuccinate synthetase 1 (ASS1)-deficient malignant pleural mesothelioma (MPM). Optimisation of ADI-PEG20-based therapy will require a deeper understanding of resistance mechanisms, including those mediated by the tumor microenvironment. Here, we sought to reverse translate increased tumoral macrophage infiltration in patients with ASS1-deficient MPM relapsing on pegargiminase therapy. Methods Macrophage-MPM tumor cell line (2591, MSTO, JU77) co-cultures treated with ADI-PEG20 were analyzed by flow cytometry. Microarray experiments of gene expression profiling were performed in ADI-PEG20-treated MPM tumor cells, and macrophage-relevant genetic “hits” were validated by qPCR, ELISA, and LC/MS. Cytokine and argininosuccinate analyses were performed using plasma from pegargiminase-treated patients with MPM. Results We identified that ASS1-expressing macrophages promoted viability of ADI-PEG20-treated ASS1-negative MPM cell lines. Microarray gene expression data revealed a dominant CXCR2-dependent chemotactic signature and co-expression of VEGF-A and IL-1α in ADI-PEG20-treated MPM cell lines. We confirmed that ASS1 in macrophages was IL-1α-inducible and that the argininosuccinate concentration doubled in the cell supernatant sufficient to restore MPM cell viability under co-culture conditions with ADI-PEG20. For further validation, we detected elevated plasma VEGF-A and CXCR2-dependent cytokines, and increased argininosuccinate in patients with MPM progressing on ADI-PEG20. Finally, liposomal clodronate depleted ADI-PEG20-driven macrophage infiltration and suppressed growth significantly in the MSTO xenograft murine model. Conclusions Collectively, our data indicate that ADI-PEG20-inducible cytokines orchestrate argininosuccinate fuelling of ASS1-deficient mesothelioma by macrophages. This novel stromal-mediated resistance pathway may be leveraged to optimize arginine deprivation therapy for mesothelioma and related arginine-dependent cancers

The oncolytic virus dl922-947 reduces IL-8/CXCL8 and MCP-1/CCL2 expression and impairs angiogenesis and macrophage infiltration in anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human solid tumor and current treatments are ineffective in increasing patients' survival. Thus, the development of new therapeutic approaches for ATC is needed. We have previously shown that the oncolytic adenovirus dl922-947 induces ATC cell death in vitro and tumor regression in vivo. However, the impact of dl922-947 on the pro-tumorigenic ATC microenvironment is still unknown. Since viruses are able to regulate cytokine and chemokine production from infected cells, we sought to investigate whether dl922-947 virotherapy has such effect on ATC cells, thereby modulating ATC microenvironment. dl922-947 decreased IL-8/CXCL8 and MCP-1/CCL2 production by the ATC cell lines 8505-c and BHT101-5. These results correlated with dl922-947-mediated reduction of NF-κB p65 binding to IL8 promoter in 8505-c and BHT101-5 cells and CCL2 promoter in 8505-c cells. IL-8 stimulates cancer cell proliferation, survival and invasion, and also angiogenesis. dl922-947-mediated reduction of IL-8 impaired ATC cell motility in vitro and ATC-induced angiogenesis in vitro and in vivo. We also show that dl922-947-mediated reduction of the monocyte-attracting chemokine CCL2 decreased monocyte chemotaxis in vitro and tumor macrophage density in vivo. Interestingly, dl922-947 treatment induced the switch of tumor macrophages toward a pro-inflammatory M1 phenotype, likely by increasing the expression of the pro-inflammatory cytokine interferon-γ. Altogether, we demonstrate that dl922-947 treatment re-shape the pro-tumorigenic ATC microenvironment by modulating cancer-cell intrinsic factors and the immune response. An in-depth knowledge of dl922-947-mediated effects on ATC microenvironment may help to refine ATC virotherapy in the context of cancer immunotherapy

Identification of Novel Methylation Markers in Hepatocellular Carcinoma using a Methylation Array

Promoter CpG island hypermethylation has become recognized as an important mechanism for inactivating tumor suppressor genes or tumor-related genes in human cancers of various tissues. Gene inactivation in association with promoter CpG island hypermethylation has been reported to be four times more frequent than genetic changes in human colorectal cancers. Hepatocellular carcinoma is also one of the human cancer types in which aberrant promoter CpG island hypermethylation is frequently found. However, the number of genes identified to date as hypermethylated for hepatocellular carcinoma (HCC) is fewer than that for colorectal cancer or gastric cancer, which can be attributed to fewer attempts to perform genome-wide methylation profiling for HCC. In the present study, we used bead-array technology and coupled methylation-specific PCR to identify new genes showing cancer-specific methylation in HCC. Twenty-four new genes have been identified as hypermethylated at their promoter CpG island loci in a cancer-specific manner. Of these, TNFRSF10C, HOXA9, NPY, and IRF5 were frequently hypermethylated in hepatocellular carcinoma tissue samples and their methylation was found to be closely associated with inactivation of gene expression. Further study will be required to elucidate the clinicopathological implications of these newly found DNA methylation markers in hepatocellular carcinoma

Brief biopsychosocially informed education can improve insurance workers' back pain beliefs: Implications for improving claims management behaviours

Background: Biopsychosocially informed education is associated with improved back pain beliefs and positive changes in health care practitioners’ practice behaviours. Objective: Assess the effect of this type of education for insurance workers who are important non-clinical stakeholders in the rehabilitation of injured workers. Methods: Insurance workers operating in the Western Australian workers’ compensation system underwent two, 1.5 hour sessions of biopsychosocially informed education focusing on understanding and identifying barriers to recovery of injured workers with musculoskeletal conditions. Back pain beliefs were assessed pre-education, immediately post-education and at three-month follow-up (n = 32). Self-reported and Injury Management Advisor-reported assessment of change in claims management behaviours were collected at the three-month follow-up. Results: There were positive changes in the Health Care Providers’ Pain and Impairment Relationship Scale (p = 0.009) and Back Beliefs Questionnaire (p = 0.049) immediately following the education that were sustained at three-month follow-up. Positive changes in claims management behaviours were supported by self-reported and Injury Management Advisor-reported data. Conclusion: This study provides preliminary support that a brief biopsychosocially informed education program can positively influence insurance workers’ beliefs regarding back pain, with concurrent positive changes in claims management behaviours. Further research is required to ascertain if these changes result in improved claims management outcomes