There is a need for transplantable murine models of ovarian high-grade serous carcinoma (HGSC) with regard to mutations in the human disease to assist investigations of the relationships between tumor genotype, chemotherapy response, and immune microenvironment. In addressing this need, we performed wholeexome sequencing of ID8, the most widely used transplantable model of ovarian cancer, covering 194,000 exomes at a mean depth of 400Â with 90% exons sequenced >50Â. We found no functional mutations in genes characteristic of HGSC (Trp53, Brca1, Brca2, Nf1, and Rb1), and p53 remained transcriptionally active. Homologous recombination in ID8 remained intact in functional assays. Further, we found no mutations typical of clear cell carcinoma (Arid1a, Pik3ca), low-grade serous carcinoma (Braf), endometrioid (Ctnnb1) validates new CRISPR-generated models of HGSC to investigate its biology and promote mechanism-based therapeutics discovery.
The pretreatment mGPS is a useful and important predictor of cancer-specific survival in patients with inoperable NSCLC. Basing clinical assessment on the mGPS has implications for the routine monitoring and treatment of the patients.
Both the tumour growth and progression and the systemic inflammatory response have the potential to increase oxidative stress. We therefore examined the relationship between lipid-soluble antioxidant vitamins, lipid peroxidation, the systemic inflammatory response and survival in patients with primary operable (n 5 53) and advanced inoperable (n 5 53) colorectal cancer. Compared with those patients with primary operable colorectal cancer, patients with unresectable liver disease had significantly lower median concentrations of a-tocopherol (p < 0.001), lutein (p < 0.001), lycopene (p < 0.001), a-carotene (p < 0.01) and b-carotene (p < 0.001) and higher malondialdehyde concentrations. An elevated systemic inflammatory response (Glasgow prognostic score, mGPS) was associated with a greater proportion of females (p < 0.05) and more advanced tumour stage (p < 0.05), lower circulating levels of retinol (p < 0.01), lutein (p < 0.01), lycopene (p < 0.01) and a-(p < 0.01) and b-carotene but not MDA (p 5 0.633). In the liver metastases group 41 patients died of their cancer and a further 1 patient died of intercurrent disease on follow-up. On univariate survival analysis, mGPS (p < 0.01), retinol (p < 0.001), atocopherol (p < 0.05) and a-carotene (p < 0.05) were associated significantly with cancer-specific survival. On multivariate survival analysis of these significant variables, only mGPS (p < 0.01) and retinol (p < 0.001) were independently associated with cancer-specific survival. The results of the present study showed that the systemic inflammatory response was associated with a reduction of lipid-soluble antioxidant vitamins, whereas advanced tumour stage was associated with increased lipid peroxidation in patients with colorectal cancer. Of the antioxidant vitamins measured, only retinol was independently associated with cancer-specific survival. ' 2008 Wiley-Liss, Inc.Key words: colorectal cancer; vitamin A; vitamin E; carotenoids; malonyldialdehyde; TNM stage; Glasgow prognostic score; survival Colorectal cancer remains the second commonest cause of cancer deaths in Western Europe and North America. Each year in the United Kingdom, there are 35,000 new cases and 16,000 deaths attributable to the disease.1 Overall survival is poor; even in those patients who undergo potentially curative resection, more than one-third die within 5 years. It is increasingly recognised that variations in outcome in cancer patients are not solely determined by the characteristics of the tumour but also by host-immune response factors. [3][4][5] It is now accepted that the host systemic inflammatory response can be assessed by examining the changes in the circulating concentrations of acute-phase proteins, such as an elevated concentration of C-reactive protein and a low concentrations of albumin 6 and that these have prognostic values in patients with cancer. 7,8 Recently, the combination of C-reactive protein and albumin, known as the Glasgow prognostic score (GPS), has been validated as a prognostic factor in patients with color...
The amyloid-β peptide (Aβ) plays a central role in the pathogenesis of Alzheimer's disease (AD). The fibrillar form of Aβ (fAβ) exerts toxic effects on neurons through mechanisms not well understood. We have shown that the aged primate cortex is selectively vulnerable to fAβ toxicity at low concentrations. In addition to neuronal loss, fAβ induced massive activation of microglia in the aged rhesus cortex. We now demonstrate that inhibition of microglia activation abolishes fAβ toxicity. Injection or pump delivery of macrophage/microglia inhibitory factor (MIF) significantly reduced activation of microglia and the volume of damage caused by fAβ. Microglia isolated from aged rhesus cortex produced substantial reactive oxygen species when stimulated by fAβ, which was inhibited by MIF in a dose-dependent manner. This is the first definitive in vivo demonstration that the fAβ-induced microglia activation and inflammation mediate, at least in part, its toxic effects on neurons. Combined with our earlier observations, these findings suggest that aged primate microglia may display an exaggerated inflammatory response to fAβ when compared with young microglia.
The amyloid- peptide (A) deposited in plaques in Alzheimer's disease has been shown to cause degeneration of neurons in experimental paradigms in vivo and in vitro. However, it has been difficult to convincingly demonstrate toxicity of native amyloid deposits in the aged and Alzheimer brains. Here we provide evidence that the fibrillar conformation of A (fA) deposited in compact plaques is associated with the pathologies observed in Alzheimer brains. fA containing compact but not diffuse plaques in the aged rhesus cortex contained activated microglia and clusters of phosphorylated tau-positive swollen neurites. Scholl's quantitative analysis revealed that the area adjacent to fA, containing compact but not diffuse plaques in aged rhesus, aged human, and Alzheimer's disease cortex, displays significant loss of neurons and small but statistically significant reduction in the density of cholinergic axons. These observations suggest that fA toxicity may not be restricted to cultured cells and animal injection models. Rather, fA deposited in native compact plaques in aged and AD brains may exert selective toxic effects on its surrounding neural environment.
Oncolytic viruses (OVs) can trigger profound innate and adaptive immune responses, which have the potential both to potentiate and reduce the activity of OVs. Natural killer (NK) cells can mediate potent anti-viral and anti-tumoral responses, but there are no data on the role of NK cells in oncolytic adenovirus activity. Here, we have used two different oncolytic adenoviruses-the Ad5 E1A CR2-deletion mutant dl922-947 (group C) and the chimeric Ad3/Ad11p mutant enadenotucirev (group B)-to investigate the effect of NK cells on overall anti-cancer efficacy in ovarian cancer. Because human adenoviruses do not replicate in murine cells, we utilized primary human NK cells from peripheral blood and ovarian cancer ascites. Our results show that dl922-947 and enadenotucirev do not infect NK cells, but induce contact-dependent activation and anti-cancer cytotoxicity against adenovirus-infected ovarian cancer cells. Moreover, manipulation of NK receptors DNAM-1 (DNAX accessory molecule-1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains) significantly influences NK cytotoxicity against adenovirus-infected cells. Together, these results indicate that NK cells act to increase the activity of oncolytic adenovirus in ovarian cancer and suggest that strategies to augment NK activity further via the blockade of inhibitory NK receptor TIGIT could enhance therapeutic potential of OVs.
It has been suggested that lower motor neurons containing calcium-binding proteins (CBP) may be resistant to degeneration in motor neuron disease. The testing of this hypothesis is hampered by lack of comprehensive information regarding the presence of CBPs in motor neurons. To address this shortcoming, we investigated the distribution of the CBPs calbindin-D28K (CB), parvalbumin (PV) and calretinin (CRT) in lower motor neurons in the normal human and two non-human primates (rhesus monkey and common marmoset) using immunohistochemistry. A variable proportion of motor neurons in cranial nerve motor nuclei contained immunoreactivity for one or more CBPs. A subpopulation of spinal cord alpha-motor neurons was also CBP-positive. Comparison of staining for choline acetyltransferase (ChAT) and CBPs in the human spinal cord demonstrated that approximately 63% of ventral horn motor neurons contained PV, 53% contained CRT and 56% contained CB. CBP immunoreactivity within motor neurons was of variable staining intensity. It remains to be established whether the presence of these CBPs confers protection against the pathogenic mechanisms of motor neuron disease.
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