The allograft inflammatory factor-1 (AIF-1) is a 17 kDa interferon-Q Q-inducible Ca 2+ -binding EF-hand protein that is encoded within the HLA class III genomic region. Three proteins are probably identical with AIF-1 termed Iba1 (ionized Ca 2+ -binding adapter), MRF-1 (microglia response factor) and daintain. Considerable but not complete sequence identity with AIF-1 has been described for IRT-1 (interferon-responsive transcript), BART-1 (balloon angioplasty-responsive transcript), and other, yet unassigned alternatively spliced variants. In this review, genomic and functional characteristics of AIF-1-related proteins are summarized and a common nomenclature is proposed. ß

Objective-In vitro studies indicate a role of apoptosis regulatory proteins of the BCL-2 family in the resistance of glioblastoma multiforme to irradiation and chemotherapy. To date, no study has compared the expression of these proteins in initial and recurrent tumours. The diVerences of expression of BCL-2, BCL-X, BAX, and MCL-1 proteins of paired first resection and recurrence glioblastoma specimens were examined. Methods-Immunohistochemistry was performed in 37 cases of glioblastoma multiforme with paraYn embedded tissue from first resections and their recurrences in three treatment groups (15 radiochemotherapy, 15 irradiation, seven untreated). Ten high power fields were evaluated with an arbitrary score (< 5%=1, 5-50%=2, >50%=3), and cumulative scores for each antigen calculated. Results-In the whole group, we found a significant up regulation of antiapoptotic BCL-2 (median cumulative score of 15 in the primary, 19 at recurrence; p<0.0001 in the Wilcoxon test), BCLX (median scores 20 and 25, respectively, p<0.0001), and MCL-1 (median scores 11 and 14, p=0.0395), and a significant down regulation of proapoptotic BAX (median scores 14 and 11, p<0.0001). In the subgroups, these trends were also found. No association between protein expression and treatment regimen was found, although significant changes were restricted to the subgroups that received adjuvant chemotherapy. No significant correlation with clinical prognosis was detected with the Kaplan-Meier method. Conclusions-In the development from initial to recurrent glioblastoma multiforme, the BCL-2 family rheostat shifts towards antiapoptotic adjustment in vivo. Importantly, the changes in BCL-2 family protein expression characterised here were also seen in the subgroup of patients who did not receive adjuvant radiotherapy or chemotherapy, suggesting that the changes of BCL-2 family protein expression result not only from radiochemotherapy but also reflect the natural course of disease.

Cyclooxygenases (COX, prostaglandin endoperoxide synthases, PGG/H synthases) are potent mediators of inflammation. While COX-1 is constitutively expressed in a wide range of tissues, COX-2 is cytokine inducible. Although COX-1 expression is observed in normal tissue, enhanced COX-2 expression has been attributed a key role in the development of edema, impeding blood flow and immunomodulation observed in pathologically altered tissues. Here, we have analyzed the expression of COX-1 and COX-2 in 50 gliomas and 10 control brains with no neuropathological alterations by immunohistochemistry; 22 glioblastoma multiforme, 9 anaplastic astrocytomas, 5 protoplasmic astrocytomas, 1 gemistocytic astrocytoma and 13 fibrillary astrocytomas were included in the study. Compared with control brains, accumulation of COX-1 was detected in 20-50% of all cells in both low- and high-grade gliomas. Double-labeling experiments revealed COX-1 expression in subsets of macrophages/microglial cells within the tumor parenchyma and in areas of infiltrative tumor growth. Of the COX-1-positive cells, 90% expressed MHC class II antigens. No COX-1 immunoreactivity was observed in tumor cells. COX-2-positive cells accumulated in tumor cells and in single macrophages/microglial cells in the immediate vicinity of necroses. Further studies are required to determine whether COX-2 is involved in the development of necrosis or, more likely, whether COX-2 is a part of the tumor tissue response to necrosis.

Allograft inflammatory factor-1 (AIF-1) is a Ca2+-binding peptide that constitutes a potential modulator of macrophage activation and function during the immune response of the brain. Peptides termed microglia response factor-1 or ionized calcium-binding adaptor molecule- have been reported to be identical with AIF-1. We have investigated the expression of AIF-1 in the rat C6 glioblastoma and 9L gliosarcoma tumor models and additionally assessed AIF- expression in a diverse range of human astrocytomas by immunohistochemistry. AIF-1 was expressed by activated microglial cells and a subset of infiltrating macrophages in areas of infiltrative tumor growth and in compact tumor areas in both rat and human gliomas. Double-labeling experiments in rats and humans characterized the nature and the functional status of AIF-1+ cells. AIF-1 expression was detected in cells expressing major histocompatibility complex class II molecules and in a subset of activated macrophages/microglial cells. All MRP-8+ cells coexpressed AIF-1. In humans, there was a strong correlation of AIF-1-expressing activated macrophages/microglial cells with tumor malignancy (P < 0.0001). These results suggest that AIF-1 defines a distinct subset of tumor-associated activated macrophages/ microglial cells.

PROSPERO CRD42015021967.

Cerebrovascular pathology is common in Alzheimer's disease (AD) and is considered to contribute to cerebral malfunction. However, distinct antiangiogenic proteins that accumulate in AD brains have not yet been identified. Endostatin is a 20 kDa C-terminal fragment of collagen XVIII that, when added exogenously, inhibits endothelial proliferation and migration in vitro and angiogenesis and tumor growth in vivo by inducing apoptosis in endothelial cells. We produced a monoclonal antibody directed against endostatin and observed significantly more (p < 0.0001) immunoreactive cortical neurons in AD brains compared with age-matched neuropathologically unaltered controls. High numbers of extracellular and frequently perivascular endostatin deposits were detected in the cerebral hemispheres. Double-labeling experiments revealed colocalization of endostatin in amyloid-beta(1-40) (Abeta(1-40)), tau protein, and periodic acid-Schiff stain-positive plaques that were surrounded by focal gliosis. Western blotting revealed more 20 kDa endostatin in an AD patient compared with a control. In unstimulated SKNSH supernatants, endostatin was detected that increased predominantly after hypoxia in supernatants and cellular lysates. Abeta(1-40) (80 microg/ml) supplementation to SKNSH neurons for 24 hr completely abolished the release of endostatin. These data show that endostatin is released by neurons to accumulate in amyloid plaques in Alzheimer's disease. Induction by hypoxia and complete abrogation of endostatin release after Abeta(1-40) challenge reveals intricate interactions between the two proteins and opens new avenues for the development of novel treatment strategies of AD patients.

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