Our results demonstrate that reduced 26S proteasome activity is a general feature of CICs that can easily be exploited to identify, track, and target them in vitro and in vivo.

A B S T R A C T PurposeEvaluation of treatment effects in malignant brain tumors is challenging because of the lack of reliable response predictors of tumor response. This study examines the predictive value of positron emission tomography (PET) using [18 F] fluorothymidine (FLT), an imaging biomarker of cell proliferation, in patients with recurrent malignant gliomas treated with bevacizumab in combination with irinotecan. Patients and MethodsPatients with recurrent malignant gliomas treated with biweekly cycles of bevacizumab and irinotecan were prospectively studied with FLT-PET at baseline, after 1 to 2 weeks, and after 6 weeks from start of treatment. A more than 25% reduction in tumor FLT uptake as measured by standardized uptake value was defined as a metabolic response. FLT responses were compared with response as shown by magnetic resonance imaging (MRI) and patient survival. ResultsTwenty-one patients were included, and 19 were assessable for metabolic response evaluation with FLT-PET. There were nine responders (47%) and 10 nonresponders (53%). Metabolic responders survived three times as long as nonresponders (10.8 v 3.4 months; P ϭ .003), and tended to have a prolonged progression-free survival (P ϭ .061). Both early and later FLT-PET responses were more significant predictors of overall survival (1 to 2 weeks, P ϭ .006; 6 weeks, P ϭ .002), compared with the MRI responses (P ϭ .060 for both 6-week and best responses). ConclusionFLT-PET as an imaging biomarker seems to be predictive of overall survival in bevacizumab and irinotecan treatment of recurrent gliomas. Whether FLT-PET performed as early as 1 to 2 week after starting treatment is as predictive as the study indicates at 6 weeks warrants further investigation.

We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-␤ (A␤) clearance from the brain of patients with sporadic Alzheimer's disease (AD). Macrophages of a majority of AD patients do not transport A␤ into endosomes and lysosomes, and AD monocytes do not efficiently clear A␤ from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport A␤ to endosomes and lysosomes, and monocytes of these subjects clear A␤ in AD brain sections. Upon A␤ stimulation, mononuclear cells of normal subjects up-regulate the transcription of ␤-1,4-mannosyl-glycoprotein 4-␤-N-acetylglucosaminyltransferase (MGAT3) (P < 0.001) and other genes, including Toll like receptors (TLRs), whereas mononuclear cells of AD patients generally down-regulate these genes. Defective phagocytosis of A␤ may be related to down-regulation of MGAT3, as suggested by inhibition of phagocytosis by using MGAT3 siRNA and correlation analysis. Transcription of TLR3, bditTLR4, TLR5, bditTLR7, TLR8, TLR9, and TLR10 upon A␤ stimulation is severely depressed in mononuclear cells of AD patients in comparison to those of control subjects. In mononuclear cells of some AD patients, the curcuminoid compound bisdemethoxycurcumin may enhance defective phagocytosis of A␤, the transcription of MGAT3 and TLRs, and the translation of TLR2-4. Thus, bisdemethoxycurcumin may correct immune defects of AD patients and provide a previously uncharacterized approach to AD immunotherapy.amyloid-␤ ͉ phagocytosis ͉ endocytosis ͉ MGAT3 siRNA A ccording to the amyloid-␤ (A␤) hypothesis, amyloidosis occurring in the brain of patients with Alzheimer's disease (AD) by fibrillar A␤ 1-42 and 1-40 (1) and A␤ oligomers (2) is a leading cause of neurodegeneration in AD (3). Macrophages and microglia are the innate immune cells responsible for clearance of pathogens and waste products. We have shown that blood-borne monocyte/ macrophages of AD patients migrate across the blood-brain barrier into AD brain but are defective in clearance of A␤ in neuritic plaques (4), and they overexpress cyclooxygenase-2 and inducible NO synthase (4). Resident microglia in AD brain display markers of inflammation (5, 6), phagocytosis (7), and proinflammatory but not prophagocytic genes (8). However, most microglia invading A␤ plaques in transgenic mouse models are bone marrow-derived, not resident microglia (9). Thus, the brains of AD patients and transgenic mice seem to display inflammatory responses by microglia and defective A␤ clearance by blood-borne macrophages. Consequently, the defective innate immune system of AD patients might be a culprit in brain amyloidosis leading to brain inflammation.The mechanisms of neurodegeneration produced by abnormally folded proteins, A␤, and phosphorylated remain an enigma (10).The pathogenesis of neurodegeneration in AD involves the impact of polymorphic proteins, such as amyloid precursor...

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