Soluble amyloid-beta (Abeta) peptide converts to structures with high beta-sheet content in Alzheimer's disease (AD). Soluble Abeta is released by neurons into the brain interstitial fluid (ISF), in which it can convert into toxic aggregates. Because assessment of ISF Abeta levels may provide unique insights into Abeta metabolism and AD, an in vivo microdialysis technique was developed to measure it. Our Abeta microdialysis technique was validated ex vivo with human CSF and then in vivo in awake, freely moving mice. Using human amyloid precursor protein (APP) transgenic mice, we found that, before the onset of AD-like pathology, ISF Abeta in hippocampus and cortex correlated with levels of APP in those tissues. After the onset of Abeta deposition, significant changes in the ISF Abeta40/Abeta42 ratio developed without changes in Abeta1-x. These changes differed from changes seen in tissue lysates from the same animals. By rapidly inhibiting Abeta production, we found that ISF Abeta half-life was short ( approximately 2 hr) in young mice but was twofold longer in mice with Abeta deposits. This increase in half-life, without an increase in steady-state levels, suggests that inhibition of Abeta synthesis reveals a portion of the insoluble Abeta pool that is in dynamic equilibrium with ISF Abeta. This now measurable in vivo pool is a likely target for new diagnostic and therapeutic strategies.
Previous glioma classification based primarily on tumour histology resulted in considerable interoberver variability and substantial variation in patient survival within grades. Furthermore, there were few known risk factors for glioma. Discoveries over the past decade have deepened our understanding of the molecular alterations underlying glioma and have led to the identification of numerous heritable genetic risk factors. The advances in glioma molecular characterization reframed our understanding of glioma biology and led the World Health Organization (WHO) to develop a new classification system for glioma. The WHO 2016 classification system comprises five glioma subtypes categorized by both tumour morphology and molecular genetic information, which led to reduced misclassification and more-uniform outcomes within glioma subtypes. To date, 25 risk loci for glioma have been identified and several rare inherited mutations that might cause glioma in some families have been discovered. This Review focuses on the two dominant trends in glioma science: the characterization of diagnostic and prognostic tumour markers and the identification of genetic and non-genetic risk factors. An overview of the many challenges still facing glioma researchers is also included.
Studies have shown that clusterin (also called apolipoprotein J) can influence the structure and toxicity of amyloid-␤ (A␤) in vitro. To determine whether endogenous clusterin plays a role in influencing A␤ deposition, structure, and toxicity in vivo, we bred PDAPP mice, a transgenic mouse model of Alzheimer's disease, to clusterin ؊/؊ mice. By 12 months of age, PDAPP, clusterin ؊/؊ mice had similar levels of brain A␤ deposition as did PDAPP, clusterin ؉/؉ mice. Although A␤ deposition was similar, PDAPP, clusterin ؊/؊ mice had significantly fewer fibrillar A␤ (amyloid) deposits than PDAPP mice expressing clusterin. In the absence of clusterin, neuritic dystrophy associated with the deposited amyloid was markedly reduced, resulting in a dissociation between fibrillar amyloid formation and neuritic dystrophy. These findings demonstrate that clusterin markedly influences A␤ structure and neuritic toxicity in vivo and is likely to play an important role in Alzheimer's disease pathogenesis.A myloid-␤ (A␤) peptides are predominantly 39-43 aa in length and are derived from the amyloid precursor protein (APP) through endoproteolytic cleavage. Abundant evidence suggests that the conversion of A␤ from soluble to insoluble forms in the brain is a key event in the pathogenesis of Alzheimer's disease (AD). Genetic and biochemical evidence supporting this idea is that all known mutations that cause early-onset forms of familial AD or 〈␤-related cerebral amyloid angiopathy map to three genes [APP, presenilin-1 (PS-1), and PS-2] (1, 2). Most of these mutations result in relative overproduction of A␤ 42 , a particularly amyloidogenic form of A␤, which over time increases the probability of A␤ aggregation. Some mutations in APP within the A␤-coding region that result in familial cerebral amyloid angiopathy do not seem to increase A␤ production but increase its propensity for aggregation and toxicity (3, 4). Although these mutations have given insight into a central role for A␤ in both AD and cerebral amyloid angiopathy, cases of ''sporadic,'' late-onset AD (age Ͼ60 years), which accounts for most AD cases, are not associated with increased A␤ production or altered A␤ sequence. The probability that A␤ will aggregate into different insoluble forms in the brain can be influenced by A␤-binding proteins, a process which occurs after A␤ generation. One example of a protein that seems to influence A␤ in this way is apolipoprotein E (apoE). The apoE4 isoform of apoE is the only proven genetic risk factor for both late-onset AD and cerebral amyloid angiopathy, and studies suggest that apoE influences A␤ structure, clearance, and neuritic toxicity both in vitro and in vivo with no clear effect on A␤ production (5-7). Whether apolipoproteins other than apoE influence A␤ aggregation and toxicity in vivo is unknown, although a good candidate for such effects is apolipoprotein J, also known as clusterin.The two most abundantly expressed apolipoproteins in the central nervous system that are present at similar concentrations are apoE and cluste...
Inhibition of the vascular endothelial growth factor (VEGF) pathway has failed to improve overall survival of patients with glioblastoma (GBM). We previously showed that angiopoietin-2 (Ang-2) overexpression compromised the benefit from anti-VEGF therapy in a preclinical GBM model. Here we investigated whether dual Ang-2/VEGF inhibition could overcome resistance to anti-VEGF treatment. We treated mice bearing orthotopic syngeneic (Gl261) GBMs or human (MGG8) GBM xenografts with antibodies inhibiting VEGF (B20), or Ang-2/VEGF (CrossMab, A2V). We examined the effects of treatment on the tumor vasculature, immune cell populations, tumor growth, and survival in both the Gl261 and MGG8 tumor models. We found that in the Gl261 model, which displays a highly abnormal tumor vasculature, A2V decreased vessel density, delayed tumor growth, and prolonged survival compared with B20. In the MGG8 model, which displays a low degree of vessel abnormality, A2V induced no significant changes in the tumor vasculature but still prolonged survival. In both the Gl261 and MGG8 models A2V reprogrammed protumor M2 macrophages toward the antitumor M1 phenotype. Our findings indicate that A2V may prolong survival in mice with GBM by reprogramming the tumor immune microenvironment and delaying tumor growth.
IMPORTANCEPer the World Health Organization 2016 integrative classification, newly diagnosed glioblastomas are separated into isocitrate dehydrogenase gene 1 or 2 (IDH)-wild-type and IDH-mutant subtypes, with median patient survival of 1.2 and 3.6 years, respectively. Although maximal resection of contrast-enhanced (CE) tumor is associated with longer survival, the prognostic importance of maximal resection within molecular subgroups and the potential importance of resection of non-contrast-enhanced (NCE) disease is poorly understood.OBJECTIVE To assess the association of resection of CE and NCE tumors in conjunction with molecular and clinical information to develop a new road map for cytoreductive surgery.
The “integrated diagnosis” for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II–IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined. All cases were assigned to one of 5 groups following the WHO 2016 diagnostic criteria based on their morphologic features, and IDH and 1p/19q codeletion status. These groups are: 1-Oligodendroglioma, IDH-mutant and 1p/19q-codeleted; 2- Astrocytoma, IDH-mutant; 3- Glioblastoma, IDH-mutant; 4- Glioblastoma, IDH-wildtype; and 5-Astrocytoma, IDH-wildtype. Within each group, we used univariate and multivariate Cox proportional hazards models to assess associations of overall survival with patient age at diagnosis, grade, and ATRX alteration status and/or TERT promoter mutation status. Among Group 1 IDH-mutant 1p/19q-codeleted oligodendrogliomas, the TERT-WT group had significantly worse overall survival than the TERT-MUT group (HR: 2.72, 95%CI: 1.05–7.04, p=0.04). In both Group 2, IDH-mutant astrocytomas and Group 3, IDH-mutant glioblastomas, neither TERT mutations nor ATRX alterations were significantly associated with survival. Among Group 4, IDH-wildtype glioblastomas, ATRX alterations were associated with favorable outcomes (HR: 0.36, 95% CI: 0.17–0.81, p=0.01). Among Group 5, IDH-wildtype astrocytomas, the TERT-WT group had significantly better overall survival than the TERT-MUT group (HR: 0.48, 95% CI: 0.27–0.87), p=0.02). Thus, we present evidence that in certain WHO 2016 diagnostic groups, testing for TERT promoter mutations or ATRX alterations may provide additional useful prognostic information.
Why Conservationists Should Heed PokémonAccording to E. O. Wilson's Biophilia hypothesis (1), humans have an innate desire to catalog, understand, and spend time with other life-forms. This in turn provides a powerful aesthetic argument for combating the present extinction crisis. Yet, as industrialization and urbanization reduce our direct interactions with nature, our interest in the variety of living things is perhaps becoming redirected toward human artifacts, with potentially grave consequences for biodiversity conservation (2-5). As Robert Pyle writes, "what is the extinction of the condor to a child who has never seen a wren?" (6, p. 147).To quantify children's knowledge of nature and shed light on the premise that their innate interest in diversity is nowadays being met by man-made variety, we surveyed 109 UK primary schoolchildren aged 4 to 11 to assess their knowledge of both natural and unnatural history. Each child was asked to identify from flashcards 10 types of British wildlife and 10 "species" of Pokémon, characters in the card-trading game invented by Satoshi Tajiri to give today's urban children a chance to collect creatures in the way he did as a child (7). Each child's set of 10 wildlife cards included at least two plants, two invertebrates, two mammals, and two birds picked randomly from a set of 100 common UK species, and the 10 Pokémon cards were drawn randomly from among 100 of the basic set of 150 Pokémon types; the order of presentation of Pokemón and wildlife cards was randomized, and a different card set was used for each child. Children aged 4 to 7 were interviewed orally, whereas older children wrote their answers down. For wildlife, the level of detail needed for identifications to be scored as correct varied across taxa, with mammals requiring genus level identification (e.g., "hare") and invertebrates requiring only ordinal classification (e.g., "beetle").Overall identification scores varied markedly across children, but there was only a moderate correlation between individuals' scores for wildlife and for Pokémon (r s corr = 0.31, N = 109, P < 0.01), with the effects of pupils' age and sex differing between card types. A generalized linear model of overall score with a Poisson error structure and with child's age, age 2 , the child's sex, the organism type (wildlife or Pokémon), and their interactions as possible predictors accounted for 43.2% of the deviance in scores. Identification success showed a hump-shaped relation with age (age + age 2 : χ 2 = 105.0, df = 2, P < 0.001; see figure). On average, boys scored slightly better than girls (sex: χ 2 = 19.59, df = 1, P < 0.001), but only because of girls' poorer performance at Pokémon (organism type * sex: χ 2 = 23.92, df = 1, P < 0.001). The effect of age differed with organism type (organism type * age + organism type * age 2 : χ 2 = 18.85, df = 2, P < 0.001). For wildlife, mean identification success rose from 32% at age 4 to 53% at age 8 and then fell slightly; for Pokémon, it rose from 7% at age 4 to 78% by age 8, with child...
Antiangiogenic therapy is associated with increased radiographic responses in glioblastomas, but tumors invariably recur. Because tumor-associated macrophages have been shown to mediate escape from antiangiogenic therapy in preclinical models, we examined the role of macrophages in patients with recurrent glioblastoma. We compared autopsy brain specimens from 20 patients with recurrent glioblastoma who received antiangiogenic treatment and chemoradiation with 8 patients who received chemotherapy and/or radiotherapy without antiangiogenic therapy or no treatment. Tumor-associated macrophages were morphologically and phenotypically analyzed using flow cytometry and immunohistochemistry for CD68, CD14, CD163, and CD11b expression. Flow cytometry showed an increase in macrophages in the antiangiogenic-treated patients. Immunohistochemical analysis demonstrated an increase in CD68+ macrophages in the tumor bulk (P , .01) and infiltrative areas (P ¼ .02) in antiangiogenic-treated patients. We also observed an increase in CD11b+ cells in the tumor bulk (P , .01) and an increase in CD163+ macrophages in infiltrative tumor (P ¼ .02). Of note, an increased number of CD11b+ cells in bulk and infiltrative tumors (P ¼ .05 and P ¼ .05, respectively) correlated with poor overall survival among patients who first received antiangiogenic therapy at recurrence. In summary, recurrent glioblastomas showed an increased infiltration in myeloid populations in the tumor bulk and in the infiltrative regions after antiangiogenic therapy. Higher numbers of CD11b+ cells correlated with poor survival among these patients. These data suggest that tumor-associated macrophages may participate in escape from antiangiogenic therapy and may represent a potential biomarker of resistance and a potential therapeutic target in recurrent glioblastoma.
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