The Prognosis of Anti-Angiogenesis Treatments Combined with Standard Therapy for Newly Diagnosed Glioblastoma: A Meta-Analysis of Randomized Controlled Trials

Background and Purpose: Although bevacizumab (BV) has been approved as second-line therapy for recurrent glioblastoma (GB), the efficacy and safety of BV for patients with newly diagnosed GB remain unclear. Methodology/Principal Findings: We systematically searched electronic databases (PubMed, EMBASE, OVID, etc.) to identify related studies published from January 1966 and August 2016. Eight randomized controlled trials including a total of 2,185 patients with GB were included. We found that the median progression-free survival (PFS) was higher in the BV group than in the standard therapy (ST) group (pooled hazard ratio, 0.73;95% CI, 0.62-0.86;P = 0.0001). Compared with ST, BV improved the PFS rate at 6 months (OR 3.33, 95% CI 2.73-4.06, p<0.00001) and 12 months (OR 2.10, 95% CI 1.74-2.54, p< 0.00001). There were no significant differences in median overall survival between the BV and ST groups (OR, 1.01;95% CI, 0.83-1.23;P = 0.95). The BV group had higher survival rates at 6 months (OR, 1.41;95% CI, 1.09-1.84;P = 0.01) and 12 months (OR, 1.23;95% CI, 1.02-1.48;P = 0.03), but a low survival rate at the 36-month follow-up (OR, 0.57;95% CI, 0.32-0.98;P = 0.04). For the incidence of adverse events, three adverse outcomes were found to be significantly different between BV and ST groups, including hypertension (8.37% vs. 1.62%, p<0.000001), proteinuria (7.65% vs. 0%, p<0.001), and fatigue (14.54% vs. 9.01%, p = 0.05). Conclusions/Significance: Our study indicates that combination of BV with ST for newly diagnosed GB did not improve the median overall survival but result in longer median PFS, maintaining the quality of life and functional status. However, the long-term use of BV is associated with a higher incidence of adverse events and mortality

TAMEP are brain tumor parenchymal cells controlling neoplastic angiogenesis and progression

Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor parenchymal cells may promote specific phases of disease progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Notably, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell population, by conditional Sox2-knockout, drastically reduced glioblastoma vascularization and size. Hence, TAMEP emerge as a tumor parenchymal component with a strong impact on glioblastoma progression

The pooled HR of median PFS comparing BV with ST in patients with GB.

<p>The pooled HR of median PFS comparing BV with ST in patients with GB.</p

The PRISMA flow chart of the meta-analysis.

<p>The PRISMA flow chart of the meta-analysis.</p

The funnel plot of OS on patients with newly diagnosed GB.

<p>The funnel plot of OS on patients with newly diagnosed GB.</p

The pooled HR of median OS comparing BV with ST in patients with GB.

<p>The pooled HR of median OS comparing BV with ST in patients with GB.</p

Table_2_Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders.docx

The development of autism spectrum disorders (ASDs) involves both environmental factors such as maternal diabetes and genetic factors such as neuroligins (NLGNs). NLGN2 and NLGN3 are two members of NLGNs with distinct distributions and functions in synapse development and plasticity. The relationship between maternal diabetes and NLGNs, and the distinct working mechanisms of different NLGNs currently remain unclear. Here, we first analyzed the expression levels of NLGN2 and NLGN3 in a streptozotocin-induced ASD mouse model and different brain regions to reveal their differences and similarities. Then, cryogenic electron microscopy (cryo-EM) structures of human NLGN2 and NLGN3 were determined. The overall structures are similar to their homologs in previous reports. However, structural comparisons revealed the relative rotations of two protomers in the homodimers of NLGN2 and NLGN3. Taken together with the previously reported NLGN2–MDGA1 complex, we speculate that the distinct assembly adopted by NLGN2 and NLGN3 may affect their interactions with MDGAs. Our results provide structural insights into the potential distinct mechanisms of NLGN2 and NLGN3 implicated in the development of ASD.</p

Image_5_Expression and structural analysis of human neuroligin 2 and neuroligin 3 implicated in autism spectrum disorders.tiff

The development of autism spectrum disorders (ASDs) involves both environmental factors such as maternal diabetes and genetic factors such as neuroligins (NLGNs). NLGN2 and NLGN3 are two members of NLGNs with distinct distributions and functions in synapse development and plasticity. The relationship between maternal diabetes and NLGNs, and the distinct working mechanisms of different NLGNs currently remain unclear. Here, we first analyzed the expression levels of NLGN2 and NLGN3 in a streptozotocin-induced ASD mouse model and different brain regions to reveal their differences and similarities. Then, cryogenic electron microscopy (cryo-EM) structures of human NLGN2 and NLGN3 were determined. The overall structures are similar to their homologs in previous reports. However, structural comparisons revealed the relative rotations of two protomers in the homodimers of NLGN2 and NLGN3. Taken together with the previously reported NLGN2–MDGA1 complex, we speculate that the distinct assembly adopted by NLGN2 and NLGN3 may affect their interactions with MDGAs. Our results provide structural insights into the potential distinct mechanisms of NLGN2 and NLGN3 implicated in the development of ASD.</p

Characteristics of included studies.

<p>Characteristics of included studies.</p

The incidence of all severe AEs in patients with newly diagnosed GB.

<p>The incidence of all severe AEs in patients with newly diagnosed GB.</p