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Gliomas are thought to form by clonal expansion from a single cell-of-origin, and progression-associated mutations to occur in its progeny cells. Glioma progression is associated with elevated growth factor signaling and loss of function of tumor suppressors Ink4a, Arf and Pten. Yet, gliomas are cellularly heterogeneous; they recruit and trap normal cells during infiltration. We performed lineage tracing in a retrovirally mediated, molecularly and histologically accurate mouse model of hPDGFb-driven gliomagenesis. We were able to distinguish cells in the tumor that were derived from the cell-of-origin from those that were not. Phenotypic, tumorigenic and expression analyses were performed on both populations of these cells. Here we show that during progression of hPDGFb-induced murine gliomas, tumor suppressor loss can expand the recruited cell population not derived from the cell-of-origin within glioma microenvironment to dominate regions of the tumor, with essentially no contribution from the progeny of glioma cell-of-origin. Moreover, the recruited cells can give rise to gliomas upon transplantation and passaging, acquire polysomal expression profiles and genetic aberrations typically present in glioma cells rather than normal progenitors, aid progeny cells in glioma initiation upon transplantation, and become independent of PDGFR signaling. These results indicate that non-cell-of-origin derived cells within glioma environment in the mouse can be corrupted to become bona fide tumor, and deviate from the generally established view of gliomagenesis.

Glioblastoma is the most common adult primary brain tumor and has a dismal median survival. Radiation is a mainstay of treatment and significantly improves survival, yet recurrence is nearly inevitable. Better understanding the radiation response of glioblastoma will help improve strategies to treat this devastating disease. Here, we present a comprehensive study of the in vivo radiation response of glioma cells in a mouse model of proneural glioblastoma. These tumors are a heterogeneous mix of cell types with differing radiation sensitivities. To explicitly study the gene expression changes comprising the radiation response of the Olig2 ⁺ tumor bulk cells, we used translating ribosome affinity purification (TRAP) from Olig2-TRAP transgenic mice. Comparing both ribosome-associated and total pools of mRNA isolated from Olig2 ⁺ cells indicated that the in vivo gene expression response to radiation occurs primarily at the total transcript level. Genes related to apoptosis and cell growth were significantly altered. p53 and E2F were implicated as major regulators of the radiation response, with p53 activity needed for the largest gene expression changes after radiation. Additionally, radiation induced a marked shift away from a proneural expression pattern toward a mesenchymal one. This shift occurs in Olig2 ⁺ cells within hours and in multiple genetic backgrounds. Targets for Stat3 and CEBPB, which have been suggested to be master regulators of a mesenchymal shift, were also up-regulated by radiation. These data provide a systematic description of the events following radiation and may be of use in identifying biological processes that promote glioma radioresistance.

The tumor microenvironment contains normal, non-neoplastic cells that may contribute to tumor growth and maintenance. Within PDGF-driven murine gliomas, tumor-associated astrocytes (TAAs) are a large component of the tumor microenvironment. The function of non-neoplastic astrocytes in the glioma microenvironment has not been fully elucidated; moreover, the differences between these astrocytes and normal astrocytes are unknown. We therefore sought to identify genes and pathways that are increased in TAAs relative to normal astrocytes and also to determine whether expression of these genes correlates with glioma behavior. We compared the gene expression profiles of TAAs to normal astrocytes and found the Antigen Presentation Pathway to be significantly increased in TAAs. We then identified a gene signature for glioblastoma (GBM) TAAs and validated the expression of some of those genes within the tumor. We also show that TAAs are derived from the non-tumor, stromal environment, in contrast to the Olig2+ tumor cells that constitute the neoplastic elements in our model. Finally, we validate this GBM TAA signature in patients and show that a TAA-derived gene signature predicts survival specifically in the human proneural subtype of glioma. Our data identifies unique gene expression patterns between populations of TAAs and suggests potential roles for stromal astrocytes within the glioma microenvironment. We show that certain stromal astrocytes in the tumor microenvironment express a GBM-specific gene signature and that the majority of these stromal astrocyte genes can predict survival in the human disease.

Large‐scale cancer genomics projects are profiling hundreds of tumors at multiple molecular layers, including copy number, mRNA and miRNA expression, but the mechanistic relationships between these layers are often excluded from computational models. We developed a supervised learning framework for integrating molecular profiles with regulatory sequence information to reveal regulatory programs in cancer, including miRNA‐mediated regulation. We applied our approach to 320 glioblastoma profiles and identified key miRNAs and transcription factors as common or subtype‐specific drivers of expression changes. We confirmed that predicted gene expression signatures for proneural subtype regulators were consistent with in vivo expression changes in a PDGF‐driven mouse model. We tested two predicted proneural drivers, miR‐124 and miR‐132, both underexpressed in proneural tumors, by overexpression in neurospheres and observed a partial reversal of corresponding tumor expression changes. Computationally dissecting the role of miRNAs in cancer may ultimately lead to small RNA therapeutics tailored to subtype or individual. Integration of expression, copy number, methylation, and regulatory sequence information identifies miRNAs and transcription factors that drive the global expression changes associated with different glioblastoma subtypes. Synopsis Integration of expression, copy number, methylation, and regulatory sequence information identifies miRNAs and transcription factors that drive the global expression changes associated with different glioblastoma subtypes. The proneural and mesenchymal transcriptomic subtypes of glioblastoma are associated with distinct regulatory programs. REST, miR‐124 and miR‐132 are potential drivers of expression changes in proneural glioblastoma, and the inferred extent of dysregulation of miR‐132 correlates with survival in the proneural subtype. The expression changes in proneural glioblastoma associated with key regulators in the regression model are consistent with in vivo expression changes in mouse PDGF‐driven tumors. Transfection of miR‐124 and miR‐132 in proneural neurospheres induces expression changes that are concordant with proneural tumor‐versus‐normal expression changes.

Fishing for complement Three papers in this issue report the first X-ray structures of C3b, the active form of human complement C3. The complement system is a family of blood serum proteins and cell-surface receptors that recognizes pathogens and unleashes the immune response against them. The powerhouse of the C3 protein is a thioester group: when activated it binds to an acceptor on the pathogen and marks it for destruction. There are similar thioesters in host cells too, so the C3 thioester has to be kept tightly under wraps. Knowledge of the structure of the active form of C3b is a step towards designing therapies to manipulate the complement system. Inappropriate activation of the complement system has been implicated in various diseases including arthritis, asthma, lupus erythematosus, autoimmune heart disease and multiple sclerosis. The complement system is a key part of the innate immune system, and is required for clearance of pathogens from the bloodstream 1 . After exposure to pathogens, the third component of the complement system, C3, is cleaved to C3b which, after recruitment of factor B, initiates formation of the alternative pathway convertases 2 , 3 , 4 . CRIg, a complement receptor expressed on macrophages, binds to C3b and iC3b mediating phagocytosis of the particles 5 , but it is unknown how CRIg selectively recognizes proteolytic C3-fragments and whether binding of CRIg to C3b inhibits convertase activation. Here we present the crystal structure of C3b in complex with CRIg and, using CRIg mutants, provide evidence that CRIg acts as an inhibitor of the alternative pathway of complement. The structure shows that activation of C3 induces major structural rearrangements, including a dramatic movement (>80 Å) of the thioester-bond-containing domain through which C3b attaches to pathogen surfaces. We show that CRIg is not only a phagocytic receptor, but also a potent inhibitor of the alternative pathway convertases. The structure provides insights into the complex macromolecular structural rearrangements that occur during complement activation and inhibition. Moreover, our structure–function studies relating the structural basis of complement activation and the means by which CRIg inhibits the convertases provide important clues to the development of therapeutics that target complement.

Post-transcriptional regulation of gene expression contributes to the protein output of a cell, however, methods for measuring translational regulation in complex in vivo systems are lacking. Here, we describe a sensitive method for measuring translational regulation in defined cell populations from heterogeneous tissue in vivo. We adapted the translating ribosome affinity purification (TRAP) methodology to measure the relative occupancy of individual mRNA transcripts in translating ribosomes in the Olig2-positive tumor cell population in a genetically engineered mouse model (GEM) of glioma. Global measurement of paired ribosome-bound and total cellular mRNA populations from tumor cells in vivo identified a broad distribution of relative ribosome occupancies amongst mRNA species that was highly reproducible across biological samples. Comparison of the translation state of glioma cells to non-transformed oligodendrocyte progenitor cells in normal brain identified global alteration of translation in tumor, and specifically of genes involved in cell division and synthetic metabolism. Furthermore, investigation of alteration in steady state translational efficiencies upon loss of PTEN, one of the most frequently mutated and deleted tumor suppressors in glioma, identified differential translation of proteins involved in cellular respiration, canonically regulated by PI3K/Akt signaling, and cellular glycosylation profiles, deregulation of which is known to be associated with tumor progression. Application of the translation efficiency profiling method described here to other biological contexts and conditions would extend our knowledge of the scope and impact of this important mode of gene regulation in complex in vivo systems.

To compare the mean of anteroposterior (AP) measurements of the uterus in longitudinal and oblique transverse planes, and the pulsatility index (PI) and resistive index (RI) of the uterine artery and superficial skin wound artery between patients taking Channa striatus and placebo. Channa striatus, also known as haruan, is a fresh water snakehead fish consumed in many parts of Southeast Asia. Channa striatus is also normally consumed by women postpartum to promote wound healing as well as to reduce post-operative pain. This study is a randomised, double blind, placebo-controlled study conducted in women after Lower Segment Caesarean Section (LSCS). Subjects were randomised to either a Channa striatus or a placebo group and were given a daily dosage of 500 mg of Channa striatus extract or 500 mg maltodextrin, respectively, for six weeks post LSCS. The anteroposterior measurements of the uterus in the longitudinal and oblique transverse planes, and the pulsatility index (PI) and resistive index (RI) of the uterine and superficial skin wound arteries were assessed using pelvic Gray-scale ultrasound and Doppler ultrasound at baseline (Day 3) and at two weeks, four weeks and six weeks post-operatively. Sixty-six subjects were randomised into the study with 33 in the Channa striatus group and 33 in the placebo group. No significant differences were detected in terms of the pulsatility index (PI) and the resistive index (RI) of the uterine and superficial skin wound arteries between the Channa striatus and placebo groups. However, in the Channa striatus group, the AP measurements of the uterus on the longitudinal and oblique transverse planes were significantly lower compared to the placebo group (p<0.05 and p<0.001, respectively). Daily intake of Channa striatus extract results in marked differences compared to placebo in terms of uterine involution and recovery in women post LSCS. www.isrctn.com 11960786.

Well-defined image can assist user to identify region of interest during segmentation. However, complex medical image is usually characterized by poor tissue contrast and low background luminance. The contrast improvement can lift image visual quality, but the fundamental contrast enhancement methods often overlook the sudden jump problem. In this work, the proposed bihistogram Bezier curve contrast enhancement introduces the concept of “adequate contrast enhancement” to overcome sudden jump problem in knee magnetic resonance image. Since every image produces its own intensity distribution, the adequate contrast enhancement checks on the image’s maximum intensity distortion and uses intensity discrepancy reduction to generate Bezier transform curve. The proposed method improves tissue contrast and preserves pertinent knee features without compromising natural image appearance. Besides, statistical results from Fisher’s Least Significant Difference test and the Duncan test have consistently indicated that the proposed method outperforms fundamental contrast enhancement methods to exalt image visual quality. As the study is limited to relatively small image database, future works will include a larger dataset with osteoarthritic images to assess the clinical effectiveness of the proposed method to facilitate the image inspection.

Hippocampal volume is affected by several psychiatric illnesses of old age, as well as by normal aging. It is important to have a normal data in a population to assist in diagnosis. The aim of this study is to determine hippocampal volume in normal Malay people aged 50 years old and older. This was a cross-sectional study of the normal Malay population aged 50 to 77 years. We included 43 participants, representing 19 men and 24 women. Magnetic resonance imaging (MRI) was performed using a GE Signa Horizon LX 1.0 Tesla. Oblique coronal images of temporal lobes were obtained and hippocampal volumetry was done manually and normalised with intracranial volume. Mean right and left hippocampal volumes (HCVs) were 3.43 cm³ (SD 0.32) and 3.26 cm³ (SD 0.34), with a significant difference between them (P < 0.001). Total mean HCVs exhibited no significant difference between men and women (P = 0.234). The means of the normalised right and left HCVs were 3.42 cm³ (SD 0.31) and 3.26 cm³ (SD 0.32). The mean right and left hippocampal volumes were significantly different in this study. Men had slightly larger mean HCVs but the difference was not statistically significant. It was found that normalisation further reduces the mean volume difference between the genders.

A 75-year-old lady presented with right preauricular swelling, which gradually increased in size during the past 13 years. However, in the last 2 years, she noticed the presence of pulsation. The swelling was painless and there was no history of bleeding or abscess formation. On examination, the swelling was observed in the right pre-auricular region measuring about 5x6x2 cm with well-defined margin (Figure 1). It was a pulsatile swelling with bluish discolouration of skin. There was no tenderness.