Transmembrane protein TMEM230, a target of glioblastoma therapy

Glioblastomas (GBM) are the most aggressive tumors originating in the brain. Histopathologic features include circuitous, disorganized, and highly permeable blood vessels with intermittent blood flow. These features contribute to the inability to direct therapeutic agents to tumor cells. Known targets for anti-angiogenic therapies provide minimal or no effect in overall survival of 12–15 months following diagnosis. Identification of novel targets therefore remains an important goal for effective treatment of highly vascularized tumors such as GBM. We previously demonstrated in zebrafish that a balanced level of expression of the transmembrane protein TMEM230/C20ORF30 was required to maintain normal blood vessel structural integrity and promote proper vessel network formation. To investigate whether TMEM230 has a role in the pathogenesis of GBM, we analyzed its prognostic value in patient tumor gene expression datasets and performed cell functional analysis. TMEM230 was found necessary for growth of U87-MG cells, a model of human GBM. Downregulation of TMEM230 resulted in loss of U87 migration, substratum adhesion, and re-passaging capacity. Conditioned media from U87 expressing endogenous TMEM230 induced sprouting and tubule-like structure formation of HUVECs. Moreover, TMEM230 promoted vascular mimicry-like behavior of U87 cells. Gene expression analysis of 702 patients identified that TMEM230 expression levels distinguished high from low grade gliomas. Transcriptomic analysis of patients with gliomas revealed molecular pathways consistent with properties observed in U87 cell assays. Within low grade gliomas, elevated TMEM230 expression levels correlated with reduced overall survival independent from tumor subtype. Highest level of TMEM230 correlated with glioblastoma and ATP-dependent microtubule kinesin motor activity, providing a direction for future therapeutic intervention. Our studies support that TMEM230 has both glial tumor and endothelial cell intracellular and extracellular functions. Elevated levels of TMEM230 promote glial tumor cell migration, extracellular scaffold remodeling, and hypervascularization and abnormal formation of blood vessels. Downregulation of TMEM230 expression may inhibit both low grade glioma and glioblastoma tumor progression and promote normalization of abnormally formed blood vessels. TMEM230 therefore is both a promising anticancer and antiangiogenic therapeutic target for inhibiting GBM tumor cells and tumor-driven angiogenesis

GeneUp: A Program to Select Short PCR Primer Pairs that Occur in Multiple Members of Sequence Lists

A computer program is presented that selects a small set of short primer pairs for PCR to sample all the sequences in a user-specified list of mRNAs. Such primer pairs could be used to increase the probability of sampling mRNAs of particular interest in differential display and to generate simplified hybridization probes for DNA chips or arrays. The program uses simulated PCR to find pairs of primers that sample more than one sequence in the list. A small set of such primer pairs is selected that give maximal coverage of the sequences in the list. Primer pairs are excluded that: (i) generate simulated PCR products of the same size from a number of sequences in the list, (ii) can easily form primer dimers, (iii) are outside a specified range of G+C content or (iv) occur in another list of undesirable sequences, such as rRNAs and Alu repeats. Five lists consisting of from 48—285 cDNA sequences were used to test the program. A small number of pairs of primers, 8—10 bases in length, were selected that fit the above criteria and that generate one or more simulated PCR products in all or most of the cDNAs in each list

Even violins can cry: specifically vocal emotional behaviours also drive the perception of emotions in non-vocal music

A wealth of theoretical and empirical arguments have suggested that music triggers emotional responses by resembling the inflections of expressive vocalizations, but have done so using low-level acoustic parameters (pitch, loudness, speed) that, in fact, may not be processed by the listener in reference to human voice. Here, we take the opportunity of the recent availability of computational models that allow the simulation of three specifically vocal emotional behaviours: smiling, vocal tremor and vocal roughness. When applied to musical material, we find that these three acoustic manipulations trigger emotional perceptions that are remarkably similar to those observed on speech and scream sounds, and identical across musician and non-musician listeners. Strikingly, this not only applied to singing voice with and without musical background, but also to purely instrumental material. This article is part of the theme issue ‘Voice modulation: from origin and mechanism to social impact (Part I)’.</jats:p