Epidermal Growth Factor Receptor Activation in Glioblastoma through Novel Missense Mutations in the Extracellular Domain

BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Is Neuronal Death Necessary for Acquired Epileptogenesis in the Immature Brain?

A central question concerning acquired epileptogenesis in the immature brain is whether neuronal death is required for the development of epilepsy after a brain insult. Results from three different animal models of brain injury during early development have been used to develop the hypothesis that status epilepticus, prolonged febrile seizures, or hypoxia-induced seizures can lead to chronic epilepsy without the occurrence of neuronal death. This brief review will summarize the evidence supporting the hypothesis in each model and then critique the data and published interpretations. A case will be made that the evidence to date neither rules out the occurrence of neuronal death nor demonstrates that epileptogenesis (i.e., spontaneous recurrent seizures) has actually occurred in these animal models of acquired pediatric epilepsy. We also review evidence for the opposing hypothesis: acquired epileptogenesis in the immature brain requires, or at least often involves, neuronal death

Eroding Gains in Safe Sex Behavior, HIV/AIDS Knowledge, and Risk Perceptions Among Royal Thai Navy Conscripts After 28 Years of the AIDS Epidemic in Thailand

Despite extensive early prevention efforts, recent surveys suggest that sexual risk taking may again be on the rise in Thailand. The present cross-sectional study surveyed 3,299 recruits in the Thai Navy in 2010, to examine their rates and correlates of consistent condom use. Most participants were aged 21-22 years, unmarried, and had a secondary education. Almost half were employed in labor/agriculture. Only 17 % of sexually experienced recruits were consistent condom users, and 53 % reported multiple sex partners in the past 3 months. In multiple logistic regression, residence in the Northeast (AOR 1.47), age (AOR 1.43), being single (AOR 2.13), non-MSM status (AOR 1.41), voluntary testing (AOR 1.24), and condom use at first sex (AOR 4.29) were significantly associated with consistent condom use. These findings suggest gaps in Thailand's condom campaign targeting both sexually experienced and inexperienced youth. Interventions targeting naval recruits may benefit from including sex education in the training curriculum, building drillmasters' capacities to facilitate sex education/counseling, and creating a supportive environment with better access to condoms

The Mitochondrial Transcription Factor TFAM Coordinates the Assembly of Multiple DNA Molecules into Nucleoid-like Structures

Packaging DNA into condensed structures is integral to the transmission of genomes. The mammalian mitochondrial genome (mtDNA) is a high copy, maternally inherited genome in which mutations cause a variety of multisystem disorders. In all eukaryotic cells, multiple mtDNAs are packaged with protein into spheroid bodies called nucleoids, which are the fundamental units of mtDNA segregation. The mechanism of nucleoid formation, however, remains unknown. Here, we show that the mitochondrial transcription factor TFAM, an abundant and highly conserved High Mobility Group box protein, binds DNA cooperatively with nanomolar affinity as a homodimer and that it is capable of coordinating and fully compacting several DNA molecules together to form spheroid structures. We use noncontact atomic force microscopy, which achieves near cryo-electron microscope resolution, to reveal the structural details of protein–DNA compaction intermediates. The formation of these complexes involves the bending of the DNA backbone, and DNA loop formation, followed by the filling in of proximal available DNA sites until the DNA is compacted. These results indicate that TFAM alone is sufficient to organize mitochondrial chromatin and provide a mechanism for nucleoid formation