High-Resolution Mutational Profiling Suggests the Genetic Validity of Glioblastoma Patient-Derived Pre-Clinical Models

Recent advances in the ability to efficiently characterize tumor genomes is enabling targeted drug development, which requires rigorous biomarker-based patient selection to increase effectiveness. Consequently, representative DNA biomarkers become equally important in pre-clinical studies. However, it is still unclear how well these markers are maintained between the primary tumor and the patient-derived tumor models. Here, we report the comprehensive identification of somatic coding mutations and copy number aberrations in four glioblastoma (GBM) primary tumors and their matched pre-clinical models: serum-free neurospheres, adherent cell cultures, and mouse xenografts. We developed innovative methods to improve the data quality and allow a strict comparison of matched tumor samples. Our analysis identifies known GBM mutations altering PTEN and TP53 genes, and new actionable mutations such as the loss of PIK3R1, and reveals clear patient-to-patient differences. In contrast, for each patient, we do not observe any significant remodeling of the mutational profile between primary to model tumors and the few discrepancies can be attributed to stochastic errors or differences in sample purity. Similarly, we observe ∼96% primary-to-model concordance in copy number calls in the high-cellularity samples. In contrast to previous reports based on gene expression profiles, we do not observe significant differences at the DNA level between in vitro compared to in vivo models. This study suggests, at a remarkable resolution, the genome-wide conservation of a patient’s tumor genetics in various pre-clinical models, and therefore supports their use for the development and testing of personalized targeted therapies.     

Increased Global and Local Efficiency of Human Brain Anatomical Networks Detected with FLAIR-DTI Compared to Non-FLAIR-DTI

Diffusion-weighted MRI (DW-MRI), the only non-invasive technique for probing human brain white matter structures in vivo, has been widely used in both fundamental studies and clinical applications. Many studies have utilized diffusion tensor imaging (DTI) and tractography approaches to explore the topological properties of human brain anatomical networks by using the single tensor model, the basic model to quantify DTI indices and tractography. However, the conventional DTI technique does not take into account contamination by the cerebrospinal fluid (CSF), which has been known to affect the estimated DTI measures and tractography in the single tensor model. Previous studies have shown that the Fluid-Attenuated Inversion Recovery (FLAIR) technique can suppress the contribution of the CSF to the DW-MRI signal. We acquired DTI datasets from twenty-two subjects using both FLAIR-DTI and conventional DTI (non-FLAIR-DTI) techniques, constructed brain anatomical networks using deterministic tractography, and compared the topological properties of the anatomical networks derived from the two types of DTI techniques. Although the brain anatomical networks derived from both types of DTI datasets showed small-world properties, we found that the brain anatomical networks derived from the FLAIR-DTI showed significantly increased global and local network efficiency compared with those derived from the conventional DTI. The increases in the network regional topological properties derived from the FLAIR-DTI technique were observed in CSF-filled regions, including the postcentral gyrus, periventricular regions, inferior frontal and temporal gyri, and regions in the visual cortex. Because brain anatomical networks derived from conventional DTI datasets with tractography have been widely used in many studies, our findings may have important implications for studying human brain anatomical networks derived from DW-MRI data and tractography.     

Chemical preservation of tail feathers from Anchiornis huxleyi,a theropod dinosaur from the Tiaojishan Formation (Upper Jurassic,China)

A panel of geochemical techniques is used here to investigate the taphonomy of fossil feathers preserved in association with the skeleton of the Jurassic theropod Anchiornis huxleyi. Extant feathers were analysed in parallel to test whether the soft tissues morphologically preserved in the fossil also exhibit a high degree of chemical preservation. Scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS) indicate that clays and iron oxide pseudomorphs occur in the surrounding sediment and also reveal the preservation of melanosome-like microbodies in the fossil. Carbon gradient along a depth profile and co-occurrence of carbon and sulphur are shown in the fossil by elastic backscattering (EBS) and particle-induced x-ray emission (PIXE), which are promising techniques for the elemental analysis of fossil soft tissues. The molecular composition of modern and fossil soft tissues was assessed from micro-attenuated total reflectance fourier transform infrared spectroscopy (micro-ATR FTIR), solid-state ¹³C nuclear magnetic resonance (CP-MAS ¹³C NMR) and pyrolysis gas chromatography mass spectrometry in the presence of TMAH (TMAH-Py-GC-MS). Results indicate that the proteinaceous material that comprises the modern feathers is not present in the fossil feathers. The fossil feathers and the embedding sediment exhibit a highly aliphatic character. However, substantial differences exist between these samples, revealing that the organic matter of the fossil feathers is, at least partially, derived from original constituents of the feathers. Our results suggest that, despite the morphological preservation of Anchiornis feathers, original proteins, that is keratin, were probably not preserved in the 160-myr-old feathers.     

Identification and Genetic Analysis of a Novel Allelic Variation of <i>Brittle-1</i> with Endosperm Mutant in Maize

Endosperm mutants are critical to the studies on both starch synthesis and metabolism and genetic improvement of starch quality in maize. In the present study, a novel maize endosperm mutant A0178 of natural variation was used as the experimental material and identified and then characterized. Through phenotypic identification, genetic analysis, main ingredients measurement and embryo rescue, development of genetic mapping population from A0178, the endosperm mutant gene was located. The results showed that the mutant exhibited extremely low germination ability as attributed to the inhibited embryo development, and amounts of sugars were accumulated in the mutant seeds and more sugars content was detected at 23 days after pollination (DAP) in A0178 than B73. Employing genetic linkage analysis, the mutant trait was mapped in the bin 5.04 on chromosome 5. Sequence analysis showed that two sites of base transversion and insertion presented in the protein coding region and non-coding region of the mutant brittle-1 (bt1), the adenylate translocator encoding gene involved in the starch synthesis. The single base insertion in the coding region cause frameshift mutation, early termination and lose of function of Brittle-1 (BT1). All results suggested that bt1 is a novel allelic gene and the causal gene of this endosperm mutant, providing insights on the mechanism of endosperm formation in maize.     

Efficient plant regeneration from in vitro leaves and petioles via shoot organogenesis in Sapium sebiferum Roxb.

Sapium sebiferum Roxb. is a widespread and economically important multipurpose tree due to its high value in ornamental, and biodiesel production as well as medicine. A highly efficient in vitro plant regeneration system through direct shoot organogenesis was established for the first time from leaves and petioles of S. sebiferum. The results showed that plant growth regulators (PGRs), mechanical damage, explant orientation, explant source, and developmental stage had a strong influence on the in vitro morphogenesis of S. sebiferum. For shoot organogenesis from leaves, the highest adventitious shoot induction rate (96.67%) with 25.67 shoots per explant was obtained when mechanically damaged leaves (the first three leaf explants at the top, leaf #1–3) were cultured with the abaxial surface placed down on Murashige and Skoog (MS) medium containing 0.5 mg L^?1 thidiazuron (TDZ). For in vitro morphogenesis of petioles, the combination of 1-naphthylacetic acid (NAA) and 6-benzylainopurine (6-BA) played a key role in cell fate determination. All of the in vitro petioles produced adventitious shoots on MS medium containing 1.0 mg L^?1 6-BA and 0.1 mg L^?1 NAA, while they produced green calli on medium fortified with 0.5 mg L^?1 6-BA and 1.0 mg L^?1 NAA. The shoots were subcultured in medium fortified with 0.5 mg L^?1 6-BA and 0.1 mg L^?1 NAA for multiplication and elongation. The elongated shoots successfully rooted on half-strength MS (1/2 MS) medium fortified with 0.5 mg L^?1 indole-butyric acid (IBA) and 0.25 mg L^?1 indole-3-acetic acid (IAA), and the regenerated plantlets successfully acclimatized with a survival rate of 92.56% in the greenhouse. The genetic fidelity of in vitro regenerated plants was evaluated using inter simple sequence repeat molecular markers. The in vitro regenerated plants were found to be the true to their mother plant. This study will be beneficial for the large-scale propagation as well as the genetic improvement of S. sebiferum.

     

Correlation of intensity-modulated radiation therapy at a specific radiation dose with the prognosis of nasal mucous damage after radiotherapy

Radiation and Environmental Biophysics - Objective of the present study was to investigate the tolerant radiation dose of nasal mucosa by observing and analyzing patients who received...     

Early Blood Biomarkers Distinguish Inflammation from Neonatal Hypoxic-Ischemia Encephalopathy

Neurochemical Research - Neonatal hypoxic–ischemic encephalopathy is the most common cause of neurological disability in infancy. Superimposed inflammation may further worsen neurological...