Functional Precision Medicine Identifies New Therapeutic Candidates for Medulloblastoma.

Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor. SIGNIFICANCE: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.

Pediatric Brain Tumors.

Pediatric central nervous system (CNS) tumors are the most common solid tumors in children and comprise 15% to 20% of all malignancies in children. Presentation, symptoms, and signs depend on tumor location and age of the patient at the time of diagnosis. This article summarizes the common childhood CNS tumors, presentations, classification, and recent updates in treatment approaches due to the increased understanding of the molecular pathogenesis of pediatric brain tumors.

HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma.

Medulloblastoma (MB) is a highly malignant pediatric brain tumor. Despite aggressive therapy, many patients succumb to the disease, and survivors experience severe side effects from treatment. MYC-driven MB has a particularly poor prognosis and would greatly benefit from more effective therapies. We used an animal model of MYC-driven MB to screen for drugs that decrease viability of tumor cells. Among the most effective compounds were histone deacetylase inhibitors (HDACIs). HDACIs potently inhibit survival of MYC-driven MB cells in vitro, in part by inducing expression of the FOXO1 tumor suppressor gene. HDACIs also synergize with phosphatidylinositol 3-kinase inhibitors to inhibit tumor growth in vivo. These studies identify an effective combination therapy for the most aggressive form of MB.

Atypical Teratoid Rhabdoid Tumor in a Teenager with Unusual Infiltration Into the Jugular Foramen.

BACKGROUND: Atypical teratoid rhabdoid tumor is a rare malignant neoplasm that represents 1%-2% of all pediatric central nervous system tumors. Immunohistochemistry plays an important role in establishing the diagnosis with a loss of INI-1 staining in tumor cells. In this case report, we describe a teenager with an unusual presentation and pattern of infiltration of the tumor. CASE DESCRIPTION: A 13-year-old boy presented with a history over several months of progressive nausea, weight loss, and hoarseness of voice associated with multiple lower cranial nerve palsies on neurologic examination. Magnetic resonance imaging revealed a large heterogeneously enhancing extra-axial neoplasm with extension and bony expansion of the jugular foramen. After near total resection, neuropathology demonstrated the absence of INI-1 expression consistent with a diagnosis of atypical teratoid rhabdoid tumor. CONCLUSIONS: This case highlights the diverse clinical presentation and infiltrative potential of atypical teratoid rhabdoid tumors, thus expanding the differential diagnosis of extra-axial tumors invading the jugular foramen.

Intracerebral foreign body granuloma caused by a resorbable plate with passive intraosseous translocation after cranioplasty.

Numerous reports have demonstrated the usefulness of bioresorbable materials, but few have described severe complications caused by delayed degradation. The authors present the case of an intracranial foreign body granuloma caused by plates made of unsintered hydroxyapatite (uHA) particles and poly-l-lactide (PLLA; Super Fixsorb MX, Takiron) after cranioplasty. This 1-month-old boy presented to the authors' department with Pfeiffer syndrome. He had multiple-suture synostosis causing turribrachycephaly, Chiari malformation Type 1, and obstructive sleep apnea syndrome. At 6 months old, the child was treated with multidirectional cranial distraction osteogenesis. The uHA-PLLA plates were applied as base stones to reinforce the pins. After 16 days of distraction and 3 weeks of consolidation, the pins were removed. Seventeen months postoperatively, the plate on the right temporal bone showed passive intraosseous translocation (PIT), and by 2 years postoperatively, the plate was completely left behind in the cerebrum. At 3.5 years postoperatively, MRI disclosed a contrast-enhanced mass with surrounding brain edema at the site of the plate. The lesion was resected. The clinical history and histological specimens led to a diagnosis of foreign body granuloma surrounding the nonabsorbed resorbable plate in the dura mater. Resorbable plates are clearly useful resources in cases in which delayed absorption will not prove problematic, but careful application and follow-up is required when dealing with the growing skull given the possibility of intracranial displacement after PIT.

Recurrent pediatric central nervous system low-grade gliomas: the role of surveillance neuroimaging in asymptomatic children.

OBJECT: Pediatric low-grade glioma (LGG) is the most common brain tumor of childhood. Except for the known association of gross-total resection and improved survival rates, relatively little is known about the clinical and radiographic predictors of recurrent disease and the optimal frequency of surveillance MRI. The authors sought to determine the clinical and radiographic features associated with recurrent or progressive disease in a single-institutional series of children diagnosed with primary CNS LGG. METHODS: The authors performed a retrospective analysis of data obtained in 102 consecutive patients diagnosed at Rady Children's Hospital-San Diego between 1994 and 2010 with a biopsy-proven LGG exclusive of a diagnosis of neurofibromatosis. Tumor location, patient age, sex, and symptomatology were correlated with tumor progression or recurrence. Magnetic resonance imaging characteristics and neuroimaging surveillance frequency were analyzed in those children with progressive or recurrent disease. RESULTS: Forty-six of 102 children diagnosed with an LGG had evidence of recurrent or progressive disease between 2 months and 11 years (mean 27.3 months) after diagnosis. In the larger group of 102 children, gross-total resection was associated with improved progression-free survival (p = 0.012). The location of tumor (p = 0.26), age at diagnosis (p = 0.69), duration of symptoms (p = 0.72), histological subtype (p = 0.74), sex (p = 0.53), or specific chemotherapeutic treatment regimen (p = 0.24) was not associated with tumor progression or recurrence. Sixty-four percent of children with recurrent or progressive disease were asymptomatic, and recurrence was diagnosed by surveillance MRI alone. All children less than 2 years of age in whom the tumor was diagnosed were asymptomatic at the time of progression (p = 0.04). Thirteen percent (6 of 46) of the children had disease recurrence 5 years after initial diagnosis; all of them had undergone an initial subtotal resection. Tumor progression was associated with either homogeneous or patchy T1-weighted post-Gd administration MRI enhancement in 94% of the cases (p = 0.0001). CONCLUSIONS: Children diagnosed with recurrent LGG may be asymptomatic at the time of recurrence. The authors' findings support the need for routine neuroimaging in a subset of children with LGGs, even when gross-total resection has been achieved, up to 5 years postdiagnosis. The authors found that T1-weighted MR images obtained before and after Gd administration alone may be sufficient to diagnose LGG recurrence and may represent an effective strategy worthy of further validation in a larger multiinstitutional cohort.

Direct observation of second-harmonic generation from crystalline particles in Ge-doped SiO2 glass films.

The authors report what is, to our best knowledge, the first observation of second-harmonic generation (SHG) directly from the crystalline particles in Ge-doped SiO2 (Ge:SiO2) glass films. Ge:SiO2 glass films with approximately 5 microm thickness were fabricated by chemical vapor-phase deposition. X-ray diffraction (XRD) peaks at around 2theta=22 degrees in thermally crystallized Ge:SiO2 films were observed, and obtained XRD patterns are exactly the same as those in ultraviolet-laser-poled Ge:SiO2 glasses. Using SHG microscopic technique with a Nd:YAG laser, it has been successfully found that SH emitting with 532 nm wavelength is observed directly from the crystalline particles induced in the crystallized films.

Structure and generation mechanism of the peroxy-radical defect in amorphous silica.

We provide a new model of the peroxy-radical defect in amorphous silica on the basis of quantum-chemical calculations applied to clusters of atoms to model the defect. In this model, the 29Si hyperfine splittings of the peroxy radical arise from a single silicon, in agreement with the previous experimental findings. Furthermore, we show that the present model of the peroxy radical is consistent with the diffusion-limited anneal mechanism of the E'gamma center, although our model of the E'gamma center is different from the conventional charged oxygen vacancy model.

E' centers in amorphous SiO(2) revisited: a new look at an old problem.

We present theoretical evidence that the paramagnetic E' defect centers in amorphous silicon dioxide (a-SiO(2)) do not have the same microscopic structures as those well-defined in the corresponding crystalline counterparts such as alpha-quartz. We then present alternative models of some paramagnetic defects that account for the underlying experimental features of the E'-center variants in a-SiO(2). We suggest that our new model should take the place of the conventional defect model of a-SiO(2).

Mechanism of interconversion among radiation-induced defects in amorphous silicon dioxide.

We here present a series of ab initio quantum-chemical calculations on clusters of atoms modeling several oxygen-deficiency-related defects in amorphous silica and illustrate how these defect centers will change their atomic configurations upon photoionization. We first give theoretical evidence that structural conversion from a neutral oxygen monovacancy to a divalent Si defect is possible, explaining the observed photoluminescence properties associated with these defects.

Structure and formation mechanism of Ge E (') center from divalent defects in Ge-doped SiO2 glass

We have performed ab initio quantum-chemical calculations on clusters of atoms modeling a divalent Ge defect in Ge-doped SiO (2) glasses. It has been found that the divalent Ge defect interacts with a nearby GeO (4) tetrahedron, forming complex structural units that are responsible for the observed photoabsorption band at approximately 5 eV. We have shown that these structural units can be transformed into two equivalent Ge E' centers by way of the positively charged defect center.

Interaction between a Solute Molecule and a Fluorocarbon Bonded Layer in Reversed-Phase High-Performance Liquid Chromatography.

Glassesand silica-gel packings modified with fluorocarbon and hydrocarbon silylation agents were prepared to investigate the separation mechanism of a fluorocarbon bonded layer in reversed-phase high-performance liquid chromatography (RP-HPLC). On the hydrocarbon layer the contact angles of benzene (Be) and hexafluorobenzene (FB) decreased with increasing carbon chain length of the modifier, and the mobile phase (MP) was independent of the modifier. The fluorocarbon layer gave a larger contact angle for each liquid than the hydrocarbon layer. The retention factor, k, of Be and FB on hydrocarbon packings increased with decreasing contact angle. It was demonstrated that the separation of Be and FB on hydrocarbon packings is caused by solvophobic interaction between solute molecules and the stationary layer. In contrast, k increased with increasing contact angle at the fluorocarbon layer. The retention of Be and FB on fluorocarbon packings may be attributed to the penetration of the solute molecules from the mobile phase into the fluorocarbon stationary layer. Copyright 1999 Academic Press.

Adsorption Characteristics of Silica Gels Treated with Fluorinated Silylation Agents

Branched-chain polyfluorosilane (monochlorodimethyl[4,4-bis(trifluoromethyl)-5,5,6,6,7,7,7-heptafluoroheptyl)-bonded silica gels were prepared. The surface properties of the silica gels modified with various organic silanes were evaluated by the adsorption density of polar and nonpolar gases calculated from adsorption isotherms of nitrogen, carbon dioxide, and normal butane gases. The polyfluorocarbon-bonded silica gel surface was found to be both hydrophobic and oleophobic in nature, whereas the hydrocarbon-bonded silica gel surface was characterized only as hydrophobic. The trifunctional fluorinated silane provides the silica gel surface with a more hydrophilic nature than the monofunctional silane because of the formation of a denser polymeric coating layer with a larger number of silanols.

Low-Frequency Raman Scattering and the Fast Relaxation Process in Glycerol

Ab initio molecular orbital calculations were used to determine the structure and vibrational frequencies of the cyclic glycerol trimer, which represents the region of medium-range ordering in liquid and supercooled glycerol. The calculations reproduced the experimentally observed low-frequency Raman scattering peak (or the "boson peak") at approximately50 per centimeter, which suggests that the peak results from the localized collective motions of the cooperatively hydrogen-bonded hydroxyl groups. The calculations also suggest that the fast relaxation process may result from the translational motion of each glycerol molecule in the cyclic structure. On the basis of these results, a model of the glass transition was developed.

Molecular cloning of the plc1+ gene of Schizosaccharomyces pombe, which encodes a putative phosphoinositide-specific phospholipase C.

Exploiting the polymerase chain reaction, we have isolated a gene that encodes a putative phosphoinositide-specific phospholipase C (PLC) of the fission yeast Schizosaccharomyces pombe. Inspection of the nucleotide sequence of the gene revealed an open reading frame that can encode a polypeptide of 899 amino acid residues with a calculated molecular mass of 102 kDa. This putative polypeptide contains both the X and Y regions that are conserved among three classes of mammalian PLC, and also contains a presumptive Ca(2+)-binding site (an E-F hand motif). The structure of the putative protein is most similar to that of the delta class of PLC isozymes. To investigate the role of this gene, designated plc1+, gene disruption was carried out by interrupting the coding region with the ura4+ marker. Growth of plc1 cells was temperature-sensitive in rich medium, and cells could not grow in synthetic medium. Expression of the PLC1 gene of Saccharomyces cerevisiae suppressed the growth defect phenotype of plc1- cells, a strong suggestion that the plc1+ gene encodes PLC.

Third-order nonlinear optical properties of sol-gel-derived V(2)O(5), Nb(2)O(5), and Ta(2)O(5) thin films.

The third-order nonlinear optical properties of sol-gel-derived V(2)O(5), Nb(2)O(5), and Ta(2)O(5) thin films have been investigated by the third-harmonic-generation method, and the effect of the metal-oxygen bond length on the third-order nonlinear optical susceptibility χ((3)) has been examined. The χ((3)) values of V(2)O(5), Nb(2)O(5), and Ta(2)O(5) thin films were 1.1 × 10(-11), 1.3 × 10(-12), and 6.1 × 10(-13) esu, respectively, which corresponds to an increase in the average bond length I(b) of the order of V-O (I(b) = 0.183 nm), Nb-O (I(b) = 0.200 nm), and Ta-O (I(b) = 0.204 nm). The current and previous results indicate that χ((3)) of these transition metal oxides with the empty d orbitals is dominated mainly by the metal-oxygen bond length rather than the valence of the metal cation. It is predicted on the basis of Lines' model that transition metal oxides with the shortest I(b) exhibit the highest χ((3)), whereas nontransition metal oxides with the longest I(b) exhibit the highest χ((3)).