Missense mutation of NRAS is associated with malignant progression in neurocutaneous melanosis.

Neurocutaneous melanosis (NCM) is a rare congenital neurocutaneous syndrome characterized by congenital melanocytic nevus of skin and abnormal proliferation of leptomeningeal melanocytes. Early acquisition of post-zygotic somatic mutations has been postulated to underlie the pathogenesis of NCM. The pathogenesis of NCM remains to be fully elucidated, and treatment options have not been established. Here, we report for the first time, multiregional genomic analyses in a 3-year-old autopsied girl with leptomeningeal melanomatosis associated with NCM, in which a ventriculo-peritoneal (VP) shunt was inserted for the treatment of hydrocephalus. The patient expired six months after the onset due to respiratory failure caused by abdominal dissemination via VP shunt. We performed multiregional exome sequencing to identify genomic differences among brain and abdominal tumors, nevus, and normal tissues. A total of 87 somatic mutations were found in 71 genes, with a significantly large number of gene mutations found in the tumor site. The genetic alterations detected in the nevus were only few and not shared with other sites. Three mutations, namely GNAQ R183Q, S1PR3 G89S and NRAS G12V, considered pathogenic, were found, although S1PR3 mutations have not been previously reported in melanocytic tumors. GNAQ and S1PR3 mutations were shared in both tumor and normal sites. Moreover, the mutant allele frequencies of the two mutations were markedly higher in tumor sites than in normal sites, with copy-neutral loss-of-heterozygosity (CN-LOH) occurring in tumor. NRAS mutation was found only in the abdominal tumor and was thought to be responsible for malignant progression in the present case. Multiregional comprehensive genetic analysis may lead to discovering novel driver mutations associated with tumorigenesis and targeted therapy.

Primary Intracranial Malignant Epidermoid with Multiple Metastases in Internal Organs: A Rare Autopsy Case.

Primary intracranial malignant epidermoids are rare, with most cases developing from a pre-existing benign epidermoid cyst. We report a case involving a rare autopsy finding of a primary intracranial malignant epidermoid in the brainstem with cerebellopontine angle (CPA) involvement. A 53-year-old woman with double vision was diagnosed with right abducens palsy. At her visit to our hospital 3 months after the onset of the first symptom, she presented left hypoglossal nerve paralysis and truncal ataxia in addition to right abducens palsy. Magnetic resonance imaging (MRI) revealed a mass lesion (2-cm long and 3-cm thick) in the left CPA that exhibited gadolinium enhancement. Moreover, gadolinium-enhanced magnetic resonance imaging (MRI) revealed abnormal multiple brainstem and supratentorial mass lesions with partial enhancement. Whole-body computed tomography failed to identify any possible primary lesion. Following a tentative diagnosis of an epidermoid cyst with an assumption that the tumor was highly aggressive, we performed subtotal surgical resection of the CPA tumor. Histological findings revealed a malignant epidermoid in the CPA lesion. Although the patient underwent radiation and chemotherapy after the surgical resection, she died of respiratory failure 10 months after the onset of symptoms. Herein, we report the rare clinical course and autopsy data, and discuss the characteristic features of this rare condition.

The advanced LIGO input optics.

The advanced LIGO gravitational wave detectors are nearing their design sensitivity and should begin taking meaningful astrophysical data in the fall of 2015. These resonant optical interferometers will have unprecedented sensitivity to the strains caused by passing gravitational waves. The input optics play a significant part in allowing these devices to reach such sensitivities. Residing between the pre-stabilized laser and the main interferometer, the input optics subsystem is tasked with preparing the laser beam for interferometry at the sub-attometer level while operating at continuous wave input power levels ranging from 100 mW to 150 W. These extreme operating conditions required every major component to be custom designed. These designs draw heavily on the experience and understanding gained during the operation of Initial LIGO and Enhanced LIGO. In this article, we report on how the components of the input optics were designed to meet their stringent requirements and present measurements showing how well they have lived up to their design.

Observation of Parametric Instability in Advanced LIGO.

Parametric instabilities have long been studied as a potentially limiting effect in high-power interferometric gravitational wave detectors. Until now, however, these instabilities have never been observed in a kilometer-scale interferometer. In this Letter, we describe the first observation of parametric instability in a gravitational wave detector, and the means by which it has been removed as a barrier to progress.

Angular control of optical cavities in a radiation-pressure-dominated regime: the Enhanced LIGO case.

We describe the angular sensing and control (ASC) of 4 km detectors of the Laser Interferometer Gravitational-Wave Observatory (LIGO). Enhanced LIGO, the culmination of the first generation LIGO detectors, operated between 2009 and 2010 with about 40 kW of laser power in the arm cavities. In this regime, radiation-pressure effects are significant and induce instabilities in the angular opto-mechanical transfer functions. Here we present and motivate the ASC design in this extreme case and present the results of its implementation in Enhanced LIGO. Highlights of the ASC performance are successful control of opto-mechanical torsional modes, relative mirror motions of ≤ 1×10(-7) rad rms, and limited impact on in-band strain sensitivity.

Angular instability due to radiation pressure in the LIGO gravitational-wave detector.

We observed the effect of radiation pressure on the angular sensing and control system of the Laser Interferometer Gravitational-Wave Observatory (LIGO) interferometer's core optics at LIGO Hanford Observatory. This is the first measurement of this effect in a complete gravitational-wave interferometer. Only one of the two angular modes survives with feedback control, because the other mode is suppressed when the control gain is sufficiently large. We developed a mathematical model to understand the physics of the system. This model matches well with the dynamics that we observe.