A Case of Metastatic Atypical Neuroendocrine Tumor with ALK Translocation and Diffuse Brain Metastases.

A challenge in precision medicine requires identification of actionable driver mutations. Critical to such effort is the deployment of sensitive and well-validated assays for mutation detection. Although identification of such alterations within the tumor tissue remains the gold standard, many advanced non-small cell lung cancer cases have only limited tissue samples, derived from small biopsies or fine-needle aspirates, available for testing. More recently, noninvasive methods using either circulating tumor cells or tumor DNA (ctDNA) have become an alternative method for identifying molecular biomarkers and screening patients eligible for targeted therapies. In this article, we present a case of a 52-year-old never-smoking male who presented with widely metastatic atypical neuroendocrine tumor to the bones and the brain. Molecular genotyping using DNA harvested from a bone metastasis was unsuccessful due to limited material. Subsequent ctDNA analysis revealed an ALK translocation. The clinical significance of the mutation in this particular cancer type and therapeutic strategies are discussed.Key pointsTo our knowledge, this index case represents the first reported ALK translocation identified in an atypical carcinoid tumor.Liquid biopsy such as circulating tumor DNA is a feasible alternative platform for identifying sensitizing genomic alterations.Second-generation ALK inhibitors represent a new paradigm for treating ALK-positive patients with brain metastases

Spectral signatures of photosynthesis II: coevolution with other stars and the atmosphere on extrasolar worlds

As photosynthesis on Earth produces the primary signatures of life that can be detected astronomically at the global scale, a strong focus of the search for extrasolar life will be photosynthesis, particularly photosynthesis that has evolved with a different parent star. We take planetary atmospheric compositions simulated by Segura, et al. (2003, 2005) for Earth-like planets around observed F2V and K2V stars, modeled M1V and M5V stars, and around the active M4.5V star AD Leo; our scenarios use Earth's atmospheric composition as well as very low O2 content in case anoxygenic photosynthesis dominates. We calculate the incident spectral photon flux densities at the surface of the planet and under water. We identify bands of available photosynthetically relevant radiation and find that photosynthetic pigments on planets around F2V stars may peak in absorbance in the blue, K2V in the red-orange, and M stars in the NIR, in bands at 0.93-1.1 microns, 1.1-1.4 microns, 1.5-1.8 microns, and 1.8-2.5 microns. In addition, we calculate wavelength restrictions for underwater organisms and depths of water at which they would be protected from UV flares in the early life of M stars. We estimate the potential productivity for both surface and underwater photosynthesis, for both oxygenic and anoxygenic photosynthesis, and for hypothetical photosynthesis in which longer wavelength, multi-photosystem series are used.Comment: 59 pages, 4 figures, 4 tables, forthcoming in Astrobiology ~March 200

E5501: phase II study of topotecan sequenced with etoposide/cisplatin, and irinotecan/cisplatin sequenced with etoposide for extensive-stage small-cell lung cancer.

PURPOSE: Sequence-dependent improved efficacy of topoisomerase I followed by topoisomerase 2 inhibitors was assessed in a randomized phase II study in extensive-stage small-cell lung cancer (SCLC). METHODS: Patients with previously untreated extensive-stage SCLC with measurable disease, ECOG performance status of 0-3 and stable brain metastases were eligible. Arm A consisted of topotecan (0.75 mg/m(2)) on days 1, 2 and 3, etoposide (70 mg/m(2)) and cisplatin (20 mg/m(2)) (PET) on days 8, 9 and 10 in a 3-week cycle. Arm B consisted of irinotecan (50 mg/m(2)) and cisplatin (20 mg/m(2)) on days 1 and 8 followed by etoposide (85 mg/m(2) PO bid) on days 3 and 10 (PIE) in a 3-week cycle. RESULTS: We enrolled 140 patients and randomized 66 eligible patients to each arm. Only 54.5 % of all patients completed the planned maximum 6 cycles. There were grade ≥3 treatment-related adverse events in approximately 70 % of the patients on both arms including 6 treatment-related grade 5 events. The overall response rates (CR + PR) were 69.7 % (90 % CI 59.1-78.9, 95 % CI 57.1-80.4 %) for arm A and 57.6 % (90 % CI 46.7-67.9, 95 % CI 44.8-69.7 %) for arm B. The median progression-free survival and overall survival were 6.4 months (95 % CI 5.4-7.5 months) and 11.9 months (95 % CI 9.6-13.7 months) for arm A and 6.0 months (95 % CI 5.4-7.0 months) and 11.0 months (95 % CI 8.6-13.1 months) for arm B. CONCLUSION: Sequential administration of topoisomerase inhibitors did not improve on the historical efficacy of standard platinum-doublet chemotherapy for extensive-stage SCLC

APOE Gene Associated with Cholesterol-Related Traits in the Hispanic Population

Genetic variants in the apolipoprotein E (APOE) gene are associated with lipid metabolism and lipid-related traits in the non-Hispanic population. There have been limited studies regarding the association between the APOE gene and hypercholesterolemia in the Hispanic population; therefore, our aim for this study is to examine the APOE gene’s associations with cholesterol level and its related phenotypes. The APOE gene consists of three different alleles, ε2, ε3, and ε4, with ε4 being associated with dementia and cardiovascular diseases. A total of 1,382 subjects were collected from the Texas Alzheimer’s Research and Care Consortium (TARCC, N = 1320) and the Initial Study of Longevity and Dementia from the Rio Grande Valley (ISLD-RGV, N = 62). Questionnaires on demographics, medical history, and blood/saliva samples were collected and APOE genotypes were performed. We observed allele frequencies of the APOE ε3 (96.7%), ε4 (22.6%) and ε2 (6.8%) alleles, respectively. Multivariable logistic regression revealed a significant association between the APOE ε4 allele and hypercholesteremia (p = 1.8 × 10−4 ) in our studied Hispanic population. We prove for the first time, that the APOE ε4 allele increases the risk for hypercholesterol in Hispanics. Further research is needed to confirm and supports our current findings

Characterization of healing following atherosclerotic carotid plaque rupture in acutely symptomatic patients: an exploratory study using in vivo cardiovascular magnetic resonance.

BACKGROUND: Carotid plaque rupture, characterized by ruptured fibrous cap (FC), is associated with subsequent cerebrovascular events. However, ruptured FC may heal following stroke and convey decreased risk of future events. This study aims to characterize the healing process of ruptured FC by assessing the lumen conditions, quantified by the lumen curvature and roughness, using in vivo carotid cardiovascular magnetic resonance (CMR). METHODS: Patients suffering from transient ischemic attack underwent high resolution carotid MR imaging within 72 hours of the acute cerebrovascular ischemic event. CMR imaging was repeated at 3 and 12 months in 26 patients, in whom FC rupture/erosion was observed on baseline images and subsequent cerebrovascular events were recorded during the follow-up period. Lumen curvature and roughness were quantified from carotid CMR images and changes in these values were monitored on follow-up imaging. RESULTS: Healing of ruptured plaque was observed in patients (23 out of 26) without any ischemic symptom recurrence as shown by the lumen surface becoming smoother during the follow-up period, characterized by decreasing maximum lumen curvature (p < 0.05), increasing minimum lumen curvature (p < 0.05) and decreasing lumen roughness (p < 0.05) during the one year follow-up period. CONCLUSIONS: Carotid plaque healing can be assessed by quantification of the lumen curvature and roughness and the incidence of recurrent cerebrovascular events may be high in plaques that do not heal with time. The assessment of plaque healing may facilitate risk stratification of recent stroke patients on the basis of CMR results.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Validation of integrated water vapor from OMI satellite instrument against reference GPS data at the Iberian Peninsula

This paper shows the validation of integrated water vapor (IWV) measurements retrieved from the Ozone Monitoring Instrument (OMI), using as reference nine ground-based GPS stations in the Iberian Peninsula. The study period covers from 2007 to 2009. The influence of two factors, - solar zenith angle (SZA) and IWV -, on OMI-GPS differences was studied in detail, as well as the seasonal dependence. The pseudomedian of the relative differences is −1 ± 1% and the inter-quartile range (IQR) is 41%. Linear regressions calculated over each station show an acceptable agreement (R2 up to 0.77). The OMI-GPS differences display a clear dependence on IWV values. Hence, OMI substantially overestimates the lower IWV data recorded by GPS (∼40%), while underestimates the higher IWV reference values (∼20%). In connection to this IWV dependence, the relative differences also show an evident SZA dependence when the whole range of IWV values are analyzed (OMI overestimates for high SZA values while underestimates for low values). Finally, the seasonal variation of the OMI-GPS differences is also associated with the strong IWV dependence found in this validation exercise.This work was supported by the Spanish Ministry of Economy and Competitiveness through project CGL2014-56255-C2. Manuel Antón thanks Ministerio de Ciencia e Innovación and Fondo Social Europeo (RYC-2011-08345) for the award of a postdoctoral grant (Ramón y Cajal). Support from the Junta de Extremadura (Research Group Grants GR15137) is gratefully acknowledged. Work at Universidad de Valladolid is supported by project CMT2015-66742-R. Work at Universidad de Granada was supported by the Andalusia Regional Government (project P12-RNM-2409) and the Spanish Ministry of Economy and Competitiveness and FEDER funds under the projects CGL2013-45410-R and “Juan de la Cierva-Formación” program. Work at SAO is supported by NASA’s Atmospheric Composition: Aura Science Team program (sponsor contract number NNX14AF56G). Work at Universidade de Évora is co-funded by the European Union through the European Regional Development Fund, included in the COMPETE 2020 (Operational Program Competitiveness and Internationalization) through the ICT project (UID/GEO/04683/2013) with the reference POCI-01-0145-FEDER-007690

Evaluation of environmental sampling methods for detection of Staphylococcus aureus on fomites

We evaluated a variety of methods to recover S. aureus from inanimate surfaces. Two contact agar plates and three swab sampling methods were tested on porous and non-porous surfaces and bar soap. The cost and ease of use of each method was also evaluated. S. aureus was recovered using all methods on both porous and non-porous surfaces. S. aureus could not be detected on three of four brands of soap

Enhanced stability and local structure in biologically relevant amorphous materials containing pyrophosphate

There is increasing evidence that amorphous inorganic materials play a key role in biomineralisation in many organisms, however the inherent instability of synthetic analogues in the absence of the complex in vivo matrix limits their study and clinical exploitation. To address this, we report here an approach that enhances long-term stability to >1 year of biologically relevant amorphous metal phosphates, in the absence of any complex stabilisers, by utilising pyrophosphates (P2O7 4-); species themselves ubiquitous in vivo. Ambient temperature precipitation reactions were employed to synthesise amorphous Ca2P2O7.nH2O and Sr2P2O7.nH2O (3.8 < n < 4.2) and their stability and structure were investigated. Pair distribution functions (PDF) derived from synchrotron X-ray data indicated a lack of structural order beyond ~8 A° in both phases, with this local order found to resemble crystalline analogues. Further studies, including 1H and 31P solid state NMR, suggest the unusually high stability of these purely inorganic amorphous phases is partly due to disorder in the P–O–P bond angles within the P2O7 units, which impede crystallization, and to water molecules, which are involved in H-bonds of various strengths within the structures and hamper the formation of an ordered network. In situ high temperature powder X-ray diffraction data indicated that the amorphous nature of both phases surprisingly persisted to ~450° C. Further NMR and TGA studies found that above ambient temperature some water molecules reacted with P2O7 anions, leading to the hydrolysis of some P–O–P linkages and the formation of HPO4 2- anions within the amorphous matrix. The latter anions then recombined into P2O7 ions at higher temperatures prior to crystallization. Together, these findings provide important new materials with unexplored potential for enzyme-assisted resorption and establish factors crucial to isolate further stable amorphous inorganic materials

A mutation in the serine protease TMPRSS4 in a novel pediatric neurodegenerative disorder

Background: To elucidate the genetic basis of a novel neurodegenerative disorder in an Old Order Amish pedigree by combining homozygosity mapping with exome sequencing. Methods and results. We identified four individuals with an autosomal recessive condition affecting the central nervous system (CNS). Neuroimaging studies identified progressive global CNS tissue loss presenting early in life, associated with microcephaly, seizures, and psychomotor retardation; based on this, we named the condition Autosomal Recessive Cerebral Atrophy (ARCA). Using two unbiased genetic approaches, homozygosity mapping and exome sequencing, we narrowed the candidate region to chromosome 11q and identified the c.995C \u3e T (p.Thr332Met) mutation in the TMPRSS4 gene. Sanger sequencing of additional relatives confirmed that the c.995C \u3e T genotype segregates with the ARCA phenotype. Residue Thr332 is conserved across species and among various ethnic groups. The mutation is predicted to be deleterious, most likely due to a protein structure alteration as demonstrated with protein modelling. Conclusions: This novel disease is the first to demonstrate a neurological role for a transmembrane serine proteases family member. This study demonstrates a proof-of-concept whereby combining exome sequencing with homozygosity mapping can find the genetic cause of a rare disease and acquire better understanding of a poorly described protein in human development. © 2013 Lahiry et al.; licensee BioMed Central Ltd