Pax3:Fkhr interferes with embryonic Pax3 and Pax7 function: implications for alveolar rhabdomyosarcoma cell of origin.

Journal ArticleTo investigate the role of the translocation-associated gene Pax3:Fkhr in alveolar rhabdomyosarcomas, we generated a Cre-mediated conditional knock-in of Pax3:Fkhr into the mouse Pax3 locus. Exploring embryonic tumor cell origins, we replaced a Pax3 allele with Pax3:Fkhr throughout its expression domain, causing dominant-negative effects on Pax3 and paradoxical activation of the Pax3 target gene, c-Met. Ectopic neuroprogenitor cell proliferation also occurs. In contrast, activation later in embryogenesis in cells that express Pax7 results in viable animals with a postnatal growth defect and a moderately decreased Pax7+ muscle satellite cell pool, phenocopying Pax7 deficiency but remarkably not leading to tumors

Sprouty1 regulates reversible quiescence of a self-renewing adult muscle stem cell pool during regeneration.

Satellite cells are skeletal muscle stem cells capable of self-renewal and differentiation after transplantation, but whether they contribute to endogenous muscle fiber repair has been unclear. The transcription factor Pax7 marks satellite cells and is critical for establishing the adult satellite cell pool. By using a lineage tracing approach, we show that after injury, quiescent adult Pax7(+) cells enter the cell cycle; a subpopulation returns to quiescence to replenish the satellite cell compartment, while others contribute to muscle fiber formation. We demonstrate that Sprouty1 (Spry1), a receptor tyrosine kinase signaling inhibitor, is expressed in quiescent Pax7(+) satellite cells in uninjured muscle, downregulated in proliferating myogenic cells after injury, and reinduced as Pax7(+) cells re-enter quiescence. We show that Spry1 is required for the return to quiescence and homeostasis of the satellite cell pool during repair. Our results therefore define a role for Spry1 in adult muscle stem cell biology and tissue repair

First Science Observations with SOFIA/FORCAST: Properties of Intermediate-Luminosity Protostars and Circumstellar Disks in OMC-2

We examine eight young stellar objects in the OMC-2 star forming region based on observations from the SOFIA/FORCAST early science phase, the Spitzer Space Telescope, the Herschel Space Observatory, 2MASS, APEX, and other results in the literature. We show the spectral energy distributions of these objects from near-infrared to millimeter wavelengths, and compare the SEDs with those of sheet collapse models of protostars and circumstellar disks. Four of the objects can be modelled as protostars with infalling envelopes, two as young stars surrounded by disks, and the remaining two objects have double-peaked SEDs. We model the double-peaked sources as binaries containing a young star with a disk and a protostar. The six most luminous sources are found in a dense group within a 0.15 x 0.25 pc region; these sources have luminosities ranging from 300 L_sun to 20 L_sun. The most embedded source (OMC-2 FIR 4) can be fit by a class 0 protostar model having a luminosity of ~50 L_sun and mass infall rate of ~10^-4 solar masses per year.Comment: Accepted by ApJ Letter

Uniform approximation for diffractive contributions to the trace formula in billiard systems

We derive contributions to the trace formula for the spectral density accounting for the role of diffractive orbits in two-dimensional billiard systems with corners. This is achieved by using the exact Sommerfeld solution for the Green function of a wedge. We obtain a uniformly valid formula which interpolates between formerly separate approaches (the geometrical theory of diffraction and Gutzwiller's trace formula). It yields excellent numerical agreement with exact quantum results, also in cases where other methods fail.Comment: LaTeX, 41 pages including 12 PostScript figures, submitted to Phys. Rev.

Virtual Histology of Transgenic Mouse Embryos for High-Throughput Phenotyping

A bold new effort to disrupt every gene in the mouse genome necessitates systematic, interdisciplinary approaches to analyzing patterning defects in the mouse embryo. We present a novel, rapid, and inexpensive method for obtaining high-resolution virtual histology for phenotypic assessment of mouse embryos. Using osmium tetroxide to differentially stain tissues followed by volumetric X-ray computed tomography to image whole embryos, isometric resolutions of 27 μm or 8 μm were achieved with scan times of 2 h or 12 h, respectively, using mid-gestation E9.5–E12.5 embryos. The datasets generated by this method are immediately amenable to state-of-the-art computational methods of organ patterning analysis. This technique to assess embryo anatomy represents a significant improvement in resolution, time, and expense for the quantitative, three-dimensional analysis of developmental patterning defects attributed to genetically engineered mutations and chemically induced embryotoxicity

Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma

Human cancer genomes are highly complex, making it challenging to identify specific drivers of cancer growth, progression, and tumor maintenance. To bypass this obstacle, we have applied array comparative genomic hybridization (array CGH) to zebrafish embryonal rhabdomyosaroma (ERMS) and utilized cross-species comparison to rapidly identify genomic copy number aberrations and novel candidate oncogenes in human disease. Zebrafish ERMS contain small, focal regions of low-copy amplification. These same regions were commonly amplified in human disease. For example, 16 of 19 chromosomal gains identified in zebrafish ERMS also exhibited focal, low-copy gains in human disease. Genes found in amplified genomic regions were assessed for functional roles in promoting continued tumor growth in human and zebrafish ERMS – identifying critical genes associated with tumor maintenance. Knockdown studies identified important roles for Cyclin D2 (CCND2), Homeobox Protein C6 (HOXC6) and PlexinA1 (PLXNA1) in human ERMS cell proliferation. PLXNA1 knockdown also enhanced differentiation, reduced migration, and altered anchorage-independent growth. By contrast, chemical inhibition of vascular endothelial growth factor (VEGF) signaling reduced angiogenesis and tumor size in ERMS-bearing zebrafish. Importantly, VEGFA expression correlated with poor clinical outcome in patients with ERMS, implicating inhibitors of the VEGF pathway as a promising therapy for improving patient survival. Our results demonstrate the utility of array CGH and cross-species comparisons to identify candidate oncogenes essential for the pathogenesis of human cancer

SOFIA/FORCAST and Spitzer/IRAC Imaging of the Ultra Compact H II Region W3(OH) and Associated Protostars in W3

We present infrared observations of the ultra-compact H II region W3(OH) made by the FORCAST instrument aboard SOFIA and by Spitzer/IRAC. We contribute new wavelength data to the spectral energy distribution, which constrains the optical depth, grain size distribution, and temperature gradient of the dusty shell surrounding the H II region. We model the dust component as a spherical shell containing an inner cavity with radius ~ 600 AU, irradiated by a central star of type O9 and temperature ~ 31,000 K. The total luminosity of this system is 71,000 L_solar. An observed excess of 2.2 - 4.5 microns emission in the SED can be explained by our viewing a cavity opening or clumpiness in the shell structure whereby radiation from the warm interior of the shell can escape. We claim to detect the nearby water maser source W3 (H2O) at 31.4 and 37.1 microns using beam deconvolution of the FORCAST images. We constrain the flux densities of this object at 19.7 - 37.1 microns. Additionally, we present in situ observations of four young stellar and protostellar objects in the SOFIA field, presumably associated with the W3 molecular cloud. Results from the model SED fitting tool of Robitaille et al. (2006, 2007} suggest that two objects (2MASS J02270352+6152357 and 2MASS J02270824+6152281) are intermediate-luminosity (~ 236 - 432 L_solar) protostars; one object (2MASS J02270887+6152344) is either a high-mass protostar with luminosity 3000 L_solar or a less massive young star with a substantial circumstellar disk but depleted envelope; and one object (2MASS J02270743+6152281) is an intermediate-luminosity (~ 768 L_solar) protostar nearing the end of its envelope accretion phase or a young star surrounded by a circumstellar disk with no appreciable circumstellar envelope.Comment: 12 pages, 8 figures, 2 tables, accepted by Ap

Adjuvant chemotherapy with or without bevacizumab in patients with resected non-small-cell lung cancer (E1505): an open-label, multicentre, randomised, phase 3 trial.

BackgroundAdjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC.MethodsWe did an open-label, randomised, phase 3 trial of adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (≥4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6-12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m2 on days 1 and 8), docetaxel (75 mg/m2 on day 1), gemcitabine (1200 mg/m2 on days 1 and 8), or pemetrexed (500 mg/m2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805.FindingsBetween June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9-68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82-1·19; p=0·90). Grade 3-5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3-5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment.InterpretationAddition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC.FundingNational Cancer Institute of the National Institutes of Health

Deep Functional and Molecular Characterization of a High-Risk Undifferentiated Pleomorphic Sarcoma.

Nonrhabdomyosarcoma soft-tissue sarcomas (STSs) are a class of 50+ cancers arising in muscle and soft tissues of children, adolescents, and adults. Rarity of each subtype often precludes subtype-specific preclinical research, leaving many STS patients with limited treatment options should frontline therapy be insufficient. When clinical options are exhausted, personalized therapy assignment approaches may help direct patient care. Here, we report the results of an adult female STS patient with relapsed undifferentiated pleomorphic sarcoma (UPS) who self-drove exploration of a wide array of personalized Clinical Laboratory Improvement Amendments (CLIAs) level and research-level diagnostics, including state of the art genomic, proteomic