Germline-Focused Analysis of Tumour-Only Sequencing: Recommendations from the ESMO Precision Medicine Working Group.

It is increasingly common in oncology practice to perform tumour sequencing using large cancer panels. For pathogenic sequence variants in cancer susceptibility genes identified on tumour-only sequencing, it is often unclear whether they are of somatic or constitutional (germline) origin. There is wide-spread disparity regarding both the extent to which systematic 'germline-focused analysis' is performed upon tumour sequencing data and for which variants follow-up analysis of a germline sample is performed. Here we present analyses of paired sequencing data from 17,152 cancer samples, in which 1494 pathogenic sequence variants were identified across 65 cancer susceptibility genes. From these analyses, the European Society of Medical Oncology Precision Medicine Working Group Germline Subgroup have generated (i) recommendations regarding germline-focused analyses of tumour-only sequencing data, (ii) indications for germline follow-up testing and (iii) guidance on patient information-giving and consent

Observational Diagnostics of Gas Flows: Insights from Cosmological Simulations

Galactic accretion interacts in complex ways with gaseous halos, including galactic winds. As a result, observational diagnostics typically probe a range of intertwined physical phenomena. Because of this complexity, cosmological hydrodynamic simulations have played a key role in developing observational diagnostics of galactic accretion. In this chapter, we review the status of different observational diagnostics of circumgalactic gas flows, in both absorption (galaxy pair and down-the-barrel observations in neutral hydrogen and metals; kinematic and azimuthal angle diagnostics; the cosmological column density distribution; and metallicity) and emission (Lya; UV metal lines; and diffuse X-rays). We conclude that there is no simple and robust way to identify galactic accretion in individual measurements. Rather, progress in testing galactic accretion models is likely to come from systematic, statistical comparisons of simulation predictions with observations. We discuss specific areas where progress is likely to be particularly fruitful over the next few years.Comment: Invited review to appear in Gas Accretion onto Galaxies, Astrophysics and Space Science Library, eds. A. J. Fox & R. Dave, to be published by Springer. Typos correcte

Gas Accretion and Star Formation Rates

Cosmological numerical simulations of galaxy evolution show that accretion of metal-poor gas from the cosmic web drives the star formation in galaxy disks. Unfortunately, the observational support for this theoretical prediction is still indirect, and modeling and analysis are required to identify hints as actual signs of star-formation feeding from metal-poor gas accretion. Thus, a meticulous interpretation of the observations is crucial, and this observational review begins with a simple theoretical description of the physical process and the key ingredients it involves, including the properties of the accreted gas and of the star-formation that it induces. A number of observations pointing out the connection between metal-poor gas accretion and star-formation are analyzed, specifically, the short gas consumption time-scale compared to the age of the stellar populations, the fundamental metallicity relationship, the relationship between disk morphology and gas metallicity, the existence of metallicity drops in starbursts of star-forming galaxies, the so-called G dwarf problem, the existence of a minimum metallicity for the star-forming gas in the local universe, the origin of the alpha-enhanced gas forming stars in the local universe, the metallicity of the quiescent BCDs, and the direct measurements of gas accretion onto galaxies. A final section discusses intrinsic difficulties to obtain direct observational evidence, and points out alternative observational pathways to further consolidate the current ideas.Comment: Invited review to appear in Gas Accretion onto Galaxies, Astrophysics and Space Science Library, eds. A. J. Fox & R. Dav\'e, to be published by Springe

Determinants of Restaurant Systematic Risk: A Reexamination

This study reexamines determinants of the systematic risk or beta of restaurant firms based on the financial data of 75 U.S. restaurant firms from 1996 through 1999. Our weighted least-squares regression analysis found that restaurant systematic risk correlated negatively with assets turnover but positively with quick ratio. The findings suggest that high efficiency in generating sales revenue helps lower the systematic risk, while excess liquidity tends to increase the risk

Hereditary palmoplantar keratoderma - phenotypes and mutations in 64 patients

Background Hereditary palmoplantar keratodermas (PPK) represent a heterogeneous group of rare skin disorders with epidermal hyperkeratosis of the palms and soles, with occasional additional manifestations in other tissues. Mutations in at least 69 genes have been implicated in PPK, but further novel candidate genes and mutations are still to be found. Objectives To identify mutations underlying PPK in a cohort of 64 patients. Methods DNA of 48 patients was analysed on a custom-designed in-house panel for 35 PPK genes, and 16 patients were investigated by a diagnostic genetic laboratory either by whole-exome sequencing, gene panels or targeted single-gene sequencing. Results Of the 64 PPK patients, 32 had diffuse (50%), 19 focal (30%) and 13 punctate (20%) PPK. None had striate PPK. Pathogenic mutations in altogether five genes were identified in 31 of 64 (48%) patients, the majority (22/31) with diffuse PPK. Of them, 11 had a mutation in AQP5, five in SERPINB7, four in KRT9 and two in SLURP1. AAGAB mutations were found in nine punctate PPK patients. New mutations were identified in KRT9 and AAGAB. No pathogenic mutations were detected in focal PPK. Variants of uncertain significance (VUS) in PPK-associated and other genes were observed in 21 patients that might explain their PPK. No suggestive pathogenic variants were found for 12 patients. Conclusions Diffuse PPK was the most common (50%) and striate PPK was not observed. We identified pathogenic mutations in 48% of our PPK patients, mainly in five genes: AQP5, AAGAB, KRT9, SERPINB7 and SLURP1.Peer reviewe

The Extended [C ii] under Construction? Observation of the Brightest High-z Lensed Star-forming Galaxy at z = 6.2

We present results of [C ii] 158 μm emission line observations, and report the spectroscopic redshift confirmation of a strongly lensed (μ ∼ 20) star-forming galaxy, MACS0308-zD1 at z = 6.2078 ± 0.0002. The [C ii] emission line is detected with a signal-to-noise ratio >6 within the rest-frame UV-bright clump of the lensed galaxy (zD1.1) and exhibits multiple velocity components; the narrow [C ii] has a velocity full width half maximum (FWHM) of 110 ± 20 km s−1, while broader [C ii] is seen with an FWHM of 230 ± 50 km s−1. The broader [C ii] component is blueshifted (−80 ± 20 km s−1) with respect to the narrow [C ii] component, and has a morphology that extends beyond the UV-bright clump. We find that, while the narrow [C ii] emission is most likely associated with zD1.1, the broader component is possibly associated with a physically distinct gas component from zD1.1 (e.g., outflowing or inflowing gas). Based on the nondetection of λ158μm dust continuum, we find that MACS0308-zD1's star formation activity occurs in a dust-free environment indicated by a strong upper limit of infrared luminosity ≲9 × 108L⊙. Targeting this strongly lensed faint galaxy for follow-up Atacama Large Millimeter/submillimeter Array and JWST observations will be crucial to characterize the details of typical galaxy growth in the early Universe

Reaching for the stars – JWST/NIRSpec spectroscopy of a lensed star candidate at z = 4.76

We present JWST/NIRSpec observations of a highly magnified star candidate at a photometric redshift of zphot ≃ 4.8, previously detected in JWST/NIRCam imaging of the strong lensing (SL) cluster MACS J0647+7015 (z = 0.591). The spectroscopic observation allows us to precisely measure the redshift of the host arc at zspec = 4.758 ± 0.004, and the star’s spectrum displays clear Lyman- and Balmer-breaks commensurate with this redshift. A fit to the spectrum suggests a B-type super-giant star of surface temperature  K with either a redder F-type companion (⁠ K) or significant dust attenuation (AV ≃ 0.82) along the line of sight. We also investigate the possibility that this object is a magnified young globular cluster rather than a single star. We show that the spectrum is in principle consistent with a star cluster, which could also accommodate the lack of flux variability between the two epochs. However, the lack of a counter image and the strong upper limit on the size of the object from lensing symmetry, r ≲ 0.5 pc, could indicate that this scenario is somewhat less likely – albeit not completely ruled out by the current data. The presented spectrum seen at a time when the Universe was only ∼1.2 Gyr old showcases the ability of JWST to study early stars through extreme lensing

The Ubiquitin Peptidase UCHL1 Induces G0/G1 Cell Cycle Arrest and Apoptosis Through Stabilizing p53 and Is Frequently Silenced in Breast Cancer

Background: Breast cancer (BrCa) is a complex disease driven by aberrant gene alterations and environmental factors. Recent studies reveal that abnormal epigenetic gene regulation also plays an important role in its pathogenesis. Ubiquitin carboxyl- terminal esterase L1 (UCHL1) is a tumor suppressor silenced by promoter methylation in multiple cancers, but its role and alterations in breast tumorigenesis remain unclear. Methodology/Principal Findings: We found that UCHL1 was frequently downregulated or silenced in breast cancer cell lines and tumor tissues, but readily expressed in normal breast tissues and mammary epithelial cells. Promoter methylation of UCHL1 was detected in 9 of 10 breast cancer cell lines (90%) and 53 of 66 (80%) primary tumors, but rarely in normal breast tissues, which was statistically correlated with advanced clinical stage and progesterone receptor status. Pharmacologic demethylation reactivated UCHL1 expression along with concomitant promoter demethylation. Ectopic expression of UCHL1 significantly suppressed the colony formation and proliferation of breast tumor cells, through inducing G0/G1 cell cycle arrest and apoptosis. Subcellular localization study showed that UCHL1 increased cytoplasmic abundance of p53. We further found that UCHL1 induced p53 accumulation and reduced MDM2 protein level, and subsequently upregulated the expression of p21, as well as cleavage of caspase3 and PARP, but not in catalytic mutant UCHL1 C90Sexpressed cells