Identification and Characterization of BRCA1 and BRCA2 Founder Mutations

A large number of cancer predisposing BRCA1/BRCA2 mutations have been reported, with a wide variety among populations. In some restricted groups, specific germline mutations in these tumor suppressor genes have been found with high predominance, due to a founder effect. We focused our review on the Italian founder mutations. The first Italian BRCA1 founder mutation, 5083del19, was found in Calabria: the presence of common allele in all carriers of this mutation (also in families with Calabrian origin living in other parts of Italy) confirmed its founder effect. The same BRCA1 mutation was identified in the Sicilian population, but only the haplotype analysis can reveal the common ancestor of these groups. Another BRCA1 founder mutation, 4843delC, was found in Sicily. Four distinct BRCA1 mutations are attributable to families original from Tuscany: 3348delAG, 3285delA, 1499insA and 5183delTGT; the latter has been shown to be a founder mutation from North-Eastern Italy. The first BRCA2 mutation was identified in Sardinia, 8765delAG, a mutation already described as a founder mutation in Jewish-Yemenite families and also in French-Canadian population but with independent origins of carriers in these three populations. BRCA2 3951del3 and BRCA1 917delTT have been described as founder mutations in Middle Sardinia and in South and Middle Sardinia, respectively. Studies regarding prevalence and penetrance of founder mutations can allow to quantify the degree of homogeneity within a population and can surely help the geneticist and oncologist to simplify their choices in the genetic testing on high-risk families, on the basis of their ethnical origin

The nature of the low-frequency emission of M51: First observations of a nearby galaxy with LOFAR

The grand-design spiral galaxy M51 was observed with the LOFAR High Frequency Antennas (HBA) and imaged in total intensity and polarisation. This observation covered the frequencies between 115 MHz and 175 MHz. We produced an image of total emission of M51 at the mean frequency of 151 MHz with 20 arcsec resolution and 0.3 mJy rms noise, which is the most sensitive image of a galaxy at frequencies below 300 MHz so far. The integrated spectrum of total radio emission is described well by a power law, while flat spectral indices in the central region indicate thermal absorption. We observe that the disk extends out to 16 kpc and see a break in the radial profile near the optical radius of the disk. Our main results, the scale lengths of the inner and outer disks at 151 MHz and 1.4 GHz, arm--interarm contrast, and the break scales of the radio--far-infrared correlations, can be explained consistently by CRE diffusion, leading to a longer propagation length of CRE of lower energy. The distribution of CRE sources drops sharply at about 10 kpc radius, where the star formation rate also decreases sharply. We find evidence that thermal absorption is primarily caused by HII regions. The non-detection of polarisation from M51 at 151 MHz is consistent with the estimates of Faraday depolarisation. Future searches for polarised emission in this frequency range should concentrate on regions with low star formation rates.Comment: 20 pages, 18 figures, accepted for publication in A&

Galactic interstellar filaments as probed by LOFAR and Planck

Recent Low Frequency Array (LOFAR) observations at 115-175 MHz of a field at medium Galactic latitudes (centered at the bright quasar 3C196) have shown striking filamentary structures in polarization that extend over more than 4 degrees across the sky. In addition, the Planck satellite has released full sky maps of the dust emission in polarization at 353GHz. The LOFAR data resolve Faraday structures along the line of sight, whereas the Planck dust polarization maps probe the orientation of the sky projected magnetic field component. Hence, no apparent correlation between the two is expected. Here we report a surprising, yet clear, correlation between the filamentary structures, detected with LOFAR, and the magnetic field orientation, probed by the Planck satellite. This finding points to a common, yet unclear, physical origin of the two measurements in this specific area in the sky. A number of follow-up multi- frequency studies are proposed to shed light on this unexpected finding.Comment: 6 pages, 4 figures, accepted for publication in MNRAS Letter

Reaching thermal noise at ultra-low radio frequencies: the Toothbrush radio relic downstream of the shock front

Ultra-low frequency observations (<100 MHz) are particularly challenging because they are usually performed in a low signal-to-noise ratio regime due to the high sky temperature and because of ionospheric disturbances whose effects are inversely proportional to the observing frequency. Nonetheless, these observations are crucial to study the emission from low-energy populations of cosmic rays. We aim to obtain the first thermal-noise limited (~ 1.5 mJy/beam) deep continuum radio map using the LOFAR Low Band Antenna (LBA) system. Our demonstration observation targeted the galaxy cluster RX J0603.3+4214 (the "Toothbrush" cluster). We used the resulting ultra-low frequency (58 MHz) image to study cosmic-ray acceleration and evolution in the post shock region, as well as their relation with the presence of a radio halo. We describe the data reduction we have used to calibrate LOFAR LBA observations. The resulting image is combined with observations at higher frequencies (LOFAR 150 MHz and VLA 1500 MHz) to extract spectral information. We obtained the first thermal-noise limited image from an observation carried out with the LOFAR LBA system using all Dutch stations at a central frequency of 58 MHz. With 8 hours of data, we reached an rms noise of 1.3 mJy/beam at a resolution of 18" x 11". The procedure we have developed is an important step forward towards routine high-fidelity imaging with the LOFAR LBA. The analysis of the radio spectra shows that the radio relic extends to distances of 800 kpc downstream from the shock front, larger than what allowed by electron cooling time. Furthermore, the shock wave started accelerating electrons already at a projected distance of <300 kpc from the crossing point of the two clusters. These results can be explained if electrons are reaccelerated downstream by background turbulence possibly combined with projection effects.Comment: 15 pages, 19 figures, accepted A&

Diffuse polarized emission in the LOFAR Two-meter Sky Survey

Faraday tomography allows us to map diffuse polarized synchrotron emission from our Galaxy and use it to interpret the magnetic field in the interstellar medium (ISM). We have applied Faraday tomography to 60 observations from the LOFAR Two-meter Sky Survey (LOTSS) and produced a Faraday depth cube mosaic covering 568 square degrees at high Galactic latitudes, at 4.3' angular resolution and 1 rad m$^{-2}$ Faraday depth resolution, with a typical noise level of 50--100 $\mu$Jy per point spread function (PSF) per rotation measure spread function (RMSF) (40-80 mK RMSF$^{-1}$). While parts of the images are strongly affected by instrumental polarization, we observe diffuse polarized emission throughout most of the field, with typical brightness between 1 and 6 K RMSF$^{-1}$, and Faraday depths between $-7$ and +25 rad m$^{-2}$. We observed many new polarization features, some up to 15 degrees in length. These include two regions with very uniformly structured, linear gradients in the Faraday depth; we measured the steepness of these gradients as 2.6 and 13 rad m$^{-2}$ deg$^{-1}$. We also observed a relationship between one of the gradients and an HI filament in the local ISM. Other ISM tracers were also checked for correlations with our polarization data and none were found, but very little signal was seen in most tracers in this region. We conclude that the LOTSS data are very well suited for Faraday tomography, and that a full-scale survey with all the LOTSS data has the potential to reveal many new Galactic polarization features and map out diffuse Faraday depth structure across the entire northern hemisphere.Comment: 23 pages, 16 figures, accepted by A&A. Figures have been degraded to comply with arXiv file size limits; full resolution figures will be available in the A&A versio

LOFAR MSSS: Flattening low-frequency radio continuum spectra of nearby galaxies

Accepted for publication in Astronomy and AstrophysicsAims. The shape of low-frequency radio continuum spectra of normal galaxies is not well understood, the key question being the role of physical processes such as thermal absorption in shaping them. In this work we take advantage of the LOFAR Multifrequency Snapshot Sky Survey (MSSS) to investigate such spectra for a large sample of nearby star-forming galaxies. Methods. Using the measured 150 MHz flux densities from the LOFAR MSSS survey and literature flux densities at various frequencies we have obtained integrated radio spectra for 106 galaxies characterised by different morphology and star formation rate. The spectra are explained through the use of a three-dimensional model of galaxy radio emission, and radiation transfer dependent on the galaxy viewing angle and absorption processes. Results. Our galaxies' spectra are generally flatter at lower compared to higher frequencies: the median spectral index α low measured between ≈ 50 MHz and 1.5 GHz is -0.57 ± 0.01 while the high-frequency one α high, calculated between 1.3 GHz and 5 GHz, is -0.77 ± 0.03. As there is no tendency for the highly inclined galaxies to have more flattened low-frequency spectra, we argue that the observed flattening is not due to thermal absorption, contradicting the suggestion of Israel & Mahoney (1990, ApJ, 352, 30). According to our modelled radio maps for M 51-like galaxies, the free-free absorption effects can be seen only below 30 MHz and in the global spectra just below 20 MHz, while in the spectra of starburst galaxies, like M 82, the flattening due to absorption is instead visible up to higher frequencies of about 150 MHz. Starbursts are however scarce in the local Universe, in accordance with the weak spectral curvature seen in the galaxies of our sample. Locally, within galactic disks, the absorption effects are distinctly visible in M 51-like galaxies as spectral flattening around 100-200 MHz in the face-on objects, and as turnovers in the edge-on ones, while in M 82-like galaxies there are strong turnovers at frequencies above 700 MHz, regardless of viewing angle. Conclusions. Our modelling of galaxy spectra suggests that the weak spectral flattening observed in the nearby galaxies studied here results principally from synchrotron spectral curvature due to cosmic ray energy losses and propagation effects. We predict much stronger effects of thermal absorption in more distant galaxies with high star formation rates. Some influence exerted by the Milky Way's foreground on the spectra of all external galaxies is also expected at very low frequencies.Peer reviewedFinal Accepted Versio

Polarized point sources in the LOFAR Two-meter Sky Survey: A preliminary catalog

The polarization properties of radio sources at very low frequencies (h45m–15h30m right ascension, 45°–57° declination, 570 square degrees). We have produced a catalog of 92 polarized radio sources at 150 MHz at 4.′3 resolution and 1 mJy rms sensitivity, which is the largest catalog of polarized sources at such low frequencies. We estimate a lower limit to the polarized source surface density at 150 MHz, with our resolution and sensitivity, of 1 source per 6.2 square degrees. We find that our Faraday depth measurements are in agreement with previous measurements and have significantly smaller errors. Most of our sources show significant depolarization compared to 1.4 GHz, but there is a small population of sources with low depolarization indicating that their polarized emission is highly localized in Faraday depth. We predict that an extension of this work to the full LOTSS data would detect at least 3400 polarized sources using the same methods, and probably considerably more with improved data processing

LOFAR MSSS: The Scaling Relation between AGN Cavity Power and Radio Luminosity at Low Radio Frequencies

This article has been accepted for publication in a forthcoming issue of Astronomy & Astrophysics. Reproduced with permission from Astronomy & Astrophysics. © 2018 ESO.We present a new analysis of the widely used relation between cavity power and radio luminosity in clusters of galaxies with evidence for strong AGN feedback. We study the correlation at low radio frequencies using two new surveys - the First Alternative Data Release of the TIFR GMRT Sky Survey (TGSS ADR1) at 148 MHz and LOFAR's first all-sky survey, the Multifrequency Snapshot Sky Survey (MSSS) at 140 MHz. We find a scaling relation $P_{\rm cav} \propto L_{148}^{\beta}$, with a logarithmic slope of $\beta = 0.51 \pm 0.14$, which is in good agreement with previous results based on data at 327 MHz. The large scatter present in this correlation confirms the conclusion reached at higher frequencies that the total radio luminosity at a single frequency is a poor predictor of the total jet power. We show that including measurements at 148 MHz alone is insufficient to reliably compute the bolometric radio luminosity and reduce the scatter in the correlation. For a subset of four well-resolved sources, we examine the detected extended structures at low frequencies and compare with the morphology known from higher frequency images and Chandra X-ray maps. In Perseus we discuss details in the structures of the radio mini-halo, while in the 2A 0335+096 cluster we observe new diffuse emission associated with multiple X-ray cavities and likely originating from past activity. For A2199 and MS 0735.6+7421, we confirm that the observed low-frequency radio lobes are confined to the extents known from higher frequencies. This new low-frequency analysis highlights the fact that existing cavity power to radio luminosity relations are based on a relatively narrow range of AGN outburst ages. We discuss how the correlation could be extended using low frequency data from the LOFAR Two-metre Sky Survey (LoTSS) in combination with future, complementary deeper X-ray observations.Peer reviewe

Patterns of K-ras mutation in colorectal carcinomas from Iran and Italy (a Gruppo Oncologico dell'Italia Meridionale study): influence of microsatellite instability status and country of origin.

Background: K-ras mutations are a key step in colorectal cancer progression. Such mutations have been widely studied in case series from Western countries but there are few data on the rate and spectrum of mutations in tumors from countries where the epidemiological features of the disease are different. Patients and methods: Tumor samples from 182 Iranian colorectal cancer patients (170 sporadic cases and 12 HNPCC cases) were screened for K-ras mutations at codons 12, 13 and 61 by sequencing analysis. The cases were also characterized for microsatellite instability at mononucleotide repeats by PCR and fragment analysis, and classified according to microsatellite instability status. The frequency and the spectrum of K-ras mutations were compared with those observed in a series of colorectal cancer patients from Italy. Results: K-ras mutations were observed in 68/182 (37.4%) cases. Mutation frequencies were similar in HNPCC-associated, sporadic MSI-H and sporadic microsatellite-stable (MSS) tumors. However, the G13D substitution was more frequent in HNPCC (3/ 4, 75%) and sporadic MSI- H (7/11, 63.6%) tumors compared to sporadic MSS tumors (11/ 53, 20.4%) (P < 0.01). Comparison of mutations in the two series from Iran and Italy showed a significantly higher frequency of G13D among Italian patients. Conclusions: While the frequency of K-ras mutations could be similar, the mutational spectrum could be differentially influenced by genetic and environmental factors

Cyclophilin C-associated protein (CyCAP) knock-out mice spontaneously develop colonic mucosal hyperplasia and exaggerated tumorigenesis after treatment with carcinogen azoxymethane1

<p>Abstract</p> <p>Background</p> <p>The discovery of a "serrated neoplasia pathway" has highlighted the role of hyperplastic lesions of the colon as the significant precursor of colorectal adenocarcinoma. In mice, hyperplasia of the colonic mucosa is a regular phenomenon after a challenge with colonic carcinogens indicating that mucosal hyperproliferation and thickening, even without cytological dysplasia, represents an early pre-malignant change. Cyclophilin C-associated protein (CyCAP) has been described to down-modulate endotoxin signaling in colorectal murine mucosa and is a murine orthologue of the tumor-associated antigen 90 K (TAA90K)/mac-2-binding protein.</p> <p>Methods</p> <p>Female Balb/c wild-type (WT) and CyCAP knock-out (KO) mice (6–8 weeks old) were administered 2 or 6 weekly subcutaneous injections of azoxymethane. The animals were evaluated post-injection at six weeks for aberrant crypt foci (ACF) study and at five months for colon tumor measurement. The thickness of the colon crypts was measured in microns and the number of colonocytes per crypt was also determined in well-oriented crypts. Morphometric analyses of the colon mucosa were also performed in untreated 6–8 weeks old KO and WT animals. Formalin-fixed/paraffin-embedded colon sections were also studied by immunohistochemistry to determine the Ki-67 proliferation fraction of the colon mucosa, β-catenin cellular localization, cyclin D1, c-myc, and lysozyme in Paneth cells.</p> <p>Results</p> <p>Cyclophilin C-associated protein (CyCAP)^-/-mice, spontaneously developed colonic mucosal hyperplasia early in life compared to wild-type mice (WT) (p < 0.0001, T-test) and crypts of colonic mucosa of the (CyCAP)^-/-mice show higher proliferation rate (p = 0.039, Mann-Whitney Test) and larger number of cyclin D1-positive cells (p < 0.0001, Mann-Whitney Test). Proliferation fraction and cyclin D1 expression showed positive linear association (p = 0.019, Linear-by-Linear Association). The hyperplasia was even more pronounced in CyCAP^-/-mice than in WT after challenge with azoxymethane (p = 0.005, T-test). The length of the crypts (r = 0.723, p = 0.018, Spearman Correlation) and the number of colonocytes per crypt (r = 0.863, p = 0.001, Spearman Correlation) in non-tumorous areas were positively associated with azoxymethane-induced number of tumors. CyCAP^-/-developed larger numbers of tumors than WT animals (p = 0.003, T-Test) as well as overall larger tumor mass (p = 0.016, T-Test). Membranous β-catenin was focally overexpressed in KO mice including proliferative zone of the crypts.</p> <p>Conclusion</p> <p>CyCAP^-/-represent the first described model of spontaneous colonic mucosal hyperplasia. We conclude that CyCAP-deficient mice spontaneously and after challenge with carcinogen develop significantly more colorectal mucosal hyperplasia, an early stage in murine colonic carcinogenesis.</p