Context. The present number of Galactic open clusters that have high resolution abundance determinations, not only of Fe/H, but also of other key elements, is largely insufficient to enable a clear ...modeling of the Galactic disk chemical evolution. Aims. To increase the number of Galactic open clusters with high quality measurements. Methods. We obtained high resolution (R ~ 30 000), high quality (S/N ~ 50–100 per pixel), echelle spectra with the fiber spectrograph FOCES, at Calar Alto, Spain, for three red clump stars in each of five Open Clusters. We used the classical equivalent width analysis method to obtain accurate abundances of sixteen elements: Al, Ba, Ca, Co, Cr, Fe, La, Mg, Na, Nd, Ni, Sc, Si, Ti, V, and Y. We also derived the oxygen abundance using spectral synthesis of the 6300 Å forbidden line. Results. Three of the clusters were never studied previously with high resolution spectroscopy: we found Fe/H = +0.03±0.02 (±0.10) dex for Cr 110; Fe/H = +0.01±0.05 (±0.10) dex for NGC 2099 (M 37), and Fe/H = -0.05±0.03 (±0.10) dex for NGC 2420. This last finding is higher than typical literature estimates by 0.2–0.3 dex approximately and in closer agreement with Galactic trends. For the remaining clusters, we find that Fe/H = +0.05±0.02 (±0.10) dex for M 67 and Fe/H = +0.04±0.07 (±0.10) dex for NGC 7789. Accurate (to ~0.5 km s-1) radial velocities were measured for all targets, and we provide the first velocity estimate derived from high resolution data for Cr 110, $\langle V_{\rm r}\rangle$ = 41.0±3.8 km s-1. Conclusions. With our analysis of the new clusters Cr 110, NGC 2099, and NGC 2420, we increase the sample of clusters with high-resolution-based abundances by 5%. All our program stars show abundance patterns which are typical of open clusters, very close to solar with few exceptions. This is true for all the iron-peak and s-process elements considered, and no significant α-enhancement is found. No significant (anti-)correlations for Na, Al, Mg, and O abundances are found. If anticorrelations are present, the involved spreads must be <0.2 dex. We then compile high resolution data of 57 OC from the literature and find a gradient of Fe/H with Galactocentric radius of –0.06±0.02 dex kpc-1, in agreement with past work and with results for Cepheids and B stars in the same range. A change of slope is seen outside RGC = 12 kpc and α/Fe shows a tendency to increase with RGC. We also confirm the absence of a significant age-metallicity relation, finding slopes of –2.6±1.1 $\times$ 10-11 dex Gyr-1 and 1.1±5.0 $\times$ 10-11 dex Gyr-1 for Fe/H and α/Fe respectively.
The aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by ...directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation.
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•A single aberrant transcription factor directly activates or represses enhancers•Chromatin remodeling at enhancer elements is dictated by the underlying DNA sequence•EWS-FLI1 displays divergent patterns of chromatin remodeler recruitment•De novo enhancers mediate tumor dependencies
Using integrated analyses of chromatin states in human Ewing sarcoma, Riggi et al. find that the EWS-FLI1 fusion protein drives an oncogenic regulatory program governing both survival and differentiation by either creating enhancers de novo or competing with endogenous ETS to repress conserved enhancers.
IMPORTANCE: Surgical resection remains the preferred treatment for functionally fit patients diagnosed with early-stage non–small cell lung cancer (NSCLC). Process-based intraoperative quality ...metrics (QMs) are important for optimizing long-term outcomes following curative-intent resection. OBJECTIVE: To develop a practical surgical quality score for patients diagnosed with clinical stage I NSCLC who received definitive surgical treatment. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used a uniquely compiled data set of US veterans diagnosed with clinical stage I NSCLC who received definitive surgical treatment from October 2006 through September 2016. The data were analyzed from April 1 to September 1, 2022. Based on contemporary treatment guidelines, 5 surgical QMs were defined: timely surgery, minimally invasive approach, anatomic resection, adequate lymph node sampling, and negative surgical margin. The study developed a surgical quality score reflecting the association between these QMs and overall survival (OS), which was further validated in a cohort of patients using data from the National Cancer Database (NCDB). The study also examined the association between the surgical quality score and recurrence-free survival (RFS). EXPOSURES: Surgical treatment of early-stage NSCLC. MAIN OUTCOMES AND MEASURES: Overall survival and RFS. RESULTS: The study included 9628 veterans who underwent surgical treatment between 2006 and 2016. The cohort consisted of 1446 patients who had a mean (SD) age of 67.6 (7.9) years and included 9278 males (96.4%) and 350 females (3.6%). Among the cohort, 5627 individuals (58.4%) identified as being smokers at the time of surgical treatment. The QMs were met as follows: timely surgery (6633 68.9%), minimally invasive approach (3986 41.4%), lobectomy (6843 71.1%) or segmentectomy (532 5.5%), adequate lymph node sampling (3278 34.0%), and negative surgical margin (9312 96.7%). The median (IQR) follow-up time was 6.2 (2.5-11.4) years. An integer-based score (termed the Veterans Affairs Lung Cancer Operative quality VALCAN-O score) from 0 (no QMs met) to 13 (all QMs met) was constructed, with higher scores reflecting progressively better risk-adjusted OS. The median (IQR) OS differed substantially between the score categories (score of 0-5 points, 2.6 1.0-5.7 years of OS; 6-8 points, 4.3 1.7-8.6 years; 9-11 points, 6.3 2.6-11.4 years; and 12-13 points, 7.0 3.0-12.5 years; P < .001). In addition, risk-adjusted RFS improved in a stepwise manner between the score categories (6-8 vs 0-5 points, multivariable-adjusted hazard ratio aHR, 0.62; 95% CI, 0.48-0.79; P < .001; 12-13 vs 0-5 points, aHR, 0.39; 95% CI, 0.31-0.49; P < .001). In the validation cohort, which included 107 674 nonveteran patients, the score remained associated with OS. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that adherence to intraoperative QMs may be associated with improved OS and RFS. Efforts to improve adherence to surgical QMs may improve patient outcomes following curative-intent resection of early-stage lung cancer.
Medulloblastoma is the most frequent malignant pediatric brain tumor and is divided into at least four subgroups known as WNT, SHH, Group 3, and Group 4. Here, we characterized gene regulation ...mechanisms in the most aggressive subtype, Group 3 tumors, through genome-wide chromatin and expression profiling. Our results show that most active distal sites in these tumors are occupied by the transcription factor OTX2. Highly active OTX2-bound enhancers are often arranged as clusters of adjacent peaks and are also bound by the transcription factor NEUROD1. These sites are responsive to
and
knockdown and could also be generated
upon ectopic
expression in primary cells, showing that OTX2 cooperates with NEUROD1 and plays a major role in maintaining and possibly establishing regulatory elements as a pioneer factor. Among OTX2 target genes, we identified the kinase NEK2, whose knockdown and pharmacologic inhibition decreased cell viability. Our studies thus show that OTX2 controls the regulatory landscape of Group 3 medulloblastoma through cooperative activity at enhancer elements and contributes to the expression of critical target genes.
The gene regulation mechanisms that drive medulloblastoma are not well understood. Using chromatin profiling, we find that the transcription factor OTX2 acts as a pioneer factor and, in cooperation with NEUROD1, controls the Group 3 medulloblastoma active enhancer landscape. OTX2 itself or its target genes, including the mitotic kinase NEK2, represent attractive targets for future therapies.
.
In physically realistic, scalar-field-based dynamical dark energy models (including, e.g., quintessence), one naturally expects the scalar field to couple to the rest of the model’s degrees of ...freedom. In particular, a coupling to the electromagnetic sector leads to a time (redshift) dependence in the fine-structure constant and a violation of the weak equivalence principle. Here we extend the previous
Euclid
forecast constraints on dark energy models to this enlarged (but physically more realistic) parameter space, and forecast how well
Euclid
, together with high-resolution spectroscopic data and local experiments, can constrain these models. Our analysis combines simulated
Euclid
data products with astrophysical measurements of the fine-structure constant,
α
, and local experimental constraints, and it includes both parametric and non-parametric methods. For the astrophysical measurements of
α
, we consider both the currently available data and a simulated dataset representative of Extremely Large Telescope measurements that are expected to be available in the 2030s. Our parametric analysis shows that in the latter case, the inclusion of astrophysical and local data improves the
Euclid
dark energy figure of merit by between 8% and 26%, depending on the correct fiducial model, with the improvements being larger in the null case where the fiducial coupling to the electromagnetic sector is vanishing. These improvements would be smaller with the current astrophysical data. Moreover, we illustrate how a genetic algorithms based reconstruction provides a null test for the presence of the coupling. Our results highlight the importance of complementing surveys like
Euclid
with external data products, in order to accurately test the wider parameter spaces of physically motivated paradigms.
Context. Galaxy-scale gravitational lenses are powerful tools, which can be used to address major astrophysical questions that are still open. They can be identified either through imaging or through ...spectroscopy, which is less efficient than imaging but offers the major advantage of having both source and deflector red shift previously measured at discovery. Spectroscopic identification requires huge data sets of high spectral quality, such as the SDSS, and has so far focused on early-type galaxies, as the most massive galaxies are found among them. Aims. We aimed to perform spectroscopic identification of disk galaxies acting as gravitational lenses. Methods. We have selected about 300 000 galaxy spectra with EW(Hα) ≤−10 Å from the SDSS DR 8. On these spectra, we ran our original code RES, which is a fast, reliable tool able to provide a red-shift measure and to identify discordant red-shift systems if present. We have required RES to identify only systems based on a minimum number of four emission lines. We have inspected all the (54) SDSS images of the double z systems identified by RES and discarded systems for which z duplicity could be easily ascribed to the presence of two distinct objects. The remaining 25 systems, for which double z is very likely to be due to the gravitational lensing phenomenon, constitute our sample. Results. For each gravitational lens candidate system, we provide SDSS identification and image emission lines detected by RES and activity classification, when derivable. The disky nature of our candidate lenses is confirmed by their images, stellar mass estimates, g − r rest-frame colours and occurrence of star burst phenomena.
Purpose
In order to better define the breast cancer (BC) genetic risk factors in men, a germline investigation was carried out on 81 Male BC cases by screening the 24 genes involved in BC ...predisposition, genome stability maintenance and DNA repair mechanisms by next-generation sequencing.
Methods
Germline DNAs were tested in a custom multi-gene panel focused on all coding exons and exon–intron boundaries of 24 selected genes using two amplicon-based assays on PGM-Ion Torrent (ThermoFisher Scientific) and MiSeq (Illumina) platforms. All variants were recorded and classified by using a custom pipeline.
Results
Clinical pathological data and the family history of 81 Male BC cases were gathered and analysed, revealing the average age of onset to be 61.3 years old and that in 35 cases there was a family history of BC. Our genetic screening allowed us to identify a germline mutation in 22 patients (23%) in 4 genes:
BRCA2
,
BRIP1
,
MUTYH
and
PMS2
. Moreover, 12 variants of unknown clinical significance (VUS) in 9 genes (
BARD1
,
BRCA1
,
BRIP1
,
CHEK2
,
ERCC1
,
NBN
,
PALB2
,
PMS1
,
RAD50
) were predicted as potentially pathogenic by in silico analysis bringing the mutation detection rate up to 40%.
Conclusion
As expected, a positive family history is a strong predictor of germline
BRCA2
mutations in male BC. Understanding the potential pathogenicity of VUS represents an extremely urgent need for the management of BC risk in Male BC cases and their own families.
Introduction
The oncoplastic conservative surgery was developed as a natural evolution of traditional surgery, attempting to improve the therapeutic and aesthetic outcomes where tumor resection could ...be followed by not-adequate results. Our primary aim is to evaluate how patient satisfaction and quality-of-life after conservative oncoplastic surgery, using BREAST-Q (BCT Module), change pre- and post-operatively. The secondary aim is to compare patient-reported outcome after oncoplastic or traditional conservative surgery.
Patients and methods
We enrolled 647 patients who underwent traditional conservative surgery or oncoplastic surgery from January 2020 to December 2022. Only 232 women (35.9%) completed the BREAST-Q questionnaire on a web-based platform, at the preoperative phase and 3 months after treatment.
Results
The average score of “Psychosocial well-being” and “Satisfaction with Breasts” 3 months after surgery showed a statistically significant improvement, while the average score for “Physical well-being: Chest” at 3 months showed a worsening compared to the baseline. “Sexual well-being” did not show statistically significant change. A significant difference between the post-operative outcome of oncoplastic surgery and traditional surgery was observed only for Physical well-being (better for traditional surgery).
Conclusions
The study showed significant improvement in patient-reported outcomes 3 months after the surgery, except for physical discomfort that increases especially after oncoplastic surgery. Furthermore, our data, as well as many others, point to the appropriateness of using OCS where there is an effective indication, while the perspective of patients cannot find significant superiority over TCS in any of the areas analyzed.
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