Transcript fusions as a result of chromosomal rearrangements have been a focus of attention in cancer as they provide attractive therapeutic targets. To identify novel fusion transcripts with the ...potential to be exploited therapeutically, we analyzed RNA sequencing, DNA copy number and gene mutation data from 4366 primary tumor samples. To avoid false positives, we implemented stringent quality criteria that included filtering of fusions detected in RNAseq data from 364 normal tissue samples. Our analysis identified 7887 high confidence fusion transcripts across 13 tumor types. Our fusion prediction was validated by evidence of a genomic rearrangement for 78 of 79 fusions in 48 glioma samples where whole-genome sequencing data were available. Cancers with higher levels of genomic instability showed a corresponding increase in fusion transcript frequency, whereas tumor samples harboring fusions contained statistically significantly fewer driver gene mutations, suggesting an important role for tumorigenesis. We identified at least one in-frame protein kinase fusion in 324 of 4366 samples (7.4%). Potentially druggable kinase fusions involving ALK, ROS, RET, NTRK and FGFR gene families were detected in bladder carcinoma (3.3%), glioblastoma (4.4%), head and neck cancer (1.0%), low-grade glioma (1.5%), lung adenocarcinoma (1.6%), lung squamous cell carcinoma (2.3%) and thyroid carcinoma (8.7%), suggesting a potential for application of kinase inhibitors across tumor types. In-frame fusion transcripts involving histone methyltransferase or histone demethylase genes were detected in 111 samples (2.5%) and may additionally be considered as therapeutic targets. In summary, we described the landscape of transcript fusions detected across a large number of tumor samples and revealed fusion events with clinical relevance that have not been previously recognized. Our results support the concept of basket clinical trials where patients are matched with experimental therapies based on their genomic profile rather than the tissue where the tumor originated.
With the advent of high-throughput sequencing technologies, much progress has been made in the identification of somatic structural rearrangements in cancer genomes. However, characterization of the ...complex alterations and their associated mechanisms remains inadequate. Here, we report a comprehensive analysis of whole-genome sequencing and DNA copy number data sets from The Cancer Genome Atlas to relate chromosomal alterations to imbalances in DNA dosage and describe the landscape of intragenic breakpoints in glioblastoma multiforme (GBM). Gene length, guanine-cytosine (GC) content, and local presence of a copy number alteration were closely associated with breakpoint susceptibility. A dense pattern of repeated focal amplifications involving the murine double minute 2 (MDM2)/cyclin-dependent kinase 4 (CDK4) oncogenes and associated with poor survival was identified in 5% of GBMs. Gene fusions and rearrangements were detected concomitant within the breakpoint-enriched region. At the gene level, we noted recurrent breakpoints in genes such as apoptosis regulator FAF1. Structural alterations of the FAF1 gene disrupted expression and led to protein depletion. Restoration of the FAF1 protein in glioma cell lines significantly increased the FAS-mediated apoptosis response. Our study uncovered a previously underappreciated genomic mechanism of gene deregulation that can confer growth advantages on tumor cells and may generate cancer-specific vulnerabilities in subsets of GBM.
Given the high incidence of confirmed infection by SARS-CoV-2 and mortality by COVID-19 in the Spanish population, its impact was analysed among persons with Cystic Fibrosis (CF) as a group at risk ...of a worse evolution. The possible causes of the incidence observed in them are explained and how CF Units have faced this health challenge is detailed.
Retrospective descriptive observational study, for which a Spanish CF Patients with Confirmed COVID-19 Registry is created, requesting information on number of people affected between 8 March–16 May 2020 and their clinical-demographic characteristics from the CF Units participating in the European Cystic Fibrosis Society Patient Registry (ECFSPR). The accumulated incidence is calculated, compared with that of the general population. Additionally, a survey (CF-COVID19-Spain) is carried out on prevention of SARS-CoV-2 infection, workings of CF Units and possible reasons for the incidence observed.
COVID-19 was diagnosed in eight CF patients, one of whom had received a lung transplant. The accumulated incidence was 32/10000 in CF patients and 49/10000 in the general population. General death rate was 5.85/10000 while no CF patients included in the ECFSPR died. The characteristics of those affected and the results of the survey are described.
Despite being considered a disease at high risk of severe COVID-19, the low incidence and mortality in CF patients in Spain contrasts with the figures for the general population. The possible factors that would explain such findings are discussed, with the help of the results of the CF-COVID19-Spain survey.
•SARS-CoV-2 pandemic is severely hitting Spain.•Cumulative incidence among Spanish CF patients is being lower than expected.•No fatal cases were reported in our CF patients with COVID-19 included in ECFSPR.•CF-COVID19-Spain survey was useful to explain its low incidence and mild course.
To assist GK-12 teachers in their effort to improve science and math instruction, the STARS (Students, Teachers and Resources in the Sciences) program from the University of South Florida has ...developed a science training plan for teachers in the 3-5 band. STARS is a National Science Foundation project, which aims to promote systemic change in primary grade levels by enriching the math and science courses and by encouraging long-term professional development for the teachers. This paper discusses the tools employed to facilitate the integration of advanced concepts, such as materials science and nanotechnology, into the teacher curriculum through training modules. The modules were designed to target a population of lead science and math teachers. The main objective of the training program is to form and mature lead teachers that will disseminate to other elementary science educators the advanced science modules, and will provide the necessary in-class support during the implementation phase
Antivipmyn registered is an anti-venom used in Mexico in case of poisonings by venomous snakes. Objective: In the present study we evaluated the safety of Antivipmyn registered in humans. Methods: ...Experimental protocol was approved by the Human Subjects Ethical Committee of our institution. Written informed consent was obtained from 14 (18-25 years) healthy volunteers. Clinical history, physical examination, vital signs, laboratory analyses (blood chemistry, hematology, urinalysis, HIV and hepatitis B), chest X-ray and EKG were carried out in all the cases before the study. The subjects received Antivipmyn registered by a 30 minutes intravenous infusion period (1 ampoule Antivipmyn registered dissolved in 100 ml of isotonic NaCl solution). Physical examination, vital signs and evaluation of systemic symptoms were carried out throughout the period of infusion and after 3,6,12 and 24-h. Three weeks after the first dose the subjects received a second dose of Antivipmyn registered and the same clinical parameters were evaluated. Laboratory analyses were made after the evaluation period. Results: Repeated physical examination performed during the study disclosed no abnormalities in any subject Antivipmyn registered had no significant effect on blood pressure, temperature, pulse and respiration and all clinical laboratory results were normal in all the cases. Conclusion: During die testing period no clinical drug-related symptoms were found in any subject after Antivipmyn registered intravenous administration.
Monogenetic eruptions are the most common volcanic activity in the world. However, unrest monitoring data are scarce due to the long intervening quiescence periods. This study analyzes unrest signals ...recorded in one of the largest monogenetic fields in the Canary Islands, Cumbre Vieja (La Palma). Two seismic swarms were registered in October 2017 and February 2018 with b-values of 1.6 ± 0.1 and 2.3 ± 0.2 respectively suggesting an intense magmatic fluids contribution, gas and/or magma. Both swarms were linked to changes in gas emissions. Increases in hydrogen concentration, and (R/Ra)c up to 7.52 ± 0.05, were recorded before the first swarm, at the sampling point closest to where seismicity was located, indicating a deep gas input. After the second swarm, increases in (R/Ra)c and thoron soil concentration were recorded at two locations. This dataset is compatible with a stalled magmatic intrusion at ca. 25 km depth, with an estimated volume between 5.5·10−4 km3 and 3·10−2 km3.
•Geophysical and geochemical signals recorded at La Palma suggest a reawakening of Cumbre Vieja.•Two seismic swarms with high b-value point to a magmatic fluids contribution.•Increases in δ13C-CO2 and (R/Ra)c were recorded close where seismicity was located.•A slight eastward magma migration is suggested by geochemical and geophysical data.•An increase in soil thoron concentration was recorded at two sites after the second swarm.
We present a new catalog of TeV gamma-ray sources using 1523 days of data from the High-Altitude Water Cherenkov (HAWC) Observatory. The catalog represents the most sensitive survey of the northern ...gamma-ray sky at energies above several TeV, with three times the exposure compared to the previous HAWC catalog, 2HWC. We report 65 sources detected at ≥5 significance, along with the positions and spectral fits for each source. The catalog contains eight sources that have no counterpart in the 2HWC catalog, but are within 1° of previously detected TeV emitters, and 20 sources that are more than 1° away from any previously detected TeV source. Of these 20 new sources, 14 have a potential counterpart in the fourth Fermi Large Area Telescope catalog of gamma-ray sources. We also explore potential associations of 3HWC sources with pulsars in the Australia Telescope National Facility (ATNF) pulsar catalog and supernova remnants in the Galactic supernova remnant catalog.
Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains ...debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.
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•Reduction of endosteal BM and expansion of non-endosteal BM occurs with age•β2/β3-ARs exhibit opposite and niche-dependent regulation of myelopoiesis•β2-AR overriding β3-AR promotes myeloid expansion during physiological aging•Premature HSC aging in HGPS can be improved by targeting the microenvironment
Recent studies have suggested a microenvironmental contribution to stem-cell aging, but the mechanisms are largely unexplored. Méndez-Ferrer et al. report anatomical remodeling of blood-stem-cell-supporting niches and functional switch of β adrenergic signals, leading to myeloid expansion during aging. Targeting the microenvironment can improve pathological, premature, niche-dependent hematopoietic aging in mice.
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