Non-coding regions amplified beyond oncogene borders have largely been ignored. Using a computational approach, we find signatures of significant co-amplification of non-coding DNA beyond the ...boundaries of amplified oncogenes across five cancer types. In glioblastoma, EGFR is preferentially co-amplified with its two endogenous enhancer elements active in the cell type of origin. These regulatory elements, their contacts, and their contribution to cell fitness are preserved on high-level circular extrachromosomal DNA amplifications. Interrogating the locus with a CRISPR interference screening approach reveals a diversity of additional elements that impact cell fitness. The pattern of fitness dependencies mirrors the rearrangement of regulatory elements and accompanying rewiring of the chromatin topology on the extrachromosomal amplicon. Our studies indicate that oncogene amplifications are shaped by regulatory dependencies in the non-coding genome.
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•Enhancers active in the cell of origin are co-amplified with oncogenes•Circular extrachromosomal amplicons are associated with enhancer rewiring•Endogenous and new enhancers on amplicons contribute to cell proliferation•Skewed co-amplification that selects enhancers is found across several tumor types
Extrachromosomal oncogene amplification is a common occurrence across a broad range of cancers, yet the chromatin landscape of these high-level amplifications is poorly understood. Using a combination of approaches to explore their chromatin topology and enhancer landscape, Morton et al. observed that these oncogene amplifications are shaped by regulatory dependencies in the non-coding genome.
We demonstrate the creation of entangled, spin-squeezed states using a collective, or joint, measurement and real-time feedback. The pseudospin state of an ensemble of N=5×10^{4} laser-cooled ^{87}Rb ...atoms is deterministically driven to a specified population state with angular resolution that is a factor of 5.5(8) 7.4(6) dB in variance below the standard quantum limit for unentangled atoms-comparable to the best enhancements using only unitary evolution. Without feedback, conditioning on the outcome of the joint premeasurement, we directly observe up to 59(8) times 17.7(6) dB improvement in quantum phase variance relative to the standard quantum limit for N=4×10^{5} atoms. This is one of the largest reported entanglement enhancements to date in any system.
Summary Patients with cholangiocarcinoma often present with locally advanced or metastatic disease. There is a need for effective therapeutic strategies for advanced stage cholangiocarcinoma. ...Recently, FGFR2 translocations have been identified as a potential target for tyrosine kinase inhibitor therapies. This study evaluated 152 cholangiocarcinomas and 4 intraductal papillary biliary neoplasms of the bile duct for presence of FGFR2 translocations by fluorescence in situ hybridization and characterized the clinicopathologic features of cases with FGFR2 translocations. Thirteen (10 women, 3 men; 8%) of 156 biliary tumors harbored FGFR2 translocations, including 12 intrahepatic cholangiocarcinomas (12/96; 13%) and 1 intraductal papillary neoplasm of the bile duct. Histologically, cholangiocarcinomas with FGFR2 translocations displayed prominent intraductal growth (62%) or anastomosing tubular glands with desmoplasia (38%). Immunohistochemically, the tumors with FGFR2 translocations frequently showed weak and patchy expression of CK19 (77%). Markers of the stem cell phenotype in cholangiocarcinoma, HepPar1 and CK20, were negative in all cases. The median cancer-specific survival for patients whose tumors harbored FGFR2 translocations was 123 months compared to 37 months for cases without FGFR2 translocations ( P = .039). This study also assessed 100 cholangiocarcinomas for ERBB2 amplification and ROS1 translocations. Of the cases tested, 3% and 1% were positive for ERBB2 amplification and ROS1 translocation, respectively. These results confirm that FGFR2 , ERRB2 , and ROS1 alterations are potential therapeutic targets for intrahepatic cholangiocarcinoma.
Abstract
Background
Migraine accounts for substantial suffering and disability. Previous studies show cross-sectional associations between higher pain acceptance and lower headache-related disability ...in individuals with migraine, but none has evaluated this association longitudinally during migraine treatment.
Purpose
This study evaluated whether changes in pain acceptance were associated with changes in headache-related disability and migraine characteristics in a randomized controlled trial (Women’s Health and Migraine) that compared effects of behavioral weight loss (BWL) treatment and migraine education (ME) on headache frequency in women with migraine and overweight/obesity.
Methods
This was a post hoc analysis of 110 adult women with comorbid migraine and overweight/obesity who received 16 weeks of either BWL or ME. Linear and nonlinear mixed effects modeling methods were used to test for between-group differences in change in pain acceptance, and also to examine the association between change in pain acceptance and change in headache disability.
Results
BWL and ME did not differ on improvement in pain acceptance from baseline across post-treatment and follow-up. Improvement in pain acceptance was associated with reduced headache disability, even when controlling for intervention-related improvements in migraine frequency, headache duration, and pain intensity.
Conclusions
This study is the first to show that improvements in pain acceptance following two different treatments are associated with greater reductions in headache-related disability, suggesting a potential new target for intervention development.
Clinical Trials information
NCT01197196
Adults with migraine headaches who reported being more accepting of their headache pain also reported less headache-related disability.
Site-directed nucleases (SDNs) used for targeted genome editing are powerful new tools to introduce precise genetic changes into plants. Like traditional approaches, such as conventional crossing and ...induced mutagenesis, genome editing aims to improve crop yield and nutrition. Next-generation sequencing studies demonstrate that across their genomes, populations of crop species typically carry millions of single nucleotide polymorphisms and many copy number and structural variants. Spontaneous mutations occur at rates of ∼10
to 10
per site per generation, while variation induced by chemical treatment or ionizing radiation results in higher mutation rates. In the context of SDNs, an off-target change or edit is an unintended, nonspecific mutation occurring at a site with sequence similarity to the targeted edit region. SDN-mediated off-target changes can contribute to a small number of additional genetic variants compared to those that occur naturally in breeding populations or are introduced by induced-mutagenesis methods. Recent studies show that using computational algorithms to design genome editing reagents can mitigate off-target edits in plants. Finally, crops are subject to strong selection to eliminate off-type plants through well-established multigenerational breeding, selection, and commercial variety development practices. Within this context, off-target edits in crops present no new safety concerns compared to other breeding practices. The current generation of genome editing technologies is already proving useful to develop new plant varieties with consumer and farmer benefits. Genome editing will likely undergo improved editing specificity along with new developments in SDN delivery and increasing genomic characterization, further improving reagent design and application.
Reacting hydrazones of arylaldehydes with Togni's CF
-benziodoxolone reagent, in the presence of potassium hydroxide and cesium fluoride, induces a denitrogenative hydrotrifluoromethylation event to ...produce (2,2,2-trifluoroethyl)arenes. This novel reaction was tolerant to many electronically-diverse functional groups and substitution patterns, as well as naphthyl- and heteroaryl-derived substrates. Advantages of this process include the easy access to hydrazone precursors on a large scale, speed and operational simplicity, and being transition metal-free.
The global travel and tourism industry has been rapidly expanding in the past decades. The traditional focus on border screening, and by airline and cruise industries may be inadequate due to the ...incubation period of an infectious disease. This case study highlights the potential role of the hotel industry in epidemic preparedness and response.
This case study focuses on the epidemic outbreaks of SARS in 2003 and H1N1 swine flu in 2009 in Hong Kong, and the subsequent guidelines published by the health authority in relation to the hotel industry in Hong Kong which provide the backbone for discussion.
The Metropole Hotel hastened the international spread of the 2003 SARS outbreak by the index case infecting visitors from Singapore, Vietnam, Canada as well as local people via close contact with the index case and the environmental contamination. The one-week quarantine of more than 300 guests and staff at the Metropark Hotel during the 2009 H1N1 swine flu exposed gaps in the partnership with the hotel industry. The subsequent guidelines for the hotel industry from the Centre of Health Protection focused largely on the maintenance of hygiene within the hotel premises.
Positive collaborations may bring about effective preparedness across the health and the tourism sectors for future epidemics. Regular hygiene surveillance at hotel facilities, and developing coordination mechanism for impending epidemics on the use of screening, swift reporting and isolation of infected persons may help mitigate the impact of future events. Preparedness and contingency plans for infectious disease control for the hotel industry requires continuous engagement and dialogue.
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