Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2018
YES1 amplification is a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics.
In ∼30% of patients with EGFR-mutant lung adenocarcinomas whose disease progresses on EGFR inhibitors, the basis for acquired resistance remains unclear. We have integrated transposon mutagenesis screening in an EGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify mechanisms of resistance to EGFR inhibitors. The most prominent candidate genes identified by insertions in or near the genes during the screen were MET, a gene whose amplification is known to mediate resistance to EGFR inhibitors, and the gene encoding the Src family kinase YES1. ⋯ None of 136 postinhibitor samples had detectable amplification of other Src family kinases (SRC and FYN). YES1 amplification was also found in 2 of 17 samples from ALK fusion-positive lung cancer patients who had progressed on ALK TKIs. Taken together, our findings identify acquired amplification of YES1 as a recurrent and targetable mechanism of resistance to EGFR inhibition in EGFR-mutant lung cancers and demonstrate the utility of transposon mutagenesis in discovering clinically relevant mechanisms of drug resistance.
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2018
Bright quantum dots emitting at ∼1,600 nm in the NIR-IIb window for deep tissue fluorescence imaging.
With suppressed photon scattering and diminished autofluorescence, in vivo fluorescence imaging in the 1,500- to 1,700-nm range of the near-IR (NIR) spectrum (NIR-IIb window) can afford high clarity and deep tissue penetration. However, there has been a lack of NIR-IIb fluorescent probes with sufficient brightness and aqueous stability. Here, we present a bright fluorescent probe emitting at ∼1,600 nm based on core/shell lead sulfide/cadmium sulfide (CdS) quantum dots (CSQDs) synthesized in organic phase. ⋯ It also allowed through-skin in vivo confocal 3D imaging of tumor vasculatures in mice with an imaging depth of ∼1.2 mm. The PEG-CSQDs accumulated in tumor effectively through the enhanced permeation and retention effect, affording a high tumor-to-normal tissue ratio up to ∼32 owing to the bright ∼1,600-nm emission and nearly zero autofluorescence background resulting from a large ∼800-nm Stoke's shift. The aqueous-compatible CSQDs are excreted through the biliary pathway without causing obvious toxicity effects, suggesting a useful class of ∼1,600-nm emitting probes for biomedical research.
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2018
Limiting global-mean temperature increase to 1.5-2 °C could reduce the incidence and spatial spread of dengue fever in Latin America.
The Paris Climate Agreement aims to hold global-mean temperature well below 2 °C and to pursue efforts to limit it to 1.5 °C above preindustrial levels. While it is recognized that there are benefits for human health in limiting global warming to 1.5 °C, the magnitude with which those societal benefits will be accrued remains unquantified. Crucial to public health preparedness and response is the understanding and quantification of such impacts at different levels of warming. ⋯ Furthermore, we found that by limiting global warming we can limit the expansion of the disease toward areas where incidence is currently low. We anticipate our study to be a starting point for more comprehensive studies incorporating socioeconomic scenarios and how they may further impact dengue incidence. Our results demonstrate that although future climate change may amplify dengue transmission in the region, impacts may be avoided by constraining the level of warming.
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2018
Implications of Zika virus and congenital Zika syndrome for the number of live births in Brazil.
An increase in microcephaly, associated with an epidemic of Zika virus (ZIKV) in Brazil, prompted the World Health Organization to declare a Public Health Emergency of International Concern in February 2016. While knowledge on biological and epidemiological aspects of ZIKV has advanced, demographic impacts remain poorly understood. This study uses time-series analysis to assess the impact of ZIKV on births. ⋯ Since ZIKV transmission has declined, it is unlikely that reductions in births will continue. However, the possibility of a new epidemic is real. There is a need to address gaps in reproductive health and rights, and to understand CZS risk to better inform conception decisions.
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Proc. Natl. Acad. Sci. U.S.A. · Jun 2018
Activity-dependent aberrations in gene expression and alternative splicing in a mouse model of Rett syndrome.
Rett syndrome (RTT) is a severe neurodevelopmental disorder that affects about 1 in 10,000 female live births. The underlying cause of RTT is mutations in the X-linked gene, methyl-CpG-binding protein 2 (MECP2); however, the molecular mechanism by which these mutations mediate the RTT neuropathology remains enigmatic. Specifically, although MeCP2 is known to act as a transcriptional repressor, analyses of the RTT brain at steady-state conditions detected numerous differentially expressed genes, while the changes in transcript levels were mostly subtle. ⋯ Notably, the specific splicing modalities of intron retention and exon skipping displayed a significant bias toward increased retained introns and skipped exons, respectively, in the RTT brain compared with the WT brain. Furthermore, these aberrations occur in conjunction with higher seizure susceptibility in response to neuronal activity in RTT mice. Our findings advance the concept that normal MeCP2 functioning is required for fine-tuning the robust and immediate changes in gene transcription and for proper regulation of alternative splicing induced in response to neuronal stimulation.