Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. ...Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT-mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNγ-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT-mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells.
The goals of the Earth Biogenome Project-to sequence the genomes of all eukaryotic life on earth-are as daunting as they are ambitious. The Darwin Tree of Life Project was founded to demonstrate the ...credibility of these goals and to deliver at-scale genome sequences of unprecedented quality for a biogeographic region: the archipelago of islands that constitute Britain and Ireland. The Darwin Tree of Life Project is a collaboration between biodiversity organizations (museums, botanical gardens, and biodiversity institutes) and genomics institutes. Together, we have built a workflow that collects specimens from the field, robustly identifies them, performs sequencing, generates high-quality, curated assemblies, and releases these openly for the global community to use to build future science and conservation efforts.
Lung cancer in never-smokers is an important disease often characterized by mutations in epidermal growth factor receptor (EGFR), yet risk reduction measures and effective chemopreventive strategies ...have not been established. We identify mammalian target of rapamycin (mTOR) as potentially valuable target for EGFR mutant lung cancer. mTOR is activated in human lung cancers with EGFR mutations, and this increases with acquisition of T790M mutation. In a mouse model of EGFR mutant lung cancer, mTOR activation is an early event. As a single agent, the mTOR inhibitor rapamycin prevents tumor development, prolongs overall survival, and improves outcomes after treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI). These studies support clinical testing of mTOR inhibitors in order to prevent the development and progression of EGFR mutant lung cancers.
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•mTOR activation is detected in human lung cancers with EGFR mutations•mTOR activation is an early event in a mouse model of EGFR mutant lung cancer•Rapamycin prevents growth of EGFR T790M mutant tumors and prolongs overall survival•Rapamycin improves progression-free and overall survival after EGFR TKI treatment
Lung cancer in never-smokers is often characterized by mutations in EGFR. Kawabata et al. report that mTOR activation is detected in human lung cancers with EGFR mutations and is an early event in a mouse model of EGFR mutant lung cancer. The mTOR inhibitor rapamycin prevented the growth of T790M mutant tumors and prolonged overall survival in this mouse model. In addition, rapamycin prolonged disease-free and overall survival of mice that completed treatment with an irreversible inhibitor of EGFR.
Plankton are the base of marine food webs, essential to sustaining fisheries and other marine life. Continuous Plankton Recorders (CPRs) have sampled plankton for decades in both hemispheres and ...several regional seas. CPR research has been integral to advancing understanding of plankton dynamics and informing policy and management decisions. We describe how the CPR can contribute to global plankton diversity monitoring, being cost-effective over large scales and providing taxonomically-resolved data. At OceanObs09 an integrated network of regional CPR surveys was envisaged and in 2011 the existing surveys formed the Global Alliance of CPR Surveys (GACS). GACS first focused on strengthening the dataset by identifying and documenting CPR best practices, delivering training workshops, and developing an integrated database. This resulted in the initiation of new surveys and manuals that enable regional surveys to be standardized and integrated. GACS is not yet global, but it could be expanded into the remaining oceans; tropical and Arctic regions are a priority for survey expansion. The capacity building groundwork is done, but funding is required to implement the GACS vision of a global plankton sampling program that supports decision-making for the scientific and policy communities. A key step is an analysis to optimize the global sampling design. Further developments include expanding the CPR for multidisciplinary measurements via additional sensors, thus maximising the ship-of-opportunity platform. For example, defining pelagic eco-regions based on plankton and ancillary data could support high seas Marine Protected Area design. Fulfilment of Aichi Target 15, the United Nation’s Sustainable Development Goals, and delivering the Essential Ocean Variables and Essential Biodiversity Variables that the Global Ocean Observing System and Group on Earth Observation’s Biodiversity Observation Network have respectively defined requires the taxonomic resolution, spatial scale and time-series data that the CPR approach provides. Synergies with global networks exploiting satellite data and other plankton sensors could be explored, realizing the Survey’s capacity to validate earth observation data and to ground-truth emerging plankton observing platforms. This is required for a fully integrated ocean observing system that can understand global ocean dynamics to inform sustainable marine decision-making.
Members of the human UDP-glucuronosyltransferase 2B family are located in a cluster on chromosome 4q13 and code for enzymes whose gene products are responsible for the normal catabolism of steroid ...hormones. Two members of this family,
UGT2B15 and
UGT2B17, share over 95% sequence identity. However,
UGT2B17 exhibits broader substrate specificity due to a single amino acid difference. Using gene-specific primers to explore the genomic organization of these two genes, it was determined that
UGT2B17 is absent in some human DNA samples. The gene-specific primers demonstrated the presence or absence of a 150 kb genomic interval spanning the entire
UGT2B17 gene, revealing that
UGT2B17 is present in the human genome as a deletion polymorphism linked to
UGT2B15. Furthermore, it is shown that the
UGT2B17 deletion polymorphism shows Mendelian segregation and allele frequencies that differ between African Americans and Caucasians.
We previously reported that an Nkx2-5-GFP bacterial artificial chromosome in transgenic mice recapitulated the endogenous gene activity in the heart. Here, we identified three additional previously ...uncharacterized distal enhancer modules of Nkx2-5: UH6, which directed transgene expression in the right ventricle, interventricular septum, and atrial ventricular canal; UH5, which directed expression in both atria; and UH4, which directed transgene expression in tongue muscle. Nkx2-5 enhancers drive cardiogenic gene activity from the earliest progenitors to the late-stage embryonic heart, reside within its 27 kb of 5′ flanking sequences, organized in a tandem array. Nkx2-5 enhancers involved with stomach-, tongue-, and chamber-restricted expression displayed lacZ transgene activity and chromatin histone acetylation patterns consistent with tissue-specific expression. An examination of Nkx2-5 gene activity in murine embryonic stem cells converted to beating embryoid bodies showed that only the proximal active region 2 and GATA-Smad enhancers were chromatin-remodeled. Chromatin remodeling of active region 2 and GATA-Smad enhancers were blunted by noggin coexpression, which indicated dependence on bone morphogenetic protein signaling for their chromatin activation during activation of Nkx2-5 expression.
Abstract Objectives Primary and acquired resistance to EGFR TKIs in EGFR mutant lung cancer occurs primarily through secondary mutations in EGFR or Met amplification. Drug resistance can also be ...mediated by expression of pluripotency transcription factors, such as OCT4, SOX2 and NANOG that decrease terminal differentiation. In this study, we investigated the expression and role of SOX2 in model systems of EGFR mutant tumors. Materials and methods Immunoblotting or immunohistochemistry was used to assess expression of pluripotency transcription factors in lungs of transgenic mice or in human NSCLC cell lines. Expression of SOX2 was reduced by shRNA knockdown, and response to erlotinib and cellular proliferation were assessed. Results and conclusion Induction of mutant EGFR in transgenic CCSP-rtTA/TetO-EGFRL858R/T790M mice correlated with increased OCT4 and SOX2 expression in lung tissue prior to tumor development. Established lung tumors retained SOX2 expression. To assess a role for SOX2 in tumorigenesis, a panel of NSCLC cell lines with activating EGFR mutations was assessed for SOX2 expression. Two of six cell lines with mutant EGFR showed detectable SOX2 levels, suggesting SOX2 expression did not correlate with EGFR mutation status. To assess the role of SOX2 in these cell lines, HCC827 and H1975 cells were infected with lentivirus containing SOX2 shRNA. Knockdown of SOX2 decreased proliferation in both cell lines and increased sensitivity to erlotinib in HCC827 cells. Because constitutive activation of the PI3K/Akt pathway is associated with EGFR TKI resistance, cells were treated with PI3K/AKT inhibitors and expression of SOX2 was examined. PI3K/Akt inhibitors decreased SOX2 expression in a time-dependent manner. These data suggest targeting SOX2 may provide therapeutic benefit in the subset of EGFR-mutant tumors with high constitutive levels of SOX2, and that until more direct means of inhibiting SOX2 are developed, PI3K/Akt inhibitors might be useful to inhibit SOX2 in EGFR TKI resistant tumors.
PacBio high fidelity (HiFi) sequencing reads are both long (15-20 kb) and highly accurate (> Q20). Because of these properties, they have revolutionised genome assembly leading to more accurate and ...contiguous genomes. In eukaryotes the mitochondrial genome is sequenced alongside the nuclear genome often at very high coverage. A dedicated tool for mitochondrial genome assembly using HiFi reads is still missing.
MitoHiFi was developed within the Darwin Tree of Life Project to assemble mitochondrial genomes from the HiFi reads generated for target species. The input for MitoHiFi is either the raw reads or the assembled contigs, and the tool outputs a mitochondrial genome sequence fasta file along with annotation of protein and RNA genes. Variants arising from heteroplasmy are assembled independently, and nuclear insertions of mitochondrial sequences are identified and not used in organellar genome assembly. MitoHiFi has been used to assemble 374 mitochondrial genomes (368 Metazoa and 6 Fungi species) for the Darwin Tree of Life Project, the Vertebrate Genomes Project and the Aquatic Symbiosis Genome Project. Inspection of 60 mitochondrial genomes assembled with MitoHiFi for species that already have reference sequences in public databases showed the widespread presence of previously unreported repeats.
MitoHiFi is able to assemble mitochondrial genomes from a wide phylogenetic range of taxa from Pacbio HiFi data. MitoHiFi is written in python and is freely available on GitHub ( https://github.com/marcelauliano/MitoHiFi ). MitoHiFi is available with its dependencies as a Docker container on GitHub (ghcr.io/marcelauliano/mitohifi:master).
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