The Antarctic Circumpolar Current (ACC) represents the world's largest ocean-current system and affects global ocean circulation, climate and Antarctic ice-sheet stability. Today, ACC dynamics are controlled by atmospheric forcing, oceanic density gradients and eddy activity. Whereas palaeoceanographic reconstructions exhibit regional heterogeneity in ACC position and strength over Pleistocene glacial-interglacial cycles, the long-term evolution of the ACC is poorly known.
View Article and Find Full Text PDFThe frequency and intensity of cyanobacterial blooms is increasing worldwide. Multiple factors are implicated, most of which are anthropogenic. New Zealand provides a useful location to study the impacts of human settlement on lake ecosystems.
View Article and Find Full Text PDFIntroduction: The programmed death-ligand 1 inhibitor atezolizumab improves progression-free survival (PFS) and overall survival (OS) for patients with previously treated advanced NSCLC. Preclinical studies indicate that targeting CD38-positive cells with daratumumab may synergistically enhance atezolizumab's antitumor activity by increasing the effector T-cell activity.
Methods: This phase 1b-2 study included a safety run-in (one cycle of daratumumab plus atezolizumab) and randomized phases (daratumumab plus atezolizumab versus atezolizumab alone).
The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome.
View Article and Find Full Text PDFThe success of targeted or immune therapies is often hampered by the emergence of resistance and/or clinical benefit in only a subset of patients. We hypothesized that combining targeted therapy with immune modulation would show enhanced antitumor responses. Here, we explored the combination potential of erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor under clinical development, with PD-1 blockade in an autochthonous FGFR2/p53 lung cancer mouse model.
View Article and Find Full Text PDFBronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling of endobronchial biopsies from high-risk smokers. The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways.
View Article and Find Full Text PDFDeep understanding of the genomic and immunological differences between Chinese and Western lung cancer patients is of great importance for target therapy selection and development for Chinese patients. Here we report an extensive molecular and immune profiling study of 245 Chinese patients with non-small cell lung cancer. Tumor-infiltrating lymphocyte estimated using immune cell signatures is found to be significantly higher in adenocarcinoma (ADC, 72.
View Article and Find Full Text PDFOceanic Anoxic Event 2 (OAE 2), occurring ∼94 million years ago, was one of the most extreme carbon cycle and climatic perturbations of the Phanerozoic Eon. It was typified by a rapid rise in atmospheric CO, global warming, and marine anoxia, leading to the widespread devastation of marine ecosystems. However, the precise timing and extent to which oceanic anoxic conditions expanded during OAE 2 remains unresolved.
View Article and Find Full Text PDFOur understanding of glacial flour dust storm delivery of iron to the Gulf of Alaska (GoA) is limited. Here we interpret concurrent time series satellite, meteorological, and aerosol geochemical data from the GoA to examine how interannual variability in regional weather patterns impacts offshore aerosol glacial Fe deposition. In 2011, when a northerly Aleutian Low (AL) was persistent during fall, dust emission was suppressed and highly intermittent due to prevalent wet conditions, low winds, and a deep early season snowpack.
View Article and Find Full Text PDFMol Cancer Ther
August 2017
Fibroblast growth factor receptor (FGFR) genetic alterations are frequently observed in cancer, suggesting that FGFR inhibition may be a promising therapy in patients harboring these lesions. Identification of predictive and pharmacodynamic biomarkers to select and monitor patients most likely to respond to FGFR inhibition will be the key to clinical development of this class of agents. Sensitivity to FGFR inhibition and correlation with FGFR pathway activation status were determined in molecularly annotated panels of cancer cell lines and xenograft models.
View Article and Find Full Text PDFFibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor () family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases.
View Article and Find Full Text PDFUnlabelled: We completed targeted exome sequencing of the tumors of 50 patients with pTis-pT4b bladder cancer. Mutations were categorized by type, stratified against previously identified cancer loci in the Catalogue of Somatic Mutations in Cancer and The Cancer Genome Atlas databases, and evaluated in pathway analysis and comutation plots. We analyzed mutation associations with receipt of neoadjuvant chemotherapy, nodal involvement, metastatic disease development, and survival.
View Article and Find Full Text PDFInhibition of centromere-associated protein-E (CENP-E) has demonstrated preclinical anti-tumor activity in a number of tumor types including neuroblastoma. A potent small molecule inhibitor of the kinesin motor activity of CENP-E has recently been developed (GSK923295). To identify an effective drug combination strategy for GSK923295 in neuroblastoma, we performed a screen of siRNAs targeting a prioritized set of genes that function in therapeutically tractable signaling pathways.
View Article and Find Full Text PDFBackground: MEK is a member of the MAPK signalling cascade that is commonly activated in melanoma. Direct inhibition of MEK blocks cell proliferation and induces apoptosis. We aimed to analyse safety, efficacy, and genotyping data for the oral, small-molecule MEK inhibitor trametinib in patients with melanoma.
View Article and Find Full Text PDFThe MEK1 and MEK2 inhibitor GSK1120212 is currently in phase II/III clinical development. To identify predictive biomarkers, sensitivity to GSK1120212 was profiled for 218 solid tumor cell lines and 81 hematologic malignancy cell lines. For solid tumors, RAF/RAS mutation was a strong predictor of sensitivity.
View Article and Find Full Text PDFBackground: Aurora kinases play critical roles in mitosis and are being evaluated as therapeutic targets in cancer. GSK1070916 is a potent, selective, ATP competitive inhibitor of Aurora kinase B and C. Translation of predictive biomarkers to the clinic can benefit patients by identifying the tumors that are more likely to respond to therapies, especially novel inhibitors such as GSK1070916.
View Article and Find Full Text PDFIdentification of biomarkers for positive and negative predictors of response to cancer therapeutics can help direct clinical strategies. However, challenges with tissue availability and costs are significant limiting factors for diagnostic assays. To address these challenges, we have customized a high-throughput single nucleotide polymorphism genotyping assay with the objective of simultaneously surveying known somatic mutations and copy number alterations for translational studies in cancer.
View Article and Find Full Text PDFPolo-like kinases are a family of serine threonine kinases that are critical regulators of cell cycle progression and DNA damage response. Predictive biomarkers for the Plk1-selective inhibitor GSK461364A were identified by comparing the genomics and genetics of a panel of human cancer cell lines with their response to a drug washout followed by an outgrowth assay. In this assay, cell lines that have lost p53 expression or carry mutations in the TP53 gene tended to be more sensitive to GSK461364A.
View Article and Find Full Text PDFPreclinical cellular response profiling of tumor models has become a cornerstone in the development of novel cancer therapeutics. As efforts to predict clinical efficacy using cohorts of in vitro tumor models have been successful, expansive panels of tumor-derived cell lines can recapitulate an "all comers" efficacy trial, thereby identifying which tumors are most likely to benefit from treatment. The response profile of a therapy is most often studied in isolation; however, drug treatment effect patterns in tumor models across a diverse panel of compounds can help determine the value of unique molecular target classes in specific tumor cohorts.
View Article and Find Full Text PDFThe variability of El Niño/Southern Oscillation (ENSO) during the Holocene epoch, in particular on millennial timescales, is poorly understood. Palaeoclimate studies have documented ENSO variability for selected intervals in the Holocene, but most records are either too short or insufficiently resolved to investigate variability on millennial scales. Here we present a record of sedimentation in Laguna Pallcacocha, southern Ecuador, which is strongly influenced by ENSO variability, and covers the past 12,000 years continuously.
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