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Deconstructing tumor heterogeneity: the stromal perspective.
Get PDFSignificant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive versus suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field
Virtue as the mean: Pan-human consensus genome significantly improves the accuracy of RNA-seq analyses
Get PDFGlobal Importance Analysis: An Interpretability Method to Quantify Importance of Genomic Features in Deep Neural Networks
Get PDFABSTRACT Deep neural networks have demonstrated improved performance at predicting the sequence specificities of DNA- and RNA-binding proteins compared to previous methods that rely on k -mers and position weight matrices. To gain insights into why a DNN makes a given prediction, model interpretability methods, such as attribution methods, can be employed to identify motif-like representations along a given sequence. Because explanations are given on an individual sequence basis and can vary substantially across sequences, deducing generalizable trends across the dataset and quantifying their effect size remains a challenge. Here we introduce global importance analysis (GIA), a model interpretability method that quantifies the population-level effect size that putative patterns have on model predictions. GIA provides an avenue to quantitatively test hypotheses of putative patterns and their interactions with other patterns, as well as map out specific functions the network has learned. As a case study, we demonstrate the utility of GIA on the computational task of predicting RNA-protein interactions from sequence. We first introduce a convolutional network, we call ResidualBind, and benchmark its performance against previous methods on RNAcompete data. Using GIA, we then demonstrate that in addition to sequence motifs, ResidualBind learns a model that considers the number of motifs, their spacing, and sequence context, such as RNA secondary structure and GC-bias
Dose-escalation trial of the ALK, MET & ROS1 inhibitor, crizotinib, in patients with advanced cancer
No full textAim: This first-in-human, dose-finding study evaluated safety, pharmacokinetics and pharmacodynamics of crizotinib and established a recommended Phase II dose (RP2D) among patients with advanced solid malignancies. Patients & methods: Patients received oral crizotinib in a 3 + 3 dose escalation design. Results: Thirty-six patients received crizotinib (50 mg once daily-300 mg twice daily); maximum tolerated dose (and RP2D) was 250 mg twice daily. Most patients (89%) experienced >/=1 treatment-related adverse event. Three patients had grade 3 dose-limiting toxicities: alanine aminotransferase increased (n = 1) and fatigue (n = 2). Generally, an increase in soluble MET was found with increasing crizotinib concentrations. Conclusion: Crizotinib demonstrated a favorable safety profile. The observed pharmacodynamic effect on soluble MET provide evidence for targeted MET inhibition by crizotinib. Clinicaltrials. gov identifier: NCT00585195
A framework for advancing our understanding of cancer-associated fibroblasts
No full textCancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment
Distribution and storage of inflammatory memory in barrier tissues
No full textMemories of previous immune events enable barrier tissues to rapidly recall distinct environmental exposures. To effectively inform future responses, these past experiences can be stored in cell types that are long-term residents or essential constituents of tissues. There is an emerging understanding that, in addition to antigen-specific immune cells, diverse haematopoietic, stromal, parenchymal and neuronal cell types can store inflammatory memory. Here, we explore the impact of previous immune activity on various cell lineages with the goal of presenting a unified view of inflammatory memory to environmental exposures (such as allergens, antigens, noxious agents and microorganisms) at barrier tissues. We propose that inflammatory memory is distributed across diverse cell types and stored through shifts in cell states, and we provide a framework to guide future experiments. This distribution and storage may promote adaptation or maladaptation in homeostatic, maintenance and disease settings - especially if the distribution of memory favours cellular cooperation during storage or recall
A Serine/Threonine Protein Kinase Encoding Gene KERNEL NUMBER PER ROW6 Regulates Maize Grain Yield
Get PDFIncreasing grain yield of maize (Zea mays L.) is required to meet the rapidly expanding demands for maize-derived food, feed, and fuel. Breeders have enhanced grain productivity of maize hybrids by pyramiding desirable characteristics for larger ears. However, loci selected for improving grain productivity remain largely unclear. Here, we show that a serine/threonine protein kinase encoding gene KERNEL NUMBER PER ROW6 (KNR6) determines pistillate floret number and ear length. Overexpression of KNR6 or introgression of alleles lacking the insertions of two transposable elements in the regulatory region of KNR6 can significantly enhance grain yield. Further in vitro evidences indicate that KNR6 can interact with an Arf GTPase-activating protein (AGAP) and its phosphorylation by KNR6 may affect ear length and kernel number. This finding provides knowledge basis to enhance maize hybrids grain yield
Multiplex Accurate Sensitive Quantitation (MASQ) With Application to Minimal Residual Disease in Acute Myeloid Leukemia
Get PDFMeasuring minimal residual disease in cancer has applications for prognosis, monitoring treatment and detection of recurrence. Simple sequence-based methods to detect nucleotide substitution variants have error rates (about 10-3) that limit sensitive detection. We developed and characterized the performance of MASQ (multiplex accurate sensitive quantitation), a method with an error rate below 10-6. MASQ counts variant templates accurately in the presence of millions of host genomes by using tags to identify each template and demanding consensus over multiple reads. Since the MASQ protocol multiplexes 50 target loci, we can both integrate signal from multiple variants and capture subclonal response to treatment. Compared to existing methods for variant detection, MASQ achieves an excellent combination of sensitivity, specificity and yield. We tested MASQ in a pilot study in acute myeloid leukemia (AML) patients who entered complete remission. We detect leukemic variants in the blood and bone marrow samples of all five patients, after induction therapy, at levels ranging from 10-2 to nearly 10-6. We observe evidence of sub-clonal structure and find higher target variant frequencies in patients who go on to relapse, demonstrating the potential for MASQ to quantify residual disease in AML
Lysine succinylation and SIRT5 couple nutritional status to glutamine catabolism.
No full textThe metabolic microenvironment of tumors is characterized by fluctuating and limited nutrient availability. To survive these conditions, cancer cell-intrinsic mechanisms sense and signal nutritional status. We describe how glutaminase (GLS) is destabilized by lysine succinylation and stabilized by the NAD+-dependent desuccinylase sirtuin 5 (SIRT5), coupling nutrient levels to metabolic flux
Identification of a brainstem locus that inhibits tumor necrosis factor
No full textIn the brain, compact clusters of neuron cell bodies, termed nuclei, are essential for maintaining parameters of host physiology within a narrow range optimal for health. Neurons residing in the brainstem dorsal motor nucleus (DMN) project in the vagus nerve to communicate with the lungs, liver, gastrointestinal tract, and other organs. Vagus nerve-mediated reflexes also control immune system responses to infection and injury by inhibiting the production of tumor necrosis factor (TNF) and other cytokines in the spleen, although the function of DMN neurons in regulating TNF release is not known. Here, optogenetics and functional mapping reveal cholinergic neurons in the DMN, which project to the celiac-superior mesenteric ganglia, significantly increase splenic nerve activity and inhibit TNF production. Efferent vagus nerve fibers terminating in the celiac-superior mesenteric ganglia form varicose-like structures surrounding individual nerve cell bodies innervating the spleen. Selective optogenetic activation of DMN cholinergic neurons or electrical activation of the cervical vagus nerve evokes action potentials in the splenic nerve. Pharmacological blockade and surgical transection of the vagus nerve inhibit vagus nerve-evoked splenic nerve responses. These results indicate that cholinergic neurons residing in the brainstem DMN control TNF production, revealing a role for brainstem coordination of immunity