Normal tissue transcriptional signatures for tumor-type-agnostic phenotype prediction.

Cancer transcriptional patterns reflect both unique features and shared hallmarks across diverse cancer types, but whether differences in these patterns are sufficient to characterize the full breadth of tumor phenotype heterogeneity remains an open question. We hypothesized that these shared transcriptomic signatures reflect repurposed versions of functional tasks performed by normal tissues. Starting with normal tissue transcriptomic profiles, we use non-negative matrix factorization to derive six distinct transcriptomic phenotypes, called archetypes, which combine to describe both normal tissue patterns and variations across a broad spectrum of malignancies.

Multi-scale geometric network analysis identifies melanoma immunotherapy response gene modules.

Melanoma response to immune-modulating therapy remains incompletely characterized at the molecular level. In this study, we assess melanoma immunotherapy response using a multi-scale network approach to identify gene modules with coordinated gene expression in response to treatment. Using gene expression data of melanoma before and after treatment with nivolumab, we modeled gene expression changes in a correlation network and measured a key network geometric property, dynamic Ollivier-Ricci curvature, to distinguish critical edges within the network and reveal multi-scale treatment-response gene communities.

Multi-Scale Geometric Network Analysis Identifies Melanoma Immunotherapy Response Gene Modules.

Melanoma response to immune-modulating therapy remains incompletely characterized at the molecular level. In this study, we assess melanoma immunotherapy response using a multi-scale network approach to identify gene modules with coordinated gene expression in response to treatment. Using gene expression data of melanoma before and after treatment with nivolumab, we modeled gene expression changes in a correlation network and measured a key network geometric property, dynamic Ollivier-Ricci curvature, to distinguish critical edges within the network and reveal multi-scale treatment-response gene communities.

Growth Dynamics of Ductal Carcinoma in Situ Recapitulate Normal Breast Development.

Ductal carcinoma in situ (DCIS) and invasive breast cancer share many morphologic, proteomic, and genomic alterations. Yet in contrast to invasive cancer, many DCIS tumors do not progress and may remain indolent over decades. To better understand the heterogenous nature of this disease, we reconstructed the growth dynamics of 18 DCIS tumors based on the geo-spatial distribution of their somatic mutations.

Mapping the Single-cell Differentiation Landscape of Osteosarcoma.

The genetic and intratumoral heterogeneity observed in human osteosarcomas (OS) poses challenges for drug development and the study of cell fate, plasticity, and differentiation, processes linked to tumor grade, cell metastasis, and survival. To pinpoint errors in OS differentiation, we transcriptionally profiled 31,527 cells from a tissue-engineered model that directs MSCs toward adipogenic and osteoblastic fates. Incorporating pre-existing chondrocyte data, we applied trajectory analysis and non-negative matrix factorization (NMF) to generate the first human mesenchymal differentiation atlas.

Functional transcriptional signatures for tumor-type-agnostic phenotype prediction.

Cancer transcriptional patterns exhibit both shared and unique features across diverse cancer types, but whether these patterns are sufficient to characterize the full breadth of tumor phenotype heterogeneity remains an open question. We hypothesized that cancer transcriptional diversity mirrors patterns in normal tissues optimized for distinct functional tasks. Starting with normal tissue transcriptomic profiles, we use non-negative matrix factorization to derive six distinct transcriptomic phenotypes, called archetypes, which combine to describe both normal tissue patterns and variations across a broad spectrum of malignancies.

Hypergraph geometry reflects higher-order dynamics in protein interaction networks.

Protein interactions form a complex dynamic molecular system that shapes cell phenotype and function; in this regard, network analysis is a powerful tool for studying the dynamics of cellular processes. Current models of protein interaction networks are limited in that the standard graph model can only represent pairwise relationships. Higher-order interactions are well-characterized in biology, including protein complex formation and feedback or feedforward loops.

A Bayesian hierarchical model to estimate DNA methylation conservation in colorectal tumors.

Motivation: Conservation is broadly used to identify biologically important (epi)genomic regions. In the case of tumor growth, preferential conservation of DNA methylation can be used to identify areas of particular functional importance to the tumor. However, reliable assessment of methylation conservation based on multiple tissue samples per patient requires the decomposition of methylation variation at multiple levels.

Unique Spatial Integration in Mouse Primary Visual Cortex and Higher Visual Areas.

Neurons in the visual system integrate over a wide range of spatial scales. This diversity is thought to enable both local and global computations. To understand how spatial information is encoded across the mouse visual system, we use two-photon imaging to measure receptive fields (RFs) and size-tuning in primary visual cortex (V1) and three downstream higher visual areas (HVAs: LM (lateromedial), AL (anterolateral), and PM (posteromedial)) in mice of both sexes.

Bone remodeling as a spatial evolutionary game.

Bone remodeling is a complex process involving cell-cell interactions, biochemical signaling and mechanical stimuli. Early models of the biological aspects of remodeling were non-spatial and focused on the local dynamics at a fixed location in the bone. Several spatial extensions of these models have been proposed, but they generally suffer from two limitations: first, they are not amenable to analysis and are computationally expensive, and second, they neglect the role played by bone-embedded osteocytes.

Catecholamine overflow within rat striatum: the influence of microstimulation and electroconvulsive stimulation as observed with voltammetry.

Differential pulse voltammetry with a carbon fibre microelectrode was used in chloral hydrate-anaesthetized rats for testing the influence of microstimulation and of electroconvulsive stimulation on the changes in concentration of electro-oxidizable materials (catechol derivates) in the extracellular space of the corpus striatum. Microstimulation applied in the striatum (8 V anodal pulses, 0.1 ms, 100 Hz for 40 s) caused a significant increase of the catechol-oxidative current (Ico); 5 s after microstimulation was stopped Ico ranged from 117 to 141% of the control (all values means +/- S.

Effects of electroconvulsive shock on catecholamine release in the corpus striatum of the rat: a voltammetric study.

A voltammetric technique was used (differential pulse voltammetry with a carbon fibre microelectrode) to investigate dynamics of the changes of catecholamine overflow in the corpus striatum following electroconvulsive stimulation (ECS) of chloral hydrate-anaesthetized rats. Application of "maximal" ECS (50 Hz, AC, sine wave, approximately 150 mA, 0.2 s) caused large enhancement of catechol-oxidative current (CA.

Voltammetrically determined differences in changes evoked by KCl microinjections on catecholamine levels in the reticular formation and corpus striatum of the rat.

Using a microelectrode with carbon filaments and the voltammetric technique, changes evoked in the catechol oxidation current (CA.OC) and multiple unit activity (MUA) by microinjection of 3-5 microliters 0.5 mol.

Effect of acute alcohol treatment on dopamine concentration in corpus striatum of rats: a voltammetric study.

A voltammetry technique has been used to determine changes in dopamine release in the rat corpus striatum after two doses of ethanol administration. The dopamine oxidation current reached a maximal value at 30 min after the first alcohol dose with a subsequent decrease towards the initial level at 60 min and kept to the basal level with a statistically insignificant oscillation. When a second dose of alcohol was applied at 60 min, it was followed by a decrease of the dopamine oxidation current peak to 50% of the initial value after another 60 min observation.

Monitoring of potassium-stimulated catecholamine changes in striatal synaptosomal preparations and in corpus striatum of rats: a comparative voltammetric study.

Voltammetric techniques were used to compare the effects of K(+)-induced depolarization on catecholamine levels in in vitro synaptosomal preparations of the corpus striatum with those in the in vivo corpus striatum of anaesthetized animals. In vitro, the catechol-oxidation currents could be recorded only in dopamine-preloaded synaptosomes. In isolated synaptosomes prepared in the presence of elevated concentrations of Ca2+ (1 mmol.

Adrenergic regulation of [3H]ketanserin binding sites during immobilization stress in the rat frontal cortex.

Acute immobilization stress increased serotonin and 5-hydroxyindoleacetic acid levels, the 5-hydroxyindoleacetic/serotonin ratio, and the number of [3H]ketanserin binding sites, representing serotonin-2 type receptors, in the rat frontal cortex. Peripheral administration of propranolol or central administration of 6-hydroxydopamine abolished the stress induced elevation of [3H]ketanserin binding sites. Treatment with 6-hydroxydopamine did not affect the increase in serotonin and 5-hydroxyindoleacetic acid levels, and enhanced the increase in the 5-hydroxyindoleacetic acid/serotonin ratio produced by stress.

Stressfree administration of drugs by intraperitoneal cannulation in small laboratory animals.

A simple technique of chronic intraperitoneal cannulation in small laboratory animals has been described. It can be used for repeated i.p.

3-H-ketanserin (serotonin type 2) binding in the rat frontal cortex: effect of immobilization stress.

The number of 3H-ketanserin (5-HT2) binding sites in rat frontal cortex was estimated in groups of male rats subjected to a single or repeated immobilization stress (IMO). After an acute IMO for 30 or 120 min the number of 5-HT2 binding sites was significantly increased. Similar increase was found even in a group subjected for 120 min IMO for 6 consecutive days and then allowed 24 h rest (i.

Effect of corticosterone treatment and adrenalectomy on phenylethanolamine N-methyltransferase and catecholamines in brain stem and hypothalamic nuclei and superior cervical ganglion of rats.

The effects of corticosterone treatment and adrenalectomy with or without corticosterone replacement on the activity of phenylethanolamine N-methyltransferase (PNMT) and catecholamine content has been studied in isolated brain stem nuclei containing adrenergic and noradrenergic nerve cell bodies, hypothalamic nuclei and in the superior cervical ganglion (SCG) of adult rats. Changes of PNMT activity were found only in a few brain stem areas. In adrenalectomized rats, PNMT activity was decreased in Cl area and in the locus coeruleus, but after corticosterone replacement it returned to the control values.

Intravenous thiobarbital anaesthesia for determination of liver glycogen phosphorylase activity in rats subjected to various forms of stress.

Glycogen phosphorylase activity was determined in rat livers obtained by laparotomy in thiobarbital (Inactin, PROMONTA) anaesthesia induced by injection of the drug via a polyethylene catheter into a jugular vein as described previously [Németh et al. 1983a]. Intact rats and animals exposed to open field stress without or after i.