Derivatives and Inverse of a Linear-Nonlinear Multi-Layer Spatial Vision Model

Analyzing the mathematical properties of perceptually meaningful linear-nonlinear transforms is interesting because this computation is at the core of many vision models. Here we make such analysis in detail using a specific model [Malo & Simoncelli, SPIE Human Vision Electr. Imag. 2015] which is illustrative because it consists of a cascade of standard linear-nonlinear modules. The interest of the analytic results and the numerical methods involved transcend the particular model because of the ubiquity of the linear-nonlinear structure. Here we extend [Malo&Simoncelli 15] by considering 4 layers: (1) linear spectral integration and nonlinear brightness response, (2) definition of local contrast by using linear filters and divisive normalization, (3) linear CSF filter and nonlinear local con- trast masking, and (4) linear wavelet-like decomposition and nonlinear divisive normalization to account for orientation and scale-dependent masking. The extra layers were measured using Maximum Differentiation [Malo et al. VSS 2016]. First, we describe the general architecture using a unified notation in which every module is composed by isomorphic linear and nonlinear transforms. The chain-rule is interesting to simplify the analysis of systems with this modular architecture, and invertibility is related to the non-singularity of the Jacobian matrices. Second, we consider the details of the four layers in our particular model, and how they improve the original version of the model. Third, we explicitly list the derivatives of every module, which are relevant for the definition of perceptual distances, perceptual gradient descent, and characterization of the deformation of space. Fourth, we address the inverse, and we find different analytical and numerical problems in each specific module. Solutions are proposed for all of them. Finally, we describe through examples how to use the toolbox to apply and check the above theory. In summary, the formulation and toolbox are ready to explore the geometric and perceptual issues addressed in the introductory section (giving all the technical information that was missing in [Malo&Simoncelli 15])

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies

Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation.

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation

Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers.

Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility

Tone mapping based on natural image statistics and visual perception models

Les tècniques d'imatge d'alt rang dinàmic (HDR) potencialment permeten la captura i l'emmagatzematge de tota la informació de llum en una escena. No obstant això, els dispositius comuns de visualització són limitats en termes de les seves capacitats de contrast i brillantor, per tant, les imatges HDR han de ser mapejades tonalment abans de presentar-les en un dispositiu de visualització per assegurar que es reprodueix l'aspecte original de l'escena. En aquesta tesi, es prenen dos enfocaments del problema de mapeig tonal. En primer lloc, es desenvolupa un marc general per a la millora de qualsevol imatge mapejada tonalment mitjançant la reducció de la distància a la corresponent imatge HDR en termes d'una mètrica perceptiva no local. La distància es redueix al mínim per mitjà d'un algoritme de descens de gradient. En segon lloc, es desenvolupa un operador de mapeig tonal (TMO) en temps real que s'adapta bé a les estadístiques d'escenes naturals, i concorda amb els nous descobriments psicofísics i dades neurofísiques. Determinem les correctes adaptacions no lineals necessàries per als nostres resultats de mapeig tonal per tal d'obtenir l'aparença òptima en diferents condicions de visualització, a través d'experiments psicofísics i desenvolupar un mètode automàtic per poder predir dades experimentals. El nostre TMO produeix resultats d'aspecte natural, sense cap tipus d'artefactes espacials o temporals. Els tests de preferència dels usuaris mostren que el nostre mètode obté millors resultats en comparació amb les tècniques més recents. El TMO és ràpid i podria ser implementat en el hardware de la càmera. Pot ser utilitzat per al monitoratge de càmeres HDR en pantalles regulars, com a substitut de la correcció gamma, i com una manera de proporcionar al colorista amb contingut que té alhora un aspecte natural i una aparença nítida i clara.High Dynamic Range (HDR) imaging techniques potentially allow for the capture and storage of the full information of light in a scene. However, common display devices are limited in terms of their contrast and brightness capabilities, thus HDR images must be tone mapped before presentation on a display device to ensure that the original appearance of the scene is reproduced. In this thesis, we take two approaches to the tone mapping problem. First, we develop a general framework for improving any tone mapped image by reducing the distance with the corresponding HDR image in terms of a non-local perceptual metric. The distance is minimized by means of a gradient descent algorithm. Second, we develop a real-time Tone Mapping Operator (TMO) that is well suited to the statistics of natural scenes, and is in keeping with new psychophysical findings and neurophysical data. We determine the adequate non-linear adjustments needed for our tone mapping results to look best in different viewing conditions through a psychophysical experiment and develop an automatic method that can predict the experimental data. Our TMO produces results that look natural, without any spatio-temporal artifacts. User preference tests show that our method outperforms state of the art approaches. The TMO is fast and could be implemented on camera hardware. It can be used for on-set monitoring of HDR cameras on regular displays, as a substitute for gamma correction, and as a way of providing the colorist with content that is both natural looking and has a crisp and clear appearance