Integrating Functional Genomics with Systems Biology to Discover Drivers and Therapeutic Targets of Human Malignancies

Genome-wide RNAi screening has emerged as a powerful tool for loss-of-function studies that may lead to therapeutic target discovery for human malignancies in the era of personalized medicine. However, due to high false-positive and false-negative rates arising from noise of high-throughput measurements and off-target effects, powerful computational tools and additional knowledge are much needed to analyze and complement it. Availability of high-throughput genomic data including gene expression profiles, copy number variations from large-sampled primary patients and cell lines allows us to tackle underlying drivers causally associated with tumorigenesis or drug-resistance. In my dissertation, I have developed a framework to integrate functional RNAi screens with systems biology of cancer genomics to tailor potential therapeutics for reversal of drug-resistance or treatment of aggressive tumors. I developed a series of algorithms and tools to deconvolute, QC and post-analyze high-throughput shRNA screening data by next-generation sequencing technology (shSeq), particularly a novel Bayesian hierarchical modeling approach to integrate multiple shRNAs targeting the same gene, which outperforms existing methods. In parallel, I developed a systems biology algorithm, NetBID2, to infer disease drivers from high-throughput genomic data by reverse-engineering network and Bayesian inference, which is able to detect hidden drivers that traditional methods fail to find. Integrating NetBID2 with functional RNAi screens, I have identified known and novel driver-type therapeutic targets in various disease contexts. For example, I discovered that AKT1 is a driver for glucocorticoid (GC) resistance, a problem in the treatment of T-ALL. The inhibition of AKT1 was validated to reverse GC-resistance. Additionally, upon silencing predicted master regulators of GC resistance with shRNA screens, 13 out of 16 were validated to significantly overcome resistance. In breast cancer, I discovered that STAT3 is required for transformation of HER2+ breast cancer, an aggressive breast tumor subtype. The suppression of STAT3 was confirmed in vitro and in vivo to be an effective therapy for HER2+ breast cancer. Moreover, my analysis revealed that STAT3 silencing only works in ER- cases. Using my framework, I have also identified potential therapeutic targets for ABC or GCB-type DLBCL and subtype-based breast cancer that are currently being validated

Synthesis of new zeolite structures

[EN] The search for new zeolites is of continuous interest in the field of zeolite science because of their widespread application in catalysis and adsorption¿separation. To this end, considerable efforts have been devoted to the preparation of new zeolites with novel porous architectures and compositions. Taking account of the key factors governing the formation of zeolites (e.g., guest species, framework elements, construction processes, etc.), several synthetic strategies have been developed recently. These allow the discovery of many new zeolites with unprecedented structural features, such as hierarchical pores, odd-ring numbers (11-, 15-rings), extra-large pores (16-, 18-, 20-, 28-, and 30-rings), chiral pores, and extremely complex framework topologies, etc. In this review, we will present the advances in the synthesis of new zeolite structures in the last decade, which are achieved by utilization of the synthetic strategies based on pre-designed structure-directing agents, heteroatom substitution, and topotactic transformations.Li, J.; Corma Canós, A.; Yu, J. (2015). Synthesis of new zeolite structures. Chemical Society Reviews. 44(20):7112-7127. doi:10.1039/c5cs00023hS71127127442

A novel approach to detect differentially expressed genes from count-based digital databases by normalizing with housekeeping genes

AbstractSequence tag count-based gene expression analysis is potent for the identification of candidate genes relevant to the cancerous phenotype. With the public availability of count-based data, the computational approaches for differentially expressed genes, which are mainly based on Binomial or beta-Binomial distribution, become practical and important in cancer biology. It remains a permanent need to select a proper statistical model for these methods. In this study, we developed a novel Bayesian algorithm-based method, Electronic Differential Gene Expression Screener (EDGES), in which a statistical model was determined by geometric averaging of 12 common housekeeping genes. EDGES identified a set of differentially expressed genes in lung, breast and colorectal cancers by using publically available Serial Analysis of Gene Expression (SAGE) and Expressed Sequence Tag (EST data). Gene expression microarray analysis and quantitative reverse transcription real-time PCR demonstrated the effectiveness of this procedure. We conclude that current normalization of calibrators provides a new insight into count-based digital subtraction in cancer research

Minimal BRDF Sampling for Two-Shot Near-Field Reflectance Acquisition

We develop a method to acquire the BRDF of a homogeneous flat sample from only two images, taken by a near-field perspective camera, and lit by a directional light source. Our method uses the MERL BRDF database to determine the optimal set of lightview pairs for data-driven reflectance acquisition. We develop a mathematical framework to estimate error from a given set of measurements, including the use of multiple measurements in an image simultaneously, as needed for acquisition from near-field setups. The novel error metric is essential in the near-field case, where we show that using the condition-number alone performs poorly. We demonstrate practical near-field acquisition of BRDFs from only one or two input images. Our framework generalizes to configurations like a fixed camera setup, where we also develop a simple extension to spatially-varying BRDFs by clustering the materials.</jats:p

Robust capped norm dual hyper-graph regularized non-negative matrix tri-factorization

Non-negative matrix factorization (NMF) has been widely used in machine learning and data mining fields. As an extension of NMF, non-negative matrix tri-factorization (NMTF) provides more degrees of freedom than NMF. However, standard NMTF algorithm utilizes Frobenius norm to calculate residual error, which can be dramatically affected by noise and outliers. Moreover, the hidden geometric information in feature manifold and sample manifold is rarely learned. Hence, a novel robust capped norm dual hyper-graph regularized non-negative matrix tri-factorization (RCHNMTF) is proposed. First, a robust capped norm is adopted to handle extreme outliers. Second, dual hyper-graph regularization is considered to exploit intrinsic geometric information in feature manifold and sample manifold. Third, orthogonality constraints are added to learn unique data presentation and improve clustering performance. The experiments on seven datasets testify the robustness and superiority of RCHNMTF