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Open Access Publications from the University of California

Scholarly Works (12 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2022)
Neurodevelopmental Disorders (NDDs) encompass a broad spectrum of disorders, linked because of their origins in brain developmental processes, including diverse conditions across the age span, including autism spectrum disorders (ASD) and schizophrenia (SCZ). Clinical treatment of these disorders has traditionally focused on symptom management, as the severity of developmental disruption varies widely and the precise molecular mechanisms, timing, and progression of these disorders is usually not known. Several hundred genes have been identified as major risk factors for ASD and SCZ, which creates new potential therapeutic avenues, and there is strong evidence that these genes converge upon key molecular pathways, pointing to opportunities for precision medicine. In this review, we focus on forms of ASD and SCZ with known genetic etiologies and discuss advances in research technologies that enable a more systemic understanding of disease progression. We highlight recent advances in targeted clinical treatment and discuss ongoing preclinical efforts as well as new initiatives aimed at developing scalable platforms for NDD precision medicine.
    Cover page: Challenges and opportunities for precision medicine in neurodevelopmental disorders.
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2015)
    Aberrant activation of the Wnt signaling pathway is a common cause of colon cancer and other tumor types, accomplishing many of the hallmarks of cancer including sustained proliferative signaling, replicative immortality, reprogrammed metabolism, angiogenesis, and invasion. Yet, the dominant mutation that leads to chronic Wnt signaling in colon cancer is quite different from the spectrum of mutations that activate Wnt signaling in other tumor types. In this issue of The EMBO Journal, Huels et al (2015) focus on the influential role E-cadherin plays in shaping these differences.
      Cover page: Cancer: leaping the E‐cadherin hurdle
      • Thesis
      • Peer Reviewed
      UC Irvine Electronic Theses and Dissertations (2018)

      The Wnt signaling pathway is a highly conserved cell-to-cell communication network in animals, and it regulates many gene programs essential for organism growth and development. Dysregulation of the Wnt pathway is a characteristic of many diseases, the most recognized of which is cancer. In colon cancer, Wnt-activating mutations are a key initiator of tumorigenesis, and in vitro and in vivo experiments have suggested that targeting the pathway will effectively decrease tumor burden. Despite this, years of clinical trials using Wnt pathway inhibitors in colon cancer patients have not yielded any success. As the push to develop Wnt-targeting therapies continues, a growing body of work points to a more complex understanding of Wnt signaling in colon cancer. In spite of the Wnt-activating mutations, Wnt signaling activities vary widely within a tumor, suggesting additional regulation beyond the constitutive activation. This dissertation presents two consequences of Wnt heterogeneity; first the regulation of cellular metabolism, and second, the regulation of cell migration and invasion.

      Our first story builds upon our earlier work, which demonstrated that Wnt directly regulates the expression of glycolytic metabolism genes PDK1 and MCT1. We find that observations of Wnt signaling heterogeneity in tumors are also manifest as heterogeneous metabolism. We show that the spatial patterns of Wnt and metabolic heterogeneity are directly linked and a result of cell-to-cell signaling. This heterogeneity supports growth through efficient distribution of nutrients and proliferative signaling throughout the tumor. We demonstrate that this relationship between Wnt signaling and metabolism can be exploited therapeutically using a combination of Wnt and glycolysis inhibitors.

      In the second story, we study heterogeneity in Wnt signaling levels over time, to show that a decrease in Wnt signaling primes tumor cells for invasion. By modulating the level of Wnt signaling in different ways, we show a graded increase of cell invasion and migration with decreasing Wnt levels, in both cell culture and orthotopic tumor models. Using sequencing data from Wnt-decreased cells and colon cancer patients, we identify potential drivers of this invasive phenotype, and suggest their use as therapeutic or diagnostic targets in colon cancer patients advancing to metastatic disease.

        Cover page: Wnt Signaling Regulation of Colon Cancer Metabolism and InvasionCreative Commons 'BY' version 4.0 license
        • Article
        • Peer Reviewed
        UC Berkeley Previously Published Works (2016)
        The lithium-sulfur cell has shown great prospects for future energy conversion and storage systems due to the high theoretical specific capacity of sulfur, 1675 mAh g−1. However, it has been hindered by rapid capacity decay and low energy efficiency. In this work, polypyrrole (PPy)/TiO2 nanotubes with coaxial heterogeneous structure as the substrate of the cathode is prepared and used to improve the electrochemical performance of sulfur electrodes. TiO2 nanotubes decorated with PPy provide a highly ordered conductive framework for Li+ ion diffusion and reaction with sulfur. This architecture also is helpful for trapping the produced polysulfides, and as a result attenuates the capacity decay. Furthermore, the heat treatment temperature used in the sulfur loading process has been confirmed to have an important impact on the overall performance of the resultant cell. The as-designed S/PPy/TiO2 nanotube cathode using an elevated heating temperature shows excellent cycling stability with a high discharge capacity of 1150 mAh g−1 and average coulombic efficiency of 96% after 100 cycles.
          Cover page: Polypyrrole/TiO2 nanotube arrays with coaxial heterogeneous structure as sulfur hosts for lithium sulfur batteries
          • Article
          • Peer Reviewed
          IDAV Publications (2002)
          We propose to look at light fields from a dual space point of view. The advantage, in addition to revealing some new insights, is a framework that combines the benefits of many existing works. Using the well known two-plane-parameterization, we derive the duality between the 4-D light field and the 3-D world space. In the dual light field, rays become hyper points. We introduce the concept of hyperline. Then, cameras appear as hyperlines - camera hyperline (CHL) - mostly heterogeneous in color; scene points also appear as hyperlines - geometry hyperline (GHL) - mostly homogeneous in color. CHL's and GHL's are independent. The existence of one does not require or replace the other. When both exist, they cross each other at the dual ray hyper points. Both CHL and GHL-based light field rendering results are presented.
            Cover page: Light Field Duality: Concepts and Applications
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2017)
            The highly conserved Wnt signalling pathway plays an important role in embryonic development and disease pathogenesis, most notably cancer. The 'canonical' or β-catenin-dependent Wnt signal initiates at the cell plasma membrane with the binding of Wnt proteins to Frizzled:LRP5/LRP6 receptor complexes and is mediated by the translocation of the transcription co-activator protein, β-catenin, into the nucleus. β-Catenin then forms a complex with T-cell factor (TCF)/lymphoid enhancer binding factor (LEF) transcription factors to regulate multiple gene programmes. These programmes play roles in cell proliferation, migration, vasculogenesis, survival and metabolism. Mutations in Wnt signalling pathway components lead to constitutively active Wnt signalling that drives aberrant expression of these programmes and development of cancer. It has been a longstanding and challenging goal to develop therapies that can interfere with the TCF/LEF-β-catenin transcriptional complex. This review will focus on the (i) structural considerations for targeting the TCF/LEF-β-catenin and co-regulatory complexes in the nucleus, (ii) current molecules that directly target TCF/LEF-β-catenin activity and (iii) ideas for targeting newly discovered components of the TCF/LEF-β-catenin complex and/or downstream gene programmes regulated by these complexes.

            Linked articles

            This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.
              Cover page: Inhibition of nuclear Wnt signalling: challenges of an elusive target for cancer therapy
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2017)
              Cell-intrinsic metabolic reprogramming is a hallmark of cancer that provides anabolic support to cell proliferation. How reprogramming influences tumor heterogeneity or drug sensitivities is not well understood. Here, we report a self-organizing spatial pattern of glycolysis in xenograft colon tumors where pyruvate dehydrogenase kinase (PDK1), a negative regulator of oxidative phosphorylation, is highly active in clusters of cells arranged in a spotted array. To understand this pattern, we developed a reaction-diffusion model that incorporates Wnt signaling, a pathway known to upregulate PDK1 and Warburg metabolism. Partial interference with Wnt alters the size and intensity of the spotted pattern in tumors and in the model. The model predicts that Wnt inhibition should trigger an increase in proteins that enhance the range of Wnt ligand diffusion. Not only was this prediction validated in xenograft tumors but similar patterns also emerge in radiochemotherapy-treated colorectal cancer. The model also predicts that inhibitors that target glycolysis or Wnt signaling in combination should synergize and be more effective than each treatment individually. We validated this prediction in 3D colon tumor spheroids.
                Cover page: Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancerCreative Commons 'BY' version 4.0 license
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2012)
                Receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) is expressed during embryogenesis and by certain leukemias, but not by normal adult tissues. Here we show that the neoplastic cells of many human breast cancers express the ROR1 protein and high-level expression of ROR1 in breast adenocarcinoma was associated with aggressive disease. Silencing expression of ROR1 in human breast cancer cell lines found to express this protein impaired their growth in vitro and also in immune-deficient mice. We found that ROR1 could interact with casein kinase 1 epsilon (CK1ε) to activate phosphoinositide 3-kinase-mediated AKT phosphorylation and cAMP-response-element-binding protein (CREB), which was associated with enhanced tumor-cell growth. Wnt5a, a ligand of ROR1, could induce ROR1-dependent signaling and enhance cell growth. This study demonstrates that ROR1 is expressed in human breast cancers and has biological and clinical significance, indicating that it may be a potential target for breast cancer therapy.
                  Cover page: ROR1 Is Expressed in Human Breast Cancer and Associated with Enhanced Tumor-Cell Growth
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2022)
                  The recent classification of colon cancer into molecular subtypes revealed that patients with the poorest prognosis harbor tumors with the lowest levels of Wnt signaling. This is contrary to the general understanding that overactive Wnt signaling promotes tumor progression from early initiation stages through to the later stages including invasion and metastasis. Here, we directly test this assumption by reducing the activity of ß-catenin-dependent Wnt signaling in colon cancer cell lines at either an upstream or downstream step in the pathway. We determine that Wnt-reduced cancer cells exhibit a more aggressive disease phenotype, including increased mobility in vitro and disruptive invasion into mucosa and smooth muscle in an orthotopic mouse model. RNA sequencing reveals that interference with Wnt signaling leads to an upregulation of gene programs that favor cell migration and invasion and a downregulation of inflammation signatures in the tumor microenvironment. We identify a set of upregulated genes common among the Wnt perturbations that are predictive of poor patient outcomes in early-invasive colon cancer. Our findings suggest that while targeting Wnt signaling may reduce tumor burden, an inadvertent side effect is the emergence of invasive cancer.

                  Implications

                  Decreased Wnt signaling in colon tumors leads to a more aggressive disease phenotype due to an upregulation of gene programs favoring cell migration in the tumor and downregulation of inflammation programs in the tumor microenvironment; these impacts must be carefully considered in developing Wnt-targeting therapies.
                    Cover page: Disruption of beta-catenin dependent Wnt signaling in colon cancer cells remodels the microenvironment to promote tumor invasion
                    • Article
                    • Peer Reviewed
                    ICTS Publications (2016)
                      Cover page: Increased retinal mtDNA damage in the CFH variant associated with age-related macular degenerationCreative Commons 'BY' version 4.0 license
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