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Open Access Publications from the University of California

Scholarly Works (15 results)

  • Article
  • Peer Reviewed
Nutrition Bytes, Volume 2, Issue 1 (1996)

abstract not available

    Cover page: Melatonin and its Role in Aging and Oxidative Stress
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2016)
    The introduction of nerve-sparing technique is one of the most significant advances in the surgical treatment of prostate cancer and heralded a shift from a curing cancer at all-cost model to a curing cancer and preserving quality of life model. In a recent article published in Lancet Oncology in May, Lee et al. reviewed the concept of vessel-sparing and functional anatomy-based radiotherapy as well as outcomes with respect to erectile dysfunction, bringing to light a conceptual shift in the management of localized prostate cancer with radiotherapy, which parallels the shift in the surgical management of prostate cancer with the introduction of nerve-sparing technique. The hypothesis is that utilization of vessel-sparing and functional anatomy-based radiotherapy may result in a more personalized approach to this modality based on a patient's specific anatomy, therefore improving patient outcomes.
      Cover page: How nerve-sparing technique has been applied to radiotherapy?
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2014)
      Tumor invasion and metastases represent a complex series of molecular events that portends a poor prognosis. The contribution of inflammatory pathways mediating this process is not well understood. Nod-like receptors (NLRs) of innate immunity function as intracellular sensors of pathogen motifs and danger molecules. We propose a role of NLRs in tumor surveillance and in programming tumor-infiltrating lymphocytes (TILs). In this study, we examined the downstream serine/threonine and tyrosine kinase Rip2 in a murine model of bladder cancer. In Rip2-deficient C57Bl6 mice, larger orthotopic MB49 tumors developed with more numerous and higher incidence of metastases compared to wild-type controls. As such, increased tumor infiltration of CD11b+ Gr1hi myeloid-derived suppressor cells (MDSCs) with concomitant decrease in T cells and NK cells were observed in Rip2-deficient tumor bearing animals using orthotopic and subcutaneous tumor models. Rip2-deficient tumors showed enhanced epithelial-to-mesenchymal transition, with elevated expression of zeb1, zeb2, twist, and snail in the tumor microenvironment. We found that the absence of Rip2 plays an intrinsic role in fostering the development of granulocytic MDSCs by an autocrine and paracrine effect of granulocytic colony stimulating factor (G-CSF) expression. Our findings suggest that NLR pathways may be a novel modality to program TILs and influence tumor metastases.
        Cover page: Role of Rip2 in Development of Tumor-Infiltrating MDSCs and Bladder Cancer Metastasis
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2017)

        Purpose

        Pathologic staging of bladder cancer patients remains a challenge. Standard-of-care histology exhibits limited sensitivity in detection of micrometastases, which can increase risk of cancer progression and delay potential adjuvant therapies. Here, we sought to develop a proof of concept novel molecular approach to improve detection of cancer micrometastasis.

        Experimental design

        We combined fluorescence activated cell sorting and next-generation sequencing and performed whole-exome sequencing of total cancer cells and cancer cell subpopulations in multiple tumor specimens and regional lymph nodes in a single patient with muscle-invasive urothelial carcinoma of the bladder following radical cystectomy.

        Results

        Mean allele frequency analysis demonstrated a significant correlation between primary tumor cancer cells and cancer cells isolated from the lymph nodes, confirming lymph node disease despite negative pathologic staging. RNA-sequencing revealed intratumoral heterogeneity as well as enrichment for immune system and lipid metabolism gene sets in the micrometastatic cancer cell subpopulations.

        Conclusions

        Our analysis illustrates how next-generation sequencing of cancer cell subpopulations may be utilized to enrich for cancer cell markers and enhance detection of bladder cancer micrometastases to improve pathologic staging and provide insight into cancer cell biology.
          Cover page: Sequencing of cancer cell subpopulations identifies micrometastases in a bladder cancer patient
          • Thesis
          • Peer Reviewed
          UCLA Electronic Theses and Dissertations (2016)

          The role of immune signaling in cancer is complex and conflicting. Inflammatory signaling can drive an anti-tumor response, but copious evidence suggests that chronic inflammation also promotes tumorigenesis. The most well-characterized of inflammatory pathways is the Toll-like receptor (TLR) pathway, which promotes downstream NF-κB activation. Mutations in TLRs are associated with a higher risk of prostate cancer.

          Using the TRAMP model of prostate cancer, we report the impact of TLR signaling

          disruption on tumor growth and progression. The adaptor protein MyD88 is an essential

          component of signaling for almost all TLRs, so loss of MyD88 abrogates most TLR signaling. Absence of MyD88-dependent signaling in TRAMP prostate tumors resulted in a more aggressive disease, as determined by histology. Analysis of infiltrating immune cells revealed an increase in CD11b+Gr-1+ MDSCs (myeloid-derived suppressor cells) in MyD88-/- tumors when compared to MyD88+/+ tumors, both in number and in functional output. MyD88-/- tumors also displayed increased expression of some chemokines involved in MDSC recruitment.

          An explicit link between MyD88-dependent signaling and MDSC accumulation was suggested by the expression of S100A9, a chemokine and a TLR4 ligand. Specifically, this indicates that MyD88-dependent signaling may play a role within the MDSCs themselves. In vitro differentiation of MDSCs from bone marrow skewed towards the granulocytic subset (gMDSCs) in MyD88-/- cells, supporting an internal role for MyD88 signaling. MyD88-/- MDSCs also showed an increased sensitivity to chemotaxis mediated by S100A9 and an increase in Arg-1 expression following S100A9 stimulation. We conclude that MyD88-dependent signaling may play an essential role in regulating the population of tumor-infiltrating cells by reducing MDSC activity and MDSC response to S100A9-mediated chemotaxis, thus limiting prostate tumor progression.

            Cover page: MyD88-dependent signaling in prostate cancer: Regulation of immune populations in the tumor microenvironment
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2019)
            Cancer of the urological system commonly occurs in the kidney, bladder, and prostate gland. The clear cell subtype of renal cell carcinoma (ccRCC) constitutes the great majority of kidney cancer. Metastatic ccRCC portends a very poor outcome with no effective treatment available. Prostate cancer is the most common cancer in males in the US. Despite recent advances in selective kinase inhibitors and immunotherapies, the rate of developing new treatment from bench to bedside is slow. A time-consuming step is at the animal drug testing stage, in which the mouse model is the gold standard. In the pursuit to streamline the in vivo cancer biology research and drug development, we explored the feasibility of the chicken chorioallantoic membrane (CAM) model to establish xenografts. The CAM model greatly shortens the time of tumor growth and lowers the cost comparing to immunocompromised mice. We generated CAM xenografts from ccRCC, bladder and prostate cancer, with established cancer cell lines and freshly isolated patient-derived tissues, either as primary tumor cells or small pieces of tumors. The successful CAM engraftment rate from the different tumor sources is 70% or above. Using our previously established metastatic ccRCC mouse model, we showed that the CAM xenograft maintains the same tumor growth pattern and metastatic behavior as observed in mice. Taken together, CAM can serve as a valuable platform to establish new patient-derived xenografts (PDXs) to study tumor biology, thus accelerating the development of individualized treatment to halt the deadly metastatic stage of cancer.
              Creative Commons 'BY' version 4.0 license
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2019)
              Cancer of the urological system commonly occurs in the kidney, bladder, and prostate gland. The clear cell subtype of renal cell carcinoma (ccRCC) constitutes the great majority of kidney cancer. Metastatic ccRCC portends a very poor outcome with no effective treatment available. Prostate cancer is the most common cancer in males in the US. Despite recent advances in selective kinase inhibitors and immunotherapies, the rate of developing new treatment from bench to bedside is slow. A time-consuming step is at the animal drug testing stage, in which the mouse model is the gold standard. In the pursuit to streamline the in vivo cancer biology research and drug development, we explored the feasibility of the chicken chorioallantoic membrane (CAM) model to establish xenografts. The CAM model greatly shortens the time of tumor growth and lowers the cost comparing to immunocompromised mice. We generated CAM xenografts from ccRCC, bladder and prostate cancer, with established cancer cell lines and freshly isolated patient-derived tissues, either as primary tumor cells or small pieces of tumors. The successful CAM engraftment rate from the different tumor sources is 70% or above. Using our previously established metastatic ccRCC mouse model, we showed that the CAM xenograft maintains the same tumor growth pattern and metastatic behavior as observed in mice. Taken together, CAM can serve as a valuable platform to establish new patient-derived xenografts (PDXs) to study tumor biology, thus accelerating the development of individualized treatment to halt the deadly metastatic stage of cancer.
                Cover page: Establishment of xenografts of urological cancers on chicken chorioallantoic membrane (CAM) to study metastasis
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2015)

                Purpose

                Cisplatin based chemotherapy regimens form the basis of systemic bladder cancer treatment, although they show limited response rates and efficacy. Recent molecular analysis of bladder cancer revealed a high incidence of mutations in chromatin regulatory genes, suggesting a therapeutic avenue for histone deacetylase inhibitors. We investigated the ability of the novel histone deacetylase inhibitor AR-42 to synergize with cisplatin in preclinical models of bladder cancer.

                Materials and methods

                We assessed the ability of the pan-histone deacetylase inhibitor AR-42 with and without cisplatin to destroy bladder cancer cells by survival and apoptosis assays in vitro, and by growth and differentiation in an in vivo xenograft model. We also assessed the response to the bladder cancer stem cell population by examining the effect of AR-42 on the CD44(+)CD49f(+) population with and without cisplatin. Synergy was calculated using combination indexes.

                Results

                The AR-42 and cisplatin combination synergistically destroyed bladder cancer cells via apoptosis and it influenced tumor growth and differentiation in vivo. When tested in the CD44(+)CD49f(+) bladder cancer stem cell population, AR-42 showed greater efficacy with and without cisplatin.

                Conclusions

                AR-42 may be an attractive novel histone deacetylase inhibitor with activity against bladder cancer. Its efficacy in bladder cancer stem cells and synergy with cisplatin warrant further clinical investigation. Our in vitro and animal model studies provide preclinical evidence that AR-42 may be administered in conjunction with cisplatin based chemotherapy to improve the treatment of bladder cancer in patients.
                  Cover page: Synergy of Histone-Deacetylase Inhibitor AR-42 with Cisplatin in Bladder Cancer
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2024)
                  UNLABELLED: Antagonism of the PD-1/PD-L1 axis is a critical therapeutic strategy for patients with advanced bladder cancer. IFNγ functions as a key regulator of PD-L1 in both immune as well as cancer cells. Forkhead box P3 (FOXP3) is a transcription factor synonymous in T regulatory cell function but with increasingly described functions in cancer cells. Here, we investigated the relationship between FOXP3 and PD-L1 in bladder cancer. We showed that FOXP3 is critical in the ability for IFNγ to activate PD-L1 in bladder cancer cells. FOXP3 can bind to the PD-L1 promoter and induces a gene program that leads to regulation of multiple immune-related genes and genes involved in epithelial-to-mesenchymal transition (EMT). Using in vitro and in vivo human and murine models, we showed that FOXP3 can influence bladder cancer EMT as well as promote cancer metastases. Furthermore, FOXP3 may be a convergent factor for multiple activators of PD-L1, including the chemotherapeutic drug cisplatin. SIGNIFICANCE: Historically a key transcription factor driving T regulatory cell function, FOXP3 has an increasingly recognized role in cancer cells. In bladder cancer, we defined a novel mechanism whereby FOXP3 mediates the activation of the immune checkpoint PD-L1 by the cytokine IFNγ. We also showed that FOXP3 induces other immune checkpoints as well as genes involved in EMT, promoting immune resistance and cancer metastases.
                    Cover page: Role of Forkhead Box P3 in IFNγ-Mediated PD-L1 Expression and Bladder Cancer Epithelial-to-Mesenchymal Transition.
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2024)
                    Micro-ultrasound has recently been introduced as a low-cost alternative to multi-parametric MRI for imaging prostate cancer. Early clinical studies have demonstrated promising results; however, robust validation via comparison with whole-mount pathology has yet to be achieved. Due to micro-ultrasound probe design and tissue deformation during scanning, it is difficult to accurately correlate micro-ultrasound imaging planes with ground truth whole-mount pathology slides. In this study, we developed a multi-step methodology to co-register micro-ultrasound and MRI to whole-mount pathology. The three-step process had a registration error of 3.90 ± 0.11 mm and consists of: (1) micro-ultrasound image reconstruction, (2) 3D landmark registration of micro-ultrasound to MRI, and (3) 2D capsule registration of MRI to whole-mount pathology. This process was then used in a preliminary reader study to compare the diagnostic accuracy of micro-ultrasound and MRI in 15 patients who underwent radical prostatectomy for prostate cancer. Micro-ultrasound was found to have equivalent performance to retrospective MRI review for index lesion detection (91.7% vs. 80%), while demonstrating an increased detection of tumor extent (52.5% vs. 36.7%) with similar false positive regions-of-interest (38.3% vs. 40.8%). Prospective MRI review had reduced detection of index lesions (73.3%) and tumor extent (18.9%) but improved false positive regions-of-interest (22.7%) relative to micro-ultrasound and retrospective MRI. Further evaluation is needed with a larger sample size.
                      Cover page: Evaluation of prostate cancer detection using micro-ultrasound versus MRI through co-registration to whole-mount pathology
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