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Open Access Publications from the University of California

Scholarly Works (4 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2020)

Lung cancer is one of the most frequent diagnosis cancers in the U.S. Importantly, primary lung cancer frequently metastasizes to brain, but the survival and treatment of lung cancer brain metastasis are both poor. Aryl Hydrocarbon Receptor (AHR) mediated induction of Cytochrome P450 enzymes has been linked to cancer progression via binding to AHR agonists like 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). The exposure of TCDD significantly increases CYP 1A1 and CYP 1B1 in the lung and liver.

The western diet typically contains a high ratio of omega-6 (-6) to omega-3 (-3) polyunsaturated fatty acids (PUFA). Recently, our group has demonstrated that the action of -6 and -3 PUFA metabolism on tumor progression is an AHR dependent process. TCDD promotes tumor growth and metastasis under -6 enriched diets but inhibits tumor growth and metastasis under -3 enriched diets. This finding indicates that TCDD impact on lung cancer progression can be modified by dietary PUFA. Based on this new research ground, it is also interesting to evaluate TCDD’s action on primary lung cancer metastasis to the brain depending on different ratio of -6 to -3 PUFA in diet.

We hypothesized that the lung tumor increases the metastasis to the brain through, an AHR agonist like TCDD, which induce the expression of some cytochrome P450 in the brain of the mice that were fed with rich-⍵6 diet.

To evaluate our hypothesis, we performed immunohistochemistry, digital pathology, RT-PCR, and liquid chromatography with tandem mass spectrometry. Our data demonstrated that the brain metastasis was found in mice fed with rich- ω-6 diet in mice treated with TCDD as compared with untreated mice. Further, TCDD significantly induced CYP 1A1 and CYP 1B1 in mice brain tissue under ω-6 enriched diet. In addition, the levels of oxylipins in plasma demonstrated that epoxides 5,6 EET are increases after TCCD treatment, as well as various diols like 5,6-DiHETrE, 11,12-DiHETrE, and 14,15-DiHETrE.

These results provide us a future research direction on combining effects of diets and environment carcinogens to analyze the mechanism to be involved in the metastasis to the brain from the lung tumor cells.

    Cover page: Aryl Hydrocarbon Receptor-Mediated Induction of CYP1A1 and CYP1B1 Enzymes in Brain: A Preliminary Exploration of the Role of Oxylipins in Lung Cancer Metastasis to Brain
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2022)
    Lung cancer is currently the leading cause of cancer death worldwide; it is often diagnosed at an advanced stage and bears poor prognosis. It has been shown that diet is an important environmental factor that contributes to the risk and mortality of several types of cancers. Intake of ω-3 and ω-6 PUFAs plays an important role in cancer risk and progression. Current Western populations have high consumption of ω-6 PUFAs with a ratio of ω-6/ω-3 PUFAs at 15:1 to 16.7:1 This high consumption of ω-6 PUFAs is related to increased cancer risk and progression. However, whether a diet rich in ω-6 PUFAs can contribute to tumor aggressiveness has not been well investigated. We used a murine model of pulmonary squamous cell carcinoma to study the aggressiveness of tumors in mice fed with a diet rich in ω-6 PUFAs and its relationship with oxylipins. Our results shown that the mice fed a diet rich in ω-6 showed a marked increase in proliferation, angiogenesis and pro-inflammatory markers and decreased expression of pro-apoptotic proteins in their tumors. Oxylipin profiling revealed an upregulation of various pro-tumoral oxylipins including PGs, HETEs, DiHETrEs and HODEs. These results demonstrate for the first time that high intake of ω-6 PUFAs in the diet enhances the malignancy of tumor cells by histological changes on tumor dedifferentiation and increases cell proliferation, angiogenesis, pro-inflammatory oxylipins and molecular aggressiveness targets such as NF-κB p65, YY1, COX-2 and TGF-β.
      Cover page: Omega-6 Polyunsaturated Fatty Acids Enhance Tumor Aggressiveness in Experimental Lung Cancer Model: Important Role of Oxylipins
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2021)
      Highly pathogenic avian influenza viruses (HPAIVs) in gallinaceous poultry are associated with viral infection of the endothelium, the induction of a 'cytokine storm, and severe disease. In contrast, in Pekin ducks, HPAIVs are rarely endothelial tropic, and a cytokine storm is not observed. To date, understanding these species-dependent differences in pathogenesis has been hampered by the absence of a pure culture of duck and chicken endothelial cells. Here, we use our recently established in vitro cultures of duck and chicken aortic endothelial cells to investigate species-dependent differences in the response of endothelial cells to HPAIV H5N1 infection. We demonstrate that chicken and duck endothelial cells display a different transcriptional response to HPAI H5N1 infection in vitro-with chickens displaying a more pro-inflammatory response to infection. As similar observations were recorded following in vitro stimulation with the viral mimetic polyI:C, these findings were not specific to an HPAIV H5N1 infection. However, similar species-dependent differences in the transcriptional response to polyI:C were not observed in avian fibroblasts. Taken together, these data demonstrate that chicken and duck endothelial cells display a different response to HPAIV H5N1 infection, and this may help account for the species-dependent differences observed in inflammation in vivo.
        Cover page: Primary Chicken and Duck Endothelial Cells Display a Differential Response to Infection with Highly Pathogenic Avian Influenza Virus
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2021)
        The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.
          Cover page: SARS-CoV-2 evolution during treatment of chronic infection
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