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Open Access Publications from the University of California

Scholarly Works (32 results)

  • Article
  • Peer Reviewed
UC Davis Previously Published Works (2018)
The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)-dependent pathway is one of the most integral pathways linked to cell metabolism, proliferation, differentiation, and survival. This pathway is dysregulated in a variety of diseases, including neoplasia, immune-mediated diseases, and fibroproliferative diseases such as pulmonary fibrosis. The mTOR kinase is frequently referred to as the master regulator of this pathway. Alterations in mTOR signaling are closely associated with dysregulation of autophagy, inflammation, and cell growth and survival, leading to the development of lung fibrosis. Inhibitors of mTOR have been widely studied in cancer therapy, as they may sensitize cancer cells to radiation therapy. Studies also suggest that mTOR inhibitors are promising modulators of fibroproliferative diseases such as idiopathic pulmonary fibrosis (IPF) and radiation-induced pulmonary fibrosis (RIPF). Therefore, mTOR represents an attractive and unique therapeutic target in pulmonary fibrosis. In this review, we discuss the pathological role of mTOR kinase in pulmonary fibrosis and examine how mTOR inhibitors may mitigate fibrotic progression.
    Cover page: The Role of the Mammalian Target of Rapamycin (mTOR) in Pulmonary Fibrosis.
    • Thesis
    • Peer Reviewed
    UC San Diego Electronic Theses and Dissertations (2020)

    Prion diseases are sporadic and infectious neurodegenerative disorders caused by PrPSc, a misfolded and aggregated isoform of the cellular prion protein, PrPC. PrPSc accumulates and spreads through the CNS, causing neurodegeneration, gliosis, and ultimately death. However, the mechanisms underlying prion transport and pathogenesis remain poorly defined. The goals of my thesis research are to uncover properties of both prions and cellular pathways that facilitate prion spread into the central nervous system (CNS). First, we analyzed the biochemical properties of prion strains that enable entry into the central nervous system from the peripheral organs. While prion strains have identical amino acid sequences, strains differ in the incubation period to terminal disease, lesion profile, and biophysical properties, including conformational stability, depending on the strain. In this work, we found that prion strains that neuroinvade were more soluble than the non-neuroinvasive strains, and that sonicating the non-neuroinvasive strains increased the solubility as well as the neuroinvasive properties. Second, we studied cellular pathways reported to be involved in prion spread through the CNS. We found that the ESCRT (Endosomal Complexes Required for Transport) pathway contributes to prion conversion in multivesicular bodies (MVBs) in neurons and prion spread via exosomes. Surprisingly, depletion of ESCRT-0 in the neurons of prion-infected mice worsened disease by accelerating the degeneration of synapses, without detectably increasing conversion of PrPSc. In contrast, depletion of ESCRT-0 in astrocytes or microglia had no effect on PrPSc levels or survival time. Third, we investigated pathways that contribute to prion spread by analyzing the brains of mice in a longitudinal study that included genetic, histological, and biochemical approaches. We found that synaptic alterations in the hippocampus were among the earliest (40% of disease course) and coincided with accumulation of ubiquitinated protein inclusions, suggesting degradative pathways were impaired early in disease. Fourth, we manipulated endolysosomal pathways in prion-infected neuroblastoma cells to further understand the role of both the MVB in prion conversion and exosomes in prion spread. Here, we validated that knocking down Hrs reduced PrPSc, while knocking down Vps35 conversely increased PrPSc. We found that Hrs depletion caused a decrease of PrPSc. Reduction of prion conversion was not due to a decrease in PrPC or an increase in autophagic degradation of PrPSc, or even a loss of spread through exosomes, but instead, a failure of PrPSc internalization into MVBs. This work has uncovered principal features of prion propagation and spread, as well as unveiled the essential role of the ESCRT pathway in both synapse health and neurodegeneration.

      Cover page: Mechanisms of prion aggregate spread and synaptic toxicity.
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2024)
      Cancer treatment is associated with long lasting cognitive impairment in cancer survivors. This cognitive impairment is often termed cancer related cognitive impairment (CRCI). Cancer survivors treated for tumors outside the central nervous system are increasingly diagnosed with CRCI. The development of strategies to mitigate the negative effects of cancer treatment on the brain are crucial. Although neuroimaging research has proposed several candidate mechanisms, the pathogenic underpinnings of CRCI remain uncertain. As such, preventative and treatment strategies have not been identified. To fill these gaps, animal models play a vital role in isolating underlying contributing mechanisms that promote CRCI and in testing new therapeutic approaches.
        Cover page: Cancer related cognitive impairment: a downside of cancer treatment.
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2015)
        Despite advances in chemotherapy, radiotherapy and targeted drug development, cancer remains a disease of high morbidity and mortality. The treatment of human cancer patients with chemotherapy has become commonplace and accepted over the past 100 years. In recent years, and with a similar incidence of cancer to people, the use of cancer chemotherapy drugs in veterinary patients such as the dog has also become accepted clinical practice. The poor predictability of tumour responses to cancer chemotherapy drugs in rodent models means that the standard drug development pathway is costly, both in terms of money and time, leading to many drugs failing in Phase I and II clinical trials. This has led to the suggestion that naturally occurring cancers in pet dogs may offer an alternative model system to inform rational drug development in human oncology. In this review, we will explore the species variation in tumour responses to conventional chemotherapy and highlight our understanding of the differences in pharmacodynamics, pharmacokinetics and pharmacogenomics between humans and dogs. Finally, we explore the potential hurdles that need to be overcome to gain the greatest value from comparative oncology studies.
          Cover page: Species differences in tumour responses to cancer chemotherapy.
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2023)
          Cancer survivors experience cancer-related cognitive impairment (CRCI) secondary to treatment. Chemotherapy and radiation therapy independently contribute to cognitive dysfunction; however, the underlying mechanisms leading to dysfunction remain unclear. We characterized brain gene expression changes in a mouse model of CRCI to identify the mechanistic underpinnings. Eleven-to-twelve-week-old SKH1 mice were treated with doxorubicin (DOX), hindlimb radiation (RT), concurrent hindlimb radiation and doxorubicin (DOX-RT), or no treatment (control). Sixteen days following treatment, gene expression was measured from murine brains using the NanoString nCounter® glial profiling panel. Gene expression was normalized and compared between groups. No two groups shared the same expression pattern, and only Gnb1 and Srpr were upregulated in multiple treatment groups. Brains from DOX-treated mice had upregulated Atf2, Atp5b, Gnb1, Rad23b, and Srpr and downregulated Sirt5 expression compared to control brains. Brains from RT-treated mice demonstrated increased Abcg2 and Fgf2 and decreased C1qa and C1qb expression compared to control brains. Brains from DOX-RT-treated mice had upregulated Adar, E2f3, Erlec1, Gnb1, Srpr, Vim, and Pdgfra expression and downregulated Rock2 and Inpp5f expression compared to control brains. The gene expression changes demonstrated here highlight roles for neuronal transmission and oxidative stress in the pathogenesis of doxorubicin-related CRCI and inflammation in RT-related CRCI.
            Cover page: The Distant Molecular Effects on the Brain by Cancer Treatment.
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2018)
            Radiation therapy is critical for the control of many tumors and lung is an important dose-limiting organ that impacts radiation dose prescribed to avoid irreversible pulmonary fibrosis in cancer survivors. Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible lung disease caused by aberrantly activated lung (myo)fibroblasts. The presence of pro-fibrotic, apoptosis-resistant fibroblasts in IPF promotes progressive fibrosis and may have a role in other diseases, if these resistant cells are selected for as a consequence of treatment. However, the pathological response of IPF fibroblasts to radiation compared to non-IPF lung fibroblasts is not known. To address this, we examined fibroblast viability following radiation in lung fibroblasts from IPF and non-IPF patients and the underlying mechanism that protects IPF fibroblasts from radiation-induced death. IPF fibroblasts are significantly more resistant to apoptosis compared to non-IPF lung fibroblasts, suggesting that resistance to radiation-induced cell death is a predominant mechanism leading to lung fibrosis. Analysis of γH2AX induction demonstrated that radiation-induced DNA damage is reduced in IPF fibroblasts and correlates to the activation of the transcription factor forkhead box M1 (FoxM1) and subsequent upregulation of DNA repair proteins RAD51 and BRCA2. FoxM1 activation occurs secondary to FoxO3a suppression in IPF fibroblasts while restoration of FoxO3a function sensitizes IPF fibroblasts to radiation-induced cell death and downregulates FoxM1, RAD51, and BRCA2. Our findings support that increased FoxO3a/FoxM1-dependent DNA repair may be integral to the preservation of death-resistant fibrotic fibroblasts after radiation and that selective targeting of radioresistant fibroblasts may mitigate fibrosis.
              Cover page: FoxM1-dependent RAD51 and BRCA2 signaling protects idiopathic pulmonary fibrosis fibroblasts from radiation-induced cell death.
              • Article
              • Peer Reviewed
              UC Davis Previously Published Works (2018)
              Bolus is commonly used in radiation therapy to improve radiation dose distribution to the target volume, but commercially available products do not always conform well to the patient surface. Tumor control may be compromised, particularly for superficial tumors, if bolus does not conform well and air gaps exist between the patient surface and the bolus. Three-dimensional (3D) printing technology allows the creation of highly detailed, variable shaped objects, making it an attractive and affordable option for customized, patient-specific bolus creation. The use of 3D printing in the clinical setting remains limited. Therefore, the objective of this study was to assess the implications on time and clinical fit using a workflow for 3D printing of customized bolus in companion animals with spontaneous tumors treated with radiation therapy. The primary aim of this study was to evaluate the time required to create a clinical 3D printed bolus. The secondary aims were to evaluate the clinical fit of the bolus and to verify the skin surface dose. Time to segmentation and 3D printing were documented, while the clinical fit of the bolus was assessed in comparison to the bolus created in the treatment planner. The mean and median time from segmentation to generation of 3D printed boluses was 6.15 h and 5.25 h, respectively. The 3D printed bolus was significantly less deviated from the planned bolus compared to the conventional bolus (p = 0.0078) with measured dose under the bolus within 5% agreement of expected dose in 88% of the measurements. Clinically acceptable 3D printed customized bolus was successfully created for treatment within one working day. The most significant impact on time is the 3D printing itself, which therefore has minimal implications on personnel and staffing. Quality assurance steps are recommended when implementing a 3D printing workflow to the radiotherapy clinic.
                Cover page: Workload implications for clinic workflow with implementation of three-dimensional printed customized bolus for radiation therapy: A pilot study.
                • Article
                • Peer Reviewed
                UC Davis Previously Published Works (2020)
                There is no clear guideline regarding the indication for routine lymph node extirpation and pathologic evaluation during staging of canine oral tumors, despite a relatively high reported nodal metastatic rate for select tumor types. It is particularly unclear if clinicians recommend removal of lymph nodes only when there is confirmation of metastasis, defined as the N+ neck, or if elective neck dissection (END) is routinely recommended to confirm the true pathologic metastatic status of lymph nodes in the clinical N0 neck (no evidence of metastasis on clinical staging with diagnostic imaging or cytology). When clinicians are recommending END as a staging tool to confirm nodal status, there is also ambiguity regarding the surgical extent for subsequent histopathologic evaluation. The objective of this cross-sectional survey study was to determine the current recommendations given by practicing specialists regarding lymph node removal for dogs with oral tumors. Overall, 87 responses were obtained from 49 private practices (56%) and 38 academic institutions (44%). Respondents identified as oncologists (44%, N = 38), soft tissue surgeons (40%, N = 35), and dentists (16%, N = 14). Regardless of tumor type and stage, extirpation and histopathology were most commonly recommended in the clinical N+ neck only. The recommendation to routinely perform END in the N0 neck was significantly associated with tumor type. Bilateral removal of the mandibular and retropharyngeal lymph nodes was recommended more often for oral malignant melanoma (OMM) than for oral squamous cell carcinoma (OSCC; p ≤ 0.0039) or for oral fibrosarcoma (OFSA; p ≤ 0.0007). The likelihood of recommending END increased with increasing tumor size. Academic clinicians were significantly (p < 0.01) more likely to recommend END compared to private practitioners for canine T1-T3 OMM, T3 OSCC, T2 OFSA, and MCT. This study highlights the variability in recommendations for lymph node pathology for dogs with oral tumors. While tumor type and size influenced the decision to pursue END, it was not routinely recommended, even for tumor types with a known propensity for metastasis. Prospective studies are warranted to determine the potential diagnostic and therapeutic value of END in the N0 neck in veterinary patients such that a consensus approach can be made.
                  Cover page: Variability in Recommendations for Cervical Lymph Node Pathology for Staging of Canine Oral Neoplasia: A Survey Study.
                  • Article
                  • Peer Reviewed
                  UC Davis Previously Published Works (2016)
                  Optimal chemotherapy protocols for high-risk mast cell tumours (MCTs) are unknown. The purpose of this study was to determine the tolerability and toxicity profile of a rapidly escalating vinblastine and prednisolone protocol (VPP) in which 3.00 mg/m2 was administered once 7 days apart: at day 14 and at day 21. Dogs with chemotherapy-naïve MCTs presenting to the Oncology Service of a single institution were prospectively enrolled to receive escalating vinblastine, and haematology and a standardised quality-of-life questionnaire were assessed prior to each dosage. Thirty-four dogs were included: 30 with microscopic disease treated with adequate local therapy and four with macroscopic disease. Of 220 doses of vinblastine administered, 4% were associated with grade 3 and 4 toxicity. A total of 70% of dogs tolerated 3.00 mg/m2 given 7 days apart at day 14 and 21, although 29% of dogs developed dose-limiting toxicities and 8% discontinued the protocol due to toxicity. In conclusion, VPP was well-tolerated overall, although prior to further dose intensity optimisation, it is important to determine if dose intensity is linked to outcome in canine MCT to avoid unwarranted toxicity.
                    Cover page: Tolerability of a rapid-escalation vinblastine-prednisolone protocol in dogs with mast cell tumours.
                    • Article
                    • Peer Reviewed
                    UC Davis Previously Published Works (2024)
                    INTRODUCTION: Oral malignant melanoma (OMM) is the most common malignant oral neoplasm in dogs. Tumor recurrence, progression, and regional and distant metastasis remain major obstacles despite advanced therapy. Tumor size has been a consistent, key independent prognostic factor; however, other clinical and histopathologic features impact prognosis and likely influence optimal treatment strategies. Adoption of a risk stratification scheme for canine OMM that stratifies groups of dogs on defined clinicopathologic features may improve reproducible and comparable studies by improving homogeneity within groups of dogs. Moreover, it would aid in the generation of multidisciplinary prospective studies that seek to define optimal treatment paradigms based on defined clinicopathologic features. METHODS: To build a platform upon which to develop a risk stratification scheme, we performed a systematic review of clinicopathologic features of OMM, with particular attention to levels of evidence of published research and the quantitative prognostic effect of clinicopathologic features. RESULTS: Tumor size and presence of bone lysis were repeatable features with the highest level of evidence for prognostic effects on survival. Overall, with strict inclusion criteria for paper review, the levels of evidence in support of other, previously proposed risk factors were low. Factors contributing to the challenge of defining clear prognostic features including inconsistencies in staging and reporting of prognostic variables, incomplete clinical outcome data, inhomogeneous treatment, and absence of randomized controlled studies. DISCUSSION: To overcome this in the future, we propose a risk stratification scheme that expands the TNM system to incorporate specific designations that highlight possible prognostic variables. The ability to capture key data simply from an expanded TNM description will aid in future efforts to form strong conclusions regarding prognostic variables and their influence (or lack thereof) on therapeutic decision-making and outcomes.
                      Cover page: Risk stratification scheme based on the TNM staging system for dogs with oral malignant melanoma centered on clinicopathologic presentation.
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