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Open Access Publications from the University of California

Scholarly Works (19 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2019)

Background: Pancreatic cancer is a highly lethal malignancy that is often diagnosed at advanced stages where treatment options are limited and prognosis is poor. As the immune system is intricately involved in the detection, elimination, and initiation of cancer, there has been major interest in understanding the role of immune dysregulation in the development of pancreatic cancer. Conditions associated with immune overactivity (e.g. allergies), chronic inflammation (e.g. type 2 diabetes, metabolic syndrome) and the epigenetic modification of immune genes (e.g. cytokines) may perhaps provide insight into the underlying mechanisms of pancreatic carcinogenesis. Past retrospective epidemiological studies have observed inverse associations between allergies and pancreatic cancer risk, but this finding has not been detected in prospective studies. In addition, the relationship between type 2 diabetes onset and pancreatic cancer risk has not been well explored in racially/ethnically diverse populations. Metabolic profiles of diabetes patients and pancreatic cancer risk have similarly not been evaluated in non-white individuals. Finally, there is limited literature on the influence of methylation in cytokine genes and pancreatic cancer progression.

Objectives and Specific Aims: The objective of this dissertation is to further elucidate the influence of atopic allergic conditions, type 2 diabetes, and methylation of cytokine genes on pancreatic cancer risk and survival. The specific aims were: 1) to conduct a prospective analysis of atopic allergic conditions (AACs) and the treatment of these conditions on pancreatic cancer risk in a multiethnic population; 2) to investigate the association between type 2 diabetes onset and pancreatic cancer risk in a racially diverse patient-based cohort, and to establish a metabolic profile of diabetes patients who are at high risk of developing pancreatic cancer; and 3) to evaluate the relationship between the methylation of cytokine genes in pancreatic cancer tumors and overall survival.

Methods: For specific aim 1, we analyzed prospective data from 187,266 participants from the Multiethnic Cohort (MEC). Information on AACs and antihistamine medication use was assessed via a baseline questionnaire when individuals joined the MEC in 1993-1996. Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for pancreatic cancer incidence by AACs and antihistamines were estimated using Cox regression models, adjusting for age, sex, ethnicity, education, smoking status, family history of pancreatic cancer, body mass index, diabetes, and alcohol intake. We further evaluated associations among subgroups defined by age, sex, ethnicity, follow-up time, and known pancreatic cancer risk factors. For specific aim 2, we conducted a retrospective cohort study of 1,499,627 patients from Kaiser Permanente Southern California (KPSC) from 2006-2016. Diabetes patients were identified using glucose and hemoglobin A1c (HbA1c) measurements based on diagnostic criteria by the American Diabetes Association (ADA). We used Cox regression with time-varying exposures to assess the relationship between diabetes status/duration and pancreatic cancer. For individuals with incident diabetes, we evaluated longitudinal changes in glucose, HbA1c and weight measurements leading up to the diabetes diagnosis between those with and without pancreatic cancer. We further performed Cox proportional hazards regression to examine the associations between the percent differences in glucose, HbA1c and weight and pancreatic cancer risk. All models included gender, race/ethnicity, smoking, BMI, alcohol use, family history of pancreatic cancer, history of pancreatitis, and education as covariates. For specific aim 3, we performed a retrospective cohort study of 162 pancreatic cancer patients from The Cancer Genome Atlas (TCGA). We evaluated methylation on CpG probes in proximity to seven genes: IL10, IL6, IL8, TGFβ1, TGFβ2, TGFβ3, and TNF. Methylation was assessed using the Illumina Infinium HumanMethylation450 (HM450) BeadChip methylation assay. We used Cox proportional hazards regression to evaluate the relationship between site- and region-specific DNA methylation and pancreatic cancer survival, adjusting for age, gender, stage and five independent surrogate variables associated with potential confounders measured with error (smoking, receipt of radiation, sample plate). We assessed the relationship between methylation at each given site/region and the expression of the gene in closest proximity using the Spearman’s correlation coefficient.

Results: For specific aim 1, 1,455 incident cases of pancreatic cancer were identified among the white, African American, Latino, Japanese American and Native Hawaiian participants of the MEC with an average 16-year follow-up. AACs (relative risk/risk ratio [RR] 1.00, 95% CI 0.88-1.12) and antihistamines (RR 0.92, 95% CI 0.78-1.07) were not clearly associated with pancreatic cancer incidence. While these associations were also null for most subgroups, we did observe inverse associations of AACs (RR 0.74, 95% CI 0.56-0.98) and antihistamines (RR 0.66, 95% CI 0.45-0.96) among the oldest participants (70+). For specific aim 2, we identified 2,002 incident cases of pancreatic cancer among the white, African American, Latino and Asian members of KPSC with 7.5 million person-years of follow-up. Compared to those without diabetes, individuals with incident diabetes and shorter diabetes durations (≤1 year: RR 6.91, 95% CI 5.76-8.30; >1 year: RR 1.96, 95% CI 1.62-2.38) had the highest risk of pancreatic cancer. Among incident diabetes patients, those with pancreatic cancer had steeper increases of glucose, HbA1c and greater weight loss during the time prior to diabetes. Racial/ethnic differences in metabolic changes by pancreatic cancer status were observed, with more pronounced differences in Asians and blacks for glucose, in blacks and whites for HbA1c, and in Asians and whites for weight (p-values for heterogeneity ≤0.01). For specific aim 3, we observed poorer survival for increased methylation in several CpG probes in TGFβ1 (cg03313751: hazard ratio [HR] 1.62, 95% CI 1.14-2.31), TGFβ2 (cg16658719: HR 1.58, 95% CI 1.21-2.06), TGFβ3 (cg16292972: HR 1.45, 95% CI 1.01-2.09) and IL6 (cg15703690: HR 1.03, 95% CI 1.00-1.05), specifically those near transcription start sites. Conversely, higher methylation in one CpG locus in IL10 (cg14789529: HR 0.97, 95% CI 0.94-1.00) was associated with increased survival.

Conclusions: Our study provides additional evidence of the intricate relationships between immune dysregulation and pancreatic cancer risk and progression. The findings for atopic allergic conditions support the null association for pancreatic cancer observed in prior prospective cohorts. Moreover, increased pancreatic cancer risk for new-onset diabetes is observed among racial/ethnic minorities, while the metabolic profiles for incident diabetes patients appear to vary by pancreatic cancer status and race/ethnicity. Lastly, epigenetic alterations and regulation of cytokine-related gene expression may be involved in the progression of pancreatic cancer.

    Cover page: Immune Dysregulation and Pancreatic Cancer: Overactivity, Inflammation and Epigenetic Modifications of Immune Function
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2016)
    One of the most important issues facing cartilage tissue engineering is the inability to move technologies into the clinic. Despite the multitude of current research in the field, it is known that 90% of new drugs that advance past animal studies fail clinical trials. The objective of this review is to provide readers with an understanding of the scientific details of tissue engineered cartilage products that have demonstrated a certain level of efficacy in humans, so that newer technologies may be developed upon this foundation. Compared to existing treatments, such as microfracture or autologous chondrocyte implantation, a tissue engineered product can potentially provide more consistent clinical results in forming hyaline repair tissue and in filling the entirety of the defect. The various tissue engineering strategies (e.g., cell expansion, scaffold material, media formulations, biomimetic stimuli, etc.) used in forming these products, as collected from published literature, company websites, and relevant patents, are critically discussed. The authors note that many details about these products remain proprietary, not all information is made public, and that advancements to the products are continuously made. Nevertheless, by understanding the design and production processes of these emerging technologies, one can gain tremendous insight into how to best use them and also how to design the next generation of tissue engineered cartilage products.
      Cover page: Cell-based tissue engineering strategies used in the clinical repair of articular cartilage
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2015)
      Mouse models have demonstrated utility in delineating the mechanisms underlying many aspects of malaria immunology and physiology. The most common mouse models of malaria employ the rodent-specific parasite species Plasmodium berghei, P. yoelii, and P. chabaudi, which elicit distinct pathologies and immune responses and are used to model different manifestations of human disease. In vitro culture methods are not well developed for rodent Plasmodium parasites, which thus require in vivo maintenance. Moreover, physiologically relevant immunological processes are best studied in vivo. Here, we detail the processes of infecting mice with Plasmodium, maintaining the parasite in vivo, and monitoring parasite levels and health parameters throughout infection.
        • Thesis
        • Peer Reviewed
        UCLA Electronic Theses and Dissertations (2024)

        Background: Colorectal cancer (CRC) remains a significant global health challenge, influenced by both dietary factors and genetic predispositions. Dairy/milk consumption has been suggested to be involved in CRC pathogenesis, yet the underlying mechanisms, particularly in ethnically diverse populations, remain poorly understood. This research aims to unravel the complex relationships between dairy/milk consumption, genetic polymorphisms related to dairy/milk digestion, and the influence of circulating proteins on CRC risk and progression.

        Objectives and Specific Aims: The study aims to: 1) Assess the association between dairy/milk intake (including lactose, calcium, and vitamin D) and CRC incidence and mortality across race/ethnicity; 2) Investigate the associations between genetic polymorphisms in LCT, MCM6, CASR, and VDR genes and CRC risk, including gene-diet interactions; 3) Explore the causal relationship between circulating proteins and CRC risk.

        Methods: Data from the Multiethnic Cohort study, involving 215,634 participants, were analyzed for dietary associations. Genetic analyses involved candidate SNPs on a sub-cohort of 70,000 participants. Proteomic Mendelian Randomization (MR) analyses leveraged summary-level statistics from various GWAS studies.

        Results: Higher consumption of dairy/milk and their key components was linked to a 13-17% reduced CRC risk. There was a weak association between dairy/milk intake and mortality among CRC patients. While no evident racial/ethnic heterogeneity was observed in incidence, significant differences were noted across racial/ethnic groups in mortality. No interaction was found between dairy/milk consumption and lactase persistence status. Several SNPs within LCT, MCM6, CASR, and VDR were associated with CRC risk across the different racial/ethnic groups. Elevated genetically determined lactase-phlorizin hydrolase levels were inversely associated with CRC risk. Four unique proteins (GREM1, LPH, PDE5A, LIMA1) were associated with CRC risk in the cis-MR analyses, while 15 additional proteins were identified in the analyses using all (cis+trans) protein quantitative trait loci.

        Conclusions: This study highlights the protective effects of dairy/milk intake against CRC risk, the genetic factors influencing CRC susceptibility, and the potential role of circulating proteins in CRC carcinogenesis. These findings emphasize the importance of race/ethnicity-specific dietary guidelines and genetic risk stratification in CRC prevention, suggesting targeted public health interventions for effective CRC management.

          Cover page: Dairy and Milk Intake, Genetic Predispositions, and Circulating Proteins: Unveiling the Multifaceted Landscape of Colorectal Cancer Risk and Progression
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2016)

          Unlabelled

          Chondrocyte dedifferentiation presents a major barrier in engineering functional cartilage constructs. To mitigate the effects of dedifferentiation, this study employed a post-expansion aggregate culture step to enhance the chondrogenic phenotype of passaged articular chondrocytes (ACs) before their integration into self-assembled neocartilage constructs. The objective was twofold: (1) to explore how passage number (P2, P3, P4, P5, P6, and P7), with or without aggregate culture, affected construct properties; and (2) to determine the highest passage number that could form neocartilage with functional properties. Juvenile leporine ACs were passaged to P2-P7, with or without aggregate culture, and self-assembled into 5mm discs in non-adhesive agarose molds without using any exogenous scaffolds. Construct biochemical and biomechanical properties were assessed. With aggregate culture, neocartilage constructs had significantly higher collagen content, higher tensile properties, and flatter morphologies. These beneficial effects were most obvious at higher passage numbers. Specifically, collagen content, Young's modulus, and instantaneous compressive modulus in the P7, aggregate group were 53%, 116%, and 178% higher than those in the P7, non-aggregate group. Most interestingly, these extensively passaged P7 ACs (expansion factor of 85,000), which are typically highly dedifferentiated, were able to form constructs with properties similar to or higher than those formed by lower passage number cells. This study not only demonstrated that post-expansion aggregate culture could significantly improve the properties of self-assembled neocartilage, but also that chondrocytes of exceedingly high passage numbers, expanded using the methods in this study, could be used in cartilage engineering applications.

          Statement of significance

          This work demonstrated that extensively passaged chondrocytes (up to passage 7 (P7); expansion factor of 85,000) could potentially be used for cartilage tissue engineering applications. Specifically, an aggregate culture step, employed after cell expansion and before cell integration into a neocartilage construct, was shown to enhance the ability of the chondrocytes to form neocartilage with better biochemical and biomechanical properties. The beneficial effects of this aggregate culture step was especially noticeable at the high passage numbers. Most interestingly, P7 chondrocytes, which are typically highly dedifferentiated, were able to form neocartilage with properties similar to or higher than those formed by lower passage number cells. The ability to obtain high chondrocyte yields with an enhanced chondrogenic potential could have a broad, beneficial impact in improving current therapies (e.g., using higher cell seeding densities for repair) or developing new strategies that require high cell numbers, such as a scaffold-free approach in forming engineered cartilage.
            Cover page: Effects of passage number and post-expansion aggregate culture on tissue engineered, self-assembled neocartilage
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2017)
            Recent work has established methods to engineer self-assembled, scaffold-free neocartilage from an expanded articular chondrocyte (AC) cell source. In continuing such work, the objective of the present study was to investigate the effects of cell-seeding density and dexamethasone concentration on these neocartilage constructs. Neocartilage discs (5 mm diameter) were formed by self-assembling passaged leporine articular chondrocytes into non-adherent agarose moulds. The cell-seeding densities (2, 3, 4, 5 and 6 million cells/construct) and dexamethasone concentrations (10 and 100 nm) in the culture medium were varied in a full-factorial study. After 4 weeks, the neocartilage constructs were assessed for morphological, biochemical and biomechanical properties. The cell-seeding density profoundly affected neocartilage properties. The two dexamethasone concentrations explored did not induce overall significant differences. Constructs formed using lower cell-seeding densities possessed much higher biochemical and biomechanical properties than constructs seeded with higher cell densities. Notably, the 2 million cells/construct group formed hyaline-like neocartilage with a collagen wet weight (WW) content of ~7% and a Young's modulus of ~4 MPa, representing the high end of values achieved in self-assembled neocartilage. Excitingly, the mechanical properties of these constructs were on a par with that of native cartilage tissues tested under similar conditions. Through optimization of cell-seeding density, this study shows for the first time the use of expanded ACs to form homogeneous self-assembled neocartilage with exceptionally high tensile strength. With such functional properties, these engineered neocartilage constructs provide a promising alternative for treating articular lesions. Copyright © 2016 John Wiley & Sons, Ltd.
              Cover page: Engineering biomechanically functional neocartilage derived from expanded articular chondrocytes through the manipulation of cell‐seeding density and dexamethasone concentration
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2018)

              Background

              Although advanced pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive weight loss and nutritional deterioration, the effect of cancer cachexia and body mass index (BMI) at diagnosis on survival remains unclear.

              Methods

              We retrospectively evaluated a prospectively collected internal cancer registry of PDAC cases from 2006-2014 at the Kaiser Permanente Medical Center. Cancer cachexia was defined as weight loss greater than 5% over the 6 months prior to diagnosis. Multivariate cox proportional hazards regression was used to assess the influence of cachexia on survival. To evaluate effect measure modification of this relationship, we performed additional analyses stratified by race, BMI class, stage, receipt of surgery and receipt of chemotherapy. We tested for heterogeneity by fitting models with an interaction term for cachexia and the modifying variable.

              Results

              Of the 977 patients, 611 (63%) were identified with cachexia. Cachexia in PDAC patients was prevalent across all stages of disease and BMI classes. Patients with cachexia had lower survival (median 4.3 months, IQR 1.7-10.0) compared to those without cachexia (median 5.2 months, IQR 2.0-10.6), log-rank P=0.03. In this analysis BMI at diagnosis was not associated with survival. In the multivariate Cox regression, cachexia was independently associated with decreased overall survival (HR 1.24, CI: 1.06-1.45, P=0.01). However, the effect of cachexia on survival outcomes was modified by receipt of chemotherapy. Cachectic patients who did not receive chemotherapy had a 40% increase in risk of death compared to non-cachectic patients (HR 1.40, CI: 1.12-1.75), while those receiving chemotherapy were unaffected by cachexia (HR 1.04, CI: 0.82-1.32, Pinteraction=0.01).

              Conclusions

              In the largest cohort of pancreatic cancer patients examined to date, cachexia and not obesity is independently associated with worse survival in PDA and its effect is negated by systemic chemotherapy.
                Cover page: Cachexia, and not obesity, prior to pancreatic cancer diagnosis worsens survival and is negated by chemotherapy
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2021)
                Despite the prevalence of large (>5 cm2) articular cartilage defects involving underlying bone, current tissue-engineered therapies only address small defects. Tissue-engineered, anatomically shaped, native-like implants may address the need for off-the-shelf, tissue-repairing therapies for large cartilage lesions. This study fabricated an osteochondral construct of translationally relevant geometry with robust functional properties. Scaffold-free, self-assembled neocartilage served as the chondral phase, and porous hydroxyapatite served as the osseous phase of the osteochondral constructs. Constructs in the shape and size of an ovine femoral condyle (31 × 14 mm) were assembled at day 4 (early) or day 10 (late) of neocartilage maturation. Early osteochondral assembly increased the interfacial interdigitation depth by 244%, interdigitation frequency by 438%, interfacial shear modulus by 243-fold, and ultimate interfacial shear strength by 4.9-fold, compared to late assembly. Toward the development of a bioprosthesis for the repair of cartilage lesions encompassing up to an entire condylar surface, this study generated a large, anatomically shaped osteochondral construct with robust interfacial mechanical properties and native-like neocartilage interdigitation.
                  Cover page: Engineering large, anatomically shaped osteochondral constructs with robust interfacial shear properties
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2024)
                  Previous research has found that milk is associated with a decreased risk of colorectal cancer (CRC). However, it is unclear whether the milk digestion by the enzyme lactase-phlorizin hydrolase (LPH) plays a role in CRC susceptibility. Our study aims to investigate the direct causal relationship of CRC risk with LPH levels by applying a two-sample Mendelian Randomization (MR) strategy. Genetic instruments for LPH were derived from the Fenland Study, and CRC-associated summary statistics for these instruments were extracted from the FinnGen Study, PLCO Atlas Project, and Pan-UK Biobank. Primary MR analyses focused on a cis-variant (rs4988235) for LPH levels, with results integrated via meta-analysis. MR analyses using all variants were also undertaken. This analytical approach was further extended to assess CRC subtypes (colon and rectal). Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH levels and CRC risk (OR: 0.92 [95% CI, 0.89-0.95]). Subtype analyses revealed associations of elevated LPH levels with reduced risks for both colon (OR: 0.92 [95% CI, 0.89-0.96]) and rectal cancer (OR: 0.92 [95% CI, 0.87, 0.98]). Consistency was observed across varied analytical methods and datasets. Further exploration is warranted to unveil the underlying mechanisms and validate LPHs potential role in CRC prevention.
                    Cover page: Genetically Determined Circulating Lactase/Phlorizin Hydrolase Concentrations and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study.
                    • Article
                    • Peer Reviewed
                    UC Davis Previously Published Works (2015)
                    Toward developing engineered cartilage for the treatment of cartilage defects, achieving relevant functional properties before implantation remains a significant challenge. Various chemical and mechanical stimuli have been used to enhance the functional properties of engineered musculoskeletal tissues. Recently, Ca(2+)-modulating agents have been used to enhance matrix synthesis and biomechanical properties of engineered cartilage. The objective of this study was to determine whether other known Ca(2+) modulators, digoxin and adenosine triphosphate (ATP), can be employed as novel stimuli to increase collagen synthesis and functional properties of engineered cartilage. Neocartilage constructs were formed by scaffold-free self-assembling of primary bovine articular chondrocytes. Digoxin, ATP, or both agents were added to the culture medium for 1 h/day on days 10-14. After 4 weeks of culture, neocartilage properties were assessed for gross morphology, biochemical composition, and biomechanical properties. Digoxin and ATP were found to increase neocartilage collagen content by 52-110% over untreated controls, while maintaining proteoglycan content near native tissue values. Furthermore, digoxin and ATP increased the tensile modulus by 280% and 180%, respectively, while the application of both agents increased the modulus by 380%. The trends in tensile properties were found to correlate with the amount of collagen cross-linking. Live Ca(2+) imaging experiments revealed that both digoxin and ATP were able to increase Ca(2+) oscillations in monolayer-cultured chondrocytes. This study provides a novel approach toward directing neocartilage maturation and enhancing its functional properties using novel Ca(2+) modulators.
                      Cover page: Digoxin and adenosine triphosphate enhance the functional properties of tissue-engineered cartilage.
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