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Open Access Publications from the University of California

Scholarly Works (10 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2017)

Apical periodontitis (AP) occurs as a result of bacterial infection of the root canal and subsequent inflammatory signaling at the periapex. The disease is exacerbated by oral bacterial byproducts, including lipopolysaccharide (LPS), that trigger inflammatory cytokine release and bone destruction. Our laboratory recently demonstrated that expression of KDM3C, a histone lysine demethylase, is induced by LPS exposure and that KDM3C regulates inflammatory cytokine expression. In the current study, we investigated the role of KDM3C in generation of AP in mice after pulp exposure. AP was induced in these mice by exposure of dental pulp of maxillary first molars of KDM3C knockout (KO) and wild-type (WT) mice, and apical lesion development was assessed by uCT analysis, Hematoxylin and Eosin (H&E) staining, and immunohistochemical (IHC) staining. Bone marrow-derived macrophages (BMDM) from WT and KO mice were exposed to LPS to assess the role of KDM3C in the regulation of inflammatory signaling. AP formation

occurred in mice 7 – 21 days post-pulp exposure, and the size of the AP lesion was notably increased in KDM3C KO mice when compared with the WT mice. H&E staining revealed strong infiltration of inflammatory cells to the periapex in KO mice, as well as

enrichment of macrophages when stained with F4/80 marker. Expression of inflammatory cytokines, e.g., IL-6, was significantly reduced in BMDM cultured from KDM3C KO mice. These findings indicate that KDM3C plays a critical role in immune response to oral bacterial infection in the root canal, and that loss of KDM3C compromises the inflammatory response and exacerbates development of AP.

    Cover page: The Role of KDM3C in Oral Inflammation
    • Thesis
    • Peer Reviewed
    UCLA Electronic Theses and Dissertations (2022)

    Aging is associated with a decline in innate and adaptive immune functions resulting in a weakened immune response against infection. Clinically, this decline in immune function leads to age-associated pathologies, including atherosclerosis, type II diabetes, dementia, obesity, and cancer systemically and prevalence of periapical bone loss the prevalence and severity of periodontitis orally. Previously, our lab identified an epigenetic marker KDM3C as a novel regulator of inflammatory signaling. In addition, we demonstrated that KDM3C regulate inflammatory signaling against oral bacterial infection through suppression of NK-κB signaling in macrophage (MΦ). In addition, our preliminary results showed KDM3C expression was inhibited in the aged mice compared to a younger cohort; thus, we hypothesize KDM3C is a key regulator for macrophage polarization during aging. In this project, we found that 1) old (18-20mo) mice had increase in apical bone loss and alveolar bone loss compared to young (2mo) mice following pulp exposure model (PE) and Ligature induced periodontitis model (LIP) respectively; 2) Kdm3c-/- mice revealed increased periapical bone loss compared to the Kdm3c+/+ mice upon PE. Similarly, Kdm3c-/- mice developed increased alveolar bone loss with ligature-induced periodontitis (LIP). 3) KDM3C deletion in mice resulted in increase in inflammatory cytokines levels in liver and spleen. Additionally, we characterize the KDM3C role in macrophage polarization. Here we found that, 1) Anti-inflammatory MΦ (M2) markers were significantly decreased in bone-marrow derived macrophages (BMDM) and in gingival tissue. 2) Histological staining of CD206 expression, a surface marker for M2, showed significant decrease in the positive staining of CD206 in Kdm3c-/- following LIP.

      Cover page: The Role of KDM3C in Oral and Systemic Inflammation During Aging
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2018)

      Background

      There is a lack of evidence for the association between intensive statin therapy and outcomes following vascular surgery. The aim of this study was to evaluate the association between perioperative statin intensity and in-hospital mortality following open abdominal aortic aneurysm (AAA) repair.

      Methods

      Patients undergoing open AAA repair between 2009 and 2015 were identified from the Premier Healthcare Database. Statin use was classified into low, moderate and high intensity, based on American College of Cardiology/American Heart Association guidelines. Supratherapeutic intensity was defined as doses higher than the recommended guidelines. Multivariable logistic regression analyses were undertaken to assess the association between statin intensity and postoperative major adverse events and in-hospital mortality.

      Results

      Of 6497 patients undergoing open AAA repair, 3217 (49·5 per cent) received perioperative statin. Statin users were more likely to present with three or more co-morbidities than non-users (26·5 versus 21·8 per cent; P < 0·001). Unadjusted postoperative mortality was significantly lower in statin users (2·6 versus 6·3 per cent; P < 0·001); however, there was no difference in the risk of developing major adverse events. Multivariable analysis showed that statin use was associated with lower odds of death (odds ratio 0·41, 95 per cent c.i. 0·31 to 0·54). Moderate, high and supratherapeutic statin intensities were not associated with lower odds of death or major adverse events compared with low-intensity statin therapy.

      Conclusion

      Statin use is associated with lower odds of death in hospital following open AAA repair. High-intensity statins were not associated with lower morbidity or mortality.
        Cover page: Statin intensity and postoperative mortality following open repair of intact abdominal aortic aneurysm
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2021)

        Objective

        Increasing evidence has shown that the risks associated with surgical revascularization for intermittent claudication outweigh the benefits. The aim of our study was to quantify the cost of care associated with perioperative complications after elective lower extremity bypass (LEB) in patients presenting with intermittent claudication.

        Methods

        All patients undergoing first-time LEB for claudication in the Healthcare Database (2009-2015) were included. The primary outcome was in-hospital postoperative complications, including major adverse limb events (MALE), major adverse cardiac events (MACE), acute kidney injury, and wound complications. The overall crude hospital costs are reported, and a generalized linear model with log link and inverse Gaussian distribution was used to calculate the predicted hospital costs for specific complications.

        Results

        Overall, 7154 patients had undergone elective LEB for claudication during the study period. The median age was 66 years (interquartile range, 59-73 years), 67.5% were male, and 75.3% were white. Two thirds of patients (61.2%) had Medicare insurance, followed by private insurance (26.9%), Medicaid (7.7%), and other insurance (4.2%). In-hospital complications occurred in 8.5% of patients, including acute kidney injury in 3.0%, MALE in 2.8%, wound complications in 2.3%, and MACE in 1.0%. The overall median crude hospital cost was $11,783 (interquartile range, $8911-$15,767) per patient. The incremental increase in cost associated with a postoperative complication was significant, ranging from $6183 (95% confidence interval, $4604-$7762) for MALE to $10,485 (95% confidence interval, $6529-$14,441) for MACE after risk adjustment.

        Conclusions

        Postoperative complications after elective LEB for claudication are not uncommon and increase the in-hospital costs by 46% to 78% depending on the complication. Surgical revascularization for claudication should be used sparingly in carefully selected patients.
          Cover page: Quantifying the risk-adjusted hospital costs of postoperative complications after lower extremity bypass in patients with claudication
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2021)

          Introduction

          Racial disparities in diagnosis, treatment and survival in Black patients with Parkinson's disease (PD) compared to White patients have not been well studied, largely due to limited number of studies and information on Black patients in healthcare systems. Studying racial disparities and identifying underlying factors in large populations are important to understand PD and improve care.

          Methods

          We retrospectively identified PD patients on both races from 1/1/2006 to 10/31/2017 and compared demographics, socioeconomic status (educations, incomes and insurances), comorbidities (all categories, including mood, cognition and psychosis), treatment (medications for parkinsonism and major non-motor symptoms, and frequency and locations of healthcare) and survival, and identified factors associated with medication usage and survival.

          Results

          We retrospectively studied 2033 PD patients, of whom 725 were Black. Black patients lacked male predominance, were 4 years older at first diagnosis here, more likely to smoke and live in a low education and income community, and possessed limited insurances compared to White patients. Black patients also had more comorbidities and were more likely to receive care through emergency or inpatient service, but less likely to be on medications for parkinsonism and mood disorders. Race, age, smoking status, insurance type, frequency and locations of healthcare and comorbidities were associated with medication usage. Black race, older age, inpatient admission and malignancy were associated with increased risk of death.

          Conclusion

          We revealed racial disparities in diagnosis, treatment and survival, and factors associated with medication usage and survival in the largest reported Black PD cohort from a single center.
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2018)
            High-risk human papillomavirus (HPV) is a major risk factor for oral and pharyngeal cancers (OPCs), yet the detailed mechanisms by which HPV promotes OPCs are not understood. Forkhead box M1B (FoxM1B) is an oncogene essential for cell cycle progression and tumorigenesis, and it is aberrantly overexpressed in many tumors. We previously showed that FoxM1B was the putative target of an epithelial-specific transcription factor, Grainyhead-like 2 (GRHL2). In the current study, we demonstrate that HPV type 16 (HPV-16) E6 induces FoxM1B in human oral keratinocytes (HOKs) and tonsillar epithelial cells (TECs) in part through GRHL2. FoxM1B was barely detectable in cultured normal human oral keratinocytes (NHOKs) and progressively increased in immortalized HOKs harboring HPV-16 genome (HOK-16B) and tumorigenic HOK-16B/BaP-T cells. Retroviral expression of HPV-16 E6 and/or E7 in NHOKs, TECs, and hypopharyngeal carcinoma cells (FaDu) revealed induction of FoxM1B and GRHL2 by the E6 protein but not E7. Both GRHL2 and FoxM1B were strongly induced in the epidermis of HPV-16 E6 transgenic mice and HPV+ oral squamous cell carcinomas. Ectopic expression of FoxM1B led to acquisition of transformed phenotype in HOK-16B cells. Loss of FoxM1B by lentiviral short hairpin RNA vector or chemical inhibitor led to elimination of tumorigenic characteristics of HOK-16B/BaP-T cells. Luciferase reporter assay revealed that GRHL2 directly bound and regulated the FoxM1B gene promoter activity. Using epithelial-specific Grhl2 conditional knockout mice, we exposed wild-type (WT) and Grhl2 KO mice to 4-nitroquinolin 1-oxide (4-NQO), which led to induction of FoxM1B in the tongue tissues and rampant oral tumor development in the WT mice. However, 4-NQO exposure failed to induce tongue tumors or induction of FoxM1B expression in Grhl2 KO mice. Collectively, these results indicate that HPV-16 induces FoxM1B in part through GRHL2 transcriptional activity and that elevated FoxM1B level is required for oropharyngeal cancer development.
              Cover page: Human Papillomavirus 16 E6 Induces FoxM1B in Oral Keratinocytes through GRHL2
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2019)
              Oral mucosa provides the first line of defense against a diverse array of environmental and microbial irritants by forming the barrier of epithelial cells interconnected by multiprotein tight junctions (TJ), adherens junctions, desmosomes, and gap junction complexes. Grainyhead-like 2 (GRHL2), an epithelial-specific transcription factor, may play a role in the formation of the mucosal epithelial barrier, as it regulates the expression of the junction proteins. The current study investigated the role of GRHL2 in the Porphyromonas gingivalis (Pg)-induced impairment of epithelial barrier functions. Exposure of human oral keratinocytes (HOK-16B and OKF6 cells) to Pg or Pg-derived lipopolysaccharides (Pg LPSs) led to rapid loss of endogenous GRHL2 and the junction proteins (e.g., zonula occludens, E-cadherin, claudins, and occludin). GRHL2 directly regulated the expression levels of the junction proteins and the epithelial permeability for small molecules (e.g., dextrans and Pg bacteria). To explore the functional role of GRHL2 in oral mucosal barrier, we used a Grhl2 conditional knockout (KO) mouse model, which allows for epithelial tissue-specific Grhl2 KO in an inducible manner. Grhl2 KO impaired the expression of the junction proteins at the junctional epithelium and increased the alveolar bone loss in the ligature-induced periodontitis model. Fluorescence in situ hybridization revealed increased epithelial penetration of oral bacteria in Grhl2 KO mice compared with the wild-type mice. Also, blood loadings of oral bacteria (e.g., Bacteroides, Bacillus, Firmicutes, β-proteobacteria, and Spirochetes) were significantly elevated in Grhl2 KO mice compared to the wild-type littermates. These data indicate that Pg bacteria may enhance paracellular penetration through oral mucosa in part by targeting the expression of GRHL2 in the oral epithelial cells, which then impairs the epithelial barrier by inhibition of junction protein expression, resulting in increased alveolar tissue destruction and systemic bacteremia.
                Cover page: Porphyromonas gingivalis Impairs Oral Epithelial Barrier through Targeting GRHL2
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2016)

                Introduction

                Surgical interventions such as tooth extraction increase the chances of developing osteonecrosis of the jaw in patients receiving bisphosphonates (BPs) for the treatment of bone-related diseases. Tooth extraction is often performed to eliminate preexisting pathological inflammatory conditions that make the tooth unsalvageable; however, the role of such conditions on bisphosphonate-related osteonecrosis of the jaw (BRONJ) development after tooth extraction is not clearly defined. Here, we examined the effects of periapical periodontitis on tooth extraction-induced BRONJ development in mice.

                Methods

                Periapical periodontitis was induced by exposing the pulp of the maxillary first molar for 3 weeks in C57/BL6 mice that were intravenously administered with BPs. The same tooth was extracted, and after an 3 additional weeks, the mice were harvested for histologic, histomorphometric, and histochemical staining analyses.

                Results

                Pulp exposure induced periapical radiolucency as shown by increased inflammatory cells, tartrate-resistant acid phosphatase-positive osteoclasts, and bone resorption. When BPs were administered, pulp exposure did not induce apical bone resorption despite the presence of inflammatory cells and tartrate-resistant acid phosphatase-positive osteoclasts. Although tooth extraction alone induced BRONJ lesions, pulp exposure further increased tooth extraction-induced BRONJ development as shown by the presence of more bone necrosis.

                Conclusions

                Our study demonstrates that a preexisting pathological inflammatory condition such as periapical periodontitis is a predisposing factor that may exacerbate BRONJ development after tooth extraction. Our study further provides a clinical implication wherein periapical periodontitis should be controlled before performing tooth extraction in BP users in order to reduce the risk of developing BRONJ.
                  Cover page: Preexisting Periapical Inflammatory Condition Exacerbates Tooth Extraction-induced Bisphosphonate-related Osteonecrosis of&nbsp;the&nbsp;Jaw&nbsp;Lesions in Mice.
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2018)
                  Grainyhead-Like 2 (GRHL2) is an epithelial-specific transcription factor that regulates epithelial morphogenesis and differentiation. Prior studies suggested inverse regulation between GRHL2 and TGF-β in epithelial plasticity and potential carcinogenesis. Here, we report the role of GRHL2 in oral carcinogenesis in vivo using a novel Grhl2 knockout (KO) mouse model and the underlying mechanism involving its functional interaction with TGF-β signaling. We developed epithelial-specific Grhl2 conditional KO mice by crossing Grhl2 floxed mice with those expressing CreER driven by the K14 promoter. After induction of Grhl2 KO, we confirmed the loss of GRHL2 and its target proteins, while Grhl2 KO strongly induced TGF-β signaling molecules. When exposed to 4-nitroquinoline 1-oxide (4-NQO), a strong chemical carcinogen, Grhl2 wild-type (WT) mice developed rampant oral tongue tumors, while Grhl2 KO mice completely abolished tumor development. In cultured oral squamous cell carcinoma (OSCC) cell lines, TGF-β signaling was notably induced by GRHL2 knockdown while being suppressed by GRHL2 overexpression. GRHL2 knockdown or KO in vitro and in vivo, respectively, led to loss of active p-Erk1/2 and p-JNK MAP kinase levels; moreover, ectopic overexpression of GRHL2 strongly induced the MAP kinase activation. Furthermore, the suppressive effect of GRHL2 on TGF-β signaling was diminished in cells exposed to Erk and JNK inhibitors. These data indicate that GRHL2 activates the Erk and JNK MAP kinases, which in turn suppresses the TGF -β signaling. This novel signaling represents an alternative pathway by which GRHL2 regulates carcinogenesis, and is distinct from the direct transcriptional regulation by GRHL2 binding at its target gene promoters, e.g., E-cadherin, hTERT, p63, and miR-200 family genes. Taken together, the current study provides the first genetic evidence to support the role of GRHL2 in carcinogenesis and the underlying novel mechanism that involves the functional interaction between GRHL2 and TGF-β signaling through the MAPK pathways.
                    Cover page: Grainyhead-like 2 (GRHL2) knockout abolishes oral cancer development through reciprocal regulation of the MAP kinase and TGF-β signaling pathways
                    • Article
                    • Peer Reviewed
                    UC San Diego Previously Published Works (2022)

                    Background

                    This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic.

                    Methods

                    CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality.

                    Results

                    This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121).

                    Conclusion

                    CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic.
                      Cover page: Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)
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