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Identification of Mitotic Phosphatases and Cyclin K as Novel Molecular Targets in Pancreatic Cancer
No full textPancreatic cancer is a highly lethal disease worldwide. Given the limited effectiveness of current regimens in restricting tumor progression, it is imperative that potential molecular targets be identified to offer valuable insights into alternative therapeutics. By using a phosphate-binding tag (Phos-tag) technique, previous studies have identified several Hippo pathway-related proteins and kinases required for cancer growth or paclitaxel resistance. This work has screened various phosphatases and cyclins/cyclin-dependent kinases (CDKs) as potential cancer targets, but specifically focuses on characterizing the roles of carboxy-terminal domain small phosphatase like 2 (CTDSPL2), apoptosis-stimulating protein of p53-2 (ASPP2), and Cyclin K in pancreatic cancer.
CTDSPL2 belongs to the small CTD phosphatase family and harbors phosphatase activity toward CTD of RNA polymerase II. The role of CTDSPL2 in cancer remains unclear. Our study demonstrates that CTDSPL2 is required for pancreatic cancer cell mitosis, proliferation, and motility. Furthermore, a CDK1-mediated phosphorylation mechanism of CTDSPL2 in mitosis is revealed.
ASPP2 belongs to the ASPP family of p53 interacting proteins. It also serves as a regulatory subunit of protein phosphatase 1 (PP1). While ASPP2 is widely accepted as a tumor suppressor, ASPP2-PP1 complex activates oncogenic yes-associated protein (YAP). These contradictory findings lead us to interrogate the role of ASPP2 in cancer. We find that ASPP2 is essential for pancreatic cancer growth, and YAP is the central player for ASPP2-mediated gene expression. Additionally, the phosphorylation mechanism of ASPP2 during mitosis is investigated.
Cyclin K, the regulatory subunit of CDK12 and CDK13, regulates phosphorylation of CTD and controls the transcription of genes involved in the DNA damage response, DNA replication, and cancer signaling transduction. Nevertheless, the role of Cyclin K in pancreatic cancer is unknown. This work finds that Cyclin K depletion contributes to attenuated pancreatic cancer growth (or tumor regression) in different animal models. With current Cyclin K-degrading drugs, the druggability of Cyclin K and therapeutic potential are examined.
In conclusion, studies in this dissertation characterize the functions and regulations of CTDSPL2, ASPP2, and Cyclin K in pancreatic cancer, providing promising targets for future therapeutic interventions
Cis-Regulatory Mechanisms through Stages of Erythroid Regenration
No full textProduced by steady state erythropoiesis, erythrocytes serve as vital regulators of metabolism and life by delivering oxygen to all the cells and tissues. Under acute anemia, steady state erythropoiesis is not sufficient to produce enough erythrocytes, leading to distinct mechanisms needed to regenerate large numbers of mature erythrocytes rapidly. Erythroid regeneration occurs in four stages: activation, expansion and differentiation, resolution, and post-resolution, according to the dynamics of erythrocyte numbers and progenitor activity. Erythroid regeneration throughout this timeline requires some critical extracellular cues, but the intrinsic molecular mechanisms needed to accelerate and decelerate the activity of erythroid progenitors in anemia and recovery are poorly understood. Unraveling the key transcription factors (TFs) and transcriptional mechanisms can reveal important fundamental principles of regenerative processes and relate it to disease states like chronic anemia and leukemia.
During erythroid regeneration, broad transcriptional changes are found in erythroid progenitors and precursors. Prior work revealed that an erythropoiesis-promoting cis-regulatory element (CRE) controlled by erythroid TFs GATA1/2 and TAL1 increases transcription of the Samd14 gene during erythroid regeneration, thereby accelerating erythropoiesis in anemia. My dissertation research identified a cohort of anemia-specific CREs with similar molecular features to Samd14 at the expansion and differentiation stage of erythroid regeneration. In addition, we discovered that stage-specific CREs in early activation stages have distinct features associated with AP-1 activity. To comprehensively analyze changes to chromatin accessibility, we generated ATAC-seq data over a 35-day time course post-anemia, encompassing all stages of erythroid regeneration. We found that ETS motifs are enriched, and GATA family motifs are depleted at the post-resolution stage. These findings revealed distinct chromatin accessibility dynamics before, during, and after acute anemia resolution. Remarkably, many of these dynamic changes to chromatin accessibility are at genomic regions containing naturally occurring genetic variants associated with human blood phenotypes.
Overall, these studies build a transcriptional and chromatin accessibility map through the stages of erythroid regeneration, revealing stage-specific CRE and TF activation during erythroid regeneration. Given the recent development of CREs editing-based gene therapy strategies in treating sickle cell disease and beta-thalassemia, investigating cis-regulatory mechanisms through different stages of erythroid regeneration will not only elucidate the stress erythropoiesis regulation but also shed light on new therapeutic targets of treating anemia
Cardiovascular Disease Risk Reduction Program for Hispanics in the US Midwest: A Culturally Adapted Intervention
Get PDFCardiovascular disease (CVD) represents the second leading cause of death in Nebraska (NE), accounting for approximately one in every five deaths. In the state, there are marked ethnic and rural-urban disparities in the prevalence of chronic diseases and resultant deaths. For instance, while the rates in NE of coronary heart disease and myocardial infarction between 2001 and 2010 decreased among non-Hispanic Whites, the rates for Hispanics almost tripled. There is little evidence of CVD risk factor reduction strategies being implemented in Midwestern areas and Hispanic populations.
One promising approach for reducing CVD risk involves health education and lifestyle modification programs led by community health workers (CHWs). A notable example is the Community Outreach and Cardiovascular Health (COACH) trial, which applied cognitive behavioral strategies in urban, medically underserved, predominantly African American communities, demonstrating improved clinical outcomes for CVD risks. The intervention included educational and behavioral counseling and follow-up from a primary care provider/community health worker (PCP/CHW) team. Participants in COACH showed significant enhancements in serum lipids, arterial blood pressure, glucose control, and perceptions of chronic care management. However, this intervention has not been culturally adapted or translated to assist Spanish-speaking individuals to be delivered to Hispanic populations.
Prior studies targeting the reduction of CVD risk factors among Hispanic populations in the US have typically embarked on program development. While these studies have demonstrated promising outcomes, the scientific literature highlights essential areas of improvement, particularly in research design and long-term follow-up, which can affect generalizability. In contrast, our study takes a different approach. Rather than starting from ground zero, we aimed to culturally adapt a proven program that has undergone rigorous research methodology and has yielded positive outcomes in other minority populations across the nation. This strategy builds upon existing evidence-based interventions and may enhance the likelihood of effectiveness and sustainability within Hispanic communities. Our long-term goal is to develop health education interventions that facilitate the adoption and maintenance of CVD protective factors, thereby reducing the disproportionate burden of heart diseases among minority populations
Experiences of Registered Nurses Returning to Practice after a Career Break
Get PDFThis dissertation explores the complex experiences of Registered Nurses (RNs) returning to practice, with a particular focus on the impacts of self-efficacy, recruitment strategies, and regulatory barriers. The first article, a literature review, examines the self-efficacy of RNs returning to practice, emphasizing the importance of refresher programs and support to facilitate this transition. This review also evaluated the preparedness of RNs re-entering the workforce, and evaluated the role of self-efficacy in successful reintegration into clinical practice. The second manuscript delves into the challenges of reaching and recruiting health professionals who have left the profession, identifying community partnerships, social media, and respondent-driven sampling as key strategies. It emphasizes the necessity of employing multiple recruitment approaches to engage this hard-to-reach population effectively. Lastly, the experiences of nurses returning to practice during the COVID-19 pandemic, without the usual regulatory requirements are examined. This study evaluates the influence of motivation and readiness on RNs\u27 career decisions and considered the effect that removing regulatory barriers had on the transition back into the nursing profession.
Together, these studies provide an understanding of the factors influencing RNs\u27 return to practice. They collectively argue for policy adjustments to support RNs\u27 transition back into the workforce, emphasizing the need for supportive measures that enhance self-efficacy, streamline recruitment processes, and reconsider regulatory requirements to address the nursing shortage effectively
Mucins: Drivers of Cancer Cell and Microenvironment Crosstalk in Pancreatic Cancer
No full textMucins facilitate the pancreatic cancer (PC) initiation, progression, and metastasis. Among mucins, MUC4 has been reported to inhibit lymphokine-activated cell killing and induce the apoptosis of cytotoxic T-cells. Counterintuitively, MUC4 expression is upregulated by multiple T-cell-secreted cytokines, such as IFN-γ, IL-17, and stroma-secreted factors like retinoic acid. Previously, we have identified that nuclear receptor coactivator 3 (NCOA3) regulates the MUC1 and MUC4 expression by increasing chromatin accessibility and maintaining protein stability. However, the comprehensive crosstalk mediated by MUC4 in cancer cells and T-cells and how its upstream regulator, NCOA3, modifies the cancer cell-intrinsic behavior is still elusive. Here, we show that the activated T-cell conditioned media (CM), containing IL-2, IFN-γ, and TNF-α, induced MUC4 expression in PC cells, and the subsequent RNA-seq analysis also showed the activation of cell death-associated genes. Further investigations revealed that CRISPR-Cas9-mediated knockout (KO) of MUC4 increased PC cell death upon activated T-cell CM treatment. Concurrently, the subcutaneous implantation of MUC4 proficient and deficient cells on the contralateral flanks of C57BL/6 and athymic mice demonstrated a significant reduction in the tumor weight with increased infiltration of both CD3+ and CD8+ cells (C57BL/6) in MUC4 KO tumors. Validating these findings, PanCancer Immune cell type profiling of tumors from KrasG12D/+, Tp53R127H/+, Pdx-1-Cre (KPC), and after MUC4 depletion (PKMC) showed an increased infiltration of cytotoxic cells in KPCM tumors. Mechanistically, MUC4 glycosylation modifies the interactions between MUC4 and perforin, protecting cancer cells from perforin-mediated PC cell death. Next, we generated the NCOA3 conditional KO murine model and bred it with a KPC autochthonous murine model. NCOA3 depletion reduced PC cell growth both in vitro and in vivo. The RNA-seq. analysis from KPNC/KPC tumor tissue and cell lines derived from the murine models showed upregulation of UDP-glucose dehydrogenase (UGDH), which may lead to the accumulation of UDP-glucuronic acid (UDP-GA), a toxic metabolite, and glycosaminoglycans (GAGs) synthesis, suggesting that GAGs synthesis may be an alternate route to compensate for the loss of mucins, downregulated after NCOA3 depletion. In summary, MUC4 expression protects the PC cells from T-cell mediate apoptosis through glycosylation-dependent inhibition of perforin function. Further, NCOA3 depletion leads to UDP-GA accumulation and GAGs synthesis, the impact of which will be investigated in future studies
Effect of Insufficient Sleep on Activity Limitation: Results from the BRFSS 2022 Survey
Get PDFObjective: To determine whether insufficient sleep (less than 7 hours per night) is associated with activity limitation (14 days or more of poor mental or physical health interfering with everyday activities) in Behavioral Risk Factor Surveillance System (BRFSS) survey data from 2022. Methods: BRFSS is a nationally representative cross-sectional survey of non-incarcerated US adults. The exposure of interest was insufficient sleep, and the outcome of interest was activity limitation. Other demographic variables used in a final weighted adjusted analysis include age \u3e65 years, race/ethnicity, gender, marital status, income, and total physical inactivity. Results: The weighted prevalence of insufficient sleep for US adults in 2022 was 36.1%, and activity limitation was 9.8%. A multiple logistic regression was performed, and insufficient sleep had a prevalence odds ratio of 2.05 (95% CI: 1.94, 2.16) for activity limitation. Conclusion: The prevalence of insufficient sleep for adults in the US remains high, and has a significant association with activity limitation, after controlling for several demographic variables. Results from BRFSS 2022 support recommendations that adults should get 7 hours of sleep per night
Association Between Long COVID-19 and Insurance Status Using the Behavioral Risk Factor Surveillance System (2022)
Get PDFObjective. To determine if insurance status can directly predict self-diagnosed Long COVID and what sociodemographic factors are significantly associated with a self-diagnosis of Long COVID among those who tested positive for COVID-19.
Methods. This cross-sectional study uses data from the 2022 Behavioral Risk Factor Surveillance System to conduct a multivariate logistic regression model analysis. Out of 445,132 participants, 110,402 participants were identified to be used in this study.
Results. After testing positive for COVID-19, 21.7% of individuals were self-diagnosed with Long COVID. After controlling for confounders, insurance status wasn\u27t significant (p-value: 0.8458). However, in crude analysis, individuals with Medicaid (cPOR:1.44; 95%CI:[1.30-1.58]) and no health insurance (cPOR:1.37; 95%CI:[1.22-1.54]) were associated with increased odds of self-diagnosed Long COVID. Females had a 61% greater adjusted odds (95% CI: [1.44-1.80]) of self-diagnosing Long COVID than males. Individuals aged 45 to 64 had 37% greater adjusted odds (95% CI: [1.15-1.63]) of self-diagnosed Long COVID compared to those aged 65 and over.
Conclusions. Insurance status alone shouldn\u27t be used as a direct predictor of self-diagnosed Long COVID but should be considered alongside other sociodemographic factors
Examining the Association Between Smoking Frequency and Long COVID: A BRFSS Study
Get PDFObjectives: To examine the relationship between self-reported smoking frequency and the presence of Long COVID among individuals who tested positive for COVID-19.
Methods: A cross-sectional study was conducted using a sample of 44,738 COVID-positive participants from the 2022 Behavioral Risk Factor Surveillance System (BRFSS) dataset. Logistic regression was utilised to compute prevalence odds ratios (pOR) and was adjusted for potential sociodemographic confounders.
Results: Individuals who smoked daily were found to have a greater likelihood of reporting Long COVID in comparison with nonsmokers (Crude pOR=1.22; CI= [1.10-1.35]). However, in the adjusted regression model, daily smoking was no longer significant (Adjusted pOR=1.04; CI= [0.93, 1.16]). Self-reported Long COVID was significantly prevalent among individuals in the younger age group, female gender, lower educational status, lower income status, and unemployment status.
Conclusions: Smoking habits alone do not solely determine long-term COVID-19 outcomes; instead, sociodemographic determinants play a crucial role in their prediction. Therefore, interdisciplinary interventions are essential to address health disparities in vulnerable populations. Objective examinations and longitudinal data are required to comprehend the link between smoking, sociodemographic factors, and Long COVID
Examining the Relationship Between Deafness and Mental Health Status: An Analysis of the Behavioral Risk Factor Surveillance System (BRFSS) 2022
Get PDFObjective: The objective of the research is to examine the association between mental health status as measured by number of mentally healthy days in the past month and deafness and binge drinking.
Methods: The Behavioral Risk Factor Surveillance System (BRFSS) study was conducted via telephone survey in 50 states, including the District of Columbia and US territories. The sample size is 402,156 participants. Univariate, bivariate, and multivariate regressions, odds ratio, and 95% confidence interval were used to measure the data.
Results: Deaf respondents have 1.56 times the odds of having poor mental health than those who are not deaf. (95% CI=1.44, 1.69). Age groups and education do not have a significant association with poor mental health. Black and multiracial people have higher odds of poor mental health.
Conclusion: There is an association between poor mental health and deafness. Lack of accessibility to mental health services may contribute to poor mental health. Further studies are needed to analyze improving accessibility to mental health services