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Investigating the Effects of Transcription Factor Binding and Genetic Variants in the Striatum of Post-Mortem Cohorts with Opioid Use Disorder
No full textThe opioid crisis has emerged as one of the most pressing public health challenges of our time, with Opioid Use Disorder (OUD) affecting millions of lives across the globe. Studying OUD is not merely an academic pursuit but a critical necessity in addressing this multifaceted epidemic. The urgency of this research is underscored by the staggering prevalence of OUD, with an estimated 3.7% of U.S. adults requiring treatment in 2022 alone. Despite the availability of effective medications for OUD, a significant treatment gap persists, with only a quarter of those in need receiving these life-saving interventions. The far-reaching consequences of OUD extend beyond individual health, impacting economic stability and social dynamics. Moreover, the crisis has contributed to the spread of infectious diseases and placed immense strain on healthcare systems. By delving deeper into the study of OUD, researchers aim to enhance treatment effectiveness, address barriers to care, and develop innovative prevention strategies. This thesis seeks to explore the multifaceted nature of OUD, examining its genetics and epigenetic causes, and potential avenues for improvement in both prevention and intervention. Through a comprehensive analysis of existing literature and emerging research, this study aims to contribute to the body of knowledge necessary to combat the opioid crisis and ultimately save lives in the face of this ongoing public health emergency.
This study analyzes transcription factor (TF) binding dynamics, and genetic variants of OUD post- mortem patient brain particularly in Nucleus Accumbens (NAc) and putamen and how they affect the transcriptome which further contributes to changes in addiction neurocircuitry and behavior. The first part of the study revealed that differential binding dynamics in neurons and glia of heroin users in the putamen is associated with cell-type specific epigenetic modifications and chromatin remodeling. These changes could potentially alter gene expression programs crucial for synaptic plasticity and neural circuit adaptation, thereby contributing to the neuroadaptive processes underlying addiction. In the second part, our research identified unique exonic variants in the NAc of individuals with OUD, including missense and stop-gain mutations that could disrupt protein function and neural signaling. This segment also highlighted dysregulated gene expression and lncRNA-mediated networks affecting immune and cellular stress responses, further exacerbating maladaptive neuroplasticity. Together, these findings provide an integrated perspective on how both transcriptional regulation and genetic alterations drive the complex neuroplastic changes observed in substance use disorders (SUDs), offering new avenues for targeted therapeutic interventions
Functional Importance of Pax5 and NrCAM in Highly Aggressive AR-Independent Prostate Cancer
No full textDevelopment of resistance mechanisms to the currently existing Androgen Receptor Signaling Inhibitor (ARSI) drugs has led to higher incidences of metastatic castration resistant prostate cancer (mCRPC) patients who progress in an AR-independent pathway. Compared to AR dependent mCRPC population, this increasing AR-independent mCRPC patients follow a highly aggressive disease with combined loss of tumor suppressors such as PTEN with RB1 inactivation and/or p53. AR-independent progression occurs either through a trans-differentiation program into neuroendocrine (NE) lineage, often referred as treatment-emergent neuroendocrine-like prostate cancer (t-NEPC) or via an AR-null non-NE processes, commonly addressed as double negative prostate cancer (DNPC). These AR-independent aggressive tumors show a likelihood for visceral metastasis to lungs and liver and presented with dismal survival outcomes and worst prognosis. These tumors are mostly resistant to taxane therapies and often treated with platinum-based chemotherapies in combination with etoposides with limited survival benefit. These tumors are associated with distinct epigenetic and transcriptional signatures belonging to neuronal gene signatures, thereby acquiring neuronal identities. Whether neuronal adaptation is important for the rapid growth and metastasis of these AR-independent genomic high-risk group mCRPC, is not yet defined. Moreover, whether adaptation of neural behaviors provides any survival advantage for these cells or is important for chemotherapy resistance remains unknown.
In the following study, we have carried out various high throughput analysis using RNA-seq, ChIP-seq and ATAC-seq to identify transcription factors (TF) that could be important for promoting the gene expression for neuronal characters in these AR-independent tumors. We found that Pax5 TF increases specifically during AR-independent stages and regulates neuronal gene expression involved in axonal guidance, neurotransmitter regulation, and neuronal adhesion, which are critical for strong cellular communications. Moreover, Pax5 depletion disrupts neurite-mediated cellular communication in these AR-independent cancer cells and reduces surface growth factor receptor activation, thereby, sensitizing them to docetaxel therapies. Moreover, hydroxymethylation of Pax5 promoter CpG islands favors Pbx1 binding to induce Pax5 expression in AR-independent stages.
Furthermore, our analysis reveals that Pax5 transcriptionally regulates various neuronal adhesion proteins such as NrCAM which is highly expressed during AR-independent progression and associated with clinically reduced survival. Our findings suggest that NrCAM is functionally significant for regulating cancer cells’ secretory properties to modulate the local tumor microenvironment. Additionally, NrCAM mediates a direct interaction between cancer cells and intra-tumoral nerves within the metastatic sites, thereby enhancing the growth and survival of AR-independent PCa. Therefore, targeting Pax5/NrCAM functional axis can be beneficial to block the highly metastatic growth and therapy resistance character in AR-independent PCa
Examining the Association Between Diabetes and Hypertension Among Women 40 Years and Older Using the Framingham Study
Full text linkObjectives: To investigate the association between diabetes and hypertension over 24 years using the Framingham Heart Study in women 40 or older.
Methods: The study utilized a subset of data from the Framingham Study (initiated in 1948), a longitudinal prospective cohort study, which followed participants for 24 years. The exposure was diabetes, while hypertension was the outcome. Women aged 40 years or older who had no missing data on diabetes or hypertension were included (N=2,187). Logistic regression was used to estimate unadjusted and adjusted odds ratios (OR) and 95% confidence intervals (CI). Adjusted models controlled for body mass index, smoking, and total cholesterol. A secondary stratified analysis was conducted to evaluate effect modification by total cholesterol.
Results: In the unadjusted model, women with diabetes had 2.72 times the odds of having hypertension compared with those without diabetes (95% CI: 1.16-6.35). In the adjusted model, diabetes was not statistically significantly associated with hypertension (adjusted OR 1.99, 95% CI: 0.82-4.81).
Conclusion: The results support the development of public policy and programs involving diabetes and cardiovascular disease and can guide future research
Improving Postpartum Depression Screening Rates in the DOC Family Medicine Clinic
Full text linkhttps://digitalcommons.unmc.edu/com_fam_pres/1026/thumbnail.jp
Analysis of Vaginal vs Cesarean Deliveries Based on Gestational Age in AMA OneWorld Pregnancies
Full text linkhttps://digitalcommons.unmc.edu/com_fam_pres/1024/thumbnail.jp
Coordinating Connections: A Mixed-Methods Exploration of Relational Coordination and Interprofessional Team Development with Health Professions Students and Survivors of Stroke
No full textThe need for effective healthcare teams is widely recognized, yet strategies for team education and evaluation remain areas of ongoing investigation. This study presents a longitudinal, interprofessional tele-team learning initiative designed to enhance health professions students’ collaborative skills through Salas’ “Big Five” of Teamwork and Gittell’s Relational Coordination Theory. Additionally, the project aimed to mitigate social isolation among stroke survivors by forming nine interprofessional tele-teams composed of students from medical nutrition therapy, nursing, occupational therapy, physical therapy, and speech-language pathology. Over six virtual meetings, these teams engaged with stroke survivors, assisting them in progressing toward self-selected goals.
Using an explanatory sequential mixed-methods design, the study examined outcomes for students and stroke survivors, characteristics of team dynamics and effectiveness in the context of relational coordination, and the feasibility of the Relational Coordination Survey (RCS) in assessing team communication and relationships. Quantitative data from 32 students and nine stroke survivors demonstrated significant improvements in the Relative Mastery Scale (p=0.039), RCS (p\u3c 0.001) Interprofessional Collaborative Competency Attainment Scale (p =0.031). Qualitative case analyses of two tele-teams with distinct RCS patterns provided insights into team dynamics, while RCS network mapping identified areas for improvement, including Communication Frequency, Shared Knowledge, Shared Goals, and Communication Accuracy, with Mutual Respect consistently strong. Findings suggest benefits for both students and stroke survivors, highlight effective team behaviors, and validate the RCS as a feasible tool for interprofessional education, offering practical insights for advancing healthcare team effectiveness
The Collaborative Care Model and Depression Mediation Adherence
Full text linkhttps://digitalcommons.unmc.edu/com_fam_pres/1034/thumbnail.jp