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Exploring the Therapeutic Potential of Antihistamines in Glioblastoma
No full textGlioblastoma (GBM) is one of the most common and lethal primary malignant brain and central nervous system (CNS) tumors. It accounts for 50.9% of all malignant tumors, with an annual incidence rate of 3.27 per 100,000 population in the United States. Despite the multiple treatment approaches, the median survival is only eight months with a 5-year survival rate of 6.9%, and the tumor almost always recurs with a dismal prognosis. Ionizing radiation and specific genetic syndromes are associated with a high incidence of GBM. Interestingly, patients with a history of asthma, allergy, or atopy have fewer incidences of GBM (RR = 0.59, 95% CI 0.49-0.71). Additionally, histamine, a mediator of allergy, has been studied in various cancers, demonstrating its critical involvement in proliferation, angiogenesis, migration, and invasion. Furthermore, recent literature shows that GBM patients with low HRH1 expression have better survival than those with high HRH1 expression, and electronic medical records indicate that patients taking antihistamines during treatment have better survival than those without antihistamines.
We used a bioinformatics tool, iLINCS, which analyzes the transcriptomic and proteomic datasets and signatures of cellular perturbations to identify novel targets for unique therapeutic approaches. Based on the concordance score and blood-brain barrier permeability (BBB), we selected brompheniramine (Brom), a first-generation histamine 1 receptor (HRH1) antagonist, as a potential candidate to reverse the GBM signature.
We showed that HRH1 is highly expressed in human GBM cell lines and in mouse orthograft tissue sections compared to normal astrocytes and brain parenchyma, respectively, and that expression is significantly higher in GBM than in low-grade glioma. We have shown that histamine can cause a dose-dependent increase in proliferation and decrease the sensitivity of GBM cells to TMZ. Additionally, in combination with temozolomide (TMZ), Brom enhanced TMZ\u27s antitumor efficacy in vitro by inhibiting proliferation, inducing S-phase cell cycle arrest, and promoting apoptosis.
Furthermore, we have demonstrated that the combination treatment of TMZ and Bom significantly reduces tumor burden in vivo and prolongs survival in both the orthograft and patient-derived xenograft models. These findings emphasize the promising potential of targeting HRH1 as an innovative therapeutic strategy to improve outcomes for patients facing these challenging tumors
Online Multimedia Education Effect on Breast Health Knowledge and Self-Efficacy
No full textObjective: To evaluate comprehension and retention of breast health and BSE by providing evidence-based education via a website. The researchers aimed to measure knowledge of breast health, self-efficacy of performing breast health promotion, and usability of the interventional website.
Design: A single group efficacy trial was used.
Setting: The study was conducted in two outpatient clinics in Nebraska that provided well women health care.
Participants: A convenience sample of 100 women were enrolled
Methods: Breast health knowledge was assessed with the Breast Health Assessment (BHA) and consisted of 3 subscales. The Champions Health Belief Model Scale (CHBM) assessed BSE self-efficacy and consisted of 5 subscales. The validated instruments were collected at pre-intervention (Time 1) and 1-month (Time 2) and 2-month (Time 3). Paired t-tests determined change in all outcome measures. A final instrument evaluating usability of the website was provided at Time 3.
Results: Participants included women who were primarily middle aged, white, and college educated. Ninety-two percent reported having prior education of breast health promotion. A statistically significant increase in breast health knowledge was demonstrated after one month and a retention of knowledge was demonstrated at two months after recruitment 0.66 (SD=0.13) to 0.73 (SD= 0.10), p=0.003. A positive correlation between the intervention and health beliefs was demonstrated. An increase in self-efficacy of BSE was found. The website was reported to be easily navigated and understood.
Conclusion: Study findings supported the use of multimedia delivered health education as an effective tool to improve breast health promotion
Neurodegenerative Disease Mechanisms: Mitochondrial Impairment, Tau Aggregation, and Neuroinflammation as Central Drivers of Disease Progression
No full textThe study of the intricate molecular mechanisms behind the pathology of neurodegenerative diseases has become a primary research area in the past decades. The major branches of these studies involve both disease progression and disease pathogenesis, in which neuroscientists have studied, and continue to study, the role that mitochondrial dysfunction, aberrant protein aggregation (like Tau), and immune cell reactions have on these. However, more recent studies have shined light to the fact that these three pathological features are not independent from one another and that their synchronous contributions may be the ultimate driver of neurodegeneration. This dissertation encompasses four different studies using preclinical animal models of different neurodegenerative disorders to better understand the underlying molecular mechanisms behind neurodegeneration. We tested the overarching hypothesis that both mitochondrial dysfunction and aberrant protein accumulation (like Tau) will be present in different models of neurodegenerative conditions and that the relationship between these two is a relevant contributor to disease progression. Throughout the results chapters from this dissertation, we provide evidence for the presence of not just mitochondrial dysfunction and aberrant protein accumulation, but also of neuroinflammation as a key addition to these pathologies responding to the brain damage induced by neurodegeneration. We propose the existence of two primary positive feedback loops: – Mitochondrial dysfunction and aberrant protein accumulation – Mitochondrial dysfunction and neuroinflammation – as central drivers of disease progression. The findings presented in this dissertation uncover the relationships that exist between these three primary pathologies and how they synergistically interact to accelerate the progression of neurodegenerative disease. These interconnected pathways suggest that targeting one pathology alone may not be sufficient for therapeutic intervention, and that a multi-targeted approach addressing mitochondrial dysfunction, protein aggregation, and neuroinflammation may provide more effective strategies for halting or slowing disease progression
Relationship Between Maternal Plasma Retinol and Provitamin A Carotenoids with Fetal and Infant Kidney Development
Get PDFVitamin A plays a critical role in fetal organ development. Studies suggest that maternal vitamin A deficiency affects fetal nephron numbers, potentially leading to smaller kidney sizes and an increased risk of chronic kidney disease later in life. However, human studies exploring maternal vitamin A\u27s impact on fetal kidney development lack longitudinal data and within-cohort comparisons. Furthermore, the influence of provitamin A carotenoids (α-carotene, β-carotene, β-cryptoxanthin) on kidney size remains unexplored. This dissertation addresses these gaps by analyzing relationships between maternal and cord plasma retinol and provitamin A carotenoid concentrations with fetal and infant kidney sizes. Our prospective cohort study enrolled 120 pregnant women in Nebraska before their anatomy scans (18–20 weeks). Retinol and provitamin A concentrations were measured at 24–28 weeks of gestation and at delivery in maternal circulation and umbilical cord. Ultrasounds were used to assess fetal kidney length, volume, and parenchymal thickness at 18–20 weeks and infant kidney measurements within 48–72 hours of birth. Kidney size differences were examined across retinol adequate, insufficient, and deficient groups. Most participants had adequate plasma retinol concentrations. Maternal retinol levels at 24–28 gestational weeks or at delivery and cord retinol levels were not associated with fetal or infant kidney size. However, maternal α and b-carotene at 24–28 gestational weeks were significantly and positively associated with fetal kidney lengths. Interestingly, cord a-carotene levels were significantly positively associated with infant kidney lengths. Lastly, the change in maternal plasma retinol from gestation to delivery was not associated with the change in fetal kidney size from gestation to birth. On the other hand, the changes in maternal a-carotene and b-carotene were significantly positively associated with changes in fetal kidney lengths. This study concludes that adequate maternal retinol concentrations are not associated with fetal kidney development, but fetal kidney development may be influenced by maternal provitamin A carotenoids during pregnancy. These findings emphasize the significance of maintaining adequate carotenoid levels during pregnancy to support fetal kidney development. Further studies are needed to determine the mechanism by which provitamin A carotenoids influence kidney size
Cardiovascular Disease Risk, Risk Factors, and Healthcare Utilization Among Latino Male Migrant Farmworkers in Nebraska
No full textLatino migrant farmworkers are instrumental in the U.S. agricultural industry. Research on the prevalence of chronic conditions, cardiovascular disease (CVD) risk, and healthcare use among Latino migrant farmworkers is limited in the Midwest, specifically among farmworkers on H-2A temporary agricultural visas. Estimating the prevalence of CVD risk and associated risk factors can contribute to improving Latino migrant farmworkers’ health.
A cross-sectional study was conducted in Adams and Platte counties, NE, between June and July 2024, to capture health status, health behaviors, healthcare use, and biometrics (e.g., blood pressure, weight, height, waist circumference, and point-of-care HbA1c and lipids) at health fairs (n = 4). A total of 126 farmworkers agreed to participate in the study. Most were men, with an average age of 33, from Mexico and Guatemala, and had low formal educational attainment and limited English proficiency. Among those 40 years or older (n=29), 41.4% had an immediate and moderate atherosclerotic cardiovascular disease (ASCVD) 10-year risk. ASCVD lifetime risk was 46.2% for all participants. The prevalence of obesity and diabetes was high among this sample of young male Latino migrant farmworkers in Nebraska. Smoking prevalence was three times higher than the U.S. prevalence, increasing their overall CVD risk. Age and income, as well as smoking, were associated with elevated HbA1c. Approximately 50% of participants had a routine checkup in the past 2 years. Significant predictors of preventive healthcare use included reporting a prior blood pressure and glucose measurement, as well as engaging in physical activity. Identifying risk factors for CVD and chronic conditions among this population can guide risk reduction interventions for Latino migrant farmworkers, focusing on weight loss or fitness and smoking cessation. Future research should focus on understanding health behaviors and healthcare use patterns transnationally (e.g., in home countries and in the U.S.)
Analysis of the Clinical, Socioeconomic, and Sociodemographic Characteristics of Virally Unsuppressed Children Aged 2-14 Living with HIV/AIDS in the Region of Abidjan 2 – Côte d’Ivoire (Region Supported by USAID)
Get PDFBackground: Viral suppression among children living with HIV (CLHIV) remains suboptimal in Côte d’Ivoire. This study assessed clinical, socioeconomic, and demographic characteristics associated with viral non-suppression among CLHIV aged 2–14 years in Abidjan 2 to inform targeted interventions under the U.S. Agency for International Development (USAID)-supported Reaching Impact, Saturation, and Epidemic Control (RISE) project.
Methods: A retrospective analysis was conducted using routine program data from 1,203 CLHIV across 73 health facilities. Descriptive, bivariate, and multivariate analyses were performed to examine associations with viral load suppression status. Findings guided the development of a multi-level implementation plan using Kotter’s Change Management Framework, the Socio-Ecological Model, and Transformational Leadership Theory.
Results: Of 1,203 CLHIV, 513 had documented VL results, and 14.4% were non-suppressed. Missingness was substantial for key variables, including HIV disclosure (71%) and parental HIV status (74%). In multivariate modeling, older age (10–14 years) was significantly associated with non-suppression (adjusted prevalence ratio = 2.47; 95% CI, 1.05–5.82). Other factors, including parental HIV status, ART regimen, pill burden, and Orphans and Vulnerable Children program enrollment, were not statistically significant but revealed data quality and structural service gaps.
Conclusion: Pediatric VL suppression in Abidjan 2 is compromised by both clinical and structural barriers. Strategies should focus on improving documentation, supporting age-appropriate disclosure, and implementing tailored adherence interventions. Recommendations are based on both literature and direct program experience, with future research needed to address unmeasured factors such as caregiver occupation, income level, and distance to health facilities
Targeting SGPP1 in Pancreatic Cancer: Valproic Acid as a Potential Therapeutic via HDAC Inhibition and S1P Pathway Modulation
No full textSphingosine-1-phosphate phosphatase 1 (SGPP1) is a key regulator of sphingolipid metabolism that facilitates the degradation of sphingosine-1-phosphate (S1P), a bioactive lipid mediator with significant influence on key cellular processes including proliferation, migration, invasion, and apoptosis. In pancreatic cancer, the dysregulation of SGPP1 expression may play a part in enhancing tumor aggressiveness and chemo-resistance through disrupting the balance of S1P. Most notably, elevated intracellular and nuclear levels of sphingosine-1-phosphate (S1P) have been found to function as endogenous histone deacetylase inhibitors (HDACis), replicating the action of pharmacologic HDACis such as valproic acid (VPA). As VPA is an FDA-approved HDACi, this is one enticing therapeutic approach to pharmacologically replicate the result of SGPP1 knockdown, thereby allowing S1P to accumulate within cells.
Increased nuclear S1P, either as a result of SGPP1 inhibition or VPA treatment, was associated with reduced proliferation, migration, and invasion of pancreatic cancer cells and thus an oncogenic function via epigenetic reprogramming. In this case, valproic acid can serve both as a tool for investigating the role of SGPP1 and as a drug candidate in pancreatic cancer.
This thesis investigates the functional relationship between valproic acid treatment and SGPP1 expression in pancreatic cancer cells. Through the utilization of a series of assays, including proliferation, wound healing, migration, and invasion, we determined the phenotypic effect of suppressed SGPP1 on cancer cell proliferation. In general, these experiments aim to explain how pharmacological disruption of sphingolipid metabolism can impact tumor growth and shed light on novel therapeutic strategies targeting SGPP1 pathways in pancreatic cancer
FORTIFY-med: Fostering Ongoing Research Training In First-Year Medical Students
Get PDFThis is an abstract from the Spotlight on Scholarship event in 2025
Ni1 Demonstrates Anti-Tumor Activity in Group 3 Pediatric Medulloblastomas
Get PDFMedulloblastoma is one of the most common malignant pediatric brain tumors, typically arising in the cerebellum of children between the ages of 3 and 8 years. Of the four subgroups, group 3 is the most aggressive, with a \u3c 50% 10-year overall survival rate. In group 3 medulloblastoma, alterations to chromosome 17 can result in an isochromosome (i17q) and haploinsufficiency of the 17p13.3 region. This locus houses miR-1253, a tumor suppressor gene that regulates CD276 (B7-H3), an immunomodulatory protein implicated in cancer aggressiveness. Silencing miR-1253 can trigger overexpression of B7-H3, leading to immune suppression and increased tumor growth. In this study, we investigated a small molecule inhibitor of B7-H3, B7-H3-Ni1 (Ni1). Group 3 MB cancer cells (HDMB03) were treated with varying concentrations of Ni1. The effects of Ni1 on viability, proliferation, and stemness were assessed using MTT ( 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), wound healing (scratch), and colony formation assays, respectively. Ni1 induced a dose-dependent reduction in proliferation and viability, alongside a significant impairment in cellular migratory ability. These findings suggest that Ni1 affects key oncogenic behaviors in group 3 medulloblastoma cells, warranting further investigation as a potential targeted therapeutic.https://digitalcommons.unmc.edu/surp2025/1008/thumbnail.jp
