Biology subjects

Buetow, K.

Publications and source records attributed to Buetow, K..

5 recordsLinked to original sources

bioRxiv2023

Design and implementation of an asynchronous online course-based undergraduate research experience (CURE) in computational genomics

As genomics and information technologies advance, there is a growing demand for research scientists trained in bioinformatics methods to determine gene expression underlying cell biology in health and disease. One approach to increase the number of scientists proficient in bioinformatics is to expand access through online degree programs and remotely-accessible learning materials. Fully-online learners represent a significant and growing community of historically underrepresented students who are frequently excluded from research opportunities that require in-person attendance during standard operational hours. To address this opportunity gap, we developed an asynchronous course-based undergraduate research experience (CURE) for computational genomics specifically for fully-online biology students. We generated custom learning materials and leveraged remotely-accessible resources on a high performance computing cluster to address a novel research question: the effect of changing quality trimming parameters for RNA sequencing reads on the discovery of sex-based differential gene expression in the human placenta. Here we present the process by which the instructional team devised and distributed analysis to address this question over a 7.5-week CURE and provided students with concurrent training in biology, statistics, computer programming, and professional development integral to the successful execution of the project and future publications. Scores from identical learning assessments administered before and after completion of the CURE showed significant learning gains across biology and coding course objectives. Open-response progress reports were submitted weekly and identified self-reported adaptive coping strategies for challenges encountered throughout the course. The instruction team monitored the progress reports to identify problems that could be resolved through collaboration with instructors and peers via messaging platforms and virtual meetings. Analytics from the course messaging platform demonstrated that high posting engagement was strongly correlated to high normalized learning gains, showing that students can effectively use asynchronous communication platforms to facilitate learning. The online genomics CURE resulted in unanticipated positive outcomes, including students voluntarily extending their participation beyond the course duration, presenting their findings at research symposiums, and applying to graduate school. These outcomes underscore the effectiveness of this genomics CURE for training and recruitment purposes and demonstrate that students can be successful in online STEM-based research experiences if given channels for communication, bespoke and accessible learning materials, and the support of experts in the field. Online CUREs can provide valuable research experience to harness the potential of online STEM students towards a more skilled, diverse, and inclusive workforce for the advancement of biomedical science.

genomics↗

bioRxiv2022

Multi-modal Efficacy of a Chimeric Vesiculovirus Expressing the Morreton Glycoprotein in Sarcoma

Vesiculoviruses are attractive oncolytic virus (OV) platforms due to their rapid replication, genome with appreciable transgene capacity, broad tropism, limited pre-existing immunity, and type I interferon response gradient between malignant and normal cells. We developed a synthetic chimeric virus (VMG) expressing the glycoprotein (G) from Morreton virus (MorV) with remaining genes from vesicular stomatitis virus (VSV). VMG exhibited in vitro efficacy in cell proliferation and cell death assays across a broad range of sarcoma subtypes and across multiple species. Notably, all cell lines tested showed ability of VMG to yield productive infections with rapid replication kinetics. Pilot safety evaluations of VMG in immunocompetent, non-tumor bearing mice showed absence of toxicity with intranasal doses as high as 1e10 TCID50. VMG resulted in tumor reduction in vivo in an immunodeficient subcutaneous Ewing sarcoma model at doses as low as 2e5 TCID50. In the immune competent murine syngeneic fibrosarcoma model, while no tumor inhibition was achieved with VMG, there was a robust induction of CD8+ T cells suggestive of potential for combination approaches with immunomodulatory agents such as immune checkpoint inhibitors. The studies described herein establish the potential for VMG as a novel oncolytic virotherapy platform with multi-modal anti-tumor effects in sarcoma.

immunology↗

bioRxiv2021

APOE4 is associated with elevated blood lipids and lower levels of innate immune biomarkers in a tropical Amerindian subsistence population

In post-industrial settings, APOE4 is associated with increased cardiovascular and neurological disease risk. However, the majority of human evolutionary history occurred in environments with higher pathogenic diversity and low cardiovascular risk. We hypothesize that in high-pathogen and energy-limited contexts, the APOE4 allele confers benefits by reducing baseline innate inflammation when uninfected, while maintaining higher lipid levels that buffer costs of immune activation during infection. Among Tsimane forager-farmers of Bolivia (N=1266), APOE4 is associated with 30% lower C-reactive protein, and higher total cholesterol and oxidized-LDL. Blood lipids were either not associated, or negatively associated with inflammatory biomarkers, except for associations of oxidized-LDL and inflammation which were limited to obese adults. Further, APOE4 carriers maintain higher levels of total and LDL cholesterol at low BMIs. These results suggest the relationship between APOE4 and lipids is likely beneficial for pathogen-driven immune responses, and unlikely to increase cardiovascular risk in an active subsistence population.

evolutionary biology↗

bioRxiv2020

Synergistic Combination of Cytotoxic Chemotherapy and Cyclin Dependent Kinase 4/6 Inhibitors in Biliary Tract Cancers

Biliary tract cancers (BTCs) are uncommon but highly lethal gastrointestinal malignancies. Gemcitabine/cisplatin is a standard-of-care (SOC) systemic therapy, but has a modest impact on survival and harbor toxicities including myelosuppression, nephropathy, neuropathy and ototoxicity. While BTCs are characterized by aberrations activating the cyclinD1-CDK4/6-CDKN2A-RB pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident pre-clinical efficacy and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the anti-tumor efficacy of CDK4/6 inhibitors by combination with chemotherapy-regimens but their mechanism of action remains elusive. Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy due to autophagy induced resistance. Notably, triplettherapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated RRM1 reduction, resulting in sensitization to gemcitabine. Conclusions: As such, these data provide robust pre-clinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors, and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.

cancer biology↗

bioRxiv2018

Sex-specific regulatory mechanisms underlying Hepatocellular Carcinoma

Sex-differences in cancer occurrence and mortality are evident across tumor types; men exhibit higher rates of incidence and often poorer responses to treatment. Targeted approaches to the treatment of tumors that account for these sex-differences require the characterization and understanding of the fundamental biological mechanisms that differentiate them. Hepatocellular Carcinoma (HCC) is the second leading cause of cancer death worldwide, with the incidence rapidly rising. HCC exhibits a male-bias in occurrence and mortality, but previous studies have failed to explore the sex-specific dysregulation of gene expression in HCC. Here, we characterize the sex-shared and sex-specific regulatory changes in HCC tumors in the TCGA LIHC cohort. By using a sex-specific differential expression analysis of tumor and tumor-adjacent samples, we uncovered etiologically relevant genes and pathways differentiating male and female HCC. While both sexes exhibited activation of pathways related to apoptosis and cell cycle, males and females differed in the activation of several signaling pathways, with females showing PPAR pathway enrichment while males showed PI3K, 305 PI3K/AKT, FGFR, EGFR, NGF, GF1R, Rap1, DAP12, and IL-2 signaling pathway enrichment. Using eQTL analyses, we discovered germline variants with differential effects on tumor gene expression between the sexes. 24.3% of the discovered eQTLs exhibit differential effects between the sexes, illustrating the substantial role of sex in modifying the effects of eQTLs in HCC. The genes that showed sex-specific dysregulation in tumors and those that harbored a sex-specific eQTL converge in clinically relevant pathways, suggesting that the molecular etiologies of male and female HCC are partially driven by differential genetic effects on gene expression. Overall, our results provide new insight into the role of inherited genetic regulation of transcription in modulating sex-differences in HCC etiology and provide a framework for future studies on sex-biased cancers.

genomics↗