Indiana University-Purdue University Indianapolis (IUPUI) / The aldehyde dehydrogenase (ALDH) superfamily comprises a group of NAD(P)+-dependent enzymes that catalyze the conversion of aldehydes to their corresponding carboxylic acids. Of the nineteen human ALDH enzymes, members of the ALDH1A subfamily consisting of ALDH1A1, ALDH1A2, and ALDH1A3 have attracted interest as markers of cancer stem cells (CSCs) in several cancer types including lung, breast, and ovarian. CSCs represent a distinct subpopulation of highly tumorigenic cells that promote metastasis, recurrence, and resistance to conventional cancer therapies. The increased expression and activity of ALDH1A in CSCs is well-documented, as is the correlation between ALDH1A and a more aggressive cancer phenotype with poorer treatment outcomes. However, the actual functional role of ALDH1A in the context of CSCs has yet to be clearly defined. Elucidating this role will lead to a greater understanding of CSC biology and evaluate ALDH1A as a potential anti-CSC therapeutic target. In this study, previously developed and characterized selective small-molecule inhibitors of ALDH1A were used in conjunction with global transcriptomic, proteomic, and metabolomic analyses to identify pathways that could potentially establish a link between ALDH1A activity and early events in CSC formation in a triple-negative breast cancer (TNBC) model. These approaches revealed that ALDH1A inhibition is associated with mitochondrial and metabolic dysfunction and perturbation of the electron transport chain. ALDH1A inhibition also resulted in an increase in markers of endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), specifically mediated through the Protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway. These effects appear to occur independently of both the canonical function of ALDH1A in detoxifying reactive aldehydes as well as its potential metabolic contribution through the generation of NADH. Together, these results suggest a separate role for ALDH1A in TNBC CSCs in protecting against ER stress that warrants further study. / 2024-10-03

Young people today are increasingly disengaged from their education. Studies indicate that of all school subjects, American students struggle to engage in STEM subjects more than others. For decades, we have known that student engagement/disengagement impacts teachers. Researchers have also claimed that engagement/disengagement can be described as a construct made up of affective, behavioral, and cognitive dimensions (ABC). However, we do not understand how teachers experience student disengagement in these three areas. At a crucial time in education, investigation into the experiences of teachers with disengaged students is needed to uncover insights which may help us understand how teachers interpret student disengagement as well as how they cope with or mitigate it. In this study, we report findings from interviews with STEM teachers where they used an operationalized form of the ABC disengagement construct to interpret previous experiences with disengaged students. We discuss their recommendations for coping and mitigation. Chief among our findings is that when our subjects were introduced to the construct, they were then able to identify strategies to help address student's disengagement patterns. An operationalized form of the ABC disengagement construct may be useful for practitioners to diagnose and remedy student disengagement.

Are our students just consumers of technology or do their interests in technology translate into positive perceptions about STEM majors and careers? This research aimed to describe the role of the Internet in undergraduate students’ academic and career perceptions in STEM areas. The purpose of the research was addressed in three parts. First, the attitudes of undergraduate students towards five functions of the Internet namely tool, toy, treasure, telephone and territory were described. Second, students’ STEM career-related perceptions were described in terms of their science and mathematics self-efficacy, outcome expectations, and attitudes towards a STEM career. Third, the relationship between the five Internet functions and the three STEM career-related perceptions was examined. The participants for this study were 566 undergraduate students from a large Southern university. The research design followed a mixed methods approach using multivariate analyses and content analyses. The findings of the research indicated that there was a small but meaningful relationship between undergraduate students’ Internet and STEM perceptions. In their daily lives, the students perceived the Internet more as a toy and a tool. For general career related purposes, they perceived the Internet more as a treasure and a tool. For STEM areas in particular, they perceived the treasure and toy dimensions of the Internet more relevant. Findings on the differences in students’ Internet and STEM career-related perceptions based on gender, major and enrollment in an Honors program are also discussed.

Rapidly progressive diffuse systemic sclerosis (dSSc) is a life-threatening condition characterized by increased mortality with few effective therapies, typically only helpful in stabilizing disease. Autologous hematopoietic stem cell transplantation (AHSCT) is the only treatment that has demonstrated improved survival. Despite promising results from three randomized controlled trials (RCTs), best practice use of AHSCT in the real-world setting is not well established. The primary objective of this thesis was to summarize the clinical efficacy, limitations and utilization of AHSCT in the management of rapidly progressive dSSc. Specifically, we conducted (1) a systematic review to describe the efficacy of AHSCT in dSSc as well as practice variation in patient selection and treatment regimens; and (2) a multicenter retrospective cohort study to compare outcomes for subjects who received AHSCT in France compared to those who received conventional care in Canada. There was important variability in the criteria for patient selection and treatment protocols. While AHSCT is associated with improved overall survival, skin fibrosis and lung function, further studies are needed to understand its potential for expanded eligibility and effects on other disease manifestations.

This study focuses on ETV7, a transcriptional repressor, known to be up-regulated in breast cancer (BC). Firstly, we demonstrated a new role of ETV7 in promoting breast cancer stem-like cell (BCSC) plasticity and resistance to chemotherapy in BC cells. We observed that ETV7 repressed a large panel of interferon response genes and increased BCSC cell plasticity, leading to resistance to 5-fluorouracil. Then, we investigated the role of ETV7 in inflammatory and immune responses in BC cells. We identified TNFRSF1A, encoding for TNFR1, as one of the genes repressed by ETV7. We demonstrated that ETV7 directly bound to the intron I of this gene, and we showed that the ETV7-mediated down-regulation of TNFRSF1A reduced the activation of NF-κB signaling. These results suggest that ETV7 can reduce the inflammatory responses in BC cells by repressing the TNFR1/NF-κB axis. Moreover, we analyzed the role of ETV7 in the regulation of antigen presentation and confirmed that ETV7 downregulated genes involved in the antigen-presenting pathway, potentially leading to cancer immune evasion We also analyzed if the silencing of ETV7 affected the viability of cancer cells and observed that knock-down of ETV7 can induce p53-mediated apoptosis in cancer cells. Lastly, we analyzed the pro-tumorigenic potential of ETV7 using in vivo model and we observed that mammary gland tumor cells overexpressing ETV7 formed bigger tumors with higher proliferation potential. Taken collectively, the data acquired during this project confirm the role of ETV7 as an important regulator of BC aggressiveness both in vitro and in vivo and propose ETV7 as a novel player in BC immunity, opening a new research direction and giving useful insights for more effective therapeutic strategies.

Screening for resistance to Aspergillus flavus and aflatoxin contamination in maize is an ongoing effort by universities, state and federal agencies. We evaluated two techniques to screen for resistance; quantitative polymerase reaction (QPCR) and solid-phase microextraction (SPME). Methods were adapted to accurately detect and quantify the fungus in culture and in the vegetative stage of plant tissues. These assays can eliminate microbiological techniques. The primary objectives of the study were to utilize 1) QPCR to detect and quantify fungal biomass in maize stem tissues to evaluate resistance in maize genotypes to A. flavus colonization in situ and in vivo and 2) SPME to identify key MVOC’s to differentiate aflatoxigenic and non-aflatoxigenic strains of A. flavus in situ. A novel QPCR TaqMan probe (OMG3) was designed to detect a region in the aflP gene. The OMG3 probe detected 98.3% of the aflatoxigenic strains. The predominant MVOC’s extracted from both aflatoxigenic and non-aflatoxigenic strains were alcohols, ketones and hydrocarbons. The aflatoxigenic strain produced 39 compounds and the non-aflatoxigenic strain produced 41 compounds. Dimethylsulfide and 2-heptanol were key MVOC biomarkers produced only by the aflatoxigenic strain of A. flavus. Accuracy of the QPCR OMG3 probe, in vivo and in situ procedures were developed. A toothpick inoculation method was used to artificially inoculate maize stems in the vegetative stage five (V5). Plants were harvested at V7 and sampled at predetermined sites. This method was 91% consistent for infecting maize plants. The OMG3 probe was evaluated in in vivo and in situ studies conducted in the greenhouse, growth chamber, and field. Lesion length was greater in susceptible lines in 4 of 7 greenhouse trials. Based on inoculation data, subsequent research should focus on refining tissue-sampling methods and increasing length of plant growth time for tissue sampling post-inoculation.

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