The University of Nebraska Medical Center (UNMC) is a public medical school in Omaha, Nebraska. Founded in 1869 and chartered as a private medical college in 1881, UNMC became part of the University of Nebraska System in 1902. Rapidly expanding in the early 20th century, the university founded a hospital, dental college, pharmacy college, college of nursing, and college of medicine. It later added colleges of public health and allied health professions. One of Omaha's top employers, UNMC has an annual budget of $841.6 million for 2020 to 2021, and an economic impact of $4.8 billion.
Homeobox (HOX) genes are essential regulators of embryonic development and cellular differentiation under physiological conditions. Among this gene family, HOXA10 has emerged as a pivotal factor in gastrointestinal (GI) cancers, influencing tumor growth, metastasis, disease progression, and resistance to therapy. HOXA10 functions as a transcription factor and plays key roles not only in embryogenesis but also in immunomodulation. HOXA10 and its transcriptional targets play a crucial role in cancer development, promoting cell growth, invasion, migration, metastasis, and resistance to cell death. Recent studies have explored the influence of HOXA10 on the tumor immune microenvironment, particularly its role in modulating immune cell recruitment and signaling pathways that enable tumor immune evasion. Our recent research identified a HOXA10-regulated five-gene signature that distinguishes long-term from short-term survivors of pancreatic cancer, with HOXA10 expression correlating with increased regulatory T cell (Treg) infiltration. HOXA10 impacts genes and pathways involving macrophages, Tregs, and other immune cells, potentially creating an immunosuppressive niche that promotes metastasis and diminishes the effectiveness of immunotherapies. In this review, we examine the diverse functions of HOXA10 in GI cancers, offering a comprehensive comparison with other HOX family proteins to elucidate their overlapping and distinct roles in malignancy. Our goal is to provide a thorough overview of how HOXA10 contributes to tumor development and its microenvironment. We highlight its critical role in facilitating cancer progression and metastasis, supported by data from cell lines, patient tumor samples, and clinical studies. Recognizing existing gaps in the understanding of HOXA10’s role in cancer, we also explore potential strategies to target this gene, with an emphasis on synergistic approaches that combine HOXA10 inhibition and immunotherapy. Ultimately, these insights aim to identify vulnerabilities within GI cancers that could be exploited through novel therapeutic agents and combination treatments, paving the way for improved clinical outcomes.
Triple-negative breast cancer (TNBC) lacks targeted therapies and is driven by dysregulated signaling networks that promote migration, invasion, and survival. Connexin43 (Cx43), a gap junction protein essential for maintaining normal mammary epithelial homeostasis, becomes aberrantly phosphorylated and mislocalized in breast cancer, contributing to disease progression. Because the tyrosine kinases Pyk2 and Src regulate Cx43 and multiple pro-tumorigenic pathways, we investigated whether their combined inhibition could suppress malignant behaviors in TNBC. In MDA-MB-231 cells, the Pyk2 inhibitor PF4618433 and Src inhibitor Saracatinib modestly reduced metabolic activity at high concentrations; however dual treatment produced a dose-dependent and synergistic reduction in viability. In migration and invasion assays, each inhibitor reduced motility, however dual inhibition produced the strongest suppression. Cx43 knockdown impaired baseline migration and invasion and altered the response to Pyk2/Src inhibition, indicating that Cx43 modulates sensitivity to these agents. PF4618433 increased Cx43 plaque formation without changing total protein levels. Mechanistically, Pyk2 inhibition reduced phosphorylation of Cx43 at Y265 and decreased levels of TAZ, p-Erk1/2, p130Cas, and Notch1, whereas Src inhibition only reduced p-Erk1/2. Dual treatment did not further decrease these signaling nodes but nonetheless produced stronger functional inhibition of viability and motility, and the shared regulation of p-Erk1/2 by Pyk2 and Src may help explain how compensatory Pyk2 activation limits the effectiveness of Src-targeted therapies. Together, these findings show that coordinated Pyk2 and Src inhibition restores Cx43 organization and disrupts multiple malignant traits in TNBC cells, supporting this combination as a promising therapeutic strategy.
This review aims to systematically evaluate the environmental impacts of key cardiac imaging modalities, identify current operational practices that disproportionately contribute to the carbon footprint, and propose evidence-based strategies to optimize imaging protocols for climate sustainability while preserving diagnostic accuracy and patient outcomes. There has been a significant increase in the utilization of cardiac magnetic resonance imaging (CMR), cardiac computed tomography (CT), cardiac positron emission tomography (PET) and single-photon emission computed tomography (SPECT) which comes with an unacknowledged cost to our environment with respect to carbon footprint, energy consumption and barriers to safe disposal of contrast agents. However, we are yet to incorporate environmental sustainability metrics in our major diagnostic guidelines. In CMR, protocol refinements such as limiting the number of localizing images, using specific faster mapping sequence and optimizing protocols such that cine SSFP can be moved into the contrast wait period can lower energy use and scan time. PET/SPECT/CT sustainability is enhanced by stress-first protocols, tailoring CT dose to clinical need, and promoting circular manufacturing of scanners and cyclotron components. In echocardiography, the major opportunity lies in redesigning ultrasound contrast agent packaging to enable multi-dose use, minimizing single-use plastic waste. Collectively, climate-conscious imaging is achievable by powering down devices, integrating the use of sustainability index, utilizing green data storage centers and optimizing protocols and machines both of the acquisition and vendor side. Future research should quantify the environmental savings of these strategies and support scalable implementation across diverse practice settings.
Functional analyses are important in developing function-based interventions. Although functional analyses often result in clear outcomes identifying one or more variables maintaining challenging behavior, they sometimes produce unclear or inconclusive outcomes due to the relevant antecedent and/or consequence events not being programmed. The objective of the current study was to conduct a retrospective consecutive case series to analyze the prevalence of clinical cases in which clinicians found challenging behavior was maintained by one or more idiosyncratic variables. For the 24 cases included in this review, we present a quantitative analysis of the functional analysis modifications made to identify the idiosyncratic variable(s), prevalence of idiosyncratic outcomes, and population demographics (e.g., age, diagnoses, vocal language level). The reinforcer maintaining challenging behavior was most frequently found in the mand compliance and interruption test conditions. In addition, we observed some differences in the vocal language level of the individuals across idiosyncratic FA outcomes.
Human diabetic heart failure (diHF) is a major contributor to cardiovascular morbidity and mortality and is characterized by myocardial lipid overload and oxidative injury; however, the specific lipid species and molecular mechanisms driving myocardial dysfunction remain unclear. To identify lipid species and integrated molecular networks underlying human diHF using an untargeted multi-omics approach. We performed integrated lipidomic, metabolomic, and proteomic profiling of human diabetic failing hearts and matched non-diabetic controls. Lipidomic and metabolomic analyses were conducted using high-resolution UPLC-MS/MS, and quantitative proteomics was performed using tandem mass tag-based LC-MS/MS. Multivariate modeling, differential abundance testing, pathway enrichment, and cross-platform network integration were used to define coordinated lipid-metabolite-protein signatures associated with diHF. Multi-omics integration identified “electrostatic lipidopathy”, a charge-dependent remodeling of membrane and metabolic lipid species, as a defining feature of diHF. Diabetic hearts exhibited enrichment of negatively charged polyunsaturated phospholipids and sphingolipids together with increased diradylglycerols, ceramides, and lactosylceramides, generating a highly anionic lipid environment consistent with increased susceptibility to lipid peroxidation and ferroptosis-related injury. Metabolomic profiling revealed disruption of the myocardial lipid-energy axis characterized by a pattern consistent with increased fatty-acid influx, acylcarnitine accumulation, incomplete β-oxidation, and metabolic inflexibility. Proteomic remodeling demonstrated coordinated suppression of oxidative phosphorylation, mitochondrial dysfunction, inflammatory activation, and extracellular matrix remodeling. Network analysis linked lipid charge remodeling with mitochondrial energetic failure, oxidative stress, and fibrotic remodeling in diHF myocardium. Electrostatic lipidopathy represents a previously unrecognized mechanism of diabetic cardiac remodeling. By linking membrane lipid charge architecture with mitochondrial dysfunction, redox imbalance, and inflammatory-fibrotic signaling, these findings highlight lipid charge imbalance and ferroptosis-related vulnerability as potential therapeutic targets in diabetic heart failure. What is currently known about this topic? Diabetic heart failure (diHF) is associated with excess cardiovascular mortality and is characterized by myocardial lipid overload, mitochondrial dysfunction, oxidative stress, and metabolic inflexibility. However, the specific lipid species and integrated molecular networks that drive diabetic cardiac remodeling in humans remain unclear. What is the key research question? What lipid species and coordinated lipid-metabolite-protein networks define human diHF, and could charge-dependent lipid remodeling represent a systems-level organizing feature of diabetic cardiac dysfunction? What is new? This study identifies electrostatic lipidopathy - a charge-dependent remodeling of membrane and metabolic lipid species - as a previously unrecognized molecular phenotype of human diHF. Integrated multi-omics analysis reveals enrichment of negatively charged lipid species, disruption of the myocardial lipid-energy axis, mitochondrial dysfunction, ferroptosis-associated signatures, and inflammatory activation, defining a coordinated lipid-metabolic-proteomic remodeling network. How might this study influence clinical practice? By reframing diabetic cardiac remodeling through the lens of membrane electrostatics and metabolic inflexibility, these findings highlight charge-defined lipid species and ferroptosis-associated pathways as potential biomarkers and therapeutic targets, supporting future studies aimed at precision risk stratification and treatment of diabetic heart failure.
