Space Radiation Alters Genotype–Phenotype Correlations in Fear Learning and Memory Tests

Behavioral and cognitive traits have a genetic component even though contributions from individual genes and genomic loci are in many cases modest. Changes in the environment can alter genotype–phenotype relationships. Space travel, which includes exposure to ionizing radiation, constitutes environmental challenges and is expected to induce not only dramatic behavioral and cognitive changes but also has the potential to induce physical DNA damage. In this study, we utilized a genetically heterogeneous mouse model, dense genotype data, and shifting environmental challenges, including ionizing radiation exposure, to explore and quantify the size and stability of the genetic component of fear learning and memory-related measures. Exposure to ionizing radiation and other external stressors altered the genotype–phenotype correlations, although different behavioral and cognitive measures were affected to different extents. Utilizing an integrative genomic approach, we identified pathways and functional ontology categories associated with these behavioral and cognitive measures

Complete Genome Sequences of Chop, DelRio, and GrandSlam, Three Gordonia Phages Isolated from Soil in Central Arkansas

Chop, DelRio, and GrandSlam are phage with a Siphoviridae morphotype isolated from soil in Arkansas using the host Gordonia terrae 3612. All three are temperate, and their genomes share at least 96% nucleotide identity. These phage are assigned to cluster DI based on gene content similarity to other sequenced actinobacteriophage

Tumor Biology and Immune Infiltration Define Primary Liver Cancer Subsets Linked to Overall Survival After Immunotherapy

Primary liver cancer is a rising cause of cancer deaths in the US. Although immunotherapy with immune checkpoint inhibitors induces a potent response in a subset of patients, response rates vary among individuals. Predicting which patients will respond to immune checkpoint inhibitors is of great interest in the field. In a retrospective arm of the National Cancer Institute Cancers of the Liver: Accelerating Research of Immunotherapy by a Transdisciplinary Network (NCI-CLARITY) study, we use archived formalin-fixed, paraffin-embedded samples to profile the transcriptome and genomic alterations among 86 hepatocellular carcinoma and cholangiocarcinoma patients prior to and following immune checkpoint inhibitor treatment. Using supervised and unsupervised approaches, we identify stable molecular subtypes linked to overall survival and distinguished by two axes of aggressive tumor biology and microenvironmental features. Moreover, molecular responses to immune checkpoint inhibitor treatment differ between subtypes. Thus, patients with heterogeneous liver cancer may be stratified by molecular status indicative of treatment response to immune checkpoint inhibitors

Determining the cancer risks presented by space radiation: Genomic mapping in outbred mice reveals overlap in genetic susceptibility for HZE ion and γ-ray induced tumors

Carcinogenesis following space radiation exposures is considered the primary impediment to human space exploration. Calculating the actual risks confronted by spaceflight crews is complicated by our limited understanding of the carcinogenic effects of high charge, high energy (HZE) ions—a radiation type for which no human exposure data exists. The current NASA model to calculate cancer risk from space radiation exposures is built largely upon epidemiological data from the survivors of the Hiroshima and Nagasaki atomic bombings, a cohort of individuals exposed predominantly to γ-rays. This dissertation examines some of the assumptions underpinning the current NASA model used to assess space radiation cancer risk. Through a genetics approach using carcinogenesis data from a mouse model of population diversity, we find that not only is the spectrum of tumors induced by accelerator produced HZE ions similar to the spectra of spontaneous and γ ray-induced tumors, but that the QTL controlling susceptibilities often overlap between groups. This overlap indicates shared tumorigenesis mechanisms between γ-ray and HZE ion exposures and supports the use of human epidemiological data from γ-ray exposures to predict cancer risk from galactic cosmic rays. Permissible exposure limits for astronauts are based on the risk of death from cancer rather than cancer incidence. Because the incidence to mortality conversion used in current risk calculations is based on mortality from background cancers in the U.S. population, there is an assumption that radiogenic tumors are no more lethal than spontaneous tumors. We find that malignancy, as measured by metastases endpoints, is comparable for spontaneous tumors and tumor induced following HZE ion or γ-ray exposures. To efficiently utilize the vast genetic resources produced in this study, cataractogenesis endpoints are characterized and QTL mapping is performed. The progression of radiation-induced ocular changes is followed by dilated slit lamp biomicroscopy, with each mouse being examined up to seven times post-irradiation. Progressive, radiation-associated lens changes are noted in both HZE ion and γ-ray exposed populations. QTL controlling latencies for radiation-induced cataracts are identified and overlap in susceptibility loci are observed for mice exposed to HZE ion and γ-ray radiation. Finally, because sufficiently powered lifetime carcinogenesis studies have not been previously undertaken in highly recombinant outbred mouse populations, many of the QTL presented here are novel. QTL are described for 11 tumor histotypes, radiation-induced cataractogenesis, and neurobehavioral endpoints. For tumor incidence, 51 QTL are presented with an average confidence interval of 3.4 megabases and effect sizes averaging 3.7% (range: 0.75 - 7.46%). Commonly for these endpoints, the genetic architecture of the phenotypic variance is complex with multiple QTL individually explaining only a small proportion of the total variance. Although loci with moderate effects on the phenotype were most common, 11 large effect QTL are described for 7 tumor histotypes, with effect sizes greater than 5%. The results presented in this dissertation indicate that cancer risks following space radiation exposures are largely determined by genetic background and can be calculated based on epidemiologic data from terrestrial radiation exposures. Therefore, the subpopulations at increased risk for radiation-induced tumors on Earth are likely to substantially overlap with subpopulations at increased risk in the space radiation environment. These findings support the assumptions underlying the current model used by NASA to estimate fatal cancer risks from space radiation exposures. Additionally, this work indicates that individualized cancer risk assessment may be warranted to mitigate cancer and health risks from space radiation exposures. (Abstract shortened by ProQuest.

Cholecystokinin-B Receptor-Targeted Nanoparticle for Imaging and Detection of Precancerous Lesions in the Pancreas

Survival from pancreatic cancer remains extremely poor, in part because this malignancy is not diagnosed in the early stages, and precancerous pancreatic intraepithelial neoplasia (PanIN) lesions are not seen on routine radiographic imaging. Since the cholecystokinin-B receptor (CCK-BR) becomes over-expressed in PanIN lesions, it may serve as a target for early detection. We developed a biodegradable fluorescent polyplex nanoparticle (NP) that selectively targets the CCK-BR. The NP was complexed to a fluorescent oligonucleotide with Alexa Fluor 647 for far-red imaging and to an oligonucleotide conjugated to Alexa Fluor 488 for localization by immunohistochemistry. Fluorescence was detected over the pancreas of five- to ten-month-old LSL-KrasG12D/+; P48-Cre (KC) mice only after the injection of the receptor target-specific NP and not after injection of untargeted NP. Ex vivo tissue imaging and selective immunohistochemistry confirmed particle localization only to PanIN lesions in the pancreas and not in other organs, supporting the tissue specificity. A human pancreas tissue microarray demonstrated immunoreactivity for the CCK-BR only in the PanIN lesions and not in normal pancreas tissue. The long-term goal would be to develop this imaging tool for screening human subjects at high risk for pancreatic cancer to enable early cancer detection

Small-Molecule Natural Product Physachenolide C Potentiates Immunotherapy Efficacy by Targeting BET Proteins

Screening for sensitizers of cancer cells to TRAIL-mediated apoptosis identified a natural product of the 17β-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), as a promising hit. In this study, we show that PCC was also able to sensitize melanoma and renal carcinoma cells to apoptosis in response not only to TRAIL, but also to the synthetic polynucleotide poly I:C, a viral mimetic and immune activator, by reducing levels of antiapoptotic proteins cFLIP and Livin. Both death receptor and TLR3 signaling elicited subsequent increased assembly of a proapoptotic ripoptosome signaling complex. Administration of a combination of PCC and poly I:C in human M14 melanoma xenograft and a syngeneic B16 melanoma model provided significant therapeutic benefit as compared with individual agents. In addition, PCC enhanced melanoma cell death in response to activated human T cells in vitro and in vivo in a death ligand-dependent manner. Biochemical mechanism-of-action studies established bromo and extraterminal domain (BET) proteins as major cellular targets of PCC. Thus, by targeting of BET proteins to reduce antiapoptotic proteins and enhance caspase-8-dependent apoptosis of cancer cells, PCC represents a unique agent that can potentially be used in combination with various immunotherapeutic approaches to promote tumor regression and improve outcome. SIGNIFICANCE: These findings demonstrate that PCC selectively sensitizes cancer cells to immune-mediated cell death, potentially improving the efficacy of cancer immunotherapies.12 month embargo; published first 09 April 2021This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer

Abstract Background Epithelial ovarian cancer (EOC) is a global health burden, with the poorest five-year survival rate of the gynecological malignancies due to diagnosis at advanced stage and high recurrence rate. Recurrence in EOC is driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that are supported by a complex extracellular matrix and immunosuppressive microenvironment. To target TICs to prevent recurrence, we identified genes critical for TIC viability from a whole genome siRNA screen. A top hit was the cancer-associated, proteoglycan subunit synthesis enzyme UDP-glucose dehydrogenase (UGDH). Methods Immunohistochemistry was used to characterize UGDH expression in histological and molecular subtypes of EOC. EOC cell lines were subtyped according to the molecular subtypes and the functional effects of modulating UGDH expression in vitro and in vivo in C1/Mesenchymal and C4/Differentiated subtype cell lines was examined. Results High UGDH expression was observed in high-grade serous ovarian cancers and a distinctive survival prognostic for UGDH expression was revealed when serous cancers were stratified by molecular subtype. High UGDH was associated with a poor prognosis in the C1/Mesenchymal subtype and low UGDH was associated with poor prognosis in the C4/Differentiated subtype. Knockdown of UGDH in the C1/mesenchymal molecular subtype reduced spheroid formation and viability and reduced the CD133 + /ALDH high TIC population. Conversely, overexpression of UGDH in the C4/Differentiated subtype reduced the TIC population. In co-culture models, UGDH expression in spheroids affected the gene expression of mesothelial cells causing changes to matrix remodeling proteins, and fibroblast collagen production. Inflammatory cytokine expression of spheroids was altered by UGDH expression. The effect of UGDH knockdown or overexpression in the C1/ Mesenchymal and C4/Differentiated subtypes respectively was tested on mouse intrabursal xenografts and showed dynamic changes to the tumor stroma. Knockdown of UGDH improved survival and reduced tumor burden in C1/Mesenchymal compared to controls. Conclusions These data show that modulation of UGDH expression in ovarian cancer reveals distinct roles for UGDH in the C1/Mesenchymal and C4/Differentiated molecular subtypes of EOC, influencing the tumor microenvironmental composition. UGDH is a strong potential therapeutic target in TICs, for the treatment of EOC, particularly in patients with the mesenchymal molecular subtype