Publications by authors named "Susan Kennedy"

196 Publications

Endometrial Mesonephric-like Adenocarcinoma Presenting as an Ocular Lesion: A Case Report.

Int J Gynecol Pathol 2021 May 3. Epub 2021 May 3.

Department of Pathology, St. Vincent's University Hospital (S.A.L.N., A.D., S.K., D.G.) UCD School of Medicine and Medical Specialties (S.K., R.M.V., J.C., D.G.) Departments of Gynecological Oncology (R.M.V.) Oncology (J.C.), St. Vincent's University Hospital.

Endometrial mesonephric-like carcinoma (ML-CA) is a recently recognized subtype of aggressive endometrial adenocarcinoma that is morphologically and immunophenotypically similar to mesonephric carcinoma but not typically associated with mesonephric remnants. Here, we report a case of 58-yr-old female who had a past medical history of fibroids and of irregular menstrual bleeding for ~20 yr who presented with visual disturbance. On further investigation, she was found to have a large choroidal peri-papillary tumor of the right eye. A presumptive diagnosis of choroidal melanoma was made. Right eye enucleation was performed, and microscopy revealed moderately differentiated metastatic adenocarcinoma. Further work up was advised. A uterine mass was identified on imaging followed by endometrial biopsy that showed a morphologically and immunohistochemically similar tumor to that in the eye. A hysterectomy was carried out and a malignant neoplasm with varying morphologic patterns including gland formation, solid sheets of tumor cells, cribriform, glomeruloid, spindled and papillary areas was seen. The immunohistochemical profile showed diffuse strong positivity for AE1/AE3, TTF1, P16, and vimentin. CD56, GATA3, Napsin A, and CD10 were focally positive. The neoplastic cells were negative for the following markers ER, PR, WT1, calretinin, and synaptophysin. PDL-1 was negative and mismatch repair protein was proficient. An identical KRAS mutation was detected in both the uterine corpus and ocular tumors. The findings are in keeping with a uterine mesonephric-like adenocarcinoma with an ocular metastasis. An Oncomine Focus-Mutation profile, Thermo-Fisher Scientific Inc., a 60 gene oncologic panel, performed on the ocular tumor, revealed no further mutations.
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http://dx.doi.org/10.1097/PGP.0000000000000781DOI Listing
May 2021

Proteomic signatures of radioresistance: Alteration of inflammation, angiogenesis and metabolism-related factors in radioresistant oesophageal adenocarcinoma.

Cancer Treat Res Commun 2021 18;27:100376. Epub 2021 Apr 18.

Department of Surgery, Trinity Translational Medicine Institute, Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland.

The clinical management of locally advanced oesophageal adenocarcinoma (OAC) involves neoadjuvant chemoradiotherapy (CRT), but as radioresistance remains a major clinical challenge, complete pathological response to CRT only occurs in 20-30% of patients. In this study we used an established isogenic cell line model of radioresistant OAC to detect proteomic signatures of radioresistance to identify novel molecular and cellular targets of radioresistance in OAC. A total of 5785 proteins were identified of which 251 were significantly modulated in OE33R cells, when compared to OE33P. Gene ontology and pathway analysis of these significantly modulated proteins demonstrated altered metabolism in radioresistant cells accompanied by an inhibition of apoptosis. In addition, inflammatory and angiogenic pathways were positively regulated in radioresistant cells compared to the radiosensitive cells. In this study, we demonstrate, for the first time, a comprehensive proteomic profile of the established isogenic cell line model of radioresistant OAC. This analysis provides insights into the molecular and cellular pathways which regulate radioresistance in OAC. Furthermore, it identifies pathway specific signatures of radioresistance that will direct studies on the development of targeted therapies and personalised approaches to radiotherapy.
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http://dx.doi.org/10.1016/j.ctarc.2021.100376DOI Listing
April 2021

Shifts in morphology, gene expression, and selection underlie web loss in Hawaiian Tetragnatha spiders.

BMC Ecol Evol 2021 03 22;21(1):48. Epub 2021 Mar 22.

Department of Environmental Science, Policy and Management, University of California, Berkeley, 130 Mulford Hall, #3114, Berkeley, CA, 94720-3114, USA.

Background: A striking aspect of evolution is that it often converges on similar trajectories. Evolutionary convergence can occur in deep time or over short time scales, and is associated with the imposition of similar selective pressures. Repeated convergent events provide a framework to infer the genetic basis of adaptive traits. The current study examines the genetic basis of secondary web loss within web-building spiders (Araneoidea). Specifically, we use a lineage of spiders in the genus Tetragnatha (Tetragnathidae) that has diverged into two clades associated with the relatively recent (5 mya) colonization of, and subsequent adaptive radiation within, the Hawaiian Islands. One clade has adopted a cursorial lifestyle, and the other has retained the ancestral behavior of capturing prey with sticky orb webs. We explore how these behavioral phenotypes are reflected in the morphology of the spinning apparatus and internal silk glands, and the expression of silk genes. Several sister families to the Tetragnathidae have undergone similar web loss, so we also ask whether convergent patterns of selection can be detected in these lineages.

Results: The cursorial clade has lost spigots associated with the sticky spiral of the orb web. This appears to have been accompanied by loss of silk glands themselves. We generated phylogenies of silk proteins (spidroins), which showed that the transcriptomes of cursorial Tetragnatha contain all major spidroins except for flagelliform. We also found an uncharacterized spidroin that has higher expression in cursorial species. We found evidence for convergent selection acting on this spidroin, as well as genes involved in protein metabolism, in the cursorial Tetragnatha and divergent cursorial lineages in the families Malkaridae and Mimetidae.

Conclusions: Our results provide strong evidence that independent web loss events and the associated adoption of a cursorial lifestyle are based on similar genetic mechanisms. Many genes we identified as having evolved convergently are associated with protein synthesis, degradation, and processing, which are processes that play important roles in silk production. This study demonstrates, in the case of independent evolution of web loss, that similar selective pressures act on many of the same genes to produce the same phenotypes and behaviors.
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http://dx.doi.org/10.1186/s12862-021-01779-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983290PMC
March 2021

Connecting high-throughput biodiversity inventories: Opportunities for a site-based genomic framework for global integration and synthesis.

Mol Ecol 2021 03 2;30(5):1120-1135. Epub 2021 Feb 2.

Island Ecology and Evolution Research Group, Instituto de Productos Naturales y Agrobiología (IPNA-CSIC), San Cristóbal de la Laguna, Spain.

High-throughput sequencing (HTS) is increasingly being used for the characterization and monitoring of biodiversity. If applied in a structured way, across broad geographical scales, it offers the potential for a much deeper understanding of global biodiversity through the integration of massive quantities of molecular inventory data generated independently at local, regional and global scales. The universality, reliability and efficiency of HTS data can potentially facilitate the seamless linking of data among species assemblages from different sites, at different hierarchical levels of diversity, for any taxonomic group and regardless of prior taxonomic knowledge. However, collective international efforts are required to optimally exploit the potential of site-based HTS data for global integration and synthesis, efforts that at present are limited to the microbial domain. To contribute to the development of an analogous strategy for the nonmicrobial terrestrial domain, an international symposium entitled "Next Generation Biodiversity Monitoring" was held in November 2019 in Nicosia (Cyprus). The symposium brought together evolutionary geneticists, ecologists and biodiversity scientists involved in diverse regional and global initiatives using HTS as a core tool for biodiversity assessment. In this review, we summarize the consensus that emerged from the 3-day symposium. We converged on the opinion that an effective terrestrial Genomic Observatories network for global biodiversity integration and synthesis should be spatially led and strategically united under the umbrella of the metabarcoding approach. Subsequently, we outline an HTS-based strategy to collectively build an integrative framework for site-based biodiversity data generation.
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http://dx.doi.org/10.1111/mec.15797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986105PMC
March 2021

Combining 1,4-dihydroxy quininib with Bevacizumab/FOLFOX alters angiogenic and inflammatory secretions in ex vivo colorectal tumors.

BMC Cancer 2020 Oct 2;20(1):952. Epub 2020 Oct 2.

Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland.

Background: Colorectal cancer (CRC) is the second most common cause of cancer-related mortality worldwide with one in every five patients diagnosed with metastatic CRC (mCRC). In mCRC cases, the 5-year survival rate remains at approximately 14%, reflecting the lack of effectiveness of currently available treatments such as the anti-VEGF targeting antibody Bevacizumab combined with the chemotherapy folinic acid, fluorouracil and oxaliplatin (FOLFOX). Approximately 60% of patients do not respond to this combined treatment. Furthermore, Bevacizumab inhibits dendritic cell (DC) maturation in poor responders, a key process for tumor eradication.

Method: Following drug treatment, secreted expression levels of angiogenic and inflammatory markers in tumor conditioned media generated from human ex vivo colorectal tumors were measured by ELISA. Dendritic cell phenotypic and maturation markers were assessed by flow cytometry.

Results: Our novel compound, 1,4-dihydroxy quininib, acts in an alternative pathway compared to the approved therapy Bevacizumab. 1,4-dihydroxy quininib alone, and in combination with Bevacizumab or FOLFOX significantly reduced TIE-2 expression which is involved in the promotion of tumor vascularization. Combination treatment with 1,4-dihydroxy quininib significantly increased the expression level of DC phenotypic and maturation markers.

Conclusion: Our results indicate the anti-angiogenic small molecule 1,4-dihydroxy quininib could be an alternative novel treatment in combination therapy for CRC patients.
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http://dx.doi.org/10.1186/s12885-020-07430-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532092PMC
October 2020

A study of the immune infiltrate and patient outcomes in esophageal cancer.

Carcinogenesis 2021 04;42(3):395-404

Department of Surgery, Cancer Immunology and Immunotherapy Group, Trinity Translational Medicine Institute, Trinity College Dublin, St James's Hospital, Dublin, Ireland.

Objectives: Cancer patient outcomes and selection for novel therapies are heavily influenced by the immune contexture of the tumor microenvironment. Esophageal cancer is associated with poor outcomes. In contrast to colorectal cancer, where the immunoscore is increasingly used in prognostic staging, little is known about the immune cell populations in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (SCC), and their clinical significance.

Methods: Tissue microarrays were constructed from resected tumor tissue of 72 EAC patients and 23 SCC patients. Immunohistochemical staining of CD3, CD8, CD56, CD68, CD45RO, CD69, IFN-γ, IL-10, IL-4, IL-17, TGF-β, FOXP3 and CD107a was performed. Positivity was examined in both the stromal and epithelial compartments. Statistical analysis was performed to identify differences in immune cell infiltration and functional phenotypes between cancer subtypes and tissue compartments.

Results: This study identified that esophageal tumors are enriched with CD45RO+ and CD8+ cells and such positivity is significantly higher in SCC compared with EAC. Furthermore, the expression of CD45RO positively correlates with that of CD8 within the tumors of both patient cohorts, suggesting a dominance of memory cytotoxic T cells. This is supported by strong positivity of degranulation marker CD107a in the stromal compartment of EAC and SCC tumors. Cytokine staining revealed a mixed pro- and anti-inflammatory profile within EAC tumors.

Conclusions: Esophageal tumors are enriched with memory cytotoxic T cells. Applying these measurements to a larger cohort will ascertain the clinical utility of assessing specific lymphocyte infiltrates in EAC and SCC tumors with regards to future immunotherapy use, patient prognosis and outcomes.
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http://dx.doi.org/10.1093/carcin/bgaa101DOI Listing
April 2021

A Dedicated Evolutionarily Conserved Molecular Network Licenses Differentiated Cells to Return to the Cell Cycle.

Dev Cell 2020 10 7;55(2):178-194.e7. Epub 2020 Aug 7.

Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Differentiated cells can re-enter the cell cycle to repair tissue damage via a series of discrete morphological and molecular stages coordinated by the cellular energetics regulator mTORC1. We previously proposed the term "paligenosis" to describe this conserved cellular regeneration program. Here, we detail a molecular network regulating mTORC1 during paligenosis in both mouse pancreatic acinar and gastric chief cells. DDIT4 initially suppresses mTORC1 to induce autodegradation of differentiated cell components and damaged organelles. Later in paligenosis, IFRD1 suppresses p53 accumulation. Ifrd1 cells do not complete paligenosis because persistent p53 prevents mTORC1 reactivation and cell proliferation. Ddit4 cells never suppress mTORC1 and bypass the IFRD1 checkpoint on proliferation. Previous reports and our current data implicate DDIT4/IFRD1 in governing paligenosis in multiple organs and species. Thus, we propose that an evolutionarily conserved, dedicated molecular network has evolved to allow differentiated cells to re-enter the cell cycle (i.e., undergo paligenosis) after tissue injury. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.devcel.2020.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606764PMC
October 2020

Real-time metabolic profiling of oesophageal tumours reveals an altered metabolic phenotype to different oxygen tensions and to treatment with Pyrazinib.

Sci Rep 2020 07 21;10(1):12105. Epub 2020 Jul 21.

Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland.

Oesophageal cancer is the 6th most common cause of cancer related death worldwide. The current standard of care for oesophageal adenocarcinoma (OAC) focuses on neoadjuvant therapy with chemoradiation or chemotherapy, however the 5-year survival rates remain at < 20%. To improve treatment outcomes it is critical to further investigate OAC tumour biology, metabolic phenotype and their metabolic adaptation to different oxygen tensions. In this study, by using human ex-vivo explants we demonstrated using real-time metabolic profiling that OAC tumour biopsies have a significantly higher oxygen consumption rate (OCR), a measure of oxidative phosphorylation compared to extracellular acidification rate (ECAR), a measure of glycolysis (p = 0.0004). Previously, we identified a small molecule compound, pyrazinib which enhanced radiosensitivity in OAC. Pyrazinib significantly inhibited OCR in OAC treatment-naïve biopsies (p = 0.0139). Furthermore, OAC biopsies can significantly adapt their metabolic rate in real-time to their environment. Under hypoxic conditions pyrazinib produced a significant reduction in both OCR (p = 0.0313) and ECAR in OAC treatment-naïve biopsies. The inflammatory secretome profile from OAC treatment-naïve biopsies is heterogeneous. OCR was positively correlated with three secreted factors in the tumour conditioned media: vascular endothelial factor A (VEGF-A), IL-1RA and thymic stromal lymphopoietin (TSLP). Pyrazinib significantly inhibited IL-1β secretion (p = 0.0377) and increased IL-3 (p = 0.0020) and IL-17B (p = 0.0181). Importantly, pyrazinib did not directly alter the expression of dendritic cell maturation markers or reduce T-cell viability or activation markers. We present a new method for profiling the metabolic rate of tumour biopsies in real-time and demonstrate the novel anti-metabolic and anti-inflammatory action of pyrazinib ex-vivo in OAC tumours, supporting previous findings in-vitro whereby pyrazinib significantly enhanced radiosensitivity in OAC.
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http://dx.doi.org/10.1038/s41598-020-68777-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374542PMC
July 2020

DNA barcoding and community assembly-A simple solution to a complex problem.

Mol Ecol 2020 07 14;29(13):2318-2320. Epub 2020 Jul 14.

Department of Biogeography, Trier University, Trier, Germany.

Identifying the current and past processes driving community assembly is critical in the effort to understand the Earth's biodiversity and its response to future environmental change. But while studies on community assembly often emphasize the role of contemporary ecological drivers, it has been particularly challenging to account for the effects of past processes in shaping present-day communities. In this issue of Molecular Ecology, Hao et al. (2020) provide a holistic analysis of factors driving the assembly of diverse communities of Lepidoptera in two mountain ranges in northeastern China. The authors use an impressively large data set and exceptionally comprehensive analyses to test how processes of range expansion and gene flow, speciation and extinction, dispersal limitation, environmental filtering and competition have led to present-day diversity patterns. A key novelty of this work is the exhaustive use of DNA barcodes, relatively simple yet powerful molecular markers, to tackle complex biological questions. The authors elegantly show the utility of DNA barcoding data for research beyond simple taxonomic assignment. Their approach is remarkable as it manages to integrate population genetics, phylogenetic history, species diversity and ecology into a well-rounded picture of community assembly. With this work, Hao et al. demonstrate the great promise of DNA barcoding for exhaustive community analysis of even highly diverse and complex systems, raising the bar for future research.
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http://dx.doi.org/10.1111/mec.15519DOI Listing
July 2020

The tumour microenvironment of the upper and lower gastrointestinal tract differentially influences dendritic cell maturation.

BMC Cancer 2020 Jun 17;20(1):566. Epub 2020 Jun 17.

Department of Surgery, Trinity Translational Medicine Institute, Trinity College Dublin, St James's Hospital, Dublin 8, Ireland.

Background: Only 10-30% of oesophageal and rectal adenocarcinoma patients treated with neoadjuvant chemoradiotherapy have a complete pathological response. Inflammatory and angiogenic mediators in the tumour microenvironment (TME) may enable evasion of anti-tumour immune responses.

Methods: The TME influence on infiltrating dendritic cells (DCs) was modelled by treating immature monocyte-derived DCs with Tumour Conditioned Media (TCM) from distinct gastrointestinal sites, prior to LPS-induced maturation.

Results: Cell line conditioned media from gastrointestinal cell lines inhibited LPS-induced DC markers and TNF-α secretion. TCM generated from human tumour biopsies from oesophageal, rectal and colonic adenocarcinoma induced different effects on LPS-induced DC markers - CD54, CD80, HLA-DR, CD86 and CD83 were enhanced by oesophageal cancer; CD80, CD86 and CD83 were enhanced by rectal cancer, whereas CD54, HLA-DR, CD86, CD83 and PD-L1 were inhibited by colonic cancer. Notably, TCM from all GI cancer types inhibited TNF-α secretion. Additionally, TCM from irradiated biopsies inhibited DC markers. Profiling the TCM showed that IL-2 levels positively correlated with maturation marker CD54, while Ang-2 and bFGF levels negatively correlated with CD54.

Conclusion: This study identifies that there are differences in DC maturational capacity induced by the TME of distinct gastrointestinal cancers. This could potentially have implications for anti-tumour immunity and response to radiotherapy.
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http://dx.doi.org/10.1186/s12885-020-07012-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302160PMC
June 2020

Willing mothers: ectogenesis and the role of gestational motherhood.

Authors:
Susan Kennedy

J Med Ethics 2020 05 25;46(5):320-327. Epub 2020 Feb 25.

Philosophy, Boston University, Boston, MA 02215, USA

While artificial womb technology (ectogenesis) is currently being studied for the purpose of improving neonatal care, I contend that this technology ought to be pursued as a means to address the unprecedented rate of unintended pregnancies. But ectogenesis, alongside other emerging reproductive technologies, is problematic insofar as it threatens to disrupt the natural link between procreation and parenthood that is normally thought to generate rights and responsibilities for biological parents. I argue that there remains only one potentially viable account of parenthood: the voluntarist account, which construes parental rights as robust moral obligations that must be voluntarily undertaken. The problem is that this account mistakenly presumes a patriarchal divide between procreation and parenthood. I propose a reframing of procreation and parenthood from a feminist perspective that recognises gestational motherhood as involving robust moral obligations that ought to be voluntarily undertaken. If this were the case, all gestational mothers would be, by definition, willing mothers. To make this happen I argue that ectogenesis technology must be a widely available reproductive option.
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http://dx.doi.org/10.1136/medethics-2019-105847DOI Listing
May 2020

Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples.

J Transl Med 2020 02 22;18(1):99. Epub 2020 Feb 22.

Medical Oncology Lab, Department of Molecular Medicine, Royal College of Surgeons in Ireland, RCSI Smurfit Building, Beaumont Hospital, Dublin, Ireland.

Background: An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient's tumor that can confer clinical efficacy or drug resistance.

Methods: The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development.

Results: Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors.

Conclusions: Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.
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http://dx.doi.org/10.1186/s12967-020-02273-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036178PMC
February 2020

High-throughput sequencing for community analysis: the promise of DNA barcoding to uncover diversity, relatedness, abundances and interactions in spider communities.

Dev Genes Evol 2020 03 10;230(2):185-201. Epub 2020 Feb 10.

Department of Biogeography, Trier University, Trier, Germany.

Large-scale studies on community ecology are highly desirable but often difficult to accomplish due to the considerable investment of time, labor and, money required to characterize richness, abundance, relatedness, and interactions. Nonetheless, such large-scale perspectives are necessary for understanding the composition, dynamics, and resilience of biological communities. Small invertebrates play a central role in ecosystems, occupying critical positions in the food web and performing a broad variety of ecological functions. However, it has been particularly difficult to adequately characterize communities of these animals because of their exceptionally high diversity and abundance. Spiders in particular fulfill key roles as both predator and prey in terrestrial food webs and are hence an important focus of ecological studies. In recent years, large-scale community analyses have benefitted tremendously from advances in DNA barcoding technology. High-throughput sequencing (HTS), particularly DNA metabarcoding, enables community-wide analyses of diversity and interactions at unprecedented scales and at a fraction of the cost that was previously possible. Here, we review the current state of the application of these technologies to the analysis of spider communities. We discuss amplicon-based DNA barcoding and metabarcoding for the analysis of community diversity and molecular gut content analysis for assessing predator-prey relationships. We also highlight applications of the third generation sequencing technology for long read and portable DNA barcoding. We then address the development of theoretical frameworks for community-level studies, and finally highlight critical gaps and future directions for DNA analysis of spider communities.
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http://dx.doi.org/10.1007/s00427-020-00652-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127999PMC
March 2020

Are you what you eat? A highly transient and prey-influenced gut microbiome in the grey house spider Badumna longinqua.

Mol Ecol 2020 03 24;29(5):1001-1015. Epub 2020 Feb 24.

Environmental Science, Policy, and Management, University of California Berkeley, Berkeley, CA, USA.

Stable core microbial communities have been described in numerous animal species and are commonly associated with fitness benefits for their hosts. Recent research, however, highlights examples of species whose microbiota are transient and environmentally derived. Here, we test the effect of diet on gut microbial community assembly in the spider Badumna longinqua. Using 16S rRNA gene amplicon sequencing combined with quantitative PCR, we analyzed diversity and abundance of the spider's gut microbes, and simultaneously characterized its prey communities using nuclear rRNA markers. We found a clear correlation between community similarity of the spider's insect prey and gut microbial DNA, suggesting that microbiome assembly is primarily diet-driven. This assumption is supported by a feeding experiment, in which two types of prey-crickets and fruit flies-both substantially altered microbial diversity and community similarity between spiders, but did so in different ways. After cricket consumption, numerous cricket-derived microbes appeared in the spider's gut, resulting in a rapid homogenization of microbial communities among spiders. In contrast, few prey-associated bacteria were detected after consumption of fruit flies; instead, the microbial community was remodelled by environmentally sourced microbes, or abundance shifts of rare taxa in the spider's gut. The reshaping of the microbiota by both prey taxa mimicked a stable core microbiome in the spiders for several weeks post feeding. Our results suggest that the spider's gut microbiome undergoes pronounced temporal fluctuations, that its assembly is dictated by the consumed prey, and that different prey taxa may remodel the microbiota in drastically different ways.
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http://dx.doi.org/10.1111/mec.15370DOI Listing
March 2020

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS.

Nat Commun 2020 01 24;11(1):499. Epub 2020 Jan 24.

Systems Biology Ireland, University College Dublin, Dublin, Ireland.

Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRAS) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRAS (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.
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http://dx.doi.org/10.1038/s41467-019-14224-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981206PMC
January 2020

Rapid and cost-effective generation of single specimen multilocus barcoding data from whole arthropod communities by multiple levels of multiplexing.

Sci Rep 2020 01 9;10(1):78. Epub 2020 Jan 9.

Department of Environmental Sciences, Policy and Management, University of California Berkeley, Mulford Hall, Berkeley, California, USA.

In light of the current biodiversity crisis, molecular barcoding has developed into an irreplaceable tool. Barcoding has been considerably simplified by developments in high throughput sequencing technology, but still can be prohibitively expensive and laborious when community samples of thousands of specimens need to be processed. Here, we outline an Illumina amplicon sequencing approach to generate multilocus data from large collections of arthropods. We reduce cost and effort up to 50-fold, by combining multiplex PCRs and DNA extractions from pools of presorted and morphotyped specimens and using two levels of sample indexing. We test our protocol by generating a comprehensive, community wide dataset of barcode sequences for several thousand Hawaiian arthropods from 14 orders, which were collected across the archipelago using various trapping methods. We explore patterns of diversity across the Archipelago and compare the utility of different arthropod trapping methods for biodiversity explorations on Hawaii, highlighting undergrowth beating as highly efficient method. Moreover, we show the effects of barcode marker, taxonomy and relative biomass of the targeted specimens and sequencing coverage on taxon recovery. Our protocol enables rapid and inexpensive explorations of diversity patterns and the generation of multilocus barcode reference libraries across whole ecosystems.
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http://dx.doi.org/10.1038/s41598-019-54927-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952404PMC
January 2020

PRDX3 is associated with metastasis and poor survival in uveal melanoma.

J Clin Pathol 2020 Jul 26;73(7):408-412. Epub 2019 Nov 26.

National Institute for Cellular Biotechnology, Dublin, Ireland.

Aims: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and 40% develop fatal metastatic disease. Overexpression of thioredoxin-dependent peroxidase reductase (PRDX3) has been implicated in several cancers, including prostate, breast, colorectal and lung cancer. The aim of this study was to compare the immunohistochemical expression of PRDX3 in formalin-fixed, paraffin-embedded (FFPE) primary UM tissues of patients who did and did not develop metastatic disease.

Methods: Immunohistochemical staining of PRDX3 was performed on FFPE tissue microarray samples of 92 primary UM tumours from patients who did and did not develop metastatic disease. The immunohistochemical staining was assessed by two observers who were blinded to all clinicopathological and cytogenetic details including metastatic/non-metastatic information. Based on a scoring system, expression of PRDX3 was graded as high or low.

Results: There were 55 tumours (59.8%) from patients who developed metastatic disease, while 37 (40.2%) were from patients who did not develop metastasis. A statistically significant difference in PRDX3 expression was observed in patients who did and did not develop metastasis (p=0.001). A significant positive correlation between high PRDX3 expression and metastasis was observed (p=0.001). A significant negative correlation between PRDX3 expression and survival was found (p=0.005). Kaplan-Meier survival analysis showed a statistically significant difference in overall survival between tumours that demonstrated low and high expression of PRDX3 (67.61 vs 130.64 months, respectively, p=0.013).

Conclusions: High immunohistochemical expression of PRDX3 in primary UM tissue is associated with metastasis and poor survival.
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http://dx.doi.org/10.1136/jclinpath-2019-206173DOI Listing
July 2020

Innovative Solutions for State Medicaid Programs to Leverage Their Data, Build Their Analytic Capacity, and Create Evidence-Based Policy.

EGEMS (Wash DC) 2019 Aug 5;7(1):41. Epub 2019 Aug 5.

University of Pittsburgh Graduate School of Public Health, US.

As states have embraced additional flexibility to change coverage of and payment for Medicaid services, they have also faced heightened expectations for delivering high-value care. Efforts to meet these new expectations have increased the need for rigorous, evidence-based policy, but states may face challenges finding the resources, capacity, and expertise to meet this need. By describing state-university partnerships in more than 20 states, this commentary describes innovative solutions for states that want to leverage their own data, build their analytic capacity, and create evidence-based policy. From an integrated web-based system to improve long-term care to evaluating the impact of permanent supportive housing placements on Medicaid utilization and spending, these state partnerships provide significant support to their state Medicaid programs. In 2017, these partnerships came together to create a distributed research network that supports multi-state analyses. The Medicaid Outcomes Distributed Research Network (MODRN) uses a common data model to examine Medicaid data across states, thereby increasing the analytic rigor of policy evaluations in Medicaid, and contributing to the development of a fully functioning Medicaid innovation laboratory.
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http://dx.doi.org/10.5334/egems.311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688544PMC
August 2019

Mucosal-Associated Invariant T Cells Display Diminished Effector Capacity in Oesophageal Adenocarcinoma.

Front Immunol 2019 10;10:1580. Epub 2019 Jul 10.

Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Dublin, Ireland.

Oesophageal adenocarcinoma (OAC) is an aggressive malignancy with poor prognosis, and incidence is increasing rapidly in the Western world. Mucosal-associated invariant T (MAIT) cells recognize bacterial metabolites and kill infected cells, yet their role in OAC is unknown. We aimed to elucidate the role of MAIT cells during cancer development by characterizing the frequency, phenotype, and function of MAIT cells in human blood and tissues, from OAC and its pre-malignant inflammatory condition Barrett's oesophagus (BO). Blood and tissues were phenotyped by flow cytometry and conditioned media from explanted tissue was used to model the effects of the tumor microenvironment on MAIT cell function. Associations were assessed between MAIT cell frequency, circulating inflammatory markers, and clinical parameters to elucidate the role of MAIT cells in inflammation driven cancer. MAIT cells were decreased in BO and OAC blood compared to healthy controls, but were increased in oesophageal tissues, compared to BO-adjacent tissue, and remained detectable after neo-adjuvant treatment. MAIT cells in tumors expressed CD8, PD-1, and NKG2A but lower NKG2D than BO cohorts. MAIT cells produced less IFN-γ and TNF-α in the presence of tumor-conditioned media. OAC cell line viability was reduced upon exposure to expanded MAIT cells. Serum levels of chemokine IP-10 were inversely correlated with MAIT cell frequency in both tumors and blood. MAIT cells were higher in the tumors of node-negative patients, but were not significantly associated with other clinical parameters. This study demonstrates that OAC tumors are infiltrated by MAIT cells, a type of CD8 T cell featuring immune checkpoint expression and cytotoxic potential. These findings may have implications for immunotherapy and immune scoring approaches.
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http://dx.doi.org/10.3389/fimmu.2019.01580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635552PMC
October 2020

1,4-dihydroxy quininib attenuates growth of colorectal cancer cells and xenografts and regulates the TIE-2 signaling pathway in patient tumours.

Oncotarget 2019 Jun 4;10(38):3725-3744. Epub 2019 Jun 4.

UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, Dublin, Ireland.

Colorectal cancer (CRC) is the second leading cause of cancer associated deaths in developed countries. Cancer progression and metastatic spread is reliant on new blood vasculature, or angiogenesis. Tumour-related angiogenesis is regulated by pro- and anti-angiogenic factors secreted from malignant tissue in a stepwise process. Previously we structurally modified the small anti-angiogenic molecule quininib and discovered a more potent anti-angiogenic compound 1, 4 dihydroxy quininib (Q8), an antagonist of cysteinyl leukotriene receptor-1 with VEGF-independent bioactivity. Here, Q8, quininib (Q1) and five structural analogues were assayed for anti-tumorigenic effects in pre-clinical cancer models. Q8 reduced clone formation of the human colorectal cancer cell line HT29-Luc2. Gene silencing of CysLT in HT29-Luc2 cells significantly reduced expression of calpain-2. In human colorectal cancer tumour explants, Q8 significantly decreased the secretion of both TIE-2 and VCAM-1 expression. Q8 was well tolerated up to 50 mg/kg by Balb/C mice and significantly more effective at reducing tumour volume in colorectal tumour xenografts compared to the parent drug quininib. In tumour xenografts, Q8 significantly reduced expression of the angiogenic marker calpain-2. In summary, we propose Q8 may act on the TIE-2-Angiopoietin signalling pathway to significantly inhibit the process of tumour angiogenesis in colorectal cancer.
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http://dx.doi.org/10.18632/oncotarget.26966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557215PMC
June 2019

Uveal Melanoma in Ireland.

Ocul Oncol Pathol 2019 Apr 13;5(3):195-204. Epub 2018 Sep 13.

Royal Victoria Eye and Ear Hospital, Dublin, Ireland.

Purpose: To report the clinical features and epidemiology of uveal melanoma in Ireland.

Methods: This was an observational study of 253 patients with a new diagnosis of uveal melanoma between June 2010 and December 2015. Main outcome measures included demographics, clinical features, age-adjusted incidence, relative survival, overall survival, and distant metastases-free survival.

Results: The mean patient age was 61.7 years. Tumour location was choroidal in 82%, ciliochoroidal in 9%, iridociliary in 2%, and iris in 7%. Treatment modalities included brachytherapy (ruthenium-106 and iodine-125 [64%]), enucleation (27%), and proton beam radiation (8%). The mean age-adjusted incidence of uveal melanoma in Ireland from 2010 to 2015 was 9.5 per million of the population (95% confidence interval [CI]: 8.4-10.7). Four-year relative survival was 81.3% (95% CI: 72.8-87.3). Four-year overall survival was 84% (95% CI: 78-90) and 4-year distant metastases-free survival was 79% (95% CI: 73-86).

Conclusion: Based on this data, the incidence of uveal melanoma in Ireland is high when compared with other reported incidence rates in Europe and worldwide. Relative and observed survival were in keeping with other reported European survival rates.
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http://dx.doi.org/10.1159/000492391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489068PMC
April 2019

Impaired Chylomicron Assembly Modifies Hepatic Metabolism Through Bile Acid-Dependent and Transmissible Microbial Adaptations.

Hepatology 2019 10 23;70(4):1168-1184. Epub 2019 May 23.

Department of Medicine, Washington University School of Medicine, St. Louis, MO.

The mechanisms by which alterations in intestinal bile acid (BA) metabolism improve systemic glucose tolerance and hepatic metabolic homeostasis are incompletely understood. We examined metabolic adaptations in mice with conditional intestinal deletion of the abetalipoproteinemia (ABL) gene microsomal triglyceride transfer protein (Mttp-IKO), which blocks chylomicron assembly and impairs intestinal lipid transport. Mttp-IKO mice exhibit improved hepatic glucose metabolism and augmented insulin signaling, without weight loss. These adaptations included decreased BA excretion, increased pool size, altered BA composition, and increased fibroblast growth factor 15 production. Mttp-IKO mice absorb fructose normally but are protected against dietary fructose-induced hepatic steatosis, without weight loss or changes in energy expenditure. In addition, Mttp-IKO mice exhibit altered cecal microbial communities, both at baseline and following fructose feeding, including increased abundance of Bacteroides and Lactobacillus genera. Transplantation of cecal microbiota from chow-fed Mttp-IKO mice into antibiotic-treated wild-type recipients conferred transmissible protection against fructose-induced hepatic steatosis in association with a bloom in Akkermansia and increased Clostridium XIVa genera, whose abundance was positively correlated with fecal coprostanol and total neutral sterol excretion in recipient mice. However, antibiotic-treated Mttp-IKO mice were still protected against fructose-induced hepatic steatosis, suggesting that changes in microbiota are not required for this phenotype. Nevertheless, we found increased abundance of fecal Akkermansia from two adult ABL subjects with MTTP mutations compared to their heterozygous parents and within the range noted in six healthy control subjects. Furthermore, Akkermansia abundance across all subjects was positively correlated with fecal coprostanol excretion. Conclusion: The findings collectively suggest multiple adaptive pathways of metabolic regulation following blocked chylomicron assembly, including shifts in BA signaling and altered microbial composition that confer a transmissible phenotype.
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http://dx.doi.org/10.1002/hep.30669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783349PMC
October 2019

Cognitive Control as a 5-HT-Based Domain That Is Disrupted in Major Depressive Disorder.

Front Psychol 2019 29;10:691. Epub 2019 Mar 29.

The Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, United States.

Heterogeneity within Major Depressive Disorder (MDD) has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT [(11C)WAY-100635], as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets.
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http://dx.doi.org/10.3389/fpsyg.2019.00691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450211PMC
March 2019

Nanopore sequencing of long ribosomal DNA amplicons enables portable and simple biodiversity assessments with high phylogenetic resolution across broad taxonomic scale.

Gigascience 2019 05;8(5)

Department of Integrative Biology, University of California, Berkeley, California, 94720, USA.

Background: In light of the current biodiversity crisis, DNA barcoding is developing into an essential tool to quantify state shifts in global ecosystems. Current barcoding protocols often rely on short amplicon sequences, which yield accurate identification of biological entities in a community but provide limited phylogenetic resolution across broad taxonomic scales. However, the phylogenetic structure of communities is an essential component of biodiversity. Consequently, a barcoding approach is required that unites robust taxonomic assignment power and high phylogenetic utility. A possible solution is offered by sequencing long ribosomal DNA (rDNA) amplicons on the MinION platform (Oxford Nanopore Technologies).

Findings: Using a dataset of various animal and plant species, with a focus on arthropods, we assemble a pipeline for long rDNA barcode analysis and introduce a new software (MiniBar) to demultiplex dual indexed Nanopore reads. We find excellent phylogenetic and taxonomic resolution offered by long rDNA sequences across broad taxonomic scales. We highlight the simplicity of our approach by field barcoding with a miniaturized, mobile laboratory in a remote rainforest. We also test the utility of long rDNA amplicons for analysis of community diversity through metabarcoding and find that they recover highly skewed diversity estimates.

Conclusions: Sequencing dual indexed, long rDNA amplicons on the MinION platform is a straightforward, cost-effective, portable, and universal approach for eukaryote DNA barcoding. Although bulk community analyses using long-amplicon approaches may introduce biases, the long rDNA amplicons approach signifies a powerful tool for enabling the accurate recovery of taxonomic and phylogenetic diversity across biological communities.
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http://dx.doi.org/10.1093/gigascience/giz006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503943PMC
May 2019

Characterisation of an Isogenic Model of Cisplatin Resistance in Oesophageal Adenocarcinoma Cells.

Pharmaceuticals (Basel) 2019 Feb 20;12(1). Epub 2019 Feb 20.

Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland.

Cisplatin (cis-diamminedichloroplatinum) is widely used for the treatment of solid malignancies; however, the development of chemoresistance hinders the success of this chemotherapeutic in the clinic. This study provides novel insights into the molecular and phenotypic changes in an isogenic oesophageal adenocarcinoma (OAC) model of acquired cisplatin resistance. Key differences that could be targeted to overcome cisplatin resistance are highlighted. We characterise the differences in treatment sensitivity, gene expression, inflammatory protein secretions, and metabolic rate in an isogenic cell culture model of acquired cisplatin resistance in OAC. Cisplatin-resistant cells (OE33 Cis R) were significantly more sensitive to other cytotoxic modalities, such as 2 Gy radiation ( = 0.0055) and 5-fluorouracil (5-FU) ( = 0.0032) treatment than parental cisplatin-sensitive cells (OE33 Cis P). Gene expression profiling identified differences at the gene level between cisplatin-sensitive and cisplatin-resistant cells, uncovering 692 genes that were significantly altered between OE33 Cis R cells and OE33 Cis P cells. OAC is an inflammatory-driven cancer, and inflammatory secretome profiling identified 18 proteins secreted at significantly altered levels in OE33 Cis R cells compared to OE33 Cis P cells. IL-7 was the only cytokine to be secreted at a significantly higher levels from OE33 Cis R cells compared to OE33 Cis P cells. Additionally, we profiled the metabolic phenotype of OE33 Cis P and OE33 Cis R cells under normoxic and hypoxic conditions. The oxygen consumption rate, as a measure of oxidative phosphorylation, is significantly higher in OE33 Cis R cells under normoxic conditions. In contrast, under hypoxic conditions of 0.5% O₂, the oxygen consumption rate is significantly lower in OE33 Cis R cells than OE33 Cis P cells. This study provides novel insights into the molecular and phenotypic changes in an isogenic OAC model of acquired cisplatin resistance, and highlights therapeutic targets to overcome cisplatin resistance in OAC.
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http://dx.doi.org/10.3390/ph12010033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469161PMC
February 2019

Pyrazinib (P3), [(E)-2-(2-Pyrazin-2-yl-vinyl)-phenol], a small molecule pyrazine compound enhances radiosensitivity in oesophageal adenocarcinoma.

Cancer Lett 2019 04 19;447:115-129. Epub 2019 Jan 19.

Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Ireland. Electronic address:

Oesophageal adenocarcinoma (OAC) is an aggressive disease with 5-year survival rates of <20%. Only 20-30% OAC patients show a beneficial response to neoadjuvant therapy. Altered mitochondrial function is linked with radioresistance in OAC. We identified pyrazinib (P3), a pyrazine phenol small molecule drug with anti-angiogenic and anti-metabolic activity in-vivo in zebrafish and in-vitro isogenic models of OAC radioresistance. Pyrazinib (P3) significantly inhibited blood vessel development in zebrafish (p < 0.001). In-vivo in zebrafish and in-vitro in an isogenic model of OAC radioresistance, pyrazinib (P3) significantly reduced measures of oxidative phosphorylation and glycolysis. Pyrazinib (P3) significantly reduced the surviving fraction in OE33P; radiation-sensitive and OE33R; radiation-resistant cells following irradiation. Under hypoxic conditions pyrazinib (P3) significantly reduced OE33R cell survival following 4 Gy irradiation (p = 0.0216). Multiplex ELISA showed significantly higher secreted levels of 9 of 30 detected inflammatory and angiogenic factors in OE33R radioresistant cells compared to OE33P cells; IL-8, IL-4, IL-6, IL-2, IL-12p70, IL-10, MCP-1, IP-10, ICAM (p < 0.05). Pyrazinib (P3) significantly reduced the secretions of IL-6 (p = 0.0006), IL-8 (p = 0.0488), and IL-4 (p = 0.0111) in OE33R cells. Collectively, these findings support further development of pyrazinib (P3) as a novel therapeutic radiosensitiser in OAC.
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http://dx.doi.org/10.1016/j.canlet.2019.01.009DOI Listing
April 2019

Raising Awareness About Prescription and Stimulant Abuse in College Students Through On-Campus Community Involvement Projects.

Authors:
Susan Kennedy

J Undergrad Neurosci Educ 2018 15;17(1):A50-A53. Epub 2018 Dec 15.

Psychology Department and Neuroscience Program, Denison University, Granville, OH 43023.

As prescription stimulants become more common on college campuses, concerns have been raised about the abuse of these drugs by college students. Estimates are that up to 20% of college students abuse prescription stimulants, most often by ingesting medications not prescribed to them. In an effort to raise awareness and disseminate information about the potential harmful effects of abusing prescription stimulants, students enrolled in a Health Psychology course participated in small-group community involvement projects. This paper describes the value of such projects, details the specific projects completed by the students, how the projects were graded and assessed, and discusses the usefulness of these and similar projects in neuroscience-related courses.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312145PMC
December 2018

Hepatocyte and stellate cell deletion of liver fatty acid binding protein reveals distinct roles in fibrogenic injury.

FASEB J 2019 03 21;33(3):4610-4625. Epub 2018 Dec 21.

Gastroenterology Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Liver fatty acid binding protein (L-Fabp) modulates lipid trafficking in enterocytes, hepatocytes, and hepatic stellate cells (HSCs). We examined hepatocyte vs. HSC L-Fabp deletion in hepatic metabolic adaptation and fibrotic injury. Floxed L-Fabp mice were bred to different transgenic Cre mice or injected with adeno-associated virus type 8 (AAV8) Cre and fed diets to promote steatosis and fibrosis or were subjected to either bile duct ligation or CCl injury. Albumin-Cre-mediated L-Fabp deletion revealed recombination in hepatocytes and HSCs; these findings were confirmed with 2 other floxed alleles. Glial fibrillary acid protein-Cre and platelet-derived growth factor receptor β-Cre-mediated L-Fabp deletion demonstrated recombination only in HSCs. Mice with albumin promoter-driven Cre recombinase (Alb-Cre)-mediated or AAV8-mediated L-Fabp deletion were protected against food withdrawal-induced steatosis. Mice with Alb-Cre-mediated L-Fabp deletion were protected against high saturated fat-induced steatosis and fibrosis, phenocopying germline L-Fabp mice. Mice with HSC-specific L-Fabp deletion exhibited retinyl ester depletion yet demonstrated no alterations in fibrosis. On the other hand, fibrogenic resolution after CCl administration was impaired in mice with Alb-Cre-mediated L-Fabp deletion. These findings suggest cell type-specific roles for L-Fabp in mitigating hepatic steatosis and in modulating fibrogenic injury and reversal.-Newberry, E. P., Xie, Y., Lodeiro, C., Solis, R., Moritz, W., Kennedy, S., Barron, L., Onufer, E., Alpini, G., Zhou, T., Blaner, W. S., Chen, A., Davidson, N. O. Hepatocyte and stellate cell deletion of liver fatty acid binding protein reveal distinct roles in fibrogenic injury.
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http://dx.doi.org/10.1096/fj.201801976RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404585PMC
March 2019

Apobec1 complementation factor (A1CF) and RBM47 interact in tissue-specific regulation of C to U RNA editing in mouse intestine and liver.

RNA 2019 01 11;25(1):70-81. Epub 2018 Oct 11.

Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63105, USA.

Mammalian C to U RNA is mediated by APOBEC1, the catalytic deaminase, together with RNA binding cofactors (including A1CF and RBM47) whose relative physiological requirements are unresolved. Although A1CF complements APOBEC1 for in vitro RNA editing, mice exhibited no change in apolipoproteinB (apoB) RNA editing, while mutant mice exhibited impaired intestinal RNA editing of apoB as well as other targets. Here we examined the role of A1CF and RBM47 in adult mouse liver and intestine, following deletion of either one or both gene products and also following forced (liver or intestinal) transgenic A1CF expression. There were minimal changes in hepatic and intestinal apoB RNA editing in mice and no changes in either liver- or intestine-specific A1CF transgenic mice. liver-specific knockout ( ) mice demonstrated reduced editing in a subset (11 of 20) of RNA targets, including apoB. By contrast, apoB RNA editing was virtually eliminated (<6% activity) in intestine-specific ( ) mice with only five of 53 targets exhibiting C-to-U RNA editing. Double knockout of and in liver ( ) eliminated apoB RNA editing and reduced editing in the majority of other targets, with no changes following adenoviral APOBEC1 administration. Intestinal double knockout mice ( ) demonstrated further reduced editing (<10% activity) in four of five of the residual APOBEC1 targets identified in mice. These data suggest that A1CF and RBM47 each function independently, yet interact in a tissue-specific manner, to regulate the activity and site selection of APOBEC1 dependent C-to-U RNA editing.
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http://dx.doi.org/10.1261/rna.068395.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298562PMC
January 2019