bluuebunny/crossref_metadata_2025_split huggingface dataset:
Performance of preoperative plasma tumor markers HE4 and CA125 in predicting ovarian cancer mortality in women with epithelial ovarian cancer
Authors: Furrer Daniela , Grégoire Jean , Turcotte Stéphane , Plante Marie , Bachvarov Dimcho , Trudel Dominique , Têtu Bernard , Douville Pierre , Bairati Isabelle 
Published: June 2021

ObjectiveClinical utility of new biomarkers often requires the identification of their optimal threshold. This external validation study was conducted to assess the performance of the preoperative plasma tumor markers HE4 and CA125 optimal cut‐offs to predict cancer mortality in women with epithelial ovarian cancer (EOC).MethodsParticipating women had upfront debulking surgery in the University Hospital of Quebec City (Canada) between 1988 and 2013. A total of 136 women participated in the training cohort (cohort 1) and 177 in the validation cohort (cohort 2). Preoperative plasma HE4 and CA125 levels were measured by Elecsys®. Optimal thresholds were identified in the cohort 1 using time‐dependent receiver operating characteristic (ROC) curves. Multivariate Cox models were used to validate the biomarkers using their optimal cut‐offs in the cohort 2. The likelihood ratio (LR) test was done to test the prognostic value of each biomarker.ResultsThe Areas Under the Curves (AUC) for HE4 and CA125 were respectively 64.2 (95% CI: 54.7–73.6) and 63.1 (95%CI: 53.6–72.6). The optimal thresholds were 277 pmol/L for HE4 and 282 U/ml for CA125. Only HE4 (≥277 pmol/L) was significantly associated with EOC mortality (adjusted hazard ratio: 1.80; 95% CI: 1.03–3.15). In addition, HE4 added prediction for death over the standard prognostic markers (p‐value for LR‐test: 0.03).ConclusionsPreoperative HE4 is a promising prognostic biomarker and performs better in predicting EOC mortality than CA125. This prognostic information provided by this optimal HE4 cut‐off, before surgery, could be useful for clinicians to better plan treatment strategies.Support or Funding InformationThis study was partly funded by the “Banque de tissus et de données du Réseau de recherche sur le cancer, Fonds de Recherche du Québec‐Santé », which is affiliated with the Canadian Tumor Repository Network. We thank Roche Diagnostics (Laval, Canada) for providing the HE4 and CA125 kits and the funds for the dosages and the statistical analyses.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Grey Parrot Anatomy Project—A study for science
Authors: Echols Scott Scott 
Published: June 2021

The Grey Parrot Anatomy Project is a collaborative effort to define the anatomy of one bird (Psittacus erithacus erithacus), utilize and develop new imaging technology that can potentially be used on any species including humans, collaborate with multiple scientific disciplines and share the data. This presentation will highlight the Project, demonstrate some of the new technology developed and show how the information is being utilized to better understand anatomy and diagnose and treat disease in multiple species. The Project has been funded by private donations and has been centered at the University of Utah. Many collaborators at other institutions and clinical practices have contributed to and/or benefited from the Project. In addition to being informative, this presentation is an invitation to collaborate.Support or Funding InformationPrivate donationsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Personalized 3D Craniofacial Morphometrics
Authors: Cevidanes Lucia H , Bianchi Jonas , de Oliveira Ruellas Antonio Carlos , Yatabe Ioshida Marilia S , Paniagua Beatriz , Goncalves Joao R , Prieto Juan Carlos 
Published: June 2021

This presentation will review current state of the art in 3D image analysis including 3D superimpositions relative to the cranial base and different regional superimpositions, the development of open source and commercial tools for 3D analysis, how this technology has increased clinical research collaborations from centers all around the globe, some insight on how to incorporate artificial intelligence for big data analysis and progress towards personalized facial morphometry assessments. Clinical applications of 3D image registration and superimposition have contributed to better understanding growth changes and clinical outcomes. The use of 3D dental and craniofacial imaging in dentistry requires validated image analysis methods for improved diagnosis, treatment planning, navigation and assessment of treatment response. Advanced 3D facial morphometry utilizes shape correspondence to train a neural network for shape variation analyses.Support or Funding InformationNIDCR R01 DE024450 and R21 DE025306This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Doxorubicin in myocardial lysophosphatidic acid signaling
Authors: Miriyala Sumitra , Sharma Sudha , Bhattarai Susmita , Leon Anthony , Panchatcharam Manikandan 
Published: June 2021

Generation of reactive oxygen species has been implicated in the toxicity of nearly 50% of the current FDA approved cancer therapeutic drugs. Mitochondrial respiration is a major source of reactive oxygen species production and that the presence of the mitochondrial antioxidant enzyme, manganese superoxide dismutase, is essential for the survival of all aerobic life. Our studies of animals using the prototype redox‐active anticancer drug, doxorubicin, indicate that overexpression of manganese superoxide dismutase protects the heart against doxorubicin‐induced cardiac injury and reduction of manganese superoxide dismutase by heterozygous knockout mice increases cardiac injury after exposure to doxorubicin. While the bioactive glycerophospholipid lysophosphatidic acid rises by seven‐fold over control subjects, suggesting lysophosphatidic acid may contribute to the doxorubicin‐induced cardiac toxicity. Lysophosphatidic acid production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate phosphatase‐3 (LPP3) catalyzes lysophosphatidic acid dephosphorylation to generate lipid products that are not receptor active. In this application, we present the first evidence that doxorubicin‐induced cardiac injury enhances myocardial autotaxin levels and decreases myocardial LPP3 expression, and this is associated with increased serum lysophosphatidic acid levels. Reactive oxygen species production arises as a burst of superoxide from mitochondria following doxorubicin‐induced cardiac injury. The redox‐sensitive transcription factor NFAT (a nuclear factor of activated T‐cells) has been shown to bind to the autotaxin promoter and induce its expression. Similarly, oxidant stress may deplete LPP3 levels in the context of cardiac injury through reduced LPP3 expression or enhanced LPP3 degradation. Thus, we hypothesize that doxorubicin‐induced cardiac injury alters autotaxin and LPP3 expression through mitochondrial superoxide production to drive lysophosphatidic acid signaling and cardiomyocyte dysfunction. The following interrelated specific aims are designed to provide step‐wise and in‐depth studies in vitro, in vivo, and in experimental therapeutics settings. Specific aim 1 will assess the role of myocardial superoxide production in autotaxin expression and lysophosphatidic acid production in doxorubicin‐induced cardiac injury. Specific aim 2 will determine the role of mitochondrial superoxide production in LPP3 depletion and lysophosphatidic acid regulation in doxorubicin‐induced cardiac injury. We could identify whether modulation of cellular versus mitochondrial antioxidant status confers a differential protective effect in doxorubicin‐induced cardiac injury models.Support or Funding InformationAAA‐ FGAP Fellow grant funded by the American Association of Anatomists.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Targeting Epithelial Expressed Sialyl Lewis A Improves Intestinal Mucosal Wound Healing and Protects Against Colitis
Authors: Kelm Matthias , Quiros Miguel , Cummings Richard D. , Nusrat Asma , Parkos Charles A. , Brazil Jennifer C. 
Published: June 2021

Dysregulated healing of mucosal wounds is a hallmark of many pathological conditions including inflammatory bowel disease (IBD). Mucosal wound healing involves a complex interplay between epithelial cells and infiltrating immune cells that trigger cell signaling events and epithelial cell migration, proliferation and differentiation that are necessary for mucosal homeostasis. Specific alterations in surface glycosylation have been reported in intestinal epithelial cells following injury, and we have shown that targeting the inflammation induced epithelial glycan sialyl Lewis A (sLea) with a specific mAb termed GM35 results in inhibition of neutrophil (PMN) trafficking in the inflamed intestine. Despite this observation, the role of glycans in intestinal wound healing has not been examined. Here we report that, in addition to inhibiting PMN transepithelial migration, targeting epithelial expressed sLea increases intestinal epithelial wound healing and recovery from barrier disruption in vitro. We report that these protective effects are mediated through deactivation of Akt (a kinase previously shown to destabilize epithelial adherens junctions) downstream of sLea engagement. Furthermore, wound bed injection of GM35 directly into biopsy‐induced colonic wounds resulted in a significant increase in mucosal wound healing in vivo. Finally, administration of GM35 to C57BL/6J mice followed by induction of colitis with dextran sodium sulfate resulted in reduced disease activity as assessed clinically and histologically, compared to mice treated with an isotype control mAb. Given our observations of robust upregulation of epithelial sLea during intestinal inflammation in mice and humans, these data suggest that targeting sLea may represent a promising new target for regulating intestinal trafficking of PMNs. In addition, targeting of this glycan may also provide an additional therapeutic strategy for improved recovery of epithelial barrier function and restitution of intestinal homeostasis following inflammation or injury.Support or Funding InformationThis work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 410855404), a senior Research Award from the Crohn's and Colitis Foundation (CCF) and R01 awards from the NIH (DK072564 and DK079392).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Endogenous DNA damage as a driver of senescence and aging
Authors: Niedernhofer Laura J 
Published: June 2021

Aging is defined as a loss of tissue homeostasis and resilience in the face of stress and is attributed to stochastic damage that occurs over time. However, in measuring the various types of cellular damage it is impossible to determine what damage caused aging and what is a consequence of it. Genetic depletion of the DNA repair enzyme in mice or cells leads to the accelerated accumulation of spontaneous endogenous DNA damage, which cannot be repaired. With this as an initiating event, we found that deletion of ERCC1‐XPF in primary fibroblasts causes a rapid acceleration of senescence. In vivo, depletion of ERCC1‐XPF also causes accelerated accumulation of senescent cells in numerous tissues including lung, heart, pancreas, liver, spleen, skin and brain. There is accelerated onset of age‐related pathology and spontaneous onset of multiple age‐related diseases including cerebral atrophy, chronic kidney disease, loss of vision and hearing, osteoporosis and disc degeneration. We also discovered increased production of reactive oxygen species and evidence of oxidative damage to multiple types of macromolecules in cells. Furthermore, in ERCC1‐XPF deficient mice we see loss of stem cell function, mitochondrial dysfunction, epigenetic changes, alterations in autophagy and stress responses. In all cases, changes seen in ERCC1‐XPF‐deficient mice were recapitulated in aged wild‐type mice. Finally, tissue‐specific deletion of ERCC1‐XPF is enough to cause rapid onset of age‐related disease such as cardiomyopathy, diabetes and dementia. These data establish endogenous DNA damage as a driver of aging. Furthermore, the response to DNA damage impacts all pillars of aging.Support or Funding InformationNIA P01 AG043376, NIA U19 AG056278, The Glenn FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Acetyl‐CoA metabolism and the response to dietary sugar
Authors: Wellen Kathryn 
Published: June 2021

Acetyl‐CoA is a central metabolite at the interface of metabolism, signaling, and epigenetics due to its functions in energetics, lipid metabolism, and as the acetyl group donor for lysine acetylation. Generation of the nuclear‐cytoplasmic pools of acetyl‐CoA that are needed for lipid synthesis and histone acetylation occurs largely from the export of citrate from mitochondria and cleavage by ATP‐citrate lyase (ACLY). Sugar consumption has increased dramatically in the United States and around the world in recent decades. ACLY levels increase in response to carbohydrate consumption in adipose tissue and in liver, and we hypothesized that ACLY in these tissues might be important for both the metabolic and transcriptional responses to carbohydrate consumption. In this presentation, I will discuss new findings using genetic models in which Acly is deleted from adipocytes or from the liver. Our data point to unexpected and distinct roles for ACLY in gene regulation and in lipid metabolism in response to dietary sugar.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Capsaicin and natural capsaicin‐like compounds suppress metastasis in lung adenocarcinoma
Authors: Friedman Jamie R , Richbart Stephen D , Merritt Justin C , Brown Kathleen C , Denning Krista L , Brown Linda G , Egleton Richard D , Dasgupta Piyali 
Published: June 2021

Lung adenocarcinoma (LAC) accounts for the majority of all non‐small cell lung cancer (NSCLC) cases. A substantial proportion of LAC patients present with local and distant metastasis at the time of their diagnosis. One of the earliest events of the metastatic process is the invasion of malignant cells through the surrounding extracellular basement membrane into the blood and lymph. The long‐term goal of our laboratory is to identify nutrition‐based agents which will suppress the growth and progression of human LACs. Capsaicin is the pungent ingredient of chili peppers. Published reports have revealed that capsaicin inhibits the invasion and metastasis of several types of human cancers including melanoma, prostate cancer, and cholangiosarcoma. However, the clinical application of capsaicin as an anti‐cancer drug is limited by its unpleasant side‐effect profile. This led us to compare the anti‐metastatic activity of capsaicin with natural non‐pungent capsaicin‐like compounds, namely capsiate and capsiconiate. The structure and bioactivity of capsaicin closely resembles capsiate. There are no published reports involving the biological activity of capsiconiate. We measured the anti‐invasive activity of these compounds by two independent invasion assays, namely the Boyden chamber assay and spherical invasion assay. We found that capsaicin and capsiate displayed anti‐invasive activity in three human LAC cell lines. In contrast, capsiconiate did not suppress the invasion of any LAC cell lines. Furthermore, we tested the anti‐metastatic activity of capsaicin in a syngeneic mouse model of metastasis. We observed that the daily dietary administration of capsaicin in AIN‐76A diet (with 5% lipid level) robustly decreased the area metastatic foci (in the lung) relative to vehicle‐treated mice. We investigated the signaling pathway underlying the anti‐metastatic activity of capsaicin. Our results show that capsaicin directly interacts with Src and inhibits Src activation to suppress the metastasis of LAC. The results of our studies may foster the development of novel anti‐metastatic therapies for human LAC.Support or Funding InformationFunding for our study was supported by an NIH R15‐AREA Grant (2R15CA161491‐02) and a NASA Undergraduate Fellowship to NAN.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Role of Endothelial RhoA in Melanoma and Lung Cancer Trans‐endothelial Migration and Metastasis
Authors: Sajib Md Sanaullah , Zahra Fatema Tuz , Park Jee Hyun , Tullar Paul , Srivastava Sanjay K. , Bickel Ulrich , Mikelis Constantinos M 
Published: June 2021

Vascular permeability, regulated by the balanced control of endothelial monolayer integrity, is altered in cancer. We have previously shown that activation of RhoA, a small GTPase, modulates actin cytoskeleton dynamics in endothelial cells, thus regulating the barrier function of the blood vessels. The barrier function is a limiting factor during metastasis, as the cancer cells need to cross the endothelial monolayer twice, during intravasation and extravasation. In this study, we explored the role of endothelial RhoA during the transmigration and metastatic dissemination of melanoma and lung carcinoma cells. We used a highly reproducible and quantifiable transwell‐based model to study trans‐endothelial migration in vitro, where fluorescently‐labelled cancer cells transmigrate through an endothelial monolayer. RhoA and its downstream signaling molecule Rho‐associated protein kinase (ROCK) were blocked by both pharmacological and knockdown approaches. Syngeneic murine melanoma (B16‐F10) and lung carcinoma (LLC‐LL3) cell lines were selected and tested in trans‐endothelial cell migration in vitro and experimental metastasis in vivo. Experimental metastasis experiments were performed through intravenous and intra‐cardiac administration in endothelial‐specific RhoA deficient mice or in the presence of clinically‐relevant ROCK inhibitors. Conditioned medium from both melanoma and cancer cells significantly increased in RhoA activation in primary endothelial cells. In vitro, blockade of endothelial RhoA‐ROCK pathway by either C3 toxin or the ROCK inhibitors decreased the trans‐endothelial migration of both cancer types and knock‐down of RhoA by siRNA in endothelial cells had similar effect. In vivo, decreased number of lung metastases was observed in mice deficient of endothelial RhoA in both intravenous and intra‐cardiac models, when compared to their littermate controls. Furthermore, treatment with a ROCK inhibitor, Fasudil, decreased the metastatic burden in the lungs without any visible toxicity. Taken together, these findings highlight the importance of endothelial RhoA as a target for melanoma and lung cancer metastasis.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mast Cell‐Derived Histamine Promotes Large Cholangiocyte Damage via H2 Histamine Receptor Signaling
Authors: Kennedy Lindsey , Hargrove Laura , Demieville Jennifer , Meadows Vik , Reinhart Evan , Virani Shohaib , Alpini Gianfranco , Glaser Shannon , Francis Heather 
Published: June 2021

The biliary tree contains both small and large ducts, that are surrounded by small and large cholangiocytes, respectively. Large cholangiocytes are more susceptible to damage, and proliferate following bile duct ligation (BDL). Further, we have shown that large cholangiocytes undergo senescence following cholestatic injury. Mast cells (MCs) infiltrate the liver following BDL, reside near large ducts, and secrete histamine that promotes biliary proliferation via cAMP/ERK signaling. Histamine signals through four histamine receptors (HRs), and H2HR is expressed by large cholangiocytes. The aim of our study was to identify the mechanism by which MC‐derived histamine promotes large cholangiocyte damage.12 wk old male wild‐type (WT) and KitW‐sh (MC‐deficient) mice were subjected to sham or BDL for 1 wk and selected WT and KitW‐sh mice received one tail vein injection of cultured MCs 3 days prior to sacrifice. Large ductal mass was measured by CK‐19 staining and semi‐quantification, and qPCR for PCNA is isolated large cholangiocytes. Large cholangiocyte senescence was shown by immunofluorescence (IF) for p16 and p21 (co‐stained with CK‐19) in liver sections, and qPCR in isolated large cholangiocytes. In large ducts, we evaluated H2HR expression and cAMP and pERK, expression by IF. In vitro, MCs were treated with control or the l‐histidine decarboxylase (HDC) inhibitor (3 mM, a‐methyl‐dl‐histidine (a‐Me)) for 48 hrs. Supernatants from treated MCs were placed on cultured large cholangiocytes and evaluated for: (i) proliferation; (ii) senescence; (iii) H2HR expression; (iv) cAMP expression and activity; and (v) pERK expression .BDL WT mice had increased large (but not small) ductal mass, which was reversed in BDL KitW‐sh mice. MC injection into WT and KitW‐sh mice increased large duct mass. Similarly, large cholangiocyte senescence increased following MC injections and in BDL WT mice, but was reduced in BDL KitW‐sh mice. MC injection and BDL WT mice had enhanced large cholangiocyte H2HR/cAMP/pERK expression; however, this was decreased in BDL KitW‐sh mice. In vitro, large cholangiocytes treated with MC supernatants had increased (i) proliferation, (ii) senescence, and (iii) H2HR/cAMP/pERK signaling. However, these parameters were reduced in large cholangiocytes treated with supernatants from MCs treated with a‐Me.During cholestatic liver injury, MCs primarily induce large cholangiocyte damage and MC‐derived histamine promotes large cholangiocyte proliferation and senescence via H2HR/cAMP/pERK signaling. Inhibition of MC‐derived histamine or large cholangiocyte H2HR signaling may be therapeutic for patients with large ductal damage.Support or Funding InformationVA Merit and NIH NIDDK R01This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.