bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes of urinary proteins in DDC‐induced chronic pancreatitis rat model
Authors: Zhang Linpei , Gao Youhe 
Published: June 2021

Biomarkers are changes associated with the disease. Without homeostasis mechanisms, theoretically urine can be better and earlier biomarker source than blood especially for chronic diseases. Chronic pancreatitis is a chronic inflammatory disease characterized by pancreatic fibrosis as a major pathological change. If diagnosed earlier, effective preventive measures may be used. In this study, we test if early changes can be detected in rat model of chronic pancreatitis induced by intraperitoneal injection of sodium diethyldithiocarbamate. Urine samples before injection and 2 weeks, 3 weeks and 4 weeks after injection were collected. Urinary proteins from three rats were profiled by liquid chromatography coupled with tandem mass spectrometry (LC‐MS/MS). Compared with before injection, the urinary patterns have changed significantly in all three rats. At week 2, fifteen differential proteins were identified when there was no obvious pathological changes yet. Twelve of these differential proteins were altered at other two time points and five proteins had previously been associated with chronic pancreatitis. At week 3, twenty‐nine differential proteins were identified, when inflammatory cytokines infiltration, acinar disruption, and slight fibrosis occurred. Significant fibrosis was detected at week 4 and thirty‐eight differential proteins were identified. At the stages of week 3 and week 4, fourteen urinary proteins had been reported to deferentially expressed in the serum or pancreatic tissue of chronic pancreatitis patients and other animal model studies. These findings demonstrate that changes caused by chronic pancreatitis can be reflected early in urinary proteins. Interesting clues can be found with only small number of modeled animals for further validation.Support or Funding InformationThis work was supported by the National Key Research and Development Program of China (2016YFC1306300), Beijing Natural Science Foundation (7173264, 7172076), and funds from Beijing Normal University (11100704, 10300‐310421102).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Identification of FZD5 as Genetic Vulnerability in RNF43 Mutant Cancer
Authors: Steinhart Zachary , Pavlovic Zvezdan , Chandrashekhar Megha , Mascall Keith , Hart Traver , Wang Xiaowei , Zhang Xiaoyu , Brown Kevin R. , Adams Jarrett , Pan James , Sidhu Sachdev , Moffat Jason , Angers Stephane 
Published: June 2021

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and novel effective treatments are greatly needed. Recent research revealed that a subset of PDAC cell lines is dependent on the Wnt cell‐signaling pathway for cell proliferation and survival. Wnt‐dependent PDAC all contain mutations in the gene encoding RNF43. RNF43 acts as a negative regulator of the Wnt pathway through ubiquitination and degradation of the Frizzled (FZD) family of Wnt receptors. RNF43 mutation status may therefore serve as a suitable biomarker for targeted therapy against the Wnt pathway in PDAC. In order to find novel genetic vulnerabilities in RNF43 mutant PDAC, we used genome‐wide CRISPR/Cas9 knockout screens in RNF43 mutant and wild‐type PDAC cell lines. Comparison of essential genes between RNF43 mutant and wild‐type groups was used to find context‐dependent essential genes for the RNF43 mutant genotype. This revealed the unexpected unique requirement of FZD5 (one of ten FZD homologs in humans) as a common genetic vulnerability in RNF43 mutant PDAC lines. This finding was validated through cell proliferation assays in vitro in both established cell lines and a primary patient derived cell line containing RNF43 mutation. Monoclonal antibodies derived against FZD5 were found to be remarkably effective as a single agent therapy both in vitro and in vivo, in subcutaneous and orthotopic xenograft models. Anti‐FZD5 biologics represent a novel potential targeted therapy in RNF43 mutant pancreatic cancers.Support or Funding InformationThis work was supported from grants funded by the Canadian Institutes for Health Research to S.A. (CIHR‐273548) and J.M. (CIHR‐342551) and by the Ontario Research Fund to S.S. J.M. holds a Canada Research Chair in Functional Genomics of Cancer and S.A. holds a Canada Research Chair in Functional Architecture of Signal Transduction. Z.S. is supported by a scholarship from the Centre for Pharmaceutical Oncology at the Leslie Dan Faculty of Pharmacy, University of Toronto.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Evaluating the Role of the Na+‐H+ Exchanger Isoform 1 (NHE1) in Non‐small Cell Lung Cancer
Authors: Kooiker Amanda J. , Provost Joseph J. , Wallert Mark 
Published: June 2021

Lung cancer is a debilitating disease with 222,000 new cases diagnosed each year and causing 156,000 deaths each year in the United States. Approximately 80% of lung cancers are categorized as non‐small cell lung cancer (NSCLC). Of these NSCLCs, 50% are comprised of adenocarcinomas, or tumors that originated within glandular epithelium, while 30% are due to squamous cell carcinomas, or a cancer that began at in a squamous epithelial lining. The Na+‐H+ Exchanger Isoform 1 (NHE1) acts as a key regulator in cellular proliferation, migration, and metastasis in a variety of solid tumors. NHE1 exchanges 1 extracellular Na+ ion for 1 intracellular H+ ion driving changes in both intracellular and extracellular pH in these developing tumors. To evaluate the role of NHE1 in NSCLC, we employed three cells types: 1) NCI‐H1299 a carcinoma cell line, 2) NCI‐H520 a squamous cell carcinoma cell line, and 3) NCI‐H23 and adenocarcinoma cell line. For each cell type, changing the media conditions from 0.5% serum to 10% serum increased the rate of cell proliferation 2 to 3 fold. This increased proliferation was blocked when the NHE1 inhibitors EIPA (ethylisopropylamiloride) or cariporide were present. Similarly, the change in serum concentration increase cell migrations rates in an NHE1‐dependent manner. To further evaluate the role of NHE1 in these cells, western blot analysis was completed to evaluate NHE1 expression in both low and normal serum conditions for each cell type. We also employed CRISPR‐Cas9 technology to develop an NHE1‐knockout (NHE1‐KO) cell line for each cell type. The rates of cell proliferation and migration where then evaluated in the NHE1‐KO cells as compared to NHE1 expressing cells.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The aggressive nature of prostate cancer of African Americans is correlated with massive down‐regulation of many immunoregulatory genes of microenvironment
Authors: Rahmatpanah Farah , Zi Xiaolin , Sawyers Anne , Agrawal Anshu , Lilly Michael , McClelland Michael , Mercola Dan 
Published: June 2021

BackgroundThe overall survival of prostate cancer for African Americans (AAs) is significantly worse than for European‐Americans (EA) which cannot be attributed to social‐economic status and may be related to racial‐genetic differences. We previously applied expression analysis (U133A) and observed significantly decreased expression of AA patient compared to EA patients especially in the tumor‐adjacent stroma. We tested the hypothesis that gene express in the stroma AA patients was significantly decreased compared to EA.MethodsWe developed primary cultures of turmor‐adjacent carcinoma‐associated fibroblasts (CAFs) of AA and EA tumors and matching distant contralateral fibroblasts (dCAFs), ~100 lines in all. We examined secretion of immunomodulators from the CAFs and dCAFs from prostate cancer of AA and EA tumors and distant stroma (dCAFs) as controls and applied RNAseq of the same cells as well as archived FFPE (formal‐fixed paraffin‐embedded) blocks of AA and EA patients.ResultsAll 30 measured secreted immunomodulators were lower for AA CAFs. In contrast, few if any differences were seen between dCAFs of AA and EA. In particular Interferon‐alpha2 (IFN‐a2) is significantly reduced which is in keeping with the reduced immunomodulatory and Interferon‐induced genes (ISGs) observed for AA patients. The widespread reduction in immunomodulatory chemokines and cytokines observed in AA CAF supernatants suggests a state of significant immunosuppression as compared to the EA CAFs. The higher expression levels of chemokines Eotaxin, IP‐10, MIP1‐a, MIP‐1b, and MCP‐1, in the EA stroma may attract and activate immune cells to the tumor microenvironment thereby improving prognosis. Higher levels of several of inflammatory cytokines such as IL‐17, IL‐12, IL‐1a, IL‐1b in EA patients also may help activate immune cells leading to greater inflammation and immune responses in EA patients. The RNAseq data of AA and EA CAFs and for the FFPE tissue of AA and EA patients supported the decreased expression of the immunomodulatory genes in the stroma of AA patients compared to EA patients.ConclusionThe detection of many statistically significant differences among ISGs and other immunomodulatory genes between the races is supported by RNAseq analysis of FFPE stroma tissue and by in vitro analysis of primary tumor‐adjacent stroma indicating that differences in immunomodulatory mechanisms may be a factor in the poor prognosis of AA prostate cancer. The primary lines of AA and EA CAFs and dCAFs may be a valid system to test role of these factors.Support or Funding InformationDOD/CDMRP W81XWH‐15‐1‐0696This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Comparative analysis of RORA expression in brain tissue from multiple sclerosis and normal individuals:a pilot study
Authors: Schroeder Stephanie C. , Heath Leah 
Published: June 2021

The key to understanding the autoimmune disease multiple sclerosis (MS) lies in a deeper analysis of the genes that play a role in the pathology of the disease. A new gene of interest encodes the retinoic acid receptor‐related orphan receptor alpha (RORA). This receptor is expressed in several tissues and plays a critical role in regulating inflammatory response, neuronal cell development, bone metabolism, and has been proposed to promote the differentiation of Th17 cells. Th17 cells play a role in initiating autoimmune central nervous system inflammation, which is the cause of this debilitating disease. To better understand the significance of RORA in MS, the focus of this study was to observe the expression of this receptor and determine its role in susceptibility of multiple sclerosis. We did so by isolating RNA from 10 brain samples, 5 from multiple sclerosis patients and 5 from healthy controls. We then subjected the RNA to quantitative RT‐PCR and normalized the samples to control RNAs TBP and GAPDH. We found that there was a significant increase in expression of RORA (P<0.05) in brain samples from MS patients compared with healthy controls. This novel finding could be used as diagnostic criteria for susceptibility of multiple sclerosis and could potentially be a target for new treatments.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Using Human Cerebral Organoids to Study the Role of the Microbiome in Neuroinflammation
Authors: DiUbaldi Gianluca , Toth Charles 
Published: June 2021

All cells within the central nervous system (CNS), including neurons and glial cells, respond to inflammatory mediators. It is integral to understand how these inflammatory pathways are activated within the CNS by both endogenous and exogenous factors. Diverse neuro‐immune and neuro‐psychiatric disorders are correlated with or modulated by changes of microbiome or microbiota‐derived metabolites. To study such a complex system, it is best to develop a model that best recapitulates in vivo biology. As a model of the CNS, cortical spheroids, derived from human pluripotent stem cells, were used to study inflammatory responses since they are a physiologically relevant 3D co‐culture of neurons and glial cells. For this experiment, spheroids were treated for 24 hours with the inflammatory mediators poly (I:C) (10 mg/mL) and indoxyl‐3‐sulfate (I3S) (50 mM). Poly (I:C) is a Toll‐like receptor agonist (TLR3), and I3S is a metabolite from tryptophan generated by the resident microbiome and an aryl hydrocarbon receptor agonist. The degree of neuroinflammation were analyzed using immunofluorescence of iNOS co‐localization with neurons and astrocytes in organoid sections. qPCR was also used to analyze the expression levels of TNF alpha and iNOS. Metabolic remodeling of treated spheroids was determined by using a Seahorse XFe96 Analyzer to show changes in metabolic pathways in the treated cells. These inflammatory responses have known biological links to many neurodegenerative disorders such as Huntington's and ALS, so the use of human cerebral organoids to examine these responses is pertinent to disease research and drug discovery.Support or Funding InformationThe authors would like to thank the Walsh Fund from Providence College and alumni Dr. John Mullen, Dr. Herbert Brennan and Roderick Lichtenfels for their generous research support.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Biological and Health Aspects of Edible Wild Omani Plants in the Primary Prevention of Oxidative Stress‐mediated Colon Cancer
Authors: Waly Mostafa I. , Guizani Nejib , Rahman Mohammad Shafiur , Al‐Attabi Zaher 
Published: June 2021

BackgroundEpidemiological, clinical trials and observational studies continue to support the notion that colon cancer is a nutritionally modified disease in which oxidative stress is a cofactor. Oxidative stress is involved in the pathogenesis of colon cancer. Although edible wild Omani plants (Portulaca oleracea, Pteropyrum scoparium, and Oxalis corniculata) are rich in phytonutrients (polyphenols and flavonoids), yet their medicinal use in relation to cancer was not well studied.ObjectiveThis study aimed to identify the antioxidant potential properties of three different edible wild Omani plants (Portulaca oleracea, Pteropyrum scoparium, and Oxalis corniculata) against colon cancer pathogenesis in rats.MethodsA colon specific carcinogen, azoxymethane, was used to induce cancer in rat colon. The animals were allocated into 8 groups (10 rats/group) as follow; control group and azoxymethane‐injected group. Meanwhile the other 6 groups were rats fed one of the three plants extracts in the presence or absence of azoxymethane. After 12 weeks, all rats were sacrificed and colon tissues were dissected and used for aberrant crypt foci enumeration as well as for biochemical analysis of oxidative stress markers.ResultsIt was observed that, the assayed three plants extracts had a protective role against colon cancer by abrogating the azoxymethane‐induced colonic carcinogenesis and oxidative stress.ConclusionEdible wild Omani plants act as a dietary bioactive agents and combat oxidative stress‐mediated colon cancer disease. It is recommended to be utilized in the daily food chain of the first degree relatives of colon cancer patients. This nutrition intervention approach might be effective in the primary prevention of colon cancer.Support or Funding InformationThis research was supported by Internal Grant Funding (IG/AGR/FOOD/17/1), College of Agricultural and Marine Sciences, Sultan Qaboos UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Determining Neuronal Fate in C. elegans
Authors: Chalfie Martin 
Published: June 2021

Neuronal differentiation is not simply the turning on of a developmental switch that results in the production of cell‐specific expression and features. We have used the six touch receptor neurons (TRNs) in C. elegans to identify and study the factors needed to initiate and maintain the differentiation of a specific type of neuron. We have identified transcription factors that specify, maintain, and restrict cell fate and others transcription factors, including Hox proteins, that reduce stochastic variability and ensure differentiation. The first class of transcription factors includes selectors, which direct the production of cell‐characteristic proteins, but also transcription factors that restrict and allow the selectors to act. We are calling the second class of transcription factors, which allow maximal function of selectors, guarantors. Our most recent studies are directed at understanding how different subtypes of TRNs are specified. One particular differences between the cells is that some are monopolar cells whereas others are bipolar cells.Support or Funding InformationThis work was supported by grants GM30997 and GM122522 from the National Institutes of HealthThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Glucocorticoid Receptor‐Dependent Gene Expression in the Central Amygdala of Alcohol‐Dependent Animals
Authors: McGinn Mary Adrienne , Edwards Kim , Edwards Scott 
Published: June 2021

Alcohol Use Disorder (AUD) is a chronic, relapsing psychiatric disorder that is characterized by the development of motivational symptoms (e.g., escalation of alcohol intake) and the parallel emergence of negative emotional states (e.g., dysphoria, anxiety, pain). Consequently, the transition from recreational, limited alcohol consumption to uncontrolled, escalated intake is proposed to involve a transition from positive to negative reinforcement mechanisms. Our previous research indicates that alcohol dependence is associated with potentiated glucocorticoid signaling in brain regions that mediate stress and nociception, namely the central amygdala (CeA). Glucocorticoid receptor (GR) antagonism with mifepristone has demonstrated promising efficacy in reducing alcohol consumption in humans with AUD and rodent models of alcohol dependence. However, mifepristone's mechanism of action remains unclear. Given the role of GR as a transcription factor, we hypothesized that potentiated GR activity increases the expression of downstream neuropeptide system genes, and mifepristone normalizes these transcriptional effects. We tested our hypothesis in a well‐ established rodent model of AUD that utilizes chronic intermittent ethanol vapor exposure (CIEV). One day prior to the start of vapor exposure, animals were implanted with either placebo or 30d chronic release mifepristone pellets. After the 4‐week treatment regimen, we utilized a fluorescent bead‐based multiplex assay to determine brain region‐specific changes in mRNA levels of expected GR‐regulated genes. Results were analyzed via two‐way ANOVA, with alcohol vapor exposure (modeling alcohol dependence) and mifepristone treatment as factors. We found that within the CeA, alcohol dependence was associated with increased mRNA coding for the nociceptin peptide as well as its receptor, opioid receptor‐like 1 (Orl1), while mifepristone treatment significantly attenuated this effect. The nociceptin system is a part of the endogenous opioid class of signaling molecules, and previous research has demonstrated a role for nociceptin in both chronic pain and the manifestation of negative affect during alcohol withdrawal. Our findings suggest that the therapeutic benefits of mifepristone could be associated with a blunting of the nociceptin system in the central amygdala.Support or Funding InformationOur research is supported by the following grants from the National Institute on Alcohol Abuse and Alcoholism: F31AA025812 (MAM) and R00AA020839 (SE).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Baroreflex Influence on Left Ventricle Energetics and Changes after Myocardial Infarct
Authors: Bras‐Rosario Luis , Apura Joao , Rocha Isabel , Tiago Jorge , Pinto Fausto , Sequeira Adélia 
Published: June 2021

In the classic description the Baroreflex is a negative feedback mechanism that controls arterial blood pressure, as sensed by the baroreceptors. It is a key component of the Autonomic regulation of the circulation in normal conditions and during Myocardial Infarction.As the Baroreflex influences the heart rate, cardiac contractility and vascular resistance, we hypothesised that it must influence the mechanical interaction between the left ventricle and the arterial tree as well as cardiac energy consumption and efficiency during Myocardial Infarction.The Baroreflex was evaluated in 11 rabbits by partial occlusion of the common carotid artery before and after the induction of cardiac ischemia by the occlusion of the left anterior descending artery. The left ventricular pressure and left ventricular volume were measured with an intraventricular pressure and impedance catheter.We designed a custom software to characterize beat by beat left‐ventricular and arterial physiologic properties. From this data, left‐ventricle end‐systolic elastance (Ees), arterial elastance (Ea) and the coupling ratio (Ea/Ees) were computed. We also calculated left‐ventricular stroke work (SW), total energy expenditure (PVA), mechanical efficiency measured by the ratio of the SW to its theoretical maximum (Qload) and cardiac energetic efficiency (CEE=SW/PVA).In Basal conditions upon the application of the Baroreflex, the Ees, Ea showed an approximately similar increase which resulted in a constant Ea/Ees. SW and PVA increased while Qload and CEE remained similar. After Myocardial Infarction there is an alteration in the Baroreflex response that increases Ea and Ees differently which resulted in an increase in Ea/Ees ratio. SW and PVA increased while Qload decreased and CEE remained similar (Table). The main difference between Basal and Myocardial Infarct responses during the Baroreflex are the increase in Ea/Ees and the decrease in Qload.In conclusion the Baroreflex is a control mechanism of the cardiovascular system which exerts a feedback modulation on the arterial pressure through a balanced increase in cardiac contractility and arterial elastance, that preserves both its mechanical and energetic efficiency in Basal conditions. After Myocardial Infarct the Baroreflex changes its behaviour and increases cardiac contractility and arterial elastance maintaining the energetic efficiency crucial during ischemia at the expense of a decrease in mechanical efficiency.Support or Funding InformationModelação Matemática e Computacional da Fisiologia Humana (2013) Fundação para a Ciência e Tecnologia EXCL/MAT‐NAN/0114/2012This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.