1  720 135 CALPAIN-14 AND ITS ASSOCIATION WITH EOSINOPHILIC ESOPHAGITIS. CALPAINS ARE A FAMILY OF INTRACELLULAR, CALCIUM-DEPENDENT CYSTEINE PROTEASES INVOLVED IN A VARIETY OF REGULATORY PROCESSES, INCLUDING CYTOSKELETAL DYNAMICS, CELL-CYCLE PROGRESSION, SIGNAL TRANSDUCTION, GENE EXPRESSION, AND APOPTOSIS. THESE ENZYMES HAVE BEEN IMPLICATED IN A NUMBER OF DISEASE PROCESSES, NOTABLY FOR THIS REVIEW INVOLVING EOSINOPHILIC TISSUE INFLAMMATION, SUCH AS EOSINOPHILIC ESOPHAGITIS (EOE), A CHRONIC INFLAMMATORY DISORDER TRIGGERED BY ALLERGIC HYPERSENSITIVITY TO FOOD AND ASSOCIATED WITH GENETIC VARIANTS IN CALPAIN 14 (CAPN14). HEREIN WE REVIEW THE GENETIC, STRUCTURAL, AND BIOCHEMICAL PROPERTIES OF CAPN14 AND ITS GENE PRODUCT CAPN14, AND ITS EMERGING ROLE IN PATIENTS WITH EOE. THE CAPN14 GENE IS LOCALIZED AT CHROMOSOME 2P23.1-P21 AND IS MOST HOMOLOGOUS TO CAPN13 (36% SEQUENCE IDENTITY), WHICH IS LOCATED 365 KB DOWNSTREAM OF CAPN14. STRUCTURALLY, CAPN14 HAS CLASSICAL CALPAIN MOTIFS, INCLUDING A CYSTEINE PROTEASE CORE. IN COMPARISON WITH OTHER HUMAN CALPAINS, CAPN14 HAS A UNIQUE EXPRESSION PATTERN, WITH THE HIGHEST LEVELS IN THE UPPER GASTROINTESTINAL TRACT, PARTICULARLY IN THE SQUAMOUS EPITHELIUM OF THE ESOPHAGUS. THE CAPN14 GENE IS POSITIONED IN AN EPIGENETIC HOTSPOT REGULATED BY IL-13, A T(H)2 CYTOKINE WITH INCREASED LEVELS IN PATIENTS WITH EOE THAT HAS BEEN SHOWN TO BE A MEDIATOR OF THE DISEASE. CAPN14 INDUCES DISRUPTIVE EFFECTS ON THE ESOPHAGEAL EPITHELIUM BY IMPAIRING EPITHELIAL BARRIER FUNCTION IN ASSOCIATION WITH LOSS OF DESMOGLEIN-1 EXPRESSION AND HAS A REGULATORY ROLE IN REPAIRING EPITHELIAL CHANGES INDUCED BY IL-13. THUS CAPN14 IS A UNIQUE PROTEASE WITH DISTINCT TISSUE-SPECIFIC EXPRESSION AND FUNCTION IN PATIENTS WITH EOE AND IS A POTENTIAL THERAPEUTIC TARGET FOR EOE AND RELATED EOSINOPHILIC AND ALLERGIC DISEASES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
2 3051  42 GENOME-WIDE ASSOCIATION ANALYSIS OF EOSINOPHILIC ESOPHAGITIS PROVIDES INSIGHT INTO THE TISSUE SPECIFICITY OF THIS ALLERGIC DISEASE. EOSINOPHILIC ESOPHAGITIS (EOE) IS A CHRONIC INFLAMMATORY DISORDER ASSOCIATED WITH ALLERGIC HYPERSENSITIVITY TO FOOD. WE INTERROGATED >1.5 MILLION GENETIC VARIANTS IN EOE CASES OF EUROPEAN ANCESTRY AND SUBSEQUENTLY IN A MULTI-SITE COHORT WITH LOCAL AND OUT-OF-STUDY CONTROL SUBJECTS. IN ADDITION TO REPLICATING ASSOCIATION OF THE 5Q22 LOCUS (META-ANALYSIS P=1.9X10(-16)), WE IDENTIFIED AN ASSOCIATION AT 2P23 SPANNING CAPN14 (P=2.5X10(-10)). CAPN14 WAS SPECIFICALLY EXPRESSED IN THE ESOPHAGUS, WAS DYNAMICALLY UPREGULATED AS A FUNCTION OF DISEASE ACTIVITY AND GENETIC HAPLOTYPE AND AFTER EXPOSURE OF EPITHELIAL CELLS TO INTERLEUKIN (IL)-13, AND WAS LOCATED IN AN EPIGENETIC HOTSPOT MODIFIED BY IL-13. GENES NEIGHBORING THE TOP 208 EOE-ASSOCIATED SEQUENCE VARIANTS WERE ENRICHED FOR ESOPHAGEAL EXPRESSION, AND MULTIPLE LOCI FOR ALLERGIC SENSITIZATION WERE ASSOCIATED WITH EOE SUSCEPTIBILITY (4.8X10(-2)<P<5.1X10(-11)). WE PROPOSE A MODEL TO EXPLAIN THE TISSUE-SPECIFIC NATURE OF EOE THAT INVOLVES THE INTERPLAY OF ALLERGIC SENSITIZATION WITH AN EOE-SPECIFIC, IL-13-INDUCIBLE ESOPHAGEAL RESPONSE INVOLVING CAPN14.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
3 4164  32 MEDIATORS OF CAPILLARY-TO-VENULE CONVERSION IN THE CHRONIC INFLAMMATORY SKIN DISEASE PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EPIDERMAL HYPERPLASIA AND HYPERKERATOSIS, IMMUNE CELL INFILTRATION AND VASCULAR REMODELING. DESPITE THE EMERGING RECOGNITION OF VASCULAR NORMALIZATION AS A POTENTIAL STRATEGY FOR MANAGING PSORIASIS, AN IN-DEPTH DELINEATION OF THE REMODELED DERMAL VASCULATURE HAS BEEN MISSING. IN THIS STUDY, WE EXPLOITED 5' SINGLE-CELL RNA SEQUENCING TO INVESTIGATE THE TRANSCRIPTOMIC ALTERATIONS IN DIFFERENT SUBPOPULATIONS OF BLOOD VASCULAR AND LYMPHATIC ENDOTHELIAL CELLS DIRECTLY ISOLATED FROM PSORIATIC AND HEALTHY HUMAN SKIN. INDIVIDUAL SUBTYPES OF ENDOTHELIAL CELLS UNDERWENT SPECIFIC MOLECULAR REPATTERNING ASSOCIATED WITH CELL ADHESION AND EXTRACELLULAR MATRIX ORGANIZATION. BLOOD CAPILLARIES, IN PARTICULAR, SHOWED UPREGULATION OF THE MELANOMA CELL ADHESION MOLECULE AS WELL AS ITS BINDING PARTNERS AND ADOPTED POSTCAPILLARY VENULE?LIKE CHARACTERISTICS DURING CHRONIC INFLAMMATION THAT ARE MORE PERMISSIVE TO LEUKOCYTE TRANSMIGRATION. WE ALSO IDENTIFIED PSORIASIS-SPECIFIC INTERACTIONS BETWEEN CIS-REGULATORY ENHANCERS AND PROMOTERS FOR EACH ENDOTHELIAL CELL SUBTYPE, REVEALING THE DYSREGULATED GENE REGULATORY NETWORKS IN PSORIASIS. TOGETHER, OUR RESULTS PROVIDE MORE INSIGHTS INTO THE SPECIFIC TRANSCRIPTIONAL RESPONSES AND EPIGENETIC SIGNATURES OF ENDOTHELIAL CELLS LINING DIFFERENT VESSEL COMPARTMENTS IN CHRONIC SKIN INFLAMMATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4 2022  42 EPIGENETIC CHANGES ASSOCIATED WITH DISEASE PROGRESSION IN A MOUSE MODEL OF CHILDHOOD ALLERGIC ASTHMA. DEVELOPMENT OF ASTHMA IN CHILDHOOD IS LINKED TO VIRAL INFECTIONS OF THE LOWER RESPIRATORY TRACT IN EARLY LIFE, WITH SUBSEQUENT CHRONIC EXPOSURE TO ALLERGENS. PROGRESSION TO PERSISTENT ASTHMA IS ASSOCIATED WITH A TH2-BIASED IMMUNOLOGICAL RESPONSE AND STRUCTURAL REMODELLING OF THE AIRWAYS. THE UNDERLYING MECHANISMS ARE UNCLEAR, BUT COULD INVOLVE EPIGENETIC CHANGES. TO INVESTIGATE THIS, WE EMPLOYED A RECENTLY DEVELOPED MOUSE MODEL IN WHICH SELF-LIMITED NEONATAL INFECTION WITH A PNEUMOVIRUS, FOLLOWED BY SENSITISATION TO OVALBUMIN VIA THE RESPIRATORY TRACT AND LOW-LEVEL CHRONIC CHALLENGE WITH AEROSOLISED ANTIGEN, LEADS TO DEVELOPMENT OF AN ASTHMATIC PHENOTYPE. WE ASSESSED EXPRESSION OF MICRORNA BY CELLS IN THE PROXIMAL AIRWAYS, COMPARING CHANGES OVER THE PERIOD OF DISEASE PROGRESSION, AND USED TARGET PREDICTION DATABASES TO IDENTIFY GENES LIKELY TO BE UP- OR DOWNREGULATED AS A CONSEQUENCE OF ALTERED REGULATION OF MICRORNA. IN PARALLEL, WE ASSESSED DNA METHYLATION IN PULMONARY CD4(+) T CELLS. WE FOUND THAT A LIMITED NUMBER OF MICRORNAS EXHIBITED MARKED UP- OR DOWNREGULATION FOLLOWING EARLY-LIFE INFECTION AND SENSITISATION, FOR MANY OF WHICH THE LEVELS OF EXPRESSION WERE FURTHER CHANGED FOLLOWING CHRONIC CHALLENGE WITH THE SENSITIZING ANTIGEN. TARGETS OF THESE MICRORNAS INCLUDED GENES INVOLVED IN IMMUNE OR INFLAMMATORY RESPONSES (E.G. GATA3, KITL) AND IN TISSUE REMODELLING (E.G. IGF1, TGFBR1), AS WELL AS GENES FOR VARIOUS TRANSCRIPTION FACTORS AND SIGNALLING PROTEINS. IN PULMONARY CD4(+) T CELLS, THERE WAS SIGNIFICANT DEMETHYLATION AT PROMOTER SITES FOR INTERLEUKIN-4 AND INTERFERON-GAMMA, THE LATTER INCREASING FOLLOWING CHRONIC CHALLENGE. WE CONCLUDE THAT, IN THIS MODEL, PROGRESSION TO AN ASTHMATIC PHENOTYPE IS LINKED TO EPIGENETIC REGULATION OF GENES ASSOCIATED WITH INFLAMMATION AND STRUCTURAL REMODELLING, AND WITH T-CELL COMMITMENT TO A TH2 IMMUNOLOGICAL RESPONSE. EPIGENETIC CHANGES ASSOCIATED WITH THIS PATTERN OF GENE ACTIVATION MIGHT PLAY A ROLE IN THE DEVELOPMENT OF CHILDHOOD ASTHMA.	2013	
                                                                                                                                                                                                                                                                                                                                                                               
5  655  33 BLOCKADE OF IMMUNE-CHECKPOINT B7-H4 AND LYSINE DEMETHYLASE 5B IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA CONFERS PROTECTIVE IMMUNITY AGAINST P. GINGIVALIS INFECTION. PATHOGENS ARE CAPABLE OF HIJACKING IMMUNE DEFENSE MECHANISMS, THEREBY CREATING A TOLEROGENIC ENVIRONMENT FOR HYPERMUTATED MALIGNANT CELLS THAT ARISE WITHIN THE SITE OF INFECTION. IMMUNE CHECKPOINT-ORIENTED IMMUNOTHERAPIES HAVE SHOWN CONSIDERABLE PROMISE. EQUALLY IMPORTANT, THE EPIGENETIC REPROGRAMMING OF AN IMMUNE-EVASIVE PHENOTYPE THAT ACTIVATES THE IMMUNE SYSTEM IN A SYNERGISTIC MANNER CAN IMPROVE IMMUNOTHERAPY OUTCOMES. THESE ADVANCES HAVE LED TO COMBINATIONS OF EPIGENETIC- AND IMMUNE-BASED THERAPEUTICS. WE PREVIOUSLY DEMONSTRATED THAT PORPHYROMONAS GINGIVALIS ISOLATED FROM ESOPHAGEAL SQUAMOUS CELL CARCINOMA (ESCC) LESIONS REPRESENTS A MAJOR PATHOGEN ASSOCIATED WITH THIS DEADLY DISEASE. IN THIS STUDY, WE EXAMINED THE MECHANISMS ASSOCIATED WITH HOST IMMUNITY DURING P. GINGIVALIS INFECTION AND DEMONSTRATED THAT EXPERIMENTALLY INFECTED ESCC RESPONDS BY INCREASING THE EXPRESSION OF B7-H4 AND LYSINE DEMETHYLASE 5B, WHICH ALLOWED SUBSEQUENT IN VIVO ANALYSIS OF THE IMMUNOTHERAPEUTIC EFFECTS OF ANTI-B7-H4 AND HISTONE DEMETHYLASE INHIBITORS IN MODELS OF CHRONIC INFECTION AND IMMUNITY AGAINST XENOGRAFTED HUMAN TUMORS. USING THREE DIFFERENT PRECLINICAL MOUSE MODELS RECEIVING COMBINED THERAPY, WE SHOWED THAT MICE MOUNTED STRONG RESISTANCE AGAINST P. GINGIVALIS INFECTION AND TUMOR CHALLENGE. THIS MAY HAVE OCCURRED VIA GENERATION OF A T CELL-MEDIATED RESPONSE IN THE MICROENVIRONMENT AND FORMATION OF IMMUNE MEMORY. IN ESCC SUBJECTS, COEXPRESSION OF B7-H4 AND KDM5B CORRELATED MORE SIGNIFICANTLY WITH BACTERIAL LOAD THAN WITH THE EXPRESSION OF EITHER MOLECULE ALONE. THESE RESULTS HIGHLIGHT THE UNIQUE ABILITY OF P. GINGIVALIS TO EVADE IMMUNITY AND DEFINE POTENTIAL TARGETS THAT CAN BE EXPLOITED THERAPEUTICALLY TO IMPROVE THE CONTROL OF P. GINGIVALIS INFECTION AND THE DEVELOPMENT OF ASSOCIATED NEOPLASIA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6 6906  35 [THE ROLE OF GLYCANS IN CANCER DEVELOPMENT AND PROGRESSION. CLINICAL APPLICATIONS]. CHANGES IN GLYCOSYLATION PATTERN OF CELL SURFACE, BODY FLUIDS AND EXTRACELLULAR MATRIX GLYCOCONJUGATES IS A CHARACTERISTIC FEATURE OF TUMOR CELL MALIGNANCY. THESE CHANGES ARE THE RESULT OF MUTATIONS OF TUMOR-ASSOCIATED GENES AS WELL AS EPIGENETIC CHANGES IN THE TUMOR ENVIRONMENT, INCLUDING NUTRIENT INFLUX, HYPOXIA, CYTOKINE EXPRESSION AND STIMULATION OF CHRONIC INFLAMMATION. THE UNIQUE SET OF CELL SURFACE GLYCOANTIGENS ON NEOPLASTIC CELLS IS RECOGNIZED BY ENDOGENOUS LECTINS LOCATED IN THE EXTRACELLULAR MATRIX, VASCULAR ENDOTHELIUM, ON LEUKOCYTES OR PLATELETS, AND HAS AN IMPACT ON DISRUPTING BASIC CELLULAR PROCESSES, SUCH AS INTERCELLULAR RECOGNITION, CELL-CELL ADHESION OR CELL-ECM INTERACTION. THESE CHANGES HAVE A CRITICAL IMPACT ON THE MIGRATION, INVASIVE AND METASTATIC POTENTIAL OF NEOPLASTIC CELLS AND MODULATE THE IMMUNE RESPONSE. THIS UNIQUE PATTERN OF SUGAR ANTIGENS ON THE CANCER CELLS CAN BE A VAULABLE MARKER TO IDENTIFY THEM, DETERMINE THE STAGE OF THE DISEASE AS WELL AS BE A TARGET OF ANTI-CANCER THERAPY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
7 6708  40 VIRAL INDUCED EFFECTS ON A VULNERABLE EPITHELIUM; LESSONS LEARNED FROM PAEDIATRIC ASTHMA AND EOSINOPHILIC OESOPHAGITIS. THE EPITHELIUM IS INTEGRAL TO THE PROTECTION OF MANY DIFFERENT BIOLOGICAL SYSTEMS AND FOR THE MAINTENANCE OF BIOCHEMICAL HOMEOSTASIS. EMERGING EVIDENCE SUGGESTS THAT PARTICULAR CHILDREN HAVE EPITHELIAL VULNERABILITIES LEADING TO DYSREGULATED BARRIER FUNCTION AND INTEGRITY, THAT RESULTANTLY CONTRIBUTES TO DISEASE PATHOGENESIS. THESE EPITHELIAL VULNERABILITIES LIKELY DEVELOP IN UTERO OR IN EARLY LIFE DUE TO VARIOUS GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. ALTHOUGH VARIOUS EPITHELIA ARE UNIQUELY STRUCTURED WITH SPECIFIC FUNCTION, PREVALENT ALLERGIC-TYPE EPITHELIAL DISEASES IN CHILDREN POTENTIALLY HAVE COMMON OR PARALLEL DISEASE PROCESSES. THESE INCLUDE INFLAMMATION AND IMMUNE RESPONSE DYSREGULATION STEMMING FROM ATYPICAL EPITHELIAL BARRIER FUNCTION AND INTEGRITY. TWO DISEASES WHERE AETIOLOGY AND PATHOGENESIS ARE POTENTIALLY LINKED TO EPITHELIAL VULNERABILITIES INCLUDE PAEDIATRIC ASTHMA AND EOSINOPHILIC OESOPHAGITIS (EOE). FOR EXAMPLE, RHINOVIRUS C (RV-C) IS A KNOWN RISK FACTOR FOR PAEDIATRIC ASTHMA DEVELOPMENT AND IS KNOWN TO DISRUPT RESPIRATORY EPITHELIAL BARRIER FUNCTION CAUSING ACUTE INFLAMMATION. IN ADDITION, EOE, A PREVALENT ATOPIC CONDITION OF THE OESOPHAGEAL EPITHELIUM, IS CHARACTERISED BY SIMILAR INNATE IMMUNE AND EPITHELIAL RESPONSES TO VIRAL INJURY. THIS REVIEW EXAMINES THE CURRENT LITERATURE AND IDENTIFIES THE GAPS IN THE FIELD DEFINING VIRAL-INDUCED EFFECTS ON A VULNERABLE RESPIRATORY EPITHELIUM AND RESULTING CHRONIC INFLAMMATION, DRAWING FROM KNOWLEDGE GENERATED IN ACUTE WHEEZING ILLNESS, PAEDIATRIC ASTHMA AND EOE. BESIDES HIGHLIGHTING THE IMPORTANCE OF EPITHELIAL STRUCTURE AND BARRIER FUNCTION IN ALLERGIC DISEASE PATHOGENESIS REGARDLESS OF SPECIFIC EPITHELIAL SUB-TYPES, THIS REVIEW FOCUSES ON THE IMPORTANCE OF EXAMINING OTHER PARALLEL ALLERGIC-TYPE DISEASE PROCESSES THAT MAY UNCOVER COMMONALITIES DRIVING DISEASE PATHOGENESIS. THIS IN TURN MAY BE BENEFICIAL IN THE DEVELOPMENT OF COMMON THERAPEUTICS FOR CURRENT CLINICAL MANAGEMENT AND DISEASE PREVENTION IN THE FUTURE.	2021	
                                                                                                                                                                                                                                                                                                                                                            
8 6010  34 THE ANTIMICROBIAL PEPTIDE GAMMA-THIONIN FROM HABANERO CHILE (CAPSICUM CHINENSE) INDUCES CASPASE-INDEPENDENT APOPTOSIS ON HUMAN K562 CHRONIC MYELOID LEUKEMIA CELLS AND REGULATES EPIGENETIC MARKS. CANCER IS A RELEVANT HEALTH PROBLEM WORLDWIDE. IN 2020, LEUKEMIAS REPRESENTED THE 13TH MOST COMMONLY REPORTED CANCER CASES WORLDWIDE BUT THE 10TH MOST LIKELY TO CAUSE DEATHS. THERE HAS BEEN A PROGRESSIVE INCREASE IN THE EFFICACY OF TREATMENTS FOR LEUKEMIAS; HOWEVER, THESE STILL GENERATE IMPORTANT SIDE EFFECTS, SO IT IS IMPERATIVE TO SEARCH FOR NEW ALTERNATIVES. DEFENSINS ARE A GROUP OF ANTIMICROBIAL PEPTIDES WITH ACTIVITY AGAINST CANCER CELLS. HOWEVER, THE CYTOTOXIC MECHANISM OF THESE PEPTIDES HAS BEEN DESCRIBED MAINLY FOR ANIMAL DEFENSINS. THIS STUDY SHOWS THAT DEFENSIN GAMMA-THIONIN (CAPSICUM CHINENSE) IS CYTOTOXIC TO THE K562 LEUKEMIA CELLS WITH AN IC(50) = 290 MUG/ML (50.26 MUM) BUT NOT FOR HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS. RESULTS SHOWED THAT GAMMA-THIONIN DID NOT AFFECT THE MEMBRANE POTENTIAL; HOWEVER, THE PEPTIDE MODIFIED THE MITOCHONDRIAL MEMBRANE POTENTIAL (DELTAPSIM) AND THE INTRACELLULAR CALCIUM RELEASE. IN ADDITION, GAMMA-THIONIN INDUCED APOPTOSIS IN K562 CELLS, BUT THE ACTIVATION OF CASPASES 8 AND 9 WAS NOT DETECTED. MOREOVER, THE ACTIVATION OF CALPAINS WAS DETECTED AT ONE HOUR OF TREATMENT, SUGGESTING THAT GAMMA-THIONIN ACTIVATES THE CASPASE-INDEPENDENT APOPTOSIS. FURTHERMORE, THE GAMMA-THIONIN INDUCED EPIGENETIC MODIFICATIONS ON HISTONE 3 IN K562 CELLS, INCREASED GLOBAL ACETYLATION (~2-FOLD), AND SPECIFIC ACETYLATION MARKS AT LYSINE 9 (H3K9AC) (~1.5-FOLD). IN ADDITION, GAMMA-THIONIN INCREASED THE LYSINE 9 METHYLATION (H3K9ME) AND DIMETHYLATION MARKS (H3K9ME2) (~2-FOLD), AS WELL AS THE TRIMETHYLATION MARK (H3K9ME3) (~2-FOLD). TO OUR KNOWLEDGE, THIS IS THE FIRST REPORT OF A DEFENSIN THAT TRIGGERS CASPASE-INDEPENDENT APOPTOSIS IN CANCER CELLS VIA CALPAINS AND REGULATING CHROMATIN REMODELATION, A NOVEL PROPERTY FOR A PLANT DEFENSIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9 2994  28 GENETIC PATHOGENESIS OF INFLAMMATION-ASSOCIATED CANCERS IN DIGESTIVE ORGANS. EPIDEMIOLOGICAL, CLINICAL, AND BIOLOGICAL STUDIES CONVINCINGLY DEMONSTRATE THAT CHRONIC INFLAMMATION PREDISPOSES TO THE DEVELOPMENT OF HUMAN CANCERS. IN DIGESTIVE ORGANS, INFLAMMATION-ASSOCIATED CANCERS INCLUDE COLITIS-ASSOCIATED COLORECTAL CANCERS, HELICOBACTER PYLORI-ASSOCIATED GASTRIC CANCER, AS WELL AS BARRETT'S ESOPHAGUS AND ESOPHAGEAL ADENOCARCINOMA ASSOCIATED WITH CHRONIC DUODENOGASTRIC-ESOPHAGEAL REFLUX. CANCER IS A GENOMIC DISEASE, AND STEPWISE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS OF TUMOR-RELATED GENES LEADS TO THE DEVELOPMENT OF TUMOR CELLS. RECENT GENOME ANALYSES SHOW THAT GENETIC ALTERATIONS, WHICH ARE EVOKED BY INFLAMMATION, ARE LATENTLY ACCUMULATED IN INFLAMED EPITHELIAL CELLS OF DIGESTIVE ORGANS. PRODUCTION OF REACTIVE OXYGEN AND ABERRANT EXPRESSION OF ACTIVATION-INDUCED CYTIDINE DEAMINASE, A NUCLEOTIDE-EDITING ENZYME, COULD BE INDUCED IN INFLAMED GASTROINTESTINAL EPITHELIAL CELLS AND PLAY A ROLE AS A GENOMIC MODULATOR OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. UNDERSTANDING THE MOLECULAR LINKAGE BETWEEN INFLAMMATION AND GENETIC ALTERATIONS WILL OPEN UP A NEW FIELD OF TUMOR BIOLOGY AND PROVIDE A NOVEL STRATEGY FOR THE PREVENTION OF INFLAMMATION-ASSOCIATED TUMORIGENESIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
10 3525  27 IL-1BETA, IL-8, AND MATRIX METALLOPROTEINASES-1, -2, AND -10 ARE ENRICHED UPON MONOCYTE-BREAST CANCER CELL COCULTIVATION IN A MATRIGEL-BASED THREE-DIMENSIONAL SYSTEM. BREAST CANCER REMAINS THE FIRST CANCER-RELATED CAUSE OF DEATH IN WOMEN WORLDWIDE, PARTICULARLY IN DEVELOPING COUNTRIES IN WHICH MOST CASES ARE DIAGNOSED IN LATE STAGES. ALTHOUGH MOST CANCER STUDIES ARE BASED IN THE GENETIC OR EPIGENETIC CHANGES OF THE TUMOR CELLS, IMMUNE CELLS WITHIN THE TUMOR STROMA OFTEN COOPERATE WITH CANCER PROGRESSION. PARTICULARLY, MONOCYTES ARE ATTRACTED TO THE TUMOR PRIMARY SITE IN WHICH THEY ARE DIFFERENTIATED INTO TUMOR-ASSOCIATED MACROPHAGES THAT FACILITATE TUMOR CELL INVASION AND METASTASIS. IN THIS STUDY, WE USED THREE-DIMENSIONAL CULTURES TO FORM ACINI-LIKE STRUCTURES TO ANALYZE THE INFLAMMATORY SECRETION PROFILE OF TUMOR CELLS INDIVIDUALLY OR IN CO-CULTURE WITH MONOCYTES. BREAST CANCER CELL LINES AND PRIMARY ISOLATES FROM EIGHT MEXICAN PATIENTS WITH BREAST CANCER WERE USED. WE FOUND HIGH LEVELS OF RANTES/CCL5, MCP-1/CCL2, AND G-CSF IN THE BREAST CANCER INDIVIDUAL CULTURES, SUPPORTING AN IMPORTANT RECRUITMENT CAPACITY OF MONOCYTES, BUT ALSO OF NEUTROPHILS. THE CO-CULTURES OF THE TUMOR CELLS AND MONOCYTES WERE SIGNIFICANTLY ENRICHED WITH THE POTENT PRO-INFLAMMATORY CYTOKINES INTERLEUKIN (IL)-1BETA AND IL-8, KNOWN TO SUPPORT MALIGNANT PROGRESSION. WE ALSO FOUND THAT THE INTERACTION OF TUMOR CELLS WITH MONOCYTES PROMOTED HIGH LEVELS OF MATRIX METALLOPROTEINASES (MMP)-1, MMP-2, AND MMP-10. OUR STUDY SUPPORTS THAT A KEY EVENT FOR MALIGNANT PROGRESSION IS THE RECRUITMENT OF DIFFERENT IMMUNE CELL POPULATIONS, WHICH HELP TO SUSTAIN AND ENHANCE A CHRONIC INFLAMMATORY MICROENVIRONMENT THAT HIGHLY FAVORS TUMOR MALIGNANCY.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
11 4738  41 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
12   45  34 A COMPREHENSIVE REVIEW ON RNA INTERFERENCE-MEDIATED TARGETING OF INTERLEUKINS AND ITS POTENTIAL THERAPEUTIC IMPLICATIONS IN COLON CANCER. COLON CANCER IS THE WORLD'S FOURTH LEADING CAUSE OF DEATH. IT IS CANCER OF THE LATTER PART OF THE LARGE INTESTINE, I.E. THE COLON. CHRONIC INFLAMMATION OVER A LONG PERIOD ALSO LEADS TO THE DEVELOPMENT OF CANCER. CANCER IN THE COLON REGION IS ARDUOUS TO DIAGNOSE AND IS DETECTED AT A LATER STAGE WHEN IT METASTASIZES TO OTHER PARTS OF THE BODY LIKE THE LIVER, LUNGS, PERITONEUM, ETC. COLON CANCER IS A GREAT EXAMPLE OF SOLID TUMOURS ASSOCIATED WITH CHRONIC INFLAMMATION. ALTHOUGH CONVENTIONAL THERAPIES ARE EFFECTIVE, THEY LOSE THEIR EFFECTIVENESS BEYOND A CERTAIN POINT. RELAPSE OF THE DISEASE OCCURS FREQUENTLY. RNA INTERFERENCE (RNAI) IS EMERGING AS A GREAT TOOL TO SPECIFICALLY ATTACK THE CANCER CELLS OF A TARGET SITE LIKE THE COLON. RNAI DEALS WITH EPIGENETIC CHANGES MADE IN THE DEFECTIVE CELLS WHICH ULTIMATELY LEADS TO THEIR DEATH WITHOUT HARMING THE HEALTHY CELLS. IN THIS REVIEW, TWO TYPES OF EPIGENETIC MODULATORS HAVE BEEN CONSIDERED, NAMELY SIRNA AND MIRNA, AND THEIR EFFECT ON INTERLEUKINS. INTERLEUKINS, A CLASS OF CYTOKINES, ARE MAJOR INFLAMMATORY RESPONSES OF THE BODY THAT ARE RELEASED BY IMMUNE CELLS LIKE LEUKOCYTES AND MACROPHAGES. SOME OF THESE INTERLEUKINS ARE PRO-INFLAMMATORY, THEREBY PROMOTING INFLAMMATION WHICH EVENTUALLY CAUSES CANCER. RNAI CAN PREVENT COLON CANCER BY INHIBITING PRO-INFLAMMATORY INTERLEUKINS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13 2055  31 EPIGENETIC CONTROL DURING LYMPHOID DEVELOPMENT AND IMMUNE RESPONSES: ABERRANT REGULATION, VIRUSES, AND CANCER. METHYLATION OF CYTOSINES CONTROLS A NUMBER OF BIOLOGIC PROCESSES SUCH AS IMPRINTING AND X CHROMOSOMAL INACTIVATION. DNA HYPERMETHYLATION IS CLOSELY ASSOCIATED WITH TRANSCRIPTIONAL SILENCING, WHILE DNA HYPOMETHYLATION IS ASSOCIATED WITH TRANSCRIPTIONAL ACTIVATION. HYPOACETYLATION OF HISTONES LEADS TO COMPACT CHROMATIN WITH REDUCED ACCESSIBILITY TO THE TRANSCRIPTIONAL MACHINERY. METHYL-CPG BINDING PROTEINS CAN RECRUIT COREPRESSORS AND HISTONE DEACETYLASES; THUS, THE INTERPLAY BETWEEN THESE EPIGENETIC MECHANISMS REGULATES GENE ACTIVATION. METHYLATION HAS BEEN IMPLICATED AS AN IMPORTANT MECHANISM DURING IMMUNE DEVELOPMENT, CONTROLLING VDJ RECOMBINATION, LINEAGE-SPECIFIC EXPRESSION OF CELL SURFACE ANTIGENS, AND TRANSCRIPTIONAL REGULATION OF CYTOKINE GENES DURING IMMUNE RESPONSES. ABERRATIONS IN EPIGENETIC MACHINERY, EITHER BY GENETIC MUTATIONS OR BY SOMATIC CHANGES SUCH AS VIRAL INFECTIONS, ARE ASSOCIATED WITH EARLY ALTERATIONS IN CHRONIC DISEASES SUCH AS IMMUNODEFICIENCY AND CANCER.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14 1326  26 DEPLETION OF NUCLEAR HISTONE H2A VARIANTS IS ASSOCIATED WITH CHRONIC DNA DAMAGE SIGNALING UPON DRUG-EVOKED SENESCENCE OF HUMAN SOMATIC CELLS. CELLULAR SENESCENCE IS ASSOCIATED WITH GLOBAL CHROMATIN CHANGES, ALTERED GENE EXPRESSION, AND ACTIVATION OF CHRONIC DNA DAMAGE SIGNALING. THESE EVENTS ULTIMATELY LEAD TO MORPHOLOGICAL AND PHYSIOLOGICAL TRANSFORMATIONS IN PRIMARY CELLS. IN THIS STUDY, WE SHOW THAT CHRONIC DNA DAMAGE SIGNALS CAUSED BY GENOTOXIC STRESS IMPACT THE EXPRESSION OF HISTONES H2A FAMILY MEMBERS AND LEAD TO THEIR DEPLETION IN THE NUCLEI OF SENESCENT HUMAN FIBROBLASTS. OUR DATA REINFORCE THE HYPOTHESIS THAT PROGRESSIVE CHROMATIN DESTABILIZATION MAY LEAD TO THE LOSS OF EPIGENETIC INFORMATION AND IMPAIRED CELLULAR FUNCTION ASSOCIATED WITH CHRONIC DNA DAMAGE UPON DRUG-EVOKED SENESCENCE. WE PROPOSE THAT CHANGES IN THE HISTONE BIOSYNTHESIS AND CHROMATIN ASSEMBLY MAY DIRECTLY CONTRIBUTE TO CELLULAR AGING. IN ADDITION, WE ALSO OUTLINE THE METHOD THAT ALLOWS FOR QUANTITATIVE AND UNBIASED MEASUREMENT OF THESE CHANGES.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15 2338  33 EPIGENETIC REGULATION OF INFLAMMATORY SIGNALING AND INFLAMMATION-INDUCED CANCER. EPIGENETICS COMPRISE A DIVERSE ARRAY OF REVERSIBLE AND DYNAMIC MODIFICATIONS TO THE CELL'S GENOME WITHOUT IMPLICATING ANY DNA SEQUENCE ALTERATIONS. BOTH THE EXTERNAL ENVIRONMENT SURROUNDING THE ORGANISM, AS WELL AS THE INTERNAL MICROENVIRONMENT OF CELLS AND TISSUES, CONTRIBUTE TO THESE EPIGENETIC PROCESSES THAT PLAY CRITICAL ROLES IN CELL FATE SPECIFICATION AND ORGANISMAL DEVELOPMENT. ON THE OTHER HAND, DYSREGULATION OF EPIGENETIC ACTIVITIES CAN INITIATE AND SUSTAIN CARCINOGENESIS, WHICH IS OFTEN AUGMENTED BY INFLAMMATION. CHRONIC INFLAMMATION, ONE OF THE MAJOR HALLMARKS OF CANCER, STEMS FROM PROINFLAMMATORY CYTOKINES THAT ARE SECRETED BY TUMOR AND TUMOR-ASSOCIATED CELLS IN THE TUMOR MICROENVIRONMENT. AT THE SAME TIME, INFLAMMATORY SIGNALING CAN ESTABLISH POSITIVE AND NEGATIVE FEEDBACK CIRCUITS WITH CHROMATIN TO MODULATE CHANGES IN THE GLOBAL EPIGENETIC LANDSCAPE. IN THIS REVIEW, WE PROVIDE AN IN-DEPTH DISCUSSION OF THE INTERCONNECTED CROSSTALK BETWEEN EPIGENETICS AND INFLAMMATION, SPECIFICALLY HOW EPIGENETIC MECHANISMS AT DIFFERENT HIERARCHICAL LEVELS OF THE GENOME CONTROL INFLAMMATORY GENE TRANSCRIPTION, WHICH IN TURN ENACT CHANGES WITHIN THE CELL'S EPIGENOMIC PROFILE, ESPECIALLY IN THE CONTEXT OF INFLAMMATION-INDUCED CANCER.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16 6510  38 TRANSCRIPTION FACTORS AND EPIGENETIC MODULATION: ITS THERAPEUTIC IMPLICATION IN CHRONIC KIDNEY DISEASE. RECENTLY EMERGING EVIDENCE HAS SHOWN THAT EPIGENETIC MECHANISMS ARE INVOLVED IN INITIATION AND PROGRESSION OF VARIOUS DISEASES, INCLUDING KIDNEY DISEASES. IN THE PRESENT ARTICLE, WE REVIEW THE CURRENT DATA REGARDING THE ROLE OF EPIGENETIC MODULATION IN CHRONIC KIDNEY DISEASE (CKD) AND KIDNEY FIBROSIS, INCLUDING DNA METHYLATION AND HISTONE MODIFICATION. ESPECIALLY WE FOCUSED ON THE ROLE OF TRANSCRIPTION FACTORS IN EPIGENETIC MODULATION AND THE POSSIBILITY OF THERAPEUTIC TARGET OF CKD. WE HAVE RECENTLY REPORTED THAT TRANSCRIPTION FACTOR KRUPPEL-LIKE FACTOR 4 (ALSO KNOWN AS GUT-ENRICHED KRUPPEL-LIKE FACTOR) IS EXPRESSED IN KIDNEY PODOCYTES (VISCERAL EPITHELIAL CELLS) AND MODULATES PODOCYTE PHENOTYPE BY GENE-SELECTIVE EPIGENETIC CONTROL. TARGETING TRANSCRIPTION FACTORS FOR EPIGENETIC MODIFICATION MAY BE A GOOD CANDIDATE FOR REMISSION AND REGRESSION OF CKD. IT IS NECESSARY FOR THE THERAPY OF CKD WITH AN EPIGENETIC-BASED APPROACH TO INVESTIGATE ORGAN-, TISSUE-, OR GENE-SPECIFIC TREATMENT METHODS FOR REDUCTION OF SIDE EFFECTS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17 1508  39 DNA METHYLATION AND MRNA AND MICRORNA EXPRESSION OF SLE CD4+ T CELLS CORRELATE WITH DISEASE PHENOTYPE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN AUTOIMMUNE DISEASE WELL KNOWN FOR ITS CLINICAL HETEROGENEITY, AND ITS ETIOLOGY SECONDARY TO A CROSS-TALK INVOLVING GENETIC PREDISPOSITION AND ENVIRONMENTAL STIMULI. ALTHOUGH GENOME-WIDE ANALYSIS HAS CONTRIBUTED GREATLY TO OUR UNDERSTANDING OF THE GENETIC BASIS OF SLE, THERE IS INCREASING EVIDENCE FOR A ROLE OF EPIGENETICS. INDEED, RECENT DATA HAVE DEMONSTRATED THAT IN PATIENTS WITH SLE, THERE ARE STRIKING ALTERATIONS OF DNA METHYLATION, HISTONE MODIFICATIONS, AND DEREGULATED MICRORNA EXPRESSION, THE SUM OF WHICH CONTRIBUTE TO OVER-EXPRESSION OF SELECT AUTOIMMUNE-RELATED GENES AND LOSS OF TOLERANCE. TO ADDRESS THIS ISSUE AT THE LEVEL OF CLINICAL PHENOTYPE, WE PERFORMED DNA METHYLATION, MRNA AND MICRORNA EXPRESSION SCREENING USING HIGH-THROUGHPUT SEQUENCING OF PURIFIED CD4+ T CELLS FROM PATIENTS WITH SLE, COMPARED TO AGE AND SEX MATCHED CONTROLS. IN PARTICULAR, WE STUDIED 42 PATIENTS WITH SLE AND DIVIDED THIS GROUP INTO THREE CLINICAL PHENOTYPES: A) THE PRESENCE OF SKIN LESIONS WITHOUT SIGNS OF SYSTEMIC PATHOLOGY; B) SKIN LESIONS BUT ALSO CHRONIC RENAL PATHOLOGY; AND C) SKIN LESIONS, CHRONIC RENAL PATHOLOGY AND POLYARTICULAR DISEASE. INTERESTINGLY, AND AS EXPECTED, SEQUENCING DATA REVEALED CHANGES IN DNA METHYLATION IN SLE COMPARED TO CONTROLS. HOWEVER, AND MORE IMPORTANTLY, ALTHOUGH THERE WERE COMMON METHYLATION CHANGES FOUND IN ALL GROUPS OF SLE COMPARED TO CONTROLS, THERE WAS SPECIFIC DNA METHYLATION CHANGES THAT CORRELATED WITH CLINICAL PHENOTYPE. THESE INCLUDED CHANGES IN THE NOVEL KEY TARGET GENES NLRP2, CD300LB AND S1PR3, AS WELL AS CHANGES IN THE CRITICAL PATHWAYS, INCLUDING THE ADHERENS JUNCTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION. WE ALSO NOTED THAT A SIGNIFICANT PROPORTION OF GENES UNDERGOING DNA METHYLATION CHANGES WERE INVERSELY CORRELATED WITH GENE EXPRESSION AND THAT MIRNA SCREENING REVEALED THE EXISTENCE OF SUBSETS WITH CHANGES IN EXPRESSION. INTEGRATED ANALYSIS OF THIS DATA HIGHLIGHTS SPECIFIC SETS OF MIRNAS CONTROLLED BY DNA METHYLATION, AND GENES THAT ARE ALTERED BY METHYLATION AND TARGETED BY MIRNAS. IN CONCLUSION, OUR FINDINGS SUGGEST SELECT EPIGENETIC MECHANISMS THAT CONTRIBUTE TO CLINICAL PHENOTYPES AND FURTHER SHED LIGHT ON A NEW VENUE FOR BASIC SLE RESEARCH.	2014	
                                                                                                                    
18 2914  41 GENE REGULATORY NETWORK UNDERLYING THE IMMORTALIZATION OF EPITHELIAL CELLS. BACKGROUND: TUMORIGENIC TRANSFORMATION OF HUMAN EPITHELIAL CELLS IN VITRO HAS BEEN DESCRIBED EXPERIMENTALLY AS THE POTENTIAL RESULT OF SPONTANEOUS IMMORTALIZATION. THIS PROCESS IS CHARACTERIZED BY A SERIES OF CELL-STATE TRANSITIONS, IN WHICH NORMAL EPITHELIAL CELLS ACQUIRE FIRST A SENESCENT STATE WHICH IS LATER SURPASSED TO ATTAIN A MESENCHYMAL STEM-LIKE PHENOTYPE WITH A POTENTIALLY TUMORIGENIC BEHAVIOR. IN THIS PAPER WE AIM TO PROVIDE A SYSTEM-LEVEL MECHANISTIC EXPLANATION TO THE EMERGENCE OF THESE CELL TYPES, AND TO THE TIME-ORDERED TRANSITION PATTERNS THAT ARE COMMON TO NEOPLASIAS OF EPITHELIAL ORIGIN. TO THIS END, WE FIRST INTEGRATE PUBLISHED FUNCTIONAL AND WELL-CURATED MOLECULAR DATA OF THE COMPONENTS AND INTERACTIONS THAT HAVE BEEN FOUND TO BE INVOLVED IN SUCH CELL STATES AND TRANSITIONS INTO A NETWORK OF 41 MOLECULAR COMPONENTS. WE THEN REDUCE THIS INITIAL NETWORK BY REMOVING SIMPLE MEDIATORS (I.E., LINEAR PATHWAYS), AND FORMALIZE THE RESULTING REGULATORY CORE INTO LOGICAL RULES THAT GOVERN THE DYNAMICS OF EACH OF THE NETWORK COMPONENTS AS A FUNCTION OF THE STATES OF ITS REGULATORS. RESULTS: COMPUTATIONAL DYNAMIC ANALYSIS SHOWS THAT OUR PROPOSED GENE REGULATORY NETWORK MODEL RECOVERS EXACTLY THREE ATTRACTORS, EACH OF THEM DEFINED BY A SPECIFIC GENE EXPRESSION PROFILE THAT CORRESPONDS TO THE EPITHELIAL, SENESCENT, AND MESENCHYMAL STEM-LIKE CELLULAR PHENOTYPES, RESPECTIVELY. WE SHOW THAT ALTHOUGH A MESENCHYMAL STEM-LIKE STATE CAN BE ATTAINED EVEN UNDER UNPERTURBED PHYSIOLOGICAL CONDITIONS, THE LIKELIHOOD OF CONVERGING TO THIS STATE IS INCREASED WHEN PRO-INFLAMMATORY CONDITIONS ARE SIMULATED, PROVIDING A SYSTEMS-LEVEL MECHANISTIC EXPLANATION FOR THE CARCINOGENIC ROLE OF CHRONIC INFLAMMATORY CONDITIONS OBSERVED IN THE CLINIC. WE ALSO FOUND THAT THE REGULATORY CORE YIELDS AN EPIGENETIC LANDSCAPE THAT RESTRICTS TEMPORAL PATTERNS OF PROGRESSION BETWEEN THE STEADY STATES, SUCH THAT RECOVERED PATTERNS RESEMBLE THE TIME-ORDERED TRANSITIONS OBSERVED DURING THE SPONTANEOUS IMMORTALIZATION OF EPITHELIAL CELLS, BOTH IN VIVO AND IN VITRO. CONCLUSION: OUR STUDY STRONGLY SUGGESTS THAT THE IN VITRO TUMORIGENIC TRANSFORMATION OF EPITHELIAL CELLS, WHICH STRONGLY CORRELATES WITH THE PATTERNS OBSERVED DURING THE PATHOLOGICAL PROGRESSION OF EPITHELIAL CARCINOGENESIS IN VIVO, EMERGES FROM UNDERLYING REGULATORY NETWORKS INVOLVED IN EPITHELIAL TRANS-DIFFERENTIATION DURING DEVELOPMENT.	2017	

19 2926  30 GENERATION OF AN EPIGENETIC SIGNATURE BY CHRONIC HYPOXIA IN PROSTATE CELLS. INCREASING LEVELS OF TISSUE HYPOXIA HAVE BEEN REPORTED AS A NATURAL FEATURE OF THE AGING PROSTATE GLAND AND MAY BE A RISK FACTOR FOR THE DEVELOPMENT OF PROSTATE CANCER. IN THIS STUDY, WE HAVE USED PWR-1E BENIGN PROSTATE EPITHELIAL CELLS AND AN EQUIVALENTLY AGED HYPOXIA-ADAPTED PWR-1E SUB-LINE TO IDENTIFY PHENOTYPIC AND EPIGENETIC CONSEQUENCES OF CHRONIC HYPOXIA IN PROSTATE CELLS. WE HAVE IDENTIFIED A SIGNIFICANTLY ALTERED CELLULAR PHENOTYPE IN RESPONSE TO CHRONIC HYPOXIA AS CHARACTERIZED BY INCREASED RECEPTOR-MEDIATED APOPTOTIC RESISTANCE, THE INDUCTION OF CELLULAR SENESCENCE, INCREASED INVASION AND THE INCREASED SECRETION OF IL-1 BETA, IL6, IL8 AND TNFALPHA CYTOKINES. IN ASSOCIATION WITH THESE PHENOTYPIC CHANGES AND THE ABSENCE OF HIF-1 ALPHA PROTEIN EXPRESSION, WE HAVE DEMONSTRATED SIGNIFICANT INCREASES IN GLOBAL LEVELS OF DNA METHYLATION AND H3K9 HISTONE ACETYLATION IN THESE CELLS, CONCOMITANT WITH THE INCREASED EXPRESSION OF DNA METHYLTRANSFERASE DMNT3B AND GENE-SPECIFIC CHANGES IN DNA METHYLATION AT KEY IMPRINTING LOCI. IN CONCLUSION, WE HAVE DEMONSTRATED A GENOME-WIDE ADJUSTMENT OF DNA METHYLATION AND HISTONE ACETYLATION UNDER CHRONIC HYPOXIC CONDITIONS IN THE PROSTATE. THESE EPIGENETIC SIGNATURES MAY REPRESENT AN ADDITIONAL MECHANISM TO PROMOTE AND MAINTAIN A HYPOXIC-ADAPTED CELLULAR PHENOTYPE WITH A POTENTIAL ROLE IN TUMOUR DEVELOPMENT.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
20 3921  44 LINKING INFLAMMATION TO CELL CYCLE PROGRESSION. RISK OF GASTROINTESTINAL CANCERS IS CLOSELY RELATED TO INCREASED LEVELS OF OXIDANTS IN THE BALANCE BETWEEN OXIDANT AND ANTI-OXIDANT AGENTS. A POSSIBLE EXPLANATION OF THIS EPIDEMIOLOGICAL OBSERVATION IS THE LOCAL LOSS OF THE EPITHELIAL BARRIER FUNCTION WITH A FOCAL INFLAMMATORY RESPONSE. ACCORDINGLY, CHRONIC INFLAMMATORY DISEASES REPRESENT WELL-KNOWN RISK FACTORS FOR CANCER AND, ON THE OTHER HAND, IT IS KNOWN THAT ANTI-INFLAMMATORY AGENTS, DEMULCENTS AND ANTIOXIDANTS MARKEDLY INHIBIT THE DEVELOPMENT OF COLON CANCER IN ANIMAL MODELS AS WELL IN HUMANS. AT MOLECULAR LEVEL A KEY ROLE IN THE PROCESS THAT LINK INFLAMMATION TO CELLULAR TRANSFORMATION SEEMS TO BE PLAYED BY ACTIVATION OF CYCLOOXYGENASE-2 (COX-2) TOGETHER WITH PRODUCTION OF REACTIVE OXYGEN INTERMEDIATE (ROI). BOTH THESE EVENTS HAVE BEEN STRICTLY LINKED WITH CELL PROLIFERATION AND TRANSFORMATION, ALTHOUGH THE INTRACELLULAR PATHWAYS INVOLVED IN THESE PROCESSES ARE STILL NOT COMPLETELY UNDERSTOOD. THE UNCONTROLLED PROLIFERATION, WHICH IS A LANDMARK OF CELLULAR TRANSFORMATION, IS ACCOMPANIED BY THE DEREGULATION OF PROTEINS INVOLVED IN THE CONTROL OF CELL CYCLE CHECKPOINTS. ALTERED EXPRESSION AND FUNCTION OF CYCLOOXYGENASE AND NITRIC OXIDE SYNTHASE SEEM TO INFLUENCE, AMONG OTHERS, THE EXPRESSION OF PROTEINS INVOLVED IN THE REGULATION OF CELL CYCLE PROGRESSION. SIMILARLY, ANTI-INFLAMMATORY AND ANTIOXIDANT AGENTS MAY ALSO ACT ON THE EXPRESSION AND FUNCTION OF SEVERAL CELL CYCLE REGULATING PROTEINS. UNDERSTANDING THE MECHANISMS BY WHICH CHRONIC INFLAMMATION CONTRIBUTES TO GENETIC AND EPIGENETIC CHANGES INVOLVED IN THE REGULATION OF CRITICAL CELL CYCLE CHECKPOINTS MAY HELP TO DEVELOP MORE AND MORE SPECIFIC TREATMENT STRATEGIES FOR REDUCING MALIGNANT TRANSFORMATION OF THESE INFLAMMATORY DISEASES.	2004