1  2405 183 EPIGENETIC RESPONSE IN MICE MASTITIS: ROLE OF HISTONE H3 ACETYLATION AND MICRORNA(S) IN THE REGULATION OF HOST INFLAMMATORY GENE EXPRESSION DURING STAPHYLOCOCCUS AUREUS INFECTION. BACKGROUND: THERE IS RENEWED INTEREST TOWARDS UNDERSTANDING THE HOST-PATHOGEN INTERACTION IN THE LIGHT OF EPIGENETIC MODIFICATIONS. ALTHOUGH EPITHELIAL TISSUE IS THE MAJOR SITE FOR HOST-PATHOGEN INTERACTIONS, THERE IS HANDFUL OF STUDIES TO SHOW HOW EPITHELIAL CELLS RESPOND TO PATHOGENS. BACTERIAL INFECTION IN THE MAMMARY GLAND PARENCHYMA INDUCES LOCAL AND SUBSEQUENTLY SYSTEMIC INFLAMMATION THAT RESULTS IN A COMPLEX DISEASE CALLED MASTITIS. GLOBALLY STAPHYLOCOCCUS AUREUS IS THE SINGLE LARGEST MASTITIS PATHOGEN AND THE INFECTION CAN ULTIMATELY RESULT IN EITHER SUBCLINICAL OR CHRONIC AND SOMETIMES LIFELONG INFECTION. RESULTS: IN THE PRESENT REPORT WE HAVE ADDRESSED THE DIFFERENTIAL INFLAMMATORY RESPONSE IN MICE MAMMARY TISSUE DURING INTRAMAMMARY INFECTION AND THE ALTERED EPIGENETIC CONTEXT INDUCED BY TWO CLOSELY RELATED STRAINS OF S. AUREUS, ISOLATED FROM FIELD SAMPLES. IMMUNOHISTOCHEMICAL AND IMMUNOBLOTTING ANALYSIS SHOWED STRAIN SPECIFIC HYPERACETYLATION AT HISTONE H3K9 AND H3K14 RESIDUES. GLOBAL GENE EXPRESSION ANALYSIS IN S. AUREUS INFECTED MICE MAMMARY TISSUE REVEALED A SELECTIVE SET OF UPREGULATED GENES THAT SIGNIFICANTLY CORRELATED WITH THE PROMOTER SPECIFIC, HISTONE H3K14 ACETYLATION. FURTHERMORE, WE HAVE IDENTIFIED SEVERAL DIFFERENTIALLY EXPRESSED KNOWN MIRNAS AND 3 NOVEL MIRNAS IN S. AUREUS INFECTED MICE MAMMARY TISSUE BY SMALL RNA SEQUENCING. BY EMPLOYING THESE GENE EXPRESSION DATA, AN ATTEMPT HAS BEEN MADE TO DELINEATE THE GENE REGULATORY NETWORKS IN THE STRAIN SPECIFIC INFLAMMATORY RESPONSE. APPARENTLY, ONE OF THE ISOLATES OF S. AUREUS ACTIVATED THE NF-KAPPAB SIGNALING LEADING TO DRASTIC INFLAMMATORY RESPONSE AND INDUCTION OF IMMUNE SURVEILLANCE, WHICH COULD POSSIBLY LEAD TO RAPID CLEARANCE OF THE PATHOGEN. THE OTHER STRAIN REPRESSED MOST OF THE INFLAMMATORY RESPONSE, WHICH MIGHT HELP IN ITS SUSTENANCE IN THE HOST TISSUE. CONCLUSION: TAKEN TOGETHER, OUR STUDIES SHED SUBSTANTIAL LIGHTS TO UNDERSTAND THE MECHANISMS OF STRAIN SPECIFIC DIFFERENTIAL INFLAMMATORY RESPONSE TO S. AUREUS INFECTION DURING MASTITIS. IN A BROADER PERSPECTIVE THIS STUDY ALSO PAVES THE WAY TO UNDERSTAND HOW CERTAIN BACTERIA CAN EVADE THE IMMUNE SURVEILLANCE AND CAUSE SUSTAINED INFECTION WHILE OTHERS ARE RAPIDLY CLEARED FROM THE HOST BODY.	2014	
    
2  1357  47 DEVELOPMENT OF INNATE IMMUNE MEMORY BY NON-IMMUNE CELLS DURING STAPHYLOCOCCUS AUREUS INFECTION DEPENDS ON REACTIVE OXYGEN SPECIES. INTRODUCTION: THE MECHANISMS UNDERLYING INNATE IMMUNE MEMORY (TRAINED IMMUNITY) COMPRISE EPIGENETIC REPROGRAMMING OF TRANSCRIPTIONAL PATHWAYS ASSOCIATED WITH ALTERATIONS OF INTRACELLULAR METABOLISM. WHILE THE MECHANISMS OF INNATE IMMUNE MEMORY CARRIED OUT BY IMMUNE CELLS ARE WELL CHARACTERIZED, SUCH PROCESSES IN NON-IMMUNE CELLS, ARE POORLY UNDERSTOOD. THE OPPORTUNISTIC PATHOGEN, STAPHYLOCOCCUS AUREUS, IS RESPONSIBLE FOR A MULTITUDE OF HUMAN DISEASES, INCLUDING PNEUMONIA, ENDOCARDITIS AND OSTEOMYELITIS, AS WELL AS ANIMAL INFECTIONS, INCLUDING CHRONIC CATTLE MASTITIS THAT ARE EXTREMELY DIFFICULT TO TREAT. AN INDUCTION OF INNATE IMMUNE MEMORY MAY BE CONSIDERED AS A THERAPEUTIC ALTERNATIVE TO FIGHT S. AUREUS INFECTION. METHODS: IN THE CURRENT WORK, WE DEMONSTRATED THE DEVELOPMENT OF INNATE IMMUNE MEMORY IN NON-IMMUNE CELLS DURING S. AUREUS INFECTION EMPLOYING A COMBINATION OF TECHNIQUES INCLUDING ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), MICROSCOPIC ANALYSIS, AND CYTOMETRY. RESULTS: WE OBSERVED THAT TRAINING OF HUMAN OSTEOBLAST-LIKE MG-63 CELLS AND LUNG EPITHELIAL A549 CELLS WITH BETA-GLUCAN INCREASED IL-6 AND IL-8 PRODUCTION UPON A STIMULATION WITH S. AUREUS, CONCOMITANT WITH HISTONES MODIFICATIONS. IL-6 AND IL-8 PRODUCTION WAS POSITIVELY CORRELATED WITH AN ACETYLATION OF HISTONE 3 AT LYSINE 27 (H3K27), THUS SUGGESTING EPIGENETIC REPROGRAMMING IN THESE CELLS. AN ADDITION OF THE ROS SCAVENGER N-ACETYLCYSTEINE, NAC, PRIOR TO BETA-GLUCAN PRETREATMENT FOLLOWED BY AN EXPOSURE TO S. AUREUS, RESULTED IN DECREASED IL-6 AND IL-8 PRODUCTION, THEREBY SUPPORTING THE INVOLVEMENT OF ROS IN THE INDUCTION OF INNATE IMMUNE MEMORY. EXPOSURE OF CELLS TO LACTOCOCCUS LACTIS RESULTED IN INCREASED IL-6 AND IL-8 PRODUCTION BY MG-63 AND A549 CELLS UPON A STIMULATION WITH S. AUREUS THAT WAS CORRELATED WITH H3K27 ACETYLATION, SUGGESTING THE ABILITY OF THIS BENEFICIAL BACTERIUM TO INDUCE INNATE IMMUNE MEMORY. DISCUSSION: THIS WORK IMPROVES OUR UNDERSTANDING OF INNATE IMMUNE MEMORY IN NON-IMMUNE CELLS IN THE CONTEXT OF S. AUREUS INFECTION. IN ADDITION TO KNOWN INDUCERS, PROBIOTICS MAY REPRESENT GOOD CANDIDATES FOR THE INDUCTION OF INNATE IMMUNE MEMORY. OUR FINDINGS MAY HELP THE DEVELOPMENT OF ALTERNATIVE THERAPEUTIC APPROACHES FOR THE PREVENTION OF S. AUREUS INFECTION.	2023	
                               
3  6542  49 TRANSCRIPTOME ARCHITECTURE OF OSTEOBLASTIC CELLS INFECTED WITH STAPHYLOCOCCUS AUREUS REVEALS STRONG INFLAMMATORY RESPONSES AND SIGNATURES OF METABOLIC AND EPIGENETIC DYSREGULATION. STAPHYLOCOCCUS AUREUS IS AN OPPORTUNISTIC PATHOGEN THAT CAUSES A RANGE OF DEVASTATING DISEASES INCLUDING CHRONIC OSTEOMYELITIS, WHICH PARTIALLY RELIES ON THE INTERNALIZATION AND PERSISTENCE OF S. AUREUS IN OSTEOBLASTS. THE IDENTIFICATION OF THE MECHANISMS OF THE OSTEOBLAST RESPONSE TO INTRACELLULAR S. AUREUS IS THUS CRUCIAL TO IMPROVE THE KNOWLEDGE OF THIS INFECTIOUS PATHOLOGY. SINCE THE SIGNAL FROM SPECIFICALLY INFECTED BACTERIA-BEARING CELLS IS DILUTED AND THE RESULTS ARE CONFOUNDED BY BYSTANDER EFFECTS OF UNINFECTED CELLS, WE DEVELOPED A NOVEL MODEL OF LONG-TERM INFECTION. USING A FLOW CYTOMETRIC APPROACH WE ISOLATED ONLY S. AUREUS-BEARING CELLS FROM MIXED POPULATIONS THAT ALLOWS TO IDENTIFY SIGNALS SPECIFIC TO INTRACELLULAR INFECTION. HERE WE PRESENT AN IN-DEPTH ANALYSIS OF THE EFFECT OF LONG-TERM S. AUREUS INFECTION ON THE TRANSCRIPTIONAL PROGRAM OF HUMAN OSTEOBLAST-LIKE CELLS. AFTER RNA-SEQ AND KEGG AND REACTOME PATHWAY ENRICHMENT ANALYSIS, THE REMODELED TRANSCRIPTOMIC PROFILE OF INFECTED CELLS REVEALED EXACERBATED IMMUNE AND INFLAMMATORY RESPONSES, AS WELL AS METABOLIC DYSREGULATIONS THAT LIKELY INFLUENCE THE INTRACELLULAR LIFE OF BACTERIA. NUMEROUS GENES ENCODING EPIGENETIC REGULATORS WERE DOWNREGULATED. THE LATER INCLUDED GENES CODING FOR COMPONENTS OF CHROMATIN-REPRESSIVE COMPLEXES (E.G., NURD, BAHD1 AND PRC1) AND EPIFACTORS INVOLVED IN DNA METHYLATION. SETS OF GENES ENCODING PROTEINS OF CELL ADHESION OR NEUROTRANSMISSION WERE ALSO DEREGULATED. OUR RESULTS SUGGEST THAT INTRACELLULAR S. AUREUS INFECTION HAS A LONG-TERM IMPACT ON THE GENOME AND EPIGENOME OF HOST CELLS, WHICH MAY EXERT PATHO-PHYSIOLOGICAL DYSFUNCTIONS ADDITIONALLY TO THE DEFENSE RESPONSE DURING THE INFECTION PROCESS. OVERALL, THESE RESULTS NOT ONLY IMPROVE OUR CONCEPTUAL UNDERSTANDING OF BIOLOGICAL PROCESSES INVOLVED IN THE LONG-TERM S. AUREUS INFECTIONS OF OSTEOBLAST-LIKE CELLS, BUT ALSO PROVIDE AN ATLAS OF DEREGULATED HOST GENES AND BIOLOGICAL PATHWAYS AND IDENTIFY NOVEL MARKERS AND POTENTIAL CANDIDATES FOR PROPHYLACTIC AND THERAPEUTIC APPROACHES.	2022	
                                                                                                                                                                                                          
4  6368  45 THE ROLE OF MICRORNAS IN CHRONIC PSEUDOMONAS LUNG INFECTION IN CYSTIC FIBROSIS. BACKGROUND: CYSTIC FIBROSIS (CF) IS THE MOST COMMON LIFE LIMITING GENETIC DISORDER, CHARACTERIZED BY CHRONIC RESPIRATORY FAILURE SECONDARY TO INFLAMMATION AND CHRONIC BACTERIAL LUNG INFECTION. PSEUDOMONAS AERUGINOSA LUNG INFECTION IS ASSOCIATED WITH MORE SEVERE LUNG DISEASE AND RAPID PROGRESSION OF RESPIRATORY FAILURE WHEN COMPARED TO STAPHYLOCOCCUS AUREUS INFECTION. WE HYPOTHESIZED THAT A SPECIFIC SIGNATURE OF EPIGENETIC FACTORS TARGETING SPECIFIC GENE TRANSCRIPTS CONTRIBUTES TO THE INCREASED MORBIDITY SEEN IN CF PATIENTS WITH CHRONIC PSEUDOMONAS INFECTION. METHODS: WE COLLECTED EXHALED BREATH CONDENSATE (EBC) FROM 27 SUBJECTS AND EVALUATED MIRNA SIGNATURES IN THESE SAMPLES USING COMMERCIAL PCR ARRAY. WE IDENTIFIED PREDICTED MRNA TARGETS AND ASSOCIATED SIGNALING PATHWAYS USING INGENUITY PATHWAY ANALYSIS. RESULTS: WE FOUND 11 DIFFERENTIALLY EXPRESSED MIRNAS IN EBC OF PATIENTS INFECTED WITH PSEUDOMONAS AERUGINOSA COMPARED TO EBC FROM CF PATIENTS WHO WERE NOT CHRONICALLY INFECTED WITH PSEUDOMONAS AERUGINOSA (P < 0.05). SIX OF THESE MIRNAS (HSA-MIRNA-1247, HSA-MIRNA-1276, HSA-MIRNA-449C, HSA-MIRNA-3170, HSA-MIRNA-432-5P AND HSA-MIR-548) WERE SIGNIFICANTLY DIFFERENT IN THE CF PSEUDOMONAS POSITIVE GROUP WHEN COMPARED TO BOTH THE CF PSEUDOMONAS NEGATIVE GROUP AND HEALTHY CONTROL GROUP. INGENUITY PATHWAY ANALYSIS (IPA) REVEALED ORGANISMAL INJURY AND ABNORMALITIES, REPRODUCTIVE SYSTEM DISEASE AND CANCER AS THE TOP DISEASES AND BIO FUNCTIONS ASSOCIATED WITH THESE MIRNAS. IPA ALSO DETECTED RELA, JUN, TNF, IL-10, CTNNB1, IL-13, SERPINB8, CALM1, STARD3NL, SFI1, CD55, RPS6KA4, TTC36 AND HIST1H3D AS THE TOP TARGET GENES FOR THESE MIRNAS. CONCLUSION: OUR STUDY IDENTIFIED 6 MIRNAS AS EPIGENETIC FACTORS SPECIFICALLY ASSOCIATED WITH CHRONIC PSEUDOMONAS INFECTION IN PATIENTS WITH CF.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
5  3060  55 GENOME-WIDE DNA METHYLATION ANALYSIS OF MAMMARY GLAND TISSUES FROM CHINESE HOLSTEIN COWS WITH STAPHYLOCOCCUS AUREUS INDUCED MASTITIS. STAPHYLOCOCCUS AUREUS INTRAMAMMARY INFECTION IS ONE OF THE MOST COMMON CAUSES OF CHRONIC MASTITIS IN DAIRY COWS, WHOSE DEVELOPMENT MAY BE ASSOCIATED WITH EPIGENETIC CHANGES IN THE EXPRESSION OF IMPORTANT HOST DEFENSE GENES. THIS STUDY AIMED TO CONSTRUCT A GENOME-WIDE DNA METHYLATION PROFILE OF THE MAMMARY GLAND OF CHINESE HOLSTEIN COWS (N = 3) FOLLOWING EXPERIMENTALLY INDUCED S. AUREUS MASTITIS, AND TO EXPLORE THE POTENTIAL GENE REGULATORY MECHANISMS AFFECTED BY DNA METHYLATION DURING S. AUREUS MASTITIS. DNA WAS EXTRACTED FROM S. AUREUS-POSITIVE (N = 3) AND S. AUREUS-NEGATIVE (N = 3) MAMMARY GLAND QUARTERS AND SUBJECTED TO METHYLATION-DEPENDENT RESTRICTION-SITE ASSOCIATED DNA SEQUENCING (METHYL-RAD SEQ). RESULTS SHOWED THAT C(M)CGG/C(M)CWGG DNA METHYLATION SITES WERE UNEVENLY DISTRIBUTED AND CONCENTRATED ON CHROMOSOMES 5, 11, AND 19, AND WITHIN INTERGENIC REGIONS AND INTRON REGIONS OF GENES. COMPARED WITH HEALTHY CONTROL QUARTERS, 9,181 SIGNIFICANTLY DIFFERENTIALLY METHYLATED (DM) C(M)CGG SITES AND 1,790 DM C(M)CWGG SITES WERE FOUND IN THE S. AUREUS-POSITIVE QUARTERS (P < 0.05, |LOG2FC| > 1). FURTHERMORE, 363 C(M)CGG DIFFERENTLY METHYLATED GENES (DMGS) AND 301 C(M)CWGG DMGS (ADJUSTED P < 0.05, |LOG2FC| > 1) WERE IDENTIFIED. GENE ONTOLOGY AND KEGG ENRICHMENT ANALYSIS INDICATED THAT C(M)CGG DMGS ARE INVOLVED IN IMMUNE RESPONSE PATHWAYS, WHILE THE C(M)CWGG DMGS WERE MAINLY ENRICHED IN GENE ONTOLOGY TERMS RELATED TO METABOLISM. THE MRNAS OF 526 DIFFERENTIALLY METHYLATED C(M)CGG GENES AND 124 DIFFERENTIALLY METHYLATED C(M)CWGG GENES WERE ALSO SIGNIFICANTLY DIFFERENTIALLY EXPRESSED (RNA-SEQ DATA) IN THE SAME SAMPLES, HEREIN DENOTED DIFFERENTIALLY METHYLATED AND EXPRESSED GENES (DMEGS) (P < 0.05). FUNCTIONAL ENRICHMENT ANALYSIS OF DMEGS REVEALED ROLES RELATED TO BIOLOGICAL PROCESSES, ESPECIALLY THE REGULATION OF IMMUNE RESPONSE TO DISEASES. C(M)CGG DMEGS LIKE IL6R, TNF, BTK, IL1R2, AND TNFSF8 ENRICHED IN SEVERAL IMMUNE-RELATED GO TERMS AND PATHWAYS INDICATED THEIR IMPORTANT ROLES IN HOST IMMUNE RESPONSE AND THEIR POTENTIAL AS CANDIDATE GENES FOR S. AUREUS MASTITIS. THESE RESULTS SUGGEST POTENTIAL REGULATORY ROLES FOR DNA METHYLATION IN BOVINE MAMMARY GLAND PROCESSES DURING S. AUREUS MASTITIS AND SERVES AS A REFERENCE FOR FUTURE EPIGENETIC REGULATION AND MECHANISTIC STUDIES.	2020	

6  2406  48 EPIGENETIC RESPONSES TO RHINOVIRUS EXPOSURE IN AIRWAY EPITHELIAL CELLS ARE CORRELATED WITH KEY TRANSCRIPTIONAL PATHWAYS IN CHRONIC RHINOSINUSITIS. BACKGROUND: VIRUSES MAY DRIVE IMMUNE MECHANISMS RESPONSIBLE FOR CHRONIC RHINOSINUSITIS WITH NASAL POLYPOSIS (CRSWNP), BUT LITTLE IS KNOWN ABOUT THE UNDERLYING MOLECULAR MECHANISMS. OBJECTIVES: TO IDENTIFY EPIGENETIC AND TRANSCRIPTIONAL RESPONSES TO A COMMON UPPER RESPIRATORY PATHOGEN, RHINOVIRUS (RV), THAT ARE SPECIFIC TO PATIENTS WITH CRSWNP USING A PRIMARY SINONASAL EPITHELIAL CELL CULTURE MODEL. METHODS: AIRWAY EPITHELIAL CELLS WERE COLLECTED AT SURGERY FROM PATIENTS WITH CRSWNP (CASES) AND FROM CONTROLS WITHOUT SINUS DISEASE, CULTURED, AND THEN EXPOSED TO RV OR VEHICLE FOR 48 H. DIFFERENTIAL GENE EXPRESSION AND DNA METHYLATION (DNAM) BETWEEN CASES AND CONTROLS IN RESPONSE TO RV WERE DETERMINED USING LINEAR MIXED MODELS. WEIGHTED GENE CO-EXPRESSION ANALYSIS (WGCNA) WAS USED TO IDENTIFY (A) CO-REGULATED GENE EXPRESSION AND DNAM SIGNATURES, AND (B) GENES, PATHWAYS, AND REGULATORY MECHANISMS SPECIFIC TO CRSWNP. RESULTS: WE IDENTIFIED 5585 DIFFERENTIAL TRANSCRIPTIONAL AND 261 DNAM RESPONSES (FDR <0.10) TO RV BETWEEN CRSWNP CASES AND CONTROLS. THESE DIFFERENTIAL RESPONSES FORMED THREE CO-EXPRESSION/CO-METHYLATION MODULES THAT WERE RELATED TO CRSWNP AND THREE THAT WERE RELATED TO RV (BONFERRONI CORRECTED P < .01). MOST (95%) OF THE DIFFERENTIALLY METHYLATED CPGS (DMCS) WERE IN MODULES RELATED TO CRSWNP, WHEREAS THE DIFFERENTIALLY EXPRESSED GENES (DEGS) WERE MORE EQUALLY DISTRIBUTED BETWEEN THE CRSWNP- AND RV-RELATED MODULES. GENES IN THE CRSWNP-RELATED MODULES WERE ENRICHED IN KNOWN CRS AND/OR VIRAL RESPONSE IMMUNE PATHWAYS. CONCLUSION: RV ACTIVATES SPECIFIC EPIGENETIC PROGRAMS AND CORRELATED TRANSCRIPTIONAL NETWORKS IN THE SINONASAL EPITHELIUM OF INDIVIDUALS WITH CRSWNP. THESE NOVEL OBSERVATIONS SUGGEST EPIGENETIC SIGNATURES SPECIFIC TO PATIENTS WITH CRSWNP MODULATE RESPONSE TO VIRAL PATHOGENS AT THE MUCOSAL ENVIRONMENTAL INTERFACE. DETERMINING HOW VIRAL RESPONSE PATHWAYS ARE INVOLVED IN EPITHELIAL INFLAMMATION IN CRSWNP COULD LEAD TO THERAPEUTIC TARGETS FOR THIS BURDENSOME AIRWAY DISORDER.	2023	
                                                                                                                                                                                                                                                                               
7  2973  54 GENETIC AND EPIGENETIC STUDIES OF ATOPIC DERMATITIS. BACKGROUND: ATOPIC DERMATITIS (AD) IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY THE COMPLEX INTERACTION OF GENETIC, IMMUNE AND ENVIRONMENTAL FACTORS. THERE HAVE MANY RECENT DISCOVERIES INVOLVING THE GENETIC AND EPIGENETIC STUDIES OF AD. METHODS: A RETROSPECTIVE PUBMED SEARCH WAS CARRIED OUT FROM JUNE 2009 TO JUNE 2016 USING THE TERMS "ATOPIC DERMATITIS", "ASSOCIATION", "ECZEMA", "GENE", "POLYMORPHISM", "MUTATION", "VARIANT", "GENOME WIDE ASSOCIATION STUDY", "MICROARRAY" "GENE PROFILING", "RNA SEQUENCING", "EPIGENETICS" AND "MICRORNA". A TOTAL OF 132 PUBLICATIONS IN ENGLISH WERE IDENTIFIED. RESULTS: TO ELUCIDATE THE GENETIC FACTORS FOR AD PATHOGENESIS, CANDIDATE GENE ASSOCIATION STUDIES, GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND TRANSCRIPTOMIC PROFILING ASSAYS HAVE BEEN PERFORMED IN THIS PERIOD. EPIGENETIC MECHANISMS FOR AD DEVELOPMENT, INCLUDING GENOMIC DNA MODIFICATION AND MICRORNA POSTTRANSCRIPTIONAL REGULATION, HAVE BEEN EXPLORED. TO DATE, CANDIDATE GENE ASSOCIATION STUDIES INDICATE THAT FILAGGRIN (FLG) NULL GENE MUTATIONS ARE THE MOST SIGNIFICANT KNOWN RISK FACTOR FOR AD, AND GENES IN THE TYPE 2 T HELPER LYMPHOCYTE (TH2) SIGNALING PATHWAYS ARE THE SECOND REPLICATED GENETIC RISK FACTOR FOR AD. GWAS STUDIES IDENTIFIED 34 RISK LOCI FOR AD, THESE LOCI ALSO SUGGEST THAT GENES IN IMMUNE RESPONSES AND EPIDERMAL SKIN BARRIER FUNCTIONS ARE ASSOCIATED WITH AD. ADDITIONALLY, GENE PROFILING ASSAYS DEMONSTRATED AD IS ASSOCIATED WITH DECREASED GENE EXPRESSION OF EPIDERMAL DIFFERENTIATION COMPLEX GENES AND ELEVATED TH2 AND TH17 GENES. HYPOMETHYLATION OF TSLP AND FCER1G IN AD WERE REPORTED; AND MIR-155, WHICH TARGET THE IMMUNE SUPPRESSOR CTLA-4, WAS FOUND TO BE SIGNIFICANTLY OVER-EXPRESSED IN INFILTRATING T CELLS IN AD SKIN LESIONS. CONCLUSIONS: THE RESULTS SUGGEST THAT TWO MAJOR BIOLOGIC PATHWAYS ARE RESPONSIBLE FOR AD ETIOLOGY: SKIN EPITHELIAL FUNCTION AND INNATE/ADAPTIVE IMMUNE RESPONSES. THE DYSFUNCTIONAL EPIDERMAL BARRIER AND IMMUNE RESPONSES RECIPROCALLY AFFECT EACH OTHER, AND THEREBY DRIVE DEVELOPMENT OF AD.	2016	
                                                                                                                                                                                                                                                                                                                                                              
8  3553  40 IMMUNOTOLERANCE OF DAIRY HEIFERS IN RESPONSE TO REPEATED EXPOSURE TO BACTERIAL LIPOPOLYSACCHARIDE ENDOTOXIN. DAIRY CATTLE FACE A VARIETY OF STRESSFUL EVENTS ON A DAILY BASIS. MORE SPECIFICALLY, CLIMATE CHANGE HAS RESULTED IN MORE FREQUENT HEAT STRESS EVENTS THAT INCREASE THE INCIDENCE OF CHRONIC BACTERIAL INFECTIONS BY INDUCING CONDITIONS LIKE LEAKY GUT SYNDROME, WHEREBY THE INTEGRITY OF THE INTESTINAL EPITHELIUM IS COMPROMISED ALLOWING FOR LUMINAL BACTERIAL LIPOPOLYSACCHARIDE (LPS) ENDOTOXIN TO INFILTRATE THE HOST'S BLOODSTREAM RESULTING IN ACUTE OR CHRONIC SYSTEMIC STIMULATION OF THE INNATE IMMUNE SYSTEM. REPEATED EXPOSURE TO LPS OVER A SHORT PERIOD OF TIME IS REPORTED TO INDUCE IMMUNOTOLERANCE WITHIN THE HOST. THIS LPS TOLERANCE IS AN ESSENTIAL IMMUNOHOMEOSTATIC RESPONSE THAT CAN PROTECT AGAINST OVER ACTIVATION OF THE INFLAMMATORY RESPONSE DURING SUBSEQUENT EXPOSURE TO LPS. IN THE PRESENT STUDY, HOLSTEIN CALVES (N = 20) WERE INITIALLY STRESS CHALLENGED WITH EITHER SALINE, OR 100, 200 OR 400 NG/KG OF LPS ADMINISTERED INTRAMUSCULAR, AND AGAIN RE-CHALLENGED WITH 200 NG/KG OF LPS 2-WEEKS LATER. SERUM WAS COLLECTED EVERY 2 HR FOR 6 HR TO PROFILE CHANGES IN CIRCULATORY STRESS BIOMARKERS AFTER THE REPEATED LPS EXPOSURES. HEIFERS THAT WERE INITIALLY CHALLENGED WITH 100, 200 AND 400 NG/KG OF LPS DEMONSTRATED SIGNIFICANTLY ATTENUATED CORTISOL RESPONSES IN THE SECOND CHALLENGE (P < 0.01, 0.01 AND 0.05, RESPECTIVELY), WHEREAS CONTROL ANIMALS WHO PREVIOUSLY RECEIVED SALINE DEMONSTRATED A STRONG CORTISOL RESPONSE AT 2 HR AFTER RECEIVING 200 NG/KG OF LPS (P < 0.05). THE CYTOKINE/CHEMOKINE (IL-6, CCL2, CCL3 AND CCL4) RESPONSES WERE ALSO ATTENUATED DURING THE LPS RECHALLENGE (P < 0.05). FINALLY, MICRORNA EXPRESSION PROFILES WERE DETERMINED TO ASSESS THE EPIGENETIC RESPONSE TO REPEATED LPS EXPOSURE. INTERESTINGLY, MIR-31 AND MIR-223 WERE DOWNREGULATED IN RESPONSE TO THE SECOND LPS CHALLENGE. THE PRESENT STUDY DEMONSTRATES THE DYNAMIC NATURE OF THE STRESS RESPONSE IN DAIRY CATTLE AS IT RELATES TO THE DEVELOPMENT OF LPS TOLERANCE. UNDERSTANDING THE ROLES OF VARIOUS STRESS BIOMARKERS IN THE CONTEXT OF INNATE IMMUNE CELL TOLERANCE IS ESSENTIAL FOR EVALUATING THEIR IMPACT ON IMMUNE SYSTEM HOMEOSTASIS.	2023	
                                                                                                                                                                                                                             
9  4947  50 PATERNAL SEPSIS INDUCES ALTERATIONS OF THE SPERM METHYLOME AND DAMPENS OFFSPRING IMMUNE RESPONSES-AN ANIMAL STUDY. BACKGROUND: SEPSIS REPRESENTS THE UTMOST SEVERE CONSEQUENCE OF INFECTION, INVOLVING A DYSREGULATED AND SELF-DAMAGING IMMUNE RESPONSE OF THE HOST. WHILE DIFFERENT ENVIRONMENTAL EXPOSURES LIKE CHRONIC STRESS OR MALNUTRITION HAVE BEEN WELL DESCRIBED TO REPROGRAM THE GERMLINE AND SUBSEQUENTLY OFFSPRING ATTRIBUTES, THE INTERGENERATIONAL IMPACT OF SEPSIS AS A TREMENDOUS IMMUNOLOGICAL STRESSOR HAS NOT BEEN EXAMINED YET. METHODS: POLYMICROBIAL SEPSIS IN 12-WEEK-OLD MALE C57BL/6 MICE WAS INDUCED BY CECAL LIGATION AND PUNCTURE (CLP), FOLLOWED BY A MATING OF THE MALE SURVIVORS (OR APPROPRIATE SHAM CONTROL ANIMALS) 6 WEEKS LATER WITH HEALTHY FEMALES. ALVEOLAR MACROPHAGES OF OFFSPRING ANIMALS WERE ISOLATED AND STIMULATED WITH EITHER LPS OR ZYMOSAN, AND SUPERNATANT LEVELS OF TNF-ALPHA WERE QUANTIFIED BY ELISA. FURTHERMORE, SYSTEMIC CYTOKINE RESPONSE TO INTRAPERITONEALLY INJECTED LPS WAS ASSESSED AFTER 24 H. ALSO, MORPHOLOGY, MOTILITY, AND GLOBAL DNA METHYLATION OF THE SEPSIS SURVIVORS' SPERM WAS EXAMINED. RESULTS: COMPARATIVE REDUCED REDUCTION BISULFITE SEQUENCING (RRBS) OF SPERM REVEALED CHANGES OF DNA METHYLATION (N = 381), MOST PRONOUNCED IN THE INTERGENIC GENOME AS WELL AS WITHIN INTRONS OF DEVELOPMENTALLY RELEVANT GENES. OFFSPRING OF SEPSIS FATHERS EXHIBITED A SLIGHT DECREASE IN BODY WEIGHT, WITH A MORE PRONOUNCED WEIGHT DIFFERENCE IN MALE ANIMALS (CLP VS. SHAM). MALE DESCENDANTS OF SEPSIS FATHERS, BUT NOT FEMALE DESCENDANTS, EXHIBITED LOWER PLASMA CONCENTRATIONS OF IL-6, TNF-ALPHA, AND IL-10 24 H AFTER INJECTION OF LPS. IN LINE, ONLY ALVEOLAR MACROPHAGES OF MALE DESCENDANTS OF SEPSIS FATHERS PRODUCED LESS TNF-ALPHA UPON ZYMOSAN STIMULATION COMPARED TO SHAM DESCENDANTS, WHILE LPS RESPONSES KEPT UNCHANGED. CONCLUSION: WE CAN PROVE THAT MALE-BUT SURPRISINGLY NOT FEMALE-DESCENDANTS OF POST-SEPSIS FATHERS SHOW A DAMPENED SYSTEMIC AS WELL AS PULMONARY IMMUNE RESPONSE. BASED ON THIS OBSERVATION OF AN IMMUNE HYPO-RESPONSIVITY, WE PROPOSE THAT MALE DESCENDANTS OF SEPSIS FATHERS ARE AT RISK TO DEVELOP FUNGAL AND BACTERIAL INFECTIONS AND MIGHT BENEFIT FROM THERAPEUTIC IMMUNE MODULATION.	2018	
                                                                                                                                                                                                                              
10  2340  44 EPIGENETIC REGULATION OF LEUKOCYTE INFLAMMATORY MEDIATOR PRODUCTION DICTATES STAPHYLOCOCCUS AUREUS CRANIOTOMY INFECTION OUTCOME. STAPHYLOCOCCUS AUREUS IS A COMMON CAUSE OF SURGICAL-SITE INFECTIONS, INCLUDING THOSE ARISING AFTER CRANIOTOMY, WHICH IS PERFORMED TO ACCESS THE BRAIN FOR THE TREATMENT OF TUMORS, EPILEPSY, OR HEMORRHAGE. CRANIOTOMY INFECTION IS CHARACTERIZED BY COMPLEX SPATIAL AND TEMPORAL DYNAMICS OF LEUKOCYTE RECRUITMENT AND MICROGLIAL ACTIVATION. WE RECENTLY IDENTIFIED UNIQUE TRANSCRIPTIONAL PROFILES OF THESE IMMUNE POPULATIONS DURING S. AUREUS CRANIOTOMY INFECTION. EPIGENETIC PROCESSES ALLOW RAPID AND REVERSIBLE CONTROL OVER GENE TRANSCRIPTION; HOWEVER, LITTLE IS KNOWN ABOUT HOW EPIGENETIC PATHWAYS INFLUENCE IMMUNITY TO LIVE S. AUREUS. AN EPIGENETIC COMPOUND LIBRARY SCREEN IDENTIFIED BROMODOMAIN AND EXTRATERMINAL DOMAIN-CONTAINING (BET) PROTEINS AND HISTONE DEACETYLASES (HDACS) AS CRITICAL FOR REGULATING TNF, IL-6, IL-10, AND CCL2 PRODUCTION BY PRIMARY MOUSE MICROGLIA, MACROPHAGES, NEUTROPHILS, AND GRANULOCYTIC MYELOID-DERIVED SUPPRESSOR CELLS IN RESPONSE TO LIVE S. AUREUS. CLASS I HDACS (C1HDACS) WERE INCREASED IN THESE CELL TYPES IN VITRO AND IN VIVO DURING ACUTE DISEASE IN A MOUSE MODEL OF S. AUREUS CRANIOTOMY INFECTION. HOWEVER, SUBSTANTIAL REDUCTIONS IN C1HDACS WERE OBSERVED DURING CHRONIC INFECTION, HIGHLIGHTING TEMPORAL REGULATION AND THE IMPORTANCE OF THE TISSUE MICROENVIRONMENT FOR DICTATING C1HDAC EXPRESSION. MICROPARTICLE DELIVERY OF HDAC AND BET INHIBITORS IN VIVO CAUSED WIDESPREAD DECREASES IN INFLAMMATORY MEDIATOR PRODUCTION, WHICH SIGNIFICANTLY INCREASED BACTERIAL BURDEN IN THE BRAIN, GALEA, AND BONE FLAP. THESE FINDINGS IDENTIFY HISTONE ACETYLATION AS AN IMPORTANT MECHANISM FOR REGULATING CYTOKINE AND CHEMOKINE PRODUCTION ACROSS DIVERSE IMMUNE CELL LINEAGES THAT IS CRITICAL FOR BACTERIAL CONTAINMENT. ACCORDINGLY, ABERRANT EPIGENETIC REGULATION MAY BE IMPORTANT FOR PROMOTING S. AUREUS PERSISTENCE DURING CRANIOTOMY INFECTION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
11  3518  38 IGE SENSITIZATION PROFILES DIFFER BETWEEN ADULT PATIENTS WITH SEVERE AND MODERATE ATOPIC DERMATITIS. BACKGROUND: ATOPIC DERMATITIS (AD) IS A COMPLEX CHRONIC INFLAMMATORY DISEASE WHERE ALLERGENS CAN ACT AS SPECIFIC TRIGGERING FACTORS. AIM: TO CHARACTERIZE THE SPECIFICITIES OF IGE-REACTIVITY IN PATIENTS WITH AD TO A BROAD PANEL OF EXOGENOUS ALLERGENS INCLUDING MICROBIAL AND HUMAN ANTIGENS. METHODOLOGY: ADULT PATIENTS WITH AD WERE GROUPED ACCORDING TO THE SCORAD INDEX, INTO SEVERE (N = 53) AND MODERATE AD (N = 126). AS CONTROLS 43 PATIENTS WERE INCLUDED WITH SEBORRHOEIC ECZEMA AND 97 INDIVIDUALS WITHOUT HISTORY OF ALLERGY OR SKIN DISEASES. SPECIFIC IGE REACTIVITY WAS ASSESSED IN PLASMA USING PHADIATOP(R), IMMUNOCAP, MICRO-ARRAYED ALLERGENS, DOT-BLOTTED RECOMBINANT MALASSEZIA SYMPODIALIS ALLERGENS, AND IMMUNE-BLOTTED MICROBIAL AND HUMAN PROTEINS. RESULTS: IGE REACTIVITY WAS DETECTED IN 92% OF PATIENTS WITH SEVERE AND 83% OF PATIENTS WITH MODERATE AD. SENSITIZATION TO CAT ALLERGENS OCCURRED MOST FREQUENTLY, FOLLOWED BY SENSITIZATION TO BIRCH POLLEN, GRASS POLLEN, AND TO THE SKIN COMMENSAL YEAST M. SYMPODIALIS. PATIENTS WITH SEVERE AD SHOWED A SIGNIFICANTLY HIGHER FREQUENCY OF IGE REACTIVITY TO ALLERGENS LIKE CAT (RFEL D 1) AND HOUSE DUST MITE (RDER P 4 AND 10), TO STAPHYLOCOCCUS AUREUS, M. SYMPODIALIS, AND TO HUMAN ANTIGENS. IN CONTRAST, THERE WERE NO SIGNIFICANT DIFFERENCES IN THE FREQUENCIES OF IGE REACTIVITY TO THE GRASS POLLEN ALLERGENS RPHL P 1, 2, 5B, AND 6 BETWEEN THE TWO AD GROUPS. FURTHERMORE THE IGE REACTIVITY PROFILE OF PATIENTS WITH SEVERE AD WAS MORE SPREAD TOWARDS SEVERAL DIFFERENT ALLERGEN MOLECULES AS COMPARED TO PATIENTS WITH MODERATE AD. CONCLUSION: WE HAVE REVEALED A HITHERTO UNKNOWN DIFFERENCE REGARDING THE MOLECULAR SENSITIZATION PROFILE IN PATIENTS WITH SEVERE AND MODERATE AD. MOLECULAR PROFILING TOWARDS ALLERGEN COMPONENTS MAY PROVIDE A BASIS FOR FUTURE INVESTIGATIONS AIMING TO EXPLORE THE ENVIRONMENTAL, GENETIC AND EPIGENETIC FACTORS WHICH COULD BE RESPONSIBLE FOR THE DIFFERENT APPEARANCE AND SEVERITY OF DISEASE PHENOTYPES IN AD.	2016	
                                                                                                                                                                                                                                                                                                                                                                    
12  3019  38 GENETICS AND EPIGENETICS OF NASAL POLYPOSIS: A SYSTEMATIC REVIEW. CHRONIC RHINOSINUSITIS (CRS) IS AN INFLAMMATORY DISEASE OF THE NOSE AND PARANASAL SINUSES THAT IS OFTEN ASSOCIATED WITH NASAL POLYPOSIS (CRSWNP) IN THE MOST SEVERE CASES. AS IN OTHER COMPLEX DISEASES, GENETIC FACTORS ARE THOUGHT TO PLAY AN IMPORTANT ROLE IN THE RISK AND DEVELOPMENT OF THE DISEASE. ENVIRONMENT MAY ALSO MODULATE THE EPIGENETIC SIGNATURE IN AFFECTED PATIENTS. IN THE PRESENT SYSTEMATIC REVIEW, WE AIMED TO COMPILE ALL PUBLISHED DATA ON GENETIC AND EPIGENETIC VARIATIONS IN CRSWNP SINCE 2000. WE FOUND 104 ARTICLES, 24 OF WHICH WERE RELATED TO EPIGENETIC STUDIES. WE IDENTIFIED MORE THAN 150 GENETIC VARIANTS IN 99 GENES INVOLVED IN THE PATHOGENESIS OF NASAL POLYPOSIS. THESE WERE CLUSTERED INTO 8 MAIN NETWORKS, LINKING GENES INVOLVED IN INFLAMMATION AND IMMUNE RESPONSE (EG, MHC), CYTOKINE GENES (EG, TNF), LEUKOTRIENE METABOLISM, AND THE EXTRACELLULAR MATRIX. A TOTAL OF 89 MIRNAS WERE ALSO IDENTIFIED; THESE ARE ASSOCIATED MAINLY WITH BIOLOGICAL FUNCTIONS SUCH AS THE CELL CYCLE, INFLAMMATION, AND THE IMMUNE RESPONSE. WE PROPOSE A POTENTIAL RELATIONSHIP BETWEEN GENES AND THE MIRNAS IDENTIFIED THAT MAY OPEN NEW LINES OF INVESTIGATION. AN IN-DEPTH KNOWLEDGE OF GENE VARIANTS AND EPIGENETIC TRAITS COULD HELP US TO DESIGN MORE TAILORED TREATMENT FOR PATIENTS WITH CRSWNP.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
13  5031  45 PERSPECTIVES ON THE ETIOLOGY OF CHRONIC RHINOSINUSITIS: AN IMMUNE BARRIER HYPOTHESIS. BACKGROUND: CHRONIC RHINOSINUSITIS (CRS) HAS BEEN DEFINED AS PERSISTENT SYMPTOMATIC INFLAMMATION OF THE NASAL AND SINUS MUCOSA RESULTING FROM THE INTERACTION OF MULTIPLE HOST AND ENVIRONMENTAL FACTORS. RECENT STUDIES HAVE IMPLICATED ALTERNARIA FUNGI OR TOXIGENIC STAPHYLOCOCCUS AUREUS AS CRITICAL AGENTS IN CRS PATHOGENESIS. THE EMPHASIS ON ENVIRONMENTAL AGENTS IN CRS ETIOLOGY HAS FOCUSED INTEREST TOWARD ELIMINATION OF THOSE AGENTS AS THE PRIME MECHANISM OF THERAPY. THIS VIEWPOINT IS IN MARKED CONTRAST TO THE CURRENT PERSPECTIVE ON SOME OTHER CHRONIC INFLAMMATORY EPITHELIAL DISORDERS THAT AFFLICT THE SKIN, LUNGS, AND GUT, WHEREIN HOST FACTORS ARE BELIEVED TO PREDISPOSE TO DISEASE EXPRESSION IN THE PRESENCE OF UBIQUITOUS ENVIRONMENTAL AGENTS. METHODS: THE CURRENT REVIEW EVALUATES CRS ETIOLOGY FROM THIS PERSPECTIVE AND CONSIDERS THAT CRS DEVELOPS, IN PART, AS AN OUTCOME OF A DYSFUNCTIONAL HOST RESPONSE. SPECIFICALLY, EVIDENCE FROM OUR LABORATORY AND OTHERS WILL BE REVIEWED INDICATING THAT CRS IS ASSOCIATED WITH A FAILURE OF THE MECHANICAL AND IMMUNOLOGIC BARRIERS ACROSS THE NASAL MUCOSA. THE HYPOTHESIS WOULD FURTHER PROPOSE THAT GENETIC AND EPIGENETIC VARIATION PREDISPOSES SUSCEPTIBLE INDIVIDUALS TO BARRIER FAILURE IN THE PRESENCE OF ENVIRONMENTAL STRESS LEADING TO CRS. RESULTS: FROM THIS UNIFYING PERSPECTIVE, BACTERIA AND FUNGI ARE SEEN AS DISEASE MODIFIERS RATHER THAN PRIMARY ETIOLOGIC AGENTS. CONCLUSION: THE GOAL IS TO PLACE CONCEPTS OF CRS PATHOPHYSIOLOGY IN A FRAMEWORK CONSISTENT WITH A CURRENT UNDERSTANDING OF CHRONIC INFLAMMATION IN GENERAL AND EPITHELIAL DISEASE IN PARTICULAR.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  4015  44 LOW-DOSE EXPOSURE TO BISPHENOLS A, F AND S OF HUMAN PRIMARY ADIPOCYTE IMPACTS CODING AND NON-CODING RNA PROFILES. BISPHENOL A (BPA) EXPOSURE HAS BEEN SUSPECTED TO BE ASSOCIATED WITH DELETERIOUS EFFECTS ON HEALTH INCLUDING OBESITY AND METABOLICALLY-LINKED DISEASES. ALTHOUGH BISPHENOLS F (BPF) AND S (BPS) ARE BPA STRUCTURAL ANALOGS COMMONLY USED IN MANY MARKETED PRODUCTS AS A REPLACEMENT FOR BPA, ONLY SPARSE TOXICOLOGICAL DATA ARE AVAILABLE YET. OUR OBJECTIVE WAS TO COMPREHENSIVELY CHARACTERIZE BISPHENOLS GENE TARGETS IN A HUMAN PRIMARY ADIPOCYTE MODEL, IN ORDER TO DETERMINE WHETHER THEY MAY INDUCE CELLULAR DYSFUNCTION, USING CHRONIC EXPOSURE AT TWO CONCENTRATIONS: A "LOW-DOSE" SIMILAR TO THE DOSE USUALLY ENCOUNTERED IN HUMAN BIOLOGICAL FLUIDS AND A HIGHER DOSE. THEREFORE, BPA, BPF AND BPS HAVE BEEN ADDED AT 10 NM OR 10 MUM DURING THE DIFFERENTIATION OF HUMAN PRIMARY ADIPOCYTES FROM SUBCUTANEOUS FAT OF THREE NON-DIABETIC CAUCASIAN FEMALE PATIENTS. GENE EXPRESSION (MRNA/LNCRNA) ARRAYS AND MICRORNA ARRAYS, HAVE BEEN USED TO ASSESS CODING AND NON-CODING RNA CHANGES. WE DETECTED SIGNIFICANTLY DEREGULATED MRNA/LNCRNA AND MIRNA AT LOW AND HIGH DOSES. ENRICHMENT IN "CANCER" AND "ORGANISMAL INJURY AND ABNORMALITIES" RELATED PATHWAYS WAS FOUND IN RESPONSE TO THE THREE PRODUCTS. SOME LONG INTERGENIC NON-CODING RNAS AND SMALL NUCLEOLAR RNAS WERE DIFFERENTIALLY EXPRESSED SUGGESTING THAT BISPHENOLS MAY ALSO ACTIVATE MULTIPLE CELLULAR PROCESSES AND EPIGENETIC MODIFICATIONS. THE ANALYSIS OF UPSTREAM REGULATORS OF DEREGULATED GENES HIGHLIGHTED HORMONES OR HORMONE-LIKE CHEMICALS SUGGESTING THAT BPS AND BPF CAN BE SUSPECTED TO INTERFERE, JUST LIKE BPA, WITH HORMONAL REGULATION AND HAVE TO BE CONSIDERED AS ENDOCRINE DISRUPTORS. ALL THESE RESULTS SUGGEST THAT AS BPA, ITS SUBSTITUTES BPS AND BPF SHOULD BE USED WITH THE SAME RESTRICTIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  6748  42 WHOLE GENOME METHYLATION ARRAY ANALYSIS REVEALS NEW ASPECTS IN BALKAN ENDEMIC NEPHROPATHY ETIOLOGY. BACKGROUND: BALKAN ENDEMIC NEPHROPATHY (BEN) REPRESENTS A CHRONIC PROGRESSIVE INTERSTITIAL NEPHRITIS IN STRIKING CORRELATION WITH UROEPITHELIAL TUMOURS OF THE UPPER URINARY TRACT. THE DISEASE HAS ENDEMIC DISTRIBUTION IN THE DANUBE RIVER REGIONS IN SEVERAL BALKAN COUNTRIES.DNA METHYLATION IS A PRIMARY EPIGENETIC MODIFICATION THAT IS INVOLVED IN MAJOR PROCESSES SUCH AS CANCER, GENOMIC IMPRINTING, GENE SILENCING, ETC. THE SIGNIFICANCE OF CPG ISLAND METHYLATION STATUS IN NORMAL DEVELOPMENT, CELL DIFFERENTIATION AND GENE EXPRESSION IS WIDELY RECOGNIZED, ALTHOUGH STILL STAYS POORLY UNDERSTOOD. METHODS: WE PERFORMED WHOLE GENOME DNA METHYLATION ARRAY ANALYSIS ON DNA POOL SAMPLES FROM PERIPHERAL BLOOD FROM 159 AFFECTED INDIVIDUALS AND 170 HEALTHY INDIVIDUALS. THIS TECHNIQUE ALLOWED US TO DETERMINE THE METHYLATION STATUS OF 27 627 CPG ISLANDS THROUGHOUT THE WHOLE GENOME IN HEALTHY CONTROLS AND BEN PATIENTS. THUS WE OBTAINED THE METHYLATION PROFILE OF BEN PATIENTS FROM BULGARIAN AND SERBIAN ENDEMIC REGIONS. RESULTS: USING SPECIFICALLY DEVELOPED SOFTWARE WE COMPARED THE METHYLATION PROFILES OF BEN PATIENTS AND CORRESPONDING CONTROLS AND REVEALED THE DIFFERENTLY METHYLATED REGIONS. WE THEN COMPARED THE DMRS BETWEEN ALL PATIENT-CONTROL PAIRS TO DETERMINE COMMON CHANGES IN THE EPIGENETIC PROFILES.SEC61G, IL17RA, HDAC11 PROVED TO BE DIFFERENTLY METHYLATED THROUGHOUT ALL PATIENT-CONTROL PAIRS. THE CPG ISLANDS OF ALL 3 GENES WERE HYPOMETHYLATED COMPARED TO CONTROLS. THIS SUGGESTS THAT DYSREGULATION OF THESE GENES INVOLVED IN IMMUNOLOGICAL RESPONSE COULD BE A COMMON MECHANISM IN BEN PATHOGENESIS IN BOTH ENDEMIC REGIONS AND IN BOTH GENDERS. CONCLUSION: OUR DATA PROPOSE A NEW HYPOTHESIS THAT IMMUNOLOGIC DYSREGULATION HAS A PLACE IN BEN ETIOPATHOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16  3767  41 INTEGRATIVE EPIGENOMIC ANALYSIS IN DIFFERENTIATED HUMAN PRIMARY BRONCHIAL EPITHELIAL CELLS EXPOSED TO CIGARETTE SMOKE. CIGARETTE SMOKE (CS) IS ONE OF THE MAJOR RISK FACTORS FOR MANY PULMONARY DISEASES, INCLUDING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER. THE FIRST LINE OF DEFENSE FOR CS EXPOSURE IS THE BRONCHIAL EPITHELIAL CELLS. ELUCIDATION OF THE EPIGENETIC CHANGES DURING CS EXPOSURE IS KEY TO GAINING A MECHANISTIC UNDERSTANDING INTO HOW MATURE AND DIFFERENTIATED BRONCHIAL EPITHELIAL CELLS RESPOND TO CS. THEREFORE, WE PERFORMED EPIGENOMIC PROFILING IN CONJUNCTION WITH TRANSCRIPTIONAL PROFILING IN WELL-DIFFERENTIATED HUMAN BRONCHIAL EPITHELIAL (HBE) CELLS CULTURED IN AIR-LIQUID INTERFACE (ALI) EXPOSED TO THE VAPOR PHASE OF CS. THE GENOME-WIDE ENRICHMENT OF HISTONE 3 LYSINE 27 ACETYLATION WAS DETECTED BY CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY NEXT GENERATION SEQUENCING (CHIP-SEQ) IN HBE CELLS AND SUGGESTED THE PLAUSIBLE BINDING OF SPECIFIC TRANSCRIPTION FACTORS RELATED TO CS EXPOSURE. ADDITIONALLY, INTERROGATION OF CHIP-SEQ DATA WITH GENE EXPRESSION PROFILING OF HBE CELLS AFTER CS EXPOSURE FOR DIFFERENT DURATIONS (3 HOURS, 2 DAYS, 4 DAYS) SUGGESTED THAT EARLIER EPIGENETIC CHANGES (3 HOURS AFTER CS EXPOSURE) MAY BE ASSOCIATED WITH LATER GENE EXPRESSION CHANGES INDUCED BY CS EXPOSURE (4 DAYS). THE INTEGRATION OF EPIGENETICS AND GENE EXPRESSION DATA REVEALED SIGNALING PATHWAYS RELATED TO CS-INDUCED EPIGENETIC CHANGES IN HBE CELLS THAT MAY IDENTIFY NOVEL REGULATORY PATHWAYS RELATED TO CS-INDUCED COPD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17  1606  41 DNA METHYLATION, BACTERIA AND AIRWAY INFLAMMATION: LATEST INSIGHTS. PURPOSE OF REVIEW: DNA METHYLATION IS AN EPIGENETIC MECHANISM THAT HAS BEEN IMPLICATED IN THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES BY REGULATING DIFFERENTIATION, PROLIFERATION, APOPTOSIS, AND ACTIVATION OF IMMUNE CELLS. CHANGES IN THE METHYLATION STATUS OF RELEVANT GENES HAVE BEEN LINKED TO THE ORIGIN, PERPETUATION, AND SEVERITY OF AIRWAY DISEASES. THE DNA METHYLATION PROFILE CAN BE ALSO MODIFIED BY THE ACTION OF VIRAL AND BACTERIAL COLONIZATION. BACTERIA AND SPECIALLY STAPHYLOCOCCUS AUREUS TOXINS ARE RECOGNIZED INFLAMMATORY AMPLIFYING FACTORS IN BOTH LOWER AND UPPER AIRWAY CHRONIC DISEASES. THIS REVIEW SUMMARIZES THE EXISTENT KNOWLEDGE ABOUT THE ROLE OF DNA METHYLATION CHANGES IN CHRONIC AIRWAY DISEASES AND THE CONTRIBUTION OF BACTERIAL INFECTION ON THIS EVENT. RECENT FINDINGS: IT HAS BEEN DEMONSTRATED THAT CHANGES IN DNA METHYLATION, EITHER INTRINSIC OR INDUCED BY ALLERGEN OR INFECTION, MAY BE LINKED TO THE PATHOGENESIS OF ASTHMA AND ALLERGY. THESE CHANGES IN METHYLATION MAY SUPPRESS THE PRODUCTION OF ANTI-INFLAMMATORY MEDIATORS AND INCREASE THE SURVIVAL AND ACTIVATION OF PRO-INFLAMMATORY CELLS, AS WELL AS MODIFY THE IMMUNE RESPONSE IN RESPONSE TO BACTERIAL INFECTION, INCREASING THEIR SURVIVAL AND PATHOGENICITY WITHIN THE INFECTED ORGANISM. SUMMARY: UNDERSTANDING THE INTRINSIC EPIGENETIC MECHANISMS, AS WELL AS THE EFFECT OF ENVIRONMENT -FOR EXAMPLE, BACTERIAL INFECTION IN THE PATHOGENESIS OF AIRWAYS DISEASES - WILL GREATLY IMPROVE THE MANAGEMENT AND THE DIAGNOSIS OF THESE DISEASES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
18  3460  34 HYPOMETHYLATION OF THE IL8 PROMOTER IN NASAL EPITHELIAL CELLS OF PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND: IL-8 IS AN IMPORTANT CHEMOKINE IMPLICATED IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS (CRS), BUT LITTLE IS KNOWN ABOUT EPIGENETIC REGULATION OF IL8 IN THE PATHOGENESIS OF CRS. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE RELATIONSHIP BETWEEN THE DNA METHYLATION LEVEL IN THE IL8 PROXIMAL PROMOTER AND CRS IN HAN CHINESE SUBJECTS. METHODS: PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP; N = 187), PATIENTS WITH CHRONIC RHINOSINUSITIS WITHOUT NASAL POLYPS (CRSSNP; N = 89), AND CONTROL SUBJECTS (N = 57) WERE ENROLLED IN 2 INDEPENDENT COHORTS. PURIFIED HUMAN NASAL EPITHELIAL CELLS FROM EACH PARTICIPANT WERE ASSESSED FOR PERCENTAGE DNA METHYLATION OF CPG SITES IN THE IL8 PROXIMAL PROMOTER BY USING BISULFITE PYROSEQUENCING AND FOR FUNCTIONAL ASPECTS OF METHYLATION STATUS BY USING IN VITRO ASSAYS. RESULTS: DNA METHYLATION OF CPG SITES 1, 2, AND 3, RESPECTIVELY, IN THE IL8 PROXIMAL PROMOTER WAS SIGNIFICANTLY DECREASED IN HUMAN NASAL EPITHELIAL CELLS OF PATIENTS WITH CRSWNP COMPARED WITH THAT IN PATIENTS WITH CRSSNP (P < .001) AND CONTROL SUBJECTS (P < .001). PERCENTAGE OF DNA METHYLATION OF THE CPG3 SITE WAS CORRELATED NEGATIVELY WITH BOTH TISSUE EOSINOPHILIC CATIONIC PROTEIN (P < .01) AND MYELOPEROXIDASE (P < .05) LEVELS. IL-1BETA (P < .001) AND TNF-ALPHA (P < .01) SIGNIFICANTLY INCREASED IL8 EXPRESSION ACCOMPANIED BY A REDUCTION IN METHYLATION AT THE CPG3 SITE (P < .001). ELECTROPHORETIC MOBILITY SHIFT ASSAYS DEMONSTRATED THAT METHYLATION STATUS OF CPG3 CHANGED THE BINDING OF OCTAMER-BINDING TRANSCRIPTION FACTOR 1 AND NUCLEAR FACTOR KAPPAB. CONCLUSION: DECREASED DNA METHYLATION OF PARTICULARLY CPG SITES IN THE IL8 PROXIMAL PROMOTER MIGHT PLAY A ROLE IN THE PATHOGENESIS OF CRSWNP.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19  3075  42 GENOME-WIDE EPIGENETIC STUDY OF CHRONIC RHINOSINUSITIS TISSUES REVEALS DYSREGULATED INFLAMMATORY, IMMUNOLOGIC AND REMODELING PATHWAYS. BACKGROUND: EPIGENETICS STUDIES MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNAS, AND ALTERNATIVE POLYADENYLATION THAT CAN MODIFY GENE ACTIVITY WITHOUT CHANGING THE UNDERLYING DNA NUCLEOTIDE BASE-PAIR STRUCTURE. BECAUSE THESE CHANGES ARE REVERSIBLE, THEY HAVE POTENTIAL IN DEVELOPING NOVEL THERAPEUTICS. CURRENTLY, SEVEN PHARMACEUTICAL AGENTS TARGETING EPIGENETIC CHANGES ARE FDA APPROVED AND COMMERCIALLY AVAILABLE FOR TREATMENT OF CERTAIN CANCERS. HOWEVER, STUDIES INVESTIGATING EPIGENETICS IN CHRONIC RHINOSINUSITIS (CRS) HAVE NOT BEEN UNDERTAKEN PREVIOUSLY IN THE UNITED STATES. OBJECTIVES: THE GOAL OF THIS STUDY WAS TO INVESTIGATE SINONASAL DNA METHYLATION PATTERNS IN CRS VERSUS CONTROLS, TO DISCERN ENVIRONMENTALLY-INDUCED EPIGENETIC CHANGES IMPACTING CRS SUBJECTS. METHODS AND RESULTS: ETHMOIDAL SAMPLES FROM CRS AND INFERIOR TURBINATE MUCOSAL TISSUE SAMPLES FROM CONTROLS WITHOUT CRS WERE STUDIED. DNA METHYLATION WAS STUDIED BY REDUCED REPRESENTATION BISULFITE SEQUENCING. RADMETH(R) BIOSTATISTICAL PACKAGE WAS USED TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS) BETWEEN CRS AND CONTROLS. INGENUITY PATHWAY ANALYSIS OF DMRS WAS PERFORMED TO IDENTIFY TOP UPSTREAM REGULATORS AND CANONICAL PATHWAYS. NINETY-THREE SAMPLES FROM 64 CRS SUBJECTS (36 CRSWNP; 28 CRSSNP) AND 29 CONTROLS WERE STUDIED. CRS AND CONTROL SAMPLES DIFFERED IN 13 662 CPGS SITES AND 1381 DMRS. TOP UPSTREAM REGULATORS IDENTIFIED INCLUDED: 1. CRS VERSUS CONTROLS: TGFB1, TNF, TP53, DGCR8, AND BETA-ESTRADIOL. 2. CRSWNP VERSUS CONTROLS: TGFB1, CTNNB1, LIPOPOLYSACCHARIDE, ID2, AND TCF7L2. 3. CRSSNP VERSUS CONTROLS: MYOD1, ACETONE, ID2, ST8SIA4, AND LEPR. CONCLUSIONS: DIFFERENTIAL PATTERNS OF METHYLATION WERE IDENTIFIED BETWEEN CONTROLS AND CRS, CRSWNP, AND CRSSNP. EPIGENETIC, ENVIRONMENTALLY-INDUCED CHANGES RELATED TO NOVEL, INFLAMMATORY, IMMUNOLOGIC, AND REMODELING PATHWAYS APPEAR TO AFFECT EPITHELIAL INTEGRITY, CELL PROLIFERATION, HOMEOSTASIS, VASCULAR PERMEABILITY, AND OTHER YET UNCHARACTERIZED PATHWAYS AND GENES.	2023	
                                                                                                                                                                                                                                                                               
20  6568  38 TRANSMATERNAL HELICOBACTER PYLORI EXPOSURE REDUCES ALLERGIC AIRWAY INFLAMMATION IN OFFSPRING THROUGH REGULATORY T CELLS. BACKGROUND: TRANSMATERNAL EXPOSURE TO TOBACCO, MICROBES, NUTRIENTS, AND OTHER ENVIRONMENTAL FACTORS SHAPES THE FETAL IMMUNE SYSTEM THROUGH EPIGENETIC PROCESSES. THE GASTRIC MICROBE HELICOBACTER PYLORI REPRESENTS AN ANCESTRAL CONSTITUENT OF THE HUMAN MICROBIOTA THAT CAUSES GASTRIC DISORDERS ON THE ONE HAND AND IS INVERSELY ASSOCIATED WITH ALLERGIES AND CHRONIC INFLAMMATORY CONDITIONS ON THE OTHER. OBJECTIVE: HERE WE INVESTIGATE THE CONSEQUENCES OF TRANSMATERNAL EXPOSURE TO H PYLORI IN UTERO AND/OR DURING LACTATION FOR SUSCEPTIBILITY TO VIRAL AND BACTERIAL INFECTION, PREDISPOSITION TO ALLERGIC AIRWAY INFLAMMATION, AND DEVELOPMENT OF IMMUNE CELL POPULATIONS IN THE LUNGS AND LYMPHOID ORGANS. METHODS: WE USE EXPERIMENTAL MODELS OF HOUSE DUST MITE- OR OVALBUMIN-INDUCED AIRWAY INFLAMMATION AND INFLUENZA A VIRUS OR CITROBACTER RODENTIUM INFECTION ALONG WITH METAGENOMICS ANALYSES, MULTICOLOR FLOW CYTOMETRY, AND BISULFITE PYROSEQUENCING, TO STUDY THE EFFECTS OF H PYLORI ON ALLERGY SEVERITY AND IMMUNOLOGIC AND MICROBIOME CORRELATES THEREOF. RESULTS: PERINATAL EXPOSURE TO H PYLORI EXTRACT OR ITS IMMUNOMODULATOR VACUOLATING CYTOTOXIN CONFERS ROBUST PROTECTIVE EFFECTS AGAINST ALLERGIC AIRWAY INFLAMMATION NOT ONLY IN FIRST- BUT ALSO SECOND-GENERATION OFFSPRING BUT DOES NOT INCREASE SUSCEPTIBILITY TO VIRAL OR BACTERIAL INFECTION. IMMUNE CORRELATES OF ALLERGY PROTECTION INCLUDE SKEWING OF REGULATORY OVER EFFECTOR T CELLS, EXPANSION OF REGULATORY T-CELL SUBSETS EXPRESSING CXCR3 OR RETINOIC ACID-RELATED ORPHAN RECEPTOR GAMMAT, AND DEMETHYLATION OF THE FORKHEAD BOX P3 (FOXP3) LOCUS. THE COMPOSITION AND DIVERSITY OF THE GASTROINTESTINAL MICROBIOTA IS MEASURABLY AFFECTED BY PERINATAL H PYLORI EXPOSURE. CONCLUSION: WE CONCLUDE THAT EXPOSURE TO H PYLORI HAS CONSEQUENCES NOT ONLY FOR THE CARRIER BUT ALSO FOR SUBSEQUENT GENERATIONS THAT CAN BE EXPLOITED FOR INTERVENTIONAL PURPOSES.	2019