1  4484 170 MOLECULAR SIGNATURE OF CAID SYNDROME: NONCANONICAL ROLES OF SGO1 IN REGULATION OF TGF-BETA SIGNALING AND EPIGENOMICS. BACKGROUND & AIMS: A GENERALIZED HUMAN PACEMAKING SYNDROME, CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA (CAID) (OMIM 616201), IS CAUSED BY A HOMOZYGOUS SGO1 MUTATION (K23E), LEADING TO CHRONIC INTESTINAL PSEUDO-OBSTRUCTION AND ARRHYTHMIAS. BECAUSE CAID PATIENTS DO NOT SHOW PHENOTYPES CONSISTENT WITH PERTURBATION OF KNOWN ROLES OF SGO1, WE HYPOTHESIZED THAT NONCANONICAL ROLES OF SGO1 DRIVE THE CLINICAL MANIFESTATIONS OBSERVED. METHODS: TO IDENTIFY A MOLECULAR SIGNATURE FOR CAID SYNDROME, WE ACHIEVED UNBIASED SCREENS IN CELL LINES AND GUT TISSUES FROM CAID PATIENTS VS WILD-TYPE CONTROLS. WE PERFORMED RNA SEQUENCING ALONG WITH STABLE ISOTOPE LABELING WITH AMINO ACIDS IN CELL CULTURE. IN ADDITION, WE DETERMINED THE GENOME-WIDE DNA METHYLATION AND CHROMATIN ACCESSIBILITY SIGNATURES USING REDUCED REPRESENTATIVE BISULFITE SEQUENCING AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN WITH HIGH-THROUGHPUT SEQUENCING. FUNCTIONAL STUDIES INCLUDED PATCH-CLAMP, QUANTITATION OF TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) SIGNALING, AND IMMUNOHISTOCHEMISTRY IN CAID PATIENT GUT BIOPSY SPECIMENS. RESULTS: PROTEOME AND TRANSCRIPTOME STUDIES CONVERGE ON CELL-CYCLE REGULATION, CARDIAC CONDUCTION, AND SMOOTH MUSCLE REGULATION AS DRIVERS OF CAID SYNDROME. SPECIFICALLY, THE INWARD RECTIFIER CURRENT, AN IMPORTANT REGULATOR OF CELLULAR FUNCTION, WAS DISRUPTED. IMMUNOHISTOCHEMISTRY CONFIRMED OVEREXPRESSION OF BUDDING UNINHIBITED BY BENZIMIDAZOLES 1 (BUB1) IN PATIENTS, IMPLICATING THE TGF-BETA PATHWAY IN CAID PATHOGENESIS. CANONICAL TGF-BETA SIGNALING WAS UP-REGULATED AND UNCOUPLED FROM NONCANONICAL SIGNALING IN CAID PATIENTS. REDUCED REPRESENTATIVE BISULFITE SEQUENCING AND ASSAY FOR TRANSPOSASE-ACCESSIBLE CHROMATIN WITH HIGH-THROUGHPUT SEQUENCING EXPERIMENTS SHOWED SIGNIFICANT CHANGES OF CHROMATIN STATES IN CAID, POINTING TO EPIGENETIC REGULATION AS A POSSIBLE PATHOLOGIC MECHANISM. CONCLUSIONS: OUR FINDINGS POINT TO IMPAIRED INWARD RECTIFIER POTASSIUM CURRENT, DYSREGULATION OF CANONICAL TGF-BETA SIGNALING, AND EPIGENETIC REGULATION AS POTENTIAL DRIVERS OF INTESTINAL AND CARDIAC MANIFESTATIONS OF CAID SYNDROME. TRANSCRIPT PROFILING AND GENOMICS DATA ARE AS FOLLOWS: REPOSITORY URL: HTTPS://WWW.NCBI.NLM.NIH.GOV/GEO; SUPERSERIES GSE110612 WAS COMPOSED OF THE FOLLOWING SUBSERIES: GSE110309, GSE110576, AND GSE110601.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  1118  34 COMPARATIVE GENOTYPING AND PHENOTYPING OF ASPERGILLUS FUMIGATUS ISOLATES FROM HUMANS, DOGS AND THE ENVIRONMENT. BACKGROUND: ASPERGILLUS FUMIGATUS IS A UBIQUITOUS SAPROTROPHIC FUNGUS AND AN OPPORTUNISTIC PATHOGEN OF HUMANS AND ANIMALS. HUMANS AND ANIMALS CAN INHALE HUNDREDS OF A. FUMIGATUS SPORES DAILY. NORMALLY THIS IS HARMLESS FOR HUMANS, BUT IN CASE OF IMMUNODEFICIENCY, INVASIVE PULMONARY ASPERGILLOSIS (IPA) CAN DEVELOP WITH A HIGH MORTALITY RATE. A. FUMIGATUS ALSO CAUSES NON-INVASIVE MYCOSES LIKE SINO-NASAL ASPERGILLOSIS (SNA) IN DOGS. RESULTS: IN THIS STUDY WE COMPARED A. FUMIGATUS ISOLATES FROM HUMANS WITH SUSPECTED IPA, DOGS WITH SNA, AND A SET OF ENVIRONMENTAL ISOLATES. PHYLOGENETIC INFERENCE BASED ON CALMODULIN (CAM) AND BETA-TUBULIN (BENA) SEQUENCES DID NOT REVEAL A. FUMIGATUS SUB-GROUPS LINKED TO THE ORIGIN OF THE ISOLATES. GENOTYPING AND MICROSATELLITE ANALYSIS SHOWED THAT EACH DOG WAS INFECTED BY ONE A. FUMIGATUS GENOTYPE, WHEREAS HUMAN PATIENTS HAD MIXED INFECTIONS. AZOLE RESISTANCE WAS DETERMINED BY ANTIFUNGAL SUSCEPTIBILITY TESTING AND SEQUENCING OF THE CYP51A GENE. A TOTAL OF 12 OUT OF 29 HUMAN ISOLATES AND 1 OUT OF 27 ENVIRONMENTAL ISOLATES WERE AZOLE RESISTANT. OF THE AZOLE RESISTANT STRAINS, 11 HUMAN ISOLATES SHOWED TR(34)/L98H (N = 6) OR TR46/Y121F/T289A (N = 5). PHENOTYPICALLY, ISOLATES FROM DOGS WERE MORE VARIABLE IN GROWTH SPEED AND MORPHOLOGY WHEN COMPARED TO THOSE ISOLATED FROM HUMAN AND THE ENVIRONMENT. CONCLUSIONS: 1. A. FUMIGATUS FROM DOGS WITH SNA ARE PHENOTYPICALLY VERY DIVERSE IN CONTRAST TO THEIR ENVIRONMENTAL AND HUMAN COUNTERPARTS. 2. PHENOTYPIC VARIABILITY CAN BE INDUCED DURING THE CHRONIC INFECTION PROCESS IN THE SINUS OF THE DOGS. THE BASIS OF THIS HETEROGENEITY MIGHT BE DUE TO GENOMIC DIFFERENCES AND/OR EPIGENETIC VARIATIONS. 3. DIFFERENCES IN DOGS IS A COULD BE A RESULT OF WITHIN-HOST ADAPTION AND MIGHT BE TRIGGERED BY ENVIRONMENTAL FACTORS IN THE SINUS, HOWEVER THIS HYPOTHESIS STILL NEEDS TO BE TESTED.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3  6145  53 THE EXPANDING PHENOTYPES OF COHESINOPATHIES: ONE RING TO RULE THEM ALL! PRESERVATION AND DEVELOPMENT OF LIFE DEPEND ON THE ADEQUATE SEGREGATION OF SISTER CHROMATIDS DURING MITOSIS AND MEIOSIS. THIS PROCESS IS ENSURED BY THE COHESIN MULTI-SUBUNIT COMPLEX. MUTATIONS IN THIS COMPLEX HAVE BEEN ASSOCIATED WITH AN INCREASING NUMBER OF DISEASES, TERMED COHESINOPATHIES. THE BEST CHARACTERIZED COHESINOPATHY IS CORNELIA DE LANGE SYNDROME (CDLS), IN WHICH INTELLECTUAL AND GROWTH RETARDATIONS ARE THE MAIN PHENOTYPIC MANIFESTATIONS. DESPITE SOME OVERLAP, THE CLINICAL MANIFESTATIONS OF COHESINOPATHIES VARY CONSIDERABLY. NOVEL ROLES OF THE COHESIN COMPLEX HAVE EMERGED DURING THE PAST DECADES, SUGGESTING THAT IMPORTANT CELL CYCLE REGULATORS EXERT IMPORTANT BIOLOGICAL EFFECTS THROUGH NON-COHESION-RELATED FUNCTIONS AND BROADENING THE POTENTIAL PATHOMECHANISMS INVOLVED IN COHESINOPATHIES. THIS REVIEW FOCUSES ON NON-COHESION-RELATED FUNCTIONS OF THE COHESIN COMPLEX, GENE DOSAGE EFFECT, EPIGENETIC REGULATION AND TGF-BETA IN COHESINOPATHY CONTEXT, ESPECIALLY IN COMPARISON TO CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA (CAID) SYNDROME, A VERY DISTINCT COHESINOPATHY CAUSED BY A HOMOZYGOUS SHUGOSHIN-1 (SGO1) MUTATION (K23E) AND CHARACTERIZED BY PACEMAKER FAILURE IN BOTH HEART (SICK SINUS SYNDROME FOLLOWED BY ATRIAL FLUTTER) AND GUT (CHRONIC INTESTINAL PSEUDO-OBSTRUCTION) WITH NO INTELLECTUAL OR GROWTH DELAY. WE DISCUSS THE POSSIBLE IMPACT OF SGO1 ALTERATIONS IN HUMAN PATHOLOGIES AND THE POTENTIAL IMPACT OF THE SGO1 K23E MUTATION IN THE SINUS NODE AND GUT DEVELOPMENT AND FUNCTIONS. WE SUGGEST THAT THE HUMAN PHENOTYPES OBSERVED IN CDLS, CAID SYNDROME AND OTHER COHESINOPATHIES CAN INFORM FUTURE STUDIES INTO THE LESS WELL-KNOWN NON-COHESION-RELATED FUNCTIONS OF COHESIN COMPLEX GENES. ABBREVIATIONS: AD: ALZHEIMER DISEASE; AFF4: AF4/FMR2 FAMILY MEMBER 4; ANKRD11: ANKYRIN REPEAT DOMAIN 11; APC: ANAPHASE PROMOTER COMPLEX; ASD: ATRIAL SEPTAL DEFECT; ATRX: ATRX CHROMATIN REMODELER; ATRX: ALPHA THALASSEMIA X-LINKED INTELLECTUAL DISABILITY SYNDROME; BIRC5: BACULOVIRAL IAP REPEAT CONTAINING 5; BMP: BONE MORPHOGENETIC PROTEIN; BRD4: BROMODOMAIN CONTAINING 4; BUB1: BUB1 MITOTIC CHECKPOINT SERINE/THREONINE KINASE; CAID: CHRONIC ATRIAL AND INTESTINAL DYSRHYTHMIA; CDK1: CYCLIN DEPENDENT KINASE 1; CDLS: CORNELIA DE LANGE SYNDROME; CHD: CONGENITAL HEART DISEASE; CHOPS: COGNITIVE IMPAIRMENT, COARSE FACIES, HEART DEFECTS, OBESITY, PULMONARY INVOLVEMENT, SHORT STATURE, AND SKELETAL DYSPLASIA; CIPO: CHRONIC INTESTINAL PSEUDO-OBSTRUCTION; C-KIT: KIT PROTO-ONCOGENE RECEPTOR TYROSINE KINASE; COATS: COHESIN ACETYLTRANSFERASES; CTCF: CCCTC-BINDING FACTOR; DDX11: DEAD/H-BOX HELICASE 11; ERG: TRANSCRIPTIONAL REGULATOR ERG; ESCO2: ESTABLISHMENT OF SISTER CHROMATID COHESION N-ACETYLTRANSFERASE 2; GJC1: GAP JUNCTION PROTEIN GAMMA 1; H2A: HISTONE H2A; H3K4: HISTONE H3 LYSINE 4; H3K9: HISTONE H3 LYSINE 9; HCN4: HYPERPOLARIZATION ACTIVATED CYCLIC NUCLEOTIDE GATED POTASSIUM AND SODIUM CHANNEL 4;P HDAC8: HISTONE DEACETYLASES 8; HP1: HETEROCHROMATIN PROTEIN 1; ICC: INTERSTITIAL CELLS OF CAJAL; ICC-MP: MYENTERIC PLEXUS INTERSTITIAL CELLS OF CAJAL; ICC-DMP: DEEP MUSCULAR PLEXUS INTERSTITIAL CELLS OF CAJAL; I(F): PACEMAKER FUNNY CURRENT; IP3: INOSITOL TRISPHOSPHATE; JNK: C-JUN N-TERMINAL KINASE; LDS: LOEYS-DIETZ SYNDROME; LOAD: LATE-ONSET ALZHEIMER DISEASE; MAPK: MITOGEN-ACTIVATED PROTEIN KINASE; MAU: MAU SISTER CHROMATID COHESION FACTOR; MFS: MARFAN SYNDROME; NIPBL: NIPBL, COHESIN LOADING FACTOR; OCT4: OCTAMER-BINDING PROTEIN 4; P38: P38 MAP KINASE; PDA: PATENT DUCTUS ARTERIOSUS; PDS5: PDS5 COHESIN ASSOCIATED FACTOR; P-H3: PHOSPHO HISTONE H3; PLK1: POLO LIKE KINASE 1; POPDC1: POPEYE DOMAIN CONTAINING 1; POPDC2: POPEYE DOMAIN CONTAINING 2; PP2A: PROTEIN PHOSPHATASE 2; RAD21: RAD21 COHESIN COMPLEX COMPONENT; RBS: ROBERTS SYNDROME; REC8: REC8 MEIOTIC RECOMBINATION PROTEIN; RNAP2: RNA POLYMERASE II; SAN: SINOATRIAL NODE; SCN5A: SODIUM VOLTAGE-GATED CHANNEL ALPHA SUBUNIT 5; SEC: SUPER ELONGATION COMPLEX; SGO1: SHOGOSHIN-1; SMAD: SMAD FAMILY MEMBER; SMC1A: STRUCTURAL MAINTENANCE OF CHROMOSOMES 1A; SMC3: STRUCTURAL MAINTENANCE OF CHROMOSOMES 3; SNV: SINGLE NUCLEOTIDE VARIANT; SOX2: SRY-BOX 2; SOX17: SRY-BOX 17; SSS: SICK SINUS SYNDROME; STAG2: COHESIN SUBUNIT SA-2; TADS: TOPOLOGY ASSOCIATED DOMAINS; TBX: T-BOX TRANSCRIPTION FACTORS; TGF-BETA: TRANSFORMING GROWTH FACTOR BETA; TGFBR: TRANSFORMING GROWTH FACTOR BETA RECEPTOR; TOF: TETRALOGY OF FALLOT; TREK1: TREK-1 K(+) CHANNEL SUBUNIT; VSD: VENTRICULAR SEPTAL DEFECT; WABS: WARSAW BREAKAGE SYNDROME; WAPL: WAPL COHESIN RELEASE FACTOR.	2019	

4  2406  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5  1826  35 EFFECTS OF HISTONE DEACETYLASE INHIBITOR ON EXTRACELLULAR MATRIX PRODUCTION IN HUMAN NASAL POLYP ORGAN CULTURES. BACKGROUND: NASAL POLYPOSIS IS ASSOCIATED WITH A CHRONIC INFLAMMATORY CONDITION OF THE SINONASAL MUCOSA AND INVOLVES MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX (ECM) ACCUMULATION. EPIGENETIC MODULATION BY HISTONE DEACETYLASE (HDAC) INHIBITORS INCLUDING TRICHOSTATIN A (TSA) HAS BEEN REPORTED TO HAVE INHIBITORY EFFECTS ON MYOFIBROBLAST DIFFERENTIATION IN LUNG AND RENAL FIBROBLASTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE INHIBITORY EFFECT OF TSA ON MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION IN NASAL POLYP ORGAN CULTURES. METHODS: NASAL POLYP TISSUES FROM 18 PATIENTS WERE ACQUIRED DURING ENDOSCOPIC SINUS SURGERY. AFTER ORGAN CULTURE, NASAL POLYPS WERE STIMULATED WITH TGF-BETA1 AND THEN TREATED WITH TSA. ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), FIBRONECTIN, AND COLLAGEN TYPE I EXPRESSION LEVELS WERE EXAMINED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION (PCR), REAL-TIME PCR, WESTERN BLOT, AND IMMUNOFLUORESCENT STAINING. HDAC2, HDAC4, AND ACETYLATED H4 EXPRESSION LEVELS WERE ASSAYED BY WESTERN BLOT. CYTOTOXICITY WAS ANALYZED BY THE TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE BIOTIN-DUTP NICK END LABELING ASSAY. RESULTS: THE EXPRESSION LEVELS OF ALPHA-SMA, FIBRONECTIN, AND COLLAGEN TYPE 1 WERE INCREASED IN NASAL POLYP AFTER TRANSFORMING GROWTH FACTOR (TGF) BETA1 TREATMENT. TSA-INHIBITED TGF-BETA1 INDUCED THESE GENE AND PROTEIN EXPRESSION LEVELS. FURTHERMORE, TSA SUPPRESSED PROTEIN EXPRESSION LEVELS OF HDAC2 AND HDAC4. HOWEVER, TSA INDUCED HYPERACETYLATION OF HISTONES H4. TREATMENT WITH TGF-BETA1 WITH OR WITHOUT TSA DID NOT HAVE CYTOTOXIC EFFECT. CONCLUSION: THESE FINDINGS PROVIDE NOVEL INSIGHTS INTO THE EPIGENETIC REGULATION IN MYOFIBROBLAST DIFFERENTIATION AND ECM PRODUCTION OF NASAL POLYP. TSA COULD BE A CANDIDATE OF A THERAPEUTIC AGENT FOR REVERSING THE TGF-BETA1-INDUCED ECM SYNTHESIS THAT LEADS TO NASAL POLYP DEVELOPMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6  6662  30 UPREGULATION OF FZD5 IN EOSINOPHILIC CHRONIC RHINOSINUSITIS WITH NASAL POLYPS BY EPIGENETIC MODIFICATION. EOSINOPHILIC CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP) IS ONE OF THE MOST CHALLENGING PROBLEMS IN CLINICAL RHINOLOGY. FZD5 IS A RECEPTOR FOR WNT5A, AND ITS COMPLEX WITH WNT5A CONTRIBUTES TO ACTIVATING INFLAMMATION AND TISSUE MODIFICATION. NASAL POLYPS AND EOSINOPHIL/NON-EOSINOPHIL COUNTS ARE REPORTED TO BE DIRECTLY CORRELATED. THIS STUDY INVESTIGATED THE EXPRESSION AND DISTRIBUTION OF FZD5, AND THE ROLE OF EOSINOPHIL INFILTRATION AND FZD5 IN EOSINOPHILIC CRSWNP PATHOGENESIS. THE PROGNOSTIC ROLE OF EOSINOPHIL LEVELS WAS EVALUATED IN SEVEN PATIENTS WITH CRSWNP. FIFTEEN PATIENTS WITH CRS WERE CLASSIFIED BASED ON THE PERCENTAGE OF EOSINOPHILS IN NASAL POLYP TISSUE. METHYLATED GENES WERE DETECTED USING METHYL-CPG-BINDING DOMAIN SEQUENCING, AND QRT-PCR AND IMMUNOHISTOCHEMISTRY WERE USED TO DETECT FZD5 EXPRESSION IN NASAL POLYP TISSUE SAMPLES. THE RESULTS SHOWED THAT MRNA EXPRESSION OF FZD5 WAS UPREGULATED IN NASAL POLYPS. FZD5 EXPRESSION WAS SIGNIFICANTLY HIGHER IN NASAL POLYP SAMPLES FROM PATIENTS WITH EOSINOPHILIC CRSWNP THAN IN THOSE FROM PATIENTS WITH NON-EOSINOPHILIC CRSWNP, AS INDICATED BY IMMUNOHISTOCHEMISTRY. FURTHERMORE, INFLAMMATORY CYTOKINE LEVELS WERE HIGHER IN EOSINOPHILIC CRSWNP-DERIVED EPITHELIAL CELLS THAN IN NORMAL TISSUES. IN CONCLUSION, FZD5 EXPRESSION IN NASAL MUCOSAL EPITHELIAL CELLS IS CORRELATED WITH INFLAMMATORY CELLS AND MIGHT PLAY A ROLE IN THE PATHOGENESIS OF EOSINOPHILIC CRSWNP.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7  3075  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
8  2349  38 EPIGENETIC REGULATION OF MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX PRODUCTION IN NASAL POLYP-DERIVED FIBROBLASTS. BACKGROUND: NASAL POLYPOSIS IS A MULTI-FACTORIAL DISEASE ASSOCIATED WITH CHRONIC INFLAMMATORY CONDITION OF THE PARANASAL SINUSES. MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLULAR MATRIX (ECM) ACCUMULATION ARE INVOLVED IN THE PATHOGENESIS OF NASAL POLYPOSIS. OBJECTIVE: THE AIM OF THIS STUDY WAS TO STUDY THE EFFECT OF TRICHOSTATIN A (TSA), A HISTONE DEACETYLASE (HDAC) INHIBITOR, ON TRANSFORMING GROWTH FACTOR (TGF)-BETA1-INDUCED MYOFIBROBLAST DIFFERENTIATION AND ECM ACCUMULATION IN NASAL POLYP-DERIVED FIBROBLASTS (NPDFS). METHODS: NASAL POLYP-DERIVED FIBROBLASTS WERE ISOLATED FROM NASAL POLYPS OF PATIENTS WHO HAVE CHRONIC RHINOSINUSITIS WITH NASAL POLYP. TSA WAS TREATED IN TGF-BETA1-INDUCED NPDFS. EXPRESSION LEVELS OF HDAC2, ALPHA-SMOOTH MUSCLE ACTIN (SMA), TGF-BETA1, COLLAGEN TYPE I, ACETYLATED HISTONE H3, ACETYLATED HISTONE H4, PHOSPHORYLATED SMAD2/3 AND SMAD7 WERE DETERMINED BY RT-PCR, WESTERN BLOT AND/OR IMMUNOFLUORESCENT STAINING. THE TOTAL COLLAGEN AMOUNT PRODUCTION WAS ANALYSED BY SIRCOL SOLUBLE COLLAGEN ASSAY AND CONTRACTILE ACTIVITY WAS MEASURED BY COLLAGEN GEL CONTRACTION ASSAY. HDAC2 INHIBITION BY TSA OR HDAC2 SILENCING WAS ESTABLISHED BY RT-PCR AND WESTERN BLOT. THE EPIGENETIC EFFECT ON ALPHA-SMA GENE INACTIVATION WAS EXAMINED BY CHROMATIN IMMUNOPRECIPITATION ASSAY. PROLIFERATION WAS DETERMINED BY KI67-POSITIVE CELL STAINING AND CYTOTOXICITY WAS ASSESSED BY 3-(4,5- DIMETHYLTHIAZOL-2YL)-2,5-DIPHENYL-2H-TETRAZOLIUM BROMIDE (MTT) ASSAY. RESULTS: THE EXPRESSION LEVELS OF HDAC2, ALPHA-SMA AND TGF-BETA1 WERE INCREASED IN NASAL POLYP TISSUES COMPARED TO NORMAL INFERIOR TURBINATE TISSUES. TSA AND HDAC2 SILENCING INHIBITED EXPRESSION LEVELS ALPHA-SMA, COLLAGEN AND HDAC2. TSA INDUCED HYPERACETYLATION OF HISTONE AND SUPPRESSED OPENING OF ALPHA-SMA GENE PROMOTER IN TGF-BETA1-INDUCED NPDFS. TSA INHIBITED TGF-BETA1-INDUCED SMAD 2/3 AND RESCUED TGF-BETA1-SUPPRESSED SMAD7 SIGNALLING PATHWAY. FINALLY, TSA BLOCKED PROLIFERATION IN TGF-BETA1-INDUCED NPDFS AND HAS NO CYTOTOXIC EFFECT IN NPDFS. CONCLUSIONS AND CLINICAL RELEVANCE: THESE RESULTS SUGGEST THAT HDAC INHIBITION IS ASSOCIATED WITH MYOFIBROBLAST DIFFERENTIATION AND EXTRACELLUAR MATRIX ACCUMULATION IN NASAL POLYPOSIS. TSA MAY BE USEFUL AS AN INHIBITOR OF NASAL POLYP GROWTH, AND THUS HAS POTENTIAL TO BE USED AS A NOVEL TREATMENT OPTION FOR NASAL POLYPOSIS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9  3758  36 INTEGRATED MRNA AND MICRORNA TRANSCRIPTOME PROFILING DURING DIFFERENTIATION OF HUMAN NASAL POLYP EPITHELIUM REVEALS AN ALTERED CILIOGENESIS. BACKGROUND: HUMAN ADULT BASAL STEM/PROGENITOR CELLS (BSCS) OBTAINED FROM CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP) WHEN DIFFERENTIATED IN AN AIR-LIQUID INTERFACE (ALI) USUALLY PROVIDE A PSEUDOSTRATIFIED AIRWAY EPITHELIUM WITH SIMILAR ABNORMALITIES THAN ORIGINAL IN VIVO PHENOTYPE. HOWEVER, THE INTRINSIC MECHANISMS REGULATING THIS COMPLEX PROCESS ARE NOT WELL DEFINED AND THEIR UNDERSTANDING COULD OFFER POTENTIAL NEW THERAPIES FOR CRSWNP (INCURABLE DISEASE). METHODS: WE PERFORMED A TRANSCRIPTOME-WIDE ANALYSIS DURING IN VITRO MUCOCILIARY DIFFERENTIATION OF HUMAN ADULT BSCS FROM CRSWNP, COMPARED TO THOSE ISOLATED FROM CONTROL NASAL MUCOSA (CONTROL-NM), IN ORDER TO IDENTIFY WHICH KEY MRNA AND MICRORNAS ARE REGULATING THIS COMPLEX PROCESS IN PATHOLOGICAL AND HEALTHY CONDITIONS. RESULTS: A NUMBER OF GENES, MIRS, BIOLOGICAL PROCESSES, AND PATHWAYS WERE IDENTIFIED DURING MUCOCILIARY DIFFERENTIATION OF BOTH CRSWNP AND CONTROL-NM EPITHELIA, AND NOTABLY, WE HAVE DEMONSTRATED FOR THE FIRST TIME THAT GENETIC TRANSCRIPTIONAL PROGRAM RESPONSIBLE OF CILIOGENESIS AND CILIA FUNCTION IS SIGNIFICANTLY IMPAIRED IN CRSWNP EPITHELIUM, PRESUMABLY PRODUCED BY AN ALTERED EXPRESSION OF MICRORNAS, PARTICULARLY OF THOSE MIRS BELONGING TO MIR-34 AND MI-449 FAMILIES. CONCLUSIONS: THIS STUDY PROVIDES FOR THE FIRST TIME A NOVEL INSIGHT INTO THE MOLECULAR BASIS OF SINONASAL MUCOCILIARY DIFFERENTIATION, DEMONSTRATING THAT TRANSCRIPTOME RELATED TO CILIOGENESIS AND CILIA FUNCTION IS SIGNIFICANTLY IMPAIRED DURING DIFFERENTIATION OF CRSWNP EPITHELIUM DUE TO AN ALTERED EXPRESSION OF MICRORNAS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10  3285  25 HIDRADENITIS SUPPURATIVA: A PERSPECTIVE ON GENETIC FACTORS INVOLVED IN THE DISEASE. HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE OF THE PILOSEBACEOUS UNIT, CLINICALLY CONSISTING OF PAINFUL NODULES, ABSCESSES, AND SINUS TRACTS MOSTLY IN, BUT NOT LIMITED TO, INTERTRIGINOUS SKIN AREAS. HS CAN BE DEFINED AS A COMPLEX SKIN DISEASE WITH MULTIFACTORIAL ETIOLOGIES, INCLUDING-AMONG OTHERS-GENETIC, IMMUNOLOGIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. BASED ON GENETIC HETEROGENEITY AND COMPLEXITY, THREE DIFFERENT FORMS CAN BE RECOGNIZED AND CONSIDERED SEPARATELY AS SPORADIC, FAMILIAL, AND SYNDROMIC. TO DATE, SEVERAL GENETIC VARIANTS ASSOCIATED TO DISEASE SUSCEPTIBILITY, DISEASE-ONSET, AND/OR TREATMENT RESPONSE HAVE BEEN REPORTED; SOME OF THESE RESIDE IN GENES ENCODING THE GAMMA-SECRETASE SUBUNITS WHEREAS OTHERS INVOLVE AUTOINFLAMMATORY AND/OR KERATINIZATION GENES. THE AIM OF THIS PERSPECTIVE WORK IS TO PROVIDE AN OVERVIEW OF THE CONTRIBUTION OF SEVERAL GENETIC STUDIES ENCOMPASSING FAMILY LINKAGE ANALYSES, TARGET CANDIDATE GENE STUDIES, AND -OMIC STUDIES IN THIS FIELD. IN OUR VIEWPOINT, WE DISCUSS THE ROLE OF GENETICS IN HIDRADENITIS SUPPURATIVA CONSIDERING FINDINGS BASED ON SANGER SEQUENCING AS WELL AS THE MORE RECENT NEXT GENERATION SEQUENCING (I.E., EXOME SEQUENCING OR RNA SEQUENCING) WITH THE AIM OF BETTER UNDERSTANDING THE ETIO-PATHOGENESIS OF THE DISEASE AS WELL AS IDENTIFYING NOVEL THERAPEUTIC STRATEGIES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11  3460  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12  3019  28 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  6569  24 TRANSPLANTATION OF EPIGENETICALLY MODIFIED ADULT CARDIAC C-KIT+ CELLS RETARDS REMODELING AND IMPROVES CARDIAC FUNCTION IN ISCHEMIC HEART FAILURE MODEL. CARDIAC C-KIT+ CELLS HAVE A MODEST CARDIOGENIC POTENTIAL THAT COULD LIMIT THEIR EFFICACY IN HEART DISEASE TREATMENT. THE PRESENT STUDY WAS DESIGNED TO AUGMENT THE CARDIOGENIC POTENTIAL OF CARDIAC C-KIT+ CELLS THROUGH CLASS I HISTONE DEACETYLASE (HDAC) INHIBITION AND EVALUATE THEIR THERAPEUTIC POTENCY IN THE CHRONIC HEART FAILURE (CHF) ANIMAL MODEL. MYOCARDIAL INFARCTION (MI) WAS CREATED BY CORONARY ARTERY OCCLUSION IN RATS. C-KIT+ CELLS WERE TREATED WITH MOCETINOSTAT (MOCE), A SPECIFIC CLASS I HDAC INHIBITOR. AT 3 WEEKS AFTER MI, CHF ANIMALS WERE RETROGRADELY INFUSED WITH UNTREATED (CONTROL) OR MOCE-TREATED C-KIT+ CELLS (MOCE/C-KIT+ CELLS) AND EVALUATED AT 3 WEEKS AFTER CELL INFUSION. WE FOUND THAT CLASS I HDAC INHIBITION IN C-KIT+ CELLS ELEVATED THE LEVEL OF ACETYLATED HISTONE H3 (ACH3) AND INCREASED ACH3 LEVELS IN THE PROMOTER REGIONS OF PLURIPOTENT AND CARDIAC-SPECIFIC GENES. EPIGENETIC CHANGES WERE ACCOMPANIED BY INCREASED EXPRESSION OF CARDIAC-SPECIFIC MARKERS. TRANSPLANTATION OF CHF RATS WITH EITHER CONTROL OR MOCE/C-KIT+ CELLS RESULTED IN AN IMPROVEMENT IN CARDIAC FUNCTION, RETARDATION OF CHF REMODELING MADE EVIDENT BY INCREASED VASCULARIZATION AND SCAR SIZE, AND CARDIOMYOCYTE HYPERTROPHY REDUCTION. COMPARED WITH CHF INFUSED WITH CONTROL CELLS, INFUSION OF MOCE/C-KIT+ CELLS RESULTED IN A FURTHER REDUCTION IN LEFT VENTRICLE END-DIASTOLIC PRESSURE AND TOTAL COLLAGEN AND AN INCREASE IN INTERLEUKIN-6 EXPRESSION. THE LOW ENGRAFTMENT OF INFUSED CELLS SUGGESTS THAT PARACRINE EFFECTS MIGHT ACCOUNT FOR THE BENEFICIAL EFFECTS OF C-KIT+ CELLS IN CHF. IN CONCLUSION, SELECTIVE INHIBITION OF CLASS I HDACS INDUCED EXPRESSION OF CARDIAC MARKERS IN C-KIT+ CELLS AND PARTIALLY AUGMENTED THE EFFICACY OF THESE CELLS FOR CHF REPAIR. SIGNIFICANCE: THE STUDY HAS SHOWN THAT SELECTIVE CLASS 1 HISTONE DEACETYLASE INHIBITION IS SUFFICIENT TO REDIRECT C-KIT+ CELLS TOWARD A CARDIAC FATE. EPIGENETICALLY MODIFIED C-KIT+ CELLS IMPROVED CONTRACTILE FUNCTION AND RETARDED REMODELING OF THE CONGESTIVE HEART FAILURE HEART. THIS STUDY PROVIDES NEW INSIGHTS INTO THE EFFICACY OF CARDIAC C-KIT+ CELLS IN THE ISCHEMIC HEART FAILURE MODEL.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  1092  29 COHESIN MUTATIONS IN MYELOID MALIGNANCIES. COHESIN IS A MULTISUBUNIT PROTEIN COMPLEX THAT FORMS A RING-LIKE STRUCTURE AROUND DNA. IT IS ESSENTIAL FOR SISTER CHROMATID COHESION, CHROMATIN ORGANIZATION, TRANSCRIPTIONAL REGULATION, AND DNA DAMAGE REPAIR AND PLAYS A MAJOR ROLE IN DYNAMICALLY SHAPING THE GENOME ARCHITECTURE AND MAINTAINING DNA INTEGRITY. THE CORE COMPLEX SUBUNITS STAG2, RAD21, SMC1, AND SMC3, AS WELL AS ITS MODULATORS PDS5A/B, WAPL, AND NIPBL, HAVE BEEN FOUND TO BE RECURRENTLY MUTATED IN HEMATOLOGIC AND SOLID MALIGNANCIES. THESE MUTATIONS ARE FOUND ACROSS THE FULL SPECTRUM OF MYELOID NEOPLASIA, INCLUDING PEDIATRIC DOWN SYNDROME-ASSOCIATED ACUTE MEGAKARYOBLASTIC LEUKEMIA, MYELODYSPLASTIC SYNDROMES, CHRONIC MYELOMONOCYTIC LEUKEMIA, AND DE NOVO AND SECONDARY ACUTE MYELOID LEUKEMIAS. THE MECHANISMS BY WHICH COHESIN MUTATIONS ACT AS DRIVERS OF CLONAL EXPANSION AND DISEASE PROGRESSION ARE STILL POORLY UNDERSTOOD. RECENT STUDIES HAVE DESCRIBED THE IMPACT OF COHESIN ALTERATIONS ON SELF-RENEWAL AND DIFFERENTIATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS, WHICH ARE ASSOCIATED WITH CHANGES IN CHROMATIN AND EPIGENETIC STATE DIRECTING LINEAGE COMMITMENT, AS WELL AS GENOMIC INTEGRITY. HEREIN, WE REVIEW THE ROLE OF THE COHESIN COMPLEX IN HEALTHY AND MALIGNANT HEMATOPOIESIS. WE DISCUSS CLINICAL IMPLICATIONS OF COHESIN MUTATIONS IN MYELOID MALIGNANCIES AND DISCUSS OPPORTUNITIES FOR THERAPEUTIC TARGETING.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15  5399  38 REDUCED TEN-ELEVEN TRANSLOCATION AND ISOCITRATE DEHYDROGENASE EXPRESSION IN INFLAMMATORY HIDRADENITIS SUPPURATIVA LESIONS. BACKGROUND: AS ENVIRONMENTAL FACTORS APPEAR TO PREDISPOSE PATIENTS TO HIDRADENITIS SUPPURATIVA (HS), STUDYING EPIGENETIC MODIFICATIONS IS OF INTEREST TO FURTHER UNDERSTAND THE PATHOGENESIS OF HS. OBJECTIVES: TO STUDY THE EXPRESSION OF DNA HYDROXYMETHYLATION REGULATORS, NAMELY THE TEN-ELEVEN TRANSLOCATION (TET) AND ISOCITRATE DEHYDROGENASE (IDH) FAMILY, IN THE SKIN OF HS PATIENTS. MATERIALS & METHODS: TWENTY PATIENTS WITH HS AND 12 HEALTHY SUBJECTS WERE RECRUITED. WE ANALYSED THE EXPRESSION OF TET1, TET2, TET3, IDH1, IDH2, IDH3A, AND IDH3B IN LESIONAL AND PERILESIONAL HS TISSUE AS WELL AS TISSUE FROM HEALTHY CONTROLS BY QUANTITATIVE REAL-TIME REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION (RT-PCR). IN ADDITION, IMMUNOHISTOCHEMISTRY WAS PERFORMED FOR TET1, TET2, AND TET3. RESULTS: RT-PCR ANALYSIS SHOWED THAT MRNA OF ALL THE STUDIED GENES WAS SIGNIFICANTLY UNDER-EXPRESSED IN LESIONAL HS SKIN COMPARED TO HEALTHY SKIN. IDH1 AND IDH2 MRNA EXPRESSION WAS ALSO SIGNIFICANTLY LOWER IN PERILESIONAL HS SKIN COMPARED TO HEALTHY SKIN, AND TET3 MRNA EXPRESSION WAS SIGNIFICANTLY LOWER IN LESIONAL HS SKIN COMPARED TO PERILESIONAL HS SKIN. RT-PCR ANALYSIS FOR TET1, TET2, AND TET3 MRNA EXPRESSION WAS CONFIRMED BY IMMUNOHISTOCHEMICAL ANALYSIS. CORRELATION ANALYSIS REVEALED A SIGNIFICANT POSITIVE CORRELATION BETWEEN TET AND IDH GENE EXPRESSION IN PERILESIONAL AND LESIONAL HS SKIN. CONCLUSIONS: OUR RESULTS SUGGEST THAT EPIGENETIC CHANGES OCCUR IN HS TISSUE AND THAT ABERRANT EXPRESSION OF THE DNA HYDROXYMETHYLATION REGULATORS MAY PLAY A ROLE IN THE PATHOGENESIS OF HS. AS EPIGENETIC MODIFICATIONS ARE REVERSIBLE, FURTHER RESEARCH INTO THE CAUSE OF THESE ABERRANT EXPRESSION PATTERNS IS WARRANTED IN ORDER TO DEVELOP POSSIBLE NOVEL THERAPEUTIC APPROACHES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  6368  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
17  5822  16 STRESS IN THE ONSET AND AGGRAVATION OF LEARNING DISABILITIES. DESPITE SUBSTANTIAL GROUNDS FOR SUCH RESEARCH, THE ROLE OF CHRONIC EXPOSURE TO STRESSORS IN THE ONSET AND AGGRAVATION OF LEARNING DISABILITIES (LDS) IS LARGELY UNEXPLORED. IN THIS REVIEW, WE FIRST CONSIDER THE HORMONAL, (EPI)GENETIC, AND NEUROBIOLOGICAL MECHANISMS THAT MIGHT UNDERLIE THE IMPACT OF ADVERSE CHILDHOOD EXPERIENCES, A FORM OF CHRONIC STRESSORS, ON THE ONSET OF LDS. WE THEN FOUND THAT STRESS FACTORS COMBINED WITH FEELINGS OF INFERIORITY, LOW SELF-ESTEEM, AND PEER VICTIMIZATION COULD POTENTIALLY FURTHER AGGRAVATE ACADEMIC FAILURES IN CHILDREN WITH LDS. SINCE EFFECTIVE EVIDENCE-BASED INTERVENTIONS FOR REDUCING CHRONIC STRESS IN CHILDREN WITH LDS COULD IMPROVE THEIR ACADEMIC PERFORMANCE, CONSIDERATION OF THE ROLE OF EXPOSURE TO STRESSORS IN CHILDREN WITH LDS HAS BOTH THEORETICAL AND PRACTICAL IMPORTANCE, ESPECIALLY WHEN DELIVERED IN COMBINATION WITH ACADEMIC INTERVENTIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
18  6349  28 THE ROLE OF EPIGENETICS IN THE CHRONIC SINUSITIS WITH NASAL POLYP. PURPOSE OF REVIEW: CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP) IS A COMMON AND HETEROGENEOUS INFLAMMATORY DISEASE. THE UNDERLYING EPIGENETIC MECHANISMS AND TREATMENT OF CRSWNP ARE PARTIALLY UNDERSTOOD. OF THE DIFFERENT EPIGENETIC CHANGES IN CRSWNP, HISTONE DEACETYLASES (HDACS), METHYLATION OF DNA, AND THE LEVELS OF MIRNA ARE WIDELY STUDIED. HERE, WE REVIEW THE HUMAN STUDIES OF EPIGENETIC MECHANISMS IN CRSWNP. RECENT FINDINGS: THE PROMOTERS OF COL18A1, PTGES, PLAT, AND TSLP GENES ARE HYPERMETHYLATED IN CRSWNP COMPARED WITH THOSE OF CONTROLS, WHILE THE PROMOTERS OF PGDS, ALOX5AP, LTB4R, IL-8, AND FZD5 GENES ARE HYPOMETHYLATED IN CRSWNP. PROMOTER HYPERMETHYLATION SUPPRESSES THE GENE EXPRESSION, WHILE PROMOTER HYPOMETHYLATION INCREASES THE GENE EXPRESSION. STUDIES HAVE SHOWN THE ELEVATION IN THE LEVELS OF HDAC2, HDAC4, AND H3K4ME3 IN CRSWNP. IN CRSWNP PATIENTS, THERE IS ALSO AN UPREGULATION OF CERTAIN MIRNAS INCLUDING MIR-125B, MIR-155, MIR-19A, MIR-142-3P, AND MIR-21 AND DOWNREGULATION OF MIR-4492. EPIGENETICS TAKES PART IN THE IMMUNOLOGY OF CRSWNP AND MAY GIVE RISE TO ENDOTYPES OF CRSWNP. BOTH HDAC2 AND THE MIRNA INCLUDING MIR-18A, MIR-124A, AND MIR-142-3P MAY TAKE FUNCTION IN THE REGULATION OF GLUCOCORTICOID RESISTANCE. HDAC INHIBITORS AND KDM2B HAVE SHOWN EFFECTIVENESS IN DECREASING NASAL POLYP, AND DNA METHYLTRANSFERASE (DNMT) OR HDAC INHIBITORS MAY HAVE A POTENTIAL EFFICACY FOR THE TREATMENT OF CRSWNP. RECENT ADVANCES IN THE EPIGENETICS OF CRSWNP HAVE LED TO THE IDENTIFICATION OF SEVERAL POTENTIAL THERAPEUTIC TARGETS FOR THIS DISEASE. THE USE OF EPIGENETICS MAY PROVIDE NOVEL AND EFFECTIVE BIOMARKERS AND THERAPIES FOR THE TREATMENT OF NASAL POLYP.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
19  5553  32 ROLE OF EPIGENETICS IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. CHRONIC RHINOSINUSITIS (CRS) IS A HIGHLY PREVALENT DISEASE CHARACTERIZED BY MUCOSAL INFLAMMATION OF THE NOSE AND PARANASAL SINUSES. CRS CAN BE DIVIDED INTO TWO MAIN CATEGORIES, CRS WITH NASAL POLYPS (NPS; CRSWNP) AND CRS WITHOUT NPS (CRSSNP). ALTHOUGH THE PATHOPHYSIOLOGY OF CRS REMAINS UNCLEAR, DNA METHYLATION HAS BEEN IMPLICATED IN THE ETIOLOGY OF CRSWNP. THE AIM OF THE PRESENT STUDY WAS TO ELUCIDATE WHETHER DNA METHYLATION OF SPECIFIC GENES IS INVOLVED IN THE DEVELOPMENT OF NPS. IN TOTAL, 18 INDIVIDUALS WERE INCLUDED IN THE PRESENT STUDY, AND WERE DIVIDED INTO THREE GROUPS: CRSWNP (N=7), CRSSNP (N=7) AND HEALTHY CONTROLS (N=4). NP TISSUES WERE OBTAINED FROM THE SEVEN PATIENTS WITH CRSWNP AND BIOPSIES OF THE INFERIOR TURBINATE MUCOSA FROM ALL THREE GROUPS WERE USED AS CONTROLS. METHYLATED GENES DETECTED BY METHYL?CPG?BINDING DOMAIN SEQUENCING WERE VALIDATED BY METHYLATION?SPECIFIC POLYMERASE CHAIN REACTION (PCR), BISULFITE SEQUENCING, AND REVERSE TRANSCRIPTION?QUANTITATIVE PCR (RT?QPCR). METHYL?CPG?BINDING DOMAIN SEQUENCING IDENTIFIED 43,674 CPG ISLANDS IN 518 GENES. THE PROMOTOR REGIONS OF 10 AND 30 GENES WERE HYPERMETHYLATED AND HYPOMETHYLATED, RESPECTIVELY, IN NP SAMPLES COMPARED WITH CONTROLS. THE TOP FOUR GENES WITH ALTERED HYPOMETHYLATION IN NP TISSUES WERE, KERATIN 19 (KRT19), NUCLEAR RECEPTOR SUBFAMILY 2 GROUP F MEMBER 2 (NR2F2), A DISINTEGRIN?LIKE AND METALLOPEPTIDASE (REPROLYSIN TYPE) WITH THROMBOSPONDIN TYPE 1 MOTIF 1 (ADAMTS1) AND ZINC FINGER PROTEIN 222 (ZNF222). RT?QPCR DEMONSTRATED THAT THE EXPRESSION LEVELS OF KRT19, NR2F2 AND ADAMTS1 WERE SIGNIFICANTLY INCREASED IN NP TISSUES; HOWEVER, THERE WAS NO DIFFERENCE IN THE LEVELS OF ZNF222 BETWEEN NP AND CONTROL TISSUES. FURTHER STUDIES ARE REQUIRED TO CONFIRM THE RELEVANCE OF THESE EPIGENETIC MODIFICATIONS IN THE MECHANISMS UNDERLYING NP FORMATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20  5031  32 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