1  6239 190 THE MANAGEMENT OF POLYPS IN FEMALE REPRODUCTIVE ORGANS. POLYPS OF THE LOWER REPRODUCTIVE TRACT ARE FOUND IN 7.8-50% OF WOMEN. IT HAS BEEN HYPOTHESIZED THAT CYTOGENETIC MODIFICATIONS ON CHROMOSOMES 6, 7 AND 12 AS WELL AS EPIGENETIC FACTORS INVOLVING ENZYME AND METABOLIC ACTIVITIES MAY CAUSE POLYPS TO DEVELOP. CERVICAL POLYPS FOUND IN 2-5% OF CASES ARE OF LOW CLINICAL SIGNIFICANCE AND CAN CAUSE, ALTHOUGH RARELY, POST COITAL BLEEDINGS. CERVICAL POLYPS GROW DURING PREGNANCY AND MUCORRHOEA. TRANS VAGINAL ULTRASOUND (TVU) PROVIDES AN EXCELLENT DIAGNOSTIC TECHNIQUE TO DIAGNOSE THE SIZE AND THE ANATOMIC LOCATION OF ENDOMETRIAL POLYPS (EPS). IN ASYMPTOMATIC YOUNG WOMAN WITH SMALL EPS <10 MM IN SIZE, CONSERVATIVE MANAGEMENT CAN BE SAFELY FOLLOWED BY MONITORING THE POLYP GROWTH. EPS LOCATED AT THE FUNDAL AND TUBOCORNUAL REGIONS MECHANICALLY AFFECT FERTILITY AND DISTURB NORMAL CELLULAR FUNCTION DUE TO CHRONIC INFLAMMATION. IN CASES WHERE EPS ARE A CAUSE OF SUBFERTILITY MECHANICAL HYSTEROSCOPIC RESECTION IS ADVISABLE. WHEN THE SOLE REASON FOR INFERTILITY IS AN EP, THE PATIENT OFTEN BECOMES SPONTANEOUSLY PREGNANT SHORTLY AFTER REMOVAL. EP DETECTION IN EITHER PERI- OR POST-MENOPAUSAL AGE, IN SYMPTOMATIC OR ASYMPTOMATIC PATIENTS CALLS FOR METICULOUS HYSTEROSCOPIC EXAMINATION AND POLYPECTOMY IS MANDATORY. ENDOMETRIAL CURETTAGE IS ALSO RECOMMENDED TO RULE OUT SUB CLINICAL ENDOMETRIAL HYPERPLASIA OR CANCER. HYSTEROSCOPIC SURGERY FOR LARGE EPS USING BIPOLAR RESECTOSCOPES, HYSTEROSCOPIC MORCELLATORS OR SHAVERS ARE CONSIDERED EQUALLY EFFICIENT AND SAFE UNDER GENERAL ANAESTHESIA. RECURRENCE RATE OF EPS AFTER RESECTION IS UNKNOWN. THE RECENT ADVANCES IN TVU AND HYSTEROSCOPY, HOWEVER, SHOULD PROVIDE AN ACCURATE DIAGNOSIS AND EFFECTIVE TREATMENT OF POLYP IN THE FEMALE REPRODUCTIVE TRACT WITH MINIMAL RECURRENCE OR SURGERY COMPLICATIONS. THE SIGNIFICANTLY INCREASED INCIDENCE OF COLORECTAL POLYPS IN COHORTS THAT ALSO HAD EPS MIGHT INDICATE THAT PATIENTS WITH EPS SHOULD BE ALSO REFERRED FOR COLONOSCOPY. EPS HAVE THE LOWEST INCIDENCE OF MALIGNANT TRANSFORMATION AS COMPARED TO COLON, URINARY BLADDER, OROPHARYNGEAL, NASAL AND LARYNGEAL CARCINOMAS.	2017	
                                                                                                                                                                                                              
2   327  31 ALLERGIC INFLAMMATORY MEMORY IN HUMAN RESPIRATORY EPITHELIAL PROGENITOR CELLS. BARRIER TISSUE DYSFUNCTION IS A FUNDAMENTAL FEATURE OF CHRONIC HUMAN INFLAMMATORY DISEASES(1). SPECIALIZED SUBSETS OF EPITHELIAL CELLS-INCLUDING SECRETORY AND CILIATED CELLS-DIFFERENTIATE FROM BASAL STEM CELLS TO COLLECTIVELY PROTECT THE UPPER AIRWAY(2-4). ALLERGIC INFLAMMATION CAN DEVELOP FROM PERSISTENT ACTIVATION(5) OF TYPE 2 IMMUNITY(6) IN THE UPPER AIRWAY, RESULTING IN CHRONIC RHINOSINUSITIS, WHICH RANGES IN SEVERITY FROM RHINITIS TO SEVERE NASAL POLYPS(7). BASAL CELL HYPERPLASIA IS A HALLMARK OF SEVERE DISEASE(7-9), BUT IT IS NOT KNOWN HOW THESE PROGENITOR CELLS(2,10,11) CONTRIBUTE TO CLINICAL PRESENTATION AND BARRIER TISSUE DYSFUNCTION IN HUMANS. HERE WE PROFILE PRIMARY HUMAN SURGICAL CHRONIC RHINOSINUSITIS SAMPLES (18,036 CELLS, N = 12) THAT SPAN THE DISEASE SPECTRUM USING SEQ-WELL FOR MASSIVELY PARALLEL SINGLE-CELL RNA SEQUENCING(12), REPORT TRANSCRIPTOMES FOR HUMAN RESPIRATORY EPITHELIAL, IMMUNE AND STROMAL CELL TYPES AND SUBSETS FROM A TYPE 2 INFLAMMATORY DISEASE, AND MAP KEY MEDIATORS. BY COMPARISON WITH NASAL SCRAPINGS (18,704 CELLS, N = 9), WE DEFINE SIGNATURES OF CORE, HEALTHY, INFLAMED AND POLYP SECRETORY CELLS. WE REVEAL MARKED DIFFERENCES BETWEEN THE EPITHELIAL COMPARTMENTS OF THE NON-POLYP AND POLYP CELLULAR ECOSYSTEMS, IDENTIFYING AND VALIDATING A GLOBAL REDUCTION IN CELLULAR DIVERSITY OF POLYPS CHARACTERIZED BY BASAL CELL HYPERPLASIA, CONCOMITANT DECREASES IN GLANDULAR CELLS, AND PHENOTYPIC SHIFTS IN SECRETORY CELL ANTIMICROBIAL EXPRESSION. WE DETECT AN ABERRANT BASAL PROGENITOR DIFFERENTIATION TRAJECTORY IN POLYPS, AND PROPOSE CELL-INTRINSIC(13), EPIGENETIC(14,15) AND EXTRINSIC FACTORS(11,16,17) THAT LOCK POLYP BASAL CELLS INTO THIS UNCOMMITTED STATE. FINALLY, WE FUNCTIONALLY DEMONSTRATE THAT EX VIVO CULTURED BASAL CELLS RETAIN INTRINSIC MEMORY OF IL-4/IL-13 EXPOSURE, AND TEST THE POTENTIAL FOR CLINICAL BLOCKADE OF THE IL-4 RECEPTOR ALPHA-SUBUNIT TO MODIFY BASAL AND SECRETORY CELL STATES IN VIVO. OVERALL, WE FIND THAT REDUCED EPITHELIAL DIVERSITY STEMMING FROM FUNCTIONAL SHIFTS IN BASAL CELLS IS A KEY CHARACTERISTIC OF TYPE 2 IMMUNE-MEDIATED BARRIER TISSUE DYSFUNCTION. OUR RESULTS DEMONSTRATE THAT EPITHELIAL STEM CELLS MAY CONTRIBUTE TO THE PERSISTENCE OF HUMAN DISEASE BY SERVING AS REPOSITORIES FOR ALLERGIC MEMORIES.	2018	

3  6662  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4   169  37 ABNORMALITIES OF AMPK ACTIVATION AND GLUCOSE UPTAKE IN CULTURED SKELETAL MUSCLE CELLS FROM INDIVIDUALS WITH CHRONIC FATIGUE SYNDROME. BACKGROUND: POST EXERTIONAL MUSCLE FATIGUE IS A KEY FEATURE IN CHRONIC FATIGUE SYNDROME (CFS). ABNORMALITIES OF SKELETAL MUSCLE FUNCTION HAVE BEEN IDENTIFIED IN SOME BUT NOT ALL PATIENTS WITH CFS. TO TRY TO LIMIT POTENTIAL CONFOUNDERS THAT MIGHT CONTRIBUTE TO THIS CLINICAL HETEROGENEITY, WE DEVELOPED A NOVEL IN VITRO SYSTEM THAT ALLOWS COMPARISON OF AMP KINASE (AMPK) ACTIVATION AND METABOLIC RESPONSES TO EXERCISE IN CULTURED SKELETAL MUSCLE CELLS FROM CFS PATIENTS AND CONTROL SUBJECTS. METHODS: SKELETAL MUSCLE CELL CULTURES WERE ESTABLISHED FROM 10 SUBJECTS WITH CFS AND 7 AGE-MATCHED CONTROLS, SUBJECTED TO ELECTRICAL PULSE STIMULATION (EPS) FOR UP TO 24H AND EXAMINED FOR CHANGES ASSOCIATED WITH EXERCISE. RESULTS: IN THE BASAL STATE, CFS CULTURES SHOWED INCREASED MYOGENIN EXPRESSION BUT DECREASED IL6 SECRETION DURING DIFFERENTIATION COMPARED WITH CONTROL CULTURES. CONTROL CULTURES SUBJECTED TO 16 H EPS SHOWED A SIGNIFICANT INCREASE IN BOTH AMPK PHOSPHORYLATION AND GLUCOSE UPTAKE COMPARED WITH UNSTIMULATED CELLS. IN CONTRAST, CFS CULTURES SHOWED NO INCREASE IN AMPK PHOSPHORYLATION OR GLUCOSE UPTAKE AFTER 16 H EPS. HOWEVER, GLUCOSE UPTAKE REMAINED RESPONSIVE TO INSULIN IN THE CFS CELLS POINTING TO AN EXERCISE-RELATED DEFECT. IL6 SECRETION IN RESPONSE TO EPS WAS SIGNIFICANTLY REDUCED IN CFS COMPARED WITH CONTROL CULTURES AT ALL TIME POINTS MEASURED. CONCLUSION: EPS IS AN EFFECTIVE MODEL FOR ELICITING MUSCLE CONTRACTION AND THE METABOLIC CHANGES ASSOCIATED WITH EXERCISE IN CULTURED SKELETAL MUSCLE CELLS. WE FOUND FOUR MAIN DIFFERENCES IN CULTURED SKELETAL MUSCLE CELLS FROM SUBJECTS WITH CFS; INCREASED MYOGENIN EXPRESSION IN THE BASAL STATE, IMPAIRED ACTIVATION OF AMPK, IMPAIRED STIMULATION OF GLUCOSE UPTAKE AND DIMINISHED RELEASE OF IL6. THE RETENTION OF THESE DIFFERENCES IN CULTURED MUSCLE CELLS FROM CFS SUBJECTS POINTS TO A GENETIC/EPIGENETIC MECHANISM, AND PROVIDES A SYSTEM TO IDENTIFY NOVEL THERAPEUTIC TARGETS.	2015	
                                                                                                                                                                                                                                                                                         
5  1826  34 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  3460  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7  6272  28 THE ORIGIN AND PATHOGENESIS OF ENDOMETRIOSIS. RECENT MOLECULAR GENETIC FINDINGS ON ENDOMETRIOSIS AND NORMAL ENDOMETRIUM SUGGEST A MODIFIED MODEL IN WHICH CIRCULATING EPITHELIAL PROGENITOR OR STEM CELLS INTENDED TO REGENERATE UTERINE ENDOMETRIUM AFTER MENSTRUATION MAY BECOME OVERREACTIVE AND TRAPPED OUTSIDE THE UTERUS. THESE TRAPPED EPITHELIUM-COMMITTED PROGENITOR CELLS FORM NASCENT GLANDS THROUGH CLONAL EXPANSION AND RECRUIT POLYCLONAL STROMAL CELLS, LEADING TO THE ESTABLISHMENT OF DEEP INFILTRATING ENDOMETRIOSIS. ONCE FORMED, THE ECTOPIC TISSUE BECOMES SUBJECT TO IMMUNE SURVEILLANCE, RESULTING IN CHRONIC INFLAMMATION. THE INFLAMMATORY RESPONSE ORCHESTRATED BY NUCLEAR FACTOR-KAPPAB SIGNALING IS EXACERBATED BY ABERRATIONS IN THE ESTROGEN RECEPTOR-BETA AND PROGESTERONE RECEPTOR PATHWAYS, WHICH ARE ALSO AFFECTED BY LOCAL INFLAMMATION, FORMING A DYSREGULATED INFLAMMATION-HORMONAL LOOP. GLANDULAR EPITHELIUM WITHIN ENDOMETRIOTIC TISSUE HARBORS CANCER-ASSOCIATED MUTATIONS THAT ARE FREQUENTLY DETECTED IN ENDOMETRIOSIS-RELATED OVARIAN CANCERS. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES THAT HAVE ILLUMINATED THE ORIGIN AND PATHOGENESIS OF ENDOMETRIOSIS AND HAVE PROVIDED NEW AVENUES FOR RESEARCH THAT PROMISE TO IMPROVE THE EARLY DIAGNOSIS AND MANAGEMENT OF ENDOMETRIOSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8  4116  25 MECHANISMS OF AIRWAY EPITHELIAL INJURY AND ABNORMAL REPAIR IN ASTHMA AND COPD. THE AIRWAY EPITHELIUM COMPRISES OF DIFFERENT CELL TYPES AND ACTS AS A PHYSICAL BARRIER PREVENTING PATHOGENS, INCLUDING INHALED PARTICLES AND MICROBES, FROM ENTERING THE LUNGS. GOBLET CELLS AND SUBMUCOSAL GLANDS PRODUCE MUCUS THAT TRAPS PATHOGENS, WHICH ARE EXPELLED FROM THE RESPIRATORY TRACT BY CILIATED CELLS. BASAL CELLS ACT AS PROGENITOR CELLS, DIFFERENTIATING INTO DIFFERENT EPITHELIAL CELL TYPES, TO MAINTAIN HOMEOSTASIS FOLLOWING INJURY. ADHERENS AND TIGHT JUNCTIONS BETWEEN CELLS MAINTAIN THE EPITHELIAL BARRIER FUNCTION AND REGULATE THE MOVEMENT OF MOLECULES ACROSS IT. IN THIS REVIEW WE DISCUSS HOW ABNORMAL EPITHELIAL STRUCTURE AND FUNCTION, CAUSED BY CHRONIC INJURY AND ABNORMAL REPAIR, DRIVES AIRWAY DISEASE AND SPECIFICALLY ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN BOTH DISEASES, INHALED ALLERGENS, POLLUTANTS AND MICROBES DISRUPT JUNCTIONAL COMPLEXES AND PROMOTE CELL DEATH, IMPAIRING THE BARRIER FUNCTION AND LEADING TO INCREASED PENETRATION OF PATHOGENS AND A CONSTANT AIRWAY IMMUNE RESPONSE. IN ASTHMA, THE INFLAMMATORY RESPONSE PRECIPITATES THE EPITHELIAL INJURY AND DRIVES ABNORMAL BASAL CELL DIFFERENTIATION. THIS LEADS TO REDUCED CILIATED CELLS, GOBLET CELL HYPERPLASIA AND INCREASED EPITHELIAL MESENCHYMAL TRANSITION, WHICH CONTRIBUTE TO IMPAIRED MUCOCILIARY CLEARANCE AND AIRWAY REMODELLING. IN COPD, CHRONIC OXIDATIVE STRESS AND INFLAMMATION TRIGGER PREMATURE EPITHELIAL CELL SENESCENCE, WHICH CONTRIBUTES TO LOSS OF EPITHELIAL INTEGRITY AND AIRWAY INFLAMMATION AND REMODELLING. INCREASED NUMBERS OF BASAL CELLS SHOWING DEREGULATED DIFFERENTIATION, CONTRIBUTES TO CILIARY DYSFUNCTION AND MUCOUS HYPERPRODUCTION IN COPD AIRWAYS. DEFECTIVE ANTIOXIDANT, ANTIVIRAL AND DAMAGE REPAIR MECHANISMS, POSSIBLY DUE TO GENETIC OR EPIGENETIC FACTORS, MAY CONFER SUSCEPTIBILITY TO AIRWAY EPITHELIAL DYSFUNCTION IN THESE DISEASES. THE CURRENT EVIDENCE SUGGESTS THAT A CONSTANT CYCLE OF INJURY AND ABNORMAL REPAIR OF THE EPITHELIUM DRIVES CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA AND COPD. MECHANISTIC UNDERSTANDING OF INJURY SUSCEPTIBILITY AND DAMAGE RESPONSE MAY LEAD TO IMPROVED THERAPIES FOR THESE DISEASES.	2023	
                                                                                                                               
9  3174  31 H19 LNCRNA IDENTIFIED AS A MASTER REGULATOR OF GENES THAT DRIVE UTERINE LEIOMYOMAS. UTERINE LEIOMYOMAS OR FIBROIDS (UFS) ARE BENIGN TUMORS CHARACTERIZED BY HYPERPLASTIC SMOOTH MUSCLE CELLS AND EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX (ECM). AFFLICTING ~80% OF WOMEN, AND SYMPTOMATIC IN 25%, UFS BRING TREMENDOUS SUFFERING AND ARE AN ECONOMIC BURDEN WORLDWIDE; THEY CAUSE SEVERE PAIN AND BLEEDING, AND ARE THE LEADING CAUSE OF HYSTERECTOMY. YET, UFS ARE SEVERELY UNDERSTUDIED WITH FEW EFFECTIVE TREATMENT OPTIONS AVAILABLE; THOSE THAT ARE AVAILABLE FREQUENTLY HAVE SIGNIFICANT SIDE EFFECTS SUCH AS MENOPAUSAL SYMPTOMS. RECENTLY, INTEGRATED GENOME-SCALE STUDIES HAVE REVEALED MUTATIONS AND FIBROID SUBTYPE-SPECIFIC EXPRESSION CHANGES IN KEY DRIVER GENES, WITH MED12 AND HMGA2 TOGETHER CONTRIBUTING TO NEARLY 90% OF ALL UFS, BUT THEIR REGULATION OF EXPRESSION IS POORLY CHARACTERIZED. HERE WE REPORT THAT THE EXPRESSION OF H19 LONG NONCODING RNA (LNCRNA) IS ABERRANTLY INCREASED IN UFS. USING CELL CULTURE AND GENOME-WIDE TRANSCRIPTOME AND METHYLATION PROFILING ANALYSES, WE DEMONSTRATE THAT H19 PROMOTES EXPRESSION OF MED12, HMGA2, AND KEY ECM-REMODELING GENES VIA MULTIPLE MECHANISMS INCLUDING A NEW CLASS OF EPIGENETIC MODIFICATION BY TET3. OUR RESULTS MARK THE FIRST EXAMPLE OF AN EVOLUTIONARILY CONSERVED LNCRNA IN PATHOGENESIS OF UFS AND REGULATION OF TET EXPRESSION. GIVEN THE LINK BETWEEN A H19 SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) AND INCREASED RISK AND TUMOR SIZE OF UFS, AND THE EXISTENCE OF MULTIPLE FIBROID SUBTYPES DRIVEN BY KEY PATHWAY GENES REGULATED BY H19, WE PROPOSE A UNIFYING MECHANISM FOR PATHOGENESIS OF UTERINE FIBROIDS MEDIATED BY H19 AND IDENTIFY A PATHWAY FOR FUTURE EXPLORATION OF NOVEL TARGET THERAPIES FOR UTERINE LEIOMYOMAS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10  4947  34 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	
                                                                                                                                          
11  2656  29 EPIMUTATION AND CANCER: A NEW CARCINOGENIC MECHANISM OF LYNCH SYNDROME (REVIEW). EPIMUTATION IS DEFINED AS ABNORMAL TRANSCRIPTIONAL REPRESSION OF ACTIVE GENES AND/OR ABNORMAL ACTIVATION OF USUALLY REPRESSED GENES CAUSED BY ERRORS IN EPIGENETIC GENE REPRESSION. EPIMUTATION ARISES IN SOMATIC CELLS AND THE GERMLINE, AND CONSTITUTIONAL EPIMUTATION MAY ALSO OCCUR. EPIMUTATION IS THE FIRST STEP OF TUMORIGENESIS AND CAN BE A DIRECT CAUSE OF CARCINOGENESIS. CANCERS ASSOCIATED WITH EPIMUTATION INCLUDE LYNCH SYNDROME (HEREDITARY NON-POLYPOSIS COLORECTAL CANCER, HNPCC), CHRONIC LYMPHOCYTIC LEUKEMIA, BREAST CANCER AND OVARIAN CANCER. EPIMUTATION HAS BEEN SHOWN FOR MANY TUMOR SUPPRESSOR GENES, INCLUDING RB, VHL, HMLH1, APC AND BRCA1, IN SPORADIC CANCERS. METHYLATION HAS RECENTLY BEEN SHOWN IN DNA FROM NORMAL TISSUES AND PERIPHERAL BLOOD IN CASES OF SPORADIC COLORECTAL CANCER AND MANY STUDIES SHOW CONSTITUTIVE EPIMUTATION IN CANCERS. EPIMUTATION OF DNA MISMATCH REPAIR (MMR) GENES (BRCA1, HMLH1 AND HMSH2) INVOLVED IN DEVELOPMENT FAMILIAL CANCERS HAS ALSO BEEN FOUND. THESE RESULTS HAVE LED TO A FOCUS ON EPIMUTATION AS A NOVEL ONCOGENIC MECHANISM.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
12   852  47 CHOLANGIOCARCINOMA IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC): A COMPREHENSIVE REVIEW. CHOLANGIOCARCINOMA (CCA) IS THE MOST COMMON MALIGNANCY IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) AND CARRIES A HIGH RATE OF MORTALITY. ALTHOUGH THE PATHOGENESIS OF CCA IN PSC IS LARGELY UNKNOWN, INFLAMMATION-DRIVEN CARCINOGENESIS CONCOMITANT WITH VARIOUS GENETIC AND EPIGENETIC ABNORMALITIES ARE UNDERLYING FACTORS. THE MAJORITY OF CCA CASES DEVELOP FROM A DOMINANT STRICTURE (DS), WHICH IS DEFINED AS A STRICTURE WITH A DIAMETER < 1.5 MM IN THE COMMON BILE DUCT OR < 1.0 MM IN THE HEPATIC DUCT. IN PSC PATIENTS PRESENTING WITH AN ABRUPT AGGRAVATION OF JAUNDICE, PAIN, FATIGUE, PRURITUS, WEIGHT LOSS, OR WORSENING LIVER BIOCHEMISTRIES, CCA SHOULD BE SUSPECTED AND EVALUATED UTILIZING A VARIETY OF DIAGNOSTIC MODALITIES. HOWEVER, EARLY RECOGNITION OF CCA IN PSC REMAINS A MAJOR CHALLENGE. IMPORTANTLY, 30-50% OF CCA IN PSC PATIENTS ARE OBSERVED WITHIN THE FIRST YEAR FOLLOWING THE DIAGNOSIS OF PSC FOLLOWED BY AN ANNUAL INCIDENCE RANGING FROM 0.5 TO 1.5 PER 100 PERSONS, WHICH IS NEARLY 10 TO 1000 TIMES HIGHER THAN THAT IN THE GENERAL POPULATION. CUMULATIVE 5-YEAR, 10-YEAR, AND LIFETIME INCIDENCES ARE 7%, 8-11%, AND 9-20%, RESPECTIVELY. WHEN PSC-ASSOCIATED CCA IS DIAGNOSED, MOST TUMORS ARE UNRESECTABLE, AND NO EFFECTIVE MEDICATIONS ARE AVAILABLE. GIVEN THE POOR THERAPEUTIC OUTCOME, THE SURVEILLANCE AND MANAGEMENT OF PSC PATIENTS WHO ARE AT AN INCREASED RISK OF DEVELOPING CCA ARE OF IMPORTANCE. SUCH PATIENTS INCLUDE OLDER MALES WITH LARGE-DUCT PSC AND POSSIBLY CONCURRENT ULCERATIVE COLITIS. THUS, MORE ATTENTION SHOULD BE PAID TO PATIENTS WITH THESE CLINICAL FEATURES, IN PARTICULAR WITHIN THE FIRST YEAR AFTER PSC DIAGNOSIS. IN CONTRAST, CCA IS LESS FREQUENTLY OBSERVED IN PEDIATRIC OR FEMALE PSC PATIENTS OR IN THOSE WITH SMALL-DUCT PSC OR CONCURRENT CROHN'S DISEASE. RECENTLY, NEW BIOMARKERS SUCH AS ANTIBODIES TO GLYCOPROTEIN 2 HAVE BEEN FOUND TO BE ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING CCA IN PSC. HEREIN, WE REVIEW THE LITERATURE ON THE PATHOGENESIS, INCIDENCE, CLINICAL FEATURES, AND RISK FACTORS, WITH A FOCUS ON VARIOUS DIAGNOSTIC MODALITIES OF PSC-ASSOCIATED CCA.	2020	
                                                                                                                                                           
13  1891  36 ENDOMETRIOSIS. PELVIC ENDOMETRIOSIS IS A COMPLEX SYNDROME CHARACTERIZED BY AN ESTROGEN-DEPENDENT CHRONIC INFLAMMATORY PROCESS THAT AFFECTS PRIMARILY PELVIC TISSUES, INCLUDING THE OVARIES. IT IS CAUSED WHEN SHED ENDOMETRIAL TISSUE TRAVELS RETROGRADE INTO THE LOWER ABDOMINAL CAVITY. ENDOMETRIOSIS IS THE MOST COMMON CAUSE OF CHRONIC PELVIC PAIN IN WOMEN AND IS ASSOCIATED WITH INFERTILITY. THE UNDERLYING PATHOLOGIC MECHANISMS IN THE INTRACAVITARY ENDOMETRIUM AND EXTRAUTERINE ENDOMETRIOTIC TISSUE INVOLVE DEFECTIVELY PROGRAMMED ENDOMETRIAL MESENCHYMAL PROGENITOR/STEM CELLS. ALTHOUGH ENDOMETRIOTIC STROMAL CELLS, WHICH COMPOSE THE BULK OF ENDOMETRIOTIC LESIONS, DO NOT CARRY SOMATIC MUTATIONS, THEY DEMONSTRATE SPECIFIC EPIGENETIC ABNORMALITIES THAT ALTER EXPRESSION OF KEY TRANSCRIPTION FACTORS. FOR EXAMPLE, GATA-BINDING FACTOR-6 OVEREXPRESSION TRANSFORMS AN ENDOMETRIAL STROMAL CELL TO AN ENDOMETRIOTIC PHENOTYPE, AND STEROIDOGENIC FACTOR-1 OVEREXPRESSION CAUSES EXCESSIVE PRODUCTION OF ESTROGEN, WHICH DRIVES INFLAMMATION VIA PATHOLOGICALLY HIGH LEVELS OF ESTROGEN RECEPTOR-BETA. PROGESTERONE RECEPTOR DEFICIENCY CAUSES PROGESTERONE RESISTANCE. POPULATIONS OF ENDOMETRIAL AND ENDOMETRIOTIC EPITHELIAL CELLS ALSO HARBOR MULTIPLE CANCER DRIVER MUTATIONS, SUCH AS KRAS, WHICH MAY BE ASSOCIATED WITH THE ESTABLISHMENT OF PELVIC ENDOMETRIOSIS OR OVARIAN CANCER. IT IS NOT KNOWN HOW INTERACTIONS BETWEEN EPIGENOMICALLY DEFECTIVE STROMAL CELLS AND THE MUTATED GENES IN EPITHELIAL CELLS CONTRIBUTE TO THE PATHOGENESIS OF ENDOMETRIOSIS. ENDOMETRIOSIS-ASSOCIATED PELVIC PAIN IS MANAGED BY SUPPRESSION OF OVULATORY MENSES AND ESTROGEN PRODUCTION, CYCLOOXYGENASE INHIBITORS, AND SURGICAL REMOVAL OF PELVIC LESIONS, AND IN VITRO FERTILIZATION IS FREQUENTLY USED TO OVERCOME INFERTILITY. ALTHOUGH NOVEL TARGETED TREATMENTS ARE BECOMING AVAILABLE, AS ENDOMETRIOSIS PATHOPHYSIOLOGY IS BETTER UNDERSTOOD, PREVENTIVE APPROACHES SUCH AS LONG-TERM OVULATION SUPPRESSION MAY PLAY A CRITICAL ROLE IN THE FUTURE.	2019	
                                                                                                                                                                                                                                                                                                                                                                            
14  3773  31 INTERACTION OF CERVICAL MICROBIOME WITH EPIGENOME OF EPITHELIAL CELLS: SIGNIFICANCE OF INFLAMMATION TO PRIMARY HEALTHCARE. ONE PILLAR OF THE PREDICTIVE, PREVENTIVE, AND PERSONALIZED MEDICINE FRAMEWORK STRATEGIES IS THE FEMALE HEALTH. THE EVALUATION OF WOMEN'S LIFESTYLE AND DIETARY HABITS IN CONTEXT WITH GENETIC AND MODIFIABLE RISK FACTORS MAY REFLECT THE PREVENTION OF CERVICAL CANCER BEFORE THE OCCURRENCE OF CLINICAL SYMPTOMS AND PREDICTION OF CERVICAL LESION BEHAVIOR. THE MAIN AIM OF THIS REVIEW IS TO ANALYZE PUBLICATIONS IN THE FIELD OF PRECISION MEDICINE THAT ALLOW THE USE OF RESEARCH KNOWLEDGE OF CERVICAL MICROBIOME, EPIGENETIC MODIFICATIONS, AND INFLAMMATION IN POTENTIAL APPLICATION IN CLINICAL PRACTICE. PERSONALIZED APPROACH IN EVALUATING PATIENT'S RISK OF FUTURE DEVELOPMENT OF CERVICAL ABNORMALITY SHOULD CONSIDER THE BIOMARKERS OF THE LOCAL MICROENVIRONMENT CHARACTERIZED BY THE MICROBIAL COMPOSITION, EPIGENETIC PATTERN OF CERVICAL EPITHELIUM, AND PRESENCE OF CHRONIC INFLAMMATION. NOVEL SEQUENCING TECHNIQUES ENABLE A MORE DETAILED CHARACTERIZATION OF ACTUAL STATE IN CERVICAL EPITHELIUM. BETTER UNDERSTANDING OF ALL CHANGES IN MULTIOMICS LEVEL ENABLES A BETTER ASSESSMENT OF DISEASE PROGNOSIS AND SELECTS THE ELIGIBLE TARGETED THERAPY IN PERSONALIZED MEDICINE. RESTORING OF HEALTHY VAGINAL MICROFLORA AND REVERSING THE OUTBREAK OF CERVICAL ABNORMALITY CAN BE ALSO ACHIEVED BY DIETARY HABITS AS WELL AS UPTAKE OF PREBIOTICS, PROBIOTICS, SYNBIOTICS, MICROBIAL TRANSPLANTATION, AND OTHERS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
15  6540  30 TRANSCRIPTIONAL, EPIGENETIC, AND FUNCTIONAL REPROGRAMMING OF MONOCYTES FROM NON-HUMAN PRIMATES FOLLOWING CHRONIC ALCOHOL DRINKING. CHRONIC HEAVY DRINKING (CHD) OF ALCOHOL IS A KNOWN RISK FACTOR FOR INCREASED SUSCEPTIBILITY TO BACTERIAL AND VIRAL INFECTION AS WELL AS IMPAIRED WOUND HEALING. EVIDENCE SUGGESTS THAT THESE DEFECTS ARE MEDIATED BY A DYSREGULATED INFLAMMATORY RESPONSE ORIGINATING FROM MYELOID CELLS, NOTABLY MONOCYTES AND MACROPHAGES, BUT THE MECHANISMS REMAIN POORLY UNDERSTOOD. OUR ABILITY TO STUDY CHD IS IMPACTED BY THE COMPLEXITIES OF HUMAN DRINKING PATTERNS AND BEHAVIOR AS WELL AS COMORBIDITIES AND CONFOUNDING RISK FACTORS FOR PATIENTS WITH ALCOHOL USE DISORDERS. TO OVERCOME THESE CHALLENGES, WE UTILIZED A TRANSLATIONAL RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION THAT CLOSELY RECAPITULATES HUMAN DRINKING PATTERNS AND CHRONICITY. IN THIS STUDY, WE EXAMINED THE EFFECTS OF CHD ON BLOOD MONOCYTES IN CONTROL AND CHD FEMALE MACAQUES AFTER 12 MONTHS OF DAILY ETHANOL CONSUMPTION. WHILE MONOCYTES FROM CHD FEMALE MACAQUES GENERATED A HYPER-INFLAMMATORY RESPONSE TO EX VIVO LPS STIMULATION, THEIR RESPONSE TO E. COLI WAS DAMPENED. IN DEPTH SCRNA-SEQ ANALYSIS OF PURIFIED MONOCYTES REVEALED SIGNIFICANT SHIFTS IN CLASSICAL MONOCYTE SUBSETS WITH ACCUMULATION OF CELLS EXPRESSING MARKERS OF HYPOXIA (HIF1A) AND INFLAMMATION (NFKB SIGNALING PATHWAY) IN CHD MACAQUES. THE INCREASED PRESENCE OF MONOCYTE SUBSETS SKEWED TOWARDS INFLAMMATORY PHENOTYPES WAS COMPLEMENTED BY EPIGENETIC ANALYSIS, WHICH REVEALED HIGHER ACCESSIBILITY OF PROMOTER REGIONS THAT REGULATE GENES INVOLVED IN CYTOKINE SIGNALING PATHWAYS. COLLECTIVELY, DATA PRESENTED IN THIS MANUSCRIPT DEMONSTRATE THAT CHD SHIFTS CLASSICAL MONOCYTE SUBSET COMPOSITION AND PRIMES THE MONOCYTES TOWARDS A MORE HYPER-INFLAMMATORY RESPONSE TO LPS, BUT COMPROMISED PATHOGEN RESPONSE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16  5127  31 POSTMENOPAUSAL UTERINE LEIOMYOMAS AND CHRONIC LYMPHADENOPATHY: EXPLORING EPIGENETIC CHANGES AND PATHOPHYSIOLOGY. UTERINE LEIOMYOMAS (LM) ARE TUMORS ARISING FROM THE NON-NEOPLASTIC PROLIFERATION OF SMOOTH MUSCLE CELLS WITHIN THE MYOMETRIUM. LIKE BENIGN TUMORS, LM ARE NOT GENERALLY SPREAD THROUGH THE LYMPHATIC SYSTEM, AND THEREFORE SHOULD NOT BE ASSOCIATED WITH LYMPHADENOPATHY. HEREIN, WE PRESENT A CASE OF A 60-YEAR-OLD FEMALE WHO PRESENTED TO THE CLINIC WITH POSTMENOPAUSAL BLEEDING IN THE SETTING OF SONOGRAPHICALLY EVIDENT UTERINE LM AND ABDOMINAL LYMPHADENOPATHY. A LYMPH NODE BIOPSY REVEALED PLASMA CELLS AND AN EOSINOPHILIC MATERIAL PRESUMPTIVELY DIAGNOSED AS AMYLOID. SHE THEN UNDERWENT AN ABDOMINAL HYSTERECTOMY FOR DEFINITIVE TREATMENT OF LM. SURGICAL PATHOLOGY CONFIRMED THE CLINICAL DIAGNOSIS OF UTERINE AND CERVICAL LEIOMYOMA. CURRENT LITERATURE SUGGESTS THAT GENETIC AND EPIGENETIC ABNORMALITIES CONTRIBUTE TO THE PATHOGENESIS OF LM IN ADDITION TO HORMONAL SIGNALS SUCH AS ESTROGEN AND PROGESTERONE. IT IS UNUSUAL FOR LM TO OCCUR IN POST-MENOPAUSAL WOMEN DUE TO REDUCED HORMONAL INFLUENCE. THEREFORE, THIS CASE EXPLORED AN ALTERNATIVE MECHANISM OF TUMOR PROLIFERATION. THIS CASE HYPOTHESIZES THAT GENETIC MUTATIONS AND EPIGENETIC CHANGES RESULTING FROM CHRONIC INFLAMMATORY OFFENSES CONTRIBUTED TO LM GROWTH AND LYMPHADENOPATHY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17  4413  29 MOLECULAR AND CELLULAR INSIGHTS INTO THE DEVELOPMENT OF UTERINE FIBROIDS. UTERINE LEIOMYOMAS REPRESENT THE MOST COMMON BENIGN GYNECOLOGIC TUMOR. THESE HORMONE-DEPENDENT SMOOTH-MUSCLE FORMATIONS OCCUR WITH AN ESTIMATED PREVALENCE OF ~70% AMONG WOMEN OF REPRODUCTIVE AGE AND CAUSE SYMPTOMS INCLUDING PAIN, ABNORMAL UTERINE BLEEDING, INFERTILITY, AND RECURRENT ABORTION. DESPITE THE PREVALENCE AND PUBLIC HEALTH IMPACT OF UTERINE LEIOMYOMAS, AVAILABLE TREATMENTS REMAIN LIMITED. AMONG THE POTENTIAL CAUSES OF LEIOMYOMAS, EARLY HORMONAL EXPOSURE DURING PERIODS OF DEVELOPMENT MAY RESULT IN DEVELOPMENTAL REPROGRAMMING VIA EPIGENETIC CHANGES THAT PERSIST IN ADULTHOOD, LEADING TO DISEASE ONSET OR PROGRESSION. RECENT DEVELOPMENTS IN UNBIASED HIGH-THROUGHPUT SEQUENCING TECHNOLOGY ENABLE POWERFUL APPROACHES TO DETECT DRIVER MUTATIONS, YIELDING NEW INSIGHTS INTO THE GENOMIC INSTABILITY OF LEIOMYOMAS. CURRENT DATA ALSO SUGGEST THAT EACH LEIOMYOMA ORIGINATES FROM THE CLONAL EXPANSION OF A SINGLE TRANSFORMED SOMATIC STEM CELL OF THE MYOMETRIUM. IN THIS REVIEW, WE PROPOSE AN INTEGRATED CELLULAR AND MOLECULAR VIEW OF THE ORIGINS OF LEIOMYOMAS, AS WELL AS PARADIGM-SHIFTING STUDIES THAT WILL LEAD TO BETTER UNDERSTANDING AND THE FUTURE DEVELOPMENT OF NON-SURGICAL TREATMENTS FOR THESE HIGHLY FREQUENT TUMORS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18   518  40 ASSOCIATIONS BETWEEN ANTIBIOTIC EXPOSURE DURING PREGNANCY, BIRTH WEIGHT AND ABERRANT METHYLATION AT IMPRINTED GENES AMONG OFFSPRING. OBJECTIVES: LOW BIRTH WEIGHT (LBW) HAS BEEN ASSOCIATED WITH COMMON ADULT-ONSET CHRONIC DISEASES, INCLUDING OBESITY, CARDIOVASCULAR DISEASE, TYPE II DIABETES AND SOME CANCERS. THE ETIOLOGY OF LBW IS MULTI-FACTORIAL. HOWEVER, RECENT EVIDENCE SUGGESTS EXPOSURE TO ANTIBIOTICS MAY ALSO INCREASE THE RISK OF LBW. THE MECHANISMS UNDERLYING THIS ASSOCIATION ARE UNKNOWN, ALTHOUGH EPIGENETIC MECHANISMS ARE HYPOTHESIZED. IN THIS STUDY, WE EVALUATED THE ASSOCIATION BETWEEN MATERNAL ANTIBIOTIC USE AND LBW AND EXAMINED THE POTENTIAL ROLE OF ALTERED DNA METHYLATION THAT CONTROLS GROWTH REGULATORY IMPRINTED GENES IN THESE ASSOCIATIONS. METHODS: BETWEEN 2009-2011, 397 PREGNANT WOMEN WERE ENROLLED AND FOLLOWED UNTIL DELIVERY. PRENATAL ANTIBIOTIC USE WAS ASCERTAINED THROUGH MATERNAL SELF-REPORT. IMPRINTED GENES METHYLATION LEVELS WERE MEASURED AT DIFFERENTIALLY METHYLATED REGIONS (DMRS) USING BISULFITE PYROSEQUENCING. GENERALIZED LINEAR MODELS WERE USED TO EXAMINE ASSOCIATIONS AMONG ANTIBIOTIC USE, BIRTH WEIGHT AND DMR METHYLATION FRACTIONS. RESULTS: AFTER ADJUSTING FOR INFANT GENDER, RACE/ETHNICITY, MATERNAL BODY MASS INDEX, DELIVERY ROUTE, GESTATIONAL WEIGHT GAIN, GESTATIONAL AGE AT DELIVERY, FOLIC ACID INTAKE, PHYSICAL ACTIVITY, MATERNAL SMOKING AND PARITY, ANTIBIOTIC USE DURING PREGNANCY WAS ASSOCIATED WITH 138 G LOWER BIRTH WEIGHT COMPARED WITH NON-ANTIBIOTIC USE (BETA-COEFFICIENT=-132.99, S.E.=50.70, P=0.008). THESE ASSOCIATIONS WERE STRONGEST IN NEWBORNS OF WOMEN WHO REPORTED ANTIBIOTIC USE OTHER THAN PENICILLINS (BETA-COEFFICIENT=-135.57, S.E.=57.38, P=0.02). METHYLATION AT FIVE DMRS, IGF2 (P=0.05), H19 (P=0.15), PLAGL1 (P=0.01), MEG3 (P=0.006) AND PEG3 (P=0.08), WAS ASSOCIATED WITH MATERNAL ANTIBIOTIC USE; AMONG THESE, ONLY METHYLATION AT THE PLAGL1 DMR WAS ALSO ASSOCIATED WITH BIRTH WEIGHT. CONCLUSION: WE REPORT AN INVERSE ASSOCIATION BETWEEN IN UTERO EXPOSURE TO ANTIBIOTICS AND LOWER INFANT BIRTH WEIGHT AND PROVIDE THE FIRST EMPIRICAL EVIDENCE SUPPORTING IMPRINTED GENE PLASTICITY IN THESE ASSOCIATIONS.	2013	
                                                                                                                                                                                                    
19  5786  33 SPORT AND MALE SEXUALITY. THE RELATIONSHIPS BETWEEN SPORT AND SEXUALITY IN MALES ARE OF GREAT SOCIAL AND CLINICAL INTEREST, BECAUSE OF SPORTS AND MOTOR ACTIVITIES THAT HIGHLY PROMOTE SOCIAL AND SEXUAL RELATIONSHIPS. EVEN IF FEW LITERATURE EXIST, TWO MAIN QUESTIONS SHOULD BE TAKEN INTO ACCOUNT: WHETHER AND HOW PHYSICAL EXERCISE AND SPORT POSITIVELY OR NEGATIVELY INFLUENCE SEXUAL HEALTH AND BEHAVIOR AND/OR WHETHER AND HOW SEXUAL BEHAVIOR MAY AFFECT A SUB-SEQUENT SPORT PERFORMANCE. PHYSICAL EXERCISE AND SPORT PER SE CAN INFLUENCE, POSITIVELY OR NEGATIVELY, THE HYPOTHALAMIC-PITUITARY-TESTICULAR AXIS FUNCTION AND, CONSEQUENTLY, THE INDIVIDUAL'S REPRODUCTIVE AND/OR SEXUAL HEALTH. THIS DEPENDS ON INDIVIDUAL FACTORS SUCH AS GENETIC AND EPIGENETIC ONES AND ON DIFFERENT VARIABLES INVOLVED IN THE PRACTICE OF SPORT ACTIVITIES (TYPE OF SPORT, INTENSITY AND DURATION OF TRAINING, DOPING AND DRUG USE AND ABUSE, NUTRITION, SUPPLEMENTS, PSYCHOLOGICAL STRESS, ALLOSTATIC LOAD, ETC.). IF WELL CONDUCTED, MOTOR AND SPORT ACTIVITIES COULD HAVE BENEFICIAL EFFECTS ON SEXUAL HEALTH IN MALES. AMONG DIFFERENT LIFESTYLE CHANGES, INFLUENCING SEXUAL HEALTH, REGULAR PHYSICAL ACTIVITY IS FUNDAMENTAL TO ANTAGONIZE THE ONSET OF ERECTILE DYSFUNCTION (ED). HOWEVER, COMPETITIVE SPORT CAN LEAD BOTH REPRODUCTIVE AND/OR SEXUAL TRACT DAMAGES AND DYSFUNCTIONS, TRANSIENT (GENITAL PAIN, HYPOESTHESIA OF THE GENITALIA, HYPOGONADISM, DE, ALTERED SEXUAL DRIVE, ETC.) OR PERMANENT (HYPOGONADISM, DE, ETC.), BY ACTING DIRECTLY (TRAUMAS OF THE EXTERNAL GENITALIA, SADDLE-RELATED DISORDERS IN CYCLISTS, ETC.) OR INDIRECTLY (EXERCISE-RELATED HYPOGONADISM, DRUG ABUSE, DOPING, STRESS, ETC.). SEXUAL ACTIVITIES SHORTLY PERFORMED BEFORE A SPORT COMPETITION COULD DIFFERENTLY INFLUENCE SPORT PERFORMANCE. DUE TO THE FEW EXISTING DATA, IT IS ADVISABLE TO AVOID AN ABSOLUTE PRE-COMPETITION SEXUAL ABSTINENCE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  1564  32 DNA METHYLATION OF PROXIMAL PLAT PROMOTER IN CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND NASAL POLYPS (NP) ARE CHARACTERIZED BY PSEUDOCYSTS DERIVED FROM STROMAL TISSUE EDEMA AND CAUSE PERSISTENT INFECTIONS IN PATIENTS WITH CHRONIC RHINOSINUSITIS (CRS). A LOW LEVEL OF TISSUE-TYPE PLASMINOGEN ACTIVATOR (GENE NAME PLAT) IS CONSIDERED A CAUSE OF STROMAL TISSUE EDEMA BECAUSE OF INSUFFICIENT PLASMIN ACTIVATION IN NP; HOWEVER, THE MECHANISM REGULATING PLAT GENE EXPRESSION LEVELS IS STILL UNCLEAR. THE EPIGENETIC MECHANISM REGULATING THE PLAT GENE EXPRESSION HAS BEEN STUDIED IN OTHER TISSUES. OBJECTIVE WE AIMED TO INVESTIGATE THE METHYLATION LEVELS IN THE PROXIMAL PLAT PROMOTER AND THEIR EFFECTS ON GENE EXPRESSION IN NP TISSUE. METHODS WE INVESTIGATED THE METHYLATION LEVELS AT 3 CPG SITES IN THE PROXIMAL PLAT PROMOTER REGIONS (-618, -121, AND -105 WITH RESPECT TO THE TRANSCRIPTION INITIATION SITE) BY BISULFITE PYROSEQUENCING AND THEIR EFFECTS ON THE GENE EXPRESSION BY QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR) IN 20 PAIRED SAMPLES OF NP AND INFERIOR TURBINATE TISSUE (IT) FROM PATIENTS WITH CRS. RESULTS THE DNA METHYLATION LEVELS AT ALL CPG SITES WERE HIGHER ( P < .01), AND THE PLAT EXPRESSION WAS LOWER ( P < .001) IN NP COMPARED WITH IT. THE METHYLATION CHANGES AT THE -618 SITE SHOWED A NEGATIVE CORRELATION WITH THE GENE EXPRESSION CHANGES BETWEEN NP AND IT ( R = -.65, P < .01). CONCLUSIONS HYPERMETHYLATION OF PLAT PROMOTER MAY DOWNREGULATE THE GENE EXPRESSION IN NP, LEADING TO EXCESSIVE FIBRIN DEPOSITION BY ABERRANT COAGULATION CASCADE. DNA METHYLATION OF PROXIMAL PLAT PROMOTER MAY CONTRIBUTE TO NP GROWTH AND HAVE A POTENTIAL AS A NEW THERAPEUTIC TARGET.	2018