1 1890 183 ENDOMETRIOSIS-ASSOCIATED OVARIAN CARCINOMAS: INSIGHTS INTO PATHOGENESIS, DIAGNOSTICS, AND THERAPEUTIC TARGETS-A NARRATIVE REVIEW. ENDOMETRIOSIS IS A BENIGN GYNECOLOGIC CONDITION AFFECTING UP TO ONE WOMAN OUT OF TEN OF REPRODUCTIVE AGE. IT IS DEFINED BY THE PRESENCE OF ENDOMETRIAL-LIKE TISSUE IN LOCALIZATIONS OUTSIDE OF THE UTERINE CAVITY. IT OFTEN CAUSES SYMPTOMS SUCH AS CHRONIC PAIN, MOST FREQUENTLY ASSOCIATED WITH THE MENSTRUAL CYCLE, AND INFERTILITY, BUT MAY ALSO BE OLIGO- OR ASYMPTOMATIC. THERE IS EVIDENCE THAT SOME OVARIAN CARCINOMA (OC) HISTOTYPES, MAINLY THE OVARIAN CLEAR CELL (OCCC) AND ENDOMETRIOID (ENOC) CARCINOMA, MAY ARISE FROM ENDOMETRIOSIS. THE MOST FREQUENT GENOMIC ALTERATIONS IN THESE CARCINOMAS ARE MUTATIONS IN THE AT-RICH INTERACTING DOMAIN CONTAINING PROTEIN 1A (ARID1A) GENE, A SUBUNIT OF THE SWI/SNF CHROMATIN REMODELING COMPLEX, AND ALTERATIONS IN THE PHOSPHATIDYLINOSITOL 3-KINASE (PI3K)/AKT/MTOR PATHWAY, WHICH FREQUENTLY CO-OCCUR. IN ARID1A DEFICIENT CANCERS PRECLINICAL EXPERIMENTAL DATA SUGGEST DIFFERENT TARGETABLE MECHANISMS INCLUDING EPIGENETIC REGULATION, CELL CYCLE, GENOMIC INSTABILITY, THE PI3K/AKT/MTOR PATHWAY, INFLAMMATORY PATHWAYS, IMMUNE MODULATION, OR METABOLIC ALTERATIONS AS POTENTIAL PRECISION ONCOLOGY APPROACHES. MOST OF THESE STRATEGIES ARE RELYING ON THE CONCEPT OF SYNTHETIC LETHALITY IN WHICH TUMORS DEFICIENT IN ARID1A ARE MORE SENSITIVE TO THE DIFFERENT COMPOUNDS. SOME OF THESE APPROACHES ARE CURRENTLY BEING OR HAVE RECENTLY BEEN INVESTIGATED IN EARLY CLINICAL TRIALS. THE REMARKABLY FREQUENT OCCURRENCE OF THESE MUTATIONS IN ENDOMETRIOSIS-ASSOCIATED OVARIAN CANCER, THE OCCURRENCE IN A RELATIVELY YOUNG POPULATION, AND THE HIGH PROPORTION OF PLATINUM-RESISTANT DISEASE CERTAINLY WARRANTS FURTHER INVESTIGATION OF PRECISION ONCOLOGY OPPORTUNITIES IN THIS POPULATION. FURTHERMORE, ADVANCED KNOWLEDGE ABOUT ONCOGENIC MUTATIONS INVOLVED IN ENDOMETRIOSIS-ASSOCIATED OVARIAN CARCINOMAS MAY BE POTENTIALLY USEFUL FOR EARLY CANCER DETECTION. HOWEVER, THIS APPROACH MAY BE COMPLICATED BY THE FREQUENT OCCURRENCE OF SOMATIC MUTATIONS IN BENIGN ENDOMETRIOTIC TISSUE AS RECENT STUDIES SUGGEST. IN THIS NARRATIVE REVIEW OF THE CURRENT LITERATURE, WE WILL DISCUSS THE DATA AVAILABLE ON ENDOMETRIOSIS-ASSOCIATED OVARIAN CARCINOMA, WITH SPECIAL EMPHASIS ON EPIDEMIOLOGY, DIAGNOSIS AND MOLECULAR CHANGES THAT COULD HAVE THERAPEUTIC IMPLICATIONS AND CLINICAL APPLICABILITY IN THE FUTURE. 2020 2 5105 54 POLYCYSTIC OVARIAN SYNDROME: A COMPLEX DISEASE WITH A GENETICS APPROACH. POLYCYSTIC OVARIAN SYNDROME (PCOS) IS A COMPLEX ENDOCRINE DISORDER AFFECTING FEMALES IN THEIR REPRODUCTIVE AGE. THE EARLY DIAGNOSIS OF PCOS IS COMPLICATED AND COMPLEX DUE TO OVERLAPPING SYMPTOMS OF THIS DISEASE. THE MOST ACCEPTED DIAGNOSTIC APPROACH TODAY IS THE ROTTERDAM CONSENSUS (2003), WHICH SUPPORTS THE POSITIVE DIAGNOSIS OF PCOS WHEN PATIENTS PRESENT TWO OUT OF THE FOLLOWING THREE SYMPTOMS: BIOCHEMICAL AND CLINICAL SIGNS OF HYPERANDROGENISM, OLIGO, AND ANOVULATION, ALSO POLYCYSTIC OVARIAN MORPHOLOGY ON SONOGRAPHY. GENETIC VARIANCE, EPIGENETIC CHANGES, AND DISTURBED LIFESTYLE LEAD TO THE DEVELOPMENT OF PATHOPHYSIOLOGICAL DISTURBANCES, WHICH INCLUDE HYPERANDROGENISM, INSULIN RESISTANCE, AND CHRONIC INFLAMMATION IN PCOS FEMALES. AT THE MOLECULAR LEVEL, DIFFERENT PROTEINS AND MOLECULAR AND SIGNALING PATHWAYS ARE INVOLVED IN DISEASE PROGRESSION, WHICH LEADS TO THE FAILURE OF A SINGLE GENETIC DIAGNOSTIC APPROACH. THE GENETIC APPROACH TO ELUCIDATE THE MECHANISM OF PATHOGENESIS OF PCOS WAS RECENTLY DEVELOPED, WHEREBY FOUR PHENOTYPIC VARIANCES OF PCOS CATEGORIZE PCOS PATIENTS INTO CLASSIC, OVULATORY, AND NON-HYPERANDROGENIC TYPES. GENETIC STUDIES HELP TO IDENTIFY THE ROOT CAUSE FOR THE DEVELOPMENT OF THIS PCOS. PCOS GENETIC INHERITANCE IS AUTOSOMAL DOMINANT BUT THE LATEST INVESTIGATIONS REVEALED IT AS A MULTIGENE ORIGIN DISEASE. DIFFERENT GENETIC LOCI AND SPECIFIC GENES HAVE BEEN IDENTIFIED SO FAR AS BEING ASSOCIATED WITH THIS DISEASE. GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND RELATED GENETIC STUDIES HAVE CHANGED THE SCENARIO FOR THE DIAGNOSIS AND TREATMENT OF THIS REPRODUCTIVE AND METABOLIC CONDITION KNOWN AS PCOS. THIS REVIEW ARTICLE BRIEFLY DISCUSSES DIFFERENT GENES ASSOCIATED DIRECTLY OR INDIRECTLY WITH DISEASE DEVELOPMENT AND PROGRESSION. 2022 3 4746 28 NOVEL LNC RNA REGULATED BY HIF-1 INHIBITS APOPTOTIC CELL DEATH IN THE RENAL TUBULAR EPITHELIAL CELLS UNDER HYPOXIA. CHRONIC TUBULOINTERSTITIAL HYPOXIA PLAYS AN IMPORTANT ROLE AS THE FINAL COMMON PATHWAY TO END-STAGE RENAL DISEASE. HIF-1 (HYPOXIA-INDUCIBLE FACTOR-1) IS A MASTER TRANSCRIPTIONAL FACTOR UNDER HYPOXIA, REGULATING DOWNSTREAM TARGET GENES. GENOME-WIDE ANALYSIS OF HIF-1 BINDING SITES USING HIGH-THROUGHPUT SEQUENCERS HAS CLARIFIED VARIOUS KINDS OF DOWNSTREAM TARGETS AND MADE IT POSSIBLE TO DEMONSTRATE THE NOVEL ROLES OF HIF-1. OUR AIM OF THIS STUDY IS TO IDENTIFY NOVEL HIF-1 DOWNSTREAM EPIGENETIC TARGETS WHICH MAY PLAY IMPORTANT ROLES IN THE KIDNEY. IMMORTALIZED TUBULAR CELL LINES (HK2; HUMAN KIDNEY-2) AND PRIMARY CULTURED CELLS (RPTEC; RENAL PROXIMAL TUBULAR CELL LINES) WERE EXPOSED TO 1% HYPOXIA FOR 24-72 H. WE PERFORMED RNA-SEQ TO CLARIFY THE EXPRESSION OF MRNA AND LONG NON-CODING RNA (LNCRNA). WE ALSO EXAMINED CHIP-SEQ TO IDENTIFY HIF-1 BINDING SITES UNDER HYPOXIA. RNA-SEQ IDENTIFIED 44 LNCRNAS WHICH ARE UP-REGULATED UNDER HYPOXIC CONDITION IN BOTH CELLS. CHIP-SEQ ANALYSIS DEMONSTRATED THAT HIF-1 ALSO BINDS TO THE LNCRNAS UNDER HYPOXIA. THE EXPRESSION OF NOVEL LNCRNA, DARS-AS1 (ASPARTYL-TRNA SYNTHETASE ANTI-SENSE 1), IS UP-REGULATED ONLY UNDER HYPOXIA AND HIF-1 BINDS TO ITS PROMOTER REGION, WHICH INCLUDES TWO HYPOXIA-RESPONSIVE ELEMENTS. ITS EXPRESSION IS ALSO UP-REGULATED WITH COBALT CHLORIDE EXPOSURE, WHILE IT IS NOT UNDER HYPOXIA WHEN HIF-1 IS KNOCKED DOWN BY SIRNA TO CLARIFY THE BIOLOGICAL ROLES OF DARS-AS1, WE MEASURED THE ACTIVITY OF CASPASE 3/7 USING ANTI-SENSE OLIGO OF DARS-AS1. KNOCKDOWN OF DARS-AS1 DETERIORATED APOPTOTIC CELL DEATH. IN CONCLUSION, WE IDENTIFIED THE NOVEL LNCRNAS REGULATED BY HIF-1 UNDER HYPOXIA AND CLARIFIED THAT DARS-AS1 PLAYS AN IMPORTANT ROLE IN INHIBITING APOPTOTIC CELL DEATH IN RENAL TUBULAR CELLS. 2017 4 5104 18 POLYCYSTIC OVARIAN SYNDROME. WOMEN WITH PCOS PRESENT WITH SIGNS OF CHRONIC ANOVULATION, HYPERANDROGENISM, AND METABOLIC ABNORMALITIES. THE NIH RECENTLY EMBRACED THE ROTTERDAM CRITERIA TO BROADLY IDENTIFY ALL THE PHENOTYPES OF PCOS. WOMEN WITH PCOS ARE OFTEN OBESE WITH INSULIN RESISTANCE AND HENCE HAVE AN INCREASED SUSCEPTIBILITY TO GLUCOSE INTOLERANCE AND TYPE 2 DIABETES. FUTURE RESEARCH SHOULD FOCUS ON THE GENETIC, EPIGENETIC, AND ENVIRONMENTAL DETERMINANTS OF PCOS TO DEVELOP NEW THERAPIES TO ADDRESS THE PREVENTION OF THIS DISORDER AND ITS LONG-TERM COMPLICATIONS. 2015 5 4892 36 OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: OXIDATIVE STRESS IN POLYCYSTIC OVARY SYNDROME. IN BRIEF: A GENETIC, EPIGENETIC, AND ENVIRONMENTAL ASSOCIATION EXISTS BETWEEN OXIDATIVE STRESS (OS) AND POLYCYSTIC OVARY SYNDROME (PCOS), EXPRESSED IN A MULTIFACETED CLINICAL PROFILE. THIS REVIEW SUMMARIZES AND DISCUSSES THE ROLE OF OS IN THE PATHOGENESIS OF PCOS SYNDROME, FOCUSING ON METABOLIC, REPRODUCTIVE, AND CANCER COMPLICATIONS. ABSTRACT: OXIDATIVE STRESS (OS), AN IMBALANCE BETWEEN OXIDANTS AND ANTIOXIDANTS IN CELLS, IS ONE OF MANY FACTORS PLAYING ESSENTIAL ROLES IN THE PATHOGENESIS OF POLYCYSTIC OVARY SYNDROME (PCOS). PCOS IS DESCRIBED MAINLY AS A DISPROPORTION OF REPRODUCTIVE HORMONES, LEADING TO CHRONIC ANOVULATION AND INFERTILITY IN WOMEN. INTERESTINGLY, OS IN PCOS MAY BE ASSOCIATED WITH MANY DISORDERS AND DISEASES. THIS REVIEW FOCUSES ON CHARACTERISTIC MARKERS OF OS IN PCOS AND THE RELATIONSHIP BETWEEN OS AND PCOS RELATED TO INSULIN RESISTANCE (IR), HYPERANDROGENEMIA, OBESITY, CHRONIC INFLAMMATION, CARDIOVASCULAR DISEASES, AND CANCER. INTERESTINGLY, IN PATIENTS WITH PCOS, AN INCREASE IN OXIDATIVE STATUS AND INSUFFICIENT COMPENSATION OF THE INCREASE IN ANTIOXIDANT STATUS BEFORE ANY CARDIOVASCULAR COMPLICATIONS ARE OBSERVED. MOREOVER, FREE RADICALS PROMOTE CARCINOGENESIS IN PCOS PATIENTS. HOWEVER, DESPITE THESE DATA, IT HAS NOT BEEN ESTABLISHED WHETHER OXYGEN STRESS INFLUENCES PCOS DEVELOPMENT OR A SECONDARY DISORDER RESULTING FROM HYPERGLYCEMIA, IR, AND CARDIOVASCULAR AND CANCER COMPLICATIONS IN WOMEN. 2022 6 6116 34 THE EPIGENETIC CORRELATION AMONG OVARIAN CANCER, ENDOMETRIOSIS AND PCOS: A REVIEW. OVARIAN CANCER IS A FREQUENT MALIGNANCY THAT AFFECTS A LARGE PERCENTAGE OF WOMEN. ENDOMETRIOSIS IS A CHRONIC CONDITION, WHERE THERE IS A PRODUCTION OF BENIGN LESIONS WERE OBSERVED IN THE UTERINE ENVIRONMENT. PCOS IS A METABOLIC DISORDER CHARACTERIZED BY THE PRESENCE OF NUMEROUS CYSTS IN THE OVARIES. THE RELATION BETWEEN OVARIAN MALIGNANCIES AND PCOS, BY AN INCREASED RATIO OF OVARIAN STROMAL TISSUES IN PCOS PATIENTS. THE DIRECT CORRELATION IS NOT YET CONFIRMED AMONG THE THREE DISORDERS, BUT IT IS OFTEN NOTED THAT THEY SHARE RISK FACTORS, SUCH AS OBESITY, HORMONAL IMBALANCES. EPIGENETIC FACTORS HAVE SHOWN TO BE AN IMPORTANT REASON FOR CANCER PROGRESSION. OUR FINDINGS AT THE EPIGENETIC LEVEL INCLUDES A COMPARATIVE ANALYSIS, POINT MUTATIONS IN GENES, OVERACTIVATION OF SIGNALING PATHWAYS. THIS REVIEW PAPER, HIGHLIGHT THE POSSIBLE CORRELATION BETWEEN THE THREE DISORDERS IN TERMS OF GENETIC AND EPIGENETIC FACTORS AND HOW IT COULD TOGETHER TRIGGER THE CANCER PROGRESSION AND METASTASIS. 2022 7 1028 53 CIRCULATING MIRNAS RELATED TO EPITHELIAL-MESENCHYMAL TRANSITIONS (EMT) AS THE NEW MOLECULAR MARKERS IN ENDOMETRIOSIS. ENDOMETRIOSIS IS A CHRONIC GYNECOLOGICAL DISEASE DEFINED BY THE PRESENCE OF ENDOMETRIAL-LIKE TISSUE FOUND OUTSIDE THE UTERUS, MOST COMMONLY IN THE PERITONEAL CAVITY. ENDOMETRIOSIS LESIONS ARE HETEROGENOUS BUT USUALLY CONTAIN ENDOMETRIAL STROMAL CELLS AND EPITHELIAL GLANDS, IMMUNE CELL INFILTRATES AND ARE VASCULARIZED AND INNERVATED BY NERVES. THE COMPLEX ETIOPATHOGENESIS AND HETEROGENITY OF THE CLINICAL SYMPTOMS, AS WELL AS THE LACK OF A SPECIFIC NON-INVASIVE DIAGNOSTIC BIOMARKERS, UNDERLINE THE NEED FOR MORE ADVANCED DIAGNOSTIC TOOLS. UNFORTUNATELY, THE CONTRIBUTION OF ENVIRONMENTAL, HORMONAL AND IMMUNOLOGICAL FACTORS IN THE DISEASE ETIOLOGY IS INSUFFICIENT, AND THE CONTRIBUTION OF GENETIC/EPIGENETIC FACTORS IS STILL FRAGMENTARY. THEREFORE, THERE IS A NEED FOR MORE FOCUSED STUDY ON THE MOLECULAR MECHANISMS OF ENDOMETRIOSIS AND NON-INVASIVE DIAGNOSTIC MONITORING SYSTEMS. MICRORNAS (MIRNAS) DEMONSTRATE HIGH STABILITY AND TISSUE SPECIFICITY AND PLAY A SIGNIFICANT ROLE IN MODULATING A RANGE OF MOLECULAR PATHWAYS, AND HENCE MAY BE SUITABLE DIAGNOSTIC BIOMARKERS FOR THE ORIGIN AND DEVELOPMENT OF ENDOMETRIOSIS. OF THESE, THE MOST FREQUENTLY STUDIED ARE THOSE RELATED TO ENDOMETRIOSIS, INCLUDING THOSE INVOLVED IN EPITHELIAL-MESENCHYMAL TRANSITION (EMT), WHOSE EXPRESSION IS ALTERED IN PLASMA OR ENDOMETRIOTIC LESION BIOPSIES; HOWEVER, THE RESULTS ARE AMBIGUOUS. SPECIFIC MIRNAS EXPRESSED IN ENDOMETRIOSIS MAY SERVE AS DIAGNOSTICS MARKERS WITH PROGNOSTIC VALUE, AND THEY HAVE BEEN PROPOSED AS MOLECULAR TARGETS FOR TREATMENT. THE AIM OF THIS REVIEW IS TO PRESENT SELECTED MIRNAS ASSOCIATED WITH EMT KNOWN TO HAVE EXPERIMENTALLY CONFIRMED SIGNIFICANCE, AND DISCUSS THEIR UTILITY AS BIOMARKERS IN ENDOMETRIOSIS. 2021 8 459 45 APPLYING SINGLE-CELL TECHNOLOGIES TO CLINICAL PATHOLOGY: PROGRESS IN NEPHROPATHOLOGY. CELLS REPRESENT THE BASIC BUILDING BLOCKS OF LIVING ORGANISMS. ACCURATE CHARACTERISATION OF CELLULAR PHENOTYPE, INTERCELLULAR SIGNALLING NETWORKS, AND THE SPATIAL ORGANISATION OF CELLS WITHIN ORGANS IS CRUCIAL TO DELIVER A BETTER UNDERSTANDING OF THE PROCESSES UNDERPINNING PHYSIOLOGY, AND THE PERTURBATIONS THAT LEAD TO DISEASE. SINGLE-CELL METHODOLOGIES HAVE INCREASED RAPIDLY IN SCALE AND SCOPE IN RECENT YEARS AND ARE SET TO GENERATE IMPORTANT INSIGHTS INTO HUMAN DISEASE. HERE, WE REVIEW CURRENT PRACTICES IN NEPHROPATHOLOGY, WHICH ARE DOMINATED BY RELATIVELY SIMPLE MORPHOLOGICAL DESCRIPTIONS OF TISSUE BIOPSIES BASED ON THEIR APPEARANCE USING LIGHT MICROSCOPY. BULK TRANSCRIPTOMICS HAVE MORE RECENTLY BEEN USED TO EXPLORE GLOMERULAR AND TUBULOINTERSTITIAL KIDNEY DISEASE, RENAL CANCER, AND THE RESPONSES TO INJURY AND ALLOIMMUNITY IN KIDNEY TRANSPLANTATION, GENERATING NOVEL DISEASE INSIGHTS AND PROGNOSTIC BIOMARKERS. THESE STUDIES SET THE STAGE FOR SINGLE-CELL TRANSCRIPTOMIC APPROACHES THAT REVEAL CELL-TYPE-SPECIFIC GENE EXPRESSION PATTERNS IN HEALTH AND DISEASE. THESE TECHNOLOGIES ALLOW GENOME-WIDE DISEASE SUSCEPTIBILITY GENES TO BE INTERPRETED WITH THE KNOWLEDGE OF THE SPECIFIC CELL POPULATIONS WITHIN ORGANS THAT EXPRESS THEM, IDENTIFYING CANDIDATE CELL TYPES FOR FURTHER STUDY. SINGLE-CELL TECHNOLOGIES ARE ALSO MOVING BEYOND ASSAYING INDIVIDUAL CELLULAR TRANSCRIPTOMES, TO MEASURING THE EPIGENETIC LANDSCAPE OF SINGLE CELLS. SINGLE-CELL ANTIGEN-RECEPTOR GENE SEQUENCING ALSO ENABLES SPECIFIC T- AND B-CELL CLONES TO BE TRACKED IN DIFFERENT TISSUES AND DISEASE STATES. IN THE COMING YEARS THESE RICH 'MULTI-OMIC' DESCRIPTIONS OF KIDNEY DISEASE WILL ENABLE HISTOPATHOLOGICAL DESCRIPTIONS TO BE COMPREHENSIVELY INTEGRATED WITH MOLECULAR PHENOTYPES, ENABLING BETTER DISEASE CLASSIFICATION AND PROGNOSTICATION AND THE APPLICATION OF PERSONALISED TREATMENT STRATEGIES. (C) 2020 THE AUTHORS. THE JOURNAL OF PATHOLOGY PUBLISHED BY JOHN WILEY & SONS LTD ON BEHALF OF PATHOLOGICAL SOCIETY OF GREAT BRITAIN AND IRELAND. 2020 9 1031 48 CIRCULATING TUMOR DNA DETECTION AND ITS APPLICATION STATUS IN GASTRIC CANCER: A NARRATIVE REVIEW. CIRCULATING TUMOR DNA (CTDNA) IS THE SMALL GENOMIC FRAGMENT RELEASED BY TUMOR CELLS INTO THE CIRCULATING SYSTEM, WHICH CARRIES THE GENE VARIATION FEATURES, SUCH AS MUTATION, INSERTION, DELETION, REARRANGEMENT, COPY NUMBER VARIATION (CNV) AND METHYLATION, RENDERING IT AN IMPORTANT BIOMARKER. IT CAN BE USED NOT ONLY TO DIAGNOSE CERTAIN TYPES OF SOLID TUMORS, BUT ALSO TO MONITOR THE THERAPEUTIC RESPONSE AND EXPLORE THE MINIMAL RESIDUAL DISEASE (MRD) AND RESISTANT MUTATION OF TARGETED THERAPY. THEREFORE, CTDNA DETECTION MAY BECOME THE PREFERRED NON-INVASIVE TUMOR SCREENING METHOD. FOR PATIENTS WHO CANNOT RECEIVE FURTHER GENE DETECTION DUE TO INSUFFICIENT OR RESTRICTED SAMPLE COLLECTION WITH THE DEFINED PATHOLOGICAL DIAGNOSIS, CTDNA DETECTION CAN BE CARRIED OUT TO DETERMINE THE GENE MUTATION TYPE, WITH NO NEED FOR REPEATED SAMPLING. GASTRIC CANCER (GC) IS A MALIGNANCY WITH EXTREMELY HIGH MORBIDITY AND MORTALITY, AND ITS GENESIS AND DEVELOPMENT ARE THE CONSEQUENCE OF INTERACTIONS OF MULTIPLE FACTORS, INCLUDING ENVIRONMENT, DIET, HEREDITY, HELICOBACTER PYLORI INFECTION, CHRONIC INFLAMMATORY INFILTRATION, AND PRECANCEROUS LESION. AS THE RESEARCH ON GC MOVES FORWARD, THE EXISTING RESEARCH MAINLY FOCUSES ON GENETIC AND EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, NON-CODING RNA CHANGES, GENE MUTATION, GENE HETEROZYGOSITY LOSS AND MICROSATELLITE INSTABILITY. THIS PAPER AIMED TO SUMMARIZE THE CONTENTS OF CTDNA DETECTION, ITS APPLICATION STATUS IN GC AND CLINICAL SIGNIFICANCE. 2021 10 3000 39 GENETIC VARIATIONS IN UCA1, A LNCRNA FUNCTIONING AS A MIRNA SPONGE, DETERMINE ENDOMETRIOSIS DEVELOPMENT AND THE POTENTIAL ASSOCIATED INFERTILITY VIA REGULATING LIPOGENESIS. ENDOMETRIOSIS IS A HORMONE-ASSOCIATED DISEASE WHICH HAS BEEN CONSIDERED AS THE PRECURSOR FOR CERTAIN TYPES OF OVARIAN CANCER. IN RECENT YEARS, EMERGING EVIDENCE DEMONSTRATED POTENT ROLES OF LNCRNA IN REGULATING CANCER DEVELOPMENT. SINCE ENDOMETRIOSIS SHARES SEVERAL FEATURES WITH CANCER, WE INVESTIGATED THE POSSIBLE INVOLVEMENT OF CANCER-RELATED LNCRNAS IN ENDOMETRIOSIS, INCLUDING UCA1, GAS5 AND PTENP1. BY USING MASSARRAY SYSTEM, WE INVESTIGATED CERTAIN GENETIC VARIATIONS IN CANCER-RELATED LNCRNAS THAT CAN CHANGE THE THERMO-STABILITY, LEADING TO UP-REGULATION OR DOWN-REGULATION OF THOSE LNCRNAS. OUR DATA INDICATED THREE RISK GENETIC HAPLOTYPES IN UCA1 WHICH CAN STABILIZE THE RNA STRUCTURE AND INCREASE THE SUSCEPTIBILITY OF ENDOMETRIOSIS. OF NOTE, SUCH ALTERATIONS WERE FOUND TO BE ASSOCIATED WITH LONG-TERM PAIN AND INFERTILITY IN PATIENTS. IT HAS BEEN KNOWN THAT UCA1 CAN FUNCTION AS A CERNA TO SPONGE AND INHIBIT MIRNAS, RESULTING IN LOSS-OF-CONTROL ON DOWNSTREAM TARGET GENES. GENE NETWORK ANALYSES REVEALED FATTY ACID METABOLISM AND MITOCHONDRIA BETA-OXIDATION AS THE MAJOR PATHWAYS ASSOCIATED WITH ALTERED UCA1 EXPRESSION IN ENDOMETRIOSIS PATIENTS. OUR STUDY THUS PROVIDES EVIDENCE TO HIGHLIGHT FUNCTIONAL/EPIGENETIC ROLES OF UCA1 IN ENDOMETRIOSIS DEVELOPMENT VIA REGULATING FATTY ACID METABOLISM IN WOMEN. 2022 11 1891 49 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 12 261 46 ADVANCES IN TARGET THERAPY FOR LUNG CANCER. RECENT PROGRESS IN MOLECULAR BIOLOGY HAS SHOWN THAT CANCER CELLS ACQUIRE COMMON PHENOTYPES SUCH AS SELF-SUFFICIENCY OF GROWTH SIGNALS, RESISTANCE TO ANTI-PROLIFERATIVE AND APOPTOTIC SIGNALS THROUGH THE ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES. RECENTLY DEVELOPED ANTICANCER DRUGS TARGET THESE MOLECULAR MECHANISMS AND GOOD RESULTS HAVE BEEN REPORTED FOR VARIOUS CANCER TYPES. IN LUNG CANCER, TYROSINE KINASE INHIBITORS SPECIFIC FOR THE EPIDERMAL GROWTH FACTOR RECEPTOR SUCH AS GEFITINIB AND ERLOTINIB HAVE CHANGED CLINICAL PRACTICE DRAMATICALLY. ABOUT HALF OF THE JAPANESE PATIENTS WITH LUNG CANCERS HARBOR AN ACTIVATING MUTATION OF THE EPIDERMAL GROWTH FACTOR RECEPTOR GENE AND THEY ARE VERY SENSITIVE TO EPIDERMAL GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITORS. PROGRESSION-FREE SURVIVAL OF SUCH PATIENTS IS APPROXIMATELY 10 MONTHS WHEN TREATED WITH GEFITINIB, WHEREAS THE SURVIVAL FOR THOSE TREATED WITH PLATINUM DOUBLET THERAPY IS APPROXIMATELY 6 MONTHS. TARGET THERAPIES AGAINST ECHINODERM MICROTUBULE-ASSOCIATED PROTEIN-LIKE 4-ANAPLASTIC LYMPHOMA KINASE FUSION PROTEIN OR A MUTATED ERBB2 (V-ERB-B AVIAN ERYTHROBLASTIC LEUKEMIA VIRAL ONCOGENE HOMOLOGUE 2) PRESENT IN APPROXIMATELY 5% AND APPROXIMATELY 3% OF THE JAPANESE PATIENTS WITH ADENOCARCINOMAS, RESPECTIVELY, ARE CURRENTLY UNDER DEVELOPMENT. ADDITION OF AN ANTI-EPIDERMAL GROWTH FACTOR RECEPTOR ANTIBODY, CETUXIMAB, OR ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR ANTIBODY, BEVACIZUMAB, TO PLATINUM DOUBLET THERAPY SIGNIFICANTLY BUT MODESTLY PROLONGED THE SURVIVAL IN RECENT CLINICAL TRIALS. HOWEVER, CLINICAL DEVELOPMENT OF SMALL MOLECULE MULTI-KINASE INHIBITORS INCLUDING THOSE TARGETING VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTORS, SUCH AS VANDETANIB, SUNITINIB AND SORAFENIB, HAS NOT BEEN VERY SUCCESSFUL. THROUGH THESE COLLABORATIONS AMONG CLINICIANS, BASIC RESEARCHERS AND PHARMACEUTICAL COMPANIES, IT SHOULD BE POSSIBLE TO INDIVIDUALIZE LUNG CANCER TREATMENT TO TURN THIS FATAL DISEASE INTO A CHRONIC DISORDER AND, EVENTUALLY, TO CURE IT. 2010 13 3470 30 HYPOXIA-INDUCIBLE KDM3A ADDICTION IN MULTIPLE MYELOMA. IN MULTIPLE MYELOMA (MM), THE BONE MARROW (BM) MICROENVIRONMENT MAY CONTAIN A MYELOMA CELL FRACTION THAT HAS ACQUIRED TREATMENT RESISTANCE BY UNDERGOING AN EPIGENETIC GENE EXPRESSION CHANGE. HYPOXIC STRESS IS AN IMPORTANT FACTOR IN THE BM MICROENVIRONMENT. RECENTLY, WE DEMONSTRATED THAT MIR-210 WAS UPREGULATED IN HYPOXIA AND DOWNREGULATED IRF4, WHICH IS KNOWN AS AN ESSENTIAL FACTOR IN MYELOMA ONCOGENESIS IN NORMOXIA. IN THE STUDY, WE DEMONSTRATED THAT MYELOMA CELLS STILL SHOWED A STRONG ANTIAPOPTOTIC PHENOTYPE DESPITE IRF4 DOWNREGULATION, SUGGESTING THAT ANOTHER ANTIAPOPTOTIC FACTOR MIGHT BE INVOLVED UNDER HYPOXIC STRESS. TO DETERMINE THE FACTOR OR FACTORS, WE CONDUCTED GENE EXPRESSION ANALYSIS ON MYELOMA CELLS (PRIMARY SAMPLES AND CELL LINES) THAT WERE EXPOSED TO CHRONIC HYPOXIA AND OBSERVED UPREGULATION OF GLYCOLYTIC GENES AND GENES ENCODING H3K9 DEMETHYLASES IN MYELOMA CELLS WITH HYPOXIA. AMONG THESE, KDM3A WAS MOST SIGNIFICANTLY UPREGULATED IN ALL EXAMINED CELLS, AND ITS KNOCKDOWN INDUCED APOPTOSIS OF MYELOMA CELLS IN CHRONIC HYPOXIA. EXPRESSION OF KDM3A WAS DEPENDENT ON HIF-1ALPHA, WHICH IS A TRANSCRIPTION FACTOR SPECIFICALLY UPREGULATED IN HYPOXIA. WE FURTHER DEMONSTRATED THAT AN ESSENTIAL TARGET OF KDM3A WAS A NONCODING GENE, MALAT1, WHOSE UPREGULATION CONTRIBUTED TO ACQUISITION OF AN ANTIAPOPTOTIC PHENOTYPE BY ACCUMULATION OF HIF-1ALPHA, LEADING TO UPREGULATION OF GLYCOLYTIC GENES UNDER HYPOXIA. THIS PROCESS WAS INDEPENDENT FROM IRF4. THESE RESULTS LED US TO CONCLUDE THAT THE HYPOXIA-INDUCIBLE HIF-1ALPHA-KDM3A-MALAT1 AXIS ALSO CONTRIBUTES TO ACQUISITION OF THE ANTIAPOPTOTIC PHENOTYPE VIA UPREGULATION OF GLYCOLYSIS-PROMOTING GENES. THUS, THIS AXIS IS A PROMISING THERAPEUTIC TARGET AGAINST MYELOMA CELLS IN THE BM MICROENVIRONMENT. 2018 14 259 42 ADVANCES IN PCOS PATHOGENESIS AND PROGRESSION-MITOCHONDRIAL MUTATIONS AND DYSFUNCTION. POLYCYSTIC OVARY SYNDROME (PCOS) IS A COMMON FEMALE ENDOCRINE DISORDER, WHICH STILL REMAINS LARGELY UNSOLVED IN TERMS OF ETIOLOGY AND PATHOGENESIS DESPITE IMPORTANT ADVANCES IN OUR UNDERSTANDING OF ITS GENETIC, EPIGENETIC, OR ENVIRONMENTAL FACTOR IMPLICATIONS. IT IS A HETEROGENEOUS DISEASE, FREQUENTLY ASSOCIATED WITH INSULIN RESISTANCE, CHRONIC INFLAMMATION, AND OXIDATIVE STRESS AND PROBABLY ACCOMPANIED WITH SUBCLINICAL CARDIOVASCULAR DISEASE (CVD) AND SOME MALIGNANT LESIONS AS WELL, SUCH AS ENDOMETRIAL CANCER. DISCREPANCIES IN THE CLINICAL PHENOTYPE AND PROGRESSION OF PCOS EXIST BETWEEN DIFFERENT POPULATION GROUPS, WHICH NUCLEAR GENETIC STUDIES HAVE SO FAR FAILED TO EXPLAIN. OVER THE LAST YEARS, MITOCHONDRIAL DYSFUNCTION HAS BEEN INCREASINGLY RECOGNIZED AS AN IMPORTANT CONTRIBUTOR TO AN ARRAY OF DISEASES. BECAUSE MITOCHONDRIA ARE UNDER THE DUAL GENETIC CONTROL OF BOTH THE MITOCHONDRIAL AND NUCLEAR GENOMES, MUTATIONS WITHIN EITHER DNA MOLECULE MAY RESULT IN DEFICIENCY IN RESPIRATORY CHAIN FUNCTION THAT LEADS TO A REDUCED ABILITY TO PRODUCE CELLULAR ADENOSINE-5'-TRIPHOSPHATE AND TO AN EXCESSIVE PRODUCTION OF REACTIVE OXYGEN SPECIES. HOWEVER, THE ASSOCIATION BETWEEN VARIANTS IN MITOCHONDRIAL GENOME, MITOCHONDRIAL DYSFUNCTION, AND PCOS HAS BEEN INVESTIGATED TO A LESSER EXTENT. MAY MUTATIONS IN MITOCHONDRIAL DNA (MTDNA) BECOME AN ADDITIONAL TARGET OF INVESTIGATIONS ON THE MISSING PCOS HERITABILITY? ARE MUTATIONS IN MTDNA IMPLICATED IN THE INITIATION AND PROGRESSION OF PCOS COMPLICATIONS, E.G., CVDS, DIABETES MELLITUS, CANCERS? 2018 15 5222 30 PRIMARY BILIARY CIRRHOSIS: FAMILY STORIES. PRIMARY BILIARY CIRRHOSIS (PBC) IS A CHRONIC IMMUNE-MEDIATED CHOLESTATIC LIVER DISEASE OF UNKNOWN AETIOLOGY WHICH AFFECTS MOSTLY WOMEN IN MIDDLE AGE. FAMILIAL PBC IS WHEN PBC AFFECTS MORE THAN ONE MEMBER OF THE SAME FAMILY, AND DATA SUGGEST THAT FIRST-DEGREE RELATIVES OF PBC PATIENTS HAVE AN INCREASED RISK OF DEVELOPING THE DISEASE. MOST OFTEN, THESE FAMILIAL CLUSTERS INVOLVE MOTHER-DAUGHTER PAIRS, WHICH IS CONSISTENT WITH THE FEMALE PREPONDERANCE OF THE DISEASE. THESE CLUSTERS PROVIDE EVIDENCE TOWARDS A GENETIC BASIS UNDERLYING PBC. HOWEVER, CLUSTERS OF NONRELATED INDIVIDUALS HAVE ALSO BEEN REPORTED, GIVING STRENGTH TO AN ENVIRONMENTAL COMPONENT. TWIN STUDIES HAVE DEMONSTRATED A HIGH CONCORDANCE FOR PBC IN MONOZYGOTIC TWINS AND A LOW CONCORDANCE AMONG DIZYGOTIC TWINS. IN CONCLUSION, STUDIES OF PBC IN FAMILIES CLEARLY DEMONSTRATE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS PLAY A ROLE IN THE DEVELOPMENT OF THE DISEASE. 2011 16 4403 39 MODULATION OF THE INFLAMMATORY RESPONSE IN POLYCYSTIC OVARY SYNDROME (PCOS)-SEARCHING FOR EPIGENETIC FACTORS. POLYCYSTIC OVARY SYNDROME (PCOS) IS THE MOST COMMON ENDOCRINE DISORDER IN WOMEN OF REPRODUCTIVE AGE. DESPITE ITS INCIDENCE, THE SYNDROME IS POORLY UNDERSTOOD AND REMAINS UNDERDIAGNOSED, AND FEMALE PATIENTS ARE DIAGNOSED WITH A DELAY. THE HETEROGENOUS NATURE OF THIS COMPLEX DISORDER RESULTS FROM THE COMBINED OCCURRENCE OF GENETIC, ENVIRONMENTAL, ENDOCRINE, AND BEHAVIORAL FACTORS. PRIMARY CLINICAL MANIFESTATIONS OF PCOS ARE DERIVED FROM THE EXCESS OF ANDROGENS (ANOVULATION, POLYCYSTIC OVARY MORPHOLOGY, LACK OF OR SCANTY, IRREGULAR MENSTRUAL PERIODS, ACNE AND HIRSUTISM), WHEREAS THE SECONDARY MANIFESTATIONS INCLUDE MULTIPLE METABOLIC, CARDIOVASCULAR, AND PSYCHOLOGICAL DISORDERS. DIETARY AND LIFESTYLE FACTORS PLAY IMPORTANT ROLES IN THE DEVELOPMENT AND COURSE OF PCOS, WHICH SUGGESTS STRONG EPIGENETIC AND ENVIRONMENTAL INFLUENCES. MANY STUDIES HAVE SHOWN A STRONG ASSOCIATION BETWEEN PCOS AND CHRONIC, LOW-GRADE INFLAMMATION BOTH IN THE OVARIAN TISSUE AND THROUGHOUT THE BODY. IN THE VAST MAJORITY OF PCOS PATIENTS, ELEVATED VALUES OF INFLAMMATORY MARKERS OR THEIR GENE MARKERS HAVE BEEN REPORTED. DEVELOPMENT OF THE VICIOUS CYCLE OF THE CHRONIC INFLAMMATORY STATE IN PCOS IS ADDITIONALLY STIMULATED BY HYPERINSULINEMIA AND OBESITY. CHANGES IN DNA METHYLATION, HISTONE ACETYLATION AND NONCODING RNA LEVELS ARE PRESENTED IN THIS REVIEW IN THE CONTEXT OF OXIDATIVE STRESS, REACTIVE OXYGEN SPECIES, AND INFLAMMATORY SIGNALING IN PCOS. EPIGENETIC MODULATION OF ANDROGENIC ACTIVITY IN RESPONSE TO INFLAMMATORY SIGNALING IS ALSO DISCUSSED. 2022 17 1889 44 ENDOMETRIOSIS MALIGNANT TRANSFORMATION: EPIGENETICS AS A PROBABLE MECHANISM IN OVARIAN TUMORIGENESIS. ENDOMETRIOSIS, DEFINED AS THE PRESENCE OF ECTOPIC ENDOMETRIAL GLANDS AND STROMA OUTSIDE THE UTERINE CAVITY, IS A CHRONIC, HORMONE-DEPENDENT GYNECOLOGIC DISEASE AFFECTING MILLIONS OF WOMEN ACROSS THE WORLD, WITH SYMPTOMS INCLUDING CHRONIC PELVIC PAIN, DYSMENORRHEA, DYSPAREUNIA, DYSURIA, AND SUBFERTILITY. IN ADDITION, THERE IS WELL-ESTABLISHED EVIDENCE THAT, ALTHOUGH ENDOMETRIOSIS IS CONSIDERED BENIGN, IT IS ASSOCIATED WITH AN INCREASED RISK OF MALIGNANT TRANSFORMATION, WITH THE INVOLVEMENT OF VARIOUS MECHANISMS OF DEVELOPMENT. MORE AND MORE EVIDENCE REVEALS AN IMPORTANT CONTRIBUTION OF EPIGENETIC MODIFICATION NOT ONLY IN ENDOMETRIOSIS BUT ALSO IN MECHANISMS OF ENDOMETRIOSIS MALIGNANT TRANSFORMATION, INCLUDING DNA METHYLATION AND DEMETHYLATION, HISTONE MODIFICATIONS, AND MIRNA ABERRANT EXPRESSIONS. IN THIS PRESENT REVIEW, WE MAINLY SUMMARIZE THE RESEARCH PROGRESS ABOUT THE CURRENT KNOWLEDGE REGARDING THE EPIGENETIC MODIFICATIONS OF THE RELATIONS BETWEEN ENDOMETRIOSIS MALIGNANT TRANSFORMATION AND OVARIAN CANCER IN AN EFFORT TO IDENTIFY SOME RISK FACTORS PROBABLY ASSOCIATED WITH ECTOPIC ENDOMETRIUM TRANSFORMATION. 2018 18 2876 45 FUNCTIONAL ROLES OF LONG NONCODING RNA MALAT1 IN GYNECOLOGIC CANCERS. GYNECOLOGIC CANCERS ARE REPRODUCTIVE DISORDERS CHARACTERIZED BY PELVIC PAIN AND INFERTILITY. THE IDENTIFICATION OF NEW PREDICTIVE MARKERS AND THERAPEUTIC TARGETS FOR THE TREATMENT OF GYNECOLOGIC CANCERS IS URGENTLY NECESSARY. ONE OF THE RECENT SUCCESSES IN GYNECOLOGIC CANCERS RESEARCH IS IDENTIFYING THE ROLE OF SIGNALING PATHWAYS IN THE PATHOGENESIS OF THE DISEASE. RECENT EXPERIMENTS SHOWED LONG NONCODING RNAS (LNCRNA) CAN BE NOVEL THERAPEUTIC APPROACHES FOR THE DIAGNOSIS AND TREATMENT OF GYNECOLOGIC CANCERS. LNCRNA ARE TRANSCRIBED RNA MOLECULES THAT PLAY PIVOTAL ROLES IN MULTIPLE BIOLOGICAL PROCESSES BY REGULATING THE DIFFERENT STEPS OF GENE EXPRESSION. METASTASIS-ASSOCIATED LUNG ADENOCARCINOMA TRANSCRIPT-1 (MALAT1) IS A WELL-KNOWN LNCRNA THAT PLAYS FUNCTIONAL ROLES IN GENE EXPRESSION, RNA PROCESSING, AND EPIGENETIC REGULATION. HIGH EXPRESSION OF MALAT1 IS CLOSELY RELATED TO NUMEROUS HUMAN DISEASES. IT IS GENERALLY BELIEVED THAT MALAT1 EXPRESSION IS ASSOCIATED WITH CANCER CELL GROWTH, AUTOPHAGY, INVASION, AND METASTASIS. MALAT1 BY TARGETING MULTIPLE SIGNALING PATHWAYS AND MICRORNAS (MIRNAS) COULD CONTRIBUTE TO THE PATHOGENESIS OF GYNECOLOGIC CANCERS. IN THIS REVIEW, WE WILL SUMMARIZE FUNCTIONAL ROLES OF MALAT1 IN THE MOST COMMON GYNECOLOGIC CANCERS, INCLUDING ENDOMETRIUM, BREAST, OVARY, AND CERVIX. 2023 19 329 39 ALPHA-OXOGLUTARATE INHIBITS THE PROLIFERATION OF IMMORTALIZED NORMAL BLADDER EPITHELIAL CELLS VIA AN EPIGENETIC SWITCH INVOLVING ARID1A. INTERSTITIAL CYSTITIS (IC) IS A CHRONIC URINARY TRACT DISEASE THAT IS CHARACTERIZED BY UNPLEASANT SENSATIONS, SUCH AS PERSISTENT PELVIC PAIN, IN THE ABSENCE OF INFECTION OR OTHER IDENTIFIABLE CAUSES. WE PREVIOUSLY PERFORMED COMPREHENSIVE METABOLOMICS PROFILING OF URINE SAMPLES FROM IC PATIENTS USING NUCLEAR MAGNETIC RESONANCE AND GAS-CHROMATOGRAPHY/MASS SPECTROMETRY AND FOUND THAT URINARY ALPHA-OXOGLUTARATE (ALPHA-OG), WAS SIGNIFICANTLY ELEVATED. ALPHA-OG, A TRICARBOXYLIC ACID (TCA) CYCLE INTERMEDIATE, REPORTEDLY FUNCTIONS TO SUPPRESS THE PROLIFERATION OF IMMORTALIZED NORMAL HUMAN BLADDER EPITHELIAL CELLS. HERE, WE IDENTIFIED AT-RICH INTERACTIVE DOMAIN 1 A (ARID1A), A KEY CHROMATIN REMODELER, AS BEING HYPOMETHYLATED AND UPREGULATED BY ALPHA-OG TREATMENT. THIS WAS DONE THROUGH EPIC DNA METHYLATION PROFILING AND SUBSEQUENT BIOCHEMICAL APPROACHES, INCLUDING QUANTITATIVE RT-PCR AND WESTERN BLOT ANALYSES. FURTHERMORE, WE FOUND THAT ALPHA-OG ALMOST COMPLETELY SUPPRESSES TEN-ELEVEN TRANSLOCATION (TET) ACTIVITY, BUT DOES NOT AFFECT DNA METHYLTRANSFERASE (DNMT) ACTIVITY. ALTOGETHER, OUR STUDIES REVEAL THE POTENTIAL ROLE OF ALPHA-OG IN EPIGENETIC REMODELING THROUGH ITS EFFECTS ON ARID1A AND TET EXPRESSION IN THE BLADDER. THIS MAY PROVIDE A NEW POSSIBLE THERAPEUTIC STRATEGY IN TREATING IC. 2018 20 1502 39 DNA METHYLATION AND EPIGENETIC EVENTS UNDERLYING RENAL CELL CARCINOMAS. RENAL CELL CARCINOMA (RCC) REFERS TO A GROUP OF TUMORS THAT DEVELOP FROM THE EPITHELIUM OF THE KIDNEY TUBES, INCLUDING CLEAR CELL RCC, PAPILLARY RCC, AND CHROMOPHOBE RCC. MOST CLEAR CELL RENAL CARCINOMAS HAVE A LARGE HISTOLOGIC SUBTYPE, GENETIC OR EPIGENETIC VON HIPPEL-LINDAU (VHL). A COMPREHENSIVE ANALYSIS OF THE GENETIC MODIFICATION GENOME SUGGESTED THAT CHROMOSOME 3P LOSS AND CHROMOSOME GAINS 5Q AND 7 MAY BE SIGNIFICANT COPY DEFECTS IN THE DEVELOPMENT OF CLEAR RCC. A MORE POTENT RCC MAY DEVELOP IF CHROMOSOME 1P, 4, 9, 13Q, OR 14Q IS ALSO LOST. RENAL CARCINOGENESIS IS NOT ASSOCIATED WITH CHRONIC INFLAMMATION OR HISTOLOGICAL CHANGES. HOWEVER, IF REGIONAL HYPERMETHYLATION OF DNA IN CPG C-TYPE ISLANDS HAS ALREADY ACCUMULATED IN CANCER-FREE KIDNEY TISSUE, IT IMPLIES THAT THE PRESENCE OF MALIGNANT KIDNEY LESIONS MAY ALSO BE DETECTED BY MODIFIED DNA METHYLATION. MODIFICATION OF DNA METHYLATION IN CANCEROUS KIDNEY TISSUE MAY ADVANCE KIDNEY TISSUE TO EPIGENETIC MUTATIONS AND GENES, LEADING TO MORE SERIOUS CANCERS AND EVEN DETERMINING A PATIENT'S OUTCOME. THE GENETIC AND EPIGENETIC PROFILE PROVIDES ACCURATE PREDICTORS FOR PATIENTS WITH KIDNEY CANCER. NEW GENETIC AND EPIGENETIC ANALYSIS TECHNOLOGIES WILL HELP TO SPEED UP THE IDENTIFICATION OF VITAL CELLS FOR KIDNEY CANCER PREVENTION, DIAGNOSIS, AND TREATMENT. 2022