1 3025 153 GENETICS AND PATHOPHYSIOLOGY OF GRANULOMATOSIS WITH POLYANGIITIS (GPA) AND ITS MAIN AUTOANTIGEN PROTEINASE 3. GRANULOMATOSIS WITH POLYANGIITIS (GPA) IS A SEVERE AUTOIMMUNE DISEASE AND ONE OF THE SMALL VESSEL ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-ASSOCIATED VASCULITIDES. ALTHOUGH ITS ETIOLOGY AND PATHOPHYSIOLOGY ARE STILL WIDELY UNKNOWN, IT IS ACCEPTED THAT INFECTIONS, ENVIRONMENTAL FACTORS, EPIGENETIC MODIFICATIONS, AND A GENETIC PREDISPOSITION PROVIDE THE BASIS FOR THIS SYSTEMIC DISORDER. GPA TYPICALLY EVOLVES INTO TWO PHASES: AN INITIAL PHASE CHARACTERIZED BY EAR, NOSE AND THROAT (ENT) MANIFESTATIONS, SUCH AS CHRONIC SINUSITIS AND OTITIS, ULCERATION OF THE ORAL CAVITY AND PHARYNX, AS WELL AS PULMONARY NODULES AND A SEVERE GENERALIZED PHASE, DEFINED BY THE OCCURRENCE OF RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS, PULMONARY HEMORRHAGE, AND ARTHRITIS. ANCAS, DIRECTED AGAINST THE NEUTROPHILIC ENZYMES PROTEINASE 3 AND MYELOPEROXIDASE, ARE PRESENT IN UP TO 90% OF THE AFFECTED PATIENTS IN THE SYSTEMIC PHASE. AS THE HUMORAL IMMUNITY IS PREDOMINANTLY DIRECTED AGAINST NEUTROPHILIC ANTIGENS, IT IS APPARENT THAT NEUTROPHILS PLAY A CRITICAL ROLE IN GPA BOTH AS TARGET AND EFFECTOR CELLS. ALTHOUGH GPA PATHOGENESIS IS NOT WELL KNOWN, SOME SUSCEPTIBILITY GENES AND LOCI HAVE BEEN IDENTIFIED BY CANDIDATE GENE APPROACHES, GENOME-WIDE ASSOCIATION STUDIES, AND META-ANALYSES, AS WELL AS FAMILIAL ASSOCIATION STUDIES. SUCH GENES ARE CTLA4, PTPN22, COL11A2, SERPINA1, AND THE MHC CLASS II GENE CLUSTER. THIS REVIEW HIGHLIGHTS THE CLINICAL, PATHOPHYSIOLOGICAL, AND GENETIC BACKGROUND OF GPA AND AIMS TO GIVE AN OVERVIEW OF RECENT EFFORTS TO IDENTIFY GPA SUSCEPTIBILITY GENES. WE POINT OUT THE GENETIC BASIS OF THE MAIN AUTOANTIGEN PR3 AND WHY IT IS SO DIFFICULT TO ESTABLISH A MURINE GPA MODEL. 2016 2 1484 28 DLEU2: A MEANINGFUL LONG NONCODING RNA IN ONCOGENESIS. BACKGROUND: LONG NON-CODING RNA (LNCRNA) WITH LITTLE OR NO CODING ABILITY HAS SHOWN A VARIETY OF BIOLOGICAL FUNCTIONS IN CANCER, INCLUDING EPIGENETIC REGULATION, DNA DAMAGE, REGULATION OF MICRORNAS, AND PARTICIPATION IN SIGNAL TRANSDUCTION PATHWAYS. LNCRNA CAN BE USED AS AN ONCOGENE AND TUMOR SUPPRESSOR GENE THROUGH TRANSCRIPTIONAL REGULATION IN CANCER. FOR EXAMPLE, THE OVER-EXPRESSED LNCRNA DLEU2 PROMOTES THE OCCURRENCE OF LARYNGEAL CANCER, LUNG CANCER, HEPATOCELLULAR CARCINOMA, ETC., AND INHIBITS THE PROGRESSION OF CHRONIC LYMPHOCYTIC LEUKEMIA. DELETED IN LYMPHOCYTIC LEUKEMIA 2 (DLEU2), AS ONE OF THE LONG NON-CODING RNAS, WAS FIRST FOUND IN CHRONIC LYMPHOBLASTIC LEUKEMIA AND DRAWN INTO THE PROGRESS OF INNUMERABLE CANCERS. THE MOLECULAR MECHANISM OF DLEU2 IN MULTIPLE TUMORS WILL BE REVEALED. METHODS: IN THIS REVIEW, CURRENT STUDIES ON THE BIOLOGICAL FUNCTIONS AND MECHANISMS OF DLEU2 IN TUMORS ARE SUMMARIZED AND ANALYZED; RELATED RESEARCHES ARE SYSTEMATICALLY RETRIEVED AND COLLECTED THROUGH PUBMED. RESULTS: DLEU2, A NOVEL CANCER-RELATED LNCRNA, HAS BEEN DEMONSTRATED TO BE ABNORMALLY EXPRESSED IN VARIOUS MALIGNANT TUMORS, INCLUDING LEUKEMIA, ESOPHAGEAL CANCER, LUNG CANCER, GLIOMA, HEPATOCELLULAR CARCINOMA, MALIGNANT PLEURAL MESOTHELIOMA, BLADDER CANCER, PANCREATIC CANCER, PHARYNX AND THROAT CANCER, RENAL CLEAR CELL CARCINOMA, BREAST CANCER, OSTEOSARCOMA. BESIDES, LNCRNA DLEU2 HAS BEEN SHOWN TO BE INVOLVED IN THE PROCESS OF PROLIFERATION, MIGRATION, INVASION AND INHIBITION OF APOPTOSIS OF CANCER CELLS. CONCLUSION: DUE TO THE BIOLOGICAL FUNCTIONS AND MECHANISMS INVOLVED IN DLEU2, IT MAY REPRESENT AN AVAILABLE BIOMARKER OR POTENTIAL THERAPEUTIC TARGET IN A VARIETY OF MALIGNANT TUMORS. 2021 3 4964 41 PATHOGENETIC AND CLINICAL ASPECTS OF ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODY-ASSOCIATED VASCULITIDES. ANTI-NEUTROPHIL CYTOPLASMIC AUTOANTIBODIES (ANCA) TARGETING PROTEINASE 3 (PR3) AND MYELOPEROXIDASE EXPRESSED BY INNATE IMMUNE CELLS (NEUTROPHILS AND MONOCYTES) ARE SALIENT DIAGNOSTIC AND PATHOGENIC FEATURES OF SMALL VESSEL VASCULITIS, COMPRISING GRANULOMATOSIS WITH POLYANGIITIS (GPA), MICROSCOPIC POLYANGIITIS, AND EOSINOPHILIC GPA. GENETIC STUDIES SUGGEST THAT ANCA-ASSOCIATED VASCULITIDES (AAV) CONSTITUTE SEPARATE DISEASES, WHICH SHARE COMMON IMMUNOLOGICAL AND PATHOLOGICAL FEATURES, BUT ARE OTHERWISE HETEROGENEOUS. THE SUCCESSFUL THERAPEUTIC USE OF ANTI-CD20 ANTIBODIES EMPHASIZES THE PROMINENT ROLE OF ANCA AND POSSIBLY OTHER AUTOANTIBODIES IN THE PATHOGENESIS OF AAV. HOWEVER, TO ELUCIDATE CAUSAL EFFECTS IN AAV, A BETTER UNDERSTANDING OF THE COMPLEX INTERPLAY LEADING TO THE EMERGENCE OF B LYMPHOCYTES THAT PRODUCE PATHOGENIC ANCA REMAINS A CHALLENGE. DIFFERENT SCENARIOS SEEM POSSIBLE; E.G., THE BREAK OF TOLERANCE INDUCED BY A SHIFT FROM NON-PATHOGENIC TOWARD PATHOGENIC AUTOANTIGEN EPITOPES IN INFLAMED TISSUE. THIS REVIEW GIVES A BRIEF OVERVIEW ON CURRENT KNOWLEDGE ABOUT GENETIC AND EPIGENETIC FACTORS, BARRIER DYSFUNCTION AND CHRONIC NON-RESOLVING INFLAMMATION, NECRO-INFLAMMATORY AUTO-AMPLIFICATION OF CELLULAR DEATH AND INFLAMMATION, ALTERED AUTOANTIGEN PRESENTATION, ALTERNATIVE COMPLEMENT PATHWAY ACTIVATION, ALTERATIONS WITHIN PERIPHERAL AND INFLAMED TISSUE-RESIDING T- AND B-CELL POPULATIONS, ECTOPIC LYMPHOID TISSUE NEOFORMATION, THE CHARACTERIZATION OF PR3-SPECIFIC T-CELLS, PROPERTIES OF ANCA, LINKS BETWEEN AUTOIMMUNE DISEASE AND INFECTION-TRIGGERED PATHOLOGY, AND ANIMAL MODELS IN AAV. 2018 4 740 33 CANCER/TESTIS ANTIGENS: EXPRESSION, REGULATION, TUMOR INVASION, AND USE IN IMMUNOTHERAPY OF CANCERS. CANCER/TESTIS ANTIGENS (CTAS) ARE NAMED BASED ON THEIR EXPRESSION PATTERN THAT IS RESTRICTED IN A NUMBER OF NORMAL AND ABNORMAL TISSUES. TUMOR CELLS FREQUENTLY EXPRESS ANTIGENS WHOSE EXPRESSION IS TYPICALLY RESTRICTED TO GERM CELLS. THEIR UNIQUE EXPRESSION PATTERN IS GUARANTEED BY PRECISE EPIGENETIC REGULATORY MECHANISMS. BECAUSE OF THEIR TUMOR-LIMITED, HIGH IMMUNOGENICITY, AND BIASED EXPRESSION, DISCOVERY OF THESE MOLECULES PROVIDES UNPRECEDENTED OPPORTUNITIES FOR FURTHER RESEARCH AND CLINICAL DEVELOPMENT IN THE FIELD OF CANCER DIAGNOSIS AND IMMUNOTHERAPY. EVOLVING EVIDENCE REVEALS THAT A NUMBER OF CTAS STIMULATE EPITHELIAL MESENCHYMAL TRANSITION (EMT) AND GENERATION OF CANCER STEM-LIKE CELLS, INTENSIFYING METASTASIS, INVASION, AND TUMORIGENESIS. BASED ON THESE FEATURES, CTAS ATTRACT ATTENTION TO BE CONSIDERED AS IDEAL TARGETS FOR DEVELOPING SEVERAL CLINICAL TRIALS, MANY OF THEM CONCENTRATING ON CTA VACCINE THERAPY. ACCORDING TO RECENT PRACTICAL CLINICAL INTEREST, MORE CHARACTERIZATIONS OF CTA REGULATION ARE IDENTIFIED. CTA EXPRESSION HAS BEEN DEMONSTRATED IN A VARIETY OF HUMAN CANCER TISSUES, AND SOME OF THEM HAVE BEEN FOUND TO ELICIT HUMORAL AND/OR CELLULAR IMMUNE RESPONSES IN CANCER PATIENTS. CTAS ARE BRILLIANT TARGETS FOR ANTICANCER DRUG DISCOVERY, TARGETED TUMOR THERAPY, AND DIAGNOSTIC BIOMARKERS, FURTHERMORE, VALUED GENES IN THE STUDY OF IMMUNOTHERAPY, PROMOTING TUMORIGENESIS, AND MALIGNANT PROGRESSION. THIS REVIEW OUTLINES AND CATEGORIZES OUR CURRENT UNDERSTANDING OF THE COMPLEX AND BIASED PROCESS OF CTAS MRNA AND PROTEIN EXPRESSION IN CANCER, AND SUPPLIES THE MOST RECENT INFORMATION ON THEIR REGULATION AND FUNCTION. BESIDES, A CONCISE SYNOPSIS OF THE MAJOR CLINICAL TRIALS INVOLVING CTAS, AS THERAPEUTIC AVENUES, IS DISCUSSED. ABBREVIATIONS: AIRE: AUTOIMMUNE REGULATOR; CAMP: CYCLIC ADENOSINE 3',5'-CYCLIC MONOPHOSPHATE; CEA: CARCINOEMBRYONIC ANTIGEN; CML: CHRONIC MYELOID LEUKEMIA; CREB: CYCLICAMP RESPONSE ELEMENT BINDING; CSCS: CANCER STEM CELLS; CTAS: CANCER/TESTIS ANTIGENS; CTL: CYTOTOXIC T LYMPHOCYTE; DCS: DENDRITIC CELLS; EMT: EPITHELIAL-MESENCHYMAL TRANSITION; ERK: EXTRACELLULAR SIGNAL-REGULATED KINASE; ESCC: ESOPHAGEAL SQUAMOUS CELL CARCINOMA; ETS: E26 TRANSFORMATION-SPECIFIC; HIS: HISTIDINE; HLA: HUMAN LEUKOCYTE ANTIGEN; HNSCC: HEAD AND NECK SQUAMOUS CELL CARCINOMA; IFN-GAMMA: INTERFERON-GAMMA; IHC: IMMUNOHISTOCHEMISTRY; IL-7: INTERLEUKIN7; MHC: MAJOR HISTOCOMPATIBILITY COMPLEX; MMP2: MATRIX METALLOPROTEINASE 2; MTECS: MEDULLARY THYMUS EPITHELIAL CELLS; MUC1: MUCIN 1; NSCLC: NON-SMALL CELL LUNG CANCER; PRAME: PREFERENTIALLY EXPRESSED ANTIGEN IN MELANOMA; RDA: REPRESENTATIONAL DIFFERENCE ANALYSIS; SEREX: SEROLOGICAL ANALYSIS OF CDNA EXPRESSION; SSX: SYNOVIAL SARCOMA X CHROMOSOME; TAAS: TUMOR-ASSOCIATED ANTIGENS; TCR: T-CELL RECEPTOR; TCGA: THE CANCER GENOME ATLAS; TGF-BETA: TRANSFORMING GROWTH FACTOR-BETA. 2016 5 2556 26 EPIGENETICS IN RHEUMATOID ARTHRITIS. EPIGENETICS IS A STEADILY GROWING RESEARCH AREA. IN MANY HUMAN DISEASES, ESPECIALLY IN CANCERS, BUT ALSO IN AUTOIMMUNE DISEASES, EPIGENETIC ABERRATIONS HAVE BEEN FOUND. RHEUMATOID ARTHRITIS IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION AND DESTRUCTION OF SYNOVIAL JOINTS. EVEN THOUGH THE ETIOLOGY IS NOT YET FULLY UNDERSTOOD, RHEUMATOID ARTHRITIS IS GENERALLY CONSIDERED TO BE CAUSED BY A COMBINATION OF GENETIC PREDISPOSITION, DEREGULATED IMMUNOMODULATION, AND ENVIRONMENTAL INFLUENCES. TO GAIN A BETTER UNDERSTANDING OF THIS DISEASE, RESEARCHERS HAVE BECOME INTERESTED IN STUDYING EPIGENETIC CHANGES IN RHEUMATOID ARTHRITIS. HERE, WE WANT TO REVIEW THE CURRENT KNOWLEDGE ON EPIGENETICS IN RHEUMATOID ARTHRITIS. 2010 6 4334 19 MICRORNAS: NOVEL DIAGNOSTIC AND THERAPEUTIC TOOLS FOR PANCREATIC DUCTAL ADENOCARCINOMA? PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS KNOWN FOR ITS VERY POOR OVERALL PROGNOSIS, MAKING TOOLS FOR EARLY DIAGNOSIS AND NEW THERAPEUTIC MODALITIES URGENTLY NEEDED. MICRORNAS (MIRNAS), ENDOGENOUS NONCODING RNA MOLECULES OF APPROXIMATELY 22 NT, HAVE GAINED ATTENTION AS AN EPIGENETIC COMPONENT INVOLVED IN THE DEVELOPMENT OF MANY CANCERS, INCLUDING PDAC. MIRNA EXPRESSION PROFILES OF VARYING PANCREATIC TISSUES HAVE IDENTIFIED A NUMBER OF DIFFERENTIALLY EXPRESSED MIRNAS AND SEEM TO BE ABLE TO DIFFERENTIATE BETWEEN THREE TISSUES OF CLINICAL IMPORTANCE: NORMAL PANCREAS, CHRONIC PANCREATITIS, AND PDAC. THIS ARTICLE GATHERS OUR CURRENT KNOWLEDGE OF DIFFERENTIALLY EXPRESSED MIRNAS IN PANCREATIC TISSUES WITH RELEVANCE TO PDAC AND PRESENTS POTENTIAL DIAGNOSTIC AND THERAPEUTIC OPPORTUNITIES. 2009 7 1726 30 DYSREGULATION OF LNCRNAS IN RHEUMATOID ARTHRITIS: BIOMARKERS, PATHOGENESIS AND POTENTIAL THERAPEUTIC TARGETS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE OF UNKNOWN ETIOLOGY, MAINLY MANIFESTED BY PERSISTENT ABNORMAL PROLIFERATION OF FIBROBLAST-LIKE SYNOVIOCYTES (FLSS), INFLAMMATION, SYNOVIAL HYPERPLASIA AND CARTILAGE EROSION, ACCOMPANIED BY JOINT SWELLING AND JOINT DESTRUCTION. ABNORMAL EXPRESSION OR FUNCTION OF LONG NONCODING RNAS (LNCRNAS) ARE CLOSELY RELATED TO HUMAN DISEASES, INCLUDING CANCERS, MENTAL DISEASES, AUTOIMMUNE DISEASES AND OTHERS. THE ABNORMAL SEQUENCE AND SPATIAL STRUCTURE OF LNCRNAS, THE DISORDER EXPRESSION AND THE ABNORMAL INTERACTION WITH THE BINDING PROTEIN WILL LEAD TO THE CHANGE OF GENE EXPRESSION IN THE WAY OF EPIGENETIC MODIFICATION. INCREASING EVIDENCE DEMONSTRATED THAT LNCRNAS WERE INVOLVED IN THE ACTIVATION OF FLSS, WHICH PLAYED A KEY ROLE IN THE PATHOGENESIS OF RA. IN THIS REVIEW, THE RESEARCH PROGRESS OF LNCRNAS IN THE PATHOGENESIS OF RA WAS SYSTEMATICALLY SUMMARIZED, INCLUDING THE ROLE OF LNCRNAS IN THE DIAGNOSIS OF RA, THE REGULATORY MECHANISM OF LNCRNAS IN THE PATHOGENESIS OF RA, AND THE INTERVENTION ROLE OF LNCRNAS IN THE TREATMENT OF RA. FURTHERMORE, THE ACTIVATED SIGNAL PATHWAYS, THE ROLE OF DNA METHYLATION AND OTHER MECHANISM HAVE ALSO BEEN OVERVIEW IN THIS REVIEW. 2021 8 2876 29 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 9 3170 28 GUT INFLAMMATION AND TUMORIGENESIS: EVERY SITE HAS A DIFFERENT TALE TO TELL. GUT INFLAMMATION HAS BEEN CORRELATED WITH CANCEROGENESIS BY DISRUPTING GASTROINTESTINAL HOMEOSTASIS. NUMEROUS CHRONIC INFLAMMATORY DISORDERS OF THE TUBULAR GASTROINTESTINAL TRACT (E.G., GASTROESOPHAGEAL REFLUX DISEASE, HELICOBACTER PYLORI-INDUCED AND AUTOIMMUNE CHRONIC GASTRITIS, CELIAC DISEASE, AND INFLAMMATORY BOWEL DISEASES) HAVE BEEN VARIABLY ASSOCIATED WITH AN INCREASED NEOPLASTIC RISK. GASTROINTESTINAL INFLAMMATION-INDUCED NEOPLASMS INCLUDE EPITHELIAL TUMORS (ESOPHAGEAL SQUAMOUS CELL CARCINOMA AND ADENOCARCINOMA, GASTRIC ADENOCARCINOMA AND NEUROENDOCRINE TUMORS, SMALL BOWEL ADENOCARCINOMA AND NEUROENDOCRINE TUMORS, AND COLORECTAL CANCER) AND LYMPHOMAS (SUCH AS GASTRIC MARGINAL ZONE LYMPHOMAS AND ENTEROPATHY-ASSOCIATED T CELL LYMPHOMA). IN THE LAST DECADES, NUMEROUS STUDIES HAVE INVESTIGATED THE PATHOGENETIC MECHANISMS AND THE MICROENVIRONMENTAL/MICROBIOME CHANGES THAT TRIGGER GENETIC AND/OR EPIGENETIC ALTERATIONS EVENTUALLY LEADING TO TUMORIGENESIS, OFTEN THROUGH A HISTOLOGICALLY RECOGNIZABLE INFLAMMATION-DYSPLASIA-CARCINOMA CANCEROGENIC SEQUENCE. IN THE PRESENT REVIEW, AN OVERVIEW OF THE CURRENT KNOWLEDGE ON THE LINKS BETWEEN INFLAMMATORY DISEASES AND NEOPLASMS OF THE TUBULAR GI TRACT, APPLYING A SITE-BY-SITE APPROACH, IS PROVIDED. 2023 10 2720 41 EXOSOMAL MIRNAS IN HEPATITIS B VIRUS RELATED LIVER DISEASE: A NEW HOPE FOR BIOMARKER. THE WORLD HEALTH ORGANISATION, IN ITS 2019 PROGRESS REPORT ON HIV, VIRAL HEPATITIS AND STDS INDICATES THAT 257 MILLION PEOPLE ARE AFFLICTED WITH CHRONIC HBV INFECTIONS, OF WHICH, 1 MILLION PATIENTS LOSE THEIR LIVES EVERY YEAR DUE TO HBV RELATED CHRONIC LIVER DISEASES INCLUDING SERIOUS COMPLICATIONS SUCH AS LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. THE COURSE OF HBV INFECTION AND ASSOCIATED LIVER INJURY DEPEND ON SEVERAL HOST FACTORS, GENETIC VARIABILITY OF THE VIRUS, AND THE HOST VIRAL INTERPLAY. THE CHALLENGE OF MEDICAL SCIENCE IS THE EARLY DIAGNOSIS/IDENTIFICATION OF THE POTENTIAL FOR DEVELOPMENT OF FATAL COMPLICATIONS LIKE LIVER CIRRHOSIS AND HCC SO THAT TIMELY MEDICAL INTERVENTION CAN IMPROVE THE CHANCES OF SURVIVAL. CURRENTLY, NEITHER THE VACCINATION REGIME NOR THE DIAGNOSTIC METHODS ARE COMPLETELY EFFECTIVE AS REFLECTED IN THE HIGH NUMBER OF ANNUAL DEATHS. IT IS EVIDENT FROM NUMEROUS PUBLICATIONS THAT MICRORNAS (MIRNAS) ARE THE CRITICAL REGULATORS OF GENE EXPRESSION AND VARIOUS CELLULAR PROCESSES LIKE PROLIFERATION, DEVELOPMENT, DIFFERENTIATION, APOPTOSIS AND TUMORIGENESIS. EXPRESSIONS OF THESE DIMINUTIVE RNAS ARE SIGNIFICANTLY AFFECTED IN CANCEROUS TISSUES AS A RESULT OF NUMEROUS GENOMIC AND EPIGENETIC MODIFICATIONS. EXOSOMES ARE MEMBRANE-DERIVED VESICLES (30-100 NM) SECRETED BY NORMAL AS WELL AS MALIGNANT CELLS, AND ARE PRESENT IN ALL BODY FLUIDS. THEY ARE RECOGNIZED AS CRITICAL MOLECULES IN INTERCELLULAR COMMUNICATION BETWEEN CELLS THROUGH HORIZONTAL TRANSFER OF INFORMATION VIA THEIR CARGO, WHICH INCLUDES SELECTIVE PROTEINS, MRNAS AND MIRNAS. EXOSOMAL MIRNAS ARE TRANSFERRED TO RECIPIENT CELLS WHERE THEY CAN REGULATE TARGET GENE EXPRESSION. THIS PROVIDES AN INSIGHT INTO THE ELEMENTARY BIOLOGY OF CANCER PROGRESSION AND THEREFORE THE DEVELOPMENT OF THERAPEUTIC APPROACHES. THIS CONCISE REVIEW OUTLINES VARIOUS ON-GOING RESEARCH ON MIRNA MEDIATED REGULATION OF HBV PATHOGENESIS WITH SPECIAL EMPHASIS ON ASSOCIATION OF EXOSOMAL MIRNA IN ADVANCED STAGE LIVER DISEASE LIKE HEPATOCELLULAR CARCINOMA. THIS REVIEW ALSO DISCUSSES THE POSSIBLE USE OF EXOSOMAL MIRNAS AS BIOMARKERS IN THE EARLY DETECTION OF HCC AND LIVER CIRRHOSIS. 2020 11 5372 38 RECENT ADVANCES IN UNDERSTANDING THE PATHOGENESIS OF RHEUMATOID ARTHRITIS: NEW TREATMENT STRATEGIES. RHEUMATOID ARTHRITIS (RA) IS CONSIDERED A CHRONIC SYSTEMIC, MULTI-FACTORIAL, INFLAMMATORY, AND PROGRESSIVE AUTOIMMUNE DISEASE AFFECTING MANY PEOPLE WORLDWIDE. WHILE PATIENTS SHOW VERY INDIVIDUAL COURSES OF DISEASE, WITH RA FOCUSING ON THE MUSCULOSKELETAL SYSTEM, JOINTS ARE OFTEN SEVERELY AFFECTED, LEADING TO LOCAL INFLAMMATION, CARTILAGE DESTRUCTION, AND BONE EROSION. TO PREVENT JOINT DAMAGE AND PHYSICAL DISABILITY AS ONE OF MANY SYMPTOMS OF RA, EARLY DIAGNOSIS IS CRITICAL. AUTO-ANTIBODIES PLAY A PIVOTAL CLINICAL ROLE IN PATIENTS WITH SYSTEMIC RA. AS BIOMARKERS, THEY COULD HELP TO MAKE A MORE EFFICIENT DIAGNOSIS, PROGNOSIS, AND TREATMENT DECISION. BESIDES AUTO-ANTIBODIES, SEVERAL OTHER FACTORS ARE INVOLVED IN THE PROGRESSION OF RA, SUCH AS EPIGENETIC ALTERATIONS, POST-TRANSLATIONAL MODIFICATIONS, GLYCOSYLATION, AUTOPHAGY, AND T-CELLS. UNDERSTANDING THE INTERPLAY BETWEEN THESE FACTORS WOULD CONTRIBUTE TO A DEEPER INSIGHT INTO THE CAUSES, MECHANISMS, PROGRESSION, AND TREATMENT OF THE DISEASE. IN THIS REVIEW, THE LATEST RA RESEARCH FINDINGS ARE DISCUSSED TO BETTER UNDERSTAND THE PATHOGENESIS, AND FINALLY, TREATMENT STRATEGIES FOR RA THERAPY ARE PRESENTED, INCLUDING BOTH CONVENTIONAL APPROACHES AND NEW METHODS THAT HAVE BEEN DEVELOPED IN RECENT YEARS OR ARE CURRENTLY UNDER INVESTIGATION. 2021 12 1114 33 COMMONALITIES AND DISPARITIES BETWEEN ENDOMETRIOSIS AND CHRONIC ENDOMETRITIS: THERAPEUTIC POTENTIAL OF NOVEL ANTIBIOTIC TREATMENT STRATEGY AGAINST ECTOPIC ENDOMETRIUM. CHRONIC ENDOMETRITIS (CE) IS A LOCAL MUCOSAL INFLAMMATORY DISORDER OF THE UTERINE LINING, WHICH IS HISTOPATHOLOGICALLY RECOGNIZED AS THE UNUSUAL INFILTRATION OF CD138(+) PLASMACYTES INTO THE ENDOMETRIAL STROMAL COMPARTMENT. ACCUMULATING BODY OF RESEARCH DOCUMENTED THAT CE IS ASSOCIATED WITH FEMALE INFERTILITY AND SEVERAL OBSTETRIC/NEONATAL COMPLICATIONS. THE MAJOR CAUSE OF CE IS THOUGHT TO BE INTRAUTERINE INFECTION REPRESENTED BY COMMON BACTERIA (ESCHERICHIA COLI, ENTEROCOCCUS FAECALIS, STREPTOCOCCUS, AND STAPHYLOCOCCUS), MYCOPLASMA/UREAPLASMA, AND MYCOBACTERIUM. ADDITIONALLY, LOCAL DYSBIOSIS IN THE FEMALE REPRODUCTIVE TRACT MAY BE INVOLVED IN THE ONSET AND DEVELOPMENT OF CE. ANTIBIOTIC TREATMENTS AGAINST THESE MICROORGANISMS ARE EFFECTIVE IN THE ELIMINATION OF ENDOMETRIAL STROMAL PLASMACYTES IN THE AFFECTED PATIENTS. MEANWHILE, ENDOMETRIOSIS IS A COMMON FEMALE REPRODUCTIVE TRACT DISEASE CHARACTERIZED BY ENDOMETRIOTIC TISSUES (ECTOPIC ENDOMETRIUM) GROWING OUTSIDE THE UTERUS AND POTENTIALLY CAUSES CHRONIC PELVIC SYMPTOMS (DYSMENORRHEA, DYSPAREUNIA, DYSCHEZIA, AND DYSURIA), INFERTILITY, AND OVARIAN CANCERS. ENDOMETRIOSIS INVOLVES ENDOCRINOLOGICAL, GENETIC, AND EPIGENETIC FACTORS IN ITS ETIOLOGY AND PATHOGENESIS. RECENT STUDIES FOCUS ON IMMUNOLOGICAL, INFLAMMATORY, AND INFECTIOUS ASPECTS OF ENDOMETRIOSIS AND DEMONSTRATE SEVERAL COMMON CHARACTERISTICS BETWEEN ENDOMETRIOSIS AND CE. THIS REVIEW AIMED TO BETTER UNDERSTAND THE IMMUNOLOGICAL AND MICROBIAL BACKGROUNDS UNDERLYING ENDOMETRIOSIS AND CE AND LOOK INTO THE THERAPEUTIC POTENTIAL OF THE NOVEL ANTIBIOTIC TREATMENT STRATEGY AGAINST ENDOMETRIOSIS IN LIGHT OF ENDOMETRIAL INFECTIOUS DISEASE. 2023 13 2731 25 EXPLORING THE COMPLEX RELATIONSHIP BETWEEN MICROBIOTA AND SYSTEMIC LUPUS ERYTHEMATOSUS. PURPOSE OF REVIEW: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY VARIOUS AUTOANTIBODIES AND MULTI-ORGAN. MICROBIOTA DYSBIOSIS IN THE GUT, SKIN, ORAL, AND OTHER SURFACES HAS A SIGNIFICANT IMPACT ON SLE DEVELOPMENT. THIS ARTICLE SUMMARIZES RELEVANT RESEARCH AND PROVIDES NEW MICROBIOME-RELATED STRATEGIES FOR EXPLORING THE MECHANISMS AND TREATING PATIENTS WITH SLE. RECENT FINDINGS: SLE PATIENTS HAVE DISRUPTIONS IN MULTIPLE MICROBIOMES, WITH THE GUT MICROBIOTA (BACTERIA, VIRUSES, AND FUNGI) AND THEIR METABOLITES BEING THE MOST THOROUGHLY RESEARCHED. THIS DYSBIOSIS CAN PROMOTE SLE PROGRESSION THROUGH MECHANISMS SUCH AS THE LEAKY GUT, MOLECULAR MIMICRY, AND EPIGENETIC REGULATION. NOTWITHSTANDING STUDY CONSTRAINTS ON THE RELATIONSHIP BETWEEN MICROBIOTA AND SLE, SPECIFIC INTERVENTIONS TARGETING THE GUT MICROBIOTA, SUCH AS PROBIOTICS, DIETARY MANAGEMENT, AND FECAL MICROBIOTA TRANSPLANTATION, HAVE EMERGED AS PROMISING SLE THERAPEUTICS. 2023 14 1257 32 CURRENT TRENDS IN EPIGENETIC, CELLULAR AND MOLECULAR PATHWAYS IN MANAGEMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS IS A SYSTEMIC CHRONIC POLYARTICULAR AUTOIMMUNE DISORDER OF JOINTS AND JOINT MEMBRANE MAINLY AFFECTING FEET AND HANDS. THE PATHOLOGICAL MANIFESTATION OF THE DISEASE INCLUDES INFILTRATION OF IMMUNE CELLS, HYPERPLASIA OF THE LINING OF SYNOVIUM, FORMATION OF PANNUS AND BONE AND CARTILAGE DESTRUCTION. IF LEFT UNTREATED, THE APPEARANCE OF SMALL FOCAL NECROSIS, ADHESION OF GRANULATION, AND FORMATION OF FIBROUS TISSUE ON THE SURFACE OF ARTICULAR CARTILAGE IS NOTED. THE DISEASE PRIMARILY AFFECTS NEARLY 1% OF THE POPULATION GLOBALLY, WOMEN BEING MORE AFFECTED THAN MEN WITH A RATIO 2:1 AND CAN INITIATE REGARDLESS OF ANY AGE. THE SYNOVIAL FIBROBLAST IN RHEUMATOID ARTHRITIS INDIVIDUALS EXHIBITS AN AGGRESSIVE PHENOTYPE WHICH UPREGULATES THE MANIFESTATION OF PROTOONCOGENES, ADHESIVE COMPOUNDS, INFLAMMATORY CYTOKINES AND MATRIX-DETERIORATING ENZYMES. APART FROM THE INFLAMMATORY EFFECTS OF CYTOKINES, CHEMOKINES ARE ALSO NOTED TO INDUCE SWELLING AND PAIN IN ARTHRITIC INDIVIDUALS BY RESIDING IN SYNOVIAL MEMBRANE AND FORMING PANNUS. THE CURRENT TREATMENT OF RHEUMATOID ARTHRITIS INCLUDES TREATMENT WITH NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, DISEASE-MODIFYING ANTIRHEUMATIC DRUGS, TREATMENT WITH BIOLOGICS SUCH AS INHIBITORS OF TNF-ALPHA, INTERLEUKINS, PLATELET ACTIVATING FACTOR, ETC. WHICH PROVIDES SIGNIFICANT RELIEF FROM SYMPTOMS AND AIDS IN MANAGEMENT OF THE DISEASE. THE CURRENT REVIEW HIGHLIGHTS THE PATHOGENESIS INVOLVED IN THE ONSET OF RHEUMATOID ARTHRITIS AND ALSO COVERS EPIGENETIC, CELLULAR AND MOLECULAR PARAMETERS ASSOCIATED WITH IT TO AID BETTER AND ADVANCED THERAPEUTIC APPROACHES FOR MANAGEMENT OF THE DEBILITATING DISEASE. 2023 15 6105 33 THE EMERGING ROLE OF LNCRNA FENDRR IN MULTIPLE CANCERS: A REVIEW. LONG NONCODING RNAS (LNCRNAS) ARE PROMINENT AS CRUCIAL REGULATORS OF TUMOR ESTABLISHMENT AND ARE REPEATEDLY DYSREGULATED IN MULTIPLE CANCERS. THEREFORE, LNCRNAS HAVE BEEN IDENTIFIED TO PLAY AN ESSENTIAL FUNCTION IN CARCINOGENESIS AND PROGRESSION OF CANCER AT GENETIC AND EPIGENETIC LEVELS. FENDRR (FETAL-LETHAL NONCODING DEVELOPMENTAL REGULATORY RNA) AS A LNCRNA IS A HALLMARK OF VARIOUS MALIGNANCIES. FENDRR IS CRUCIAL FOR MULTIPLE ORGANS' DEVELOPMENT, SUCH AS THE LUNG AND HEART. THE EFFECTS OF FENDRR UNDER SIGNALING PATHWAYS IN DIFFERENT CANCERS HAVE BEEN IDENTIFIED. IN ADDITION, IT HAS BEEN VERIFIED THAT FENDRR CAN AFFECT THE DEVELOPMENT AND PROGRESSION OF VARIOUS CANCERS. IN ADDITION, FENDRR EXPRESSION HAS BEEN ASSOCIATED WITH EPIGENETIC REGULATION OF TARGET GENES PARTICIPATING IN TUMOR IMMUNITY. FURTHERMORE, FENDRR DOWNREGULATION WAS OBSERVED IN VARIOUS TYPES OF CANCERS, INCLUDING COLORECTAL CANCER, GASTRIC CANCER, PANCREATIC CANCER, CHOLANGIOCARCINOMA, LIVER CANCER, GALLBLADDER CANCER, LUNG CANCER, BREAST CANCER, ENDOMETRIAL CANCER, PROSTATE CANCER, CHRONIC MYELOID LEUKEMIA, OSTEOSARCOMA, AND CUTANEOUS MALIGNANT MELANOMA CELLS. HERE, WE REVIEW THE BIOLOGICAL FUNCTIONS AND MOLECULAR MECHANISMS OF FENDRR IN SEVERAL CANCERS, AND WE WILL DISCUSS ITS POTENTIAL AS A CANCER BIOMARKER AND AS A PROBABLE OPTION FOR CANCER TREATMENT. 2023 16 5265 29 PROMISING THERAPEUTIC TARGETS FOR TREATMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A SYSTEMIC POLY-ARTICULAR CHRONIC AUTOIMMUNE JOINT DISEASE THAT MAINLY DAMAGES THE HANDS AND FEET, WHICH AFFECTS 0.5% TO 1.0% OF THE POPULATION WORLDWIDE. WITH THE SUSTAINED DEVELOPMENT OF DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS), SIGNIFICANT SUCCESS HAS BEEN ACHIEVED FOR PREVENTING AND RELIEVING DISEASE ACTIVITY IN RA PATIENTS. UNFORTUNATELY, SOME PATIENTS STILL SHOW LIMITED RESPONSE TO DMARDS, WHICH PUTS FORWARD NEW REQUIREMENTS FOR SPECIAL TARGETS AND NOVEL THERAPIES. UNDERSTANDING THE PATHOGENETIC ROLES OF THE VARIOUS MOLECULES IN RA COULD FACILITATE DISCOVERY OF POTENTIAL THERAPEUTIC TARGETS AND APPROACHES. IN THIS REVIEW, BOTH EXISTING AND EMERGING TARGETS, INCLUDING THE PROTEINS, SMALL MOLECULAR METABOLITES, AND EPIGENETIC REGULATORS RELATED TO RA, ARE DISCUSSED, WITH A FOCUS ON THE MECHANISMS THAT RESULT IN INFLAMMATION AND THE DEVELOPMENT OF NEW DRUGS FOR BLOCKING THE VARIOUS MODULATORS IN RA. 2021 17 6009 34 THE ANTI-INFLAMMATORY MEDIATOR, VASOACTIVE INTESTINAL PEPTIDE, MODULATES THE DIFFERENTIATION AND FUNCTION OF TH SUBSETS IN RHEUMATOID ARTHRITIS. GENETIC BACKGROUND, EPIGENETIC MODIFICATIONS, AND ENVIRONMENTAL FACTORS TRIGGER AUTOIMMUNE RESPONSE IN RHEUMATOID ARTHRITIS (RA). SEVERAL PATHOGENIC INFECTIONS HAVE BEEN RELATED TO THE ONSET OF RA AND MAY CAUSE AN INADEQUATE IMMUNOLOGICAL TOLERANCE TOWARDS CRITICAL SELF-ANTIGENS LEADING TO CHRONIC JOINT INFLAMMATION AND AN IMBALANCE BETWEEN DIFFERENT T HELPER (TH) SUBSETS. VASOACTIVE INTESTINAL PEPTIDE (VIP) IS A MEDIATOR THAT MODULATES ALL THE STAGES COMPRISED BETWEEN THE ARRIVAL OF PATHOGENS AND TH CELL DIFFERENTIATION IN RA THROUGH ITS KNOWN ANTI-INFLAMMATORY AND IMMUNOMODULATORY ACTIONS. THIS "NEUROIMMUNOPEPTIDE" MODULATES THE PATHOGENIC ACTIVITY OF DIVERSE CELL SUBPOPULATIONS INVOLVED IN RA AS LYMPHOCYTES, FIBROBLAST-LIKE SYNOVIOCYTES (FLS), OR MACROPHAGES. IN ADDITION, VIP DECREASES THE EXPRESSION OF PATTERN RECOGNITION RECEPTOR (PRR) SUCH AS TOLL-LIKE RECEPTORS (TLRS) IN FLS FROM RA PATIENTS. THESE RECEPTORS ACT AS SENSORS OF PATHOGEN-ASSOCIATED MOLECULAR PATTERN (PAMP) AND DAMAGE-ASSOCIATED MOLECULAR PATTERN (DAMP) CONNECTING THE INNATE AND ADAPTIVE IMMUNE SYSTEM. MOREOVER, VIP MODULATES THE IMBALANCE BETWEEN TH SUBSETS IN RA, DECREASING PATHOGENIC TH1 AND TH17 SUBSETS AND FAVORING TH2 OR TREG PROFILE DURING THE DIFFERENTIATION/POLARIZATION OF NAIVE OR MEMORY TH CELLS. FINALLY, VIP REGULATES THE PLASTICITY BETWEEN THESES SUBSETS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF VIP EFFECTS ON THE AFOREMENTIONED FEATURES OF RA PATHOLOGY. 2018 18 3173 27 GUT MICROBIOTA-MICRORNA INTERACTIONS IN ANKYLOSING SPONDYLITIS. ANKYLOSING SPONDYLITIS (AS) IS A CHRONIC AUTOIMMUNE INFLAMMATORY DISABILITY THAT IS PART OF THE RHEUMATIC DISEASE GROUP OF SPONDYLOARTHROPATHIES. AS COMMONLY INFLUENCES THE JOINTS OF THE AXIAL SKELETON. THE CONTRIBUTIONS TO AS PATHOGENESIS OF GENETIC SUSCEPTIBILITY (PARTICULARLY HLA-B27 AND ERAP-1) AND EPIGENETIC MODIFICATIONS, LIKE NON-CODING RNAS, AS WELL AS ENVIRONMENTAL FACTORS, HAVE BEEN INVESTIGATED OVER THE LAST FEW YEARS. BUT THE FUNDAMENTAL ETIOLOGY OF AS REMAINS ELUSIVE TO DATE. THE EVIDENCE SUMMARIZED HERE INDICATES THAT IN THE IMMUNOPATHOGENESIS OF AS, MICRORNAS AND THE GUT MICROBIOME PERFORM CRITICAL FUNCTIONS. WE DISCUSS SIGNIFICANT ADVANCES IN THE IMMUNOLOGICAL MECHANISMS UNDERLYING AS AND ADDRESS POTENTIAL CROSS-TALK BETWEEN THE GUT MICROBIOME AND HOST MICRORNAS. THIS CRITICAL INTERACTION IMPLICATES A CO-EVOLUTIONARY SYMBIOTIC LINK BETWEEN HOST IMMUNITY AND THE GUT MICROBIOME. 2021 19 1051 32 CLINICAL IMPLICATIONS OF EXOSOME-DERIVED NONCODING RNAS IN LIVER. EXOSOMES, ONE OF THREE MAIN TYPES OF EXTRACELLULAR VESICLES, ARE ~30-100 NM IN DIAMETER AND HAVE A LIPID BILAYER MEMBRANE. THEY ARE WIDELY DISTRIBUTED IN ALMOST ALL BODY FLUIDS. EXOSOMES HAVE THE POTENTIAL TO REGULATE UNKNOWN CELLULAR AND MOLECULAR MECHANISMS IN INTERCELLULAR COMMUNICATION, ORGAN HOMEOSTASIS, AND DISEASES. THEY ARE CRITICAL SIGNAL CARRIERS THAT TRANSFER NUCLEIC ACIDS, PROTEINS, LIPIDS, AND OTHER SUBSTANCES INTO RECIPIENT CELLS, PARTICIPATING IN CELLULAR SIGNAL TRANSDUCTION AND MATERIAL EXCHANGE. NCRNAS ARE NON-PROTEIN-CODING GENES THAT ACCOUNT FOR OVER 90% OF THE GENOME AND INCLUDE MICRORNAS (MIRNAS), LONG NCRNAS (LNCRNAS), AND CIRCULAR RNAS (CIRCRNAS). NCRNAS ARE CRUCIAL FOR PHYSIOLOGICAL AND PATHOLOGICAL ACTIVITIES IN THE LIVER BY PARTICIPATING IN GENE TRANSCRIPTION, POSTTRANSCRIPTIONAL EPIGENETIC REGULATION, AND CELLULAR PROCESSES THROUGH INTERACTING WITH DNA, RNA, OR PROTEINS. RECENT EVIDENCE FROM BOTH CLINICAL AND PRECLINICAL STUDIES INDICATES THAT EXOSOME-DERIVED NONCODING RNAS (NCRNAS) ARE HIGHLY INVOLVED IN THE PROGRESSION OF ACUTE AND CHRONIC LIVER DISEASES BY REGULATING HEPATIC LIPID METABOLISM, INNATE IMMUNITY, VIRAL INFECTION, FIBROSIS, AND CANCER. THEREFORE, EXOSOME-DERIVED NCRNAS HAVE PROMISING POTENTIAL AND CLINICAL IMPLICATIONS FOR THE EARLY DIAGNOSIS, TARGETED THERAPY, AND PROGNOSIS OF LIVER DISEASES. 2022 20 2221 30 EPIGENETIC MODIFICATIONS IN RHEUMATOID ARTHRITIS, A REVIEW. RHEUMATOID ARTHRITIS IS AN AUTOIMMUNE DISEASE CHARACTERIZED BY CHRONIC JOINT INFLAMMATION AND PROGRESSIVE DESTRUCTION OF CARTILAGE AND BONE WHICH LEADS TO ULTIMATELY LOSS OF FUNCTION AND PAIN. ACTIVATED SYNOVIAL FIBROBLASTS ARE KEY EFFECTOR CELLS IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS. IN THE RECENT YEARS, EPIGENETIC CHANGES INCLUDING DNA METHYLATION, HISTONE ACETYLATION AND OTHER HISTONE MODIFICATIONS WERE IDENTIFIED THAT ARE ASSOCIATED WITH AN INTRINSIC ACTIVATION AND THE AGGRESSIVE PHENOTYPE OF THESE CELLS. SO FAR, NO THERAPIES TARGETING RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS EXIST. THIS REVIEW COMPRISES RECENT RESEARCH EFFORTS THAT PROPOSE EPIGENETIC MECHANISMS BEHIND THE ACTIVATION OF RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLASTS AND OTHER CELL TYPES. 2013