1 5495 149 REVIEW ON CIRCULAR RNAS AND NEW INSIGHTS INTO THEIR ROLES IN CANCER. CIRCULAR RNAS (CIRCRNAS) ARE A VERY INTERESTING CLASS OF CONSERVED SINGLE-STRANDED RNA MOLECULES DERIVED FROM EXONIC OR INTRONIC SEQUENCES BY PRECURSOR MRNA BACK-SPLICING. UNLIKE CANONICAL LINEAR RNAS, CIRCRNAS FORM COVALENTLY CLOSED, CONTINUOUS STABLE LOOPS WITHOUT A 5'END CAP AND 3'END POLY(A) TAIL, AND THEREFORE ARE RESISTANT TO EXONUCLEASE DIGESTION. THE MAJORITY OF CIRCRNAS ARE HIGHLY ABUNDANT, AND CONSERVED ACROSS DIFFERENT SPECIES WITH A TISSUE OR DEVELOPMENTAL-STAGE-SPECIFIC EXPRESSION. CIRCRNAS HAVE BEEN SHOWN TO PLAY IMPORTANT ROLES AS MICRORNA SPONGES, REGULATORS OF GENE SPLICING AND TRANSCRIPTION, RNA-BINDING PROTEIN SPONGES AND PROTEIN/PEPTIDE TRANSLATORS. EMERGING EVIDENCE REVEALS THAT CIRCRNAS FUNCTION IN VARIOUS HUMAN DISEASES, PARTICULARLY CANCERS, AND MAY FUNCTION AS BETTER PREDICTIVE BIOMARKERS AND THERAPEUTIC TARGETS FOR CANCER TREATMENT. IN CONSIDERATION OF THEIR POTENTIAL CLINICAL RELEVANCE, CIRCRNAS HAVE BECOME A NEW RESEARCH HOTSPOT IN THE FIELD OF TUMOR PATHOLOGY. IN THE PRESENT STUDY, THE CURRENT UNDERSTANDING OF THE BIOGENESIS, CHARACTERISTICS, DATABASES, RESEARCH METHODS, BIOLOGICAL FUNCTIONS SUBCELLULAR DISTRIBUTION, EPIGENETIC REGULATION, EXTRACELLULAR TRANSPORT AND DEGRADATION OF CIRCRNAS WAS DISCUSSED. IN PARTICULAR, THE MULTIPLE DATABASES AND METHODS INVOLVED IN CIRCRNA RESEARCH WERE FIRST SUMMARIZED, AND THE RECENT ADVANCES IN DETERMINING THE POTENTIAL ROLES OF CIRCRNAS IN TUMOR GROWTH, MIGRATION AND INVASION, WHICH RENDER CIRCRNAS BETTER PREDICTIVE BIOMARKERS, WERE DESCRIBED. FURTHERMORE, FUTURE PERSPECTIVES FOR THE CLINICAL APPLICATION OF CIRCRNAS IN THE MANAGEMENT OF PATIENTS WITH CANCER WERE PROPOSED, WHICH COULD PROVIDE NEW INSIGHTS INTO CIRCRNAS IN THE FUTURE. 2021 2 6004 32 THE AID DILEMMA: INFECTION, OR CANCER? ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID), WHICH IS BOTH ESSENTIAL AND SUFFICIENT FOR FORMING ANTIBODY MEMORY, IS ALSO LINKED TO TUMORIGENESIS. AID IS FOUND IN MANY B LYMPHOMAS, IN MYELOID LEUKEMIA, AND IN PATHOGEN-INDUCED TUMORS SUCH AS ADULT T CELL LEUKEMIA. ALTHOUGH THERE IS NO SOLID EVIDENCE THAT AID CAUSES HUMAN TUMORS, AID-TRANSGENIC AND AID-DEFICIENT MOUSE MODELS INDICATE THAT AID IS BOTH SUFFICIENT AND REQUIRED FOR TUMORIGENESIS. RECENTLY, AID'S ABILITY TO CLEAVE DNA HAS BEEN SHOWN TO DEPEND ON TOPOISOMERASE 1 (TOP1) AND A HISTONE H3K4 EPIGENETIC MARK. WHEN THE LEVEL OF TOP1 PROTEIN IS DECREASED BY AID ACTIVATION, IT INDUCES IRREVERSIBLE CLEAVAGE IN HIGHLY TRANSCRIBED TARGETS. THIS FINDING AND OTHERS LED TO THE IDEA THAT THERE IS AN EVOLUTIONARY LINK BETWEEN MEIOTIC RECOMBINATION AND CLASS SWITCH RECOMBINATION, WHICH SHARE H3K4 TRIMETHYL, TOPOISOMERASE, THE MRN COMPLEX, MISMATCH REPAIR FAMILY PROTEINS, AND EXONUCLEASE 3. AS TOP1 HAS RECENTLY BEEN SHOWN TO BE INVOLVED IN MANY TRANSCRIPTION-ASSOCIATED GENOME INSTABILITIES, IT IS LIKELY THAT AID TOOK ADVANTAGE OF BASIC GENOME INSTABILITY OR DIVERSIFICATION TO EVOLVE ITS MECHANISM FOR IMMUNE DIVERSITY. AID TARGETS ARE THEREFORE NOT HIGHLY SPECIFIC TO IMMUNOGLOBULIN GENES AND ARE RELATIVELY ABUNDANT, ALTHOUGH THEY HAVE STRICT REQUIREMENTS FOR TRANSCRIPTION-INDUCED H3K4 TRIMETHYL MODIFICATION AND REPETITIVE SEQUENCES PRONE TO FORMING NON-B STRUCTURES. INEVITABLY, AID-DEPENDENT CLEAVAGE TAKES PLACE IN NONIMMUNOGLOBULIN TARGETS AND EVENTUALLY CAUSES TUMORS. HOWEVER, BATTLES AGAINST INFECTION ARE WAGED IN THE CONTEXT OF ACUTE EMERGENCIES, WHILE TUMORIGENESIS IS RATHER A CHRONIC, LONG-TERM PROCESS. IN THE INTEREST OF SURVIVAL, VERTEBRATES MUST HAVE EVOLVED AID TO PREVENT INFECTION DESPITE ITS LONG-TERM RISK OF CAUSING TUMORIGENESIS. 2012 3 1021 34 CIRCULAR RNA AS AN EPIGENETIC REGULATOR IN CHRONIC LIVER DISEASES. CIRCULAR RNA (CIRCRNA) IS A TYPE OF NON-CODING RNA CHARACTERIZED BY A COVALENTLY CLOSED CONTINUOUS LOOP. CIRCRNA IS GENERATED BY PRE-MRNA THROUGH BACK-SPLICING AND IS PROBABLY CLEARED UP BY EXTRACELLULAR VESICLES. CIRCRNAS PLAY A PIVOTAL ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION AT TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL LEVELS. RECENTLY, CIRCRNAS HAVE BEEN DEMONSTRATED TO BE INVOLVED IN THE REGULATION OF LIVER HOMEOSTASIS AND DISEASES. HOWEVER, THE EPIGENETIC ROLE AND UNDERLYING MECHANISMS OF CIRCRNAS IN CHRONIC LIVER DISEASES REMAIN UNCLEAR. THIS REVIEW DISCUSSED THE ROLE OF CIRCRNAS IN NON-NEOPLASTIC CHRONIC LIVER DISEASES, INCLUDING ALCOHOLIC LIVER DISEASE (ALD), METABOLIC-ASSOCIATED FATTY LIVER DISEASE (MAFLD), VIRAL HEPATITIS, LIVER INJURY AND REGENERATION, LIVER CIRRHOSIS, AND AUTOIMMUNE LIVER DISEASE. THE REVIEW ALSO HIGHLIGHTED THAT FURTHER EFFORTS ARE URGENTLY NEEDED TO DEVELOP CIRCRNAS AS NOVEL DIAGNOSTICS AND THERAPEUTICS FOR CHRONIC LIVER DISEASES. 2021 4 1737 41 EARLY DETECTION OF ACCELERATED AGING AND CELLULAR DECLINE (AACD): A CONSENSUS STATEMENT. THE CELLULAR HALLMARKS OF ACCELERATED AGING AND THEIR CLINICAL EXPRESSION MAY BE GROUPED USING THE TERMS 'ACCELERATED AGING AND CELLULAR DECLINE' (AACD) AND/OR 'AGE-ASSOCIATED CELLULAR DECLINE'. THIS CONSTRUCT IS DESIGNED TO CAPTURE THE BIOLOGICAL BACKGROUND PREDISPOSING THE DEVELOPMENT OF AGE-RELATED CONDITIONS. BY CLASSIFYING RISK FACTORS, EARLY INDICATORS, AND CLINICAL DIFFERENTIATORS OF AACD THROUGH EXPERT CONSENSUS, THIS STUDY AIMED TO IDENTIFY THE SIGNS, SYMPTOMS, AND MARKERS INDICATIVE OF AACD. IN DOING SO, THIS WORK PAVES THE WAY FOR FUTURE IMPLEMENTATION OF THE AACD CONCEPT IN THE CLINICAL AND RESEARCH SETTINGS. AN INTERDISCIPLINARY PANEL OF EXPERTS WITH CLINICAL AND RESEARCH EXPERTISE WAS SELECTED TO PARTICIPATE IN A VIRTUAL WORKSHOP TO DISCUSS AACD. A MODIFIED NOMINAL GROUP TECHNIQUE WAS USED TO ESTABLISH CONSENSUS AMONG THE GROUP. AN EXTENDED GROUP OF INTERNATIONAL EXPERTS CRITICALLY REVIEWED AN EARLY DRAFT OF THE MANUSCRIPT, AND THEIR FEEDBACK WAS THEN INCORPORATED INTO THE MODEL. EXPERTS IDENTIFIED 13 FACTORS PREDISPOSING TO OR CLINICALLY MANIFESTING AACD. AMONG THESE, CHRONIC DISEASES, OBESITY, AND UNFAVORABLE GENETIC BACKGROUND WERE CONSIDERED AS THE MOST IMPORTANT. THERE WAS A CONSENSUS THAT A GRADUAL AND NONSPECIFIC DEVELOPMENT OFTEN CHARACTERIZES AACD, MAKING ITS CLINICAL DETECTION POTENTIALLY CHALLENGING. IN ADDITION, SIGNS AND SYMPTOMS MIGHT HAVE MULTIFACTORIAL CAUSES AND OVERLAPPING ORIGINS, SUCH AS GENETIC AND EPIGENETIC PREDISPOSITIONS. AS A RESULT, AN INITIAL CHECKLIST WAS OUTLINED, LISTING CLINICAL FACTORS OF SPECIAL RELEVANCE (E.G., FATIGUE, LOW QUALITY OF SLEEP, AND LOW MOOD) TO REPRESENT EARLY MANIFESTATIONS OF THE ORGANISM'S EXHAUSTION, WHICH ARE ALSO FREQUENTLY NEGLECTED IN THE CLINICAL SETTING. DIFFERENTIATING AACD FROM OTHER CONDITIONS IS ESSENTIAL. THE USE OF A COMBINATION OF BIOMARKERS WAS PROPOSED AS A VIABLE METHOD IN A TWO-STEP PROCESS OF DIFFERENTIATION: 1) IDENTIFICATION OF EARLY AACD CLINICAL INDICATORS, FOLLOWED BY 2) SYMPTOM AND BIOMARKER CONFIRMATION WITH A FOCUS ON SYSTEM DOMAINS (TO BE POTENTIALLY TARGETED BY FUTURE SPECIFIC INTERVENTIONS). ALTHOUGH THE AACD CONSTRUCT IS NOT YET READY FOR ROUTINE USE IN CLINICAL PRACTICE, ITS OPERATIONALIZATION MAY SUPPORT THE EARLY IDENTIFICATION OF AGE-RELATED CONDITIONS (WHEN THIS MIGHT STILL BE AMENABLE TO REVERSION) AND ALSO ENCOURAGE PREVENTATIVE INTERVENTIONS. FURTHER INVESTIGATION IS NEEDED TO ESTABLISH SPECIFIC BIOMARKERS THAT CONFIRM INDEPENDENT RISK FACTORS FOR AACD AND PROVIDE A MORE DEFINITIVE STRUCTURE TO THE CONCEPT OF AACD (AND AGE-ASSOCIATED CELLULAR DECLINE). 2021 5 6907 29 [THE ROLE OF THE CIRCULAR RNAS IN MULTIPLE SCLEROSIS AND OTHER NEUROIMMUNE DISORDERS]. IN RECENT YEARS NON-CODING RNAS HAVE RECEIVED INCREASING ATTENTION AS AN IMPORTANT EPIGENETIC MECHANISM, WITH PARTICULAR ROLE OF MICRO RNAS. AS THE REGULATION OF MIRNA EXPRESSION IS HIGHLY DYNAMIC AND COMPLEX, GROWING EVIDENCE SUGGESTS THE EXISTENCE OF ANOTHER HIGHER LEVEL OF REGULATORY MECHANISM INVOLVED IN MIRNA ACTIVITY - CIRCULAR RNAS (CIRCRNAS). CIRCRNAS REPRESENT NOVEL, UNIQUE CLASS OF ENDOGENOUS NCRNAS CONTROLLING THE EXPRESSION AND FUNCTION OF MIRNA. THEY ARE CALLED NATURAL MIRNA "SPONGES". ACCUMULATING EVIDENCE REVEALS CIRCRNAS ROLE IN PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES INCLUDING CNS AND IMMUNE REGULATION. PREVIOUS STUDIES IMPLICATED MIRNAS IN REGULATION OF AUTOIMMUNE DEMYELINATION IN MS. MULTIPLE SCLEROSIS IS A CHRONIC NEUROLOGICAL INFLAMMATORY DEMYELINATING DISORDER OF THE CENTRAL NERVOUS SYSTEM. WHILE THE ETIOLOGY OF MS IS STILL NOT FULLY UNDERSTOOD, ACCUMULATING EVIDENCE SUGGESTS THAT IT IS A MULTIFACTORIAL ENTITY WITH SIGNIFICANT INVOLVEMENT OF AUTOIMMUNE PROCESSES. 2022 6 3606 30 IMPROVING TREATMENT OF NEURODEVELOPMENTAL DISORDERS: RECOMMENDATIONS BASED ON PRECLINICAL STUDIES. INTRODUCTION: NEURODEVELOPMENTAL DISORDERS (NDDS) ARE COMMON AND SEVERELY DEBILITATING. THEIR CHRONIC NATURE AND RELIANCE ON BOTH GENETIC AND ENVIRONMENTAL FACTORS MAKES STUDYING NDDS AND THEIR TREATMENT A CHALLENGING TASK. AREAS COVERED: HEREIN, THE AUTHORS DISCUSS THE NEUROBIOLOGICAL MECHANISMS OF NDDS, AND PRESENT RECOMMENDATIONS ON THEIR TRANSLATIONAL RESEARCH AND THERAPY, OUTLINED BY THE INTERNATIONAL STRESS AND BEHAVIOR SOCIETY. VARIOUS DRUGS CURRENTLY PRESCRIBED TO TREAT NDDS ALSO REPRESENT A HIGHLY DIVERSE GROUP. ACTING ON VARIOUS NEUROTRANSMITTER AND PHYSIOLOGICAL SYSTEMS, THESE DRUGS OFTEN LACK SPECIFICITY OF ACTION, AND ARE COMMONLY USED TO TREAT MULTIPLE OTHER PSYCHIATRIC CONDITIONS. THERE HAS ALSO BEEN RELATIVELY LITTLE PROGRESS IN THE DEVELOPMENT OF NOVEL MEDICATIONS TO TREAT NDDS. BASED ON CLINICAL, PRECLINICAL AND TRANSLATIONAL MODELS OF NDDS, OUR RECOMMENDATIONS COVER A WIDE RANGE OF METHODOLOGICAL APPROACHES AND CONCEPTUAL STRATEGIES. EXPERT OPINION: TO IMPROVE PHARMACOTHERAPY AND DRUG DISCOVERY FOR NDDS, WE NEED A STRONGER EMPHASIS ON TARGETING MULTIPLE ENDOPHENOTYPES, A BETTER DISSECTION OF GENETIC/EPIGENETIC FACTORS OR "HIDDEN HERITABILITY," AND A CAREFUL CONSIDERATION OF POTENTIAL DEVELOPMENTAL/TROPHIC ROLES OF BRAIN NEUROTRANSMITTERS. THE VALIDITY OF ANIMAL NDD MODELS CAN BE IMPROVED THROUGH DISCOVERY OF NOVEL (BEHAVIORAL, PHYSIOLOGICAL AND NEUROIMAGING) BIOMARKERS, APPLYING PROPER ENVIRONMENTAL ENRICHMENT, WIDENING THE SPECTRUM OF MODEL ORGANISMS, TARGETING DEVELOPMENTAL TRAJECTORIES OF NDD-RELATED BEHAVIORS AND COMORBID CONDITIONS BEYOND TRADITIONAL NDDS. WHILE THESE RECOMMENDATIONS CANNOT BE ADDRESSED ALL IN ONCE, OUR INCREASED UNDERSTANDING OF NDD PATHOBIOLOGY MAY TRIGGER INNOVATIVE CROSS-DISCIPLINARY RESEARCH EXPANDING BEYOND TRADITIONAL METHODS AND CONCEPTS. 2016 7 4832 33 OMICS BIOMARKERS IN OBESITY: NOVEL ETIOLOGICAL INSIGHTS AND TARGETS FOR PRECISION PREVENTION. PURPOSE OF REVIEW: OMICS-BASED TECHNOLOGIES WERE SUGGESTED TO PROVIDE AN ADVANCED UNDERSTANDING OF OBESITY ETIOLOGY AND ITS METABOLIC CONSEQUENCES. THIS REVIEW HIGHLIGHTS THE RECENT DEVELOPMENTS IN "OMICS"-BASED RESEARCH AIMED TO IDENTIFY OBESITY-RELATED BIOMARKERS. RECENT FINDINGS: RECENT ADVANCES IN OBESITY AND METABOLISM RESEARCH INCREASINGLY RELY ON NEW TECHNOLOGIES TO IDENTIFY MECHANISMS IN THE DEVELOPMENT OF OBESITY USING VARIOUS "OMICS" PLATFORMS. GENETIC AND EPIGENETIC BIOMARKERS THAT TRANSLATE INTO CHANGES IN TRANSCRIPTOME, PROTEOME, AND METABOLOME COULD SERVE AS TARGETS FOR OBESITY PREVENTION. DESPITE A NUMBER OF PROMISING CANDIDATE BIOMARKERS, THERE IS AN INCREASED DEMAND FOR LARGER PROSPECTIVE COHORT STUDIES TO VALIDATE FINDINGS AND DETERMINE BIOMARKER REPRODUCIBILITY BEFORE THEY CAN FIND APPLICATIONS IN PRIMARY CARE AND PUBLIC HEALTH. "OMICS" BIOMARKERS HAVE ADVANCED OUR KNOWLEDGE ON THE ETIOLOGY OF OBESITY AND ITS LINKS WITH CHRONIC DISEASES. THEY BRING SUBSTANTIAL PROMISE IN IDENTIFYING EFFECTIVE PUBLIC HEALTH STRATEGIES THAT PAVE THE WAY TOWARDS PATIENT STRATIFICATION AND PRECISION PREVENTION. 2020 8 5139 37 POTENTIAL NOVEL BIOMARKERS IN CHRONIC GRAFT-VERSUS-HOST DISEASE. PROGNOSTIC, DIAGNOSTIC OR PREDICTIVE BIOMARKERS ARE URGENTLY NEEDED FOR ASSESSMENT OF CHRONIC GRAFT-VERSUS-HOST DISEASE (CGVHD), A MAJOR RISK FOR PATIENTS UNDERGOING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION. THE MAIN GOAL OF THIS REVIEW GENERATED WITHIN THE COST ACTION EUROGRAFT "INTEGRATED EUROPEAN NETWORK ON CHRONIC GRAFT VERSUS HOST DISEASE" WAS TO IDENTIFY POTENTIAL NOVEL BIOMARKERS FOR CGVHD BESIDES THE WIDELY ACCEPTED MOLECULAR AND CELLULAR BIOMARKERS. THUS, THE FOCUS WAS ON CELLULAR BIOMARKERS, ALLOANTIBODIES, GLYCOMICS, ENDOTHELIAL DERIVED PARTICLES, EXTRACELLULAR VESICLES, MICROBIOME, EPIGENETIC AND NEUROLOGIC CHANGES IN CGVHD PATIENTS. BOTH HOST-REACTIVE ANTIBODIES IN GENERAL, AND PARTICULARLY ALLOANTIBODIES HAVE BEEN ASSOCIATED WITH CGVHD AND REQUIRE FURTHER CONSIDERATION. GLYCANS ATTACHED TO IGG MODULATE ITS ACTIVITY AND REPRESENT A PROMISING PREDICTIVE AND/OR STRATIFICATION BIOMARKER FOR CGVHD. FURTHERMORE, EPIGENETIC CHANGES SUCH AS MICRORNAS AND DNA METHYLATION REPRESENT POTENTIAL BIOMARKERS FOR MONITORING CGVHD PATIENTS AND NOVEL TARGETS FOR DEVELOPING NEW TREATMENT APPROACHES. FINALLY, THE MICROBIOME LIKELY AFFECTS THE PATHOPHYSIOLOGY OF CGVHD; BACTERIAL STRAINS AS WELL AS MICROBIAL METABOLITES COULD DISPLAY POTENTIAL BIOMARKERS FOR DYSBIOSIS AND RISK FOR THE DEVELOPMENT OF CGVHD. IN SUMMARY, ALTHOUGH THERE ARE NO VALIDATED BIOMARKERS CURRENTLY AVAILABLE FOR CLINICAL USE TO BETTER INFORM ON THE DIAGNOSIS, PROGNOSIS OR PREDICTION OF OUTCOME FOR CGVHD, MANY NOVEL SOURCES OF POTENTIAL MARKERS HAVE SHOWN PROMISE AND WARRANT FURTHER INVESTIGATION USING WELL CHARACTERIZED, MULTI-CENTER PATIENT COHORTS. 2020 9 4288 38 MICRORNA IN LEUKEMIA: TUMOR SUPPRESSORS AND ONCOGENES WITH PROGNOSTIC POTENTIAL. LEUKEMIA IS KNOWN AS A PROGRESSIVE MALIGNANT DISEASE, WHICH DESTROYS THE BLOOD-FORMING ORGANS AND RESULTS IN ADVERSE EFFECTS ON THE PROLIFERATION AND DEVELOPMENT OF LEUKOCYTES AND THEIR PRECURSORS IN THE BLOOD AND BONE MARROW. THERE ARE FOUR MAIN CLASSES OF LEUKEMIA INCLUDING ACUTE LEUKEMIA, CHRONIC LEUKEMIA, MYELOGENOUS LEUKEMIA, AND LYMPHOCYTIC LEUKEMIA. GIVEN THAT A VARIETY OF INTERNAL AND EXTERNAL FACTORS COULD BE ASSOCIATED WITH THE INITIATION AND PROGRESSION OF DIFFERENT TYPES OF LEUKEMIA. ONE OF THE IMPORTANT FACTORS IS EPIGENETIC REGULATORS SUCH AS MICRORNAS (MIRNAS) AND LONG NONCODING RNAS (NCRNA). MIRNAS ARE SHORT NCRNAS WHICH ACT AS TUMOR SUPPRESSOR (I.E., MIR-15, MIR-16, LET-7, AND MIR-127) OR ONCOGENE (I.E., MIR-155, MIR-17-92, MIR-21, MIR-125B, MIR-93, MIR-143-P3, MIR-196B, AND MIR-223) IN LEUKEMIA. IT HAS BEEN SHOWN THAT DEREGULATION OF THESE MOLECULES ARE ASSOCIATED WITH THE INITIATION AND PROGRESSION OF LEUKEMIA. HENCE, MIRNAS COULD BE USED AS POTENTIAL THERAPEUTIC CANDIDATES IN THE TREATMENT OF PATIENTS WITH LEUKEMIA. MOREOVER, INCREASING EVIDENCE REVEALED THAT MIRNAS COULD BE USED AS DIAGNOSTIC AND PROGNOSTIC BIOMARKERS IN MONITORING PATIENTS IN EARLY STAGES OF DISEASE OR AFTER RECEIVED CHEMOTHERAPY REGIMEN. IT SEEMS THAT IDENTIFICATION AND DEVELOPMENT OF NEW MIRNAS COULD PAVE TO THE WAY TO THE DEVELOPMENT NEW THERAPEUTIC PLATFORMS FOR PATIENTS WITH LEUKEMIA. HERE, WE SUMMARIZED VARIOUS MIRNAS AS TUMOR SUPPRESSOR AND ONCOGENE WHICH COULD BE INTRODUCED AS THERAPEUTIC TARGETS IN TREATMENT OF LEUKEMIA. 2019 10 5513 38 RICHTER SYNDROME: NOVEL INSIGHTS INTO THE BIOLOGY OF TRANSFORMATION. ALTHOUGH THE GENETIC LANDSCAPE OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) HAS BEEN BROADLY PROFILED BY LARGE-SCALE SEQUENCING STUDIES PERFORMED OVER THE PAST DECADE, THE MOLECULAR BASIS OF THE TRANSFORMATION OF CLL INTO AGGRESSIVE LYMPHOMA, OR RICHTER SYNDROME (RS), HAS REMAINED INCOMPLETELY CHARACTERIZED. RECENT ADVANCES IN COMPUTATIONAL METHODS OF CLONAL DECONVOLUTION, AS WELL AS EXTENSIVE SAMPLE COLLECTION EFFORTS IN THIS RAPIDLY PROGRESSIVE MALIGNANCY, HAVE NOW ENABLED COMPREHENSIVE ANALYSIS OF PAIRED CLL AND RS SAMPLES AND HAVE LED TO MULTIPLE NEW STUDIES INVESTIGATING THE GENETIC, TRANSCRIPTOMIC, AND EPIGENETIC ORIGINS OF RS. IN PARALLEL, NEW GENETICALLY ENGINEERED AND XENOGRAFT MOUSE MODELS HAVE PROVIDED THE OPPORTUNITY FOR GLEANING FRESH BIOLOGICAL AND MECHANISTIC INSIGHTS INTO RS DEVELOPMENT AND STEPWISE EVOLUTION FROM ANTECEDENT CLL. ALTOGETHER, THESE STUDIES HAVE DEFINED RS DRIVER LESIONS AND CLL RISK LESIONS AND IDENTIFIED PATHWAYS DYSREGULATED IN TRANSFORMATION. MOREOVER, UNIQUE MOLECULAR SUBTYPES OF RS HAVE BEEN REVEALED, INCLUDING A DISEASE MARKED BY PROFOUND GENOMIC INSTABILITY WITH CHROMOTHRIPSIS/CHROMOPLEXY AND WHOLE GENOME DUPLICATION. NOVEL PROFILING APPROACHES, INCLUDING SINGLE-CELL DNA AND TRANSCRIPTOME SEQUENCING OF RS BIOPSY SPECIMENS AND CELL-FREE DNA PROFILING OF PATIENT PLASMA, DEMONSTRATE PROMISE FOR THE TIMELY IDENTIFICATION OF RS CLONES AND MAY TRANSLATE TO NONINVASIVE IDENTIFICATION AND EARLY DIAGNOSIS OF RS. THIS REVIEW SUMMARIZES THE RECENT SCIENTIFIC ADVANCES IN RS AND SUPPORTS THE INTEGRATED STUDY OF HUMAN GENOMICS WITH MOUSE MODELING TO PROVIDE AN ADVANCED UNDERSTANDING OF THE BIOLOGICAL UNDERPINNINGS OF TRANSFORMATION. THESE RECENT STUDIES HAVE MAJOR IMPLICATIONS FOR MUCH-NEEDED NOVEL THERAPEUTIC STRATEGIES FOR THIS STILL LARGELY INCURABLE MALIGNANCY. 2023 11 741 32 CANDIDATE GENES OF WALDENSTROM'S MACROGLOBULINEMIA: CURRENT EVIDENCE AND RESEARCH. WALDENSTROM'S MACROGLOBULINEMIA (WM) IS A RELATIVELY UNCOMMON, INDOLENT MALIGNANCY OF IMMUNOGLOBULIN M-PRODUCING B CELLS. THE WORLD HEALTH ORGANIZATION CLASSIFIES IT AS A LYMPHOPLASMACYTIC LYMPHOMA AND PATIENTS TYPICALLY PRESENT WITH ANEMIA, HEPATOSPLENOMEGALY AND DIFFUSE LYMPHADENOPATHIES. HISTORICALLY, THE GENETIC CHARACTERIZATION OF THE DISEASE HAS BEEN HAMPERED BY THE RELATIVELY LOW PROLIFERATIVE RATE OF WM CELLS, THUS MAKING KARYOTYPING CHALLENGING. THE USE OF NOVEL TECHNOLOGIES SUCH AS FLUORESCENCE IN SITU HYBRIDIZATION, GENE ARRAY, AND WHOLE GENOME SEQUENCING HAS CONTRIBUTED GREATLY TO ESTABLISHING CANDIDATE GENES IN THE PATHOPHYSIOLOGY OF WM AND TO IDENTIFYING POTENTIAL TREATMENT TARGETS, SUCH AS L265P MYD88. THE DISCOVERY OF MICRORNAS AND THE RECOGNITION OF EPIGENETICS AS A MAJOR MODULATORY MECHANISM OF ONCOGENE EXPRESSION AND/OR ONCOSUPPRESSOR SILENCING HAVE AIDED IN FURTHER UNDERSTANDING THE PATHOGENESIS OF WM. ONCE THOUGHT TO CLOSELY RESEMBLE MULTIPLE MYELOMA, A CANCER OF TERMINALLY DIFFERENTIATED, IMMUNOGLOBULIN-SECRETING PLASMA CELLS, WM APPEARS TO GENETICALLY CLUSTER WITH OTHER INDOLENT B-CELL LYMPHOMAS SUCH AS CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL CELL LYMPHOMA. THE RELATIVE HIGH INCIDENCE OF FAMILIAL CASES OF WM AND OTHER B-CELL MALIGNANCIES HAS BEEN HELPFUL IN IDENTIFYING HIGH-RISK GENE CANDIDATES. IN THIS REVIEW, WE FOCUS ON THE ESTABLISHED GENES INVOLVED IN THE PATHOGENESIS OF WM, WITH SPECIAL EMPHASIS ON THE KEY ROLE OF DERANGEMENT OF THE NUCLEAR FACTOR KAPPA B SIGNALING PATHWAY AND EPIGENETIC MECHANISMS. 2013 12 4344 29 MINIREVIEW: TRANSLATIONAL ANIMAL MODELS OF HUMAN MENOPAUSE: CHALLENGES AND EMERGING OPPORTUNITIES. INCREASING IMPORTANCE IS PLACED ON THE TRANSLATIONAL VALIDITY OF ANIMAL MODELS OF HUMAN MENOPAUSE TO DISCERN RISK VS. BENEFIT FOR PREDICTION OF OUTCOMES AFTER THERAPEUTIC INTERVENTIONS AND TO DEVELOP NEW THERAPEUTIC STRATEGIES TO PROMOTE HEALTH. BASIC DISCOVERY RESEARCH CONDUCTED OVER MANY DECADES HAS BUILT AN EXTENSIVE BODY OF KNOWLEDGE REGARDING REPRODUCTIVE SENESCENCE ACROSS MAMMALIAN SPECIES UPON WHICH TO ADVANCE ANIMAL MODELS OF HUMAN MENOPAUSE. MODIFICATIONS TO EXISTING ANIMAL MODELS COULD RAPIDLY ADDRESS TRANSLATIONAL GAPS RELEVANT TO CLINICAL ISSUES IN HUMAN MENOPAUSAL HEALTH, WHICH INCLUDE THE IMPACT OF 1) CHRONIC OVARIAN HORMONE DEPRIVATION AND HORMONE THERAPY, 2) CLINICALLY RELEVANT HORMONE THERAPY REGIMENS (CYCLIC VS. CONTINUOUS COMBINED), 3) CLINICALLY RELEVANT HORMONE THERAPY FORMULATIONS, AND 4) WINDOWS OF OPPORTUNITY AND OPTIMAL DURATION OF INTERVENTIONS. MODIFICATIONS IN EXISTING ANIMAL MODELS TO MORE ACCURATELY REPRESENT HUMAN MENOPAUSE AND CLINICAL INTERVENTIONS COULD RAPIDLY PROVIDE PRECLINICAL TRANSLATIONAL DATA TO PREDICT OUTCOMES REGARDING UNRESOLVED CLINICAL ISSUES RELEVANT TO WOMEN'S MENOPAUSAL HEALTH. DEVELOPMENT OF THE NEXT GENERATION OF ANIMAL MODELS OF HUMAN MENOPAUSE COULD LEVERAGE ADVANCES IN IDENTIFYING GENOTYPIC VARIATIONS IN ESTROGEN AND PROGESTERONE RECEPTORS TO DEVELOP PERSONALIZED MENOPAUSAL CARE AND TO PREDICT OUTCOMES OF INTERVENTIONS FOR PROTECTION AGAINST OR VULNERABILITY TO DISEASE. KEY TO THE SUCCESS OF THESE MODELS IS THE CLOSE COUPLING BETWEEN THE TRANSLATIONAL TARGET AND THE RANGE OF PREDICTIVE VALIDITY. PRECLINICAL TRANSLATIONAL ANIMAL MODELS OF HUMAN MENOPAUSE NEED TO KEEP PACE WITH CHANGES IN CLINICAL PRACTICE. WITH FOCUS ON PREDICTIVE VALIDITY AND STRATEGIC USE OF ADVANCES IN GENETIC AND EPIGENETIC SCIENCE, NEW ANIMAL MODELS OF HUMAN MENOPAUSE HAVE THE OPPORTUNITY TO SET NEW DIRECTIONS FOR MENOPAUSAL CLINICAL CARE FOR WOMEN WORLDWIDE. 2012 13 4666 36 NEW INSIGHTS AND OPTIONS INTO THE MECHANISMS AND EFFECTS OF COMBINED TARGETED THERAPY AND IMMUNOTHERAPY IN PROSTATE CANCER. CHRONIC INFLAMMATION IS BELIEVED TO DRIVE PROSTATE CARCINOGENESIS BY PRODUCING REACTIVE OXYGEN SPECIES OR REACTIVE NITROGEN SPECIES TO INDUCE DNA DAMAGE. THIS EFFECT MIGHT SUBSEQUENTLY CAUSE EPIGENETIC AND GENOMIC ALTERATIONS, LEADING TO MALIGNANT TRANSFORMATION. ALTHOUGH ESTABLISHED THERAPEUTIC ADVANCES HAVE EXTENDED OVERALL SURVIVAL, TUMORS IN PATIENTS WITH ADVANCED PROSTATE CANCER ARE PRONE TO METASTASIS, TRANSFORMATION INTO METASTATIC CASTRATION-RESISTANT PROSTATE CANCER, AND THERAPEUTIC RESISTANCE. THE TUMOR MICROENVIRONMENT (TME) OF PROSTATE CANCER IS INVOLVED IN CARCINOGENESIS, INVASION AND DRUG RESISTANCE. A PLETHORA OF PRECLINICAL STUDIES HAVE FOCUSED ON IMMUNE-BASED THERAPIES. UNDERSTANDING THE INTRICATE TME SYSTEM IN PROSTATE CANCER MAY HOLD MUCH PROMISE FOR DEVELOPING NOVEL THERAPIES, DESIGNING COMBINATIONAL THERAPEUTIC STRATEGIES, AND FURTHER OVERCOMING RESISTANCE TO ESTABLISHED TREATMENTS TO IMPROVE THE LIVES OF PROSTATE CANCER PATIENTS. IN THIS REVIEW, WE DISCUSS NONIMMUNE COMPONENTS AND VARIOUS IMMUNE CELLS WITHIN THE TME AND THEIR PUTATIVE ROLES DURING PROSTATE CANCER INITIATION, PROGRESSION, AND METASTASIS. WE ALSO OUTLINE THE UPDATED FUNDAMENTAL RESEARCH FOCUSING ON THERAPEUTIC ADVANCES OF TARGETED THERAPY AS WELL AS COMBINATIONAL OPTIONS FOR PROSTATE CANCER. 2023 14 1071 27 CLONAL DYNAMICS IN CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA HAS A HIGHLY VARIABLE DISEASE COURSE ACROSS PATIENTS, THOUGHT TO BE DRIVEN BY THE VAST INTER- AND INTRAPATIENT MOLECULAR HETEROGENEITY DESCRIBED IN SEVERAL LARGE-SCALE DNA-SEQUENCING STUDIES CONDUCTED OVER THE PAST DECADE. ALTHOUGH THE LAST 5 YEARS HAVE SEEN A DRAMATIC SHIFT IN THE THERAPEUTIC LANDSCAPE FOR CHRONIC LYMPHOCYTIC LEUKEMIA, INCLUDING THE REGULATORY APPROVAL OF SEVERAL POTENT TARGETED AGENTS (IE, IDELALISIB, IBRUTINIB, VENETOCLAX), THE VAST MAJORITY OF PATIENTS STILL INEVITABLY EXPERIENCE DISEASE RECURRENCE OR PERSISTENCE. RECENT GENOME-WIDE SEQUENCING APPROACHES HAVE HELPED TO IDENTIFY SUBCLONAL POPULATIONS WITHIN TUMORS THAT DEMONSTRATE A BROAD SPECTRUM OF SOMATIC MUTATIONS, DIVERSE LEVELS OF RESPONSE TO THERAPY, PATTERNS OF REPOPULATION, AND GROWTH KINETICS. UNDERSTANDING THE IMPACT OF GENETIC, EPIGENETIC, AND TRANSCRIPTOMIC FEATURES ON CLONAL GROWTH DYNAMICS AND DRUG RESPONSE WILL BE AN IMPORTANT STEP TOWARD THE SELECTION AND TIMING OF THERAPY. 2019 15 5462 25 RESEARCH PROGRESS ON EPIGENETICS OF SMALL B-CELL LYMPHOMA. SMALL B-CELL LYMPHOMA IS THE CLASSIFICATION OF B-CELL CHRONIC LYMPHOPROLIFERATIVE DISORDERS THAT INCLUDE CHRONIC LYMPHOCYTIC LEUKAEMIA/SMALL LYMPHOCYTIC LYMPHOMA, FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA. THE CLINICAL PRESENTATION IS SOMEWHAT HETEROGENEOUS, AND ITS OCCURRENCE AND DEVELOPMENT MECHANISMS ARE NOT YET PRECISE AND MAY INVOLVE EPIGENETIC CHANGES. EPIGENETIC ALTERATIONS MAINLY INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA, WHICH ARE ESSENTIAL FOR GENETIC DETECTION, EARLY DIAGNOSIS, AND ASSESSMENT OF TREATMENT RESISTANCE IN SMALL B-CELL LYMPHOMA. AS CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA HAS ALREADY BEEN REPORTED IN THE LITERATURE, THIS ARTICLE FOCUSES ON SMALL B-CELL LYMPHOMAS SUCH AS FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, AND WALDENSTROM MACROGLOBULINEMIA. IT DISCUSSES RECENT DEVELOPMENTS IN EPIGENETIC RESEARCH TO DIAGNOSE AND TREAT THIS GROUP OF LYMPHOMAS. THIS REVIEW PROVIDES NEW IDEAS FOR THE TREATMENT AND PROGNOSIS ASSESSMENT OF SMALL B-CELL LYMPHOMA BY EXPLORING THE CONNECTION BETWEEN SMALL B-CELL LYMPHOMA AND EPIGENETICS. 2022 16 1059 31 CLINICAL PERSPECTIVES OF NON-CODING RNA IN ORAL INFLAMMATORY DISEASES AND NEUROPATHIC PAIN: A NARRATIVE REVIEW. NON-CODING RNAS (NCRNAS) REPRESENT A RESEARCH HOTSPOT BY PLAYING A KEY ROLE IN EPIGENETIC AND TRANSCRIPTIONAL REGULATION OF DIVERSE BIOLOGICAL FUNCTIONS AND DUE TO THEIR INVOLVEMENT IN DIFFERENT DISEASES, INCLUDING ORAL INFLAMMATORY DISEASES. BASED ON NCRNAS' SUITABILITY FOR SALIVARY BIOMARKERS AND THEIR INVOLVEMENT IN NEUROPATHIC PAIN AND TISSUE REGENERATION SIGNALING PATHWAYS, THE PRESENT NARRATIVE REVIEW AIMS TO HIGHLIGHT THE POTENTIAL CLINICAL APPLICATIONS OF NCRNAS IN ORAL INFLAMMATORY DISEASES, WITH AN EMPHASIS ON SALIVARY DIAGNOSTICS, REGENERATIVE DENTISTRY, AND PRECISION MEDICINE FOR NEUROPATHIC OROFACIAL PAIN. 2022 17 202 22 ACTIVATION INDUCED CYTIDINE DEAMINASE: AN OLD FRIEND WITH NEW FACES. ACTIVATION INDUCED CYTIDINE DEAMINASE (AID) PROTEIN IS A MEMBER OF APOBEC FAMILY. AID CONVERTS CYTIDINE TO URACIL, WHICH IS A KEY STEP FOR SOMATIC HYPERMUTATION (SHM) AND CLASS SWITCH RECOMBINATION (CSR). AID ALSO PLAYS CRITICAL ROLES IN B CELL PRECURSOR STAGES, REMOVING POLYREACTIVE B CELLS FROM IMMUNE REPERTOIRE. SINCE THE MAIN FUNCTION OF AID IS INDUCING POINT MUTATIONS, DYSREGULATION CAN LEAD TO INCREASED MUTATION LOAD, TRANSLOCATIONS, DISTURBED GENOMIC INTEGRITY, AND LYMPHOMAGENESIS. AS SUCH, EXPRESSION OF AID AS WELL AS ITS FUNCTION IS CONTROLLED STRICTLY AT VARIOUS MOLECULAR STEPS. OTHER MEMBERS OF THE APOBEC FAMILY ALSO PLAY CRUCIAL ROLES DURING CARCINOGENESIS. CONSIDERING ALL THESE FUNCTIONS, AID REPRESENTS A BRIDGE, LINKING CHRONIC INFLAMMATION TO CARCINOGENESIS AND IMMUNE DEFICIENCIES TO AUTOIMMUNE MANIFESTATIONS. 2022 18 1037 17 CLASSIFICATION AND DIAGNOSIS OF TEMPOROMANDIBULAR DISORDERS AND TEMPOROMANDIBULAR DISORDER PAIN. DESIGNING CLASSIFICATION SYSTEMS AND DEVELOPING DIAGNOSTIC CRITERIA FOR TEMPOROMANDIBULAR DISORDERS IS DIFFICULT. AN APPRECIATION OF THE UTILITY AND APPLICABILITY OF THESE ENTITIES REQUIRES AN UNDERSTANDING OF THE IMPORTANCE OF EACH, THE DIFFERENCES BETWEEN THE TWO, AND HOW THEY MAY BE OPTIMALLY OPERATIONALIZED FOR BOTH CLINICAL AND RESEARCH ACTIVITIES IN LIGHT OF THEIR INHERENT ADVANTAGES AND LIMITATIONS. IN ADDITION, CONSIDERATION FOR ADOPTING NEWER APPROACHES, SUCH AS FOLLOWING ONTOLOGICAL AND PRECISION-BASED MEDICINE PRINCIPLES, ACCOUNTING FOR GENETICS/EPIGENETIC AND NEUROBIOLOGICAL FACTORS, AND THE INCLUSION OF BIOMARKERS WILL POTENTIALLY RESULT IN MORE THOROUGH AND COMPREHENSIVE CLASSIFICATION SYSTEMS AND DIAGNOSTIC CRITERIA. 2023 19 6676 35 USING EPIGENETIC TOOLS TO INVESTIGATE ANTIDEPRESSANT RESPONSE. MAJOR DEPRESSIVE DISORDER IS A CHRONIC AND DEBILITATING ILLNESS. IT IS MOST COMMONLY TREATED WITH ANTIDEPRESSANT DRUGS, HOWEVER, AS THE MAJORITY OF PATIENTS DO NOT RESPOND ON THEIR FIRST TRIAL OR FOLLOWING SEVERAL ADEQUATE TRIALS, THERE IS GREAT INTEREST IN IDENTIFYING BIOLOGICAL FACTORS THAT MAY HELP SELECT THE MOST APPROPRIATE TREATMENT FOR EACH PATIENT AND IN UNDERSTANDING BIOLOGICAL PROCESSES THAT MEDIATE TREATMENT RESPONSE. EPIGENETIC FACTORS, SUCH AS NON-CODING RNAS (NCRNAS), HOLD POTENTIAL AS BIOMARKERS OF ANTIDEPRESSANT RESPONSE. IN THIS CHAPTER, WE REVIEW KEY METHODOLOGICAL CONSIDERATIONS WHEN INVESTIGATING NCRNA BIOMARKERS, INCLUDING BIOLOGICAL SAMPLES AND TECHNOLOGIES WHICH HAVE BEEN USED IN THESE STUDIES. SECONDLY, WE SUMMARIZE FINDINGS FROM STUDIES INVESTIGATING NCRNAS IN ANTIDEPRESSANT TREATMENT RESPONSE. FINALLY, WE DISCUSS SOME OF THE FUTURE DIRECTIONS WHICH WILL BE NECESSARY FOR THE DEVELOPMENT OF CLINICALLY RELEVANT EPIGENETIC TOOLS. 2018 20 4716 34 NON-GENETIC RATS MODELS FOR ATHEROSCLEROSIS RESEARCH: FROM PAST TO PRESENT. ATHEROSCLEROSIS IS AN INFLAMMATORY, PROGRESSIVE, AND CHRONIC ILLNESS THAT INVOLVES SEVERAL MOLECULAR AND EPIGENETIC FACTORS. DESPITE TREATMENT LIMITATIONS, CLINICAL AND THERAPEUTIC APPROACHES HAVE UNDENIABLY CHANGED RADICALLY IN RECENT DECADES THROUGH BETTER KNOWLEDGE OF THE PATHOPHYSIOLOGICAL BASIS OF THE DISEASE, WHICH HAS CONSIDERABLY IMPROVED PATIENTS' SURVIVAL AND QUALITY OF LIFE. SOME OF THESE ADVANCES ARE ATTRIBUTABLE TO BASIC BIOMEDICAL RESEARCH THAT PROVIDES INSIGHTS INTO A BETTER UNDERSTANDING AND IDENTIFICATION OF NEW MOLECULAR AND CELLULAR TARGETS FOR ATHEROSCLEROSIS TREATMENT. ALTHOUGH RODENT MODELS HAVE CONTRIBUTED SUBSTANTIALLY TO A BETTER UNDERSTANDING OF THE DEVELOPMENT OF ATHEROSCLEROSIS, THE ACCURACY OF THESE MODELS REMAINS CONTROVERSIAL. RESEARCH THAT UTILIZES GENETIC RODENT MODELS IS WELL ESTABLISHED, BUT THE USE OF SPECIFIC DIETS THAT ARE ASSOCIATED WITH OTHER RISK FACTORS (E.G., HYPERTENSION, HORMONE DEPRIVATION, AND PHARMACOLOGICAL TOOLS) IS STILL DEBATABLE. THE PRESENT REVIEW PROVIDES AN UPDATE ON NON-GENETIC RAT MODELS OF ATHEROSCLEROSIS AND AN OVERVIEW OF THE MAIN METHODOLOGIES THAT ARE CURRENTLY AVAILABLE. 2019