1 757 129 CARTILAGE REPAIR BY MESENCHYMAL STEM CELLS: CLINICAL TRIAL UPDATE AND PERSPECTIVES. OSTEOARTHRITIS IS A DEGENERATIVE DISEASE OF JOINTS WITH DESTRUCTION OF ARTICULAR CARTILAGE ASSOCIATED WITH SUBCHONDRAL BONE HYPERTROPHY AND INFLAMMATION. OA IS THE LEADING CAUSE OF JOINT PAIN RESULTING IN SIGNIFICANT WORSENING OF THE QUALITY-OF-LIFE IN THE ELDERLY. NUMEROUS EFFORTS HAVE BEEN SPENT TO OVERCOME THE INHERENTLY POOR HEALING ABILITY OF ARTICULAR CARTILAGE. MESENCHYMAL STEM CELLS (MSCS) HAVE BEEN IN THE LIMELIGHT OF CELL-BASED THERAPIES TO PROMOTE CARTILAGE REPAIR. DESPITE PROGRESSIVE ADVANCEMENTS IN MSC MANIPULATION AND THE INTRODUCTION OF VARIOUS BIOACTIVE SCAFFOLDS AND GROWTH FACTORS IN PRECLINICAL STUDIES, CURRENT CLINICAL TRIALS ARE STILL AT EARLY STAGES WITH PRELIMINARY AIMS TO EVALUATE SAFETY, FEASIBILITY AND EFFICACY. THIS REVIEW SUMMARISES RECENTLY REPORTED MSC-BASED CLINICAL TRIALS AND DISCUSSES NEW RESEARCH DIRECTIONS WITH PARTICULAR FOCUS ON THE POTENTIAL APPLICATION OF MSC-DERIVED EXTRACELLULAR VEHICLES, MIRNAS AND ADVANCED GENE EDITING TECHNIQUES WHICH MAY SHED LIGHT ON THE DEVELOPMENT OF NOVEL TREATMENT STRATEGIES. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: THIS REVIEW SUMMARISES RECENT MSC-RELATED CLINICAL RESEARCH THAT FOCUSES ON CARTILAGE REPAIR. WE ALSO PROPOSE A NOVEL POSSIBLE TRANSLATIONAL DIRECTION FOR HYALINE CARTILAGE FORMATION AND A NEW PARADIGM MAKING USE OF EXTRA-CELLULAR SIGNALLING AND EPIGENETIC REGULATION IN THE APPLICATION OF MSCS FOR CARTILAGE REPAIR. 2017 2 2906 32 GENE EDITING FOR INFLAMMATORY DISORDERS. TECHNOLOGY FOR PRECISE AND EFFICIENT GENETIC EDITING IS CONSTANTLY EVOLVING AND IS NOW CAPABLE OF HUMAN CLINICAL APPLICATIONS. AUTOIMMUNE AND INFLAMMATORY DISEASES ARE CHRONIC, DISABLING, SOMETIMES LIFE-THREATENING, CONDITIONS THAT FEATURE HERITABLE COMPONENTS. BOTH PRIMARY GENETIC LESIONS AND THE INFLAMMATORY PATHOBIOLOGY UNDERLYING THESE DISEASES REPRESENT FERTILE SOIL FOR NEW THERAPIES BASED ON THE CAPABILITIES OF GENE EDITING. THE ABILITY TO ORCHESTRATE PRECISE TARGETED MODIFICATIONS TO THE GENOME WILL LIKELY ENABLE CELL-BASED THERAPIES FOR INFLAMMATORY DISEASES SUCH AS MONOGENIC AUTOINFLAMMATORY DISEASE, ACQUIRED AUTOIMMUNE DISEASE AND FOR REGENERATIVE MEDICINE IN THE SETTING OF AN INFLAMMATORY ENVIRONMENT. HERE, WE DISCUSS RECENT ADVANCES IN GENOME EDITING AND THEIR EVOLVING APPLICATIONS IN IMMUNOINFLAMMATORY DISEASES. STRENGTHS AND LIMITATIONS OF OLDER GENETIC MODIFICATION TOOLS ARE COMPARED WITH CRISPR/CAS9, BASE EDITING, RNA EDITING, TARGETED ACTIVATORS AND REPRESSORS OF TRANSCRIPTION AND TARGETED EPIGENETIC MODIFIERS. COMMONLY EMPLOYED DELIVERY VEHICLES TO TARGET CELLS OR TISSUES OF INTEREST WITH GENETIC MODIFICATION MACHINERY, INCLUDING VIRAL, NON-VIRAL AND CELLULAR VECTORS, ARE DESCRIBED. FINALLY, APPLICATIONS IN ANIMAL AND HUMAN MODELS OF INFLAMMATORY DISEASES ARE DISCUSSED. USE OF CHIMERIC AUTOANTIGEN RECEPTOR T CELLS, CORRECTION OF MONOGENIC DISEASES WITH GENETICALLY EDITED HAEMATOPOIETIC STEM AND PROGENITOR CELLS, ENGINEERING OF INDUCED PLURIPOTENT STEM CELLS AND EX VIVO EXPANSION AND MODIFICATION OF REGULATORY T CELLS FOR A RANGE OF CHRONIC INFLAMMATORY DISEASES ARE REVIEWED. 2019 3 1867 40 EMERGING GENE-EDITING MODALITIES FOR OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A PATHOLOGICAL DEGENERATIVE CONDITION OF THE JOINTS THAT IS WIDELY PREVALENT WORLDWIDE, RESULTING IN SIGNIFICANT PAIN, DISABILITY, AND IMPAIRED QUALITY OF LIFE. THE DIVERSE ETIOLOGY AND PATHOGENESIS OF OA CAN EXPLAIN THE PAUCITY OF VIABLE PREVENTIVE AND DISEASE-MODIFYING STRATEGIES TO COUNTER IT. ADVANCES IN GENOME-EDITING TECHNIQUES MAY IMPROVE DISEASE-MODIFYING SOLUTIONS BY ADDRESSING INHERITED PREDISPOSING RISK FACTORS AND THE ACTIVITY OF INFLAMMATORY MODULATORS. RECENT PROGRESS ON TECHNOLOGIES SUCH AS CRISPR/CAS9 AND CELL-BASED GENOME-EDITING THERAPIES TARGETING THE GENETIC AND EPIGENETIC ALTERNATIONS IN OA OFFER PROMISING AVENUES FOR EARLY DIAGNOSIS AND THE DEVELOPMENT OF PERSONALIZED THERAPIES. THE PURPOSE OF THIS LITERATURE REVIEW WAS TO CONCISELY SUMMARIZE THE GENOME-EDITING OPTIONS AGAINST CHRONIC DEGENERATIVE JOINT CONDITIONS SUCH AS OA WITH A FOCUS ON THE MORE RECENTLY EMERGING MODALITIES, ESPECIALLY CRISPR/CAS9. FUTURE ADVANCEMENTS IN NOVEL GENOME-EDITING THERAPIES MAY IMPROVE THE EFFICACY OF SUCH TARGETED TREATMENTS. 2020 4 5797 34 STEM CELL-BASED THERAPY FOR HIRSCHSPRUNG DISEASE, DO WE HAVE THE GUTS TO TREAT? HIRSCHSPRUNG DISEASE (HSCR) IS A CONGENITAL ANOMALY OF THE COLON THAT RESULTS FROM FAILURE OF ENTERIC NERVOUS SYSTEM FORMATION, LEADING TO A CONSTRICTED DYSFUNCTIONAL SEGMENT OF THE COLON WITH VARIABLE LENGTHS, AND NECESSITATING SURGICAL INTERVENTION. THE UNDERLYING PATHOPHYSIOLOGY INCLUDES A DEFECT IN NEURAL CREST CELLS MIGRATION, PROLIFERATION AND DIFFERENTIATION, WHICH ARE PARTIALLY EXPLAINED BY IDENTIFIED GENETIC AND EPIGENETIC ALTERATIONS. DESPITE THE HIGH SUCCESS RATE OF THE CURATIVE SURGERIES, THEY ARE ASSOCIATED WITH SIGNIFICANT ADVERSE OUTCOMES SUCH AS ENTEROCOLITIS, FECAL SOILING, AND CHRONIC CONSTIPATION. IN ADDITION, SOME PATIENTS SUFFER FROM EXTENSIVE LETHAL VARIANTS OF THE DISEASE, ALL OF WHICH JUSTIFY THE NEED FOR AN ALTERNATIVE CURE. DURING THE LAST 5 YEARS, THERE HAS BEEN CONSIDERABLE PROGRESS IN HSCR STEM CELL-BASED THERAPY RESEARCH. HOWEVER, MANY MAJOR ISSUES REMAIN UNSOLVED. THIS REVIEW WILL PROVIDE CONCISE BACKGROUND INFORMATION ON HSCR, OUTLINE THE FUTURE APPROACHES OF STEM CELL-BASED HSCR THERAPY, REVIEW RECENT KEY PUBLICATIONS, DISCUSS TECHNICAL AND ETHICAL CHALLENGES THE FIELD FACES PRIOR TO CLINICAL TRANSLATION, AND TACKLE SUCH CHALLENGES BY PROPOSING SOLUTIONS AND EVALUATING EXISTING APPROACHES TO PROGRESS FURTHER. 2022 5 6566 31 TRANSLATIONAL PERSPECTIVES TO TREAT EPIDERMOLYSIS BULLOSA-WHERE DO WE STAND? EPIDERMOLYSIS BULLOSA (EB) IS THE PROTOTYPICAL EXAMPLE OF GENETIC SKIN FRAGILITY DISORDERS. GENOTYPIC HETEROGENEITY, MODIFIER GENES, EPIGENETIC, BIOCHEMICAL AND ENVIRONMENTAL FACTORS ALTER AND DETERMINE PATHOGENIC TRAITS AND, ULTIMATELY, THE WIDE AND STRIKING PHENOTYPIC VARIABILITY IN EB. BESIDES THE PRIMARY STRUCTURAL-FUNCTIONAL DEFECT, CHRONIC TISSUE DAMAGE WITH INDUCTION AND DYSREGULATION OF INFLAMMATORY PATHWAYS IS A COMMON PATHOGENIC MECHANISM IN EB. IN LOCALIZED VARIANTS, THE INFLAMMATORY ABERRATIONS MAY MAINLY AFFECT THE MICROMILIEU OF LESIONAL SKIN, WHILE A SYSTEMIC INFLAMMATORY RESPONSE WAS SHOWN TO CONTRIBUTE TO THE SYSTEMIC MORBIDITY IN SEVERE EB SUBTYPES WITH EXTENSIVE CUTANEOUS INVOLVEMENT. OUR CONTINUED UNDERSTANDING OF THE PATHOPHYSIOLOGY OF EB, AS WELL AS ADVANCES IN MOLECULAR TECHNOLOGIES, HAS PAVED THE WAY FOR TRANSLATIONAL THERAPEUTIC APPROACHES. THE SPECTRUM COMPRISES OF CORRECTIVE AND SYMPTOM-RELIEVING THERAPIES THAT INCLUDE INNOVATIVE THERAPEUTIC OPTIONS GARNERED FROM THE BENCH, REPURPOSED DRUGS APPROVED FOR OTHER DISEASES, AS WELL AS STRATEGIES FOR GENE-, PROTEIN- AND CELL-BASED THERAPIES. IMMUNOLOGICAL TRAITS FURTHER DEFINE NEW TARGETS OF THERAPY, AIMED AT IMPROVING SKIN BARRIER RESTORATION, MICROBIAL SURVEILLANCE AND INFECTION CONTROL, WOUND HEALING AND ANTI-NEOPLASTIC EFFECTS. CLINICAL AVAILABILITY AND FEASIBILITY OF THESE APPROACHES FOR ALL EB PATIENTS AND SUBTYPES ARE CURRENTLY LIMITED, REFLECTING ISSUES OF EFFICACY, SPECIFICITY, TOLERABILITY AND SAFETY. A MULTISTEP TARGETING APPROACH AND HIGHLY INDIVIDUALIZED, RISK-STRATIFIED COMBINATORY TREATMENT PLANS WILL THUS BE ESSENTIAL FOR SUSTAINED EFFICACY AND IMPROVED OVERALL QUALITY OF LIFE IN EB. 2020 6 2915 32 GENE THERAPY FOR CHRONIC HBV-CAN WE ELIMINATE CCCDNA? CHRONIC INFECTION WITH THE HEPATITIS B VIRUS (HBV) IS A GLOBAL HEALTH CONCERN AND ACCOUNTS FOR APPROXIMATELY 1 MILLION DEATHS ANNUALLY. AMONGST OTHER LIMITATIONS OF CURRENT ANTI-HBV TREATMENT, FAILURE TO ELIMINATE THE VIRAL COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) AND EMERGENCE OF RESISTANCE REMAIN THE MOST WORRISOME. VIRAL REBOUND FROM LATENT EPISOMAL CCCDNA RESERVOIRS OCCURS FOLLOWING CESSATION OF THERAPY, PATIENT NON-COMPLIANCE, OR THE DEVELOPMENT OF ESCAPE MUTANTS. SIMULTANEOUS VIRAL CO-INFECTIONS, SUCH AS BY HIV-1, FURTHER COMPLICATE THERAPEUTIC INTERVENTIONS. THESE CHALLENGES HAVE PROMPTED DEVELOPMENT OF NOVEL TARGETED HEPATITIS B THERAPIES. GIVEN THE EASE WITH WHICH HIGHLY SPECIFIC AND POTENT NUCLEIC ACID THERAPEUTICS CAN BE RATIONALLY DESIGNED, GENE THERAPY HAS GENERATED INTEREST FOR ANTIVIRAL APPLICATION. GENE THERAPY STRATEGIES DEVELOPED FOR HBV INCLUDE GENE SILENCING BY HARNESSING RNA INTERFERENCE, TRANSCRIPTIONAL INHIBITION THROUGH EPIGENETIC MODIFICATION OF TARGET DNA, GENOME EDITING BY DESIGNER NUCLEASES, AND IMMUNE MODULATION WITH CYTOKINES. DNA-BINDING DOMAINS AND EFFECTORS BASED ON THE ZINC FINGER (ZF), TRANSCRIPTION ACTIVATOR-LIKE EFFECTOR (TALE), AND CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEAT (CRISPR) SYSTEMS ARE REMARKABLY WELL SUITED TO TARGETING EPISOMAL CCCDNA. THIS REVIEW DISCUSSES RECENT DEVELOPMENTS AND CHALLENGES FACING THE FIELD OF ANTI-HBV GENE THERAPY, ITS POTENTIAL CURATIVE SIGNIFICANCE AND THE PROGRESS TOWARDS CLINICAL APPLICATION. 2018 7 251 32 ADVANCED THERAPEUTIC MODALITIES IN HEPATOCELLULAR CARCINOMA: NOVEL INSIGHTS. HEPATOCELLULAR CARCINOMA (HCC), THE MOST COMMON TYPE OF LIVER CANCER, IS USUALLY A LATENT AND ASYMPTOMATIC MALIGNANCY CAUSED BY DIFFERENT AETIOLOGIES, WHICH IS A RESULT OF VARIOUS ABERRANT MOLECULAR HETEROGENEITY AND OFTEN DIAGNOSED AT ADVANCED STAGES. THE INCIDENCE AND PREVALENCE HAVE SIGNIFICANTLY INCREASED BECAUSE OF SEDENTARY LIFESTYLE, DIABETES, CHRONIC INFECTION WITH HEPATOTROPIC VIRUSES AND EXPOSURE TO AFLATOXINS. DUE TO ADVANCED INTRA- OR EXTRAHEPATIC METASTASIS, RECURRENCE IS VERY COMMON EVEN AFTER RADICAL RESECTION. IN THIS PAPER, WE HIGHLIGHTED NOVEL THERAPEUTIC MODALITIES, SUCH AS MOLECULAR-TARGETED THERAPIES, TARGETED RADIONUCLIDE THERAPIES AND EPIGENETIC MODIFICATION-BASED THERAPIES. THESE TOPICS ARE TRENDING HEADLINES AND THEIR COMBINATION WITH CELL-BASED IMMUNOTHERAPIES, AND GENE THERAPY HAS PROVIDED PROMISING PROSPECTS FOR THE FUTURE OF HCC TREATMENT. MOREOVER, A COMPREHENSIVE OVERVIEW OF CURRENT AND ADVANCED THERAPEUTIC APPROACHES IS DISCUSSED AND THE ADVANTAGES AND LIMITATIONS OF EACH STRATEGY ARE DESCRIBED. FINALLY, VERY RECENT AND APPROVED NOVEL COMBINED THERAPIES AND THEIR PROMISING RESULTS IN HCC TREATMENT HAVE BEEN INTRODUCED. 2021 8 5440 34 RENAL DIFFERENTIATION OF AMNIOTIC FLUID STEM CELLS: PERSPECTIVES FOR CLINICAL APPLICATION AND FOR STUDIES ON SPECIFIC HUMAN GENETIC DISEASES. BACKGROUND: OWING TO GROWING RATES OF DIABETES, HYPERTENSION AND THE AGEING POPULATION, THE PREVALENCE OF END-STAGE RENAL DISEASE, DEVELOPED FROM EARLIER STAGES OF CHRONIC KIDNEY DISEASE, AND OF ACUTE RENAL FAILURE IS DRAMATICALLY INCREASING. DIALYSIS AND PREFERABLE RENAL TRANSPLANTATION ARE WIDELY APPLIED THERAPIES FOR THIS INCURABLE CONDITION. HOWEVER THESE OPTIONS ARE LIMITED BECAUSE OF MORBIDITY, SHORTAGE OF COMPATIBLE ORGANS AND COSTS. THEREFORE, STEM CELL-BASED APPROACHES ARE BECOMING INCREASINGLY ACCEPTED AS AN ALTERNATIVE THERAPEUTIC STRATEGY. DESIGN: THIS REVIEW SUMMARIZES THE CURRENT FINDINGS ON THE NEPHROGENIC POTENTIAL OF AMNIOTIC FLUID STEM (AFS) CELLS AND THEIR PUTATIVE IMPLICATIONS FOR CLINICAL APPLICATIONS AND FOR STUDIES ON SPECIFIC HUMAN GENETIC DISEASES. RESULTS: SINCE THEIR DISCOVERY IN 2003, AFS CELLS HAVE BEEN SHOWN TO BE PLURIPOTENT WITH THE POTENTIAL TO FORM EMBRYOID BODIES. COMPARED TO ADULT STEM CELLS, INDUCED PLURIPOTENT STEM CELLS OR EMBRYONIC STEM CELLS, AFS CELLS HARBOUR A VARIETY OF ADVANTAGES, SUCH AS THEIR HIGH DIFFERENTIATION AND PROLIFERATIVE POTENTIAL, NO NEED FOR ECTOPIC INDUCTION OF PLURIPOTENCY AND NO SOMATIC MUTATIONS AND EPIGENETIC MEMORY OF SOURCE CELLS, AND NO TUMOURIGENIC POTENTIAL AND ASSOCIATED ETHICAL CONTROVERSIES, RESPECTIVELY. CONCLUSIONS: RECENTLY, THE RESULTS OF DIFFERENT INDEPENDENT STUDIES PROVIDED EVIDENCE THAT AFS CELLS COULD INDEED BE A POWERFUL TOOL FOR RENAL REGENERATIVE MEDICINE. 2012 9 6712 23 VIRUS-HOST INTERPLAY IN HEPATITIS B VIRUS INFECTION AND EPIGENETIC TREATMENT STRATEGIES. WORLDWIDE, CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS A MAJOR HEALTH PROBLEM AND NO CURE EXISTS. IMPORTANTLY, HEPATOCYTE INTRUSION BY HBV PARTICLES RESULTS IN A COMPLEX DEREGULATION OF BOTH VIRAL AND HOST CELLULAR GENETIC AND EPIGENETIC PROCESSES. AMONG THE ATTEMPTS TO DEVELOP NOVEL THERAPEUTIC APPROACHES AGAINST HBV INFECTION, SEVERAL OPTIONS TARGETING THE EPIGENOMIC REGULATION OF HBV REPLICATION ARE GAINING ATTENTION. THESE INCLUDE THE EXPERIMENTAL TREATMENT WITH 'EPIDRUGS'. MOREOVER, AS A TARGETED APPROACH, THE PRINCIPLE OF 'EPIGENETIC EDITING' RECENTLY IS BEING EXPLOITED TO CONTROL VIRAL REPLICATION. SILENCING OF HBV BY SPECIFIC REWRITING OF EPIGENETIC MARKS MIGHT DIMINISH VIRAL REPLICATION, VIREMIA, AND INFECTIVITY, EVENTUALLY CONTROLLING THE DISEASE AND ITS COMPLICATIONS. ADDITIONALLY, EPIGENETIC EDITING CAN BE USED AS AN EXPERIMENTAL TOOL TO INCREASE OUR LIMITED UNDERSTANDING REGARDING THE ROLE OF EPIGENETIC MODIFICATIONS IN VIRAL INFECTIONS. AIMING FOR PERMANENT EPIGENETIC REPROGRAMMING OF THE VIRAL GENOME WITHOUT UNSPECIFIC SIDE EFFECTS, THIS BREAKTHROUGH MAY PAVE THE ROADS FOR AN AMBITIOUS TECHNOLOGICAL PURSUIT: TO START DESIGNING A CURATIVE APPROACH UTILIZING MANIPULATIVE MOLECULAR THERAPIES FOR VIRAL INFECTIONS IN VIVO. 2017 10 5952 41 TARGETING VIRAL CCCDNA FOR CURE OF CHRONIC HEPATITIS B. PURPOSE OF REVIEW: CHRONIC HEPATITIS B (CHB), CAUSED BY HEPATITIS B VIRUS (HBV), IS A MAJOR CAUSE OF ADVANCED LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC) WORLDWIDE. HBV REPLICATION IS CHARACTERIZED BY THE SYNTHESIS OF COVALENTLY CLOSED CIRCULAR (CCC) DNA WHICH IS NOT TARGETED BY ANTIVIRAL NUCLEOS(T)IDE ANALOGUES (NUCS) THE KEY MODALITY OF STANDARD OF CARE. WHILE HBV REPLICATION IS SUCCESSFULLY SUPPRESSED IN TREATED PATIENTS, THEY REMAIN AT RISK FOR DEVELOPING HCC. WHILE FUNCTIONAL CURE, CHARACTERIZED BY LOSS OF HBSAG, IS THE FIRST GOAL OF NOVEL ANTIVIRAL THERAPIES, CURATIVE TREATMENTS ELIMINATING CCCDNA REMAIN THE ULTIMATE GOAL. THIS REVIEW SUMMARIZES RECENT ADVANCES IN THE DISCOVERY AND DEVELOPMENT OF NOVEL THERAPEUTIC STRATEGIES AND THEIR IMPACT ON CCCDNA BIOLOGY. RECENT FINDINGS: WITHIN THE LAST DECADE, SUBSTANTIAL PROGRESS HAS BEEN MADE IN THE UNDERSTANDING OF CCCDNA BIOLOGY INCLUDING THE DISCOVERY OF HOST DEPENDENCY FACTORS, EPIGENETIC REGULATION OF CCCDNA TRANSCRIPTION AND IMMUNE-MEDIATED DEGRADATION. SEVERAL APPROACHES TARGETING CCCDNA EITHER IN A DIRECT OR INDIRECT MANNER ARE CURRENTLY AT THE STAGE OF DISCOVERY, PRECLINICAL OR EARLY CLINICAL DEVELOPMENT. EXAMPLES INCLUDE GENOME-EDITING APPROACHES, STRATEGIES TARGETING HOST DEPENDENCY FACTORS OR EPIGENETIC GENE REGULATION, NUCLEOCAPSID MODULATORS AND IMMUNE-MEDIATED DEGRADATION. SUMMARY: WHILE DIRECT-TARGETING CCCDNA STRATEGIES ARE STILL LARGELY AT THE PRECLINICAL STAGE OF DEVELOPMENT, CAPSID ASSEMBLY MODULATORS AND IMMUNE-BASED APPROACHES HAVE REACHED THE CLINICAL PHASE. CLINICAL TRIALS ARE ONGOING TO ASSESS THEIR EFFICACY AND SAFETY IN PATIENTS INCLUDING THEIR IMPACT ON VIRAL CCCDNA. COMBINATION THERAPIES PROVIDE ADDITIONAL OPPORTUNITIES TO OVERCOME CURRENT LIMITATIONS OF INDIVIDUAL APPROACHES. 2020 11 115 28 A STEM CELL AGING FRAMEWORK, FROM MECHANISMS TO INTERVENTIONS. STEM CELLS PLAY CENTRAL ROLES IN TISSUE DEVELOPMENT, HOMEOSTASIS, AND REGENERATION. DECADES OF SCIENTIFIC RESEARCH HAVE UNCOVERED PROCESSES OF STEM CELL DECLINE IN TISSUE AND ORGANISMAL AGING, AND MORE RECENTLY, PIONEERING TECHNOLOGIES PERMIT THE DISSECTION OF ITS UNDERLYING MECHANISMS AND INFORM THERAPEUTIC DEVELOPMENT FOR AGING AND AGING-ASSOCIATED DISORDERS. IN THIS REVIEW, WE ELUCIDATE AGING-RELATED FEATURES ACROSS DIFFERENT SOMATIC STEM CELL TYPES, WITH A SPECIFIC FOCUS ON EPIGENETIC CHANGES, LOSS OF PROTEIN HOMEOSTASIS, AND SYSTEMIC INFLUENCING FACTORS, INCLUDING CHRONIC INFLAMMATION, CIRCADIAN RHYTHM DYSREGULATION, AND METABOLIC DISORDER. OUR SURVEY OF ORGANISMAL STEM CELL AGING SUMMARIZES ITS UNDERLYING BIOLOGICAL IMPLICATIONS, POINTS TO POTENTIAL BIOMARKERS OF STEM CELL AGING, AND DISCUSSES STEM CELL-BASED THERAPEUTIC STRATEGIES WITH THE POTENTIAL FOR PROMOTING HEALTHY AGING AND COMBATING AGING AND AGE-RELATED DISEASES. 2022 12 5365 24 RECENT ADVANCES IN HEPATITIS B TREATMENT. HEPATITIS B VIRUS INFECTION AFFECTS OVER 250 MILLION CHRONIC CARRIERS, CAUSING MORE THAN 800,000 DEATHS ANNUALLY, ALTHOUGH A SAFE AND EFFECTIVE VACCINE IS AVAILABLE. CURRENTLY USED ANTIVIRAL AGENTS, PEGYLATED INTERFERON AND NUCLEOS(T)IDE ANALOGUES, HAVE MAJOR DRAWBACKS AND FAIL TO COMPLETELY ERADICATE THE VIRUS FROM INFECTED CELLS. THUS, ACHIEVING A "FUNCTIONAL CURE" OF THE INFECTION REMAINS A REAL CHALLENGE. RECENT FINDINGS CONCERNING THE VIRAL REPLICATION CYCLE HAVE LED TO DEVELOPMENT OF NOVEL THERAPEUTIC APPROACHES INCLUDING VIRAL ENTRY INHIBITORS, EPIGENETIC CONTROL OF CCCDNA, IMMUNE MODULATORS, RNA INTERFERENCE TECHNIQUES, RIBONUCLEASE H INHIBITORS, AND CAPSID ASSEMBLY MODULATORS. PROMISING PRECLINICAL RESULTS HAVE BEEN OBTAINED, AND THE LEADING MOLECULES UNDER DEVELOPMENT HAVE ENTERED CLINICAL EVALUATION. THIS REVIEW SUMMARIZES THE KEY STEPS OF THE HBV LIFE CYCLE, EXAMINES THE CURRENTLY APPROVED ANTI-HBV DRUGS, AND ANALYZES NOVEL HBV TREATMENT REGIMENS. 2021 13 3380 30 HIV-1 INFECTION OF GENETICALLY ENGINEERED IPSC-DERIVED CENTRAL NERVOUS SYSTEM-ENGRAFTED MICROGLIA IN A HUMANIZED MOUSE MODEL. THE CENTRAL NERVOUS SYSTEM (CNS) IS A MAJOR HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 RESERVOIR. MICROGLIA ARE THE PRIMARY TARGET CELL OF HIV-1 INFECTION IN THE CNS. CURRENT MODELS HAVE NOT ALLOWED THE PRECISE MOLECULAR PATHWAYS OF ACUTE AND CHRONIC CNS MICROGLIAL INFECTION TO BE TESTED WITH IN VIVO GENETIC METHODS. HERE, WE DESCRIBE A NOVEL HUMANIZED MOUSE MODEL UTILIZING HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED MICROGLIA TO XENOGRAFT INTO MURINE HOSTS. THESE MICE ARE ADDITIONALLY ENGRAFTED WITH HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS THAT SERVED AS A MEDIUM TO ESTABLISH A PERIPHERAL INFECTION THAT THEN SPREAD TO THE CNS MICROGLIA XENOGRAFT, MODELING A TRANS-BLOOD-BRAIN BARRIER ROUTE OF ACUTE CNS HIV-1 INFECTION WITH HUMAN TARGET CELLS. THE APPROACH IS COMPATIBLE WITH IPSC GENETIC ENGINEERING, INCLUDING INSERTING TARGETED TRANSGENIC REPORTER CASSETTES TO TRACK THE XENOGRAFTED HUMAN CELLS, ENABLING THE TESTING OF NOVEL TREATMENT AND VIRAL TRACKING STRATEGIES IN A COMPARATIVELY SIMPLE AND COST-EFFECTIVE WAY VIVO MODEL FOR NEUROHIV. IMPORTANCE: OUR MOUSE MODEL IS A POWERFUL TOOL FOR INVESTIGATING THE GENETIC MECHANISMS GOVERNING CNS HIV-1 INFECTION AND LATENCY IN THE CNS AT A SINGLE-CELL LEVEL. A MAJOR ADVANTAGE OF OUR MODEL IS THAT IT USES IPSC-DERIVED MICROGLIA, WHICH ENABLES HUMAN GENETICS, INCLUDING GENE FUNCTION AND THERAPEUTIC GENE MANIPULATION, TO BE EXPLORED IN VIVO , WHICH IS MORE CHALLENGING TO STUDY WITH CURRENT HEMATOPOIETIC STEM CELL-BASED MODELS FOR NEUROHIV. OUR TRANSGENIC TRACING OF XENOGRAFTED HUMAN CELLS WILL PROVIDE A QUANTITATIVE MEDIUM TO DEVELOP NEW MOLECULAR AND EPIGENETIC STRATEGIES FOR REDUCING THE HIV-1 LATENT RESERVOIR AND TO TEST THE IMPACT OF THERAPEUTIC INFLAMMATION-TARGETING DRUG INTERVENTIONS ON CNS HIV-1 LATENCY. 2023 14 6143 35 THE EVOLVING LANDSCAPE OF CANCER STEM CELLS AND WAYS TO OVERCOME CANCER HETEROGENEITY. CANCER STEM CELLS (CSCS) WITH THERAPEUTIC RESISTANCE AND PLASTICITY CAN BE FOUND IN VARIOUS TYPES OF TUMORS AND ARE RECOGNIZED AS ATTRACTIVE TARGETS FOR TREATMENTS. AS CSCS ARE DERIVED FROM TISSUE STEM OR PROGENITOR CELLS, AND/OR DEDIFFERENTIATED MATURE CELLS, THEIR SIGNAL TRANSDUCTION PATHWAYS ARE CRITICAL IN THE REGULATION OF CSCS; CHRONIC INFLAMMATION CAUSES THE ACCUMULATION OF GENETIC MUTATIONS AND ABERRANT EPIGENETIC CHANGES IN THESE CELLS, POTENTIALLY LEADING TO THE PRODUCTION OF CSCS. HOWEVER, THE NATURE OF CSCS APPEARS TO BE STRONGER THAN THE TREATMENTS OF THE PAST. TO IMPROVE THE TREATMENTS TARGETING CSCS, IT IS IMPORTANT TO INHIBIT SEVERAL MOLECULES ON THE SIGNALING CASCADES IN CSCS SIMULTANEOUSLY, AND TO OVERCOME CANCER HETEROGENEITY CAUSED BY THE PLASTICITY. TO SELECT SUITABLE TARGET MOLECULES FOR CSCS, WE HAVE TO EXPLORE THE LANDSCAPE OF CSCS FROM THE PERSPECTIVE OF CANCER STEMNESS AND SIGNALING SYSTEMS, BASED ON THE CURATED DATABASES OF CANCER-RELATED GENES. WE HAVE BEEN STUDYING THE INTEGRATION OF A BROAD RANGE OF KNOWLEDGE AND EXPERIENCES FROM CANCER BIOLOGY, AND ALSO FROM OTHER INTERDISCIPLINARY BASIC SCIENCES. IN THIS REVIEW, WE HAVE INTRODUCED THE CONCEPT OF DEVELOPING NOVEL STRATEGIES TARGETING CSCS. 2019 15 5523 27 RISKS AND MECHANISMS OF ONCOLOGICAL DISEASE FOLLOWING STEM CELL TRANSPLANTATION. UNIQUE BIOLOGICAL PROPERTIES OF STEM CELLS MAKE THEM A PRECIOUS SOURCE OF CELL MATERIAL FOR TREATMENT OF A NUMBER OF PATHOLOGICAL CONDITIONS. AMONG ISSUES INHIBITING TRANSITION OF STEM CELL TECHNOLOGIES TO THE CLINICS, THE RISK OF ONCOLOGICAL COMPLICATIONS OF STEM CELL-BASED THERAPIES IS THE MOST CRITICAL. A MASSIVE AMOUNT OF CLINICAL AND EXPERIMENTAL DATA DEMONSTRATES THAT BOTH HEMATOLOGICAL (INCLUDING ACUTE AND CHRONIC MYELOID LEUKEMIA) AND NON-HEMATOLOGICAL (INCLUDING TERATOMA AND NON-TERATOMA TUMORS) MALIGNANCIES COULD ARISE FROM DONOR STEM CELLS OF DIFFERENT TYPES. A WIDE SPECTRUM OF MECHANISMS COULD UNDERLIE THE DEVELOPMENT OF ONCOLOGICAL DISEASE IN RECIPIENTS, INCLUDING: I) BLAST TRANSFORMATION OF PROLIFERATING DONOR STEM CELLS UNDER PERSISTENT ACTION OF CERTAIN FACTORS IN THE RECIPIENT, THUS CAUSING DE NOVO MALIGNANCIES; II) CONTAMINATION OF DONOR CELL MATERIAL WITH MALIGNANT CELLS; III) TRANSMISSION OF PARTICULAR VIRAL SUBTYPES WITH DONOR STEM CELLS, COMBINED WITH IMMUNOSUPPRESSION THERAPY EFFECTS; IV) UNCONTROLLABLE PROLIFERATION OF RESIDUAL UNDIFFERENTIATED STEM CELLS OF VARIOUS PLASTICITY; AND V) KARYOTYPIC INSTABILITY IN STEM CELLS FOLLOWING PROLONGED CULTURING/EXPANSION IN VITRO. POTENTIAL PREVENTIVE STRATEGIES ARE DIVERSE AND INCLUDE I) HIGH-THROUGHPUT CELL SORTING-BASED STRATEGIES; II) INTRODUCTION OF SUICIDE GENES INTO THE DONOR STEM CELL GENOME; III) APPLICATION OF APOPTOSIS-INDUCING EPIGENETIC FACTORS; AND SOME OTHER OPTIONS. 2010 16 2701 21 EXCESSIVE BRANCHED-CHAIN AMINO ACID ACCUMULATION RESTRICTS MESENCHYMAL STEM CELL-BASED THERAPY EFFICACY IN MYOCARDIAL INFARCTION. MESENCHYMAL STEM CELLS (MSCS) DELIVERED INTO THE POST-ISCHEMIC HEART MILIEU HAVE A LOW SURVIVAL AND RETENTION RATE, THUS RESTRICTING THE CARDIOREPARATIVE EFFICACY OF MSC-BASED THERAPY. CHRONIC ISCHEMIA RESULTS IN METABOLIC REPROGRAMMING IN THE HEART, BUT LITTLE IS KNOWN ABOUT HOW THESE METABOLIC CHANGES INFLUENCE IMPLANTED MSCS. HERE, WE FOUND THAT EXCESSIVE BRANCHED-CHAIN AMINO ACID (BCAA) ACCUMULATION, A METABOLIC SIGNATURE SEEN IN THE POST-ISCHEMIC HEART, WAS DISADVANTAGEOUS TO THE RETENTION AND CARDIOPROTECTION OF INTRAMYOCARDIALLY INJECTED MSCS. DISCOVERY-DRIVEN EXPERIMENTS REVEALED THAT BCAA AT PATHOLOGICAL LEVELS SENSITIZED MSCS TO STRESS-INDUCED CELL DEATH AND PREMATURE SENESCENCE VIA ACCELERATING THE LOSS OF HISTONE 3 LYSINE 9 TRIMETHYLATION (H3K9ME3). A NOVEL MTORC1/DUX4/KDM4E AXIS WAS IDENTIFIED AS THE CAUSE OF BCAA-INDUCED H3K9ME3 LOSS AND ADVERSE PHENOTYPE ACQUISITION. ENHANCING BCAA CATABOLIC CAPABILITY IN MSCS VIA GENETIC/PHARMACOLOGICAL APPROACHES GREATLY IMPROVED THEIR ADAPTATION TO THE HIGH BCAA MILIEU AND STRENGTHENED THEIR CARDIOPROTECTIVE EFFICACY. WE CONCLUDE THAT ABERRANT BCAA ACCUMULATION IS DETRIMENTAL TO IMPLANTED MSCS VIA A PREVIOUSLY UNKNOWN METABOLITE-SIGNALING-EPIGENETIC MECHANISM, EMPHASIZING THAT THE METABOLIC CHANGES OF THE POST-ISCHEMIC HEART CRUCIALLY INFLUENCE THE FATE OF IMPLANTED MSCS AND THEIR THERAPEUTIC BENEFITS. 2022 17 3682 20 INFLAMMATION, FIBROSIS AND CANCER: MECHANISMS, THERAPEUTIC OPTIONS AND CHALLENGES. UNCONTROLLED INFLAMMATION IS A SALIENT FACTOR IN MULTIPLE CHRONIC INFLAMMATORY DISEASES AND CANCERS. IN THIS REVIEW, WE PROVIDED AN IN-DEPTH ANALYSIS OF THE RELATIONSHIPS AND DISTINCTIONS BETWEEN UNCONTROLLED INFLAMMATION, FIBROSIS AND CANCERS, WHILE EMPHASIZING THE CHALLENGES AND OPPORTUNITIES OF DEVELOPING NOVEL THERAPIES FOR THE TREATMENT AND/OR MANAGEMENT OF THESE DISEASES. WE DESCRIBED HOW DRUG DELIVERY SYSTEMS, COMBINATION THERAPY AND THE INTEGRATION OF TISSUE-TARGETED AND/OR PATHWAYS SELECTIVE STRATEGIES COULD OVERCOME THE CHALLENGES OF CURRENT AGENTS FOR MANAGING AND/OR TREATING CHRONIC INFLAMMATORY DISEASES AND CANCERS. WE ALSO RECOGNIZED THE VALUE OF THE RE-EVALUATION OF THE DISEASE-SPECIFIC ROLES OF MULTIPLE PATHWAYS IMPLICATED IN THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATORY DISEASES AND CANCERS-AS WELL AS THE APPLICATION OF DATA FROM SINGLE-CELL RNA SEQUENCING IN THE SUCCESS OF FUTURE DRUG DISCOVERY ENDEAVORS. 2022 18 3275 26 HEPATOCELLULAR CARCINOMA: THERAPEUTIC ADVANCES IN SIGNALING, EPIGENETIC AND IMMUNE TARGETS. HEPATOCELLULAR CARCINOMA (HCC) REMAINS A GLOBAL MEDICAL BURDEN WITH RISING INCIDENCE DUE TO CHRONIC VIRAL HEPATITIS AND NON-ALCOHOLIC FATTY LIVER DISEASES. TREATMENT OF ADVANCED DISEASE STAGES IS STILL UNSATISFYING. BESIDES FIRST AND SECOND GENERATION TYROSINE KINASE INHIBITORS, IMMUNE CHECKPOINT INHIBITORS HAVE BECOME CENTRAL FOR THE TREATMENT OF HCC. NEW MODALITIES LIKE EPIGENETIC THERAPY USING HISTONE DEACETYLASE INHIBITORS (HDACI) AND CELL THERAPY APPROACHES WITH CHIMERIC ANTIGEN RECEPTOR T CELLS (CAR-T CELLS) ARE CURRENTLY UNDER INVESTIGATION IN CLINICAL TRIALS. DEVELOPMENT OF SUCH NOVEL DRUGS IS CLOSELY LINKED TO THE AVAILABILITY AND IMPROVEMENT OF NOVEL PRECLINICAL AND ANIMAL MODELS AND THE IDENTIFICATION OF PREDICTIVE BIOMARKERS. THE CURRENT STATUS OF TREATMENT OPTIONS FOR ADVANCED HCC, EMERGING NOVEL THERAPEUTIC APPROACHES AND DIFFERENT PRECLINICAL MODELS FOR HCC DRUG DISCOVERY AND DEVELOPMENT ARE REVIEWED HERE. 2019 19 6479 34 TOWARD A NEW ERA OF HEPATITIS B VIRUS THERAPEUTICS: THE PURSUIT OF A FUNCTIONAL CURE. HEPATITIS B VIRUS (HBV) INFECTION, ALTHOUGH PREVENTABLE BY VACCINATION, REMAINS A GLOBAL HEALTH PROBLEM AND A MAJOR CAUSE OF CHRONIC LIVER DISEASE. ALTHOUGH CURRENT TREATMENT STRATEGIES SUPPRESS VIRAL REPLICATION VERY EFFICIENTLY, THE OPTIMAL ENDPOINT OF HEPATITIS B SURFACE ANTIGEN (HBSAG) CLEARANCE IS RARELY ACHIEVED. MOREOVER, THE THORNY PROBLEMS OF PERSISTENT CHROMATIN-LIKE COVALENTLY CLOSED CIRCULAR DNA AND THE PRESENCE OF INTEGRATED HBV DNA IN THE HOST GENOME ARE IGNORED. THEREFORE, THE SCIENTIFIC COMMUNITY HAS FOCUSED ON DEVELOPING INNOVATIVE THERAPEUTIC APPROACHES TO ACHIEVE A FUNCTIONAL CURE OF HBV, DEFINED AS UNDETECTABLE HBV DNA AND HBSAG LOSS OVER A LIMITED TREATMENT PERIOD. A DEEPER UNDERSTANDING OF THE HBV LIFE CYCLE HAS LED TO THE INTRODUCTION OF NOVEL DIRECT-ACTING ANTIVIRALS THAT EXERT THEIR FUNCTION THROUGH MULTIPLE MECHANISMS, INCLUDING INHIBITION OF VIRAL ENTRY, TRANSCRIPTIONAL SILENCING, EPIGENETIC MANIPULATION, INTERFERENCE WITH CAPSID ASSEMBLY, AND DISRUPTION OF HBSAG RELEASE. IN PARALLEL, ANOTHER CATEGORY OF NEW DRUGS AIMS TO RESTORE DYSREGULATED IMMUNE FUNCTION IN CHRONIC HEPATITIS B ACCOMPANIED BY LETHARGIC CELLULAR AND HUMORAL RESPONSES. STIMULATION OF INNATE IMMUNITY BY PATTERN-RECOGNITION RECEPTOR AGONISTS LEADS TO UPREGULATION OF ANTIVIRAL CYTOKINE EXPRESSION AND APPEARS TO CONTRIBUTE TO HBV CONTAINMENT. IMMUNE CHECKPOINT INHIBITORS AND ADOPTIVE TRANSFER OF GENETICALLY ENGINEERED T CELLS ARE BREAKTHROUGH TECHNOLOGIES CURRENTLY BEING EXPLORED THAT MAY ELICIT POTENT HBV-SPECIFIC T-CELL RESPONSES. IN ADDITION, SEVERAL CLINICAL TRIALS ARE ATTEMPTING TO CLARIFY THE ROLE OF THERAPEUTIC VACCINATION IN THIS SETTING. ULTIMATELY, IT IS INCREASINGLY RECOGNIZED THAT ELIMINATION OF HBV REQUIRES A TREATMENT REGIMEN BASED ON A COMBINATION OF MULTIPLE DRUGS. THIS REVIEW DESCRIBES THE RATIONALE FOR PROGRESSIVE THERAPEUTIC INTERVENTIONS AND DISCUSSES THE LATEST FINDINGS IN THE FIELD OF HBV THERAPEUTICS. 2021 20 5490 33 REVERSING T-CELL EXHAUSTION IN IMMUNOTHERAPY: A REVIEW ON CURRENT APPROACHES AND LIMITATIONS. INTRODUCTION:T CELL FUNCTIONS ARE ALTERED DURING CHRONIC VIRAL INFECTIONS AND TUMOR DEVELOPMENT. THIS IS MAINLY MANIFESTED BY SIGNIFICANT CHANGES IN T CELLS' EPIGENETIC AND METABOLIC LANDSCAPES, PUSHING THEM INTO AN 'EXHAUSTED' STATE. REVERSING THIS T CELL EXHAUSTION HAS BEEN EMERGING AS A 'GAME-CHANGING' THERAPEUTIC APPROACH AGAINST CANCER AND CHRONIC VIRAL INFECTION.AREAS COVERED:THIS REVIEW DISCUSSES THE CELLULAR PATHWAYS RELATED TO T CELL EXHAUSTION, AND THE CLINICAL DEVELOPMENT AND POSSIBLE CELLULAR TARGETS THAT CAN BE EXPLOITED THERAPEUTICALLY TO REVERSE THIS EXHAUSTION. WE SEARCHED VARIOUS DATABASES (E.G. GOOGLE SCHOLAR, PUBMED, ELSEVIER, AND OTHER SCIENTIFIC DATABASE SITES) USING THE KEYWORDS T CELL EXHAUSTION, T CELL ACTIVATION, CO-INHIBITORY RECEPTORS, AND REVERSING T CELL EXHAUSTION.EXPERT OPINION:THE DISCOVERY OF THE IMMUNE CHECKPOINTS PATHWAYS REPRESENTS A SIGNIFICANT MILESTONE TOWARD UNDERSTANDING AND REVERSING T CELL EXHAUSTION. ANTIBODIES THAT TARGET THESE PATHWAYS HAVE ALREADY DEMONSTRATED PROMISING ACTIVITIES IN REVERSING T CELL EXHAUSTION. NEVERTHELESS, THERE ARE STILL MANY ASSOCIATED LIMITATIONS. IN THIS CONTEXT, NEXT-GENERATION ALTERNATIVES ARE ON THE HORIZON. THIS INCLUDES THE USE OF SMALL MOLECULES TO BLOCK THE IMMUNE CHECKPOINTS' RECEPTORS, COMBINING THEM WITH OTHER TREATMENTS, AND IDENTIFYING NOVEL, SAFER AND MORE EFFECTIVE IMMUNOTHERAPEUTIC TARGETS. 2021