1 6882 60 [RESEARCH PROGRESS ON NON-CODING RNAS IN THE MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA]. PRIMARY LIVER CANCER ARISES FROM CHRONIC LIVER DISEASE, AND CIRRHOTIC LIVER GRADUALLY DEVELOPS INTO DYSPLASTIC NODULES THAT EVENTUALLY FORM MALIGNANT TUMORS. IN RECENT YEARS, MOLECULAR BIOTECHNOLOGY DEVELOPMENT HAS DEEPENED PEOPLE'S UNDERSTANDING ON THE PATHOGENESIS OF LIVER CANCER. EPIGENETIC MODIFICATIONS PLAY A SIGNIFICANT ROLE IN DNA METHYLATION, NON-CODING RNAS, CHROMATIN REMODELING, AND HISTONE MODIFICATION. THIS REVIEW FOCUSES ON THE PROGRESS OF CURRENTLY IMPLICATED NON-CODING RNAS IN THE MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA, AND ITS POTENTIAL APPLICATION IN IMPROVING THE DIAGNOSIS AND TREATMENT. 2018 2 2691 14 EVOLUTION OF HEPATIC FIBROSIS RESEARCH. MOLECULAR ANALYSIS OF HEPATIC FIBROGENESIS HAS PROGRESSED WITH RESPECT TO BOTH FIBROSIS PROGRESSION AND REGRESSION BY USING CELL BIOLOGICAL, MOLECULAR BIOLOGICAL AND (EPI)GENETIC APPROACHES. RECENT RESEARCHES HAVE REVEALED SOURCES OF COLLAGEN-PRODUCING CELLS OTHER THAN HEPATIC STELLATE CELLS IN THE LIVER, AND THE INVOLVEMENT OF THE INNATE IMMUNE SYSTEM AND OXIDATIVE STRESS IN THE FIBROTIC PROCESS HAS ATTRACTED NEW ATTENTION. TOGETHER WITH THESE ADVANCEMENTS IN BASIC KNOWLEDGE ON THE CELLULAR AND MOLECULAR BIOLOGY OF HEPATIC FIBROSIS, CLINICAL RESEARCHES HAVE LINKED THE CLARIFICATION OF THE RELATIONSHIP BETWEEN PROGRESSION OF THE FIBROSIS STAGE AND THERAPEUTIC EFFICACY FOR CHRONIC VIRAL HEPATITIS AND NON-ALCOHOLIC STEATOHEPATITIS AND VALIDATION OF THE REGRESSION OF ADVANCED FIBROSIS, EVEN CIRRHOSIS, OF APPROPRIATE THERAPIES USING MODERN MEDICINES. FURTHERMORE, NON-INVASIVE ASSESSMENT OF LIVER FIBROSIS USING AN ULTRASOUND-BASED MODALITY HAS BECOME A FOCUS IN THE CLINICAL DIAGNOSIS OF LIVER FIBROSIS INSTEAD OF LIVER BIOPSY. TAKEN TOGETHER, LIVER FIBROSIS RESEARCH HAS BEEN EVOLVING BOTH BASICALLY AND CLINICALLY IN THE PAST THREE DECADES. 2011 3 1348 15 DETERMINANTS OF FIBROSIS PROGRESSION AND REGRESSION IN NASH. CIRRHOSIS HAS BECOME THE MAJOR LIVER-RELATED CLINICAL ENDPOINT IN NON-ALCOHOLIC STEATOHEPATITIS (NASH). HOWEVER, PROGRESSION TO CIRRHOSIS IS LESS PREDICTABLE IN NASH THAN IN OTHER CHRONIC LIVER DISEASES. THIS IS DUE TO THE COMPLEX AND MULTIFACTORIAL AETIOLOGY OF NASH, WHICH IS DETERMINED BY LIFESTYLE AND NUTRITION, MULTIPLE GENETIC AND EPIGENETIC FACTORS, AND A PROMINENT ROLE OF HEPATIC AND EXTRAHEPATIC COMORBIDITIES. THUS, MODEST CHANGES IN THESE COFACTORS CAN ALSO INDUCE FIBROSIS REGRESSION, AT LEAST IN PATIENTS WITH PRECIRRHOTIC LIVER DISEASE. FIBROGENESIS IN NASH CORRELATES WITH, BUT IS INDIRECTLY COUPLED TO, CLASSICAL INFLAMMATION, SINCE FIBROSIS PROGRESSION IS DRIVEN BY REPETITIVE PERIODS OF REPAIR. WHILE HEPATOCYTE LIPOAPOPTOSIS IS A KEY DRIVING FORCE OF FIBROSIS PROGRESSION, ACTIVATED HEPATIC STELLATE CELLS, MYOFIBROBLASTS, CHOLANGIOCYTES, MACROPHAGES AND COMPONENTS OF THE PATHOLOGICAL EXTRACELLULAR MATRIX ARE MAJOR FIBROGENIC EFFECTORS AND THUS PHARMACOLOGICAL TARGETS FOR THERAPIES AIMED AT INHIBITION OF FIBROSIS PROGRESSION OR INDUCTION OF FIBROSIS REVERSAL. THE ADVENT OF NOVEL, HIGHLY SENSITIVE AND SPECIFIC SERUM BIOMARKERS AND IMAGING METHODS TO ASSESS THE DYNAMICS OF LIVER FIBROSIS IN NASH WILL IMPROVE DETECTION, STRATIFICATION AND FOLLOW-UP OF PATIENTS WITH PROGRESSIVE NASH . THESE NON-INVASIVE TOOLS WILL ALSO PROMOTE THE CLINICAL DEVELOPMENT OF ANTIFIBROTIC DRUGS, BY PERMITTING THE DESIGN OF LEAN PROOF-OF-CONCEPT STUDIES, AND ENABLING DEVELOPMENT OF A PERSONALISED ANTIFIBROTIC THERAPY FOR PATIENTS WITH RAPID FIBROSIS PROGRESSION OR ADVANCED DISEASE. 2018 4 3244 20 HEPATIC STELLATE CELLS AND EXTRACELLULAR MATRIX IN HEPATOCELLULAR CARCINOMA: MORE COMPLICATED THAN EVER. HEPATOCELLULAR CARCINOMA (HCC) IS THE FIFTH MOST COMMON CANCER WORLDWIDE AND THE THIRD LEADING CAUSE OF CANCER DEATH. RECENT EPIDEMIOLOGICAL DATA INDICATE THAT THE MORTALITY RATE OF HCC WILL DOUBLE OVER THE NEXT DECADES IN THE USA AND EUROPE. LIVER CANCER PROGRESSES IN A LARGE PERCENTAGE OF CASES DURING THE CLINICAL COURSE OF CHRONIC FIBRO-INFLAMMATORY LIVER DISEASES LEADING TO CIRRHOSIS. THEREFORE, HCC DEVELOPMENT IS REGARDED AS THE RESULT OF DIFFERENT ENVIRONMENTAL RISK FACTORS EACH INVOLVING DIFFERENT GENETIC, EPIGENETIC- AND CHROMOSOMAL ALTERATIONS AND GENE MUTATIONS. DURING TUMOUR PROGRESSION, THE MALIGNANT HEPATOCYTES AND THE ACTIVATED HEPATIC STELLATE CELLS ARE ACCOMPANIED BY CANCER-ASSOCIATED FIBROBLASTS, MYOFIBROBLASTS AND IMMUNE CELLS GENERALLY CALLED TUMOUR STROMAL CELLS. THIS NEW AND DYNAMIC MILIEU FURTHER ENHANCES THE RESPONSIVENESS OF TUMOUR CELLS TOWARDS SOLUBLE MEDIATORS SECRETED BY TUMOUR STROMAL CELLS, THUS DIRECTLY AFFECTING THE MALIGNANT HEPATOCYTES. THIS RESULTS IN ALTERED MOLECULAR PATHWAYS WITH CELL PROLIFERATION AS THE MOST IMPORTANT MECHANISM OF LIVER CANCER PROGRESSION. GIVEN THIS CONTEXTUAL COMPLEXITY, IT IS OF UTMOST IMPORTANCE TO CHARACTERIZE THE MOLECULAR PATHOGENESIS OF HCC, AND TO IDENTIFY THE DOMINANT PATHWAYS/DRIVERS AND ABERRANT SIGNALLING PATHWAYS. THIS WILL ALLOW AN EFFECTIVE THERAPY FOR HCC THAT SHOULD COMBINE STRATEGIES AFFECTING BOTH CANCER AND THE TUMOUR STROMAL CELLS. THIS REVIEW PROVIDES AN OVERVIEW OF THE RECENT CHALLENGES AND ISSUES REGARDING HEPATIC STELLATE CELLS, EXTRACELLULAR MATRIX DYNAMICS, LIVER FIBROSIS/CIRRHOSIS AND THERAPY, TUMOUR MICROENVIRONMENT AND HCC. 2014 5 2283 24 EPIGENETIC REGULATION IN FIBROSIS PROGRESS. FIBROSIS, A COMMON PROCESS OF CHRONIC INFLAMMATORY DISEASES, IS DEFINED AS A REPAIR RESPONSE DISORDER WHEN ORGANS UNDERGO CONTINUOUS DAMAGE, ULTIMATELY LEADING TO SCAR FORMATION AND FUNCTIONAL FAILURE. AROUND THE WORLD, FIBROTIC DISEASES CAUSE HIGH MORTALITY, UNFORTUNATELY, WITH LIMITED TREATMENT MEANS IN CLINICAL PRACTICE. WITH THE DEVELOPMENT AND APPLICATION OF DEEP SEQUENCING TECHNOLOGY, COMPREHENSIVELY EXPLORING THE EPIGENETIC MECHANISM IN FIBROSIS HAS BEEN ALLOWED. EXTENSIVE REMODELING OF EPIGENETICS CONTROLLING VARIOUS CELLS PHENOTYPE AND MOLECULAR MECHANISMS INVOLVED IN FIBROGENESIS WAS SUBSEQUENTLY VERIFIED. IN THIS REVIEW, WE SUMMARIZE THE REGULATORY MECHANISMS OF DNA METHYLATION, HISTONE MODIFICATION, NONCODING RNAS (NCRNAS) AND N6-METHYLADENOSINE (M6A) MODIFICATION IN ORGAN FIBROSIS, FOCUSING ON HEART, LIVER, LUNG AND KIDNEY. ADDITIONALLY, WE EMPHASIZE THE DIVERSITY OF EPIGENETICS IN THE CELLULAR AND MOLECULAR MECHANISMS RELATED TO FIBROSIS. FINALLY, THE POTENTIAL AND PROSPECT OF TARGETED THERAPY FOR FIBROSIS BASED ON EPIGENETIC IS DISCUSSED. 2021 6 4666 21 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 7 4720 26 NONCODING RNAS AS ADDITIONAL MEDIATORS OF EPIGENETIC REGULATION IN NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAS EMERGED AS THE MOST COMMON CAUSE OF CHRONIC LIVER DISORDER WORLDWIDE. IT REPRESENTS A SPECTRUM THAT INCLUDES A CONTINUUM OF DIFFERENT CLINICAL ENTITIES RANGING FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS, WHICH CAN EVOLVE TO CIRRHOSIS AND IN SOME CASES TO HEPATOCELLULAR CARCINOMA, ULTIMATELY LEADING TO LIVER FAILURE. THE PATHOGENESIS OF NAFLD AND THE MECHANISMS UNDERLYING ITS PROGRESSION TO MORE PATHOLOGICAL STAGES ARE NOT COMPLETELY UNDERSTOOD. BESIDES GENETIC FACTORS, EVIDENCE INDICATES THAT EPIGENETIC MECHANISMS OCCURRING IN RESPONSE TO ENVIRONMENTAL STIMULI ALSO CONTRIBUTE TO THE DISEASE RISK. NONCODING RNAS (NCRNAS), INCLUDING MICRORNAS, LONG NONCODING RNAS, AND CIRCULAR RNAS, ARE ONE OF THE EPIGENETIC FACTORS THAT PLAY KEY REGULATORY ROLES IN THE DEVELOPMENT OF NAFLD. AS THE FIELD OF NCRNAS IS RAPIDLY EVOLVING, THE PRESENT REVIEW AIMS TO EXPLORE THE CURRENT STATE OF KNOWLEDGE ON THE ROLES OF THESE RNA SPECIES IN THE PATHOGENESIS OF NAFLD, HIGHLIGHT RELEVANT MECHANISMS BY WHICH SOME NCRNAS CAN MODULATE REGULATORY NETWORKS IMPLICATED IN NAFLD, AND DISCUSS KEY CHALLENGES AND FUTURE DIRECTIONS FACING CURRENT RESEARCH IN THE HOPES OF DEVELOPING NCRNAS AS NEXT-GENERATION NON-INVASIVE DIAGNOSTICS AND THERAPIES IN NAFLD AND SUBSEQUENT PROGRESSION TO HEPATOCELLULAR CARCINOMA. 2022 8 2502 15 EPIGENETICS AND LIVER FIBROSIS. LIVER FIBROSIS ARISES BECAUSE PROLONGED INJURY COMBINED WITH EXCESSIVE SCAR DEPOSITION WITHIN HEPATIC PARENCHYMA ARISING FROM OVERACTIVE WOUND HEALING RESPONSE MEDIATED BY ACTIVATED MYOFIBROBLASTS. FIBROSIS IS THE COMMON END POINT FOR ANY TYPE OF CHRONIC LIVER INJURY INCLUDING ALCOHOLIC LIVER DISEASE, NONALCOHOLIC FATTY LIVER DISEASE, VIRAL HEPATITIS, AND CHOLESTATIC LIVER DISEASES. ALTHOUGH GENETIC INFLUENCES ARE IMPORTANT, IT IS EPIGENETIC MECHANISMS THAT HAVE BEEN SHOWN TO ORCHESTRATE MANY ASPECTS OF FIBROGENESIS IN THE LIVER. NEW DISCOVERIES IN THE FIELD ARE LEADING TOWARD THE DEVELOPMENT OF EPIGENETIC BIOMARKERS AND TARGETED THERAPIES. THIS REVIEW CONSIDERS EPIGENETIC MECHANISMS AS WELL AS RECENT ADVANCES IN EPIGENETIC PROGRAMMING IN THE CONTEXT OF HEPATIC FIBROSIS. 2017 9 2851 21 FROM CIRRHOSIS TO HEPATOCELLULAR CARCINOMA: NEW MOLECULAR INSIGHTS ON INFLAMMATION AND CELLULAR SENESCENCE. SEQUENTIAL PROGRESSION FROM CHRONIC LIVER DISEASE TO FIBROSIS AND TO CIRRHOSIS CULMINATES IN NEOPLASIA IN HEPATOCELLULAR CARCINOMA (HCC). THE PRENEOPLASTIC SETTING OF THE CIRRHOTIC BACKGROUND PROVIDES A CONDUCIVE ENVIRONMENT FOR CELLULAR TRANSFORMATION. THE ROLE OF CLASSICAL INFLAMMATION IN CIRRHOSIS IS WIDELY KNOWN, BUT THE EXACT MECHANISM LINKING INFLAMMATION AND CANCER REMAINS ELUSIVE. RECENT STUDIES HAVE ELUCIDATED ROLES FOR NF-KAPPAB, STAT3 AND JNK AS POSSIBLE MISSING LINKS. IN ADDITION, THE "INFLAMMASOME" (A MULTIPROTEIN COMPLEX AND SENSOR OF CELLULAR DAMAGE) IS A RECENTLY IDENTIFIED PLAYER IN THIS FIELD. THE HALLMARKS OF CIRRHOSIS INCLUDE NECROINFLAMMATION, DEPOSITION OF EXTRACELLULAR MATRIX AND SHORTENING OF TELOMERES, LEADING TO SENESCENCE AND REGENERATION. ADDITIONALLY, THE ACCUMULATION OF GENETIC/EPIGENETIC CHANGES PROPELS ATYPICAL CELLS TOWARD A MALIGNANT PHENOTYPE. THIS REVIEW PROVIDES RECENT INFORMATION ON THE CLASSICAL INFLAMMATORY PATHWAY, TOGETHER WITH A SPOTLIGHT ON INFLAMMASOMES AND THE IMMUNOMODULATORY ROLE OF CELLULAR SENESCENCE DURING THE PROGRESSION FROM CIRRHOSIS TO HCC. MOREOVER, LACUNAE IN THE CURRENT KNOWLEDGE WERE IDENTIFIED AND KEY QUESTIONS RAISED ON WHETHER THE OBSERVED ADAPTIVE RESPONSES ARE BENEFICIAL OR DETRIMENTAL TO TISSUE HOMEOSTASIS IN A COMPLEX ORGAN LIKE LIVER. 2013 10 2211 21 EPIGENETIC MODIFICATIONS AND THE DEVELOPMENT OF KIDNEY GRAFT FIBROSIS. PURPOSE OF REVIEW: TO OUTLINE RECENT DISCOVERIES IN EPIGENETIC REGULATORY MECHANISMS THAT HAVE POTENTIAL IMPLICATIONS IN THE DEVELOPMENT OF RENAL FIBROSIS FOLLOWING KIDNEY TRANSPLANTATION. RECENT FINDINGS: THE CHARACTERIZATION OF RENAL FIBROSIS FOLLOWING KIDNEY TRANSPLANTATION HAS SHOWN TGFBETA/SMAD SIGNALING TO PLAY A MAJOR ROLE IN THE PROGRESSION TO CHRONIC ALLOGRAFT DYSFUNCTION. THE ONSET OF UNREGULATED PROINFLAMMATORY PATHWAYS ARE ONLY EXACERBATED BY THE DECLINE IN REGULATORY MECHANISMS LOST WITH PROGRESSIVE PATIENT AGE AND COMORBIDITIES SUCH AS HYPERTENSION AND DIABETES. HOWEVER, SIGNIFICANT DEVELOPMENTS IN THE RECOGNITION OF EPIGENETIC REGULATORY MARKERS UPSTREAM OF ABERRANT TGFBETA-SIGNALING HAS SIGNIFICANT CLINICAL POTENTIAL TO PROVIDE THERAPEUTIC TARGETS FOR THE TREATMENT OF RENAL FIBROSIS. IN ADDITION, DISCOVERIES IN EXTRACELLULAR VESICLES AND THE CHARACTERIZATION OF THEIR CARGO HAS LAID NEW FRAMEWORK FOR THE POTENTIAL TO EVALUATE PATIENT OUTCOMES INDEPENDENT OF INVASIVE BIOPSIES. SUMMARY: THE CURRENT REVIEW SUMMARIZES THE MAIN FINDINGS IN EPIGENETIC MACHINERY SPECIFIC TO THE DEVELOPMENT OF RENAL FIBROSIS AND HIGHLIGHTS THERAPEUTIC OPTIONS THAT HAVE SIGNIFICANT POTENTIAL TO TRANSLATE INTO CLINICAL PRACTICE. 2021 11 4613 18 NEOVASCULARIZATION IS A KEY FEATURE OF LIVER FIBROSIS PROGRESSION: ANTI-ANGIOGENESIS AS AN INNOVATIVE WAY OF LIVER FIBROSIS TREATMENT. LIVER FIBROSIS AFFECTS OVER 100 MILLION PEOPLE IN THE WORLD; IT REPRESENTS A MULTIFACTORIAL, FIBRO-INFLAMMATORY DISORDER CHARACTERIZED BY EXACERBATED PRODUCTION OF EXTRACELLULAR MATRIX WITH CONSEQUENT ABERRATION OF HEPATIC TISSUE. THE AETIOLOGY OF THIS DISEASE IS VERY COMPLEX AND SEEMS TO INVOLVE A BROAD SPECTRUM OF FACTORS INCLUDING THE LIFESTYLE, ENVIRONMENT FACTORS, GENES AND EPIGENETIC CHANGES. MORE EVIDENCES INDICATE THAT ANGIOGENESIS, A PROCESS CONSISTING IN THE FORMATION OF NEW BLOOD VESSELS FROM PRE-EXISTING VESSELS, PLAYS A CRUCIAL ROLE IN THE PROGRESSION OF LIVER FIBROSIS. CENTRAL TO THE PATHOGENESIS OF LIVER FIBROSIS IS THE HEPATIC STELLATE CELLS (HSCS) WHICH REPRESENT A CROSSROAD AMONG INFLAMMATION, FIBROSIS AND ANGIOGENESIS. QUIESCENT HSCS CAN BE STIMULATED BY A HOST OF GROWTH FACTORS, PRO-INFLAMMATORY MEDIATORS PRODUCED BY DAMAGED RESIDENT LIVER CELL TYPES, AS WELL AS BY HYPOXIA, CONTRIBUTING TO NEOANGIOGENESIS, WHICH IN TURN CAN BE A BRIDGE BETWEEN ACUTE AND CHRONIC INFLAMMATION. AS MATTER OF FACT, STUDIES DEMONSTRATED THAT NEUTRALIZATION OF VASCULAR ENDOTHELIAL GROWTH FACTOR AS WELL AS OTHER PROANGIOGENIC AGENTS CAN ATTENUATE THE PROGRESSION OF LIVER FIBROSIS. WITH THIS REVIEW, OUR INTENT IS TO DISCUSS THE CAUSE AND THE ROLE OF ANGIOGENESIS IN LIVER FIBROSIS FOCUSING ON THE CURRENT KNOWLEDGE ABOUT THE IMPACT OF ANTI-ANGIOGENETIC THERAPIES IN THIS PATHOLOGY. 2020 12 5950 14 TARGETING THE PROGRESSION OF CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS A DEVASTATING CONDITION THAT IS REACHING EPIDEMIC LEVELS OWING TO THE INCREASING PREVALENCE OF DIABETES MELLITUS, HYPERTENSION AND OBESITY, AS WELL AS AGEING OF THE POPULATION. REGARDLESS OF THE UNDERLYING AETIOLOGY, CKD IS SLOWLY PROGRESSIVE AND LEADS TO IRREVERSIBLE NEPHRON LOSS, END-STAGE RENAL DISEASE AND/OR PREMATURE DEATH. FACTORS THAT CONTRIBUTE TO CKD PROGRESSION INCLUDE PARENCHYMAL CELL LOSS, CHRONIC INFLAMMATION, FIBROSIS AND REDUCED REGENERATIVE CAPACITY OF THE KIDNEY. CURRENT THERAPIES HAVE LIMITED EFFECTIVENESS AND ONLY DELAY DISEASE PROGRESSION, UNDERSCORING THE NEED TO DEVELOP NOVEL THERAPEUTIC APPROACHES TO EITHER STOP OR REVERSE PROGRESSION. PRECLINICAL STUDIES HAVE IDENTIFIED SEVERAL APPROACHES THAT REDUCE FIBROSIS IN EXPERIMENTAL MODELS, INCLUDING TARGETING CYTOKINES, TRANSCRIPTION FACTORS, DEVELOPMENTAL AND SIGNALLING PATHWAYS AND EPIGENETIC MODULATORS, PARTICULARLY MICRORNAS. SOME OF THESE NEPHROPROTECTIVE STRATEGIES ARE NOW BEING TESTED IN CLINICAL TRIALS. LESSONS LEARNED FROM THE FAILURE OF CLINICAL STUDIES OF TRANSFORMING GROWTH FACTOR BETA1 (TGFBETA1) BLOCKADE UNDERSCORE THE NEED FOR ALTERNATIVE APPROACHES TO CKD THERAPY, AS STRATEGIES THAT TARGET A SINGLE PATHOGENIC PROCESS MAY RESULT IN UNEXPECTED NEGATIVE EFFECTS ON SIMULTANEOUSLY OCCURRING PROCESSES. ADDITIONAL PROMISING AVENUES INCLUDE PREVENTING TUBULAR CELL INJURY AND ANTI-FIBROTIC THERAPIES THAT TARGET ACTIVATED MYOFIBROBLASTS, THE MAIN COLLAGEN-PRODUCING CELLS. 2020 13 2538 27 EPIGENETICS IN HEPATOCELLULAR CARCINOMA: AN UPDATE AND FUTURE THERAPY PERSPECTIVES. HEPATOCELLULAR CARCINOMA (HCC), THE PREDOMINANT FORM OF ADULT LIVER MALIGNANCIES, IS A GLOBAL HEALTH CONCERN. ITS DISMAL PROGNOSIS HAS PROMPTED RECENT SIGNIFICANT ADVANCES IN THE UNDERSTANDING OF ITS ETIOLOGY AND PATHOGENESIS. THE DEREGULATION OF EPIGENETIC MECHANISMS, WHICH MAINTAIN HERITABLE GENE EXPRESSION CHANGES AND CHROMATIN ORGANIZATION, IS IMPLICATED IN THE DEVELOPMENT OF MULTIPLE CANCERS, INCLUDING HCC. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE OF EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF HCC, WITH AN EMPHASIS ON HCC MEDIATED BY CHRONIC HEPATITIS B VIRUS INFECTION. THIS REVIEW ALSO DISCUSSES THE ENCOURAGING OUTCOMES AND LESSONS LEARNT FROM EPIGENETIC THERAPIES FOR HEMATOLOGICAL AND OTHER SOLID CANCERS, AND HIGHLIGHTS THE FUTURE POTENTIAL OF SIMILAR THERAPIES IN THE TREATMENT OF HCC. 2014 14 944 17 CHRONIC LYMPHOCYTIC LEUKEMIA: FROM MOLECULAR PATHOGENESIS TO NOVEL THERAPEUTIC STRATEGIES. CHRONIC LYMPHOCYTIC LEUKEMIA IS A WELL-DEFINED LYMPHOID NEOPLASM WITH VERY HETEROGENEOUS BIOLOGICAL AND CLINICAL BEHAVIOR. THE LAST DECADE HAS BEEN REMARKABLY FRUITFUL IN NOVEL FINDINGS ELUCIDATING MULTIPLE ASPECTS OF THE PATHOGENESIS OF THE DISEASE INCLUDING MECHANISMS OF GENETIC SUSCEPTIBILITY, INSIGHTS INTO THE RELEVANCE OF IMMUNOGENETIC FACTORS DRIVING THE DISEASE, PROFILING OF GENOMIC ALTERATIONS, EPIGENETIC SUBTYPES, GLOBAL EPIGENOMIC TUMOR CELL REPROGRAMMING, MODULATION OF TUMOR CELL AND MICROENVIRONMENT INTERACTIONS, AND DYNAMICS OF CLONAL EVOLUTION FROM EARLY STEPS IN MONOCLONAL B CELL LYMPHOCYTOSIS TO PROGRESSION AND TRANSFORMATION INTO DIFFUSE LARGE B-CELL LYMPHOMA. ALL THIS KNOWLEDGE HAS OFFERED NEW PERSPECTIVES THAT ARE BEING EXPLOITED THERAPEUTICALLY WITH NOVEL TARGET AGENTS AND MANAGEMENT STRATEGIES. IN THIS REVIEW WE PROVIDE AN OVERVIEW OF THESE NOVEL ADVANCES AND HIGHLIGHT QUESTIONS AND PERSPECTIVES THAT NEED FURTHER PROGRESS TO TRANSLATE INTO THE CLINICS THE BIOLOGICAL KNOWLEDGE AND IMPROVE THE OUTCOME OF THE PATIENTS. 2020 15 2817 16 FIBROSIS IN THE LIVER: ACUTE PROTECTION AND CHRONIC DISEASE. THE UNDERSTANDING OF THE CELLULAR AND MOLECULAR MECHANISMS OF THE FIBROTIC WOUND-HEALING RESPONSE OF THE LIVER HAS MADE DRAMATIC PROGRESS IN THE PAST 20 YEARS. HEPATIC STELLATE CELLS (HSCS), WHICH AFTER LIVER INJURY PROLIFERATE AND TRANSDIFFERENTIATE TO MYOFIBROBLASTS, HAVE EMERGED AS THE PRIMARY SOURCE OF THE FIBROTIC RESPONSE, EVEN THOUGH OTHER FIBROGENIC CELLS MAY ALSO CONTRIBUTE TO THE PRODUCTION OF EXTRACELLULAR MATRIX (ECM). ADVANCES IN THE UNDERSTANDING OF HSC REGULATION INCLUDE APOPTOTIC SIGNALING, ANGIOGENIC SIGNALING, AND RESPONSES TO OXIDATIVE STRESS. THE ECM HAS EMERGED NOT ONLY AS A STRUCTURAL SCAFFOLD, BUT ALSO AS A DYNAMIC AND INTERACTIVE MATRIX REGULATING STELLATE CELL ACTIVATION. ADDITIONALLY, THE INNATE IMMUNE SYSTEM AND IMMUNE SIGNALING, AS WELL AS A BROADENING UNDERSTANDING OF THE TRANSCRIPTIONAL REGULATION INCLUDING MICRORNAS AND EPIGENETIC EVENTS OFFER POTENTIAL THERAPEUTIC TARGETS. UNRAVELING GENETIC DETERMINANTS RELATED TO MECHANISMS OF HEPATIC FIBROGENESIS PROMISE INDIVIDUALIZED THERAPY OR PREVENTION. HEPATIC FIBROSIS AND CIRRHOSIS HAVE EMERGED AS TREATABLE AND POTENTIALLY REVERSIBLE CONSEQUENCE OF CHRONIC LIVER DISEASE. 2010 16 3273 23 HEPATOCELLULAR CARCINOMA: MOLECULAR PATHWAYS AND NEW THERAPEUTIC TARGETS. HEPATOCELLULAR CARCINOMA IS OFTEN DIAGNOSED AT AN ADVANCED STAGE, WHEN IT IS NOT AMENABLE TO CURATIVE THERAPIES. THERE IS NO EFFECTIVE CHEMOTHERAPY. ADVANCES IN CANCER BIOLOGY SUGGEST THAT A LIMITED NUMBER OF PATHWAYS ARE RESPONSIBLE FOR INITIATING AND MAINTAINING DYSREGULATED CELL PROLIFERATION, WHICH IS THE MAJOR CELLULAR ALTERATION RESPONSIBLE FOR THE CANCER PHENOTYPE. NEW TREATMENTS IN DEVELOPMENT TARGET SEVERAL OF THESE CRITICAL PATHWAYS, INCLUDING AGENTS TARGETING THE RECEPTOR TYROSINE KINASE PATHWAYS, THE WNT/BETA-CATENIN SIGNALING PATHWAY, THE UBIQUITIN/PROTEASOME DEGRADATION PATHWAY, THE EPIGENETIC DNA METHYLATION AND HISTONE DEACETYLATION PATHWAYS, THE PI3 KINASE/AKT/MTOR PATHWAY, ANGIOGENIC PATHWAYS, AND TELOMERASE. SEVERAL OF THESE APPROACHES HOLD SIGNIFICANT PROMISE FOR IMPROVING THE LONG-TERM OUTCOME OF PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA. BECAUSE OF THE HIGH PREVALENCE OF LIVER CIRRHOSIS IN HEPATOCELLULAR CARCINOMA PATIENTS, THESE APPROACHES MUST BE COUPLED WITH NEW STRATEGIES FOR HALTING OR REVERSING THE PROGRESSION OF CHRONIC LIVER DISEASE. 2005 17 4448 21 MOLECULAR MECHANISM AND TREATMENT OF VIRAL HEPATITIS-RELATED LIVER FIBROSIS. HEPATIC FIBROSIS IS A WOUND-HEALING RESPONSE TO VARIOUS CHRONIC STIMULI, INCLUDING VIRAL HEPATITIS B OR C INFECTION. ACTIVATED MYOFIBROBLASTS, PREDOMINANTLY DERIVED FROM THE HEPATIC STELLATE CELLS (HSCS), REGULATE THE BALANCE BETWEEN MATRIX METALLOPROTEINASES AND THEIR TISSUE INHIBITORS TO MAINTAIN EXTRACELLULAR MATRIX HOMEOSTASIS. TRANSFORMING GROWTH FACTOR-BETA AND PLATELET-DERIVED GROWTH FACTOR ARE CLASSIC PROFIBROGENIC SIGNALS THAT ACTIVATE HSC PROLIFERATION. IN ADDITION, PROINFLAMMATORY CYTOKINES AND CHEMOKINES COORDINATE MACROPHAGES, T CELLS, NK/NKT CELLS, AND LIVER SINUSOIDAL ENDOTHELIAL CELLS IN COMPLEX FIBROGENIC AND REGRESSION PROCESSES. IN ADDITION, FIBROGENESIS INVOLVES ANGIOGENESIS, METABOLIC REPROGRAMMING, AUTOPHAGY, MICRORNA, AND EPIGENETIC REGULATIONS. HEPATIC INFLAMMATION IS THE DRIVING FORCE BEHIND LIVER FIBROSIS; HOWEVER, HOST SINGLE NUCLEOTIDE POLYMORPHISMS AND VIRAL FACTORS, INCLUDING THE GENOTYPE, VIRAL LOAD, VIRAL MUTATION, AND VIRAL PROTEINS, HAVE BEEN ASSOCIATED WITH FIBROSIS PROGRESSION. ELIMINATING THE UNDERLYING ETIOLOGY IS THE MOST CRUCIAL ANTIFIBROTIC THERAPY. GROWING EVIDENCE HAS INDICATED THAT PERSISTENT VIRAL SUPPRESSION WITH ANTIVIRAL THERAPY CAN RESULT IN FIBROSIS REGRESSION, REDUCED LIVER DISEASE PROGRESSION, DECREASED HEPATOCELLULAR CARCINOMA, AND IMPROVED CHANCES OF SURVIVAL. PRECLINICAL STUDIES AND CLINICAL TRIALS ARE CURRENTLY EXAMINING SEVERAL INVESTIGATIONAL AGENTS THAT TARGET KEY FIBROGENIC PATHWAYS; THE RESULTS ARE PROMISING AND SHED LIGHT ON THIS DEBILITATING ILLNESS. 2014 18 2579 22 EPIGENETICS OF KIDNEY DISEASE. DNA METHYLATION AND HISTONE MODIFICATIONS DETERMINE RENAL PROGRAMMING AND THE DEVELOPMENT AND PROGRESSION OF RENAL DISEASE. THE IDENTIFICATION OF THE WAY IN WHICH THE RENAL CELL EPIGENOME IS ALTERED BY ENVIRONMENTAL MODIFIERS DRIVING THE ONSET AND PROGRESSION OF RENAL DISEASES HAS EXTENDED OUR UNDERSTANDING OF THE PATHOPHYSIOLOGY OF KIDNEY DISEASE PROGRESSION. IN THIS REVIEW, WE FOCUS ON CURRENT KNOWLEDGE CONCERNING THE IMPLICATIONS OF EPIGENETIC MODIFICATIONS DURING RENAL DISEASE FROM EARLY DEVELOPMENT TO CHRONIC KIDNEY DISEASE PROGRESSION INCLUDING RENAL FIBROSIS, DIABETIC NEPHROPATHY AND THE TRANSLATIONAL POTENTIAL OF IDENTIFYING NEW BIOMARKERS AND TREATMENTS FOR THE PREVENTION AND THERAPY OF CHRONIC KIDNEY DISEASE AND END-STAGE KIDNEY DISEASE. 2017 19 2322 24 EPIGENETIC REGULATION OF HEPATIC STELLATE CELL ACTIVATION AND LIVER FIBROSIS. CHRONIC LIVER INJURY TO HEPATOCYTES OR CHOLANGIOCYTES, WHEN LEFT UNMANAGED, LEADS TO THE DEVELOPMENT OF LIVER FIBROSIS, A CONDITION CHARACTERIZED BY THE EXCESSIVE INTRAHEPATIC DEPOSITION OF EXTRACELLULAR MATRIX PROTEINS. ACTIVATED HEPATIC STELLATE CELLS CONSTITUTE THE PREDOMINANT SOURCE OF EXTRACELLULAR MATRIX IN FIBROTIC LIVERS AND THEIR TRANSITION FROM A QUIESCENT STATE DURING FIBROGENESIS IS ASSOCIATED WITH IMPORTANT ALTERATIONS IN THEIR TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPE. AREAS COVERED: WE BRIEFLY DESCRIBE THE PROCESSES INVOLVED IN HEPATIC STELLATE CELL ACTIVATION AND DISCUSS OUR CURRENT UNDERSTANDING OF ALTERATIONS IN THE EPIGENETIC LANDSCAPE, I.E DNA METHYLATION, HISTONE MODIFICATIONS AND THE FUNCTIONAL ROLE OF NON-CODING RNAS THAT ACCOMPANY THIS KEY EVENT IN THE DEVELOPMENT OF CHRONIC LIVER DISEASE. EXPERT COMMENTARY: ALTHOUGH GREAT PROGRESS HAS BEEN MADE, OUR UNDERSTANDING OF THE EPIGENETIC REGULATION OF HEPATIC STELLATE CELL ACTIVATION IS LIMITED AND, THUS FAR, INSUFFICIENT TO ALLOW THE DEVELOPMENT OF EPIGENETIC DRUGS THAT CAN SELECTIVELY INTERRUPT LIVER FIBROSIS. 2016 20 3103 20 GENOMIC LANDSCAPE OF HCC. INTRODUCTION: HEPATOCELLULAR CARCINOMA (HCC) IS A LEADING CAUSE OF CANCER RELATED MORTALITY IN THE WORLD AND IT HAS LIMITED TREATMENT OPTIONS. UNDERSTANDING THE MOLECULAR DRIVERS OF HCC IS IMPORTANT TO DEVELOP NOVEL BIOMARKERS AND THERAPEUTICS. PURPOSE OF REVIEW: HCC ARISES IN A COMPLEX BACKGROUND OF CHRONIC HEPATITIS, FIBROSIS AND LIVER REGENERATION WHICH LEAD TO GENOMIC CHANGES. HERE, WE SUMMARIZE STUDIES THAT HAVE EXPANDED OUR UNDERSTANDING OF THE MOLECULAR LANDSCAPE OF HCC. RECENT FINDINGS: RECENT TECHNOLOGICAL ADVANCES IN NEXT GENERATION SEQUENCING (NGS) HAVE ELUCIDATED SPECIFIC GENETIC AND MOLECULAR PROGRAMS INVOLVED IN HEPATOCARCINOGENESIS. WE SUMMARIZE THE MAJOR SOMATIC MUTATIONS AND EPIGENETIC CHANGES HAVE BEEN IDENTIFIED IN NGS-BASED STUDIES. WE ALSO DESCRIBE PROMISING MOLECULAR THERAPIES AND IMMUNOTHERAPIES WHICH TARGET SPECIFIC GENETIC AND EPIGENETIC MOLECULAR EVENTS. SUMMARY: THE GENOMIC LANDSCAPE OF HCC IS INCREDIBLY COMPLEX AND HETEROGENEOUS. PROMISING NEW DEVELOPMENTS ARE HELPING US DECIPHER THE MOLECULAR DRIVERS OF HCC AND LEADING TO NEW THERAPIES. 2020