1 852 176 CHOLANGIOCARCINOMA IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC): A COMPREHENSIVE REVIEW. CHOLANGIOCARCINOMA (CCA) IS THE MOST COMMON MALIGNANCY IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) AND CARRIES A HIGH RATE OF MORTALITY. ALTHOUGH THE PATHOGENESIS OF CCA IN PSC IS LARGELY UNKNOWN, INFLAMMATION-DRIVEN CARCINOGENESIS CONCOMITANT WITH VARIOUS GENETIC AND EPIGENETIC ABNORMALITIES ARE UNDERLYING FACTORS. THE MAJORITY OF CCA CASES DEVELOP FROM A DOMINANT STRICTURE (DS), WHICH IS DEFINED AS A STRICTURE WITH A DIAMETER < 1.5 MM IN THE COMMON BILE DUCT OR < 1.0 MM IN THE HEPATIC DUCT. IN PSC PATIENTS PRESENTING WITH AN ABRUPT AGGRAVATION OF JAUNDICE, PAIN, FATIGUE, PRURITUS, WEIGHT LOSS, OR WORSENING LIVER BIOCHEMISTRIES, CCA SHOULD BE SUSPECTED AND EVALUATED UTILIZING A VARIETY OF DIAGNOSTIC MODALITIES. HOWEVER, EARLY RECOGNITION OF CCA IN PSC REMAINS A MAJOR CHALLENGE. IMPORTANTLY, 30-50% OF CCA IN PSC PATIENTS ARE OBSERVED WITHIN THE FIRST YEAR FOLLOWING THE DIAGNOSIS OF PSC FOLLOWED BY AN ANNUAL INCIDENCE RANGING FROM 0.5 TO 1.5 PER 100 PERSONS, WHICH IS NEARLY 10 TO 1000 TIMES HIGHER THAN THAT IN THE GENERAL POPULATION. CUMULATIVE 5-YEAR, 10-YEAR, AND LIFETIME INCIDENCES ARE 7%, 8-11%, AND 9-20%, RESPECTIVELY. WHEN PSC-ASSOCIATED CCA IS DIAGNOSED, MOST TUMORS ARE UNRESECTABLE, AND NO EFFECTIVE MEDICATIONS ARE AVAILABLE. GIVEN THE POOR THERAPEUTIC OUTCOME, THE SURVEILLANCE AND MANAGEMENT OF PSC PATIENTS WHO ARE AT AN INCREASED RISK OF DEVELOPING CCA ARE OF IMPORTANCE. SUCH PATIENTS INCLUDE OLDER MALES WITH LARGE-DUCT PSC AND POSSIBLY CONCURRENT ULCERATIVE COLITIS. THUS, MORE ATTENTION SHOULD BE PAID TO PATIENTS WITH THESE CLINICAL FEATURES, IN PARTICULAR WITHIN THE FIRST YEAR AFTER PSC DIAGNOSIS. IN CONTRAST, CCA IS LESS FREQUENTLY OBSERVED IN PEDIATRIC OR FEMALE PSC PATIENTS OR IN THOSE WITH SMALL-DUCT PSC OR CONCURRENT CROHN'S DISEASE. RECENTLY, NEW BIOMARKERS SUCH AS ANTIBODIES TO GLYCOPROTEIN 2 HAVE BEEN FOUND TO BE ASSOCIATED WITH AN INCREASED RISK OF DEVELOPING CCA IN PSC. HEREIN, WE REVIEW THE LITERATURE ON THE PATHOGENESIS, INCIDENCE, CLINICAL FEATURES, AND RISK FACTORS, WITH A FOCUS ON VARIOUS DIAGNOSTIC MODALITIES OF PSC-ASSOCIATED CCA. 2020 2 5221 40 PRIMARY BILIARY CHOLANGITIS: PATHOGENESIS AND THERAPEUTIC OPPORTUNITIES. PRIMARY BILIARY CHOLANGITIS IS A CHRONIC, SEROPOSITIVE AND FEMALE-PREDOMINANT INFLAMMATORY AND CHOLESTATIC LIVER DISEASE, WHICH HAS A VARIABLE RATE OF PROGRESSION TOWARDS BILIARY CIRRHOSIS. SUBSTANTIAL PROGRESS HAS BEEN MADE IN PATIENT RISK STRATIFICATION WITH THE GOAL OF PERSONALIZED CARE, INCLUDING EARLY ADOPTION OF NEXT-GENERATION THERAPY WITH LICENSED USE OF OBETICHOLIC ACID OR OFF-LABEL FIBRATE DERIVATIVES FOR THOSE WITH INSUFFICIENT BENEFIT FROM URSODEOXYCHOLIC ACID, THE CURRENT FIRST-LINE DRUG. THE DISEASE BIOLOGY SPANS GENETIC RISK, EPIGENETIC CHANGES, DYSREGULATED MUCOSAL IMMUNITY AND ALTERED BILIARY EPITHELIAL CELL FUNCTION, ALL OF WHICH INTERACT AND ARISE IN THE CONTEXT OF ILL-DEFINED ENVIRONMENTAL TRIGGERS. A CURRENT FOCUS OF RESEARCH ON NUCLEAR RECEPTOR PATHWAY MODULATION THAT SPECIFICALLY AND POTENTLY IMPROVES BILIARY EXCRETION, REDUCES INFLAMMATION AND ATTENUATES FIBROSIS IS REDEFINING THERAPY. PATIENTS ARE BENEFITING FROM PHARMACOLOGICAL AGONISTS OF FARNESOID X RECEPTOR AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS. IMMUNOTHERAPY REMAINS A CHALLENGE, WITH A LACK OF TARGET DEFINITION, PLEIOTROPIC IMMUNE PATHWAYS AND AN INTERPLAY BETWEEN HEPATIC IMMUNE RESPONSES AND CHOLESTASIS, WHEREIN BILE ACID-INDUCED INFLAMMATION AND FIBROSIS ARE DOMINANT CLINICALLY. THE MANAGEMENT OF PATIENT SYMPTOMS, PARTICULARLY PRURITUS, IS A NOTABLE GOAL REFLECTED IN THE DEVELOPMENT OF RATIONAL THERAPY WITH APICAL SODIUM-DEPENDENT BILE ACID TRANSPORTER INHIBITORS. 2020 3 5454 23 REPURPOSING BELINOSTAT FOR ALLEVIATION OF ATOPIC DERMATITIS. ATOPIC DERMATITIS (AD) IS A HIGHLY PREVALENT CHRONIC INFLAMMATORY SKIN DISEASE THAT IS CHARACTERIZED BY INTENSE PRURITUS, SERIOUSLY AFFECTING PATIENTS' QUALITY OF LIFE. ITS PATHOPHYSIOLOGY, WHICH INVOLVES BOTH THE ADAPTIVE AND INNATE IMMUNE RESPONSES AS WELL AS SKIN BARRIER DEFECTS, IS STILL POORLY UNDERSTOOD. WE RECENTLY IDENTIFIED A MICRORNA, MIR-335, AS A KEY DRIVER OF KERATINOCYTE DIFFERENTIATION AND CORNIFICATION, WHICH IS ESSENTIAL FOR THE ESTABLISHMENT OF A HEALTHY SKIN BARRIER. HOWEVER, EXPRESSION OF MIR-335 IS LOST IN AD, LEADING TO BARRIER DEFECT. WE FURTHER DEMONSTRATED HOW BELINOSTAT, A HISTONE DEACETYLASE INHIBITOR, CAN EFFECTIVELY RESTORE MIR-335 AND RESOLVE THE BARRIER DEFECT IN A DRY SKIN MODEL. HERE, IN THIS COMMENTARY, WE HIGHLIGHT THE ROLE OF BELINOSTAT IN THE TREATMENT OF AD AND DISCUSS THE NEED FOR MORE RESEARCH INTO CROSSTALK BETWEEN EPIGENETIC AND NON-CODING RNA-BASED REGULATION, AS WELL AS POSSIBLE THERAPEUTIC STRATEGIES TARGETING THE EPIGENOME. 2021 4 5257 39 PROGRESSION OF MYELOPROLIFERATIVE NEOPLASMS (MPN): DIAGNOSTIC AND THERAPEUTIC PERSPECTIVES. CLASSICAL BCR-ABL-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS (MPN) ARE A HETEROGENEOUS GROUP OF HEMATOLOGIC MALIGNANCIES, INCLUDING ESSENTIAL THROMBOCYTHEMIA (ET), POLYCYTHEMIA VERA (PV), AND PRIMARY MYELOFIBROSIS (PMF), AS WELL AS POST-PV-MF AND POST-ET-MF. PROGRESSION TO MORE SYMPTOMATIC DISEASE, SUCH AS OVERT MF OR ACUTE LEUKEMIA, REPRESENTS ONE OF THE MAJOR CAUSES OF MORBIDITY AND MORTALITY. THERE ARE CLINICALLY EVIDENT BUT ALSO SUBCLINICAL TYPES OF MPN PROGRESSION. CLINICALLY EVIDENT PROGRESSION INCLUDES EVOLUTION FROM ET TO PV, ET TO POST-ET-MF, PV TO POST-PV-MF, OR PRE-PMF TO OVERT PMF, AND TRANSFORMATION OF ANY OF THESE SUBTYPES TO MYELODYSPLASTIC NEOPLASMS OR ACUTE LEUKEMIA. THROMBOSIS, MAJOR HEMORRHAGE, SEVERE INFECTIONS, OR INCREASING SYMPTOM BURDEN (E.G., PRURITUS, NIGHT SWEATS) MAY HERALD PROGRESSION. SUBCLINICAL TYPES OF PROGRESSION MAY INCLUDE INCREASES IN THE EXTENT OF BONE MARROW FIBROSIS, INCREASES OF DRIVER GENE MUTATIONAL ALLELE BURDEN, AND CLONAL EVOLUTION. THE UNDERLYING CAUSES OF MPN PROGRESSION ARE DIVERSE AND CAN BE ATTRIBUTED TO GENETIC ALTERATIONS AND CHRONIC INFLAMMATION. PARTICULARLY, BYSTANDER MUTATIONS IN GENES ENCODING EPIGENETIC REGULATORS OR SPLICING FACTORS WERE ASSOCIATED WITH PROGRESSION. FINALLY, COMORBIDITIES SUCH AS SYSTEMIC INFLAMMATION, CARDIOVASCULAR DISEASES, AND ORGAN FIBROSIS MAY AUGMENT THE RISK OF PROGRESSION. THE AIM OF THIS REVIEW WAS TO DISCUSS TYPES AND MECHANISMS OF MPN PROGRESSION AND HOW THEIR KNOWLEDGE MIGHT IMPROVE RISK STRATIFICATION AND THERAPEUTIC INTERVENTION. IN VIEW OF THESE ASPECTS, WE DISCUSS THE POTENTIAL BENEFITS OF EARLY DIAGNOSIS USING MOLECULAR AND FUNCTIONAL IMAGING AND EXPLOITABLE THERAPEUTIC STRATEGIES THAT MAY PREVENT PROGRESSION, BUT ALSO HIGHLIGHT CURRENT CHALLENGES AND METHODOLOGICAL PITFALLS. 2021 5 2936 52 GENETIC AND EPIGENETIC ABNORMALITIES IN PRIMARY SCLEROSING CHOLANGITIS-ASSOCIATED CHOLANGIOCARCINOMA. PRIMARY SCLEROSING CHOLANGITIS (PSC) IS A CHOLESTATIC LIVER DISEASE OF UNKNOWN ETIOLOGY, CHARACTERIZED BY CHRONIC INFLAMMATION OF THE BILIARY TREE WITH SUBSEQUENT FIBROSIS AND CIRRHOSIS OF THE LIVER. PATIENTS WITH PSC ARE AT INCREASED RISK FOR THE DEVELOPMENT OF CHOLANGIOCARCINOMA (CCA), A HIGHLY MALIGNANT EPITHELIAL TUMOR ARISING FROM THE INTRAHEPATIC AND EXTRAHEPATIC BILE DUCTS. CURRENTLY, ORTHOTOPIC LIVER TRANSPLANTATION IS THE ONLY CURATIVE TREATMENT. THE LACK OF EFFICIENT DIAGNOSTIC METHODS FOR EARLY DETECTION AND THE LIMITED THERAPEUTIC OPTIONS FOR CCA ARE MAJOR PROBLEMS AND ARE ASSOCIATED WITH POOR SURVIVAL. THE PATHOGENESIS OF PSC-ASSOCIATED CCA IS COMPLEX AND POORLY UNDERSTOOD. IT SEEMS THAT PRO-INFLAMMATORY CYTOKINES PLAY AN IMPORTANT ROLE IN GENETIC AND EPIGENETIC CHANGES THAT CONTRIBUTE TO THE CARCINOGENIC PROCESS. THE MAPPING OF GENETIC ALTERATIONS MAY ELUCIDATE MOLECULAR TARGETS THAT MAY BE APPLIED AS BIOMARKERS TO FACILITATE EARLY DIAGNOSIS OF MALIGNANT DEGENERATION TO IMPROVE PATIENT OUTCOME. IN THE LAST DECADE, THE INTRODUCTION OF SEVERAL NOVEL MOLECULAR TECHNIQUES AVAILABLE FOR GENOME-WIDE SCREENING HAS ADVANCED OUR KNOWLEDGE ON MANY OF THE GENETIC ABNORMALITIES THAT ARE PREVALENT IN CCA AND PSC-ASSOCIATED CCA. THIS REVIEW SUMMARIZES GENETIC AND EPIGENETIC ABNORMALITIES, WHICH HAVE IMPORTANT POTENTIAL FOR CLINICAL APPLICATION. 2013 6 1225 25 CRITICAL ROLE OF EPIGENETIC MODIFICATION IN THE PATHOGENESIS OF ATOPIC DERMATITIS. ATOPIC DERMATITIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERISED BY RECURRENT ECZEMA-LIKE LESIONS AND SEVERE PRURITUS, ALONG WITH DRYING AND DECRUSTATION OF SKIN. CURRENT RESEARCH RELATES THE PATHOGENESIS OF ATOPIC DERMATITIS MAINLY TO GENETIC SUSCEPTIBILITY, ABNORMAL SKIN BARRIER FUNCTION, IMMUNE DISORDERS, STAPHYLOCOCCUS AUREUS COLONISATION, MICROBIOLOGICAL DYSFUNCTION AND VITAMIN D INSUFFICIENCY. EPIGENETIC MODIFICATIONS ARE DISTINCT GENETIC PHENOTYPES RESULTING FROM ENVIRONMENT-DRIVEN CHANGES IN CHROMOSOME FUNCTIONS IN THE ABSENCE OF NUCLEAR DNA SEQUENCE VARIATION. CLASSIC EPIGENETIC EVENTS INCLUDE DNA METHYLATION, HISTONE PROTEIN MODIFICATIONS AND NON-CODING RNA REGULATION. INCREASING EVIDENCE HAS INDICATED THAT EPIGENETIC EVENTS ARE INVOLVED IN THE PATHOGENESIS OF ATOPIC DERMATITIS BY THEIR EFFECTS ON MULTIPLE SIGNALLING PATHWAYS WHICH IN TURN INFLUENCE THE ABOVE FACTORS. THIS REVIEW PRIMARILY ANALYSES THE FUNCTION OF EPIGENETIC REGULATION IN THE PATHOGENESIS OF ATOPIC DERMATITIS. IN ADDITION, IT TRIES TO MAKE RECOMMENDATIONS FOR PERSONALISED EPIGENETIC TREATMENT STRATEGIES FOR ATOPIC DERMATITIS IN THE FUTURE. 2023 7 5799 28 STEPPING OUT OF ANTIQUITY: AN UPDATE ON EMERGING DRUGS FOR THE TREATMENT OF POLYCYTHEMIA VERA. INTRODUCTION: POLYCYTHEMIA VERA IS A CHRONIC HEMATOLOGIC MALIGNANCY FREQUENTLY PRESENTED WITH CONSTITUTIONAL SYMPTOMS AND ASSOCIATED WITH AN INCREASED RISK OF THROMBOSIS, HEMORRHAGE, AND PROGRESSION TO MYELOFIBROSIS OR ACUTE MYELOID LEUKEMIA. CURRENT TREATMENT STRATEGIES REDUCE THROMBOHEMORRHAGIC RISK BY CONTROLLING BLOOD COUNTS AND INHIBITING PLATELETS, BUT OFTEN FAIL TO ADDRESS DISEASE-RELATED SYMPTOMS OR BIOLOGICALLY MODIFY THE DISEASE.AREAS COVERED: WE REVIEW THE CURRENT PARADIGM FOR TREATING POLYCYTHEMIA VERA, HIGHLIGHT AREAS OF UNMET NEED, REVIEW THERAPEUTIC AGENTS IN LATE STAGE CLINICAL DEVELOPMENT, AND PROVIDE AN OVERARCHING VIEW OF HOW THESE EMERGING AGENT MAY FIT INTO THE FUTURE ARMAMENTARIUM OF POLYCYTHEMIA VERA TREATMENTS.EXPERT OPINION: THE SHIFT FROM FOCUSING SOLELY ON SECONDARY PREVENTION OF THROMBOHEMORRHAGIC EVENTS TO A COMPREHENSIVE TREATMENT STRATEGY THAT ADDITIONALLY AIMS TO IMPROVE QUALITY OF LIFE AND PREVENT DISEASE PROGRESSION HAS RESULTED IN A RAPIDLY EVOLVING THERAPEUTIC LANDSCAPE THAT PROMISES TO MOVE THE TREATMENT OF POLYCYTHEMIA VERA OUT OF ANTIQUITY INTO THE MODERN AGE. 2021 8 4724 32 NONINVASIVE MULTIMODAL METHODS TO DIFFERENTIATE INFLAMED VS FIBROTIC STRICTURES IN PATIENTS WITH CROHN'S DISEASE. FIBROTIC STRICTURES OCCUR IN 30% OF PATIENTS WITH CROHN'S DISEASE (CD). HOWEVER, THERE ARE NO THERAPEUTIC AGENTS THAT PREVENT OR REVERSE FIBROTIC STRICTURES. STRICTURES ARE TREATED BY ENDOSCOPIC DILATATION PROCEDURES AND SURGICAL PROCEDURES, BUT THERE ARE HIGH RATES OF RECURRENCE. TWO ANTIFIBROTIC AGENTS (NINTEDANIB AND PIRFENIDONE) RECENTLY WERE APPROVED FOR THE TREATMENT OF IDIOPATHIC PULMONARY FIBROSIS AND INHIBITORS OF RHO-ASSOCIATED PROTEIN KINASES 1 AND 2 REVERSED FIBROSIS IN MICE WITH CHRONIC INTESTINAL INFLAMMATION. CROSS-SECTIONAL IMAGING TECHNIQUES, SUCH AS MAGNETIC RESONANCE (MR) ENTEROGRAPHY, COMPUTED TOMOGRAPHY ENTEROGRAPHY, AND BOWEL ULTRASOUND, ARE USED TO ASSESS SMALL-BOWEL AND CD-RELATED COMPLICATIONS, INCLUDING STRICTURES. IT IS IMPORTANT TO BE ABLE TO DETERMINE THE DEGREE OF INFLAMMATION AND FIBROSIS IN STRICTURES TO SELECT THE BEST THERAPY; THIS CAN BE A CHALLENGE BECAUSE INFLAMMATION AND FIBROSIS CO-EXIST TO VARYING DEGREES IN A DAMAGED BOWEL SEGMENT. DELAYED GADOLINIUM ENHANCEMENT, MAGNETIZATION TRANSFER MR IMAGING, AND ULTRASOUND ELASTOGRAPHY SEEM TO BE PROMISING TOOLS FOR ASSESSING FIBROSIS IN PATIENTS WITH CD. WE REVIEW NONINVASIVE TECHNIQUES FOR FIBROSIS ASSESSMENT, INCLUDING ANALYSES OF GENETIC, EPIGENETIC, AND PROTEIN MARKERS. WE DISCUSS THE POTENTIAL OF IMAGING TECHNIQUES SUCH AS DIFFUSION-WEIGHTED AND MAGNETIZATION TRANSFER MR IMAGING, STRAIN ELASTOGRAPHY, SHEAR-WAVE IMAGING, AND POSITRON EMISSION TOMOGRAPHY TO GUIDE THERAPEUTIC DECISIONS FOR PATIENTS WITH STRICTURING CD. 2019 9 6856 32 [NOT AVAILABLE]. BIOLOGICAL ASPECTS OF JAK/STAT SIGNALING IN BCR-ABL-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: MYELOPROLIFERATIVE DISORDERS MORE RECENTLY NAMED MYELOPROLIFERATIVE NEOPLASMS (MPN) DISPLAY SEVERAL CLINICAL ENTITIES: CHRONIC MYELOID LEUKEMIA (CML), THE CLASSICAL MPN INCLUDING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET), PRIMARY MYELOFIBROSIS (PMF) AND ATYPICAL AND UNCLASSIFIABLE NMP. THE TERM MPN IS MOSTLY USED FOR CLASSICAL BCR-ABL-NEGATIVE (MYELOPROLIFERATIVE DISORDER) (ET, PV, PMF). THESE ARE CLONAL DISEASES RESULTING FROM THE TRANSFORMATION OF AN HEMATOPOIETIC STEM CELL AND LEADING TO AN ABNORMAL PRODUCTION OF MYELOID CELLS. THE GENETIC DEFECTS RESPONSIBLE FOR THE MYELOPROLIFERATIVE ABNORMALITIES ARE CALLED << DRIVER >> MUTATIONS AND ALL RESULT IN DEREGULATION OF THE CYTOKINE RECEPTOR / JAK2 / STAT AXIS. AMONG THEM, JAK2, THE THROMBOPOIETIN RECEPTOR (MPL) AND CALRETICULIN (CALR) MUTATIONS ARE FOUND IN AROUND 90% OF THE CASES. THESE DRIVER MPN MUTATIONS CAN BE ASSOCIATED WITH OTHER DRIVER MUTATIONS ALSO FOUND IN OTHER HEMATOLOGICAL MALIGNANCIES, ESPECIALLY IN PMFS. THESE ARE CHRONIC DISEASES WITH MAJOR RISKS BEING THROMBOSIS, HEMORRHAGE AND CYTOPENIAS FOR PMF AND THE LONG-TERM PROGRESSION TO MYELOFIBROSIS AND THE TRANSFORMATION TO LEUKEMIA. MOST RECENT THERAPEUTIC HAVE FOCUSED ON TARGETING THE JAK2 SIGNALING PATHWAY DIRECTLY BY INHIBITORS OF JAK2 OR INDIRECTLY. INTERFERON A ALLOWS IN SOME CASES HEMATOLOGIC AND MOLECULAR REMISSION PATIENTS. 2016 10 5309 30 PSORIASIS PATHOGENESIS AND TREATMENT. RESEARCH ON PSORIASIS PATHOGENESIS HAS LARGELY INCREASED KNOWLEDGE ON SKIN BIOLOGY IN GENERAL. IN THE PAST 15 YEARS, BREAKTHROUGHS IN THE UNDERSTANDING OF THE PATHOGENESIS OF PSORIASIS HAVE BEEN TRANSLATED INTO TARGETED AND HIGHLY EFFECTIVE THERAPIES PROVIDING FUNDAMENTAL INSIGHTS INTO THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES WITH A DOMINANT IL-23/TH17 AXIS. THIS REVIEW DISCUSSES THE MECHANISMS INVOLVED IN THE INITIATION AND DEVELOPMENT OF THE DISEASE, AS WELL AS THE THERAPEUTIC OPTIONS THAT HAVE ARISEN FROM THE DISSECTION OF THE INFLAMMATORY PSORIATIC PATHWAYS. OUR DISCUSSION BEGINS BY ADDRESSING THE INFLAMMATORY PATHWAYS AND KEY CELL TYPES INITIATING AND PERPETUATING PSORIATIC INFLAMMATION. NEXT, WE DESCRIBE THE ROLE OF GENETICS, ASSOCIATED EPIGENETIC MECHANISMS, AND THE INTERACTION OF THE SKIN FLORA IN THE PATHOPHYSIOLOGY OF PSORIASIS. FINALLY, WE INCLUDE A COMPREHENSIVE REVIEW OF WELL-ESTABLISHED WIDELY AVAILABLE THERAPIES AND NOVEL TARGETED DRUGS. 2019 11 3129 32 GIVINOSTAT: AN EMERGING TREATMENT FOR POLYCYTHEMIA VERA. INTRODUCTION: POLYCYTHEMIA VERA (PV), A PHILADELPHIA CHROMOSOME-NEGATIVE MYELOPROLIFERATIVE NEOPLASM, IS CHARACTERIZED BY PANMYELOSIS, PANCYTOSIS, AND A JAK2 MUTATION. PATIENTS ARE AT INCREASED RISK OF THROMBOHEMORRHAGIC EVENTS, AND PROGRESSION TO MYELOFIBROSIS OR ACUTE LEUKEMIA. CURRENT TREATMENTS INCLUDE ASPIRIN, PHLEBOTOMY, AND CYTOREDUCTIVE DRUGS (MOST COMMONLY HYDROXYUREA). GIVINOSTAT IS A POTENT, CLASS I/II HISTONE DEACETYLASE (HDAC) INHIBITOR THAT IS IN PHASE I/II CLINICAL TRIALS IN PV. GIVINOSTAT WAS WELL TOLERATED AND YIELDED PROMISING CLINICO-HEMATOLOGICAL RESPONSES. A PHASE III STUDY OF GIVINOSTAT VERSUS HYDROXYUREA IN HIGH-RISK PV PATIENTS IS PLANNED. AREAS COVERED: WE PRESENT AN OVERVIEW OF PV, CURRENT TREATMENT GUIDELINES, AND THE PUTATIVE MECHANISM(S) OF ACTION OF GIVINOSTAT. WE DISCUSS THE PRECLINICAL AND CLINICAL STUDIES OF GIVINOSTAT IN PV AND BRIEFLY REVIEW APPROVED AND INVESTIGATIONAL COMPETITOR COMPOUNDS. EXPERT OPINION: HDAC INHIBITORS HAVE LONG BEEN KNOWN TO BE ACTIVE IN PV, BUT CHRONIC TOXICITIES CAN BE CHALLENGING. GIVINOSTAT, HOWEVER, IS ACTIVE AND WELL TOLERATED, AND IS ENTERING A PIVOTAL PHASE III RANDOMIZED TRIAL. GIVINOSTAT OFFERS THE POSSIBILITY OF REPLACING HYDROXYUREA AS THE STANDARD FIRST-LINE CYTOREDUCTIVE CHOICE FOR PV PATIENTS. THIS WOULD COMPLETELY CHANGE THE CURRENT THERAPEUTIC PARADIGM AND GUIDELINES FOR PV MANAGEMENT. ALTHOUGH SURROGATE CLINICAL STUDY ENDPOINTS MAY SUFFICE FOR REGULATORY PURPOSES, THROMBOSIS REDUCTION AND PREVENTION OF DISEASE PROGRESSION REMAIN MOST IMPORTANT TO PATIENTS AND CLINICIANS. 2020 12 3012 34 GENETICS AND EPIGENETICS IN THE PATHOGENESIS OF PRIMARY BILIARY CHOLANGITIS. PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC, SLOWLY PROGRESSIVE CHOLESTATIC AUTOIMMUNE LIVER DISEASE PREDOMINANTLY AFFLICTING WOMEN. PBC IS CHARACTERIZED BY THE PRESENCE OF DISEASE-SPECIFIC ANTIMITOCHONDRIAL ANTIBODIES AND THE HISTOLOGICAL DESTRUCTION OF INTRAHEPATIC BILE DUCTS, WHICH EVENTUALLY LEAD TO CIRRHOSIS AND HEPATIC FAILURE. FORTUNATELY, URSODEOXYCHOLIC ACID THERAPY HAS IMPROVED THE OUTCOME OF THE VAST MAJORITY OF PBC CASES. ALTHOUGH THE ETIOLOGY OF PBC HAS NOT YET BEEN ELUCIDATED, HUMAN LEUKOCYTE ANTIGEN (HLA) CLASS II ALLELES HAVE BEEN CONSISTENTLY ASSOCIATED WITH DISEASE ONSET FOR DECADES. PBC PATIENTS MAY ALSO HAVE GENETICALLY DETERMINED RISK FACTORS IN NON-HLA REGIONS. MEANWHILE, EXPOSURE TO ENVIRONMENTAL FACTORS, SUCH AS INFECTIOUS DISEASES AND HARMFUL CHEMICALS, CAN PRODUCE EPIGENETIC ALTERATIONS IN SOME INDIVIDUALS AND SUBSEQUENT PBC ONSET. IN THIS REVIEW, WE DESCRIBE THE INFLUENCE OF HLA ALLELES AND OTHER GENE POLYMORPHISMS ON PBC ALONG WITH THE RESULTS OF GENOME-WIDE ASSOCIATION STUDIES ON THIS DISEASE AND ITS FUTURE PROSPECTS IN TERMS OF EPIGENETICS. 2018 13 5220 31 PRIMARY BILIARY CHOLANGITIS: A TALE OF EPIGENETICALLY-INDUCED SECRETORY FAILURE? PRIMARY BILIARY CHOLANGITIS (PBC) IS A CHRONIC CHOLESTATIC LIVER DISEASE ASSOCIATED WITH AUTOIMMUNE-RELATED DESTRUCTION OF SMALL TO MEDIUM SIZE INTRAHEPATIC BILE DUCTS. THE AETIOLOGY OF PBC IS UNKNOWN AND ITS PATHOGENESIS REMAINS OBSCURE. BOTH GENETIC VARIANTS AND ENVIRONMENTAL FACTORS HAVE BEEN LINKED TO INCREASED PBC SUSCEPTIBILITY, WITH OTHER ALTERATIONS KNOWN TO COOPERATE IN DISEASE PATHOBIOLOGY. INCREASING EVIDENCE INDICATES THE PRESENCE OF EPIGENETIC ABNORMALITIES IN PBC, PARTICULARLY ALTERATIONS OF CHOLANGIOCELLULAR MICRORNAS (MIRNAS OR MIRS). THIS REVIEW HIGHLIGHTS AND DISCUSSES THE MOST RELEVANT EPIGENETIC ALTERATIONS FOUND IN PATIENTS WITH PBC, FOCUSING ON THE ROLE OF MIR-506 IN THE PROMOTION OF CHOLESTASIS AND IMMUNE ACTIVATION. 2018 14 2988 20 GENETIC FACTORS AND SYSTEMIC SCLEROSIS. SYSTEMIC SCLEROSIS (SSC) IS A RARE CONNECTIVE TISSUE DISEASE OF UNKNOWN ETIOLOGY CHARACTERIZED BY CHRONIC INFLAMMATION AND FIBROSIS OF THE SKIN, VASCULAR ABNORMALITIES, AND VARIABLE INVOLVEMENT OF ORGANS INCLUDING KIDNEYS, GASTROINTESTINAL TRACT, HEART, AND LUNGS. SSC SHOWS A COMPLEX ETIOLOGY IN WHICH BOTH ENVIRONMENTAL AND GENETIC FACTORS SEEM TO INFLUENCE THE ONSET AND OUTCOME OF THE DISEASE. WE PROVIDE AN EXTENSIVE OVERVIEW OF THE GENETIC FACTORS AND EPIGENETIC MODIFICATIONS AND WHAT THEIR KNOWLEDGE HAS REVEALED IN TERMS OF ETIOPATHOGENESIS OF SSC. 2016 15 4464 33 MOLECULAR MECHANISMS OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)/NONALCOHOLIC STEATOHEPATITIS (NASH). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST COMMON CHRONIC LIVER DISEASES WORLDWIDE AND HAS GARNERED INCREASING ATTENTION IN RECENT DECADES. NAFLD IS CHARACTERIZED BY A WIDE RANGE OF LIVER CHANGES, FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS (NASH), CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. THE PATHOGENESIS OF NAFLD/NASH IS VERY COMPLICATED AND INVOLVES LIPID ACCUMULATION, INSULIN RESISTANCE, INFLAMMATION, AND FIBROGENESIS. IN ADDITION, NAFLD IS CLOSELY ASSOCIATED WITH COMPLICATIONS SUCH AS OBESITY, DYSLIPIDEMIA, AND TYPE 2 DIABETES. IN PARTICULAR, THE CLINICAL SPECTRUM, PATHOPHYSIOLOGY, AND THERAPEUTIC OPTIONS OF NAFLD SHARE MANY THINGS IN COMMON WITH DIABETES. INSULIN RESISTANCE IS AN UNDERLYING BASIS FOR THE PATHOGENESIS OF DIABETES AND NAFLD. THIS CHAPTER FOCUSES ON THE MOLECULAR MECHANISM INVOLVED IN THE PATHOGENESIS OF INSULIN RESISTANCE, DIABETES, AND NASH/NAFLD INCLUDING THOSE THAT DRIVE DISEASE PROGRESSION SUCH AS OXIDATIVE STRESS, GENETIC AND EPIGENETIC MECHANISMS, ADIPONECTIN, CYTOKINES, AND IMMUNE CELLS. 2021 16 2731 22 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 17 1867 30 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 18 255 35 ADVANCES IN MYELOFIBROSIS: A CLINICAL CASE APPROACH. PRIMARY MYELOFIBROSIS IS A MEMBER OF THE MYELOPROLIFERATIVE NEOPLASMS, A DIVERSE GROUP OF BONE MARROW MALIGNANCIES. SYMPTOMS OF MYELOFIBROSIS, PARTICULARLY THOSE ASSOCIATED WITH SPLENOMEGALY (ABDOMINAL DISTENTION AND PAIN, EARLY SATIETY, DYSPNEA, AND DIARRHEA) AND CONSTITUTIONAL SYMPTOMS, REPRESENT A SUBSTANTIAL BURDEN TO PATIENTS. MOST PATIENTS EVENTUALLY DIE FROM THE DISEASE, WITH A MEDIAN SURVIVAL RANGING FROM APPROXIMATELY 5-7 YEARS. MUTATIONS IN JANUS KINASE 2 (JAK2), A KINASE THAT IS ESSENTIAL FOR THE NORMAL DEVELOPMENT OF ERYTHROCYTES, GRANULOCYTES, AND PLATELETS, NOTABLY THE V617F MUTATION, HAVE BEEN IDENTIFIED IN APPROXIMATELY 50% OF PATIENTS WITH MYELOFIBROSIS. THE APPROVAL OF A JAK2 INHIBITOR IN 2011 HAS IMPROVED THE OUTLOOK OF MANY PATIENTS WITH MYELOFIBROSIS AND HAS CHANGED THE TREATMENT LANDSCAPE. THIS ARTICLE FOCUSES ON SOME OF THE IMPORTANT ISSUES IN CURRENT MYELOFIBROSIS TREATMENT MANAGEMENT, INCLUDING DIFFERENTIATION OF MYELOFIBROSIS FROM ESSENTIAL THROMBOCYTHEMIA AND POLYCYTHEMIA VERA, UP-DATED DATA ON THE RESULTS OF JAK2 INHIBITOR THERAPY, THE ROLE OF EPIGENETIC MECHANISMS IN MYELOFIBROSIS PATHOGENESIS, INVESTIGATIONAL THERAPIES FOR MYELOFIBROSIS, AND ADVANCES IN HEMATOPOIETIC STEM CELL TRANSPLANT. THREE MYELOFIBROSIS CASES ARE INCLUDED TO UNDERSCORE THE ISSUES IN DIAGNOSING AND TREATING THIS COMPLEX DISEASE. 2013 19 1114 34 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 20 845 36 CHILDHOOD ATOPIC DERMATITIS: CURRENT DEVELOPMENTS, TREATMENT APPROACHES, AND FUTURE EXPECTATIONS. ATOPIC DERMATITIS (AD) IS THE MOST COMMON CHRONIC INFLAMMATORY SKIN DISORDER OF CHILDHOOD. UNDERLYING FACTORS THAT CONTRIBUTE TO AD ARE IMPAIRED EPITHELIAL BARRIER, ALTERATIONS IN THE LIPID COMPOSITION OF THE SKIN, IMMUNOLOGICAL IMBALANCE INCLUDING INCREASED TH2/TH1 RATIO, PROINFLAMMATORY CYTOKINES, DECREASED T REGULATORY CELLS, GENETIC MUTATIONS, AND EPIGENETIC ALTERATIONS. ATOPIC DERMATITIS IS A MULTIFACTORIAL DISEASE WITH A PARTICULARLY COMPLICATED PATHOPHYSIOLOGY. DISCOVERIES TO DATE MAY BE CONSIDERED THE TIP OF THE ICEBERG, AND THE INCREASING NUMBER OF STUDIES IN THIS FIELD INDICATE THAT THERE ARE MANY POINTS TO BE ELUCIDATED IN AD PATHOPHYSIOLOGY. IN THIS REVIEW, WE AIMED TO ILLUSTRATE THE CURRENT UNDERSTANDING OF THE UNDERLYING PATHOGENIC MECHANISMS IN AD, TO EVALUATE AVAILABLE TREATMENT OPTIONS WITH A FOCUS ON RECENTLY DISCOVERED THERAPEUTIC AGENTS, AND TO DETERMINE THE PERSONAL, FAMILIAL, AND ECONOMIC BURDENS OF THE DISEASE, WHICH ARE FREQUENTLY NEGLECTED ISSUES IN AD. CURRENTLY AVAILABLE THERAPIES ONLY PROVIDE TRANSIENT SOLUTIONS AND CANNOT FULLY CURE THE DISEASE. HOWEVER, ADVANCES IN THE UNDERSTANDING OF THE PATHOGENIC MECHANISMS OF THE DISEASE HAVE LED TO THE PRODUCTION OF NEW TREATMENT OPTIONS, WHILE ONGOING DRUG TRIALS ALSO HAVE HAD PROMISING RESULTS. 2019