1 6442 132 THERAPEUTIC APPROACHES IN MYELOFIBROSIS AND MYELODYSPLASTIC/MYELOPROLIFERATIVE OVERLAP SYNDROMES. THE DISCOVERY OF JAK2 (V617F) A DECADE AGO LED TO OPTIMISM FOR A RAPIDLY DEVELOPING TREATMENT REVOLUTION IN PH(-) MYELOPROLIFERATIVE NEOPLASMS. UNLIKE BCR-ABL, HOWEVER, JAK2 WAS FOUND TO HAVE A MORE HETEROGENEOUS ROLE IN CARCINOGENESIS. THEREFORE, FOR YEARS, DEVELOPMENT OF NEW THERAPIES WAS SLOW, DESPITE STANDARD TREATMENT OPTIONS THAT DID NOT ADDRESS THE OVERWHELMING SYMPTOM BURDEN IN PATIENTS WITH PRIMARY MYELOFIBROSIS (MF), POST-ESSENTIAL THROMBOCYTHEMIA MF, POST-POLYCYTHEMIA VERA MF, AND MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) SYNDROMES. JAK-STAT INHIBITORS HAVE CHANGED THIS, DRASTICALLY AMELIORATING SYMPTOMS AND ULTIMATELY BEGINNING TO SHOW EVIDENCE OF IMPACT ON SURVIVAL. NOW, THE GENETIC FOUNDATIONS OF MYELOFIBROSIS AND MDS/MPN ARE RAPIDLY BEING ELUCIDATED AND CONTRIBUTING TO TARGETED THERAPY DEVELOPMENT. THIS HAS BEEN EMPOWERED THROUGH UPDATED RESPONSE CRITERIA FOR MDS/MPN AND REFINED PROGNOSTIC SCORING SYSTEMS IN THESE DISEASES. THE AIM OF THIS ARTICLE IS TO SUMMARIZE CONCISELY THE CURRENT AND RATIONALLY DESIGNED INVESTIGATIONAL THERAPEUTICS DIRECTED AT JAK-STAT, HEDGEHOG, PI3K-AKT, BONE MARROW FIBROSIS, TELOMERASE, AND ROGUE EPIGENETIC SIGNALING. THE REVOLUTION IN IMMUNOTHERAPY AND NOVEL TREATMENTS AIMED AT PREVIOUSLY UNTARGETED SIGNALING PATHWAYS PROVIDES HOPE FOR CONSIDERABLE ADVANCEMENT IN THERAPY OPTIONS FOR THOSE WITH CHRONIC MYELOID DISEASE. 2016 2 6224 29 THE LEUCINE CATABOLITE AND DIETARY SUPPLEMENT BETA-HYDROXY-BETA-METHYL BUTYRATE (HMB) AS AN EPIGENETIC REGULATOR IN MUSCLE PROGENITOR CELLS. BETA-HYDROXY-BETA-METHYL BUTYRATE (HMB) IS A NATURAL CATABOLITE OF LEUCINE DEEMED TO PLAY A ROLE IN AMINO ACID SIGNALING AND THE MAINTENANCE OF LEAN MUSCLE MASS. ACCORDINGLY, HMB IS USED AS A DIETARY SUPPLEMENT BY SPORTSMEN AND HAS SHOWN SOME CLINICAL EFFECTIVENESS IN PREVENTING MUSCLE WASTING IN CANCER AND CHRONIC LUNG DISEASE, AS WELL AS IN AGE-DEPENDENT SARCOPENIA. HOWEVER, THE MOLECULAR CASCADES UNDERLYING THESE BENEFICIAL EFFECTS ARE LARGELY UNKNOWN. HMB BEARS A SIGNIFICANT STRUCTURAL SIMILARITY WITH BUTYRATE AND BETA-HYDROXYBUTYRATE (BETAHB), TWO COMPOUNDS RECOGNIZED FOR IMPORTANT EPIGENETIC AND HISTONE-MARKING ACTIVITIES IN MULTIPLE CELL TYPES INCLUDING MUSCLE CELLS. WE ASKED WHETHER SIMILAR CHROMATIN-MODIFYING ACTIONS COULD BE ASSIGNED TO HMB AS WELL. EXPOSURE OF MURINE C2C12 MYOBLASTS TO MILLIMOLAR CONCENTRATIONS OF HMB LED TO AN INCREASE IN GLOBAL HISTONE ACETYLATION, AS MONITORED BY ANTI-ACETYLATED LYSINE IMMUNOBLOTTING, WHILE PREVENTING MYOTUBE DIFFERENTIATION. IN THESE EFFECTS, HMB RESEMBLED, ALTHOUGH WITH LESS POTENCY, THE HISTONE DEACETYLASE (HDAC) INHIBITOR SODIUM BUTYRATE. HOWEVER, INITIAL STUDIES DID NOT CONFIRM A DIRECT INHIBITORY EFFECT OF HMB ON HDACS IN VITRO. BETA-HYDROXYBUTYRATE, A KETONE BODY PRODUCED BY THE LIVER DURING STARVATION OR INTENSE EXERCISE, HAS A MODEST EFFECT ON HISTONE ACETYLATION OF C2C12 CELLS OR IN VITRO HDAC INHIBITOR ACTIVITIES, AND, UNLIKE BUTYRATE AND HMB, DID NOT INTERFERE WITH MYOTUBE FORMATION IN A MYOBLAST DIFFERENTIATION ASSAY. INSTEAD, BETAHB DRAMATICALLY INCREASED LYSINE BETA-HYDROXYBUTYRYLATION (KBHB) OF HISTONE TAILS, AN EPIGENETIC MARK ASSOCIATED WITH FASTING RESPONSES AND MUSCLE CATABOLIC STATES. HOWEVER, WHEN C2C12 CELLS WERE EXPOSED TO BETAHB IN THE PRESENCE OF EQUIMOLAR HMB THIS CHROMATIN MODIFICATION WAS DRASTICALLY REDUCED, POINTING TO A ROLE FOR HMB IN ATTENUATING KETOSIS-ASSOCIATED MUSCLE WASTING. IN CONCLUSION, WHILE THEIR MECHANISTIC UNDERPINNINGS REMAIN TO BE CLARIFIED, THESE PRELIMINARY OBSERVATIONS HIGHLIGHT NOVEL AND POTENTIALLY IMPORTANT ACTIVITIES OF HMB AS AN EPIGENETIC REGULATOR AND BETAHB ANTAGONIST IN MUSCLE PRECURSOR CELLS, TO BE FURTHER EXPLORED IN THEIR BIOMEDICAL IMPLICATIONS. 2021 3 6573 39 TREATMENT OF ACUTE MYELOID LEUKEMIA IN THE ERA OF GENOMICS-ACHIEVEMENTS AND PERSISTING CHALLENGES. ACUTE MYELOID LEUKEMIA (AML) REPRESENTS A MALIGNANT DISORDER OF THE HEMATOPOIETIC SYSTEM THAT IS MAINLY CHARACTERIZED BY RAPID PROLIFERATION, DYSREGULATED APOPTOSIS, AND IMPAIRED DIFFERENTIATION OF LEUKEMIC BLASTS. FOR SEVERAL DECADES, THE DIAGNOSTIC APPROACH IN AML WAS LARGELY BASED ON HISTOLOGIC CHARACTERISTICS WITH LITTLE IMPACT ON THE TREATMENT DECISION-MAKING PROCESS. THIS PERSPECTIVE HAS DRASTICALLY CHANGED WITHIN THE PAST YEARS DUE TO THE ADVENT OF NOVEL MOLECULAR TECHNOLOGIES, SUCH AS WHOLE GENOME NEXT-GENERATION SEQUENCING (NGS), AND THE RESULTING KNOWLEDGE GAIN IN AML BIOLOGY AND PATHOGENESIS. AFTER MORE THAN FOUR DECADES OF INTENSIVE CHEMOTHERAPY AS A "ONE-SIZE-FITS-ALL" CONCEPT, SEVERAL TARGETED AGENTS HAVE RECENTLY BEEN APPROVED FOR THE TREATMENT OF AML, EITHER AS SINGLE AGENTS OR AS PART OF COMBINED TREATMENT REGIMENS. SEVERAL OTHER COMPOUNDS, DIRECTED AGAINST REGULATORS OF APOPTOTIC, EPIGENETIC, OR MICROENVIRONMENTAL PATHWAYS, AS WELL AS MODULATORS OF THE IMMUNE SYSTEM, ARE CURRENTLY IN DEVELOPMENT AND BEING INVESTIGATED IN CLINICAL TRIALS. THE CONSTANT PROGRESS IN AML RESEARCH HAS STARTED TO PRODUCE IMPROVED SURVIVAL RATES AND FUELED HOPES THAT A ONCE RAPIDLY FATAL DISEASE CAN BE TRANSFORMED INTO A CHRONIC CONDITION. IN THIS REVIEW, THE AUTHORS PROVIDE A SUMMARY OF RECENT ADVANCES IN THE DEVELOPMENT OF TARGETED AML THERAPIES AND DISCUSS PERSISTENT CHALLENGES. 2020 4 2141 36 EPIGENETIC INTERVENTIONS FOR EPILEPTOGENESIS: A NEW FRONTIER FOR CURING EPILEPSY. THIS ARTICLE HIGHLIGHTS THE EMERGING THERAPEUTIC POTENTIAL OF SPECIFIC EPIGENETIC MODULATORS AS PROMISING ANTIEPILEPTOGENIC OR DISEASE-MODIFYING AGENTS FOR CURING EPILEPSY. CURRENTLY, THERE IS AN UNMET NEED FOR ANTIEPILEPTOGENIC AGENTS THAT TRULY PREVENT THE DEVELOPMENT OF EPILEPSY IN PEOPLE AT RISK. THERE IS STRONG EVIDENCE THAT EPIGENETIC SIGNALING, WHICH EXERTS HIGH FIDELITY REGULATION OF GENE EXPRESSION, PLAYS A CRUCIAL ROLE IN THE PATHOPHYSIOLOGY OF EPILEPTOGENESIS AND CHRONIC EPILEPSY. THESE MODIFICATIONS ARE NOT HARD-WIRED INTO THE GENOME AND ARE CONSTANTLY REPROGRAMMED BY ENVIRONMENTAL INFLUENCES. THE POTENTIAL EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, MICRORNA-BASED TRANSCRIPTIONAL CONTROL, AND BROMODOMAIN READING ACTIVITY, CAN DRASTICALLY ALTER THE NEURONAL GENE EXPRESSION PROFILE BY EXERTING THEIR SUMMATIVE EFFECTS IN A COORDINATED FASHION. SUCH AN EPIGENETIC INTERVENTION APPEARS MORE RATIONAL STRATEGY FOR PREVENTING EPILEPSY BECAUSE IT TARGETS THE PRIMARY PATHWAY THAT INITIALLY TRIGGERS THE NUMEROUS DOWNSTREAM CELLULAR AND MOLECULAR EVENTS MEDIATING EPILEPTOGENESIS. AMONG CURRENTLY APPROVED EPIGENETIC DRUGS, THE MAJORITY ARE ANTICANCER DRUGS WITH WELL-ESTABLISHED PROFILES IN CLINICAL TRIALS AND PRACTICE. EVIDENCE FROM PRECLINICAL STUDIES SUPPORTS THE PREMISE THAT THESE DRUGS MAY BE APPLIED TO A WIDE RANGE OF BRAIN DISORDERS. TARGETING HISTONE DEACETYLATION BY INHIBITING HISTONE DEACETYLASE ENZYMES APPEARS TO BE ONE PROMISING EPIGENETIC THERAPY SINCE CERTAIN INHIBITORS HAVE BEEN SHOWN TO PREVENT EPILEPTOGENESIS IN ANIMAL MODELS. HOWEVER, DEVELOPING NEURONAL SPECIFIC EPIGENETIC MODULATORS REQUIRES RATIONAL, PATHOPHYSIOLOGY-BASED OPTIMIZATION TO EFFICIENTLY INTERCEPT THE UPSTREAM PATHWAYS IN EPILEPTOGENESIS. OVERALL, EPIGENETIC AGENTS HAVE BEEN WELL POSITIONED AS NEW FRONTIER TOOLS TOWARDS THE NATIONAL GOAL OF CURING EPILEPSY. 2017 5 2001 19 EPIGENETIC AND NON-EPIGENETIC REGULATION OF KLOTHO IN KIDNEY DISEASE. KLOTHO IS A NOVEL RENOPROTECTIVE ANTI-AGING PROTEIN AVAILABLE IN MEMBRANE-BOUND OR SOLUBLE FORM. KLOTHO IS EXPRESSED IN BRAIN, PANCREAS, AND OTHER SOLID ORGANS BUT SHOWS HIGHEST EXPRESSION LEVELS IN THE KIDNEY. KLOTHO SUSTAINS NORMAL KIDNEY PHYSIOLOGY BUT KLOTHO REGULATION ALSO CONTRIBUTES TO THE PROGRESSION OF KIDNEY DISEASE. SYSTEMIC AND INTRARENAL LEVELS OF KLOTHO FALL DRASTICALLY DURING ACUTE KIDNEY INJURY, KIDNEY FIBROSIS, DIABETIC NEPHROPATHY, AND OTHER FORMS OF CHRONIC KIDNEY DISEASE, ETC. MOREOVER, EXOGENOUS SUPPLEMENTATION OR OVEREXPRESSION OF ENDOGENOUS KLOTHO ATTENUATES KIDNEY DISEASE. THE REGULATION OF ENDOGENOUS KLOTHO EXPRESSION INVOLVES EPIGENETIC AS WELL AS NON-EPIGENETIC MECHANISMS. THE EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION, POST-TRANSLATIONAL HISTONE MODIFICATIONS, MIRNAS REGULATE THE CHANGE IN KLOTHO EXPRESSION IN KIDNEY DISEASE. NON-EPIGENETIC MECHANISMS SUCH AS ER STRESS, WNT SIGNALING, ACTIVATION OF THE RENIN ANGIOTENSIN SYSTEM (RAS), EXCESSIVE REACTIVE OXYGEN SPECIES AND CYTOKINE GENERATION, ALBUMIN OVERLOAD, AND PPAR-GAMMA SIGNALING ALSO CONTRIBUTE TO KLOTHO REGULATION. EVOLVING EVIDENCE HIGHLIGHT THE CAPACITY OF NATURAL PRODUCTS TO REGULATE KLOTHO EXPRESSION IN KIDNEY DISEASE. ALL THESE PRECLINICAL DATA SUGGEST THAT KLOTHO COULD BE A NOVEL BIOMARKER AS WELL AS THERAPEUTIC TARGET. HERE WE REVIEW THE DIFFERENT MECHANISMS OF KLOTHO REGULATION IN THE CONTEXT OF KLOTHO AS A BIOMARKER AND POTENTIAL THERAPEUTIC AGENT. 2021 6 5837 26 STRESSED MITOCHONDRIA: A TARGET TO INTRUDE ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS THE INOPERABLE, INCAPACITATING, NEUROPSYCHIATRIC, AND DEGENERATIVE MANIFESTATION THAT DRASTICALLY AFFECTS HUMAN LIFE QUALITY. THE CURRENT MEDICATIONS TARGET EXTRA-NEURONAL SENILE PLAQUES, OXIDATIVE STRESS, NEUROINFLAMMATION, INTRANEURONAL NEUROFIBRILLARY TANGLES, CHOLINERGIC DEFICITS, AND EXCITOTOXICITY. AMONG NOVEL PATHWAYS AND TARGETS, BIOENERGETIC AND RESULTANT MITOCHONDRIAL DYSFUNCTION HAS BEEN RECOGNIZED AS ESSENTIAL FACTORS THAT DECIDE THE NEURONAL FATE AND CONSEQUENT NEURODEGENERATION IN AD. THE CRUCIAL ATTRIBUTES OF MITOCHONDRIA, INCLUDING BIOENERGESIS, SIGNALING, SENSING, INTEGRATING, AND TRANSMITTING BIOLOGICAL SIGNALS CONTRIBUTE TO OPTIMUM NETWORKING OF NEURONAL DYNAMICS AND MAKE THEM INDISPENSABLE FOR CELL SURVIVAL. IN AD, MITOCHONDRIAL DYSFUNCTION AND MITOPHAGY ARE A PRELIMINARY AND CRITICAL EVENT THAT AGGRAVATES THE PATHOLOGICAL CASCADE. STRESS IS KNOWN TO PROMOTE AND EXAGGERATE THE NEUROPATHOLOGICAL ALTERATION DURING NEURODEGENERATION AND METABOLIC IMPAIRMENTS, ESPECIALLY IN THE CORTICO-LIMBIC SYSTEM, BESIDES ADVERSELY AFFECTING THE NORMAL PHYSIOLOGY AND MITOCHONDRIAL DYNAMICS. STRESS INVOLVES THE ALLOCATION OF ENERGY RESOURCES FOR NEURONAL SURVIVAL. CHRONIC AND AGGRAVATED STRESS RESPONSE LEADS TO EXCESSIVE RELEASE OF GLUCOCORTICOIDS BY ACTIVATION OF THE HYPOTHALAMIC-PITUITARYADRENAL (HPA) AXIS. BY ACTING THROUGH THEIR RECEPTORS, GLUCOCORTICOIDS INFLUENCE ADVERSE MITOCHONDRIAL CHANGES AND ALTER MTDNA TRANSCRIPTION, MTRNA EXPRESSION, HIPPOCAMPAL MITOCHONDRIAL NETWORK, AND ULTIMATELY MITOCHONDRIAL PHYSIOLOGY. CHRONIC STRESS ALSO AFFECTS MITOCHONDRIAL DYNAMICS BY CHANGING METABOLIC AND NEURO-ENDOCRINAL SIGNALLING, AGGRAVATING OXIDATIVE STRESS, PROVOKING INFLAMMATORY MEDIATORS, ALTERING TROPIC FACTORS, INFLUENCING GENE EXPRESSION, AND MODIFYING EPIGENETIC PATHWAYS. THUS, EXPLORING CHRONIC STRESS-INDUCED GLUCOCORTICOID DYSREGULATION AND RESULTANT BIO-BEHAVIORAL AND PSYCHOSOMATIC MITOCHONDRIAL ALTERATIONS MAY BE A FEASIBLE NARRATIVE TO INVESTIGATE AND UNRAVEL THE MYSTERIOUS PATHOBIOLOGY OF AD. 2021 7 3996 45 LOOKING FORWARD: NOVEL THERAPEUTIC APPROACHES IN CHRONIC AND ADVANCED PHASES OF MYELOFIBROSIS. MYELOFIBROSIS (MF) IS COMPLEX AT THE PATHOBIOLOGIC LEVEL AND HETEROGENEOUS AT THE CLINICAL LEVEL. THE ADVANCES IN MOLECULAR CHARACTERIZATION OF MF PROVIDE IMPORTANT INSIGHT INTO THE MECHANISMS DRIVING THIS CHRONIC MYELOID MALIGNANCY, REFINE RISK STRATIFICATION, OFFER NOVEL THERAPEUTIC TARGETS, AND SERVE TO MEASURE THERAPEUTIC RESPONSE. ALTHOUGH JAK2 INHIBITION HAS BEEN THE FOCUS OF LABORATORY AND CLINICAL EFFORTS OVER THE LAST DECADE, CURRENT EXPERIMENTAL THERAPEUTIC APPROACHES HAVE BROADENED TO INCLUDE INHIBITORS OF KEY ALTERNATIVE SIGNALING PATHWAYS, EPIGENETIC MODULATORS, ANTI-FIBROTICS, AND IMMUNOTHERAPIES. BASED ON COMPELLING PRECLINICAL RATIONALE, A NUMBER OF JAK2 INHIBITOR BASED COMBINATION THERAPIES ARE NOW ACTIVELY BEING EVALUATED IN THE CLINIC WITH THE GOAL OF DISEASE COURSE MODIFICATION. THE ROLE AND TIMING OF HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) FOR MF HAS BEEN CHALLENGED WITH THE AVAILABILITY OF COMMERCIAL RUXOLITINIB AND THE PLETHORA OF EXPERIMENTAL TREATMENT OPTIONS THAT EXIST. INTEGRATION OF PRECONDITIONING JAK2 INHIBITION, REDUCED INTENSITY CONDITIONING REGIMENS, AND ALTERNATIVE DONOR SOURCES ARE ALL BEING EXPLORED IN AN ATTEMPT TO OPTIMIZE THIS POTENTIALLY CURATIVE MODALITY. THIS REVIEW WILL SUMMARIZE MODERN MF RISK STRATIFICATION, CURRENT CLINICAL RESEARCH APPROACHES TO CHRONIC AND ADVANCE PHASE MF FOCUSING ON NOVEL AGENTS ALONE AND IN COMBINATION, AND UPDATE THE READER ON NEW DIRECTIONS IN HSCT. 2015 8 3928 29 LIVER CELL CIRCUITS AND THERAPEUTIC DISCOVERY FOR ADVANCED LIVER DISEASE AND CANCER. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR GLOBAL HEALTH CHALLENGE WITH RISING INCIDENCE. DESPITE THE PREVIOUS APPROVAL OF SEVERAL NOVEL THERAPEUTIC APPROACHES, HCC REMAINS THE SECOND COMMON CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE VAST MAJORITY OF HCCS ARISES IN THE CONTEXT OF CHRONIC FIBROTIC LIVER DISEASES CAUSED BY VIRAL OR METABOLIC ETIOLOGIES. IN PATIENTS WITH ADVANCED LIVER DISEASE THE RISK OF HCC PERSISTS EVEN AFTER VIRAL CURE OR CONTROL OF INFECTION. MOREOVER, GIVEN THE CHANGE IN THE LIFESTYLE AND INCREASE OF OBESITY AND METABOLIC DISORDERS, HCC INCIDENCE IS PREDICTED TO DRASTICALLY AUGMENT IN THE NEXT DECADE. EARLY DETECTION, IMPROVEMENT OF THE SCREENING METHOD IN PATIENT AT-RISK AND DEVELOPMENT OF CHEMOPREVENTIVE STRATEGIES ARE THEREFORE URGENTLY NEEDED TO REDUCE HCC RISK. THIS REVIEW SUMMARIZES THE MAJOR CHALLENGES IN THE IDENTIFICATION OF PATIENT AT RISK FOR HCC AND THE EMERGENT STRATEGIES FOR HCC PREVENTION TO IMPROVE PATIENTS' OUTCOME. 2021 9 1133 28 COMPREHENSIVE EPIGENOMIC PROFILING OF HUMAN ALVEOLAR EPITHELIAL DIFFERENTIATION IDENTIFIES KEY EPIGENETIC STATES AND TRANSCRIPTION FACTOR CO-REGULATORY NETWORKS FOR MAINTENANCE OF DISTAL LUNG IDENTITY. BACKGROUND: DISRUPTION OF ALVEOLAR EPITHELIAL CELL (AEC) DIFFERENTIATION IS IMPLICATED IN DISTAL LUNG DISEASES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE, IDIOPATHIC PULMONARY FIBROSIS, AND LUNG ADENOCARCINOMA THAT IMPACT MORBIDITY AND MORTALITY WORLDWIDE. ELUCIDATING UNDERLYING DISEASE PATHOGENESIS REQUIRES A MECHANISTIC MOLECULAR UNDERSTANDING OF AEC DIFFERENTIATION. PREVIOUS STUDIES HAVE FOCUSED ON CHANGES OF INDIVIDUAL TRANSCRIPTION FACTORS, AND TO DATE NO STUDY HAS COMPREHENSIVELY CHARACTERIZED THE DYNAMIC, GLOBAL EPIGENOMIC ALTERATIONS THAT FACILITATE THIS CRITICAL DIFFERENTIATION PROCESS IN HUMANS. RESULTS: WE COMPREHENSIVELY PROFILED THE EPIGENOMIC STATES OF HUMAN AECS DURING TYPE 2 TO TYPE 1-LIKE CELL DIFFERENTIATION, INCLUDING THE METHYLOME AND CHROMATIN FUNCTIONAL DOMAINS, AND INTEGRATED THIS WITH TRANSCRIPTOME-WIDE RNA EXPRESSION DATA. ENHANCER REGIONS WERE DRASTICALLY ALTERED DURING AEC DIFFERENTIATION. TRANSCRIPTION FACTOR BINDING ANALYSIS WITHIN ENHANCER REGIONS REVEALED DIVERSE INTERACTIVE NETWORKS WITH ENRICHMENT FOR MANY TRANSCRIPTION FACTORS, INCLUDING NKX2-1 AND FOXA FAMILY MEMBERS, AS WELL AS TRANSCRIPTION FACTORS WITH LESS WELL CHARACTERIZED ROLES IN AEC DIFFERENTIATION, SUCH AS MEMBERS OF THE MEF2, TEAD, AND AP1 FAMILIES. ADDITIONALLY, ASSOCIATIONS AMONG TRANSCRIPTION FACTORS CHANGED DURING DIFFERENTIATION, IMPLICATING A COMPLEX NETWORK OF HETEROTRIMERIC COMPLEX SWITCHING IN DRIVING DIFFERENTIATION. INTEGRATION OF AEC ENHANCER STATES WITH THE CATALOG OF ENHANCER ELEMENTS IN THE ROADMAP EPIGENOMICS MAPPING CONSORTIUM AND ENCYCLOPEDIA OF DNA ELEMENTS (ENCODE) REVEALED THAT AECS HAVE SIMILAR EPIGENOMIC STRUCTURES TO OTHER PROFILED EPITHELIAL CELL TYPES, INCLUDING HUMAN MAMMARY EPITHELIAL CELLS (HMECS), WITH NKX2-1 SERVING AS A DISTINGUISHING FEATURE OF DISTAL LUNG DIFFERENTIATION. CONCLUSIONS: ENHANCER REGIONS ARE HOTSPOTS OF EPIGENOMIC ALTERATION THAT REGULATE AEC DIFFERENTIATION. FURTHERMORE, THE DIFFERENTIATION PROCESS IS REGULATED BY DYNAMIC NETWORKS OF TRANSCRIPTION FACTORS ACTING IN CONCERT, RATHER THAN INDIVIDUALLY. THESE FINDINGS PROVIDE A ROADMAP FOR UNDERSTANDING THE RELATIONSHIP BETWEEN DISRUPTION OF THE EPIGENETIC STATE DURING AEC DIFFERENTIATION AND DEVELOPMENT OF LUNG DISEASES THAT MAY BE THERAPEUTICALLY AMENABLE. 2021 10 1947 40 EPIGENETIC ABNORMALITIES IN MYELOPROLIFERATIVE NEOPLASMS: A TARGET FOR NOVEL THERAPEUTIC STRATEGIES. THE MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE A GROUP OF CLONAL HEMATOLOGICAL MALIGNANCIES CHARACTERIZED BY A HYPERCELLULAR BONE MARROW AND A TENDENCY TO DEVELOP THROMBOTIC COMPLICATIONS AND TO EVOLVE TO MYELOFIBROSIS AND ACUTE LEUKEMIA. UNLIKE CHRONIC MYELOGENOUS LEUKEMIA, WHERE A SINGLE DISEASE-INITIATING GENETIC EVENT HAS BEEN IDENTIFIED, A MORE COMPLICATED SERIES OF GENETIC MUTATIONS APPEAR TO BE RESPONSIBLE FOR THE BCR-ABL1-NEGATIVE MPNS WHICH INCLUDE POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA, AND PRIMARY MYELOFIBROSIS. RECENT STUDIES HAVE REVEALED A NUMBER OF EPIGENETIC ALTERATIONS THAT ALSO LIKELY CONTRIBUTE TO DISEASE PATHOGENESIS AND DETERMINE CLINICAL OUTCOME. INCREASING EVIDENCE INDICATES THAT ALTERATIONS IN DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNA EXPRESSION PATTERNS CAN COLLECTIVELY INFLUENCE GENE EXPRESSION AND POTENTIALLY CONTRIBUTE TO MPN PATHOGENESIS. EXAMPLES INCLUDE MUTATIONS IN GENES ENCODING PROTEINS THAT MODIFY CHROMATIN STRUCTURE (EZH2, ASXL1, IDH1/2, JAK2V617F, AND IKZF1) AS WELL AS EPIGENETIC MODIFICATION OF GENES CRITICAL FOR CELL PROLIFERATION AND SURVIVAL (SUPPRESSORS OF CYTOKINE SIGNALING, POLYCYTHEMIA RUBRA VERA-1, CXC CHEMOKINE RECEPTOR 4, AND HISTONE DEACETYLASE (HDAC)). THESE EPIGENETIC LESIONS SERVE AS NOVEL TARGETS FOR EXPERIMENTAL THERAPEUTIC INTERVENTIONS. CLINICAL TRIALS ARE CURRENTLY UNDERWAY EVALUATING HDAC INHIBITORS AND DNA METHYLTRANSFERASE INHIBITORS FOR THE TREATMENT OF PATIENTS WITH MPNS. 2011 11 4442 33 MOLECULAR GENETICS OF MDS/MPN OVERLAP SYNDROMES. THE MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) ARE A HETEROGENOUS GROUP OF MYELOID MALIGNANCIES HALLMARKED BY CLINICOPATHOLOGIC FEATURES THAT OVERLAP WITH MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. FORMALLY RECOGNIZED BY THE WORLD HEALTH ORGANIZATION, THIS GROUP INCLUDES THE ENTITIES CHRONIC MYELOMONOCYTIC LEUKEMIA, JUVENILE MYELOMONOCYTIC LEUKEMIA, ATYPICAL CHRONIC MYELOID LEUKEMIA, MDS/MPN WITH RING SIDEROBLASTS AND THROMBOCYTOSIS AND MDS/MPN, UNCLASSIFIABLE. ADVANCEMENTS IN NEXT GENERATION SEQUENCING HAVE BEGUN TO UNRAVEL THE MOLECULAR UNDERPINNINGS OF THESE DISEASES, IDENTIFYING AN ARRAY OF RECURRENTLY MUTATED GENES INVOLVED IN EPIGENETIC REGULATION, RNA SPLICING, TRANSCRIPTION, AND CELL SIGNALING. DESPITE MOLECULAR OVERLAP WITH OTHER MYELOID MALIGNANCIES, EACH ENTITY DISPLAYS A UNIQUE SPECTRUM OF SOMATIC MUTATIONS SUPPORTING THEIR UNIQUE PATHOBIOLOGY AND CLINICAL FEATURES. IMPORTANTLY, MOLECULAR PROFILING IS BECOMING AN INTEGRAL TOOL UTILIZED IN ROUTINE CLINICAL PRACTICE. THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF OVERLAP SYNDROMES AND DETAILS THE IMPACT OF SOMATIC MUTATIONS IN DIAGNOSTIC, PROGNOSTIC, AND THERAPEUTIC DECISION-MAKING. 2020 12 3575 45 IMPACT OF MOLECULAR PROFILING ON THE MANAGEMENT OF PATIENTS WITH MYELOFIBROSIS. MYELOFIBROSIS (MF) IS A CHRONIC MYELOPROLIFERATIVE NEOPLASM (MPN) CHARACTERIZED BY A HIGHLY HETEROGENEOUS CLINICAL COURSE, WHICH CAN BE COMPLICATED BY SEVERE CONSTITUTIONAL SYMPTOMS, MASSIVE SPLENOMEGALY, PROGRESSIVE BONE MARROW FAILURE, CARDIOVASCULAR EVENTS, AND DEVELOPMENT OF ACUTE LEUKEMIA. CONSTITUTIVE SIGNALING THROUGH THE JAK-STAT PATHWAY PLAYS A FUNDAMENTAL ROLE IN ITS PATHOGENESIS, GENERALLY DUE TO ACTIVATING MUTATIONS OF JAK2, CALR AND MPL GENES (I.E., THE MPN DRIVER MUTATIONS), PRESENT IN MOST MF PATIENTS. NEXT GENERATION SEQUENCING (NGS) PANEL TESTING HAS SHOWN THAT ADDITIONAL SOMATIC MUTATIONS CAN ALREADY BE DETECTED AT THE TIME OF DIAGNOSIS IN MORE THAN HALF OF PATIENTS, AND THAT THEY ACCUMULATE ALONG THE DISEASE COURSE. THESE MUTATIONS, MOSTLY AFFECTING EPIGENETIC MODIFIERS OR SPLICEOSOME COMPONENTS, MAY COOPERATE WITH MPN DRIVERS TO FAVOR CLONAL DOMINANCE OR INFLUENCE THE CLINICAL PHENOTYPE, AND SOME, SUCH AS HIGH MOLECULAR RISK MUTATIONS, CORRELATE WITH A MORE AGGRESSIVE CLINICAL COURSE WITH POOR TREATMENT RESPONSE. THE CURRENT MAIN ROLE OF MOLECULAR PROFILING IN CLINICAL PRACTICE IS PROGNOSTICATION, PRINCIPALLY FOR SELECTING HIGH-RISK PATIENTS WHO MAY BE CANDIDATES FOR TRANSPLANTATION, THE ONLY CURATIVE TREATMENT FOR MF TO DATE. TO THIS END, CONTEMPORARY PROGNOSTIC MODELS INCORPORATING MOLECULAR DATA ARE USEFUL TOOLS TO DISCRIMINATE DIFFERENT RISK CATEGORIES. ASIDE FROM CERTAIN CLINICAL SITUATIONS, DECISIONS REGARDING MEDICAL TREATMENT ARE NOT BASED ON PATIENT MOLECULAR PROFILING, YET THIS APPROACH MAY BECOME MORE RELEVANT IN NOVEL TREATMENT STRATEGIES, SUCH AS THE USE OF VACCINES AGAINST THE MUTANT FORMS OF JAK2 OR CALR, OR DRUGS DIRECTED AGAINST ACTIONABLE MOLECULAR TARGETS. 2022 13 4337 27 MICROTUBULES AS MAJOR REGULATORS OF ENDOTHELIAL FUNCTION: IMPLICATION FOR LUNG INJURY. ENDOTHELIAL DYSFUNCTION HAS BEEN ATTRIBUTED AS ONE OF THE MAJOR COMPLICATIONS IN COVID-19 PATIENTS, A GLOBAL PANDEMIC THAT HAS ALREADY CAUSED OVER 4 MILLION DEATHS WORLDWIDE. THE DYSFUNCTION OF ENDOTHELIAL BARRIER IS CHARACTERIZED BY AN INCREASE IN ENDOTHELIAL PERMEABILITY AND INFLAMMATORY RESPONSES, AND HAS EVEN BROADER IMPLICATIONS IN THE PATHOGENESIS OF ACUTE RESPIRATORY SYNDROMES SUCH AS ARDS, SEPSIS AND CHRONIC ILLNESSES REPRESENTED BY PULMONARY ARTERIAL HYPERTENSION AND INTERSTITIAL LUNG DISEASE. THE STRUCTURAL INTEGRITY OF ENDOTHELIAL BARRIER IS MAINTAINED BY CYTOSKELETON ELEMENTS, CELL-SUBSTRATE FOCAL ADHESION AND ADHESIVE CELL JUNCTIONS. AGONIST-MEDIATED CHANGES IN ENDOTHELIAL PERMEABILITY ARE DIRECTLY ASSOCIATED WITH REORGANIZATION OF ACTOMYOSIN CYTOSKELETON LEADING TO CELL CONTRACTION AND OPENING OF INTERCELLULAR GAPS OR ENHANCEMENT OF CORTICAL ACTIN CYTOSKELETON ASSOCIATED WITH STRENGTHENING OF ENDOTHELIAL BARRIER. THE ROLE OF ACTIN CYTOSKELETON REMODELING IN ENDOTHELIAL BARRIER REGULATION HAS TAKEN THE CENTRAL STAGE, BUT THE IMPACT OF MICROTUBULES IN THIS PROCESS REMAINS LESS EXPLORED AND UNDER-APPRECIATED. THIS REVIEW WILL SUMMARIZE THE CURRENT KNOWLEDGE ON THE CROSSTALK BETWEEN MICROTUBULES DYNAMICS AND ACTIN CYTOSKELETON REMODELING, DESCRIBE THE SIGNALING MECHANISMS MEDIATING THIS CROSSTALK, DISCUSS EPIGENETIC REGULATION OF MICROTUBULES STABILITY AND ITS NEXUS WITH ENDOTHELIAL BARRIER MAINTENANCE, AND OVERVIEW A ROLE OF MICROTUBULES IN TARGETED DELIVERY OF SIGNALING MOLECULES REGULATING ENDOTHELIAL PERMEABILITY AND INFLAMMATION. 2021 14 6757 31 WNT SIGNALING IN LIVER FIBROSIS: PROGRESS, CHALLENGES AND POTENTIAL DIRECTIONS. LIVER FIBROSIS IS A COMMON WOUND-HEALING RESPONSE TO CHRONIC LIVER INJURIES, INCLUDING ALCOHOLIC OR DRUG TOXICITY, PERSISTENT VIRAL INFECTION, AND GENETIC FACTORS. MYOFIBROBLASTIC TRANSDIFFERENTIATION (MTD) IS THE PIVOTAL EVENT DURING LIVER FIBROGENESIS, AND RESEARCH IN THE PAST FEW YEARS HAS IDENTIFIED KEY MEDIATORS AND MOLECULAR MECHANISMS RESPONSIBLE FOR MTD OF HEPATIC STELLATE CELLS (HSCS). HSCS ARE UNDIFFERENTIATED CELLS WHICH PLAY AN IMPORTANT ROLE IN LIVER REGENERATION. RECENT EVIDENCE DEMONSTRATES THAT HSCS DERIVE FROM MESODERM AND AT LEAST IN PART VIA SEPTUM TRANSVERSUM AND MESOTHELIUM, AND HSCS EXPRESS MARKERS FOR DIFFERENT CELL TYPES WHICH DERIVE FROM MULTIPOTENT MESENCHYMAL PROGENITORS. THERE IS A REGULATORY COMMONALITY BETWEEN DIFFERENTIATION OF ADIPOCYTES AND THAT OF HSC, AND THE SHIFT FROM ADIPOGENIC TO MYOGENIC OR NEURONAL PHENOTYPE CHARACTERIZES HSC MTD. CENTRAL OF THIS SHIFT IS A LOSS OF EXPRESSION OF THE MASTER ADIPOGENIC REGULATOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA (PPARGAMMA). RESTORED EXPRESSION OF PPARGAMMA AND/OR OTHER ADIPOGENIC TRANSCRIPTION GENES CAN REVERSE MYOFIBROBLASTIC HSCS TO DIFFERENTIATED CELLS. VERTEBRATE WNT AND DROSOPHILA WINGLESS ARE HOMOLOGOUS GENES, AND THEIR TRANSLATED PROTEINS HAVE BEEN SHOWN TO PARTICIPATE IN THE REGULATION OF CELL PROLIFERATION, CELL POLARITY, CELL DIFFERENTIATION, AND OTHER BIOLOGICAL ROLES. MORE RECENTLY, WNT SIGNALING IS IMPLICATED IN HUMAN FIBROSING DISEASES, SUCH AS PULMONARY FIBROSIS, RENAL FIBROSIS, AND LIVER FIBROSIS. BLOCKING THE CANONICAL WNT SIGNAL PATHWAY WITH THE CO-RECEPTOR ANTAGONIST DICKKOPF-1 (DKK1) ABROGATES THESE EPIGENETIC REPRESSIONS AND RESTORES THE GENE PPARGAMMA EXPRESSION AND HSC DIFFERENTIATION. THE IDENTIFIED MORPHOGEN MEDIATED EPIGENETIC REGULATION OF PPARGAMMA AND HSC DIFFERENTIATION ALSO SERVES AS NOVEL THERAPEUTIC TARGETS FOR LIVER FIBROSIS AND LIVER REGENERATION. IN CONCLUSION, THE WNT SIGNALING PROMOTES LIVER FIBROSIS BY ENHANCING HSC ACTIVATION AND SURVIVAL, AND WE HEREIN DISCUSS WHAT WE CURRENTLY KNOW AND WHAT WE EXPECT WILL COME IN THIS FIELD IN THE NEXT FUTURE. 2013 15 3245 17 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 16 6621 29 UNDERSTANDING FIBROSIS IN SYSTEMIC SCLEROSIS: SHIFTING PARADIGMS, EMERGING OPPORTUNITIES. FIBROSIS IN MULTIPLE ORGANS IS A PROMINENT PATHOLOGICAL FINDING AND DISTINGUISHING HALLMARK OF SYSTEMIC SCLEROSIS (SSC). FINDINGS DURING THE PAST 5 YEARS HAVE CONTRIBUTED TO A MORE COMPLETE UNDERSTANDING OF THE COMPLEX CELLULAR AND MOLECULAR UNDERPINNING OF FIBROSIS IN SSC. FIBROBLASTS, THE PRINCIPAL EFFECTOR CELLS, ARE ACTIVATED IN THE PROFIBROTIC CELLULAR MILIEU BY CYTOKINES AND GROWTH FACTORS, DEVELOPMENTAL PATHWAYS, ENDOTHELIN 1 AND THROMBIN. INNATE IMMUNE SIGNALING VIA TOLL-LIKE RECEPTORS, MATRIX-GENERATED BIOMECHANICAL STRESS SIGNALING VIA INTEGRINS, HYPOXIA AND OXIDATIVE STRESS SEEM TO BE IMPLICATED IN PERPETUATING THE PROCESS. BEYOND CHRONIC FIBROBLAST ACTIVATION, FIBROSIS REPRESENTS A FAILURE TO TERMINATE TISSUE REPAIR, COUPLED WITH AN EXPANDED POPULATION OF MESENCHYMAL CELLS ORIGINATING FROM BONE MARROW AND TRANSDIFFERENTIATION OF EPITHELIAL CELLS, ENDOTHELIAL CELLS AND PERICYTES. IN ADDITION, STUDIES HAVE IDENTIFIED INTRINSIC ALTERATIONS IN SSC FIBROBLASTS RESULTING FROM EPIGENETIC CHANGES, AS WELL AS ALTERED MICRORNA EXPRESSION THAT MIGHT UNDERLIE THE CELL-AUTONOMOUS, PERSISTENT ACTIVATION PHENOTYPE OF THESE CELLS. PRECISE CHARACTERIZATION OF THE DEREGULATED EXTRACELLULAR AND INTRACELLULAR SIGNALING PATHWAYS, MEDIATORS AND CELLULAR DIFFERENTIATION PROGRAMS THAT CONTRIBUTE TO FIBROSIS IN SSC WILL FACILITATE THE DEVELOPMENT OF SELECTIVE, TARGETED THERAPEUTIC STRATEGIES. EFFECTIVE ANTIFIBROTIC THERAPY WILL ULTIMATELY INVOLVE NOVEL COMPOUNDS AND REPURPOSING OF DRUGS THAT ARE ALREADY APPROVED FOR OTHER INDICATIONS. 2011 17 5769 19 SPECIFIC EPIGENETIC REGULATORS SERVE AS POTENTIAL THERAPEUTIC TARGETS IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF), A DISORDER OBSERVED MOSTLY IN OLDER HUMAN BEINGS, IS CHARACTERISED BY CHRONIC AND PROGRESSIVE LUNG SCARRING LEADING TO AN IRREVERSIBLE DECLINE IN LUNG FUNCTION. THIS HEALTH CONDITION HAS A DISMAL PROGNOSIS AND THE CURRENTLY AVAILABLE DRUGS ONLY DELAY BUT FAIL TO REVERSE THE PROGRESSION OF LUNG DAMAGE. CONSEQUENTLY, IT BECOMES IMPERATIVE TO DISCOVER IMPROVED THERAPEUTIC COMPOUNDS AND THEIR CELLULAR TARGETS TO CURE IPF. IN THIS REGARD, A NUMBER OF RECENT STUDIES HAVE TARGETED THE EPIGENETIC REGULATION BY HISTONE DEACETYLASES (HDACS) TO DEVELOP AND CATEGORISE ANTIFIBROTIC DRUGS FOR LUNGS. THEREFORE, THIS REVIEW FOCUSES ON HOW ABERRANT EXPRESSION OR ACTIVITY OF CLASSES I, II AND III HDACS ALTER TGF-BETA SIGNALLING TO PROMOTE EVENTS SUCH AS EPITHELIAL-MESENCHYMAL TRANSITION, DIFFERENTIATION OF ACTIVATED FIBROBLASTS INTO MYOFIBROBLASTS, AND EXCESS DEPOSITION OF THE EXTRACELLULAR MATRIX TO PROPEL LUNG FIBROSIS. FURTHER, THIS STUDY DESCRIBES HOW CERTAIN CHEMICAL COMPOUNDS OR DIETARY CHANGES MODULATE DYSREGULATED HDACS TO ATTENUATE FIVE FAULTY TGF-BETA-DEPENDENT PROFIBROTIC PROCESSES, BOTH IN ANIMAL MODELS AND CELL LINES REPLICATING IPF, THEREBY IDENTIFYING PROMISING MEANS TO TREAT THIS LUNG DISORDER. 2022 18 5013 31 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AS A THERAPEUTIC TARGET FOR HEPATIC FIBROSIS: FROM BENCH TO BEDSIDE. HEPATIC FIBROSIS IS A DYNAMIC CHRONIC LIVER DISEASE OCCURRING AS A CONSEQUENCE OF WOUND-HEALING RESPONSES TO VARIOUS HEPATIC INJURIES. THIS DISORDER IS ONE OF PRIMARY PREDICTORS FOR LIVER-ASSOCIATED MORBIDITY AND MORTALITY WORLDWIDE. TO DATE, NO PHARMACOLOGICAL AGENT HAS BEEN APPROVED FOR HEPATIC FIBROSIS OR COULD BE RECOMMENDED FOR ROUTINE USE IN CLINICAL CONTEXT. CELLULAR AND MOLECULAR UNDERSTANDING OF HEPATIC FIBROSIS HAS REVEALED THAT PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA), THE FUNCTIONING RECEPTOR FOR ANTIDIABETIC THIAZOLIDINEDIONES, PLAYS A PIVOTAL ROLE IN THE PATHOBIOLOGY OF HEPATIC STELLATE CELLS (HSCS), WHOSE ACTIVATION IS THE CENTRAL EVENT IN THE PATHOGENESIS OF HEPATIC FIBROSIS. ACTIVATION OF PPARGAMMA INHIBITS HSC COLLAGEN PRODUCTION AND MODULATES HSC ADIPOGENIC PHENOTYPE AT TRANSCRIPTIONAL AND EPIGENETIC LEVELS. THESE MOLECULAR INSIGHTS INDICATE PPARGAMMA AS A PROMISING DRUG TARGET FOR ANTIFIBROTIC CHEMOTHERAPY. INTENSIVE ANIMAL STUDIES HAVE DEMONSTRATED THAT STIMULATION OF PPARGAMMA REGULATORY SYSTEM THROUGH GENE THERAPY APPROACHES AND PPARGAMMA LIGANDS HAS THERAPEUTIC PROMISE FOR HEPATIC FIBROSIS INDUCED BY A VARIETY OF ETIOLOGIES. AT THE SAME TIME, THIAZOLIDINEDIONE AGENTS HAVE BEEN INVESTIGATED FOR THEIR CLINICAL BENEFITS PRIMARILY IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS, A COMMON METABOLIC LIVER DISORDER WITH HIGH POTENTIAL TO PROGRESS TO FIBROSIS AND LIVER-RELATED DEATH. ALTHOUGH SOME STUDIES HAVE SHOWN INITIAL PROMISE, NONE HAS ESTABLISHED LONG-TERM EFFICACY IN WELL-CONTROLLED RANDOMIZED CLINICAL TRIALS. THIS COMPREHENSIVE REVIEW COVERS THE 10-YEAR DISCOVERIES OF THE MOLECULAR BASIS FOR PPARGAMMA REGULATION OF HSC PATHOPHYSIOLOGY AND THEN FOCUSES ON THE ANIMAL INVESTIGATIONS AND CLINICAL TRIALS OF VARIOUS THERAPEUTIC MODALITIES TARGETING PPARGAMMA FOR HEPATIC FIBROSIS. 2013 19 1102 29 COMBINED CHEMOSENSITIVITY AND CHROMATIN PROFILING PRIORITIZES DRUG COMBINATIONS IN CLL. THE BRUTON TYROSINE KINASE (BTK) INHIBITOR IBRUTINIB HAS SUBSTANTIALLY IMPROVED THERAPEUTIC OPTIONS FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). ALTHOUGH IBRUTINIB IS NOT CURATIVE, IT HAS A PROFOUND EFFECT ON CLL CELLS AND MAY CREATE NEW PHARMACOLOGICALLY EXPLOITABLE VULNERABILITIES. TO IDENTIFY SUCH VULNERABILITIES, WE DEVELOPED A SYSTEMATIC APPROACH THAT COMBINES EPIGENOME PROFILING (CHARTING THE GENE-REGULATORY BASIS OF CELL STATE) WITH SINGLE-CELL CHEMOSENSITIVITY PROFILING (QUANTIFYING CELL-TYPE-SPECIFIC DRUG RESPONSE) AND BIOINFORMATIC DATA INTEGRATION. BY APPLYING OUR METHOD TO A COHORT OF MATCHED PATIENT SAMPLES COLLECTED BEFORE AND DURING IBRUTINIB THERAPY, WE IDENTIFIED CHARACTERISTIC IBRUTINIB-INDUCED CHANGES THAT PROVIDE A STARTING POINT FOR THE RATIONAL DESIGN OF IBRUTINIB COMBINATION THERAPIES. SPECIFICALLY, WE OBSERVED AND VALIDATED PREFERENTIAL SENSITIVITY TO PROTEASOME, PLK1, AND MTOR INHIBITORS DURING IBRUTINIB TREATMENT. MORE GENERALLY, OUR STUDY ESTABLISHES A BROADLY APPLICABLE METHOD FOR INVESTIGATING TREATMENT-SPECIFIC VULNERABILITIES BY INTEGRATING THE COMPLEMENTARY PERSPECTIVES OF EPIGENETIC CELL STATES AND PHENOTYPIC DRUG RESPONSES IN PRIMARY PATIENT SAMPLES. 2019 20 5778 31 SPINAL CORD INJURY INDUCED NEUROPATHIC PAIN: MOLECULAR TARGETS AND THERAPEUTIC APPROACHES. NEUROPATHIC PAIN, ESPECIALLY THAT RESULTING FROM SPINAL CORD INJURY, IS A TREMENDOUS CLINICAL CHALLENGE. A MYRIAD OF BIOLOGICAL CHANGES HAVE BEEN IMPLICATED IN PRODUCING THESE PAIN STATES INCLUDING CELLULAR INTERACTIONS, EXTRACELLULAR PROTEINS, ION CHANNEL EXPRESSION, AND EPIGENETIC INFLUENCES. PHYSIOLOGICAL CONSEQUENCES OF THESE CHANGES ARE VARIED AND INCLUDE FUNCTIONAL DEFICITS AND PAIN RESPONSES. DEVELOPING THERAPIES THAT EFFECTIVELY ADDRESS THE CAUSE OF THESE SYMPTOMS REQUIRE A DEEPER KNOWLEDGE OF ALTERATIONS IN THE MOLECULAR PATHWAYS. MATRIX METALLOPROTEINASES AND TISSUE INHIBITORS OF METALLOPROTEINASES ARE TWO PROMISING THERAPEUTIC TARGETS. MATRIX METALLOPROTEINASES INTERACT WITH AND INFLUENCE MANY OF THE STUDIED PAIN PATHWAYS. GENE EXPRESSION OF ION CHANNELS AND INFLAMMATORY MEDIATORS CLEARLY CONTRIBUTES TO NEUROPATHIC PAIN. LOCALIZED AND TIME DEPENDENT TARGETING OF THESE PROTEINS COULD ALLEVIATE AND EVEN PREVENT NEUROPATHIC PAIN FROM DEVELOPING. CURRENT THERAPEUTIC OPTIONS FOR NEUROPATHIC PAIN ARE LIMITED PRIMARILY TO ANALGESICS TARGETING THE OPIOID PATHWAY. THERAPIES DIRECTED AT MOLECULAR TARGETS ARE HIGHLY DESIRABLE AND IN EARLY STAGES OF DEVELOPMENT. THESE INCLUDE TRANSPLANTATION OF EXOGENOUSLY ENGINEERED CELL POPULATIONS AND TARGETED GENE MANIPULATION. THIS REVIEW DESCRIBES SPECIFIC MOLECULAR TARGETS AMENABLE TO THERAPEUTIC INTERVENTION USING CURRENTLY AVAILABLE DELIVERY SYSTEMS. 2015