1 1108 65 COMMENTARY ON SOME RECENT THESES RELEVANT TO COMBATING AGING: JUNE 2021. THESES REVIEWED IN THIS ISSUE INCLUDE "ENGINEERING PROTEIN DISAGGREGASES TO COUNTER ALPHA-SYNUCLEIN AND AMYLOID-BETA NEUROTOXICITY," "HYPERGLYCAEMIA INDUCED IMMUNOMODULATION OF MACROPHAGES IN DIABETIC VASCULAR DISEASE," "MICROVASCULATURE-ON-A-CHIP SYSTEMS FOR HUMAN DISEASE MODELING," "SENESCENCE SURVEILLANCE: THE INTERPLAY BETWEEN THE IMMUNE SYSTEM AND SENESCENT CELLS," "THE HMG TRANSCRIPTION FACTOR TOX INDUCES A TRANSCRIPTIONAL AND EPIGENETIC PROGRAM OF CD8(+) T CELL EXHAUSTION IN CHRONIC INFECTION AND CANCER," AND "ZERO TO ONE-TRANSLATIONAL ADVANCEMENTS IN THE FIELD OF XENOTRANSPLANTATION." 2021 2 445 19 APABETALONE (RVX-208) REDUCES VASCULAR INFLAMMATION IN VITRO AND IN CVD PATIENTS BY A BET-DEPENDENT EPIGENETIC MECHANISM. BACKGROUND: APABETALONE (RVX-208) IS A BROMODOMAIN AND EXTRATERMINAL PROTEIN INHIBITOR (BETI) THAT IN PHASE II TRIALS REDUCED THE RELATIVE RISK (RR) OF MAJOR ADVERSE CARDIAC EVENTS (MACE) IN PATIENTS WITH CARDIOVASCULAR DISEASE (CVD) BY 44% AND IN DIABETIC CVD PATIENTS BY 57% ON TOP OF STATINS. A PHASE III TRIAL, BETONMACE, IS CURRENTLY ASSESSING APABETALONE'S ABILITY TO REDUCE MACE IN STATIN-TREATED POST-ACUTE CORONARY SYNDROME TYPE 2 DIABETIC CVD PATIENTS WITH LOW HIGH-DENSITY LIPOPROTEIN C. THE LEADING CAUSE OF MACE IS ATHEROSCLEROSIS, DRIVEN BY DYSFUNCTIONAL LIPID METABOLISM AND CHRONIC VASCULAR INFLAMMATION (VI). IN VITRO STUDIES HAVE IMPLICATED THE BET PROTEIN BRD4 AS AN EPIGENETIC DRIVER OF INFLAMMATION AND ATHEROGENESIS, SUGGESTING THAT BETI MAY BE CLINICALLY EFFECTIVE IN COMBATING VI. HERE, WE ASSESSED APABETALONE'S ABILITY TO REGULATE INFLAMMATION-DRIVEN GENE EXPRESSION AND CELL ADHESION IN VITRO AND INVESTIGATED THE MECHANISM BY WHICH APABETALONE SUPPRESSES EXPRESSION. THE CLINICAL IMPACT OF APABETALONE ON MEDIATORS OF VI WAS ASSESSED WITH PROTEOMIC ANALYSIS OF PHASE II CVD PATIENT PLASMA. RESULTS: IN VITRO, APABETALONE PREVENTED INFLAMMATORY (TNFALPHA, LPS, OR IL-1BETA) INDUCTION OF KEY FACTORS THAT DRIVE ENDOTHELIAL ACTIVATION, MONOCYTE RECRUITMENT, ADHESION, AND PLAQUE DESTABILIZATION. BRD4 ABUNDANCE ON INFLAMMATORY AND ADHESION GENE PROMOTERS AND ENHANCERS WAS REDUCED BY APABETALONE. BRD2-4 DEGRADATION BY MZ-1 ALSO PREVENTED TNFALPHA-INDUCED TRANSCRIPTION OF MONOCYTE AND ENDOTHELIAL CELL ADHESION MOLECULES AND INFLAMMATORY MEDIATORS, CONFIRMING BET-DEPENDENT REGULATION. TRANSCRIPTIONAL REGULATION BY APABETALONE TRANSLATED INTO A REDUCTION IN MONOCYTE ADHESION TO AN ENDOTHELIAL MONOLAYER. IN A PHASE II TRIAL, APABETALONE TREATMENT REDUCED THE ABUNDANCE OF MULTIPLE VI MEDIATORS IN THE PLASMA OF CVD PATIENTS (SOMASCAN(R) 1.3 K). THESE PROTEINS CORRELATE WITH CVD RISK AND INCLUDE ADHESION MOLECULES, CYTOKINES, AND METALLOPROTEINASES. INGENUITY(R) PATHWAY ANALYSIS (IPA(R)) PREDICTED THAT APABETALONE INHIBITS PRO-ATHEROGENIC REGULATORS AND PATHWAYS AND PREVENTS DISEASE STATES ARISING FROM LEUKOCYTE RECRUITMENT. CONCLUSIONS: APABETALONE SUPPRESSED GENE EXPRESSION OF VI MEDIATORS IN MONOCYTES AND ENDOTHELIAL CELLS BY INHIBITING BET-DEPENDENT TRANSCRIPTION INDUCED BY MULTIPLE INFLAMMATORY STIMULI. IN CVD PATIENTS, APABETALONE TREATMENT REDUCED CIRCULATING LEVELS OF VI MEDIATORS, AN OUTCOME CONDUCIVE WITH ATHEROSCLEROTIC PLAQUE STABILIZATION AND MACE REDUCTION. INHIBITION OF INFLAMMATORY AND ADHESION MOLECULE GENE EXPRESSION BY APABETALONE IS PREDICTED TO CONTRIBUTE TO MACE REDUCTION IN THE PHASE III BETONMACE TRIAL. 2019 3 3678 22 INFLAMMATION AND REGENERATION IN THE DENTIN-PULP COMPLEX: A DOUBLE-EDGED SWORD. DENTAL TISSUE INFECTION AND DISEASE RESULT IN ACUTE AND CHRONIC ACTIVATION OF THE INNATE IMMUNE RESPONSE, WHICH IS MEDIATED BY MOLECULAR AND CELLULAR SIGNALING. DIFFERENT CELL TYPES WITHIN THE DENTIN-PULP COMPLEX ARE ABLE TO DETECT INVADING BACTERIA AT ALL STAGES OF THE INFECTION. INDEED, AT RELATIVELY EARLY DISEASE STAGES, ODONTOBLASTS WILL RESPOND TO BACTERIAL COMPONENTS, AND AS THE DISEASE PROGRESSES, CORE PULPAL CELLS INCLUDING FIBROBLASTS, STEMS CELLS, ENDOTHELIAL CELLS, AND IMMUNE CELLS WILL BECOME INVOLVED. PATTERN RECOGNITION RECEPTORS, SUCH AS TOLL-LIKE RECEPTORS EXPRESSED ON THESE CELL TYPES, ARE RESPONSIBLE FOR DETECTING BACTERIAL COMPONENTS, AND THEIR LIGAND BINDING LEADS TO THE ACTIVATION OF THE NUCLEAR FACTOR-KAPPA B AND P38 MITOGEN-ACTIVATED PROTEIN (MAP) KINASE INTRACELLULAR SIGNALING CASCADES. SUBSEQUENT NUCLEAR TRANSLOCATION OF THE TRANSCRIPTION FACTOR SUBUNITS FROM THESE PATHWAYS WILL LEAD TO PROINFLAMMATORY MEDIATOR EXPRESSION, INCLUDING INCREASES IN CYTOKINES AND CHEMOKINES, WHICH TRIGGER HOST CELLULAR DEFENSE MECHANISMS. THE COMPLEX MOLECULAR SIGNALING WILL RESULT IN THE RECRUITMENT OF IMMUNE SYSTEM CELLS TARGETED AT COMBATING THE INVADING MICROBES; HOWEVER, THE TRAFFICKING AND ANTIBACTERIAL ACTIVITY OF THESE CELLS CAN LEAD TO COLLATERAL TISSUE DAMAGE. RECENT EVIDENCE SUGGESTS THAT IF INFLAMMATION IS RESOLVED RELATIVELY LOW LEVELS OF PROINFLAMMATORY MEDIATORS MAY PROMOTE TISSUE REPAIR, WHEREAS IF CHRONIC INFLAMMATION ENSUES REPAIR MECHANISMS BECOME INHIBITED. THUS, THE EFFECTS OF MEDIATORS ARE TEMPORAL CONTEXT DEPENDENT. ALTHOUGH CONTAINMENT AND REMOVAL OF THE INFECTION ARE KEYS TO ENABLE DENTAL TISSUE REPAIR, IT IS FEASIBLE THAT THE DEVELOPMENT OF ANTI-INFLAMMATORY AND IMMUNOMODULATORY APPROACHES, BASED ON MOLECULAR, EPIGENETIC, AND PHOTOBIOMODULATORY TECHNOLOGIES, MAY ALSO BE BENEFICIAL FOR FUTURE ENDODONTIC TREATMENTS. 2014 4 609 10 BEYOND MOR: CAN INDUCTION OF DOPAMINE HOMEOSTASIS ALONG WITH ELECTROTHERAPY ATTENUATE THE OPIOID CRISIS? ONE IMPORTANT AREA FOR CONSIDERATION ESPECIALLY IN TERMS OF COMBATING THE ONGOING NEVER ENDING OPIOID CRISIS, RELATES TO NOVEL NEWER ASSESSMENTS FOR ALL ADDICTIVE BEHAVIORS BOTH SUBSTANCE AND NON-SUBSTANCE BEHAVIORS (RDS). IT IS VERY IMPORTANT TO IDENTIFY EARLY IN ONE'S LIFE THE POSSIBILITY OF, BECAUSE OF KNOWN DNA ANTECEDENTS, THE PRESENCE OF PRE-ADDICTION. THE DEVELOPMENT OF THE GENETIC ADDICTION RISK SEVERITY (GARS) TEST, BLUM'S GROUP BELIEVES THAT THIS TYPE OF TESTING SHOULD BE THE "STANDARD OF CARE" FOLLOWING ADDITIONAL STUDIES. UNDERSTANDABLY THAT WHILE POLYMORPHISMS IN THE MU-OPIOID RECEPTOR (MOR) IS OF REAL CONCERN IN TERMS OF SETTING PEOPLE UP FOR PREDISPOSITION TO OPIOID DEPENDENCE, THE GENETIC AND EPIGENETIC STATUS OF DOPAMINERGIC FUNCTION MUST BE CONSIDERED AS WELL. WHILE THIS SOUNDS BOLD (WHICH IT IS) THE RESULTS SHOULD BE PROTECTED BY THE G.I. N. A. LAW ENACTED IN THE USA IN 2011. ONE AVENUE OF FURTHER INVESTIGATION, INSTEAD OF PROVIDING POWERFUL OPIOIDS FOR OPIOID DEPENDENCE, IS TO SEEK OUT NON-ADDICTIVE ALTERNATIVES. ACCORDINGLY, OTHER NON-ADDICTIVE MODALITIES INCLUDING GENETIC GUIDED KB220 (AMINO-ACID-ENKEPHALINASE-N-ACETYLCYSTEINE-NAD), NON-INVASIVE RTMS FOR PSYCHIATRY AND PAIN, EPIGENETIC REMODELING, GENE EDITS, NON-INVASIVE H-WAVE FOR PAIN MANAGEMENT AND ENHANCED FUNCTIONALITY, BRAIN SPOTTING, COGNITIVE BEHAVIORAL THERAPY AWARENESSS INTEGRATION THERAPY, NUCALM, TRAUMA THERAPY, AWARENESS TOOLS, GENOGRAMS, EXERCISE, SPORTS, FITNESS PROGRAMS (ONE HOUR PER DAY), LIGHT THERAPY AND EVEN LAUGHING THERAPY AS WELL AS ANY OTHER KNOWN MODALITIES THAT CAN INDUCE REWARD SYMMETRY. WHILE THE SHORT TERM USE OF OPIOIDS FOR OPIOID DEPENDENCE TO REDUCE HARM IS CERTAINLY ACCEPTABLE, CLINICIANS SHOULD CONSIDER A BETTER LONG-TERM PLAN. 2023 5 115 16 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 6 2206 17 EPIGENETIC MODIFICATIONS AND DIABETIC RETINOPATHY. DIABETIC RETINOPATHY REMAINS ONE OF THE MOST DEBILITATING CHRONIC COMPLICATIONS, BUT DESPITE EXTENSIVE RESEARCH IN THE FIELD, THE EXACT MECHANISM(S) RESPONSIBLE FOR HOW RETINA IS DAMAGED IN DIABETES REMAINS AMBIGUOUS. MANY METABOLIC PATHWAYS HAVE BEEN IMPLICATED IN ITS DEVELOPMENT, AND GENES ASSOCIATED WITH THESE PATHWAYS ARE ALTERED. DIABETIC ENVIRONMENT ALSO FACILITATES EPIGENETICS MODIFICATIONS, WHICH CAN ALTER THE GENE EXPRESSION WITHOUT PERMANENT CHANGES IN DNA SEQUENCE. THE ROLE OF EPIGENETICS IN DIABETIC RETINOPATHY IS NOW AN EMERGING AREA, AND RECENT WORK HAS SHOWN THAT GENES ENCODING MITOCHONDRIAL SUPEROXIDE DISMUTASE (SOD2) AND MATRIX METALLOPROTEINASE-9 (MMP-9) ARE EPIGENETICALLY MODIFIED, ACTIVATES OF EPIGENETIC MODIFICATION ENZYMES, HISTONE LYSINE DEMETHYLASE 1 (LSD1), AND DNA METHYLTRANSFERASE ARE INCREASED, AND THE MICRO RNAS RESPONSIBLE FOR REGULATING NUCLEAR TRANSCRIPTIONAL FACTOR AND VEGF ARE UPREGULATED. WITH THE GROWING EVIDENCE OF EPIGENETIC MODIFICATIONS IN DIABETIC RETINOPATHY, BETTER UNDERSTANDING OF THESE MODIFICATIONS HAS POTENTIAL TO IDENTIFY NOVEL TARGETS TO INHIBIT THIS DEVASTATING DISEASE. FORTUNATELY, THE INHIBITORS AND MIMICS TARGETED TOWARDS HISTONE MODIFICATION, DNA METHYLATION, AND MIRNAS ARE NOW BEING TRIED FOR CANCER AND OTHER CHRONIC DISEASES, AND BETTER UNDERSTANDING OF THE ROLE OF EPIGENETICS IN DIABETIC RETINOPATHY WILL OPEN THE DOOR FOR THEIR POSSIBLE USE IN COMBATING THIS BLINDING DISEASE. 2013 7 5326 16 PULP INNATE IMMUNE DEFENSE: TRANSLATIONAL OPPORTUNITIES. INTRODUCTION: THE IMPROVEMENT OF REGENERATIVE ENDODONTIC PROCEDURES REQUIRES AN UNDERSTANDING OF THE KEY CLINICAL QUESTIONS COMBINED WITH A FUNDAMENTAL BIOLOGICAL KNOWLEDGE OF HOW THE DENTAL TISSUES BEHAVE DURING HEALTH, DISEASE, AND REPAIR. THEREFORE, PARTNERSHIPS BETWEEN CLINICIANS AND BASIC SCIENTISTS ARE ESSENTIAL TO DRIVE THE FIELD FORWARD AND IMPROVE PATIENT OUTCOMES. METHODS: THIS REVIEW AIMED TO PROVIDE A BACKGROUND TO DENTIN-PULP BIOLOGY AND THE INTERACTION BETWEEN INFECTION, INFLAMMATION, AND REGENERATION. RESULTS: WE HAVE HIGHLIGHTED HOW THE RELEASE OF NEUTROPHIL EXTRACELLULAR TRAPS (NETS) WITHIN THE PULP ARE DOUBLE-EDGED; WHILE THEY AIM TO LIMIT THE BACTERIAL INFECTION, THEY MAY ACTUALLY EXACERBATE CELL DEATH AND CHRONIC INFLAMMATION. ABERRANT LEVELS OF THESE STRUCTURES MAY OCCUR BECAUSE OF INEFFECTIVE HOST IMMUNOLOGIC PROCESSES, VIRAL INFECTIONS, OR IMPAIRED CLEARANCE CAUSED BY BACTERIAL VIRULENCE FACTORS. WE ALSO POSTULATE A PROINFLAMMATORY LINK IN THE PULP BETWEEN NETS AND THE INFLAMMASOME ACTIVATED BY PATHOGEN-ASSOCIATED MOLECULAR PATTERNS AND DAMAGE-ASSOCIATED MOLECULAR PATTERNS. SUBSEQUENTLY, WE DISCUSS AREAS POTENTIALLY FRUITFUL FOR FUTURE CLINICAL EXPLOITATION INVOLVING NET INHIBITORS, INFLAMMASOME MODULATORS, PHOTOTHERAPIES, AND NOVEL EPIGENETIC APPROACHES. CONCLUSIONS: SUSTAINED SCIENTIST-CLINICIAN RESEARCH PARTNERSHIPS ALONG WITH AN INCREASED UNDERSTANDING OF THE ASSOCIATION BETWEEN INFLAMMATION AND REGENERATION WITHIN THE DENTIN-PULP COMPLEX WILL LEAD TO FUTURE PATIENT BENEFIT. 2020 8 5919 16 TARGETING CELLULAR SENESCENCE FOR AGE-RELATED DISEASES: PATH TO CLINICAL TRANSLATION. BEYOND THE PALLIATIVE REACH OF TODAY'S MEDICINES, MEDICAL THERAPIES OF TOMORROW AIM TO TREAT THE ROOT CAUSE OF AGE-RELATED DISEASES BY TARGETING FUNDAMENTAL AGING MECHANISMS. PILLARS OF AGING INCLUDE, AMONG OTHERS, GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DYSREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. THE UNITARY THEORY OF FUNDAMENTAL AGING PROCESSES POSITS THAT BY TARGETING ONE FUNDAMENTAL AGING PROCESS, IT MAY BE FEASIBLE TO IMPACT SEVERAL OR ALL OTHERS GIVEN ITS INTERDEPENDENCE. INDEED, PATHOLOGIC ACCUMULATION OF SENESCENT CELLS IS IMPLICATED IN CHRONIC DISEASES AND AGE-ASSOCIATED MORBIDITIES, SUGGESTING THAT SENESCENT CELLS ARE A GOOD TARGET FOR WHOLE-BODY AGING INTERVENTION. PRECLINICAL STUDIES USING SENOLYTICS, AGENTS THAT SELECTIVELY ELIMINATE SENESCENT CELLS, AND SENOMORPHICS, AGENTS THAT INHIBIT PRODUCTION OR RELEASE OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE FACTORS, SHOW PROMISE IN SEVERAL AGING AND DISEASE PRECLINICAL MODELS. EARLY CLINICAL TRIALS USING A SENOLYTIC COMBINATION (DASATINIB AND QUERCETIN), AND OTHER SENOLYTICS INCLUDING FLAVONOID, FISETIN, AND BCL-XL INHIBITORS, ILLUSTRATE THE POTENTIAL OF SENOLYTICS TO ALLEVIATE AGE-RELATED DYSFUNCTION AND DISEASES INCLUDING WOUND HEALING. TRANSLATION INTO CLINICAL APPLICATIONS REQUIRES PARALLEL CLINICAL TRIALS ACROSS INSTITUTIONS TO VALIDATE SENOTHERAPEUTICS AS A VANGUARD FOR DELAYING, PREVENTING, OR TREATING AGE-RELATED DISORDERS AND AESTHETIC AGING. 2022 9 5140 19 POTENTIAL REGULATORS OF THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE DURING SENESCENCE AND AGING. SENESCENT CELLS EXPRESS AND SECRETE A VARIETY OF EXTRACELLULAR MODULATORS THAT INCLUDE CYTOKINES, CHEMOKINES, PROTEASES, GROWTH FACTORS, AND SOME ENZYMES ASSOCIATED WITH EXTRACELLULAR MATRIX REMODELING, DEFINED AS THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). SASP REINFORCES SENESCENT CELL CYCLE ARREST, STIMULATES AND RECRUITS IMMUNE CELLS FOR IMMUNE-MEDIATED CLEARANCE OF POTENTIALLY TUMORIGENIC CELLS, LIMITS OR INDUCES FIBROSIS, AND PROMOTES WOUND HEALING AND TISSUE REGENERATION. ON THE OTHER HAND, SASP MEDIATES CHRONIC INFLAMMATION LEADING TO THE DESTRUCTION OF TISSUE STRUCTURE AND FUNCTION AND STIMULATING THE GROWTH AND SURVIVAL OF TUMOR CELLS. SASP IS HIGHLY HETEROGENEOUS AND THE ROLE OF SASP DEPENDS ON THE CONTEXT. THE REGULATION OF SASP OCCURS AT MULTIPLE LEVELS INCLUDING CHROMATIN REMODELING, TRANSCRIPTION, MRNA TRANSLATION, INTRACELLULAR TRAFFICKING, AND SECRETION. SEVERAL SASP MODULATORS HAVE ALREADY BEEN IDENTIFIED SETTING THE STAGE FOR FUTURE RESEARCH ON THEIR CLINICAL APPLICATIONS. IN THIS REVIEW, WE SUMMARIZE IN DETAIL THE POTENTIAL SIGNALING PATHWAYS THAT TRIGGER AND REGULATE SASP PRODUCTION DURING AGING AND SENESCENCE. 2022 10 4487 12 MOLECULARLY TARGETED DRUG COMBINATIONS DEMONSTRATE SELECTIVE EFFECTIVENESS FOR MYELOID- AND LYMPHOID-DERIVED HEMATOLOGIC MALIGNANCIES. TRANSLATING THE GENETIC AND EPIGENETIC HETEROGENEITY UNDERLYING HUMAN CANCERS INTO THERAPEUTIC STRATEGIES IS AN ONGOING CHALLENGE. LARGE-SCALE SEQUENCING EFFORTS HAVE UNCOVERED A SPECTRUM OF MUTATIONS IN MANY HEMATOLOGIC MALIGNANCIES, INCLUDING ACUTE MYELOID LEUKEMIA (AML), SUGGESTING THAT COMBINATIONS OF AGENTS WILL BE REQUIRED TO TREAT THESE DISEASES EFFECTIVELY. COMBINATORIAL APPROACHES WILL ALSO BE CRITICAL FOR COMBATING THE EMERGENCE OF GENETICALLY HETEROGENEOUS SUBCLONES, RESCUE SIGNALS IN THE MICROENVIRONMENT, AND TUMOR-INTRINSIC FEEDBACK PATHWAYS THAT ALL CONTRIBUTE TO DISEASE RELAPSE. TO IDENTIFY NOVEL AND EFFECTIVE DRUG COMBINATIONS, WE PERFORMED EX VIVO SENSITIVITY PROFILING OF 122 PRIMARY PATIENT SAMPLES FROM A VARIETY OF HEMATOLOGIC MALIGNANCIES AGAINST A PANEL OF 48 DRUG COMBINATIONS. THE COMBINATIONS WERE DESIGNED AS DRUG PAIRS THAT TARGET NONOVERLAPPING BIOLOGICAL PATHWAYS AND COMPRISE DRUGS FROM DIFFERENT CLASSES, PREFERABLY WITH FOOD AND DRUG ADMINISTRATION APPROVAL. A COMBINATION RATIO (CR) WAS DERIVED FOR EACH DRUG PAIR, AND CRS WERE EVALUATED WITH RESPECT TO DIAGNOSTIC CATEGORIES AS WELL AS AGAINST GENETIC, CYTOGENETIC, AND CELLULAR PHENOTYPES OF SPECIMENS FROM THE TWO LARGEST DISEASE CATEGORIES: AML AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). NEARLY ALL TESTED COMBINATIONS INVOLVING A BCL2 INHIBITOR SHOWED ADDITIONAL BENEFIT IN PATIENTS WITH MYELOID MALIGNANCIES, WHEREAS SELECT COMBINATIONS INVOLVING PI3K, CSF1R, OR BROMODOMAIN INHIBITORS SHOWED PREFERENTIAL BENEFIT IN LYMPHOID MALIGNANCIES. EXPANDED ANALYSES OF PATIENTS WITH AML AND CLL REVEALED SPECIFIC PATTERNS OF EX VIVO DRUG COMBINATION EFFICACY THAT WERE ASSOCIATED WITH SELECT GENETIC, CYTOGENETIC, AND PHENOTYPIC DISEASE SUBSETS, WARRANTING FURTHER EVALUATION. THESE FINDINGS HIGHLIGHT THE HEURISTIC VALUE OF AN INTEGRATED FUNCTIONAL GENOMIC APPROACH TO THE IDENTIFICATION OF NOVEL TREATMENT STRATEGIES FOR HEMATOLOGIC MALIGNANCIES. 2017 11 2239 12 EPIGENETIC MODULATION BY APABETALONE COUNTERS CYTOKINE-DRIVEN ACUTE PHASE RESPONSE IN VITRO, IN MICE AND IN PATIENTS WITH CARDIOVASCULAR DISEASE. CHRONIC SYSTEMIC INFLAMMATION CONTRIBUTES TO CARDIOVASCULAR DISEASE (CVD) AND CORRELATES WITH THE ABUNDANCE OF ACUTE PHASE RESPONSE (APR) PROTEINS IN THE LIVER AND PLASMA. BROMODOMAIN AND EXTRATERMINAL (BET) PROTEINS ARE EPIGENETIC READERS THAT REGULATE INFLAMMATORY GENE TRANSCRIPTION. WE SHOW THAT BET INHIBITION BY THE SMALL MOLECULE APABETALONE REDUCES APR GENE AND PROTEIN EXPRESSION IN HUMAN HEPATOCYTES, MOUSE MODELS, AND PLASMA FROM CVD PATIENTS. STEADY-STATE EXPRESSION OF SERUM AMYLOID P, PLASMINOGEN ACTIVATOR INHIBITOR 1, AND CERULOPLASMIN, APR PROTEINS LINKED TO CVD RISK, IS REDUCED BY APABETALONE IN CULTURED HEPATOCYTES AND IN HUMANIZED MOUSE LIVER. IN CYTOKINE-STIMULATED HEPATOCYTES, APABETALONE REDUCES THE EXPRESSION OF C-REACTIVE PROTEIN (CRP), ALPHA-2-MACROGLOBULIN, AND SERUM AMYLOID P. THE LATTER TWO ARE ALSO REDUCED BY APABETALONE IN THE LIVER OF ENDOTOXEMIC MICE. BET KNOCKDOWN IN VITRO ALSO COUNTERS CYTOKINE-MEDIATED INDUCTION OF THE CRP GENE. MECHANISTICALLY, APABETALONE REDUCES THE CYTOKINE-DRIVEN INCREASE IN BRD4 BET OCCUPANCY AT THE CRP PROMOTER, CONFIRMING THAT TRANSCRIPTION OF CRP IS BET-DEPENDENT. IN PATIENTS WITH STABLE CORONARY DISEASE, PLASMA APR PROTEINS CRP, IL-1 RECEPTOR ANTAGONIST, AND FIBRINOGEN GAMMA DECREASE AFTER APABETALONE TREATMENT VERSUS PLACEBO, RESULTING IN A PREDICTED DOWNREGULATION OF THE APR PATHWAY AND CYTOKINE TARGETS. WE CONCLUDE THAT CRP AND COMPONENTS OF THE APR PATHWAY ARE REGULATED BY BET PROTEINS AND THAT APABETALONE COUNTERS CHRONIC CYTOKINE SIGNALING IN PATIENTS. 2020 12 1650 16 DOMAIN-SELECTIVE TARGETING OF BET PROTEINS IN CANCER AND IMMUNOLOGICAL DISEASES. CANCER AND INFLAMMATION ARE STRONGLY INTERCONNECTED PROCESSES. CHRONIC INFLAMMATORY PATHOLOGIES CAN BE AT THE HEART OF TUMOR DEVELOPMENT; SIMILARLY, TUMOR-ELICITED INFLAMMATION IS A CONSEQUENCE OF MANY CANCERS. THE MECHANISTIC INTERDEPENDENCE BETWEEN CANCER AND INFLAMMATORY PATHOLOGIES POINTS TOWARD COMMON PROTEIN EFFECTORS WHICH REPRESENT POTENTIAL SHARED TARGETS FOR PHARMACOLOGICAL INTERVENTION. EPIGENETIC MECHANISMS OFTEN DRIVE RESISTANCE TO CANCER THERAPY AND IMMUNOMODULATORY STRATEGIES. THE BROMODOMAIN AND EXTRATERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC ADAPTERS WHICH PLAY A MAJOR ROLE IN CONTROLLING CELL PROLIFERATION AND THE PRODUCTION OF INFLAMMATORY MEDIATORS. A PLETHORA OF SMALL MOLECULES AIMED AT INHIBITING BET PROTEIN FUNCTION TO TREAT CANCER AND INFLAMMATORY DISEASES HAVE POPULATED ACADEMIC AND INDUSTRY EFFORTS IN THE LAST 10 YEARS. IN THIS REVIEW, WE WILL DISCUSS RECENT PHARMACOLOGICAL APPROACHES AIMED AT TARGETING A SINGLE OR A SUBSET OF THE EIGHT BROMODOMAINS WITHIN THE BET FAMILY WHICH HAVE THE POTENTIAL TO TEASE APART CLINICAL EFFICACY AND SAFETY SIGNALS OF BET INHIBITORS. 2020 13 5432 15 REJUVENATION OF MESENCHYMAL STEM CELLS TO AMELIORATE SKELETAL AGING. ADVANCED AGE IS A SHARED RISK FACTOR FOR MANY CHRONIC AND DEBILITATING SKELETAL DISEASES INCLUDING OSTEOPOROSIS AND PERIODONTITIS. MESENCHYMAL STEM CELLS DEVELOP VARIOUS AGING PHENOTYPES INCLUDING THE ONSET OF SENESCENCE, INTRINSIC LOSS OF REGENERATIVE POTENTIAL AND EXACERBATION OF INFLAMMATORY MICROENVIRONMENT VIA SECRETORY FACTORS. THIS REVIEW ELABORATES ON THE EMERGING CONCEPTS ON THE MOLECULAR AND EPIGENETIC MECHANISMS OF MSC SENESCENCE, SUCH AS THE ACCUMULATION OF OXIDATIVE STRESS, DNA DAMAGE AND MITOCHONDRIAL DYSFUNCTION. SENESCENT MSCS AGGRAVATE LOCAL INFLAMMATION, DISRUPT BONE REMODELING AND BONE-FAT BALANCE, THEREBY CONTRIBUTING TO THE PROGRESSION OF AGE-RELATED BONE DISEASES. VARIOUS REJUVENATION STRATEGIES TO TARGET SENESCENT MSCS COULD PRESENT A PROMISING PARADIGM TO RESTORE SKELETAL AGING. 2023 14 5423 15 REGULATION OF MACROPHAGE ACTIVATION AND DIFFERENTIATION IN ATHEROSCLEROSIS. CHRONIC INFLAMMATION IS A HALLMARK OF ATHEROSCLEROSIS AND MACROPHAGES PLAY A CENTRAL ROLE IN CONTROLLING INFLAMMATION AT ALL STAGES OF ATHEROSCLEROSIS. IN ATHEROSCLEROSIS, MACROPHAGES AND MONOCYTE-DERIVED MACROPHAGES ARE CONTINUOUSLY EXPOSED TO CHOLESTEROL, OXIDIZED LIPIDS, CELL DEBRIS, CYTOKINES, AND CHEMOKINES. NOT ONLY DO THESE STIMULI INDUCE A SPECIFIC MACROPHAGE PHENOTYPE, BUT THEY ALSO INTERACT EXTENSIVELY, LEADING TO MACROPHAGE HETEROGENEITY IN ATHEROSCLEROTIC PLAQUES. HEREIN, WE REVIEW THE DIVERSE PHENOTYPES OF MACROPHAGES, THE MECHANISMS UNDERLYING MACROPHAGE ACTIVATION, AND THE CONTRIBUTIONS OF MACROPHAGES TO ATHEROSCLEROSIS IN THIS CONTEXT. WE ALSO SUMMARIZE RECENT STUDIES ON FOAMY MACROPHAGES AND MONOCYTE-DERIVED MACROPHAGES IN PLAQUE DURING DISEASE PROGRESSION. WE PROVIDE A COMPREHENSIVE OVERVIEW OF TRANSCRIPTIONAL, EPIGENETIC, AND METABOLIC REPROGRAMMING OF MACROPHAGES AND DISCUSS THE EMERGING CONCEPTS OF TARGETING CYTOKINES AND MACROPHAGES TO MODULATE ATHEROSCLEROSIS. 2021 15 5632 18 SENESCENT CELLS: SASPECTED DRIVERS OF AGE-RELATED PATHOLOGIES. THE PROGRESSION OF PHYSIOLOGICAL AGEING IS DRIVEN BY INTRACELLULAR ABERRATIONS INCLUDING TELOMERE ATTRITION, GENOMIC INSTABILITY, EPIGENETIC ALTERATIONS AND LOSS OF PROTEOSTASIS. THESE IN TURN DAMAGE CELLS AND COMPROMISE THEIR FUNCTIONALITY. CELLULAR SENESCENCE, A STABLE IRREVERSIBLE CELL-CYCLE ARREST, IS ELICITED IN DAMAGED CELLS AND PREVENTS THEIR PROPAGATION IN THE ORGANISM. UNDER NORMAL CONDITIONS, SENESCENT CELLS RECRUIT THE IMMUNE SYSTEM WHICH FACILITATES THEIR REMOVAL FROM TISSUES. NEVERTHELESS, DURING AGEING, TISSUE-RESIDING SENESCENT CELLS TEND TO ACCUMULATE, AND MIGHT NEGATIVELY IMPACT THEIR MICROENVIRONMENT VIA PROFOUND SECRETORY PHENOTYPE WITH PRO-INFLAMMATORY CHARACTERISTICS, TERMED SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). INDEED, SENESCENT CELLS ARE MOSTLY ABUNDANT AT SITES OF AGE-RELATED PATHOLOGIES, INCLUDING DEGENERATIVE DISORDERS AND MALIGNANCIES. INTERESTINGLY, STUDIES ON PROGEROID MICE INDICATE THAT SELECTIVE ELIMINATION OF SENESCENT CELLS CAN DELAY AGE-RELATED DETERIORATION. THIS SUGGESTS THAT CHRONIC INFLAMMATION INDUCED BY SENESCENT CELLS MIGHT BE A MAIN DRIVER OF THESE PATHOLOGIES. IMPORTANTLY, SENESCENT CELLS ACCUMULATE AS A RESULT OF DEFICIENT IMMUNE SURVEILLANCE, AND THEIR REMOVAL IS INCREASED UPON THE USE OF IMMUNE STIMULATORY AGENTS. INSIGHTS INTO MECHANISMS OF SENESCENCE SURVEILLANCE COULD BE COMBINED WITH CURRENT APPROACHES FOR CANCER IMMUNOTHERAPY TO PROPOSE NEW PREVENTIVE AND THERAPEUTIC STRATEGIES FOR AGE-RELATED DISEASES. 2014 16 4186 16 METABOLIC AND EPIGENETIC REGULATION OF T-CELL EXHAUSTION. CURRENT IMMUNOTHERAPIES YIELD REMARKABLE CLINICAL OUTCOMES BY BOOSTING THE POWER OF HOST IMMUNITY IN CANCER CELL ELIMINATION AND VIRAL CLEARANCE. HOWEVER, AFTER PROLONGED ANTIGEN EXPOSURE, CD8(+) T CELLS DIFFERENTIATE INTO A SPECIAL DIFFERENTIATION STATE KNOWN AS T-CELL EXHAUSTION, WHICH POSES ONE OF THE MAJOR HURDLES TO ANTIVIRAL AND ANTITUMOR IMMUNITY DURING CHRONIC VIRAL INFECTION AND TUMOUR DEVELOPMENT. GROWING EVIDENCE INDICATES THAT EXHAUSTED T CELLS UNDERGO METABOLIC INSUFFICIENCY WITH ALTERED SIGNALLING CASCADES AND EPIGENETIC LANDSCAPES, WHICH DAMPEN EFFECTOR IMMUNITY AND CAUSE POOR RESPONSIVENESS TO IMMUNE-CHECKPOINT-BLOCKADE THERAPIES. HOW METABOLIC STRESS AFFECTS T-CELL EXHAUSTION REMAINS UNCLEAR; THEREFORE, IN THIS REVIEW, WE SUMMARIZE CURRENT KNOWLEDGE OF HOW T-CELL EXHAUSTION OCCURS, AND DISCUSS HOW METABOLIC INSUFFICIENCY AND PROLONGED STRESS RESPONSES MAY AFFECT SIGNALLING CASCADES AND EPIGENETIC REPROGRAMMING, THUS LOCKING T CELLS INTO AN EXHAUSTED STATE VIA SPECIALIZED DIFFERENTIATION PROGRAMMING. 2020 17 799 19 CELLULAR SIGNALING AND POTENTIAL NEW TREATMENT TARGETS IN DIABETIC RETINOPATHY. DYSFUNCTION AND DEATH OF MICROVASCULAR CELLS AND IMBALANCE BETWEEN THE PRODUCTION AND THE DEGRADATION OF EXTRACELLULAR MATRIX (ECM) PROTEINS ARE A CHARACTERISTIC FEATURE OF DIABETIC RETINOPATHY (DR). GLUCOSE-INDUCED BIOCHEMICAL ALTERATIONS IN THE VASCULAR ENDOTHELIAL CELLS MAY ACTIVATE A CASCADE OF SIGNALING PATHWAYS LEADING TO INCREASED PRODUCTION OF ECM PROTEINS AND CELLULAR DYSFUNCTION/DEATH. CHRONIC DIABETES LEADS TO THE ACTIVATION OF A NUMBER OF SIGNALING PROTEINS INCLUDING PROTEIN KINASE C, PROTEIN KINASE B, AND MITOGEN-ACTIVATED PROTEIN KINASES. THESE SIGNALING CASCADES ARE ACTIVATED IN RESPONSE TO HYPERGLYCEMIA-INDUCED OXIDATIVE STRESS, POLYOL PATHWAY, AND ADVANCED GLYCATION END PRODUCT FORMATION AMONG OTHERS. THE ABERRANT SIGNALING PATHWAYS ULTIMATELY LEAD TO ACTIVATION OF TRANSCRIPTION FACTORS SUCH AS NUCLEAR FACTOR-KAPPAB AND ACTIVATING PROTEIN-1. THE ACTIVITY OF THESE TRANSCRIPTION FACTORS IS ALSO REGULATED BY EPIGENETIC MECHANISMS THROUGH TRANSCRIPTIONAL COACTIVATOR P300. THESE COMPLEX SIGNALING PATHWAYS MAY BE INVOLVED IN GLUCOSE-INDUCED ALTERATIONS OF ENDOTHELIAL CELL PHENOTYPE LEADING TO THE PRODUCTION OF INCREASED ECM PROTEINS AND VASOACTIVE EFFECTOR MOLECULES CAUSING FUNCTIONAL AND STRUCTURAL CHANGES IN THE MICROVASCULATURE. UNDERSTANDING OF SUCH MECHANISTIC PATHWAYS WILL HELP TO DEVELOP FUTURE ADJUVANT THERAPIES FOR DIABETIC RETINOPATHY. 2007 18 3180 20 HALLMARKS OF AGING IN MACROPHAGES: CONSEQUENCES TO SKIN INFLAMMAGING. THE SKIN IS OUR LARGEST ORGAN AND THE OUTERMOST PROTECTIVE BARRIER. ITS AGING REFLECTS BOTH INTRINSIC AND EXTRINSIC PROCESSES RESULTING FROM THE CONSTANT INSULTS IT IS EXPOSED TO. AGING IN THE SKIN IS ACCOMPANIED BY SPECIFIC EPIGENETIC MODIFICATIONS, ACCUMULATION OF SENESCENT CELLS, REDUCED CELLULAR PROLIFERATION/TISSUE RENEWAL, ALTERED EXTRACELLULAR MATRIX, AND A PROINFLAMMATORY ENVIRONMENT FAVORING UNDESIRABLE CONDITIONS, INCLUDING DISEASE ONSET. MACROPHAGES (MPHI) ARE THE MOST ABUNDANT IMMUNE CELL TYPE IN THE SKIN AND COMPRISE A GROUP OF HETEROGENEOUS AND PLASTIC CELLS THAT ARE KEY FOR SKIN HOMEOSTASIS AND HOST DEFENSE. HOWEVER, THEY HAVE ALSO BEEN IMPLICATED IN ORCHESTRATING CHRONIC INFLAMMATION DURING AGING. SINCE MPHI ARE RELATED TO INNATE AND ADAPTIVE IMMUNITY, IT IS POSSIBLE THAT AGE-MODIFIED SKIN MPHI PROMOTE ADAPTIVE IMMUNITY EXACERBATION AND EXHAUSTION, FAVORING THE EMERGENCE OF PROINFLAMMATORY PATHOLOGIES, SUCH AS SKIN CANCER. IN THIS REVIEW, WE WILL HIGHLIGHT RECENT FINDINGS PERTAINING TO THE EFFECTS OF AGING HALLMARKS OVER MPHI, SUPPORTING THE RECOGNITION OF SUCH CELL TYPES AS A DRIVING FORCE IN SKIN INFLAMMAGING AND AGE-RELATED DISEASES. WE WILL ALSO PRESENT RECENT RESEARCH TARGETING MPHI AS POTENTIAL THERAPEUTIC INTERVENTIONS IN INFLAMMATORY SKIN DISORDERS AND CANCER. 2021 19 5986 19 TFEB IS A CENTRAL REGULATOR OF THE AGING PROCESS AND AGE-RELATED DISEASES. OLD AGE IS ASSOCIATED WITH A GREATER BURDEN OF DISEASE, INCLUDING NEURODEGENERATIVE DISORDERS SUCH AS ALZHEIMER'S DISEASE AND PARKINSON'S DISEASE, AS WELL AS OTHER CHRONIC DISEASES. COINCIDENTALLY, POPULAR LIFESTYLE INTERVENTIONS, SUCH AS CALORIC RESTRICTION, INTERMITTENT FASTING, AND REGULAR EXERCISE, IN ADDITION TO PHARMACOLOGICAL INTERVENTIONS INTENDED TO PROTECT AGAINST AGE-RELATED DISEASES, INDUCE TRANSCRIPTION FACTOR EB (TFEB) AND AUTOPHAGY. IN THIS REVIEW, WE SUMMARIZE EMERGING DISCOVERIES THAT POINT TO TFEB ACTIVITY AFFECTING THE HALLMARKS OF AGING, INCLUDING INHIBITING DNA DAMAGE AND EPIGENETIC MODIFICATIONS, INDUCING AUTOPHAGY AND CELL CLEARANCE TO PROMOTE PROTEOSTASIS, REGULATING MITOCHONDRIAL QUALITY CONTROL, LINKING NUTRIENT-SENSING TO ENERGY METABOLISM, REGULATING PRO- AND ANTI-INFLAMMATORY PATHWAYS, INHIBITING SENESCENCE AND PROMOTING CELL REGENERATIVE CAPACITY. FURTHERMORE, THE THERAPEUTIC IMPACT OF TFEB ACTIVATION ON NORMAL AGING AND TISSUE-SPECIFIC DISEASE DEVELOPMENT IS ASSESSED IN THE CONTEXTS OF NEURODEGENERATION AND NEUROPLASTICITY, STEM CELL DIFFERENTIATION, IMMUNE RESPONSES, MUSCLE ENERGY ADAPTATION, ADIPOSE TISSUE BROWNING, HEPATIC FUNCTIONS, BONE REMODELING, AND CANCER. SAFE AND EFFECTIVE STRATEGIES OF ACTIVATING TFEB HOLD PROMISE AS A THERAPEUTIC STRATEGY FOR MULTIPLE AGE-ASSOCIATED DISEASES AND FOR EXTENDING LIFESPAN. 2023 20 769 20 CD8 T CELL EXHAUSTION DURING CHRONIC VIRAL INFECTION AND CANCER. EXHAUSTED CD8 T (TEX) CELLS ARE A DISTINCT CELL LINEAGE THAT ARISE DURING CHRONIC INFECTIONS AND CANCERS IN ANIMAL MODELS AND HUMANS. TEX CELLS ARE CHARACTERIZED BY PROGRESSIVE LOSS OF EFFECTOR FUNCTIONS, HIGH AND SUSTAINED INHIBITORY RECEPTOR EXPRESSION, METABOLIC DYSREGULATION, POOR MEMORY RECALL AND HOMEOSTATIC SELF-RENEWAL, AND DISTINCT TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS. THE ABILITY TO REINVIGORATE TEX CELLS THROUGH INHIBITORY RECEPTOR BLOCKADE, SUCH AS ALPHAPD-1, HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF TARGETING THIS POPULATION. EMERGING INSIGHTS INTO THE MECHANISMS OF EXHAUSTION ARE INFORMING IMMUNOTHERAPIES FOR CANCER AND CHRONIC INFECTIONS. HOWEVER, LIKE OTHER IMMUNE CELLS, TEX CELLS ARE HETEROGENEOUS AND INCLUDE PROGENITOR AND TERMINAL SUBSETS WITH UNIQUE CHARACTERISTICS AND RESPONSES TO CHECKPOINT BLOCKADE. HERE, WE REVIEW OUR CURRENT UNDERSTANDING OF TEX CELL BIOLOGY, INCLUDING THE DEVELOPMENTAL PATHS, TRANSCRIPTIONAL AND EPIGENETIC FEATURES, AND CELL INTRINSIC AND EXTRINSIC FACTORS CONTRIBUTING TO EXHAUSTION AND HOW THIS KNOWLEDGE MAY INFORM THERAPEUTIC TARGETING OF TEX CELLS IN CHRONIC INFECTIONS, AUTOIMMUNITY, AND CANCER. 2019