1 5439 153 RENAL CONSEQUENCES OF PRETERM BIRTH. BACKGROUND: THE DEVELOPMENTAL ORIGIN OF HEALTH AND DISEASE CONCEPT IDENTIFIES THE BRAIN, CARDIOVASCULAR, LIVER, AND KIDNEY SYSTEMS AS TARGETS OF FETAL ADVERSE PROGRAMMING WITH ADULT CONSEQUENCES. AS THE LIMITS OF VIABILITY IN PREMATURE INFANTS HAVE BEEN PUSHED TO LOWER GESTATIONAL AGES, THE LONG-TERM IMPACT OF PREMATURITY ON KIDNEYS STILL REMAINS A SIGNIFICANT BURDEN DURING HOSPITAL STAY AND BEYOND. OBJECTIVES: THE PURPOSE OF THIS STUDY IS TO SUMMARIZE AVAILABLE EVIDENCE, MECHANISMS, AND SHORT- AND LONG-TERM RENAL CONSEQUENCES OF PREMATURITY AND IDENTIFY NEPHROPROTECTIVE STRATEGIES AND AREAS OF UNCERTAINTY. RESULTS: KIDNEY SIZE AND NEPHRON NUMBER ARE KNOWN TO BE REDUCED IN SURVIVING PREMATURE INFANTS DUE TO DISRUPTION OF ORGANOGENESIS AT A CRUCIAL DEVELOPMENTAL TIME POINT. INFLAMMATION, HYPEROXIA, AND ANTIANGIOGENIC FACTORS PLAY A ROLE IN EPIGENETIC CONDITIONING WITH POTENTIAL LIFE-LONG CONSEQUENCES. ADDITIONAL KIDNEY INJURY FROM HYPOPERFUSION AND NEPHROTOXICITY RESULTS IN STRUCTURAL AND FUNCTIONAL CHANGES OVER TIME WHICH ARE OFTEN UNNOTICED. NEPHROPATHY OF PREMATURITY AND ACUTE KIDNEY INJURY CONFOUND GLOMERULAR AND TUBULAR MATURATION OF PRETERM KIDNEYS. KIDNEY PROTECTIVE STRATEGIES MAY AMELIORATE GROWTH FAILURE AND SUBOPTIMAL NEURODEVELOPMENTAL OUTCOMES IN THE SHORT TERM. IN LATER LIFE, SUBCLINICAL CHRONIC RENAL DISEASE MAY PROGRESS, EVEN IN ASYMPTOMATIC SURVIVORS. CONCLUSION: AWARENESS OF RENAL IMPLICATIONS OF THERAPEUTIC INTERVENTIONS AND RENAL CONSERVATION EFFORTS MAY LEAD TO A VARIETY OF SHORT AND LONG-TERM BENEFITS. ADEQUATE MONITORING AND SUPPLEMENTATION OF MICROELEMENT LOSSES, GATHERING IMPROVED DATA ON RENAL HANDLING, AND EXPLORATION OF NEW AVENUES SUCH AS RELIABLE MARKERS OF INJURY AND NEW THERAPEUTIC STRATEGIES IN CONTEMPORARY POPULATIONS, AS WELL AS LONG-TERM FOLLOW-UP OF RENAL FUNCTION, IS WARRANTED. 2017 2 283 30 AGEING IS ASSOCIATED WITH MOLECULAR SIGNATURES OF INFLAMMATION AND TYPE 2 DIABETES IN RAT PANCREATIC ISLETS. AIMS/HYPOTHESIS: AGEING IS A MAJOR RISK FACTOR FOR DEVELOPMENT OF METABOLIC DISEASES SUCH AS TYPE 2 DIABETES. IDENTIFICATION OF THE MECHANISMS UNDERLYING THIS ASSOCIATION COULD HELP TO ELUCIDATE THE RELATIONSHIP BETWEEN AGE-ASSOCIATED PROGRESSIVE LOSS OF METABOLIC HEALTH AND DEVELOPMENT OF TYPE 2 DIABETES. WE AIMED TO DETERMINE MOLECULAR SIGNATURES DURING AGEING IN THE ENDOCRINE PANCREAS. METHODS: GLOBAL GENE TRANSCRIPTION WAS MEASURED IN PANCREATIC ISLETS ISOLATED FROM YOUNG AND OLD RATS BY ILUMINA BEADCHIP ARRAYS. PROMOTER DNA METHYLATION WAS MEASURED BY SEQUENOM MASSARRAY IN 46 GENES THAT SHOWED DIFFERENTIAL EXPRESSION WITH AGE, AND CORRELATIONS WITH EXPRESSION WERE ESTABLISHED. ALTERATIONS IN MORPHOLOGICAL AND CELLULAR PROCESSES WITH AGE WERE DETERMINED BY IMMUNOHISTOCHEMICAL METHODS. RESULTS: AGE-RELATED CHANGES IN GENE EXPRESSION WERE FOUND AT 623 LOCI (>1.5-FOLD, FALSE DISCOVERY RATE [FDR] <5%), WITH A SIGNIFICANT (FDR < 0.05) ENRICHMENT IN GENES PREVIOUSLY IMPLICATED IN ISLET-CELL FUNCTION (ENPP1, ABCC8), TYPE 2 DIABETES (TSPAN8, KCNQ1), INFLAMMATORY PROCESSES (CXCL9, IL33) AND EXTRACELLULAR MATRIX ORGANISATION (COL3A1, DPT). AGE-ASSOCIATED TRANSCRIPTIONAL DIFFERENCES NEGATIVELY CORRELATED WITH PROMOTER DNA METHYLATION AT SEVERAL LOCI RELATED TO INFLAMMATION, GLUCOSE HOMEOSTASIS, CELL PROLIFERATION AND CELL-MATRIX INTERACTIONS (IL33, CXCL9, GPR119, FBP2, COL3A1, DPT, SPP1). CONCLUSIONS/INTERPRETATION: OUR FINDINGS SUGGEST THAT A SIGNIFICANT PROPORTION OF PANCREATIC ISLETS DEVELOP A LOW-GRADE 'CHRONIC' INFLAMMATORY STATUS WITH AGEING AND THIS MAY TRIGGER ALTERED FUNCTIONAL PLASTICITY. FURTHERMORE, WE IDENTIFIED CHANGES IN EXPRESSION OF GENES PREVIOUSLY LINKED TO TYPE 2 DIABETES AND ASSOCIATED CHANGES IN DNA METHYLATION THAT COULD EXPLAIN THEIR AGE-ASSOCIATED DYSREGULATION. THESE FINDINGS PROVIDE NEW INSIGHTS INTO KEY (EPI)GENETIC SIGNATURES OF THE AGEING PROCESS IN ISLETS. 2016 3 4660 34 NEW APPROACHES TO THE TREATMENT OF MYELODYSPLASIA. THE THERAPEUTIC DILEMMA THAT CONFRONTS THE MANAGEMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) IS ILLUSTRATED BY THE ABSENCE OF A FOOD AND DRUG ADMINISTRATION-APPROVED AGENT WITH AN INDICATION FOR THIS DISEASE. CLINICAL HETEROGENEITY AND INADEQUATE UNDERSTANDING OF THE DISEASE PATHOBIOLOGY HAVE LIMITED PROGRESS IN THE DEVELOPMENT OF NOVEL THERAPEUTICS. PRECLINICAL INVESTIGATIONS INDICATE THAT RECIPROCAL INTERACTION BETWEEN THE MALIGNANT CLONE AND THE MICROENVIRONMENT SERVE TO CREATE A HOSTILE MILIEU THAT REINFORCES INEFFECTIVE BLOOD CELL PRODUCTION. INEFFECTIVE HEMATOPOIESIS, THE HALLMARK OF MDS, ARISES FROM IMPAIRED PROGENITOR RESPONSIVENESS TO NORMAL TROPHIC SIGNALS AND EXCESS LOCAL GENERATION OF INHIBITORY CYTOKINES, WHICH PROMOTE ACCELERATED APOPTOTIC LOSS OF PROGENITORS AND THEIR PROGENY. EVIDENCE TO SUPPORT THIS MODEL DERIVES FROM CYTOKINE NEUTRALIZATION STUDIES AND THE DIRECT RELATIONSHIP BETWEEN PLASMA TUMOR NECROSIS FACTOR-ALPHA CONCENTRATION AND DNA OXIDATION AND GLUTATHIONE DEPLETION IN MALIGNANT CD34+ PROGENITORS. RECENT INVESTIGATIONS INDICATE THAT ANGIOGENIC MOLECULES GENERATED BY MALIGNANT MYELOMONOCYTIC PRECURSORS REPRESENT INTEGRAL DIFFUSABLE SIGNALS THAT REINFORCE LEUKEMIA PROGENITOR SELF-RENEWAL WHILE PROMOTING THE GENERATION OF PROAPOPTOTIC CYTOKINES AND MEDULLARY ANGIOGENIC RESPONSE. THE POTENTIAL FOR LEUKEMIA EVOLUTION IS COMPOUNDED BY EPIGENETIC EVENTS INCLUDING METHYLATION SILENCING OF THE P15 PROTO-ONCOGENE OR ACTIVATING RAS POINT MUTATIONS. DELINEATION OF SUCH BIOLOGIC FEATURES THAT ARE CENTRAL TO THE PATHOBIOLOGY OF MDS PROVIDES A RELIABLE FRAMEWORK FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. ANTIANGIOGENIC AGENTS IN CLINICAL TESTING INCLUDE VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) RECEPTOR TYROSINE KINASE INHIBITORS, THALIDOMIDE AND RELATED ANALOGUES, AND THE RECOMBINANT VEGF NEUTRALIZING ANTIBODY, BEVACIZUMAB. AGENTS WHOSE ACTIONS MAY RESTORE DIFFERENTIATION PROGRAMS, SUCH AS THE DNA METHYLTRANSFERASE INHIBITORS OR HISTONE DEACETYLASE INHIBITORS, OFFER THE PROSPECT TO PROMOTE EFFECTIVE HEMATOPOIESIS WHILE IMPACTING THE POTENTIAL FOR LEUKEMIA EVOLUTION. RAS FARNESYL TRANSFERASE INHIBITORS HAVE SHOWN ENCOURAGING PRELIMINARY RESULTS IN ACUTE MYELOID LEUKEMIA AND ARE CURRENTLY UNDER INVESTIGATION IN ADVANCED MDS AND CHRONIC MYELOMONOCYTIC LEUKEMIA. ARSENIC TRIOXIDE (ATO) INTERACTS WITH A SPECTRUM OF BIOLOGIC TARGETS THAT MAY BE UNIQUELY SUITED TO MDS. ATO IS A POTENT INDUCER OF APOPTOSIS IN THIOL-DEPLETED MALIGNANT PROGENITORS AND NEOVASCULAR ENDOTHELIUM, WHILE PROMOTING DIFFERENTIATION THROUGH HISTONE ACETYLATION AND INACTIVATION OF TRANSCRIPTIONAL COREPRESSORS. THE IDENTIFICATION OF RELEVANT BIOLOGIC TARGETS IN MDS HAS RAISED EXPECTATIONS FOR THE DEVELOPMENT OF DISEASE-SPECIFIC THERAPIES FOR MDS IN THE YEARS THAT FOLLOW. 2002 4 537 28 ASYMPTOMATIC HYPERURICEMIA: IS IT REALLY ASYMPTOMATIC? PURPOSE OF REVIEW: HYPERURICEMIA IS HIGHLY PREVALENT, AFFECTING APPROXIMATELY 38 MILLION INDIVIDUALS IN THE UNITED STATES. HOWEVER, THE SIGNIFICANCE OF ASYMPTOMATIC HYPERURICEMIA - HYPERURICEMIA IN THE ABSENCE OF GOUT - CONTINUES TO BE DEBATED. RECENT FINDINGS: ASYMPTOMATIC HYPERURICEMIA RESULTS IN MONOSODIUM URATE CRYSTAL DEPOSITION IN TISSUES, WHICH MAY PROMOTE CHRONIC INFLAMMATION. INTRACELLULARLY, HYPERURICEMIA INHIBITS THE MASTER REGULATOR ADENOSINE MONOPHOSPHATE (AMP)-ASSOCIATED PROTEIN KINASE AND MAY CONDITION INNATE IMMUNE RESPONSES THROUGH DURABLE EPIGENETIC MODIFICATIONS. AT THE POPULATION LEVEL, ASYMPTOMATIC HYPERURICEMIA IS ASSOCIATED WITH MULTIPLE COMORBIDITIES, INCLUDING HYPERTENSION, CHRONIC KIDNEY DISEASE, CORONARY ARTERY DISEASE, AND DIABETES; LIMITATIONS OF THESE STUDIES INCLUDE THAT MOST ARE RETROSPECTIVE AND SOME DO NOT RIGOROUSLY DISTINGUISH BETWEEN ASYMPTOMATIC HYPERURICEMIA AND GOUT. TREATMENT STUDIES SUGGEST THAT URATE LOWERING MAY REDUCE THE RISK OF INCIDENCE OR PROGRESSION OF SOME OF THESE COMORBIDITIES; UNFORTUNATELY, MANY OF THESE TREATMENT STUDIES ARE SMALL OR FLAWED, AND NOT ALL STUDY RESULTS ARE CONSISTENT. SUMMARY: ACCUMULATING EVIDENCE SUGGESTS THAT ASYMPTOMATIC HYPERURICEMIA CONTRIBUTES TO THE COMORBIDITIES WITH WHICH IT ASSOCIATES AND THAT PROPER ASYMPTOMATIC HYPERURICEMIA TREATMENT MAY REDUCE FUTURE RISK. ADDITIONAL PROSPECTIVE TRIALS ARE NEEDED TO DEFINITELY ESTABLISH CAUSALITY AND SUPPORT DECISION-MAKING AS TO WHETHER, AND WHICH PATIENTS WITH ASYMPTOMATIC HYPERURICEMIA WOULD WARRANT URATE-LOWERING TREATMENT. 2020 5 1147 21 CONDYLE MODELING STABILITY, CRANIOFACIAL ASYMMETRY AND ACTN3 GENOTYPES: CONTRIBUTION TO TMD PREVALENCE IN A COHORT OF DENTOFACIAL DEFORMITIES. CRANIOFACIAL ASYMMETRY, MANDIBULAR CONDYLAR MODELING AND TEMPOROMANDIBULAR JOINT DISORDERS ARE COMMON COMORBIDITIES OF SKELETALLY DISPROPORTIONATE MALOCCLUSIONS, BUT ETIOLOGY OF OCCURRENCE TOGETHER IS POORLY UNDERSTOOD. WE COMPARED ASYMMETRY, CONDYLE MODELING STABILITY AND TEMPOROMANDIBULAR HEALTH IN A COHORT OF 128 PATIENTS HAVING ORTHODONTICS AND ORTHOGNATHIC SURGERY TO CORRECT DENTOFACIAL DEFORMITY MALOCCLUSIONS. WE ALSO COMPARED ACTN3 AND ENPP1 GENOTYPES FOR ASSOCIATION TO CLINICAL CONDITIONS. PRE-SURGICAL POSTERIOR-ANTERIOR CEPHALOMETRIC AND PANOMETRIC RADIOGRAPHIC ANALYSES; JAW PAIN AND FUNCTION QUESTIONNAIRE AND CLINICAL EXAMINATION OF TMD; AND SNP-GENOTYPE ANALYSIS FROM SALIVA SAMPLES WERE COMPARED TO ASSESS INTERRELATIONSHIPS. ALMOST HALF HAD ASYMMETRIES IN NEED OF SURGICAL CORRECTION, WHICH COULD BE SUBDIVIDED INTO FOUR DISTINCT MORPHOLOGICAL PATTERNS. ASYMMETRIC CONDYLE MODELING BETWEEN SIDES WAS SIGNIFICANTLY GREATER IN CRANIOFACIAL ASYMMETRY, BUT MOST COMMONLY HAD AN UNANTICIPATED PATTERN. OFTEN, LONGER OR LARGER CONDYLES OCCURRED ON THE SHORTER MANDIBULAR RAMUS SIDE. SUBJECTS WITH LONGER RAMUS BUT DIMENSIONALLY SMALLER CONDYLES WERE MORE LIKELY TO HAVE SELF-REPORTED TMD SYMPTOMS (P = 0.023) AND SIGNIFICANTLY GREATER CLINICAL DIAGNOSIS OF TMD (P = 0 .000001), WITH MASTICATORY MYALGIA MOST PROMINENT. GENOTYPING FOUND TWO SIGNIFICANT GENOTYPE ASSOCIATIONS FOR ACTN3 RS1671064 (Q523R MISSENSE) P = 0.02; RS678397 (INTRONIC SNP) P = 0.04 AND ONE SIGNIFICANT ALLELE ASSOCIATION RS1815739 (R577X NONSENSE) P = 0.00. SKELETAL ASYMMETRY, UNUSUAL CONDYLE MODELING AND TMD ARE COMMON AND INTERRELATED COMPONENTS OF MANY DENTOFACIAL DEFORMITIES. IMBALANCED MUSCULOSKELETAL FUNCTIONAL ADAPTATIONS AND GENETIC OR EPIGENETIC INFLUENCES CONTRIBUTE TO THE ETIOLOGY, AND REQUIRE FURTHER INVESTIGATION. 2020 6 750 26 CARDIAC INVOLVEMENT IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES. AUTHORS HAVE REVIEWED LITERATURE ABOUT THE MANAGEMENT OF PATIENTS WITH CARDIOLOGIC DISEASE OCCURRING SECONDARY TO HEMATOLOGIC PATHOLOGY ITSELF OR ITS THERAPY, WITH A FOCUS ON INFILTRATION OF MYOCARDIUM IN ACUTE AND CHRONIC LEUKEMIA, LYMPHOMA, MULTIPLE MYELOMA, AND HYPEREOSINOPHILIC SYNDROME. MOREOVER, THEY EVALUATED CHEMOTHERAPY-ASSOCIATED TOXICITY, PARTICULARLY FOR NEW DRUGS SUCH AS MONOCLONAL ANTIBODY THERAPY, TYROSINE KINASE INHIBITORS, ARSENIC TRIOXIDE, BORTEZOMIB, AND EPIGENETIC THERAPY. IN FACT, CARDIAC TOXICITY MAY RANGE FROM ASYMPTOMATIC SUBCLINICAL ABNORMALITIES, SUCH AS ELECTROCARDIOGRAPHIC CHANGES AND LEFT VENTRICULAR EJECTION DECLINE, TO LIFE-THREATENING EVENTS AND LEAD TO CHEMOTHERAPY DOSE REDUCTION AND DELAY AND, IN SOME CASES, FOR PATIENTS WITH SEVERE SIDE EFFECTS, DISCONTINUATION OF TREATMENT. FINALLY, THEY DISCUSSED ON THE IDENTIFICATION OF EARLY MARKERS OF CARDIAC INJURY AND ON CARDIAC STEM CELL THERAPY AS A PROMISING APPROACH TO FACILITATE MYOCARDIAL REGENERATION. 2010 7 961 20 CHRONIC MYELOMONOCYTIC LEUKEMIA: A GENETIC AND CLINICAL UPDATE. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL STEM CELL DISORDER, CHARACTERIZED BY PERIPHERAL BLOOD MONOCYTOSIS AND OVERLAPPING FEATURES BETWEEN MYELODYSPLASTIC SYNDROMES (MDS) AND MYELOPROLIFERATIVE NEOPLASMS (MPNS). CLONAL CYTOGENETIC CHANGES ARE SEEN IN UP TO 30 % PATIENTS, WHILE APPROXIMATELY 90 % HAVE DETECTABLE MOLECULAR ABNORMALITIES. MOST PATIENTS ARE DIAGNOSED IN THE SEVENTH DECADE OF LIFE. GENE MUTATIONS IN TEN-ELEVEN TRANSLOCATION (TET) ONCOGENE FAMILY MEMBER 2 (TET2) (60 %), SRSF2 (50 %), ASXL1 (40 %), AND RAS (20-30 %) ARE FREQUENT, WITH ONLY FRAME SHIFT AND NONSENSE ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. WITH THE LACK OF FORMAL GUIDELINES, MANAGEMENT AND RESPONSE CRITERIA ARE OFTEN EXTRAPOLATED FROM MDS AND MPN. CONTEMPORARY MOLECULARLY INTEGRATED CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) MODEL AND THE MOLECULAR MAYO MODEL, BOTH INCORPORATING ASXL1 MUTATIONAL STATUS. HYPOMETHYLATING AGENTS AND ALLOGENEIC STEM CELL TRANSPLANT REMAIN THE TWO MOST COMMONLY USED TREATMENT STRATEGIES, WITH SUBOPTIMAL RESULTS. CLINICAL TRIALS EXPLOITING EPIGENETIC AND SIGNAL PATHWAY ABNORMALITIES, FREQUENT IN CMML, OFFER HOPE AND PROMISE. 2015 8 3064 30 GENOME-WIDE DNA METHYLATION ENCODES CARDIAC TRANSCRIPTIONAL REPROGRAMMING IN HUMAN ISCHEMIC HEART FAILURE. ISCHEMIC CARDIOMYOPATHY (ICM) IS THE CLINICAL ENDPOINT OF CORONARY HEART DISEASE AND A LEADING CAUSE OF HEART FAILURE. DESPITE GROWING DEMANDS TO DEVELOP PERSONALIZED APPROACHES TO TREAT ICM, PROGRESS IS LIMITED BY INADEQUATE KNOWLEDGE OF ITS PATHOGENESIS. SINCE EPIGENETICS HAS BEEN IMPLICATED IN THE DEVELOPMENT OF OTHER CHRONIC DISEASES, THE CURRENT STUDY WAS DESIGNED TO DETERMINE WHETHER TRANSCRIPTIONAL AND/OR EPIGENETIC CHANGES ARE SUFFICIENT TO DISTINGUISH ICM FROM OTHER ETIOLOGIES OF HEART FAILURE. SPECIFICALLY, WE HYPOTHESIZE THAT GENOME-WIDE DNA METHYLATION ENCODES TRANSCRIPTIONAL REPROGRAMMING IN ICM. RNA-SEQUENCING ANALYSIS WAS PERFORMED ON HUMAN ISCHEMIC LEFT VENTRICULAR TISSUE OBTAINED FROM PATIENTS WITH END-STAGE HEART FAILURE, WHICH ENRICHED KNOWN TARGETS OF THE POLYCOMB METHYLTRANSFERASE EZH2 COMPARED TO NON-ISCHEMIC HEARTS. COMBINED RNA SEQUENCING AND GENOME-WIDE DNA METHYLATION ANALYSIS REVEALED A ROBUST GENE EXPRESSION PATTERN CONSISTENT WITH SUPPRESSION OF OXIDATIVE METABOLISM, INDUCED ANAEROBIC GLYCOLYSIS, AND ALTERED CELLULAR REMODELING. LASTLY, KLF15 WAS IDENTIFIED AS A PUTATIVE UPSTREAM REGULATOR OF METABOLIC GENE EXPRESSION THAT WAS ITSELF REGULATED BY EZH2 IN A SET DOMAIN-DEPENDENT MANNER. OUR OBSERVATIONS THEREFORE DEFINE A NOVEL ROLE OF DNA METHYLATION IN THE METABOLIC REPROGRAMMING OF ICM. FURTHERMORE, WE IDENTIFY EZH2 AS AN EPIGENETIC REGULATOR OF KLF15 ALONG WITH DNA HYPERMETHYLATION, AND WE PROPOSE A NOVEL MECHANISM THROUGH WHICH CORONARY HEART DISEASE REPROGRAMS THE EXPRESSION OF BOTH INTERMEDIATE ENZYMES AND UPSTREAM REGULATORS OF CARDIAC METABOLISM SUCH AS KLF15. 2019 9 621 38 BIOENERGETIC EVOLUTION EXPLAINS PREVALENCE OF LOW NEPHRON NUMBER AT BIRTH: RISK FACTOR FOR CKD. THERE IS GREATER THAN TENFOLD VARIATION IN NEPHRON NUMBER OF THE HUMAN KIDNEY AT BIRTH. ALTHOUGH LOW NEPHRON NUMBER IS A RECOGNIZED RISK FACTOR FOR CKD, ITS DETERMINANTS ARE POORLY UNDERSTOOD. EVOLUTIONARY MEDICINE REPRESENTS A NEW DISCIPLINE THAT SEEKS EVOLUTIONARY EXPLANATIONS FOR DISEASE, BROADENING PERSPECTIVES ON RESEARCH AND PUBLIC HEALTH INITIATIVES. EVOLUTION OF THE KIDNEY, AN ORGAN RICH IN MITOCHONDRIA, HAS BEEN DRIVEN BY NATURAL SELECTION FOR REPRODUCTIVE FITNESS CONSTRAINED BY ENERGY AVAILABILITY. OVER THE PAST 2 MILLION YEARS, RAPID GROWTH OF AN ENERGY-DEMANDING BRAIN IN HOMO SAPIENS ENABLED HOMINID ADAPTATION TO ENVIRONMENTAL EXTREMES THROUGH SELECTION FOR MUTATIONS IN MITOCHONDRIAL AND NUCLEAR DNA EPIGENETICALLY REGULATED BY ALLOCATION OF ENERGY TO DEVELOPING ORGANS. MATERNAL UNDERNUTRITION OR HYPOXIA RESULTS IN INTRAUTERINE GROWTH RESTRICTION OR PRETERM BIRTH, RESULTING IN LOW BIRTH WEIGHT AND LOW NEPHRON NUMBER. REGULATED THROUGH PLACENTAL TRANSFER, ENVIRONMENTAL OXYGEN AND NUTRIENTS SIGNAL NEPHRON PROGENITOR CELLS TO REPROGRAM METABOLISM FROM GLYCOLYSIS TO OXIDATIVE PHOSPHORYLATION. THESE PROCESSES ARE MODULATED BY COUNTERBALANCING ANABOLIC AND CATABOLIC METABOLIC PATHWAYS THAT EVOLVED FROM PROKARYOTE HOMOLOGS AND BY HYPOXIA-DRIVEN AND AUTOPHAGY PATHWAYS THAT EVOLVED IN EUKARYOTES. REGULATION OF NEPHRON DIFFERENTIATION BY HISTONE MODIFICATIONS AND DNA METHYLTRANSFERASES PROVIDE EPIGENETIC CONTROL OF NEPHRON NUMBER IN RESPONSE TO ENERGY AVAILABLE TO THE FETUS. DEVELOPMENTAL PLASTICITY OF NEPHROGENESIS REPRESENTS AN EVOLVED LIFE HISTORY STRATEGY THAT PRIORITIZES ENERGY TO EARLY BRAIN GROWTH WITH ADEQUATE KIDNEY FUNCTION THROUGH REPRODUCTIVE YEARS, THE TRADE-OFF BEING INCREASING PREVALENCE OF CKD DELAYED UNTIL LATER ADULTHOOD. THE RESEARCH IMPLICATIONS OF THIS EVOLUTIONARY ANALYSIS ARE TO IDENTIFY REGULATORY PATHWAYS OF ENERGY ALLOCATION DIRECTING NEPHROGENESIS WHILE ACCOUNTING FOR THE DIFFERENT LIFE HISTORY STRATEGIES OF ANIMAL MODELS SUCH AS THE MOUSE. THE CLINICAL IMPLICATIONS ARE TO OPTIMIZE NUTRITION AND MINIMIZE HYPOXIC/TOXIC STRESSORS IN CHILDBEARING WOMEN AND CHILDREN IN EARLY POSTNATAL DEVELOPMENT. 2020 10 3884 63 KIDNEY DISEASE IN DIABETES. PERSONS WITH DIABETES MAKE UP THE FASTEST GROWING GROUP OF KIDNEY DIALYSIS AND TRANSPLANT RECIPIENTS IN THE UNITED STATES. IN 1985, WHEN THE FIRST EDITION OF DIABETES IN AMERICA WAS PUBLISHED, 20,961 PERSONS WITH DIABETES WERE RECEIVING RENAL REPLACEMENT THERAPY, REPRESENTING 29% OF ALL NEW CASES OF END-STAGE RENAL DISEASE (ESRD). BY 2012, 239,837 PERSONS WITH DIABETES WERE ON RENAL REPLACEMENT THERAPY, ACCOUNTING FOR 44% OF ALL NEW ESRD CASES. THE INCREASED COUNT REFLECTS GROWTH IN DIABETES PREVALENCE AND INCREASED ACCESS TO DIALYSIS AND TRANSPLANTATION. THOSE WITH A PRIMARY DIAGNOSIS OF DIABETES HAVE LOWER SURVIVAL RELATIVE TO OTHER CAUSES OF ESRD, PRIMARILY BECAUSE OF THE COEXISTENT MORBIDITY ASSOCIATED WITH DIABETES, PARTICULARLY CARDIOVASCULAR DISEASES (CVD). WHILE SURVIVAL ON DIALYSIS HAS SLOWLY IMPROVED ACROSS MODALITIES SINCE THE 1990S, IT REMAINS REDUCED IN PERSONS WITH DIABETES, HALF OF WHOM DIE WITHIN 3 YEARS OF BEGINNING DIALYSIS IN THE UNITED STATES. SIMILAR TO PERSONS WITH ESRD IN GENERAL, THE LEADING CAUSES OF DEATH AMONG ADULTS WITH DIABETES WHO STARTED DIALYSIS IN 1995-2009 WERE CVD (58% OF THE DEATHS) AND INFECTIONS (13% OF THE DEATHS). KIDNEY TRANSPLANT RECIPIENTS WITH DIABETES HAVE MUCH BETTER SURVIVAL THAN THOSE ON DIALYSIS, INDICATING A SIGNIFICANT IMPACT OF THE TYPE OF RENAL REPLACEMENT THERAPY (TRANSPLANT VERSUS DIALYSIS) ON LONG-TERM SURVIVAL. KIDNEY FAILURE AFFECTS ABOUT 1% OF PERSONS WITH DIABETES IN THE UNITED STATES. A CONSIDERABLY HIGHER PROPORTION, ABOUT 40%, HAVE LESS SEVERE KIDNEY DISEASE. SINCE THE SECOND EDITION OF DIABETES IN AMERICA WAS PUBLISHED IN 1995, A WEALTH OF NEW INFORMATION HAS CONTRIBUTED SUBSTANTIALLY TO THE UNDERSTANDING OF KIDNEY DISEASE ASSOCIATED WITH DIABETES. IN 2002, THE NATIONAL KIDNEY FOUNDATION'S KIDNEY DISEASE OUTCOME QUALITY INITIATIVE PUBLISHED A UNIFORM DEFINITION OF CHRONIC KIDNEY DISEASE (CKD) AND CLASSIFICATION OF ITS STAGES IRRESPECTIVE OF UNDERLYING CAUSE, THUS PROVIDING A COMMON LANGUAGE FOR DEFINING BOTH THE SEVERITY AND PROGNOSIS OF KIDNEY DISEASE. THE DEFINITION AND CLASSIFICATION OF CKD WERE SUBSEQUENTLY UPDATED AND REFINED BY THE KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES IN 2012. ACCORDINGLY, CKD IS CLASSIFIED BASED ON BOTH ALBUMINURIA AND GLOMERULAR FILTRATION RATE (GFR) CATEGORIES, AND TOGETHER WITH KIDNEY FAILURE, THESE CONDITIONS ARE COLLECTIVELY REFERRED TO AS CKD, REGARDLESS OF ETIOLOGY. IN ADDITION, THE KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES RECOMMENDS USING EQUATIONS TO ESTIMATE GFR (EGFR), WHICH INCLUDE THE ROUTINELY OBTAINED VARIABLES SERUM CREATININE, AGE, SEX, AND RACE/ETHNICITY. THE USE OF SERUM CYSTATIN C, AN ENDOGENOUS FILTRATION MARKER LESS INFLUENCED THAN SERUM CREATININE BY VARIATIONS IN MUSCLE MASS, DIET, AND TUBULAR SECRETION, HAS EMERGED AS AN ALTERNATIVE OR AN ADJUNCT TO SERUM CREATININE-BASED EQUATIONS, PARTICULARLY IN PERSONS WITH DIABETES, IN WHOM EARLY KIDNEY DISEASE IS OFTEN CHARACTERIZED BY ELEVATED GFR. SINCE THE LATE 1990S, NEW MOLECULAR MECHANISMS HAVE BEEN DEFINED THAT ARE HELPING TO EXPLAIN THE DEVELOPMENT AND PROGRESSION OF DIABETIC KIDNEY DISEASE. GLOMERULAR STRUCTURAL LESIONS WERE FOUND TO EXPLAIN 95% OF THE VARIABILITY IN ALBUMIN EXCRETION AND 78% OF GFR VARIABILITY. THE LATTER PERCENTAGE INCREASED TO 92% BY ADDING INDICES OF GLOMERULAR-TUBULAR JUNCTION ABNORMALITIES AND INTERSTITIAL EXPANSION TO THE REGRESSION MODELS. PODOCYTE INJURY APPEARS TO PLAY AN ESSENTIAL ROLE IN THE PROGRESSION OF DIABETIC NEPHROPATHY. IN PERSONS WITH EITHER TYPE 1 OR TYPE 2 DIABETES, PODOCYTE CHANGES MAY OCCUR EVEN BEFORE THE INCREASE IN ALBUMINURIA, SUGGESTING THAT DIABETES ITSELF MAY INDUCE PODOCYTE ALTERATIONS. MUCH HAS ALSO BEEN WRITTEN ABOUT THE PROGNOSTIC IMPLICATIONS OF CKD. ELEVATED ALBUMINURIA AND LOW GFR ARE ASSOCIATED WITH ESRD, FATAL AND NONFATAL CVD, AND ALL-CAUSE MORTALITY. A META-ANALYSIS OF 1,024,977 PARTICIPANTS (NEARLY 13% WITH DIABETES) FROM 30 GENERAL POPULATION AND HIGH-RISK CARDIOVASCULAR COHORTS AND 13 CKD COHORTS INDICATED THAT WHILE THE ABSOLUTE RISKS FOR ALL-CAUSE AND CVD MORTALITY ARE HIGHER IN THE PRESENCE OF DIABETES, THE RELATIVE RISKS OF ESRD OR DEATH BY EGFR AND ALBUMINURIA ARE SIMILAR WITH OR WITHOUT DIABETES. THESE FINDINGS UNDERSCORE THE IMPORTANCE OF KIDNEY DISEASE PER SE AS A PREDICTOR OF IMPORTANT CLINICAL OUTCOMES, REGARDLESS OF THE UNDERLYING CAUSE OF KIDNEY DISEASE. NEW BIOMARKERS OF DIABETIC KIDNEY DISEASE APPEAR TO HAVE ADDITIONAL PROGNOSTIC INFORMATION BEYOND THAT PROVIDED BY ALBUMINURIA. THESE MARKERS INCLUDE KIDNEY INJURY MOLECULE 1, LIVER FATTY ACID-BINDING PROTEIN, N-ACETYL-BETA-D-GLUCOSAMINIDASE, NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN, BETA-TRACE PROTEIN, BETA(2)-MICROGLOBULIN, AND TUMOR NECROSIS FACTOR RECEPTORS 1 AND 2. MANY CONCEPTS ABOUT RISK FACTORS FOR CKD ILLUSTRATED IN THIS CHAPTER HAVE NOT CHANGED SINCE 1995, AND WHERE THEY HAVE, THOSE CHANGES ARE DISCUSSED. IN PARTICULAR, MAJOR ADVANCES HAVE BEEN MADE IN ELUCIDATING THE GENETIC AND EPIGENETIC COMPLEXITY OF CKD, WHICH CONTRIBUTED TO DEFINING CELLULAR METABOLIC MEMORY AND THE UNDERSTANDING OF THE LONGLASTING EFFECTS OF STRICT GLYCEMIC CONTROL OBSERVED IN PERSONS WITH TYPE 1 DIABETES OR TYPE 2 DIABETES. IMPROVEMENTS IN THE MANAGEMENT OF PERSONS WITH DIABETES AND CKD HAVE EXTENDED THE TIME COURSE FROM ONSET OF SEVERE ALBUMINURIA TO ESRD AND REDUCED THE OCCURRENCE OF CVD. IN TYPE 1 DIABETES, THE COMBINED DIABETES CONTROL AND COMPLICATIONS TRIAL (DCCT) AND ITS LONG-TERM FOLLOW-UP, THE EPIDEMIOLOGY OF DIABETES INTERVENTIONS AND COMPLICATIONS (EDIC) OBSERVATIONAL STUDY, INDICATED THAT INTENSIVE EARLY METABOLIC CONTROL REDUCED THE RISK OF IMPAIRED GFR BY 50% AND OF CVD OUTCOMES BY 42%, WITH A SPECIFIC 57% DECREASE IN MYOCARDIAL INFARCTION, STROKE, OR DEATH FROM CVD, EFFECTS THAT WERE PARTLY MEDIATED BY THE REDUCED INCIDENCE OF DIABETIC KIDNEY DISEASE. AMONG PERSONS WITH TYPE 2 DIABETES, A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS INDICATED THAT MORE INTENSIVE GLYCEMIC CONTROL (GLYCOSYLATED HEMOGLOBIN [A1C] <7%) WAS ASSOCIATED WITH A SIGNIFICANT 10% REDUCTION IN ALBUMINURIA BUT HAD NO EFFECTS ON MORTALITY, KIDNEY FAILURE, OR OTHER VASCULAR OUTCOMES. THE ACTION TO CONTROL CARDIOVASCULAR RISK IN DIABETES (ACCORD) TRIAL, TARGETING AN A1C LEVEL <6.0% IN THE INTENSIVE INTERVENTION ARM, REPORTED AN INCREASED RISK OF CVD DEATH FOR INTENSIVE VERSUS CONVENTIONAL GLYCEMIC CONTROL, ALTHOUGH IT REMAINS UNCLEAR WHETHER THIS EFFECT WAS RELATED TO MORE HYPOGLYCEMIC EPISODES, THE USE OF ADDITIONAL HYPOGLYCEMIC MEDICINES, OR TO THE TARGET GLYCEMIC LEVEL ITSELF. LIKEWISE, THE MODEST GAINS IN INTERMEDIATE OUTCOMES IN THE INTENSIVE TREATMENT ARMS OF THE ACTION IN DIABETES AND VASCULAR DISEASE: PRETERAX AND DIAMICRON MODIFIED RELEASE CONTROLLED EVALUATION (ADVANCE) AND THE VETERANS AFFAIRS DIABETES (VADT) TRIAL WERE COUNTERBALANCED BY A TWOFOLD TO THREEFOLD HIGHER RISK OF SEVERE HYPOGLYCEMIA. TOGETHER, THESE TRIALS INDICATE THAT GLYCEMIC CONTROL IS EXTREMELY USEFUL UP TO A POINT, BUT MORE AGGRESSIVE GLYCEMIC CONTROL MAY BE HARMFUL. SIMILARLY, FOR BLOOD PRESSURE CONTROL, 2014-2015 RECOMMENDATIONS BY THE GUIDELINE-WRITING GROUPS ENDORSE LESS INTENSIVE AND MORE INDIVIDUALIZED BLOOD PRESSURE TARGETS FOR DIABETES AND CKD THAN IN THE PAST. PERSONS WITH DIABETES AND CKD REQUIRE MULTIDISCIPLINARY MANAGEMENT INVOLVING A COMBINATION OF TREATMENTS AND BEHAVIORAL ADJUSTMENTS TO DELAY PROGRESSION OF CKD AND TO PREVENT THE ASSOCIATED COMPLICATIONS. THE STENO-2 STUDY, A LANDMARK PROSPECTIVE, RANDOMIZED TRIAL IN DENMARK, DEMONSTRATED THAT COMPARED WITH CONVENTIONAL TREATMENT, INTENSIVE MULTIFACTORIAL INTERVENTION LED TO 46% LOWER DEATH RATE, 56% LESS SEVERE ALBUMINURIA, 43% LOWER INCIDENCE OF DIABETIC RETINOPATHY, AND 47% LOWER INCIDENCE OF AUTONOMIC NEUROPATHY DURING THE 13.3-YEAR STUDY PERIOD. 2018 11 960 18 CHRONIC MYELOMONOCYTIC LEUKEMIA: 2016 UPDATE ON DIAGNOSIS, RISK STRATIFICATION, AND MANAGEMENT. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOPOIETIC STEM CELL DISORDER CHARACTERIZED BY OVERLAPPING FEATURES OF MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. DIAGNOSIS IS BASED ON THE PRESENCE OF PERSISTENT (>3 MONTHS) PERIPHERAL BLOOD MONOCYTOSIS (>1 X 10(9) /L), ALONG WITH BONE MARROW DYSPLASIA. CLONAL CYTOGENETIC ABNORMALITIES OCCUR IN APPROXIMATELY 20-30% OF PATIENTS, WHILE >90% HAVE GENE MUTATIONS. MUTATIONS INVOLVING TET2 ( APPROXIMATELY 60%), SRSF2 ( APPROXIMATELY 50%), ASXL1 ( APPROXIMATELY 40%), AND RAS ( APPROXIMATELY 30%) ARE FREQUENT; WITH ONLY ASXL1 MUTATIONS NEGATIVELY IMPACTING OVERALL SURVIVAL. TWO MOLECULARLY INTEGRATED, CMML-SPECIFIC PROGNOSTIC MODELS INCLUDE; THE GROUPE FRANCAIS DES MYELODYSPLASIES (GFM) AND THE MOLECULAR MAYO MODEL (MMM). THE GFM MODEL SEGREGATES PATIENTS INTO 3 GROUPS BASED ON: AGE >65 YEARS, WBC >15 X 10(9) /L, ANEMIA, PLATELETS <100 X 10(9) /L, AND ASXL1 MUTATION STATUS, WITH RESPECTIVE MEDIAN SURVIVALS OF 56 (LOW), 27.4 (INTERMEDIATE), AND 9.2 (HIGH) MONTHS. THE MMM IS BASED ON ASXL1 MUTATIONAL STATUS, ABSOLUTE MONOCYTE COUNT >10 X 10(9) /L, HEMOGLOBIN <10 G/DL, PLATELETS <100 X 109/L AND CIRCULATING IMMATURE MYELOID CELLS. THIS MODEL STRATIFIES PATIENTS INTO FOUR GROUPS; HIGH (>/=3 RISK FACTORS), INTERMEDIATE-2 (2 RISK FACTORS), INTERMEDIATE-1 (1 RISK FACTOR) AND LOW (NO RISK FACTORS), WITH MEDIAN SURVIVALS OF 16, 31, 59, AND 97 MONTHS, RESPECTIVELY. HYPOMETHYLATING AGENTS SUCH AS 5-AZACITIDINE AND DECITABINE ARE COMMONLY USED, WITH OVERALL RESPONSE RATES OF APPROXIMATELY 30-40% AND COMPLETE REMISSION RATES OF APPROXIMATELY 7-17%. ALLOGENEIC STEM CELL TRANSPLANT IS THE ONLY POTENTIALLY CURATIVE OPTION, BUT IS ASSOCIATED WITH SIGNIFICANT MORBIDITY AND MORTALITY. INDIVIDUALIZED THERAPY, INCLUDING EPIGENETIC MODIFIERS AND SMALL MOLECULE INHIBITORS, ARE EXCITING PROSPECTS. AM. J. HEMATOL. 91:632-642, 2016. (C) 2016 WILEY PERIODICALS, INC. 2016 12 6446 36 THERAPEUTIC INSIGHTS IN CHRONIC KIDNEY DISEASE PROGRESSION. CHRONIC KIDNEY DISEASE (CKD) HAS BEEN RECOGNIZED AS A LEADING PUBLIC HEALTH PROBLEM WORLDWIDE. THROUGH ITS EFFECT ON CARDIOVASCULAR RISK AND END-STAGE KIDNEY DISEASE, CKD DIRECTLY AFFECTS THE GLOBAL BURDEN OF MORBIDITY AND MORTALITY. CLASSICAL OPTIMAL MANAGEMENT OF CKD INCLUDES BLOOD PRESSURE CONTROL, TREATMENT OF ALBUMINURIA WITH ANGIOTENSIN-CONVERTING ENZYME INHIBITORS OR ANGIOTENSIN II RECEPTOR BLOCKERS, AVOIDANCE OF POTENTIAL NEPHROTOXINS AND OBESITY, DRUG DOSING ADJUSTMENTS, AND CARDIOVASCULAR RISK REDUCTION. DIABETES MIGHT ACCOUNT FOR MORE THAN HALF OF CKD BURDEN, AND OBESITY IS THE MOST IMPORTANT PROMPTED FACTOR FOR THIS DISEASE. NEW ANTIHYPERGLYCEMIC DRUGS, SUCH AS SODIUM-GLUCOSE-COTRANSPORTER 2 INHIBITORS HAVE SHOWN TO SLOW THE DECLINE OF GFR, BRINGING ADDITIONAL BENEFIT IN WEIGHT REDUCTION, CARDIOVASCULAR, AND OTHER KIDNEY OUTCOMES. ON THE OTHER HAND, A NEW GENERATION OF NON-STEROIDAL MINERALOCORTICOID RECEPTOR ANTAGONIST HAS RECENTLY BEEN DEVELOPED TO OBTAIN A SELECTIVE RECEPTOR INHIBITION REDUCING SIDE EFFECTS LIKE HYPERKALEMIA AND THEREBY MAKING THE DRUGS SUITABLE FOR ADMINISTRATION TO CKD PATIENTS. MOREOVER, TWO NEW POTASSIUM-LOWERING THERAPIES HAVE SHOWN TO IMPROVE TOLERANCE, ALLOWING FOR HIGHER DOSAGE OF RENIN-ANGIOTENSIN SYSTEM INHIBITORS AND THEREFORE ENHANCING THEIR NEPHROPROTECTIVE EFFECT. REGARDLESS OF ITS CAUSE, CKD IS CHARACTERIZED BY REDUCED RENAL REGENERATION CAPACITY, MICROVASCULAR DAMAGE, OXIDATIVE STRESS AND INFLAMMATION, RESULTING IN FIBROSIS AND PROGRESSIVE, AND IRREVERSIBLE NEPHRON LOSS. THEREFORE, A HOLISTIC APPROACH SHOULD BE TAKEN TARGETING THE DIVERSE PROCESSES AND BIOLOGICAL CONTEXTS THAT ARE ASSOCIATED WITH CKD PROGRESSION. TO DATE, THERAPEUTIC INTERVENTIONS WHEN TUBULOINTERSTITIAL FIBROSIS IS ALREADY ESTABLISHED HAVE PROVED TO BE INSUFFICIENT, THUS RESEARCH EFFORT SHOULD FOCUS ON UNRAVELING EARLY DISEASE MECHANISMS. AN ARRAY OF NOVEL THERAPEUTIC APPROACHES TARGETING EPIGENETIC REGULATORS ARE NOW UNDERGOING PHASE II OR PHASE III TRIALS AND MIGHT PROVIDE A SIMULTANEOUS REGULATORY ACTIVITY THAT COORDINATELY REGULATE DIFFERENT ASPECTS OF CKD PROGRESSION. 2021 13 4562 23 MYELODYSPLASTIC SYNDROME/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROMES: A FOCUSED REVIEW. MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) OVERLAP SYNDROMES ARE UNIQUE MYELOID NEOPLASMS, WITH OVERLAPPING FEATURES OF MDS AND MPN. THEY CONSIST OF FOUR ADULT ONSET ENTITIES INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), MDS/MPN-RING SIDEROBLASTS-THROMBOCYTOSIS (MDS/MPN-RS-T), BCR-ABL1 NEGATIVE ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) AND MDS/MPN-UNCLASSIFIABLE (MDS/MPN-U); WITH JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) BEING THE ONLY PEDIATRIC ONSET ENTITY. AMONG THESE OVERLAP NEOPLASMS, CMML IS THE MOST FREQUENT AND IS HALLMARKED BY THE PRESENCE OF SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS WITH RECURRENT MUTATIONS INVOLVING TET2 (60%), SRSF2 (50%) AND ASXL1 (40%); WITH RAS PATHWAY MUTATIONS AND JAK2V617F BEING RELATIVELY ENRICHED IN PROLIFERATIVE CMML SUBTYPES (WBC >/=13 X 109/L). CMML USUALLY PRESENTS IN THE 7TH DECADE OF LIFE, WITH A MALE PREPONDERANCE AND IS ASSOCIATED WITH A MEDIAN OVERALL SURVIVAL OF <36 MONTHS. ADVERSE PROGNOSTICATORS IN CMML INCLUDE INCREASING AGE, HIGH WBC, PRESENCE OF CIRCULATING IMMATURE MYELOID CELLS, ANEMIA, THROMBOCYTOPENIA AND TRUNCATING ASXL1 MUTATIONS. WHILE ALLOGENEIC STEM CELL TRANSPLANTATION REMAINS THE ONLY CURATIVE OPTION, GIVEN THE LATE ONSET OF THIS NEOPLASM AND HIGH FREQUENCY OF COMORBIDITIES, MOST PATIENTS REMAIN INELIGIBLE. HYPOMETHYLATING AGENTS SUCH AS AZACITIDINE, DECITABINE AND ORAL DECITABINE/CEDAZURIDINE HAVE BEEN US FDA APPROVED FOR THE MANAGEMENT OF CMML, WITH OVERALL RESPONSE RATES OF 40-50% AND COMPLETE REMISSION RATES OF <20%. WHILE THESE AGENTS EPIGENETICALLY RESTORE HEMATOPOIESIS IN A SUBSET OF RESPONDING PATIENTS, THEY DO NOT IMPACT MUTATIONAL ALLELE BURDENS AND EVENTUAL DISEASE PROGRESSION TO AML REMAINS INEVITABLE. NEWER TREATMENT MODALITIES EXPLOITING EPIGENETIC, SIGNALING AND SPLICING ABNORMALITIES COMMONLY SEEN IN CMML ARE MUCH NEEDED. 2020 14 246 41 ADULT STEM CELL THERAPY FOR CARDIAC REPAIR IN PATIENTS AFTER ACUTE MYOCARDIAL INFARCTION LEADING TO ISCHEMIC HEART FAILURE: AN OVERVIEW OF EVIDENCE FROM THE RECENT CLINICAL TRIALS. BACKGROUND: CARDIOVASCULAR DISEASES (CVD) STILL REPRESENT THE LEADING CAUSE OF MORTALITY WORLDWIDE, DESPITE THE REMARKABLE ADVANCES IN INTERVENTIONAL CARDIOLOGY, CARDIAC SURGERY, AND MODERN PHARMACOTHERAPY, PARTICULARLY IN THE SETTING OF ACUTE MYOCARDIAL INFARCTION (AMI), CHRONIC ISCHEMIC HEART FAILURE (HF), CARDIOMYOPATHY (CM), AND THE ASSOCIATED LEFT VENTRICULAR (LV) DYSFUNCTION. A SIGNIFICANT LOSS OF CARDIOMYOCYTES THAT UNDERLIES ALL OF THESE CONDITIONS WAS PREVIOUSLY CONSIDERED IRREVERSIBLE. HOWEVER, CURRENT EVIDENCE INDICATES THAT THE HUMAN HEART HAS SOME POTENTIAL FOR REPAIR, AND OVER THE PAST DECADE, MANY RESEARCH STUDIES HAVE BEEN EXPLORING THE USE OF STEM CELLS (SCS) TO FACILITATE RESTORATION OF MYOCARDIUM. CONSEQUENTLY, THE SAFETY, FEASIBILITY, AND EFFECTIVENESS OF SC THERAPY HAVE BEEN REPORTED IN MANY RANDOMIZED CLINICAL TRIALS (RCTS), USING DIFFERENT LINEAGES OF ADULT SCS. NEVERTHELESS, THE CLINICAL BENEFITS OF SC THERAPY ARE NOT YET WELL ESTABLISHED. IN THE NEAR FUTURE, UNDERSTANDING OF THE COMPLEX INTERRELATIONS BETWEEN SCS, PARACRINE FACTORS, GENETIC OR EPIGENETIC PREDISPOSITIONS, AND MYOCARDIAL MICROENVIRONMENT, IN THE CONTEXT OF AN INDIVIDUAL PATIENT, WILL BE CRUCIAL FOR TRANSLATION OF THIS KNOWLEDGE INTO PRACTICAL DEVELOPMENT OF SUCCESSFUL, LONG-TERM REGENERATIVE SC THERAPEUTIC APPLICATIONS, IN A GROWING POPULATION OF PATIENTS SUFFERING FROM PREVIOUS MYOCARDIAL INFARCTION (MI) LEADING TO CHRONIC ISCHEMIC CARDIOMYOPATHY. CONCLUSION: THIS OVERVIEW HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF ADULT SCS IN TERMS OF THEIR POSSIBLE REGENERATIVE CAPACITY, SAFETY, AND CLINICAL OUTCOMES, IN PATIENTS WITH AMI, AND/OR SUBSEQUENT HF (DUE TO CHRONIC ISCHEMIC CARDIOMYOPATHY). THIS REVIEW WAS BASED UPON PUBMED DATABASE SEARCH FOR TRIALS ON SC THERAPY, IN PATIENTS WITH AMI AND HF, AND THE MAIN TIMEFRAME WAS SET FROM 2006 TO 2016. 2017 15 5216 49 PRETERM BIRTH: LONG TERM CARDIOVASCULAR AND RENAL CONSEQUENCES. BACKGROUND: CARDIOVASCULAR AND CHRONIC KIDNEY DISEASES ARE A PART OF NONCOMMUNICABLE CHRONIC DISEASES, THE LEADING CAUSES OF PREMATURE DEATH WORLDWIDE. THEY ARE RECOGNIZED AS HAVING EARLY ORIGINS THROUGH ALTERED DEVELOPMENTAL PROGRAMMING, DUE TO ADVERSE ENVIRONMENTAL CONDITIONS DURING DEVELOPMENT. PRETERM BIRTH IS SUCH AN ADVERSE FACTOR. RATES OF PRETERM BIRTH INCREASED IN THE LAST DECADES, HOWEVER, WITH THE IMPROVEMENT IN PERINATAL AND NEONATAL CARE, A GROWING NUMBER OF PRETERM BORN SUBJECTS HAS NOW ENTERED ADULTHOOD. CLINICAL AND EXPERIMENTAL EVIDENCE SUGGESTS THAT PRETERM BIRTH IS ASSOCIATED WITH IMPAIRED OR ARRESTED STRUCTURAL OR FUNCTIONAL DEVELOPMENT OF KEY ORGANS/SYSTEMS MAKING PRETERM INFANTS VULNERABLE TO CARDIOVASCULAR AND CHRONIC RENAL DISEASES AT ADULTHOOD. THIS REVIEW ANALYZES THE EVIDENCE OF SUCH CARDIOVASCULAR AND RENAL CHANGES, THE ROLE OF PERINATAL AND NEONATAL FACTORS SUCH AS ANTENATAL STEROIDS AND POTENTIAL PATHOGENIC MECHANISMS, INCLUDING DEVELOPMENTAL PROGRAMMING AND EPIGENETIC ALTERATIONS. CONCLUSION: PRETERM BORN SUBJECTS ARE EXPOSED TO A SIGNIFICANTLY INCREASED RISK FOR ALTERED CARDIOVASCULAR AND RENAL FUNCTIONS AT YOUNG ADULTHOOD. ADEQUATE, SPECIFIC FOLLOW-UP MEASURES REMAIN TO BE DETERMINED. WHILE ANTENATAL STEROIDS HAVE CONSIDERABLY IMPROVED PRETERM BIRTH OUTCOMES, REPEATED THERAPY SHOULD BE CONSIDERED WITH CAUTION, AS ANTENATAL STEROIDS INDUCE LONG-TERM CARDIOVASCULAR AND METABOLIC ALTERATIONS IN ANIMALS' MODELS AND THEIR INVOLVEMENT IN THE ACCELERATED CELLULAR SENESCENCE OBSERVED IN HUMAN STUDIES CANNOT BE EXCLUDED. 2018 16 169 31 ABNORMALITIES OF AMPK ACTIVATION AND GLUCOSE UPTAKE IN CULTURED SKELETAL MUSCLE CELLS FROM INDIVIDUALS WITH CHRONIC FATIGUE SYNDROME. BACKGROUND: POST EXERTIONAL MUSCLE FATIGUE IS A KEY FEATURE IN CHRONIC FATIGUE SYNDROME (CFS). ABNORMALITIES OF SKELETAL MUSCLE FUNCTION HAVE BEEN IDENTIFIED IN SOME BUT NOT ALL PATIENTS WITH CFS. TO TRY TO LIMIT POTENTIAL CONFOUNDERS THAT MIGHT CONTRIBUTE TO THIS CLINICAL HETEROGENEITY, WE DEVELOPED A NOVEL IN VITRO SYSTEM THAT ALLOWS COMPARISON OF AMP KINASE (AMPK) ACTIVATION AND METABOLIC RESPONSES TO EXERCISE IN CULTURED SKELETAL MUSCLE CELLS FROM CFS PATIENTS AND CONTROL SUBJECTS. METHODS: SKELETAL MUSCLE CELL CULTURES WERE ESTABLISHED FROM 10 SUBJECTS WITH CFS AND 7 AGE-MATCHED CONTROLS, SUBJECTED TO ELECTRICAL PULSE STIMULATION (EPS) FOR UP TO 24H AND EXAMINED FOR CHANGES ASSOCIATED WITH EXERCISE. RESULTS: IN THE BASAL STATE, CFS CULTURES SHOWED INCREASED MYOGENIN EXPRESSION BUT DECREASED IL6 SECRETION DURING DIFFERENTIATION COMPARED WITH CONTROL CULTURES. CONTROL CULTURES SUBJECTED TO 16 H EPS SHOWED A SIGNIFICANT INCREASE IN BOTH AMPK PHOSPHORYLATION AND GLUCOSE UPTAKE COMPARED WITH UNSTIMULATED CELLS. IN CONTRAST, CFS CULTURES SHOWED NO INCREASE IN AMPK PHOSPHORYLATION OR GLUCOSE UPTAKE AFTER 16 H EPS. HOWEVER, GLUCOSE UPTAKE REMAINED RESPONSIVE TO INSULIN IN THE CFS CELLS POINTING TO AN EXERCISE-RELATED DEFECT. IL6 SECRETION IN RESPONSE TO EPS WAS SIGNIFICANTLY REDUCED IN CFS COMPARED WITH CONTROL CULTURES AT ALL TIME POINTS MEASURED. CONCLUSION: EPS IS AN EFFECTIVE MODEL FOR ELICITING MUSCLE CONTRACTION AND THE METABOLIC CHANGES ASSOCIATED WITH EXERCISE IN CULTURED SKELETAL MUSCLE CELLS. WE FOUND FOUR MAIN DIFFERENCES IN CULTURED SKELETAL MUSCLE CELLS FROM SUBJECTS WITH CFS; INCREASED MYOGENIN EXPRESSION IN THE BASAL STATE, IMPAIRED ACTIVATION OF AMPK, IMPAIRED STIMULATION OF GLUCOSE UPTAKE AND DIMINISHED RELEASE OF IL6. THE RETENTION OF THESE DIFFERENCES IN CULTURED MUSCLE CELLS FROM CFS SUBJECTS POINTS TO A GENETIC/EPIGENETIC MECHANISM, AND PROVIDES A SYSTEM TO IDENTIFY NOVEL THERAPEUTIC TARGETS. 2015 17 2941 23 GENETIC AND EPIGENETIC ALTERATIONS IN TOLL LIKE RECEPTOR 2 AND WOUND HEALING IMPAIRMENT IN TYPE 2 DIABETES PATIENTS. AIM: PERSISTENT HYPERGLYCEMIC MICROENVIRONMENT IN TYPE 2 DIABETES MELLITUS (T2DM) LEADS TO THE DEVELOPMENT OF SECONDARY COMPLICATIONS LIKE WOUND HEALING IMPAIRMENT. PROPER CO-ORDINATION OF INNATE IMMUNE SYSTEM PLAYS AN INTEGRAL ROLE IN WOUND HEALING. TOLL LIKE RECEPTORS (TLRS) ARE PROMINENT CONTRIBUTORS FOR THE INDUCTION OF THE INNATE IMMUNE AND INFLAMMATION RESPONSE. TLR2 IS AN IMPORTANT EXTRACELLULAR MEMBER IN MAMMALIAN TLR FAMILY AND HAS BEEN SHOWN TO BE A POTENT PLAYER IN THE WOUND HEALING MECHANISM. METHODS: EXPRESSIONAL STATUS OF TLR2 WAS SEEN IN WOUNDS OF T2DM CASES WITH RESPECT TO THE SEVERITY OF WOUNDS IN 110 HUMAN LOWER EXTREMITY WOUNDS. THE METHYLATION STATUS OF TLR2 PROMOTER WAS ALSO EXAMINED. RESULTS: ALTHOUGH TLR2 TRANSCRIPTS WERE DOWNREGULATED IN T2DM WOUNDS COMPARED TO CONTROL, THEIR LEVELS TEND TO INCREASE WITH THE SEVERITY OF T2DM WOUNDS. THE METHYLATION STATUS OF TLR2 GENE PROMOTER WAS NOT SIGNIFICANTLY DIFFERENT AMONG DIFFERENT GRADES OF WOUNDS IN T2DM SUBJECTS. THE CPG SITES INVESTIGATED WERE TOTALLY OR PARTIALLY METHYLATED IN MAJORITY OF DFU CASES. CONCLUSION: TLR2 DOWN REGULATION IN WOUNDS OF T2DM PATIENTS COMPARED TO NON DIABETIC PATIENTS MAY LEAD TO DEVELOPMENT OF NON HEALING CHRONIC ULCERS IN THEM. 2015 18 3502 47 IDENTIFICATION OF POTENTIAL BIOMARKERS OF CHRONIC KIDNEY DISEASE IN INDIVIDUALS WITH DIABETES: PROTOCOL FOR A CROSS-SECTIONAL OBSERVATIONAL STUDY. BACKGROUND: THE IMPORTANCE OF IDENTIFYING PEOPLE WITH DIABETES AND PROGRESSIVE KIDNEY DYSFUNCTION RELATES TO THE EXCESS MORBIDITY AND MORTALITY OF THIS GROUP. RATES OF CARDIOVASCULAR DISEASE ARE MUCH HIGHER IN PEOPLE WITH BOTH DIABETES AND KIDNEY DYSFUNCTION THAN IN THOSE WITH ONLY ONE OF THESE CONDITIONS. BY THE TIME THESE PEOPLE ARE IDENTIFIED IN CURRENT CLINICAL PRACTICE, PROTEINURIA AND RENAL DYSFUNCTION ARE ALREADY ESTABLISHED, LIMITING THE EFFECTIVENESS OF THERAPEUTIC INTERVENTIONS. THE IDENTIFICATION OF AN EPIGENETIC OR BLOOD METABOLITE SIGNATURE OR GUT MICROBIOME PROFILE MAY IDENTIFY THOSE WITH DIABETES AT RISK OF PROGRESSIVE CHRONIC KIDNEY DISEASE, IN TURN PROVIDING TARGETED INTERVENTION TO IMPROVE PATIENT OUTCOMES. OBJECTIVE: THIS STUDY AIMS TO IDENTIFY POTENTIAL BIOMARKERS IN PEOPLE WITH DIABETES AND CHRONIC KIDNEY DISEASE (CKD) ASSOCIATED WITH PROGRESSIVE RENAL INJURY AND TO DISTINGUISH BETWEEN STAGES OF CHRONIC KIDNEY DISEASE. THREE SOURCES OF BIOMARKERS WILL BE EXPLORED, INCLUDING DNA METHYLATION PROFILES IN BLOOD LYMPHOCYTES, THE METABOLOMIC PROFILE OF BLOOD-DERIVED PLASMA AND URINE, AND THE GUT MICROBIOME. METHODS: THE CROSS-SECTIONAL STUDY RECRUITED 121 PEOPLE WITH DIABETES AND VARYING STAGES (STAGES 1-5) OF CHRONIC KIDNEY DISEASE. SINGLE-POINT DATA COLLECTION INCLUDED BLOOD, URINE, AND FECAL SAMPLES IN ADDITION TO CLINICAL DATA SUCH AS ANTHROPOMETRIC MEASUREMENTS AND BIOCHEMICAL PARAMETERS. ADDITIONAL INFORMATION OBTAINED FROM MEDICAL RECORDS INCLUDED PATIENT DEMOGRAPHICS, MEDICAL COMORBIDITIES, AND MEDICATIONS. RESULTS: DATA COLLECTION COMMENCED IN JANUARY 2018 AND WAS COMPLETED IN JUNE 2018. AT THE TIME OF SUBMISSION, 121 PATIENTS HAD BEEN RECRUITED, AND 119 SAMPLES REMAINED AFTER QUALITY CONTROL. THERE WERE 83 PARTICIPANTS IN THE EARLY DIABETES-ASSOCIATED CKD GROUP WITH A MEAN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OF 61.2 ML/MIN/1.73 M2 (EARLY CKD GROUP CONSISTING OF STAGE 1, 2, AND 3A CKD), AND 36 PARTICIPANTS IN THE LATE DIABETIC CKD GROUP WITH A MEAN EGFR OF 23.9 ML/MIN/1.73 M2 (LATE CKD GROUP, CONSISTING OF STAGE 3B, 4, AND 5), P<.001. WE HAVE SUCCESSFULLY OBTAINED DNA FOR METHYLATION AND MICROBIOME ANALYSES USING THE BIOSPECIMENS COLLECTED VIA THIS PROTOCOL AND ARE CURRENTLY ANALYZING THESE RESULTS TOGETHER WITH THE METABOLOME OF THIS COHORT OF INDIVIDUALS WITH DIABETIC CKD. CONCLUSIONS: RECENT ADVANCES HAVE IMPROVED OUR UNDERSTANDING OF THE EPIGENOME, METABOLOMICS, AND THE INFLUENCE OF THE GUT MICROBIOME ON THE INCIDENCE OF DISEASES SUCH AS CANCERS, PARTICULARLY THOSE RELATED TO ENVIRONMENTAL EXPOSURES. HOWEVER, THERE IS A PAUCITY OF LITERATURE SURROUNDING THESE INFLUENCERS IN RENAL DISEASE. THIS STUDY WILL PROVIDE INSIGHT INTO THE FUNDAMENTAL UNDERSTANDING OF THE PATHOPHYSIOLOGY OF CKD IN INDIVIDUALS WITH DIABETES, ESPECIALLY IN NOVEL AREAS SUCH AS EPIGENETICS, METABOLOMICS, AND THE KIDNEY-GUT AXIS. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16277. 2020 19 2149 28 EPIGENETIC MARKERS TO PREDICT CONVERSION FROM GESTATIONAL DIABETES TO TYPE 2 DIABETES. CONTEXT: LIFESTYLE FACTORS MEDIATE EPIGENETIC CHANGES THAT CAN CAUSE CHRONIC DISEASES. ALTHOUGH ANIMAL AND LABORATORY STUDIES LINK EPIGENETIC CHANGES TO DIABETES, EPIGENETIC INFORMATION IN WOMEN WITH GESTATIONAL DIABETES (GDM) AND TYPE 2 DIABETES IS LACKING. OBJECTIVE: THIS STUDY SOUGHT TO MEASURE EPIGENETIC MARKERS ACROSS PREGNANCY AND EARLY POSTPARTUM AND IDENTIFY MARKERS THAT COULD BE USED AS PREDICTORS FOR CONVERSION FROM GDM TO TYPE 2 DIABETES. DESIGN: GLOBAL HISTONE H3 DIMETHYLATION WAS MEASURED IN WHITE BLOOD CELLS AT THREE TIME POINTS: 30 WK GESTATION, 8-10 WK POSTPARTUM, AND 20 WK POSTPARTUM, FROM FOUR GROUPS OF WOMEN WITH AND WITHOUT DIABETES. SETTING AND PARTICIPANTS: A TOTAL OF 39 PARTICIPANTS (SIX TO NINE IN EACH GROUP) WERE RECRUITED INCLUDING: NONDIABETIC WOMEN; WOMEN WITH GDM WHO DEVELOPED POSTPARTUM TYPE 2 DIABETES; WOMEN WITH GDM WITHOUT POSTPARTUM TYPE 2 DIABETES; AND WOMEN WITH TYPE 2 DIABETES. MAIN OUTCOME MEASURE: PERCENTAGES OF DIMETHYLATION OF H3 HISTONES RELATIVE TO TOTAL H3 HISTONE METHYLATION WERE COMPARED BETWEEN DIABETIC/NONDIABETIC GROUPS USING APPROPRIATE COMPARATIVE STATISTICS. RESULTS: H3K27 DIMETHYLATION WAS 50-60% LOWER AT 8-10 AND 20 WK POSTPARTUM IN WOMEN WITH GDM WHO DEVELOPED TYPE 2 DIABETES, COMPARED WITH NONDIABETIC WOMEN. H3K4 DIMETHYLATION WAS 75% LOWER AT 8-10 WK POSTPARTUM IN WOMEN WITH GDM WHO SUBSEQUENTLY DEVELOPED TYPE 2 DIABETES COMPARED WITH WOMEN WHO HAD GDM WHO DID NOT. CONCLUSIONS: THE PERCENTAGE OF DIMETHYLATION OF HISTONES H3K27 AND H3K4 VARIED WITH DIABETIC STATE AND HAS THE POTENTIAL AS A PREDICTIVE TOOL TO IDENTIFY WOMEN WHO WILL CONVERT FROM GDM TO TYPE 2 DIABETES. 2016 20 1556 30 DNA METHYLATION MODIFICATIONS ASSOCIATED WITH CHRONIC FATIGUE SYNDROME. CHRONIC FATIGUE SYNDROME (CFS), ALSO KNOWN AS MYALGIC ENCEPHALOMYELITIS, IS A COMPLEX MULTIFACTORIAL DISEASE THAT IS CHARACTERIZED BY THE PERSISTENT PRESENCE OF FATIGUE AND OTHER PARTICULAR SYMPTOMS FOR A MINIMUM OF 6 MONTHS. SYMPTOMS FAIL TO DISSIPATE AFTER SUFFICIENT REST AND HAVE MAJOR EFFECTS ON THE DAILY FUNCTIONING OF CFS SUFFERERS. CFS IS A MULTI-SYSTEM DISEASE WITH A HETEROGENEOUS PATIENT POPULATION SHOWING A WIDE VARIETY OF FUNCTIONAL DISABILITIES AND ITS BIOLOGICAL BASIS REMAINS POORLY UNDERSTOOD. STABLE ALTERATIONS IN GENE FUNCTION IN THE IMMUNE SYSTEM HAVE BEEN REPORTED IN SEVERAL STUDIES OF CFS. EPIGENETIC MODIFICATIONS HAVE BEEN IMPLICATED IN LONG-TERM EFFECTS ON GENE FUNCTION, HOWEVER, TO OUR KNOWLEDGE, GENOME-WIDE EPIGENETIC MODIFICATIONS ASSOCIATED WITH CFS HAVE NOT BEEN EXPLORED. WE EXAMINED THE DNA METHYLOME IN PERIPHERAL BLOOD MONONUCLEAR CELLS ISOLATED FROM CFS PATIENTS AND HEALTHY CONTROLS USING THE ILLUMINA HUMANMETHYLATION450 BEADCHIP ARRAY, CONTROLLING FOR INVARIANT PROBES AND PROBES OVERLAPPING POLYMORPHIC SEQUENCES. GENE ONTOLOGY (GO) AND NETWORK ANALYSIS OF DIFFERENTIALLY METHYLATED GENES WAS PERFORMED TO DETERMINE POTENTIAL BIOLOGICAL PATHWAYS SHOWING CHANGES IN DNA METHYLATION IN CFS. WE FOUND AN INCREASED ABUNDANCE OF DIFFERENTIALLY METHYLATED GENES RELATED TO THE IMMUNE RESPONSE, CELLULAR METABOLISM, AND KINASE ACTIVITY. GENES ASSOCIATED WITH IMMUNE CELL REGULATION, THE LARGEST COORDINATED ENRICHMENT OF DIFFERENTIALLY METHYLATED PATHWAYS, SHOWED HYPOMETHYLATION WITHIN PROMOTERS AND OTHER GENE REGULATORY ELEMENTS IN CFS. THESE DATA ARE CONSISTENT WITH EVIDENCE OF MULTISYSTEM DYSREGULATION IN CFS AND IMPLICATE THE INVOLVEMENT OF DNA MODIFICATIONS IN CFS PATHOLOGY. 2014