1 4101 78 MDCT AND MR UROGRAM SPECTRUM OF CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT DIAGNOSED IN ADULTHOOD. OBJECTIVE: CONGENITAL ANOMALIES OF THE KIDNEYS AND URINARY TRACT (CAKUT) ENCOMPASS A SPECTRUM OF ANOMALIES THAT RESULT FROM GENETIC, EPIGENETIC, ENVIRONMENTAL, AND MOLECULAR SIGNAL ABERRATIONS AT KEY STAGES OF URINARY TRACT DEVELOPMENT. CAKUT CAN BE SEEN INCIDENTALLY ON CROSS-SECTIONAL IMAGING OF THE ABDOMEN OR CAN BE A CAUSE FOR ADULT-ONSET CHRONIC KIDNEY DISEASE, POSING NEW CHALLENGES FOR NEPHROLOGISTS, UROLOGISTS, AND RADIOLOGISTS. CONCLUSION: AWARENESS OF CAKUT AND FAMILIARITY WITH THEIR IMAGING FINDINGS PERMIT OPTIMAL PATIENT MANAGEMENT AND THOROUGH WORKUP TO PREVENT HYPERTENSION AND PROGRESSION FROM CAKUT TO RENAL FAILURE. THE PURPOSE OF THIS ARTICLE IS TO REVIEW THE CROSS-SECTIONAL IMAGING FINDINGS OF CAKUT THAT MAY PRESENT IN ADULTHOOD. 2015 2 6160 33 THE GENETICS AND PATHOGENESIS OF CAKUT. CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT (CAKUT) COMPRISE A LARGE VARIETY OF MALFORMATIONS THAT ARISE FROM DEFECTIVE KIDNEY OR URINARY TRACT DEVELOPMENT AND FREQUENTLY LEAD TO KIDNEY FAILURE. THE CLINICAL SPECTRUM RANGES FROM SEVERE MALFORMATIONS, SUCH AS RENAL AGENESIS, TO POTENTIALLY MILDER MANIFESTATIONS, SUCH AS VESICOURETERAL REFLUX. ALMOST 50% OF CASES OF CHRONIC KIDNEY DISEASE THAT MANIFEST WITHIN THE FIRST THREE DECADES OF LIFE ARE CAUSED BY CAKUT. EVIDENCE SUGGESTS THAT A LARGE NUMBER OF CAKUT ARE GENETIC IN ORIGIN. TO DATE, MUTATIONS IN ~54 GENES HAVE BEEN IDENTIFIED AS MONOGENIC CAUSES OF CAKUT, CONTRIBUTING TO 12-20% OF THE AETIOLOGY OF THE DISEASE. PATHOGENIC COPY NUMBER VARIANTS HAVE ALSO BEEN SHOWN TO CAUSE CAKUT AND CAN BE DETECTED IN 4-11% OF PATIENTS. FURTHERMORE, ENVIRONMENTAL AND EPIGENETIC FACTORS CAN INCREASE THE RISK OF CAKUT. THE DISCOVERY OF NOVEL CAKUT-CAUSING GENES IS CHALLENGING OWING TO VARIABLE EXPRESSIVITY, INCOMPLETE PENETRANCE AND VARIABLE GENOTYPE-PHENOTYPE CORRELATION. HOWEVER, SUCH A DISCOVERY COULD ULTIMATELY LEAD TO IMPROVEMENTS IN THE ACCURATE MOLECULAR GENETIC DIAGNOSIS, ASSESSMENT OF PROGNOSIS AND MULTIDISCIPLINARY CLINICAL MANAGEMENT OF PATIENTS WITH CAKUT, POTENTIALLY INCLUDING PERSONALIZED THERAPEUTIC APPROACHES. 2023 3 1055 31 CLINICAL INTEGRATION OF GENOME DIAGNOSTICS FOR CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT. REVOLUTIONS IN GENETICS, EPIGENETICS, AND BIOINFORMATICS ARE CURRENTLY CHANGING THE OUTLINE OF DIAGNOSTICS AND CLINICAL MEDICINE. FROM A NEPHROLOGIST'S PERSPECTIVE, INDIVIDUALS WITH CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT (CAKUT) ARE AN IMPORTANT PATIENT CATEGORY: NOT ONLY IS CAKUT THE PREDOMINANT CAUSE OF KIDNEY FAILURE IN CHILDREN AND YOUNG ADULTS, BUT THE STRONG PHENOTYPIC AND GENOTYPIC HETEROGENEITY OF KIDNEY AND URINARY TRACT MALFORMATIONS HAS HAMPERED STANDARDIZATION OF CLINICAL DECISION MAKING UNTIL NOW. HOWEVER, PATIENTS WITH CAKUT MAY BENEFIT FROM PRECISION MEDICINE, INCLUDING AN INTEGRATED DIAGNOSTICS TRAJECTORY, GENETIC COUNSELING, AND PERSONALIZED MANAGEMENT TO IMPROVE CLINICAL OUTCOMES OF DEVELOPMENTAL KIDNEY AND URINARY TRACT DEFECTS. IN THIS REVIEW, WE DISCUSS THE PRESENT UNDERSTANDING OF THE MOLECULAR ETIOLOGY OF CAKUT AND THE CURRENTLY AVAILABLE GENOME DIAGNOSTIC MODALITIES IN THE CLINICAL CARE OF PATIENTS WITH CAKUT. FINALLY, WE DISCUSS HOW CLINICAL INTEGRATION OF FINDINGS FROM LARGE-SCALE GENETIC, EPIGENETIC, AND GENE-ENVIRONMENT INTERACTION STUDIES MAY IMPROVE THE PROGNOSIS OF ALL INDIVIDUALS WITH CAKUT. 2020 4 220 29 ACUTE KIDNEY DISEASE: AN OVERVIEW OF THE EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND MANAGEMENT. ACUTE KIDNEY INJURY (AKI) INCREASES THE RISK OF CHRONIC KIDNEY DISEASE (CKD), AND AKI AND CKD ARE SEEN AS INTERCONNECTED SYNDROMES. ACUTE KIDNEY DISEASE (AKD) IS DEFINED AS SUBACUTE DAMAGE AND/OR LOSS OF KIDNEY FUNCTION OCCURRING 7 TO 90 DAYS AFTER AKI, DURING WHICH PERIOD KEY INTERVENTIONS MAY BE INITIATED TO HINDER THE DEVELOPMENT OF CKD. WHILE AKD IS USUALLY UNDER-RECOGNIZED, IT IS ASSOCIATED WITH HIGH MORBIDITY AND MORTALITY GLOBALLY. THIS REVIEW ARTICLE AIMS TO SUMMARIZE THE CURRENT KNOWLEDGE CONCERNING THE EPIDEMIOLOGY, PATHOPHYSIOLOGY, AND MANAGEMENT OF AKD WITH THE AIM TO DEVELOP MONITORING STRATEGIES AND THERAPEUTIC AGENTS OF AKD. GENERALLY, AKD TENDS TO OCCUR MORE FREQUENTLY IN THE ELDERLY AND THOSE WITH CHRONIC DISEASES, SUCH AS HYPERTENSION, DIABETES MELLITUS, AND METABOLIC SYNDROME. IN ADDITION, THE SEVERITY, DURATION, AND FREQUENCY OF AKI ARE INDEPENDENT RISK FACTORS FOR AKD. INVESTIGATIONS OF SEVERAL MECHANISMS OF AKD, SUCH AS RENAL TUBULAR EPITHELIUM CELL-CYCLE ARREST, EPIGENETIC CHANGE, CHRONIC INFLAMMATION, MITOCHONDRIA DYSFUNCTION, FAILED REGENERATION OF TUBULAR CELLS, METABOLIC REPROGRAMMING, AND RENIN-ANGIOTENSIN SYSTEM (RAS) ACTIVATION, HAVE IDENTIFIED ADDITIONAL POTENTIAL PHARMACOTHERAPY TARGETS. MANAGEMENT OF AKD INCLUDES PREVENTION OF REPEATED AKI, EARLY AND REGULAR FOLLOW-UP BY A NEPHROLOGIST, RESUMPTION AND ADJUSTMENT OF ESSENTIAL MEDICATION, OPTIMIZATION OF BLOOD PRESSURE CONTROL AND NUTRITION MANAGEMENT, AND DEVELOPMENT OF NEW PHARMACEUTICAL AGENTS INCLUDING RAS INHIBITORS. FINALLY, WE OUTLINE A CARE BUNDLE FOR AKD PATIENTS BASED ON IMPORTANT LESSONS LEARNED FROM STUDIES AND REGISTRIES AND IDENTIFY THE NEED FOR CLINICAL TRIALS OF RAS INHIBITORS OR OTHER NOVEL AGENTS TO IMPEDE ENSUING CKD DEVELOPMENT. 2023 5 2693 25 EVOLUTION, KIDNEY DEVELOPMENT, AND CHRONIC KIDNEY DISEASE. THERE IS A GLOBAL EPIDEMIC OF CHRONIC KIDNEY DISEASE (CKD) CHARACTERIZED BY A PROGRESSIVE LOSS OF NEPHRONS, ASCRIBED IN LARGE PART TO A RISING INCIDENCE OF HYPERTENSION, METABOLIC SYNDROME, AND TYPE 2 DIABETES MELLITUS. THERE IS A TEN-FOLD VARIATION IN NEPHRON NUMBER AT BIRTH IN THE GENERAL POPULATION, AND A 50% OVERALL DECREASE IN NEPHRON NUMBER IN THE LAST DECADES OF LIFE. THE VICIOUS CYCLE OF NEPHRON LOSS STIMULATING HYPERTROPHY BY REMAINING NEPHRONS AND RESULTING IN GLOMERULOSCLEROSIS HAS BEEN REGARDED AS MALADAPTIVE, AND ONLY PARTIALLY RESPONSIVE TO ANGIOTENSIN INHIBITION. ADVANCES OVER THE PAST CENTURY IN KIDNEY PHYSIOLOGY, GENETICS, AND DEVELOPMENT HAVE ELUCIDATED MANY ASPECTS OF NEPHRON FORMATION, STRUCTURE AND FUNCTION. PARALLEL ADVANCES HAVE BEEN ACHIEVED IN EVOLUTIONARY BIOLOGY, WITH THE EMERGENCE OF EVOLUTIONARY MEDICINE, A DISCIPLINE THAT PROMISES TO PROVIDE NEW INSIGHT INTO THE TREATMENT OF CHRONIC DISEASE. THIS REVIEW PROVIDES A FRAMEWORK FOR UNDERSTANDING THE ORIGINS OF CONTEMPORARY DEVELOPMENTAL NEPHROLOGY, AND RECENT PROGRESS IN EVOLUTIONARY BIOLOGY. THE ESTABLISHMENT OF EVOLUTIONARY DEVELOPMENTAL BIOLOGY (EVO-DEVO), ECOLOGICAL DEVELOPMENTAL BIOLOGY (ECO-DEVO), AND DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE (DOHAD) FOLLOWED THE DISCOVERY OF THE HOX GENE FAMILY, THE RECOGNITION OF THE CONTRIBUTION OF CUMULATIVE ENVIRONMENTAL STRESSORS TO THE CHANGING PHENOTYPE OVER THE LIFE CYCLE, AND MECHANISMS OF EPIGENETIC REGULATION. THE MATURATION OF EVOLUTIONARY MEDICINE HAS CONTRIBUTED TO NEW INVESTIGATIVE APPROACHES TO CARDIOVASCULAR DISEASE, CANCER, AND INFECTIOUS DISEASE, AND PROMISES THE SAME FOR CKD. BY INCORPORATING THESE PRINCIPLES, DEVELOPMENTAL NEPHROLOGY IS IDEALLY POSITIONED TO ANSWER IMPORTANT QUESTIONS REGARDING THE FATE OF NEPHRONS FROM EMBRYO THROUGH SENESCENCE. 2019 6 3802 25 INTERSTITIAL LUNG DISEASE IN CONNECTIVE TISSUE DISEASE: A COMMON LESION WITH HETEROGENEOUS MECHANISMS AND TREATMENT CONSIDERATIONS. CONNECTIVE TISSUE DISEASE (CTD) RELATED INTERSTITIAL LUNG DISEASE (CTD-ILD) IS ONE OF THE LEADING CAUSES OF MORBIDITY AND MORTALITY OF CTD. CLINICALLY, CTD-ILD IS HIGHLY HETEROGENOUS AND INVOLVES RHEUMATIC IMMUNITY AND MULTIPLE MANIFESTATIONS OF RESPIRATORY COMPLICATIONS AFFECTING THE AIRWAYS, VESSELS, LUNG PARENCHYMA, PLEURA, AND RESPIRATORY MUSCLES. THE MAJOR PATHOLOGICAL FEATURES OF CTD ARE CHRONIC INFLAMMATION OF BLOOD VESSELS AND CONNECTIVE TISSUES, WHICH CAN AFFECT ANY ORGAN LEADING TO MULTI-SYSTEM DAMAGE. THE HUMAN LUNG IS PARTICULARLY VULNERABLE TO SUCH DAMAGE BECAUSE ANATOMICALLY IT IS ABUNDANT WITH COLLAGEN AND BLOOD VESSELS. THE COMPLEX ETIOLOGY OF CTD-ILD INCLUDES GENETIC RISKS, EPIGENETIC CHANGES, AND DYSREGULATED IMMUNITY, WHICH INTERACT LEADING TO DISEASE UNDER VARIOUS ILL-DEFINED ENVIRONMENTAL TRIGGERS. CTD-ILD EXHIBITS A BROAD SPECTRA OF CLINICAL MANIFESTATIONS: FROM ASYMPTOMATIC TO SEVERE DYSPNEA; FROM SINGLE-ORGAN RESPIRATORY SYSTEM INVOLVEMENT TO MULTI-ORGAN INVOLVEMENT. THE DISEASE COURSE IS ALSO FEATURED BY REMISSIONS AND RELAPSES. IT CAN RANGE FROM STABILITY OR SLOW PROGRESSION OVER SEVERAL YEARS TO RAPID DETERIORATION. IT CAN ALSO PRESENT CLINICALLY AS HIGHLY PROGRESSIVE FROM THE INITIAL ONSET OF DISEASE. CURRENTLY, THE DIAGNOSIS OF CTD-ILD IS PRIMARILY BASED ON DISTINCT PATHOLOGY SUBTYPE(S), IMAGING, AS WELL AS RELATED CTD AND AUTOANTIBODIES PROFILES. METICULOUS COMPREHENSIVE CLINICAL AND LABORATORY ASSESSMENT TO IMPROVE THE DIAGNOSTIC PROCESS AND MANAGEMENT STRATEGIES ARE MUCH NEEDED. IN THIS REVIEW, WE FOCUS ON EXAMINING THE PATHOGENESIS OF CTD-ILD WITH RESPECT TO GENETICS, ENVIRONMENTAL FACTORS, AND IMMUNOLOGICAL FACTORS. WE ALSO DISCUSS THE CURRENT STATE OF KNOWLEDGE AND ELABORATE ON THE CLINICAL CHARACTERISTICS OF CTD-ILD, DISTINCT PATHOHISTOLOGICAL SUBTYPES, IMAGING FEATURES, AND RELATED AUTOANTIBODIES. FURTHERMORE, WE COMMENT ON THE IDENTIFICATION OF HIGH-RISK PATIENTS AND ADDRESS HOW TO STRATIFY PATIENTS FOR PRECISION MEDICINE MANAGEMENT APPROACHES. 2021 7 6422 22 THE THIN-FAT PHENOTYPE AND GLOBAL METABOLIC DISEASE RISK. PURPOSE OF REVIEW: THERE HAS BEEN A GREAT DEAL OF INTEREST IN THE THIN-FAT PHENOTYPE EVIDENT IN ASIAN INDIANS AND ITS RISK ASSOCIATIONS IN THE EPIDEMIC OF NONCOMMUNICABLE CHRONIC DISEASE ASSOCIATED WITH IT. THE CAUSE OF THIS PHENOTYPE IS PROBABLY RELATED TO LIFESTYLE AND ENVIRONMENT; HOWEVER, GENOTYPIC AND EPIGENETIC MODIFICATIONS IN UTERO ALSO HAVE BEEN CONSIDERED. RECENT FINDINGS: THE THIN-FAT PHENOTYPE OCCURS WHEN FAT IS ADDED TO AN ALREADY THIN FRAME. THIS MAY OCCUR WITH RURAL-URBAN MIGRATION, WHEN POSITIVE ENERGY BALANCE OCCURS IN A MIGRATING POPULATION WHO WERE PREDOMINANTLY THIN AND PHYSICALLY ACTIVE TO BEGIN WITH. THE ROLE OF THE PRE-EXISTING SKELETAL MUSCLE MASS AND ITS INTERACTION WITH NEWLY DEPOSITED FAT MUST BE CONSIDERED. THE THIN-FAT PHENOTYPE MAY BE PROGRAMMED DURING FETAL GROWTH, BUT THE EVIDENCE FOR THIS PHENOMENON IS STILL NOT COMPLETELY CLEAR. FINALLY, ALTHOUGH THERE IS INCREASED CHRONIC DISEASE MORBIDITY AT LOWER BMI AND YOUNGER AGE IN SOUTH ASIAN POPULATIONS, BMI-RELATED MORTALITY DOES NOT APPEAR TO FOLLOW THIS TREND. SUMMARY: AT PRESENT, THE WEIGHT OF EVIDENCE APPEARS TO LINK THE THIN-FAT PHENOTYPE TO AN ENVIRONMENTAL AND LIFESTYLE PHENOMENON OCCURRING IN PREVIOUSLY THIN PEOPLE. THIS IS PARTICULARLY RELEVANT IN INDIA, GIVEN THE PACE OF TRANSITION OVER THE LAST TWO DECADES. 2011 8 4399 16 MODULATION OF GENOMIC AND POSTGENOMIC ALTERATIONS IN NONCANCER DISEASES AND CRITICAL PERIODS OF LIFE. GENOMIC AND POSTGENOMIC CHANGES ARE EXTENSIVELY INVESTIGATED IN CANCER RESEARCH. SIMILAR ALTERATIONS, AFFECTING GENOME, TRANSCRIPTOME, MIRNOME AND/OR PROTEOME END-POINTS, HAVE BEEN DETECTED IN A VARIETY OF OTHER CHRONIC DEGENERATIVE DISEASES, SUCH AS ATHEROSCLEROSIS, DEGENERATIVE HEART DISEASES, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEUROLOGICAL DISORDERS, EYE DISEASES, DIABETES, METABOLIC SYNDROME, SKIN AGEING AND ALOPECIA. NO GENERALIZATION CAN BE MADE DUE TO THE MYRIAD OF DIVERSE CLINICAL ENTITIES CLASSIFIED AS CHRONIC DEGENERATIVE DISEASES. MOREOVER, THE DETECTION OF MOLECULAR CHANGES DOES NOT AUTOMATICALLY IMPLY THEIR CAUSAL ROLE. NEVERTHELESS, COMMON MECHANISMS, SUCH AS DNA DAMAGE, EPIGENETIC ALTERATIONS, OXIDATIVE STRESS, AND CHRONIC INFLAMMATION, IN ADDITION TO GENETIC PREDISPOSITION, ARE OFTEN INVOLVED IN NONCANCER DISEASES. WE DEBATE HERE IN MORE DETAIL THE SUBJECTS OF CARDIOVASCULAR DISEASES AND OF SKIN DISEASES. MOREOVER, WE DISCUSS OUR EXPERIMENTAL STUDIES SUGGESTING THAT GENOMIC AND POSTGENOMIC CHANGES DO ALSO OCCUR DURING CRITICAL PERIODS OF LIFE, INCLUDING THE PRENATAL LIFE, THE PERINATAL PERIOD, AND AGEING. IN ADDITION, WE COMMENT ON THE FINDING THAT STEM-DERIVED CELLS ARE MORE SUSCEPTIBLE TO MOLECULAR DAMAGE THAN MORE DIFFERENTIATED CELLS. ALL THESE DATA ARE VIEWED IN THE PERSPECTIVE OF PREVENTIVE MEDICINE. IN FACT, THERE IS EVIDENCE THAT THE GENOMIC AND POSTGENOMIC ALTERATIONS OCCURRING NOT ONLY IN SEVERAL PATHOLOGICAL CONDITIONS BUT ALSO IN PARAPHYSIOLOGICAL SITUATIONS THAT AFFECT CRITICAL PERIODS OF LIFE CAN BE MODULATED BY MEANS OF DIETARY AND PHARMACOLOGICAL AGENTS. THE DISCOVERY THAT CHEMOPREVENTIVE AGENTS ARE ALSO ABLE TO ATTENUATE NUCLEOTIDE DAMAGE IN STEM-DERIVED CELLS WARRANTS FURTHER STUDIES IN VIEW OF POSSIBLE CLINICAL APPLICATIONS. 2009 9 4559 25 MUTATIONS OF THE TRANSCRIPTIONAL COREPRESSOR ZMYM2 CAUSE SYNDROMIC URINARY TRACT MALFORMATIONS. CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT (CAKUT) CONSTITUTE ONE OF THE MOST FREQUENT BIRTH DEFECTS AND REPRESENT THE MOST COMMON CAUSE OF CHRONIC KIDNEY DISEASE IN THE FIRST THREE DECADES OF LIFE. DESPITE THE DISCOVERY OF DOZENS OF MONOGENIC CAUSES OF CAKUT, MOST PATHOGENIC PATHWAYS REMAIN ELUSIVE. WE PERFORMED WHOLE-EXOME SEQUENCING (WES) IN 551 INDIVIDUALS WITH CAKUT AND IDENTIFIED A HETEROZYGOUS DE NOVO STOP-GAIN VARIANT IN ZMYM2 IN TWO DIFFERENT FAMILIES WITH CAKUT. THROUGH COLLABORATION, WE IDENTIFIED IN TOTAL 14 DIFFERENT HETEROZYGOUS LOSS-OF-FUNCTION MUTATIONS IN ZMYM2 IN 15 UNRELATED FAMILIES. MOST MUTATIONS OCCURRED DE NOVO, INDICATING POSSIBLE INTERFERENCE WITH REPRODUCTIVE FUNCTION. HUMAN DISEASE FEATURES ARE REPLICATED IN X. TROPICALIS LARVAE WITH MORPHOLINO KNOCKDOWNS, IN WHICH EXPRESSION OF TRUNCATED ZMYM2 PROTEINS, BASED ON INDIVIDUAL MUTATIONS, FAILED TO RESCUE RENAL AND CRANIOFACIAL DEFECTS. MOREOVER, HETEROZYGOUS ZMYM2-DEFICIENT MICE RECAPITULATED FEATURES OF CAKUT WITH HIGH PENETRANCE. THE ZMYM2 PROTEIN IS A COMPONENT OF A TRANSCRIPTIONAL COREPRESSOR COMPLEX RECENTLY LINKED TO THE SILENCING OF DEVELOPMENTALLY REGULATED ENDOGENOUS RETROVIRUS ELEMENTS. USING PROTEIN-PROTEIN INTERACTION ASSAYS, WE SHOW THAT ZMYM2 INTERACTS WITH ADDITIONAL EPIGENETIC SILENCING COMPLEXES, AS WELL AS CONFIRMING THAT IT BINDS TO FOXP1, A TRANSCRIPTION FACTOR THAT HAS ALSO BEEN LINKED TO CAKUT. IN SUMMARY, OUR FINDINGS ESTABLISH THAT LOSS-OF-FUNCTION MUTATIONS OF ZMYM2, AND POTENTIALLY THAT OF OTHER PROTEINS IN ITS INTERACTOME, AS CAUSES OF HUMAN CAKUT, OFFERING NEW ROUTES FOR STUDYING THE PATHOGENESIS OF THE DISORDER. 2020 10 4329 28 MICRORNAS: A NEW AVENUE TO UNDERSTAND, INVESTIGATE AND TREAT IMMUNOGLOBULIN A NEPHROPATHY? IGA NEPHROPATHY (IGAN) IS THE MOST COMMON CAUSE OF PRIMARY GLOMERULONEPHRITIS WORLDWIDE. UP TO 30% OF CASES DEVELOP THE PROGRESSIVE FORM OF THE DISEASE, EVENTUALLY REQUIRING RENAL REPLACEMENT THERAPY. DIAGNOSIS AND RISK STRATIFICATION RELIES ON AN INVASIVE KIDNEY BIOPSY AND MANAGEMENT OPTIONS ARE LIMITED, WITH RECURRENCE FOLLOWING RENAL TRANSPLANTATION BEING COMMON. THUS THE QUEST TO UNDERSTAND THE PATHOPHYSIOLOGY OF IGAN HAS BEEN ONE OF GREAT IMPORTANCE. MICRORNAS (MIRS) ARE SHORT NUCLEOTIDES THAT SUPPRESS GENE EXPRESSION BY HYBRIDIZING TO THE 3' UNTRANSLATED REGION OF MESSENGER RNA (MRNAS), PROMOTING MRNA DEGRADATION OR DISRUPTING TRANSLATION. FIRST DISCOVERED IN 1993, MIRS HAVE SINCE BEEN IMPLICATED IN A NUMBER OF CHRONIC CONDITIONS, INCLUDING CANCER, HEART DISEASE AND KIDNEY DISEASE. THE MOUNTING INTEREST IN THE FIELD OF MIRS HAS LED TO FASCINATING DEVELOPMENTS IN THE FIELD OF NEPHROLOGY, RANGING FROM THEIR ROLES AS BIOMARKERS FOR DISEASE TO THE DEVELOPMENT OF MIR ANTAGONISTS AS AVENUES FOR TREATMENT. THE TRANSLATIONAL POTENTIAL FOR MIRS IN IGAN IS THUS WELL GROUNDED AND MAY REPRESENT A PARADIGM SHIFT IN CURRENT APPROACHES TO THE DISEASE. THIS REVIEW AIMS TO SUMMARIZE THE LITERATURE WITH REGARD TO MIRS AND THEIR ROLES IN IGAN. 2018 11 705 18 BUILDING RISK-ON-A-CHIP MODELS TO IMPROVE BREAST CANCER RISK ASSESSMENT AND PREVENTION. PREVENTIVE ACTIONS FOR CHRONIC DISEASES HOLD THE PROMISE OF IMPROVING LIVES AND REDUCING HEALTHCARE COSTS. FOR SEVERAL DISEASES, INCLUDING BREAST CANCER, MULTIPLE RISK AND PROTECTIVE FACTORS HAVE BEEN IDENTIFIED BY EPIDEMIOLOGISTS. THE IMPACT OF MOST OF THESE FACTORS HAS YET TO BE FULLY UNDERSTOOD AT THE ORGANISM, TISSUE, CELLULAR AND MOLECULAR LEVELS. IMPORTANTLY, COMBINATIONS OF EXTERNAL AND INTERNAL RISK AND PROTECTIVE FACTORS INVOLVE COOPERATIVITY THUS, SYNERGIZING OR ANTAGONIZING DISEASE ONSET. MODELS ARE NEEDED TO MECHANISTICALLY DECIPHER CANCER RISKS UNDER DEFINED CELLULAR AND MICROENVIRONMENTAL CONDITIONS. HERE, WE BRIEFLY REVIEW BREAST CANCER RISK MODELS BASED ON 3D CELL CULTURE AND PROPOSE TO IMPROVE RISK MODELING WITH LAB-ON-A-CHIP APPROACHES. WE SUGGEST EPITHELIAL TISSUE POLARITY, DNA REPAIR AND EPIGENETIC PROFILES AS ENDPOINTS IN RISK ASSESSMENT MODELS AND DISCUSS THE DEVELOPMENT OF 'RISKS-ON-CHIPS' INTEGRATING BIOSENSORS OF THESE ENDPOINTS AND OF GENERAL TISSUE HOMEOSTASIS. RISKS-ON-CHIPS WILL HELP IDENTIFY BIOMARKERS OF RISK, SERVE AS SCREENING PLATFORMS FOR CANCER PREVENTIVE AGENTS, AND PROVIDE A BETTER UNDERSTANDING OF RISK MECHANISMS, HENCE RESULTING IN NOVEL DEVELOPMENTS IN DISEASE PREVENTION. 2013 12 2136 23 EPIGENETIC INFLUENCES IN THE OBESITY/COLORECTAL CANCER AXIS: A NOVEL THERAGNOSTIC AVENUE. THE WORLD HEALTH ORGANIZATION (WHO) CONSIDERS THAT OBESITY HAS REACHED PROPORTIONS OF PANDEMIC. EXPERTS ALSO INSIST ON THE IMPORTANCE OF CONSIDERING OBESITY AS A CHRONIC DISEASE AND ONE OF THE MAIN CONTRIBUTORS TO THE WORLDWIDE BURDEN OF OTHER NONTRANSMISSIBLE CHRONIC DISEASES, WHICH HAVE A GREAT IMPACT ON HEALTH, LIFESTYLE, AND ECONOMIC COST. ONE OF THE MOST CURRENT CHALLENGES OF BIOMEDICAL SCIENCE FACES IS TO UNDERSTAND THE ORIGIN OF THE CHRONIC NONTRANSMISSIBLE DISEASES, SUCH AS OBESITY AND CANCER. THERE IS A LARGE EVIDENCE, BOTH IN EPIDEMIOLOGICAL STUDIES IN HUMANS AND IN ANIMAL MODELS, OF THE ASSOCIATION BETWEEN OBESITY AND AN INCREASED RISK OF CANCER INCIDENCE. IN THE LAST YEARS, THE INITIAL DISCOVERY OF EPIGENETIC MECHANISMS REPRESENTS THE MOST RELEVANT FINDING TO EXPLAIN HOW THE GENOME INTERACTS WITH ENVIRONMENTAL FACTORS AND THE RIPPLE EFFECTS ON DISEASE PATHOGENESES. SINCE THEN, ALL EPIGENETIC PROCESS HAS BEEN INVESTIGATED BY THE SCIENTIFIC COMMUNITIES FOR NEARLY TWO DECADES TO DETERMINE WHICH COMPONENTS ARE INVOLVED IN THIS PROCESS. DNA/RNA METHYLATION AND MIRNA ARE CLASSIFIED AS TWO OF THE MOST IMPORTANT REPRESENTATIVE CLASSES OF SUCH EPIGENETIC MECHANISMS AND DYSREGULATED ACTIVITY OF SUCH MECHANISM CAN CERTAINLY CONTRIBUTE TO DISEASE PATHOGENESIS AND/OR PROGRESSION ESPECIALLY IN TUMORS. THIS REVIEW ARTICLE SERVES TO HIGHLIGHT THE IMPACT OF DNA/RNA METHYLATION AND MIRNA-BASED EPIGENETIC MECHANISM ACTIVITIES IN THE INTERPLAY BETWEEN OBESITY AND THE DEVELOPMENT AND CLINICAL SIGNIFICANCE OF COLORECTAL CANCER. 2019 13 6821 22 [GASTROINTESTINAL MANIFESTATIONS IN IMMUNODEFICIENCIES WITH MONOGENIC ORIGIN]. ALTHOUGH VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE THAT DEVELOPS IN EARLY CHILDHOOD (BEFORE THE AGE OF 6 YEARS) HAS A DIFFERENT ETIOLOGY FROM CROHN'S DISEASE AND ULCERATIVE COLITIS, IT IS ALSO CHARACTERIZED BY CHRONIC INFLAMMATION OF THE GASTROINTESTINAL TRACT. BASICALLY, VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE SHOULD BE CONSIDERED AS AN IMMUNODEFICIENCY WITH MONOGENIC ORIGIN WHERE BOTH GASTROINTESTINAL MANIFESTATIONS AND SYMPTOMS OF IMMUNODEFICIENCIES MAY DEVELOP IN VARIABLE COMBINATIONS. HOWEVER, IN THE FUTURE, THE EVALUATION OF GENETIC ALTERATIONS IN THE BACKGROUND OF THE DISEASE WILL PROBABLY BE PERFORMED BY NEXT-GENERATION SEQUENCING TECHNOLOGY; ONE SHOULD ALSO CONSIDER THAT THE SEQUENCE OF THE DNA STANDS IN CONTINUOUS INTERACTION WITH A WIDE VARIETY OF ENVIRONMENTAL EFFECTS, AMONG WHICH NUTRITION SHOULD BE EMPHASIZED BY ALL MEANS. EPIGENETIC ALTERATIONS THAT ARE INDUCED BY ENVIRONMENTAL FACTORS, COULD CONTRIBUTE TO THE PATHOGENESIS OF INFLAMMATORY BOWEL DISEASES THAT DEVELOP DURING CHILDHOOD, THEREFORE, THEY SHOULD ALSO BE IDENTIFIED DURING FURTHER RESEARCH. IT HAS A KEY SIGNIFICANCE TO ESTABLISH THE DIAGNOSIS OF VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE AS EARLY AS POSSIBLE, BECAUSE THIS COULD GIVE THE OPPORTUNITY TO START THE ADEQUATE TREATMENT WHICH IS BONE MARROW TRANSPLANTATION IN THE CASE OF MONOGENIC IMMUNODEFICIENCIES. ORV HETIL. 2018; 159(49): 2050-2056. 2018 14 4719 25 NONCODING RNA AND EPIGENETIC GENE REGULATION IN RENAL DISEASES. KIDNEYS HAVE A MAJOR ROLE IN NORMAL PHYSIOLOGY AND METABOLIC HOMEOSTASIS. LOSS OR IMPAIRMENT OF KIDNEY FUNCTION IS A COMMON OCCURRENCE IN SEVERAL METABOLIC DISORDERS, INCLUDING HYPERTENSION AND DIABETES. CHRONIC KIDNEY DISEASE (CKD) AFFECT NEARLY 10% OF THE POPULATION WORLDWIDE; RANKS 18TH IN THE LIST OF CAUSES OF DEATH; AND CONTRIBUTES TO A SIGNIFICANT PROPORTION OF HEALTHCARE COSTS. THE TISSUE REPAIR AND REGENERATIVE POTENTIAL OF KIDNEYS ARE LIMITED AND THEY DECLINE DURING AGING. RECENT STUDIES HAVE DEMONSTRATED A KEY ROLE FOR EPIGENETIC PROCESSES AND PLAYERS, SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, NONCODING (NC)RNA, AND SO ON, IN BOTH KIDNEY DEVELOPMENT AND DISEASE. IN THIS REVIEW, WE HIGHLIGHT THESE RECENT FINDINGS WITH AN EMPHASIS ON ABERRANT EPIGENETIC CHANGES THAT ACCOMPANY RENAL DISEASES, KEY TARGETS, AND THEIR THERAPEUTIC VALUE. 2017 15 49 21 A CURRENT GENETIC AND EPIGENETIC VIEW ON HUMAN AGING MECHANISMS. THE PROCESS OF AGING IS ONE OF THE MOST COMPLEX AND INTRIGUING BIOLOGICAL PHENOMENONS. AGING IS A GENETICALLY REGULATED PROCESS IN WHICH THE ORGANISM'S MAXIMUM LIFESPAN POTENTIAL IS PRE-DETERMINED, WHILE THE RATE OF AGING IS INFLUENCED BY ENVIRONMENTAL FACTORS AND LIFESTYLE. CONSIDERING THE COMPLEXITY OF MECHANISMS INVOLVED IN THE REGULATION OF AGING PROCESS, UP TO THIS DATE THERE ISN'T A MAJOR, UNIFYING THEORY WHICH COULD EXPLAIN THEM. AS GENETIC/EPIGENETIC AND ENVIRONMENTAL FACTORS BOTH INEVITABLY INFLUENCE THE AGING PROCESS, HERE WE PRESENT A REVIEW ON THE GENETIC AND EPIGENETIC REGULATION OF THE MOST IMPORTANT MOLECULAR AND CELLULAR MECHANISMS INVOLVED IN THE PROCESS OF AGING. BASED ON THE STUDIES ON OXIDATIVE STRESS, METABOLISM, GENOME STABILITY, EPIGENETIC MODIFICATIONS AND CELLULAR SENESCENCE IN ANIMAL MODELS AND HUMANS, WE GIVE AN OVERVIEW OF KEY GENETIC AND MOLECULAR PATHWAYS RELATED TO AGING. AS MOST OF GENETIC MANIPULATIONS WHICH INFLUENCE THE AGING PROCESS ALSO AFFECT REPRODUCTION, WE DISCUSS AGING IN HUMANS AS A POST-REPRODUCTIVE GENETICALLY DETERMINED PROCESS. AFTER THE AGE OF REPRODUCTIVE SUCCESS, AGING CONTINOUSLY PROGRESSES WHICH CLINICALLY COINCIDES WITH THE ONSET OF MOST CHRONIC DISEASES, CANCERS AND DEMENTIONS. AS EVOLUTION SHAPES THE GENOMES FOR REPRODUCTIVE SUCCESS AND NOT FOR POST-REPRODUCTIVE SURVIVAL, AGING COULD BE DEFINED AS A PROTECTIVE MECHANISM WHICH ENSURES THE PRESERVATION AND PROGRESS OF SPECIES THROUGH THE MODIFICATION, TRASMISSION AND IMPROVEMENT OF GENETIC MATERIAL. 2009 16 6825 20 [GENETIC AND EPIGENETIC FACTORS OF POLYCYSTIC OVARY SYNDROME]. THE DEVELOPMENT OF POLYCYSTIC OVARY SYNDROME AND ITS EXACT PATHOPHYSIOLOGICAL MECHANISM IS STILL UNCLEAR, BUT ENVIRONMENTAL AND GENETIC FACTORS LIKELY PLAY A ROLE. EXPOSITION TO TERATOGENIC EFFECTS DURING THE PRENATAL DEVELOPMENT CAN LEAD TO CHRONIC DISEASES IN THE POSTNATAL PERIOD. THIS FINDING CONFIRMS THE COMMON FAMILIAL AGGREGATION AS WELL. A LITERATURE SEARCH WAS CONDUCTED UP TO JANUARY 1, 2016 FOR ARTICLES DEALING WITH THE GENETIC OR EPIGENETIC FACTORS OF POLYCYSTIC OVARY SYNDROME. THIS REVIEW WILL DISCUSS THE CURRENT UNDERSTANDING OF THE GENETIC BASIS AND CLINICAL PRESENTATION OF THIS DISEASE. ORV. HETIL., 2016, 157(32), 1275-1281. 2016 17 4456 22 MOLECULAR MECHANISMS IN RENAL DEGENERATIVE DISEASE. CHRONIC KIDNEY DISEASE (CKD) HAS BECOME A MAJOR PUBLIC HEALTH PROBLEM WORLDWIDE. THEREFORE, A CONSIDERABLE EFFORT IS CURRENTLY DIRECTED TO UNDERSTAND THE MOLECULAR MECHANISMS OF RENAL DEGENERATIVE PROCESSES. REGARDLESS OF THEIR INITIATING CAUSE, ALL CHRONIC KIDNEY DISEASES (CKD) DEVELOP AT SOME LEVEL ORGAN FIBROSIS THAT INTERFERES WITH KIDNEY FUNCTION. THIS IS ALSO TRUE FOR THE TWO MOST COMMON INHERITED CKD SYNDROMES, NEPHRONOPHTHITIS AND POLYCYSTIC KIDNEY DISEASE, WHOSE PRIMARY DEFECTS RESIDE WITHIN THE CILIUM OF KIDNEY EPITHELIAL CELLS. A COHORT OF ELEGANT RECENT STUDIES HAS ELICITED THE ROLE OF THE PRIMARY CILIUM AS A VERSATILE MECHANOSENSORY ORGANELLE THAT ALSO MIGHT COORDINATE CROSS-TALK BETWEEN MULTIPLE SIGNALING PATHWAYS. IN ADDITION, EPIGENETIC MECHANISMS ARE NOW REALIZED TO BE ESSENTIAL IN THE MAINTENANCE OF ADULT RENAL ARCHITECTURE. IN THIS REVIEW, WE WILL DISCUSS RECENT ADVANCES IN OUR UNDERSTANDING OF THE SIGNALING SYSTEMS IMPLICATED IN KIDNEY HOMEOSTASIS AND REPAIR. 2010 18 931 26 CHRONIC KIDNEY DISEASE IN CHILDREN AND THE ROLE OF EPIGENETICS: FUTURE THERAPEUTIC TRAJECTORIES. GLOBAL DIFFERENCES IN THE OBSERVED CAUSES OF CHRONIC KIDNEY DISEASE (CKD) IN CHILDREN ARE WELL DOCUMENTED AND ARE ATTRIBUTED TO DISSIMILARITIES IN CLIME, RACE, HEREDITARY, AND ANCESTRY. THUS, FAMILIAL CLUSTERING AND DISPARITIES IN CKD PREVALENCE RATES ACROSS ETHNIC AND RACIAL GROUPS INDICATE THAT THE PROGRESSION OF RENAL DISEASE HAS A STRONG GENETIC COMPONENT. MAMMALIAN STUDIES HAVE DEMONSTRATED A FEASIBLE NEXUS BETWEEN NUTRITION AND NON-GENETIC EXPOSURE (AROUND THE TIME OF CONCEPTION AND IN EPIGENETIC CHANGES) IN THE EXPRESSION OF MAJOR GENES IDENTIFIED IN RENAL ORGANOGENESIS. THE MAJOR CONSEQUENCE IS A REDUCTION IN THE NUMBER OF NEPHRONS, WITH SUBSEQUENT PREDISPOSITION TO HYPERTENSION AND CKD. IDENTIFYING THESE EPIGENETIC CHANGES IS CRUCIAL (DUE TO THEIR POTENTIALLY REVERSIBLE NATURE), AS THEY MAY SERVE AS FUTURE THERAPEUTIC TARGETS TO PREVENT KIDNEY FIBROSIS AND CKD. DESPITE PROGRESS IN THE FIELD OF EPIGENETICS IN ONCOLOGY, RESEARCH IN OTHER SUBSPECIALTIES OF MEDICINE IS LARGELY EXPERIMENTAL WITH FEW EXISTING STUDIES REGARDING THE CLINICAL IMPLICATION OF EPIGENETICS IN RENAL DISEASE. THERAPEUTIC TRAJECTORIES FOR CKD IN CHILDREN BASED ON THE INFLUENCE OF EPIGENETICS MAY EVENTUALLY REVOLUTIONIZE THE MANAGEMENT OF THIS DISEASE. THE AIM OF THE CURRENT NARRATIVE REVIEW IS TO APPRAISE THE ROLE OF EPIGENETICS IN CKD, AND HIGHLIGHT THE POTENTIAL FUTURE THERAPEUTIC PATHWAYS. 2016 19 6628 22 UNDERSTANDING THE GENETICS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE, ALPHA1-ANTITRYPSIN DEFICIENCY, AND IMPLICATIONS FOR CLINICAL PRACTICE. CIGARETTE SMOKING AND POOR AIR QUALITY ARE THE GREATEST RISK FACTORS FOR DEVELOPING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BUT GROWING EVIDENCE INDICATES THAT GENETIC FACTORS ALSO AFFECT PREDISPOSITION TO AND CLINICAL EXPRESSION OF DISEASE. WITH THE EXCEPTION OF ALPHA1-ANTITRYPSIN DEFICIENCY (AATD), A RARE AUTOSOMAL RECESSIVE DISORDER THAT IS PRESENT IN 1-3% OF INDIVIDUALS WITH COPD, NO SINGLE GENE IS ASSOCIATED WITH THE DEVELOPMENT OF OBSTRUCTIVE LUNG DISEASE. INSTEAD, A COMPLEX INTERPLAY OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS IS THE BASIS FOR PERSISTENT INFLAMMATORY RESPONSES, ACCELERATED CELL AGING, CELL DEATH, AND FIBROSIS, LEADING TO THE CLINICAL SYMPTOMS OF COPD AND DIFFERENT PHENOTYPIC PRESENTATIONS. IN THIS BRIEF REVIEW, WE DISCUSS CURRENT UNDERSTANDING OF THE GENETICS OF COPD, PATHOGENETICS OF AATD, EPIGENETIC INFLUENCES ON THE DEVELOPMENT OF OBSTRUCTIVE LUNG DISEASE, AND HOW CLASSIFYING COPD BY PHENOTYPE CAN INFLUENCE CLINICAL TREATMENT AND PATIENT OUTCOMES. 2021 20 4198 19 METABOLIC PROFILING DISTINGUISHES THREE SUBTYPES OF ALZHEIMER'S DISEASE. THE CAUSE OF ALZHEIMER'S DISEASE IS INCOMPLETELY DEFINED, AND NO TRULY EFFECTIVE THERAPY EXISTS. HOWEVER, MULTIPLE STUDIES HAVE IMPLICATED METABOLIC ABNORMALITIES SUCH AS INSULIN RESISTANCE, HORMONAL DEFICIENCIES, AND HYPERHOMOCYSTEINEMIA. OPTIMIZING METABOLIC PARAMETERS IN A COMPREHENSIVE WAY HAS YIELDED COGNITIVE IMPROVEMENT, BOTH IN SYMPTOMATIC AND ASYMPTOMATIC INDIVIDUALS. THEREFORE, EXPANDING THE STANDARD LABORATORY EVALUATION IN PATIENTS WITH DEMENTIA MAY BE REVEALING. HERE I REPORT THAT METABOLIC PROFILING REVEALS THREE ALZHEIMER'S DISEASE SUBTYPES. THE FIRST IS INFLAMMATORY, IN WHICH MARKERS SUCH AS HS-CRP AND GLOBULIN:ALBUMIN RATIO ARE INCREASED. THE SECOND TYPE IS NON-INFLAMMATORY, IN WHICH THESE MARKERS ARE NOT INCREASED, BUT OTHER METABOLIC ABNORMALITIES ARE PRESENT. THE THIRD TYPE IS A VERY DISTINCTIVE CLINICAL ENTITY THAT AFFECTS RELATIVELY YOUNG INDIVIDUALS, EXTENDS BEYOND THE TYPICAL ALZHEIMER'S DISEASE INITIAL DISTRIBUTION TO AFFECT THE CORTEX WIDELY, IS CHARACTERIZED BY EARLY NON-AMNESTIC FEATURES SUCH AS DYSCALCULIA AND APHASIA, IS OFTEN MISDIAGNOSED OR LABELED ATYPICAL ALZHEIMER'S DISEASE, TYPICALLY AFFECTS APOE4-NEGATIVE INDIVIDUALS, AND IS ASSOCIATED WITH STRIKING ZINC DEFICIENCY. GIVEN THE INVOLVEMENT OF ZINC IN MULTIPLE ALZHEIMER'S-RELATED METABOLIC PROCESSES, SUCH AS INSULIN RESISTANCE, CHRONIC INFLAMMATION, ADAM10 PROTEOLYTIC ACTIVITY, AND HORMONAL SIGNALING, THIS SYNDROME OF ALZHEIMER'S-PLUS WITH LOW ZINC (APLZ) WARRANTS FURTHER METABOLIC, GENETIC, AND EPIGENETIC CHARACTERIZATION. 2015