1 3870 135 JUNCTIONAL ZONE ENDOMETRIUM ALTERATIONS IN GYNECOLOGICAL AND OBSTETRICAL DISORDERS AND IMPACT ON DIAGNOSIS, PROGNOSIS AND TREATMENT. PURPOSE OF REVIEW: TO INVESTIGATE THE JZE ALTERATIONS IN GYNECOLOGICAL AND OBSTETRICAL DISORDERS AND IMPACT ON DIAGNOSIS, PROGNOSIS AND TREATMENT. RECENT FINDINGS: JZE WAS FOUND TO BE SIGNIFICANTLY EXTENDED IN PATIENTS WITH ENDOMETRIOSIS, LEADING TO THE CONCLUSION THAT ENDOMETRIOSIS IS A PRIMARY DISEASE OF THE UTERUS, MUCH LIKE ADENOMYOSIS. STATISTICAL CORRELATION WAS THEN DEMONSTRATED BETWEEN THE SEVERITY OF ENDOMETRIOSIS AND THE DEPTH OF THE ADENOMYOSIS INFILTRATES, HENCE THE THICKENING OF THE JZE. STEM CELLS, PREDOMINANTLY FOUND IN THE JZE WERE ALSO FOUND IN HISTOLOGICAL SECTIONS OF LEIOMYOMA, SUGGESTED TO BE THE ORIGIN OF LEIOMYOMA. THIS RESERVOIR OF JZE STEM CELLS IS INFLUENCED BY DIFFERENT STRESSORS LEADING TO THEIR DIFFERENTIATION INTO LEIOMYOMA, ENDOMETRIOSIS, ADENOMYOSIS OR ENDOMETRIAL CANCER, ACCORDING TO THE STRESSOR. THE VARIABILITY IN PRESENTATION WAS HYPOTHESIZED TO BE CONNECTED TO GENETIC AND EPIGENETIC FACTORS. JZE WAS ALSO SUGGESTED TO ACT AS A BARRIER, STOPPING ENDOMETRIAL CARCINOMA CELLS INVASION AND METASTASIS. IN ADDITION, JZE PLAYS A MAJOR ROLE IN CONCEPTION, PREGNANCY AND POSTPARTUM. SUMMARY: JZE IS AN IMPORTANT ANATOMICAL LANDMARK OF THE UTERUS CONTRIBUTING TO NORMAL UTERINE FUNCTION UNDER THE INFLUENCE OF OVARIAN HORMONES. ALTERATIONS OF THE JZE THICKNESS AND CONTRACTILITY CAN BE USED AS PATHOGNOMONIC CLINICAL MARKERS IN INFERTILITY AND CHRONIC PELVIC PAIN, FOR SUBENDOMETRIAL AND MYOMETRIAL DISORDERS, FOR EXAMPLE, ADENOMYOSIS AND FIBROIDS. PROSPECTIVE RANDOMIZED CONTROL TRIALS WILL CLARIFY THE DIAGNOSTIC STEPS, IMAGING MODALITIES TO FOLLOW AND PROBABLY TRIAGE THE PATIENTS BETWEEN MEDICAL AND SURGICAL TREATMENTS. 2019 2 752 34 CARDIOMETABOLIC RISK FACTORS AND BENIGN GYNECOLOGIC DISORDERS. IMPORTANCE: WHILE IT HAS LONG BEEN KNOWN THAT POLYCYSTIC OVARIAN SYNDROME IS ASSOCIATED WITH CARDIOMETABOLIC RISK FACTORS (CMRFS), THERE IS EMERGING EVIDENCE THAT OTHER BENIGN GYNECOLOGIC CONDITIONS, SUCH AS UTERINE LEIOMYOMAS, ENDOMETRIOSIS, AND EVEN HYSTERECTOMY WITHOUT OOPHORECTOMY, CAN BE ASSOCIATED WITH CMRFS. UNDERSTANDING THE EVIDENCE AND MECHANISMS OF THESE ASSOCIATIONS CAN LEAD TO NOVEL PREVENTIVE AND THERAPEUTIC INTERVENTIONS. OBJECTIVE: THIS ARTICLE DISCUSSES THE EVIDENCE AND THE POTENTIAL MECHANISMS MEDIATING THE ASSOCIATION BETWEEN CMRFS AND BENIGN GYNECOLOGIC DISORDERS. EVIDENCE ACQUISITION: WE REVIEWED PUBMED, EMBASE, SCOPUS, AND GOOGLE SCHOLAR DATABASES TO OBTAIN PLAUSIBLE CLINICAL AND BIOLOGICAL EVIDENCE, INCLUDING HORMONAL, IMMUNOLOGIC, INFLAMMATORY, GROWTH FACTOR-RELATED, GENETIC, EPIGENETIC, ATHEROGENIC, VITAMIN D-RELATED, AND DIETARY FACTORS. RESULTS: CARDIOMETABOLIC RISK FACTORS APPEAR TO CONTRIBUTE TO UTERINE LEIOMYOMA PATHOGENESIS. FOR EXAMPLE, OBESITY CAN MODULATE LEIOMYOMATOUS CELLULAR PROLIFERATION AND EXTRACELLULAR MATRIX DEPOSITION THROUGH HYPERESTROGENIC STATES, CHRONIC INFLAMMATION, INSULIN RESISTANCE, AND ADIPOKINES. ON THE OTHER HAND, ENDOMETRIOSIS HAS BEEN SHOWN TO INDUCE SYSTEMIC INFLAMMATION, THEREBY INCREASING CARDIOMETABOLIC RISKS, FOR EXAMPLE, THROUGH INDUCING ATHEROSCLEROTIC CHANGES. CONCLUSION AND RELEVANCE: CLINICAL IMPLICATIONS OF THESE ASSOCIATIONS ARE 2-FOLD. FIRST, SCREENING AND EARLY MODIFICATION OF CMRFS CAN BE PART OF A PREVENTIVE STRATEGY FOR UTERINE LEIOMYOMAS AND HYSTERECTOMY. SECOND, PATIENTS DIAGNOSED WITH UTERINE LEIOMYOMAS OR ENDOMETRIOSIS CAN BE SCREENED AND CLOSELY FOLLOWED FOR CMRFS AND CARDIOVASCULAR DISEASE. 2019 3 6649 24 UPDATE ON ENDOMETRIOSIS PATHOGENESIS. ENDOMETRIOSIS IS A CHRONIC, INFLAMMATORY, CONDITION OF HIGH INCIDENCE AND SERIOUS REPRODUCTIVE AND GENERAL HEALTH CONSEQUENCES. UNDERSTANDING THE PATHOGENESIS OF ENDOMETRIOSIS IS CRUCIAL FOR PROPER DIAGNOSTIC AND ORDERING THE MOST EFFECTIVE TREATMENT. EVEN THOUGH THERE IS A LARGE BODY OF DATA REGARDING THIS PATHOLOGY OUR UNDERSTANDING OF THE PATHOGENESIS OF THIS DISEASE REMAINS INCOMPLETE. THE AIM OF THIS REVIEW IS TO SUMMARIZE CONTEMPORARY DATA REGARDING PATHOGENESIS OF ENDOMETRIOSIS. CURRENT DATA REGARDING ENDOMETRIAL ORIGIN, METAPLASTIC AND MULLERIAN EMBRYONIC RESTS THEORY WILL BE REVIEWED HERE. ALSO GENETIC, EPIGENETIC, ENVIRONMENTAL FACTORS AND IMMUNOLOGICAL DYSFUNCTION ROLE IN ENDOMETRIOSIS WILL BE SUMMARIZED. TO CONCLUDE, A LOT OF EFFORT MUST BE PUT TO INTEGRATE THE ABUNDANT DATA FROM GENETIC, EPIGENETIC AND IMMUNOLOGICAL STUDIES TO PROPOSE ONE COHERENT THEORY FOR THE PATHOGENESIS OF ENDOMETRIOSIS. 2017 4 1145 36 CONCURRENT DIAGNOSIS OF ADENOMYOSIS AND CONGENITAL UTERINE ANOMALIES: A REVIEW. BACKGROUND: ADENOMYOSIS AND CONGENITAL UTERINE ANOMALIES (CUAS) CAN COMPROMISE REPRODUCTIVE POTENTIAL AND MAY COEXIST IN THE SAME PATIENT, ESPECIALLY IN CASES OF INFERTILITY. THIS REVIEW (CRD42022382850) AIMS TO EVALUATE THE PUBLISHED CASES OF CONCURRENT ADENOMYOSIS AND SYNDROMIC AND NONSYNDROMIC CUAS. METHODS: A LITERATURE SEARCH FOR SUITABLE ARTICLES PUBLISHED IN THE ENGLISH LANGUAGE WAS PERFORMED USING THE FOLLOWING DATABASES FROM INCEPTION TO 30 NOVEMBER 2022: MEDLINE, EMBASE, GLOBAL HEALTH, THE COCHRANE LIBRARY, HEALTH TECHNOLOGY ASSESSMENT DATABASE, AND WEB OF SCIENCE. ARTICLES INCLUDING BOTH CUAS AND ADENOMYOSIS, WITH DATA ABOUT THEIR POTENTIAL RELATIONSHIP, WERE INCLUDED. RESULTS: THE LITERATURE SEARCH RETRIEVED 14 ARTICLES THAT MET THE PURPOSE OF THIS REVIEW AND SUMMARIZED THE MOST RECENT FINDINGS REGARDING THE CONCURRENT DIAGNOSIS OF ADENOMYOSIS AND CUAS. CONCLUSIONS: ADENOMYOSIS CAN BE FOUND IN BOTH SYNDROMIC AND NONSYNDROMIC CUAS, AND MAY ARISE FROM SEVERAL ETIOLOGIES. THE HYPOTHESIS THAT OBSTRUCTIONS IN CUAS INCREASE UTERINE PRESSURE AND PROMOTE THE DEVELOPMENT OF ADENOMYOSIS REMAINS TO BE FURTHER ELUCIDATED, AND ADDITIONAL FINDINGS MAY ALSO PLAY A ROLE. THE PATIENT'S GENETIC, EPIGENETIC, AND HORMONAL PATTERNS, AS WELL AS NORMAL PHYSIOLOGICAL PROCESSES, SUCH AS PREGNANCY, MAY INFLUENCE THE GROWTH OF ADENOMYOSIS. 2023 5 6141 35 THE ETIOLOGY OF PEYRONIE'S DISEASE: PATHOGENESIS AND GENETIC CONTRIBUTIONS. INTRODUCTION: PEYRONIE'S DISEASE (PD) IS A CHRONIC FIBROSING CONDITION THAT CONTRIBUTES TO PENILE DEFORMITY, CURVATURE, AND PAIN. INITIAL FAMILIAL STUDIES DEMONSTRATED POTENTIAL GENETIC LINKS TO PD. SINCE THAT TIME, VERY FEW INVESTIGATIONS HAVE SIGNIFICANTLY ADVANCED THE SCIENCE IN THIS AREA. HENCE, THERE IS A LARGE OPPORTUNITY AND SIGNIFICANT NEED TO BETTER STUDY THE UNDERLYING GENOMICS AND PATHOGENESIS OF PD. AIM: TO SUMMARIZE THE CURRENT GENOMIC LITERATURE RELEVANT TO PD. METHODS: A REVIEW WAS PERFORMED OF ALL PUBMED-INDEXED LITERATURE FROM 1970-2018 RELATING TO THE PATHOPHYSIOLOGY AND GENETICS OF PD. KEY FINDINGS WERE CATEGORICALLY SUMMARIZED TO INCLUDE EPIDEMIOLOGY, RISK FACTORS, INHERITANCE PATTERNS, CHROMOSOMAL INSTABILITY, GENETIC ASSOCIATIONS, EPIGENETICS, DIFFERENTIAL GENE EXPRESSION, AND PRECLINICAL MODELS OF PD. MAIN OUTCOME MEASURES: SUMMARY OF THE CURRENT LITERATURE ON THE GENETICS OF PD. RESULTS: PD IS A COMMON CONDITION AND HAS SEVERAL KNOWN RISK FACTORS AND COMORBID DISEASE ASSOCIATIONS. ALTHOUGH MEN WITH PD ARE BELIEVED TO BE GENETICALLY PREDISPOSED, THERE ARE LIKELY SEVERAL SUBTYPES OF THE CONDITION, EACH WITH VARIED PATHOPHYSIOLOGICAL DISORDERS AND CONTRIBUTING FACTORS. AVAILABLE DATA SUGGEST THAT PD IS ASSOCIATED WITH UNDERLYING GENETIC INSTABILITY, INCLUDING DYSREGULATION OF GENES RELATING TO FIBROSIS AND CELLULAR DEGRADATION, THUS, RESULTING IN ABNORMAL PLAQUE DEVELOPMENT AND PENILE DEFORMITY. PRECLINICAL MODELS, INCLUDING CELL CULTURES AND RAT MODELS, DEMONSTRATE SEVERAL CONSISTENCIES WITH PD CLINICAL AND HISTOPATHOLOGIC CHARACTERISTICS; HOWEVER, AN IDEAL MODEL WITH SPONTANEOUS DEVELOPMENT OF PD IS LACKING. CONCLUSION: BASED ON LIMITED DATA, PD LIKELY REPRESENTS A HETEROGENEOUS CONDITION, WITH BOTH HERITABLE AND ENVIRONMENTALLY-DRIVEN EPIGENETIC FACTORS CONTRIBUTING TO ITS DEVELOPMENT AND PROGRESSION. HOWEVER, THERE REMAINS A SIGNIFICANT GAP IN THE LITERATURE ON THE UNDERLYING CAUSE AND PATHOPHYSIOLOGY OF THE CONDITION, SUGGESTING A SUBSTANTIAL NEED FOR FURTHER INVESTIGATION AND STUDY. SHARMA KL, ALOM M, TROST L. THE ETIOLOGY OF PEYRONIE'S DISEASE: PATHOGENESIS AND GENETIC CONTRIBUTIONS. SEX MED REV 2020;8:314-323. 2020 6 1840 29 EFFECTS OF SELECTIVE INHIBITION OF PROSTAGLANDIN E2 RECEPTORS EP2 AND EP4 ON THE MIRNA PROFILE IN ENDOMETRIOSIS. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT, PROGESTERONE-RESISTANT, CHRONIC INFLAMMATORY GYNECOLOGICAL DISEASE OF REPRODUCTIVE-AGE WOMEN. TWO MAJOR CLINICAL SYMPTOMS OF ENDOMETRIOSIS ARE CHRONIC PELVIC PAIN AND INFERTILITY, WHICH PROFOUNDLY AFFECT THE QUALITY OF LIFE IN WOMEN. CURRENT HORMONAL THERAPIES TO INDUCE A HYPOESTROGENIC STATE ARE UNSUCCESSFUL BECAUSE OF UNDESIRABLE SIDE EFFECTS, REPRODUCTIVE HEALTH CONCERNS, AND FAILURE TO PREVENT DISEASE RECURRENCE. PROSTAGLANDIN E(2) (PGE(2)) PLAYS AN IMPORTANT ROLE IN THE SURVIVAL AND GROWTH OF ENDOMETRIOTIC LESIONS. MICRORNAS (MIRNAS) ARE SMALL, NONCODING RNAS THAT CONTROL GENE EXPRESSIONS THROUGH MULTIPLE MECHANISMS AND HAVE IMPORTANT ROLES IN THE PATHOGENESIS OF ENDOMETRIOSIS. THE OBJECTIVE OF THE PRESENT STUDY IS TO DETERMINE THE EFFECTS OF PHARMACOLOGICAL INHIBITION OF PGE(2) RECEPTORS, EP2 AND EP4, ON MIRNA PROFILE IN ENDOMETRIOSIS. THE NOVEL RESULTS COLLECTIVELY INDICATE THAT INHIBITION OF PGE(2)-EP2/EP4 SIGNALING REGULATED SEVERAL MIRNA CLUSTERS ASSOCIATED WITH CELL ADHESION, MIGRATION, INVASION, SURVIVAL AND GROWTH IN CELL-SPECIFIC AND THE CHROMOSOME-SPECIFIC MANNER AND REVERSES THE EPIGENETIC SILENCING OF PROAPOPTOTIC MIRNAS 15A AND 34C IN THE HUMAN ENDOMETRIOTIC EPITHELIAL AND STROMAL CELLS AND EXPERIMENTAL ENDOMETRIOTIC LESIONS. THUS, SELECTIVE INHIBITION OF EP2/EP4 RECEPTORS COULD EMERGE AS A POTENTIAL NONSTEROIDAL THERAPY FOR ENDOMETRIOSIS. 2022 7 6398 34 THE ROLE OF VITAMIN D AND VDR IN CARCINOGENESIS: THROUGH EPIDEMIOLOGY AND BASIC SCIENCES. IN THE LAST TWO DECADES VITAMIN D (VD) RESEARCH HAS DEMONSTRATED NEW EXTRASKELETAL ACTIONS OF THIS PRE-HORMONE, SUGGESTING A PROTECTIVE ROLE OF THIS SECOSTEROID IN THE ONSET, PROGRESSION AND PROGNOSIS OF SEVERAL CHRONIC NONCOMMUNICABLE DISEASES, SUCH AS CARDIOVASCULAR DISEASE, DIABETES MELLITUS OR CANCER. REGARDING CARCINOGENESIS, BOTH PRECLINICAL AND EPIDEMIOLOGICAL EVIDENCE AVAILABLE SHOW ONCOPROTECTIVE ACTIONS OF VD AND ITS RECEPTOR, THE VDR. HOWEVER, IN LATE NEOPLASTIC STAGES THE VD SYSTEM (VDS) SEEMS TO BE LESS FUNCTIONAL, WHICH APPEARS TO BE DUE TO AN EPIGENETIC SILENCING OF THE SYSTEM. IN PRECLINICAL EXPERIMENTAL STUDIES, VD PRESENTS ONCOPROTECTIVE ACTIONS THROUGH MODULATION OF INFLAMMATION, CELL PROLIFERATION, CELL DIFFERENTIATION, ANGIOGENESIS, INVASIVE AND METASTATIC POTENTIAL, APOPTOSIS, MIRNA EXPRESSION REGULATION AND MODULATION OF THE HEDGEHOG SIGNALLING PATHWAY. MOREOVER, EPIDEMIOLOGICAL EVIDENCE POINTS TOWARDS AN ONCOPROTECTIVE ROLE OF VITAMIN D AND VDR IN COLORECTAL CANCER. THIS ASSOCIATION IS MORE CONTROVERSIAL WITH BREAST, OVARIAN AND PROSTATE CANCERS, ALTHOUGH WITH A FEW ADVERSE EFFECTS. NONETHELESS, WE SHOULD CONSIDER OTHER FACTORS TO DETERMINE THE BENEFIT OF INCREASED SERUM CONCENTRATION OF VD. MUCH OF THE EPIDEMIOLOGICAL EVIDENCE IS STILL INCONCLUSIVE, AND WE WILL HAVE TO WAIT FOR NEW, BETTER-DESIGNED ONGOING RCTS AND THEIR RESULTS TO DISCERN THE REAL EFFECT OF VITAMIN D IN CANCER RISK REDUCTION AND THERAPY. THE OBJECTIVE OF THIS LITERATURE REVIEW IS TO OFFER AN UP-TO-DATE ANALYSIS OF THE ROLE OF THE VD AND VDR, IN THE ONSET, PROGRESSION AND PROGNOSIS OF ALL TYPES OF CANCER. WE FURTHER DISCUSS THE AVAILABLE LITERATURE AND SUGGEST NEW HYPOTHESES AND FUTURE CHALLENGES IN THE FIELD OF VD RESEARCH. 2017 8 2533 30 EPIGENETICS IN AUTOIMMUNE CONNECTIVE TISSUE DISEASES. BACKGROUND. AUTOIMMUNE CONNECTIVE TISSUE DISEASES (ACTDS) ENCOMPASS A HETEROGENEOUS GROUP OF CHRONIC IMMUNE-MEDIATED INFLAMMATORY DISORDERS, PRIMARILY AFFECTING CONNECTIVE TISSUES AND CLINICALLY CHARACTERIZED BY VARIABLE MULTISYSTEM MANIFESTATIONS, FREQUENTLY OVERLAPPING. ENVIRONMENTAL FACTORS ARE THOUGHT TO PROMOTE ACTD DEVELOPMENT IN GENETIC PREDISPOSING/ENDOCRINE PERMISSIVE BACKGROUND THROUGH THE INDUCTION OF EPIGENETIC MODIFICATIONS, CONSISTING OF STABLE, HERITABLE, BUT POTENTIALLY REVERSIBLE CHANGES IN GENE EXPRESSION, OCCURRING WITHOUT ALTERATIONS OF THE DNA SEQUENCE. ACTUALLY, EPIGENETIC MECHANISMS (SUCH AS HISTONE MODIFICATIONS, DNA METHYLATION, NUCLEOSOME POSITIONING, AND RNA INTERFERENCE) LINK GENOTYPE UPSTREAM AND PHENOTYPE DOWNSTREAM, AND, IF PERSISTENTLY ABERRANT, MAY CAUSE A VARIETY OF HUMAN DISEASES, INCLUDING ACTDS. WE AIMED TO REVIEW THE RECENT ADVANCES IN THE KNOWLEDGE OF THE ACTD EPIGENETIC ALTERATIONS. METHODS: A DETAILED SEARCH OF THE AVAILABLE LITERATURE WAS PERFORMED IN THE PUBMED (U.S. NATIONAL LIBRARY OF MEDICINE) DATABASE. RESULTS: GROWING EVIDENCE UNDERLINES THE RELEVANT ROLE OF EPIGENETIC DEFECTS IN THE ACTD PATHOGENESIS, AND SPECIFIC EPIGENETIC PATTERNS CAN REPRESENT DISEASE BIOMARKERS. IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA), EPIGENETIC VARIATIONS INTERACT DETERMINING THE TYPICAL "AGGRESSIVE" PHENOTYPE DISPLAYED BY RA SYNOVIAL FIBROBLASTS. EPIGENETIC MODIFICATIONS ARE INVOLVED IN THE PROFIBROTIC PROCESS THAT CHARACTERIZES SYSTEMIC SCLEROSIS. IN SYSTEMIC LUPUS ERYTHEMATOSUS AND SJOGREN'S SYNDROME, COMPLEX EPIGENETIC CHANGES ALTERING GENE EXPRESSION HAVE BEEN DEMONSTRATED. CONCLUSIONS: COMPREHENSIVE STUDIES WILL CONTRIBUTE TO FURTHER DEFINE THE ABERRANT EPIGENETIC MECHANISMS INVOLVED IN THE ACTDS ETIOPATHOGENESIS. MOREOVER, BEING EPIGENETIC CHANGES POTENTIALLY REVERSIBLE, THE IDENTIFICATION OF ACTDS EPIGENETIC BIOMARKERS WILL ALLOW THE DEVELOPMENT OF THERAPEUTIC STRATEGIES ADDRESSED TO TARGET DYSREGULATED GENES AND CORRECT ABERRANT EPIGENOMIC ALTERATIONS. 2014 9 6137 27 THE EPIGENETICS OF PSYCHOSIS: A STRUCTURED REVIEW WITH REPRESENTATIVE LOCI. THE EVIDENCE FOR AN ENVIRONMENTAL COMPONENT IN CHRONIC PSYCHOTIC DISORDERS IS STRONG AND RESEARCH ON THE EPIGENETIC MANIFESTATIONS OF THESE ENVIRONMENTAL IMPACTS HAS COMMENCED IN EARNEST. IN REVIEWING THIS RESEARCH, THE FOCUS IS ON THREE GENES AS MODELS FOR DIFFERENTIAL METHYLATION, MCHR1, AKT1 AND TDO2, EACH OF WHICH HAVE BEEN INVESTIGATED FOR GENETIC ASSOCIATION WITH PSYCHOTIC DISORDERS. ENVIRONMENTAL FACTORS ASSOCIATED WITH PSYCHOTIC DISORDERS, AND WHICH INTERACT WITH THESE MODEL GENES, ARE EXPLORED IN DEPTH. THE LOCATION OF TRANSCRIPTION FACTOR MOTIFS RELATIVE TO KEY METHYLATION SITES IS EVALUATED FOR PREDICTED GENE EXPRESSION RESULTS, AND FOR OTHER SITES, EVIDENCE IS PRESENTED FOR METHYLATION DIRECTING ALTERNATIVE SPLICING. EXPERIMENTAL RESULTS FROM KEY STUDIES SHOW DIFFERENTIAL METHYLATION: FOR MCHR1, IN PSYCHOSIS CASES VERSUS CONTROLS; FOR AKT1, AS A PRE-EXISTING METHYLATION PATTERN INFLUENCING BRAIN ACTIVATION FOLLOWING ACUTE ADMINISTRATION OF A PSYCHOSIS-ELICITING ENVIRONMENTAL STIMULUS; AND FOR TDO2, IN A PATTERN ASSOCIATED WITH A DEVELOPMENTAL FACTOR OF RISK FOR PSYCHOSIS, IN ALL CASES THE PREDICTED EXPRESSION IMPACT BEING HIGHLY DEPENDENT ON LOCATION. METHYLATION INDUCED BY SMOKING, A CONFOUNDING VARIABLE, EXHIBITS AN INTRIGUING PATTERN FOR ALL THREE GENES. FINALLY, HOW DIFFERENTIAL METHYLATION MESHES WITH DARWINIAN PRINCIPLES IS EXAMINED, IN PARTICULAR AS IT RELATES TO THE "FLEXIBLE STEM" THEORY OF EVOLUTION. 2022 10 6595 36 TUMOR-SPECIFIC GROWTH FACTOR (TSGF): A FUTURISTIC TUMOR BIOMARKER IN EARLY DIAGNOSIS OF CANCER. DESPITE THE SIGNIFICANT IMPROVEMENT IN THE TREATMENT MODALITIES, CANCER IS ONE OF THE FASTEST-GROWING CHRONIC DISEASE CONDITIONS ALL OVER THE WORLD. GENETIC AND EPIGENETIC ALTERATIONS IN THE NORMAL PHYSIOLOGY OF THE CELL ARE THE KEY FACTOR FOR TUMOR DEVELOPMENT. THESE CHANGES CAN TRIGGER THE PRODUCTION OF ABNORMAL PROTEIN EXPRESSIONS THROUGH STIMULATION OF DIFFERENT SIGNALING PATHWAYS AND CAN DEEPLY AFFECT NORMAL CELL GROWTH AND PROLIFERATION. ANY ALTERED PROTEIN EXPRESSION, GENETIC VARIATION, MICRO-RNA OR POST-TRANSLATIONAL PROTEIN MODIFICATIONS THAT INDICATE TUMORIGENESIS CAN ACT AS AN EARLY SIGNAL TERMED AS BIOMARKER. CANCER, BEING A MULTISTEP PROCESS WITH ACCUMULATING GENETIC AND EPIGENETIC ALTERATIONS, COULD BE DETECTED EARLY WITH SUITABLE BIOMARKERS. THERE ARE SEVERAL PROTEINS SUCH AS AFP, CA-125, PSA, TROPONIN, CEA, OSTEOPONTIN, CA 19-9 THAT ACT AS BIOMARKERS WHICH HELP IN EARLY DETECTION, PROGNOSIS, AND MONITORING OF DISEASE PROGRESSION, A HUNT FOR NEWER BIOMARKERS WITH HIGHER SPECIFICITY AND SENSITIVITY IS STILL ONGOING. TUMOR-SPECIFIC GROWTH FACTOR (TSGF) IS ONE SUCH BUDDING AND PREVAILING TUMOR BIOMARKER USED FOR THE EARLY-STAGE DETECTION OF SEVERAL TYPES OF CARCINOMAS. TSGF IS A GENE THAT HELPS IN TUMOR ANGIOGENESIS AND GETS RELEASED DURING THE PRELIMINARY STAGES FROM CANCER CELLS THAT ENSURE THE VASCULAR PROLIFERATION OF THE SAME. IN THIS REVIEW, THE CLINICAL INVESTIGATIONS OF TSGF IN DIFFERENT KINDS OF MALIGNANCY IS DISCUSSED IN DETAIL AND SUGGESTS THE POSSIBILITY OF USING TSGF AS A BIOMARKER IN EARLY DIAGNOSIS OF CANCER. 2023 11 461 36 ARCHITECTS OF PITUITARY TUMOUR GROWTH. THE PITUITARY IS A MASTER GLAND RESPONSIBLE FOR THE MODULATION OF CRITICAL ENDOCRINE FUNCTIONS. PITUITARY NEUROENDOCRINE TUMOURS (PITNETS) DISPLAY A CONSIDERABLE PREVALENCE OF 1/1106, FREQUENTLY OBSERVED AS BENIGN SOLID TUMOURS. PITNETS STILL REPRESENT A CAUSE OF IMPORTANT MORBIDITY, DUE TO HORMONAL SYSTEMIC DEREGULATION, WITH SURGICAL, RADIOLOGICAL OR CHRONIC TREATMENT REQUIRED FOR ILLNESS MANAGEMENT. THE APPARENT SCARCENESS, UNCOMMON BEHAVIOUR AND MOLECULAR FEATURES OF PITNETS HAVE RESULTED IN A RELATIVELY SLOW PROGRESS IN DEPICTING THEIR PATHOGENESIS. AN APPROPRIATE INTERPRETATION OF DIFFERENT PHENOTYPES OR CELLULAR OUTCOMES DURING TUMOUR GROWTH IS DESIRABLE, SINCE HISTOPATHOLOGICAL CHARACTERIZATION STILL REMAINS THE MAIN OPTION FOR PROGNOSIS ELUCIDATION. IMPROVED KNOWLEDGE OBTAINED IN RECENT DECADES ABOUT PITUITARY TUMORIGENESIS HAS REVEALED THAT THIS PROCESS INVOLVES SEVERAL CELLULAR ROUTES IN ADDITION TO PROLIFERATION AND DEATH, WITH ITS MODULATION DEPENDING ON MANY SIGNALLING PATHWAYS RATHER THAN BEING THE RESULT OF ABNORMALITIES OF A UNIQUE PROLIFERATION PATHWAY, AS SOMETIMES PRESENTED. PITNETS CAN DISPLAY INTRINSIC HETEROGENEITY AND CELL SUBPOPULATIONS WITH DIVERSE BIOLOGICAL, GENETIC AND EPIGENETIC PARTICULARITIES, INCLUDING TUMORIGENIC POTENTIAL. HENCE, TO OBTAIN A BETTER UNDERSTANDING OF PITNET GROWTH NEW APPROACHES ARE REQUIRED AND THE SYSTEMATIZATION OF THE AVAILABLE DATA, WITH THE ROLE OF CELL DEATH PROGRAMS, AUTOPHAGY, STEM CELLS, CELLULAR SENESCENCE, MITOCHONDRIAL FUNCTION, METABOLIC REPROGRAMMING STILL BEING EMERGING FIELDS IN PITUITARY RESEARCH. WE ENVISAGE THAT THROUGH THE COMBINATION OF MOLECULAR, GENETIC AND EPIGENETIC DATA, TOGETHER WITH THE IMPROVED MORPHOLOGICAL, BIOCHEMICAL, PHYSIOLOGICAL AND METABOLICALLY KNOWLEDGE ON PITUITARY NEOPLASTIC POTENTIAL ACCUMULATED IN RECENT DECADES, TUMOUR CLASSIFICATION SCHEMES WILL BECOME MORE ACCURATE REGARDING TUMOUR ORIGIN, BEHAVIOUR AND PLAUSIBLE CLINICAL RESULTS. 2022 12 3741 26 INSIGHT INTO THE POTENTIAL MECHANISMS OF ENDOCRINE DISRUPTION BY DIETARY PHYTOESTROGENS IN THE CONTEXT OF THE ETIOPATHOGENESIS OF ENDOMETRIOSIS. PHYTOESTROGENS (PES) ARE ESTROGEN-LIKE NONSTEROIDAL COMPOUNDS DERIVED FROM PLANTS (E.G., NUTS, SEEDS, FRUITS, AND VEGETABLES) AND FUNGI THAT ARE STRUCTURALLY SIMILAR TO 17BETA-ESTRADIOL. PES BIND TO ALL TYPES OF ESTROGEN RECEPTORS, INCLUDING ERALPHA AND ERBETA RECEPTORS, NUCLEAR RECEPTORS, AND A MEMBRANE-BOUND ESTROGEN RECEPTOR KNOWN AS THE G PROTEIN-COUPLED ESTROGEN RECEPTOR (GPER). AS ENDOCRINE-DISRUPTING CHEMICALS (EDCS) WITH PRO- OR ANTIESTROGENIC PROPERTIES, PES CAN POTENTIALLY DISRUPT THE HORMONAL REGULATION OF HOMEOSTASIS, RESULTING IN DEVELOPMENTAL AND REPRODUCTIVE ABNORMALITIES. HOWEVER, A LACK OF PES IN THE DIET DOES NOT RESULT IN THE DEVELOPMENT OF DEFICIENCY SYMPTOMS. TO PROPERLY ASSESS THE BENEFITS AND RISKS ASSOCIATED WITH THE USE OF A PE-RICH DIET, IT IS NECESSARY TO DISTINGUISH BETWEEN ENDOCRINE DISRUPTION (ENDOCRINE-MEDIATED ADVERSE EFFECTS) AND NONSPECIFIC EFFECTS ON THE ENDOCRINE SYSTEM. ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT DISEASE OF UNKNOWN ETIOPATHOGENESIS, IN WHICH TISSUE SIMILAR TO THE LINING OF THE UTERUS (THE ENDOMETRIUM) GROWS OUTSIDE OF THE UTERUS WITH SUBSEQUENT COMPLICATIONS BEING MANIFESTED AS A RESULT OF LOCAL INFLAMMATORY REACTIONS. ENDOMETRIOSIS AFFECTS 10-15% OF WOMEN OF REPRODUCTIVE AGE AND IS ASSOCIATED WITH CHRONIC PELVIC PAIN, DYSMENORRHEA, DYSPAREUNIA, AND INFERTILITY. IN THIS REVIEW, THE ENDOCRINE-DISRUPTIVE ACTIONS OF PES ARE REVIEWED IN THE CONTEXT OF ENDOMETRIOSIS TO DETERMINE WHETHER A PE-RICH DIET HAS A POSITIVE OR NEGATIVE EFFECT ON THE RISK AND COURSE OF ENDOMETRIOSIS. 2023 13 4399 28 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 14 6334 25 THE ROLE OF DNA METHYLATION AND HYDROXYMETHYLATION IN IMMUNOSENESCENCE. A HEALTHY FUNCTIONING IMMUNE SYSTEM IS CRITICAL TO STAVE OFF INFECTIOUS DISEASES, BUT AS HUMANS AND OTHER ORGANISMS AGE, THEIR IMMUNE SYSTEMS DECLINE. AS A RESULT, DISEASES THAT WERE READILY THWARTED IN EARLY LIFE POSE NONTRIVIAL HARM AND CAN EVEN BE DEADLY IN LATE LIFE. IMMUNOSENESCENCE IS DEFINED AS THE GENERAL DETERIORATION OF THE IMMUNE SYSTEM WITH AGE, AND IT IS CHARACTERIZED BY FUNCTIONAL CHANGES IN HEMATOPOIETIC STEM CELLS (HSCS) AND SPECIFIC BLOOD CELL TYPES AS WELL AS CHANGES IN LEVELS OF NUMEROUS FACTORS, PARTICULARLY THOSE INVOLVED IN INFLAMMATION. POTENTIAL MECHANISMS UNDERLYING IMMUNOSENESCENCE INCLUDE EPIGENETIC CHANGES SUCH AS CHANGES IN DNA METHYLATION (DNAM) AND DNA HYDROXYMETHYLATION (DNAHM) THAT OCCUR WITH AGE. THE PURPOSE OF THIS REVIEW IS TO DESCRIBE WHAT IS CURRENTLY KNOWN ABOUT THE RELATIONSHIP BETWEEN IMMUNOSENESCENCE AND THE AGE-RELATED CHANGES TO DNAM AND DNAHM, AND TO DISCUSS EXPERIMENTAL APPROACHES BEST SUITED TO FILL GAPS IN OUR UNDERSTANDING. 2019 15 3802 33 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 16 2461 28 EPIGENETIC THERAPY AS A PUTATIVE MOLECULAR TARGET TO MODULATE B CELL BIOLOGY AND BEHAVIOR IN THE CONTEXT OF IMMUNOLOGICAL DISORDERS. HISTONE DEACETYLASE- (HDAC-) DEPENDENT EPIGENETIC MECHANISMS HAVE BEEN WIDELY EXPLORED IN THE LAST DECADE IN DIFFERENT TYPES OF MALIGNANCIES IN PRECLINICAL STUDIES. THIS EFFORT LED TO THE DISCOVERY AND DEVELOPMENT OF A RANGE OF NEW HDAC INHIBITORS (IHDAC) WITH DIFFERENT CHEMICAL PROPERTIES AND SELECTIVE ABILITIES. IN FACT, HEMATOLOGICAL MALIGNANCIES WERE THE FIRST ONES TO HAVE NEW IHDACS APPROVED FOR CLINICAL USE, SUCH AS VORINOSTAT AND ROMIDEPSIN FOR CUTANEOUS T CELL LYMPHOMA AND PANOBINOSTAT FOR MULTIPLE MYELOMA. BESIDES THESE PROMISING ALREADY APPROVED IHDACS, WE HIGHLIGHT A RANGE OF STUDIES FOCUSING ON THE HDAC-DEPENDENT EPIGENETIC CONTROL OF B CELL DEVELOPMENT, BEHAVIOR, AND/OR FUNCTION. HERE, WE HIGHLIGHT 21 IHDACS WHICH HAVE BEEN STUDIED IN THE LITERATURE IN THE CONTEXT OF B CELL DEVELOPMENT AND/OR DYSFUNCTION MOSTLY FOCUSED ON B CELL LYMPHOMAGENESIS. REGARDLESS, WE HAVE IDENTIFIED 55 CLINICAL TRIALS USING 6 OUT OF 21 IHDACS TO APPROACH THEIR PUTATIVE ROLES ON B CELL MALIGNANCIES; NONE OF THEM FOCUSES ON PERITONEAL B CELL POPULATIONS. SINCE CELLS BELONGING TO THIS PECULIAR BODY COMPARTMENT, NAMED B1 CELLS, MAY CONTRIBUTE TO THE DEVELOPMENT OF AUTOIMMUNE PATHOLOGIES, SUCH AS LUPUS, A BETTER UNDERSTANDING OF THE HDAC-DEPENDENT EPIGENETIC MECHANISMS THAT CONTROL ITS BIOLOGY AND BEHAVIOR MIGHT SHED LIGHT ON IHDAC USE TO MANAGE THESE IMMUNOLOGICAL DYSFUNCTIONS. IN THIS SENSE, IHDACS MIGHT EMERGE AS A PROMISING NEW APPROACH FOR TRANSLATIONAL STUDIES IN THIS FIELD. IN THIS REVIEW, WE DISCUSS A PUTATIVE ROLE OF IHDACS IN THE MODULATION OF PERITONEAL B CELL SUBPOPULATION'S BALANCE AS WELL AS THEIR ROLE AS THERAPEUTIC AGENTS IN THE CONTEXT OF CHRONIC DISEASES MEDIATED BY PERITONEAL B CELLS. 2020 17 4198 21 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 18 5595 26 ROLES OF GENETIC PREDISPOSITION IN THE SEX BIAS OF PULMONARY PATHOPHYSIOLOGY, AS A FUNCTION OF ESTROGENS : SEX MATTERS IN THE PREVALENCE OF LUNG DISEASES. IN ADDITION TO STUDIES FOCUSED ON ESTROGEN MEDIATION OF SEX-DIFFERENT REGULATION OF SYSTEMIC CIRCULATIONS, THERE IS NOW INCREASING CLINICAL RELEVANCE AND RESEARCH INTERESTS IN THE PULMONARY CIRCULATION, IN TERMS OF SEX DIFFERENCES IN THE MORBIDITY AND MORTALITY OF LUNG DISEASES SUCH AS INHERENT-, ALLERGIC- AND INFLAMMATORY-BASED EVENTS. THUS, FEMALE PREDISPOSITION TO PULMONARY ARTERY HYPERTENSION (PAH) IS AN INEVITABLE TOPIC. TO BETTER UNDERSTAND THE NATURE OF SEXUAL DIFFERENTIATION IN THE PULMONARY CIRCULATION, AND HOW HERITABLE FACTORS, IN VIVO- AND/OR IN VITRO-ALTERED ESTROGEN CIRCUMSTANCES AND CHANGES IN THE LIVE ENVIRONMENT WORK IN CONCERT TO DISCERN THE SEX BIAS, THIS CHAPTER REVIEWS PULMONARY EVENTS CHARACTERIZED BY SEX-DIFFERENT FEATURES, CONCOMITANT WITH EXPLORATION OF HOW ALTERATIONS OF GENETIC EXPRESSION AND ESTROGEN METABOLISMS TRIGGER THE FEMALE-PREDOMINANT PATHOLOGICAL SIGNALING. WE ADDRESS THE FOLLOWING: PAH (SECT.7.2) IS CHARACTERIZED AS AN ESTROGENIC PROMOTION OF ITS INCIDENCE (SECT. 7.2.2), AS A FUNCTION OF SPECIFIC GERMLINE MUTATIONS, AND AS AN ESTROGEN-ELICITED PROTECTION OF ITS PROGNOSIS (SECT.7.2.1). MORE DETAIL IS PROVIDED TO INTRODUCE A LESS RECOGNIZED GENE OF EPHX2 THAT ENCODES SOLUBLE EPOXIDE HYDROLASE (SEH) TO DEGRADE EPOXYEICOSATRIENIC ACIDS (EETS). AS A SUSCEPTIBLE TARGET OF ESTROGEN, EPHX2/SEH EXPRESSION IS DOWNREGULATED BY AN ESTROGEN-DEPENDENT EPIGENETIC MECHANISM. INCREASES IN PULMONARY EETS THEN EVOKE A POTENTIATION OF PAH GENERATION, BUT MITIGATION OF ITS PROGRESSION, A PHENOMENON SIMILAR TO THE ESTROGEN-PARADOX REGULATION OF PAH. ADDITIONALLY, THE FEMALE SUSCEPTIBILITY TO CHRONIC OBSTRUCTIVE PULMONARY DISEASES (SECT. 7.3) AND ASTHMA (SECT.7.4), BUT LESS PREFERENCE TO COVID-19 (SECT. 7.5), AND ROLES OF ESTROGEN IN THEIR PATHOGENESES ARE BRIEFLY DISCUSSED. 2021 19 3899 28 LATE NEUROLOGICAL CONSEQUENCES OF ZIKA VIRUS INFECTION: RISK FACTORS AND PHARMACEUTICAL APPROACHES. ZIKA VIRUS (ZIKV) INFECTION WAS HISTORICALLY CONSIDERED A DISEASE WITH MILD SYMPTOMS AND NO MAJOR CONSEQUENCES TO HUMAN HEALTH. HOWEVER, SEVERAL LONG-TERM, LATE ONSET, AND CHRONIC NEUROLOGICAL COMPLICATIONS, BOTH IN CONGENITALLY-EXPOSED BABIES AND IN ADULT PATIENTS, HAVE BEEN REPORTED AFTER ZIKV INFECTION, ESPECIALLY AFTER THE 2015 EPIDEMICS IN THE AMERICAN CONTINENT. THE DEVELOPMENT OR SEVERITY OF THESE CONDITIONS CANNOT BE FULLY PREDICTED, BUT IT IS POSSIBLE THAT GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS MAY CONTRIBUTE TO DETERMINE ZIKV INFECTION OUTCOMES. THIS REINFORCES THE IMPORTANCE THAT INDIVIDUALS EXPOSED TO ZIKV ARE SUBMITTED TO LONG-TERM CLINICAL SURVEILLANCE AND HIGHLIGHTS THE URGENT NEED FOR THE DEVELOPMENT OF THERAPEUTIC APPROACHES TO REDUCE OR ELIMINATE THE NEUROLOGICAL BURDEN OF INFECTION. HERE, WE REVIEW THE EPIDEMIOLOGY OF ZIKV-ASSOCIATED NEUROLOGICAL COMPLICATIONS AND THE ROLE OF FACTORS THAT MAY INFLUENCE DISEASE OUTCOME. MOREOVER, WE DISCUSS EXPERIMENTAL AND CLINICAL EVIDENCE OF DRUGS THAT HAVE SHOWN PROMISING RESULTS IN VITRO OR IN VITRO AGAINST VIRAL REPLICATION AND AND/OR ZIKV-INDUCED NEUROTOXICITY. 2019 20 2602 29 EPIGENETICS, ENDOMETRIOSIS AND SEX STEROID RECEPTORS: AN UPDATE ON THE EPIGENETIC REGULATORY MECHANISMS OF ESTROGEN AND PROGESTERONE RECEPTORS IN PATIENTS WITH ENDOMETRIOSIS. ENDOMETRIOSIS IS A BENIGN GYNECOLOGICAL DISEASE AFFECTING APPROXIMATELY 10% OF REPRODUCTIVE-AGED WOMEN AND IS DEFINED AS THE PRESENCE OF ENDOMETRIAL GLANDS AND STROMA OUTSIDE THE UTERINE CAVITY. ENDOMETRIOSIS CAN CAUSE A VARIETY OF HEALTH PROBLEMS, FROM PELVIC DISCOMFORT TO CATAMENIAL PNEUMOTHORAX, BUT IT'S MAINLY LINKED WITH SEVERE AND CHRONIC PELVIC PAIN, DYSMENORRHEA, AND DEEP DYSPAREUNIA, AS WELL AS REPRODUCTIVE ISSUES. THE PATHOGENESIS OF ENDOMETRIOSIS INVOLVES AN ENDOCRINE DYSFUNCTION, WITH ESTROGEN DEPENDENCY AND PROGESTERONE RESISTANCE, AND INFLAMMATORY MECHANISM ACTIVATION, TOGETHER WITH IMPAIRED CELL PROLIFERATION AND NEUROANGIOGENESIS. THE PRESENT CHAPTER AIMS TO DISCUSS THE MAIN EPIGENETIC MECHANISMS RELATED TO ESTROGEN RECEPTORS (ERS) AND PROGESTERONE RECEPTORS (PRS) IN PATIENTS WITH ENDOMETRIOSIS. THERE ARE NUMEROUS EPIGENETIC MECHANISMS PARTICIPATING IN ENDOMETRIOSIS, REGULATING THE EXPRESSION OF THE GENES ENCODING THESE RECEPTORS BOTH INDIRECTLY, THROUGH THE REGULATION OF TRANSCRIPTION FACTORS, AND DIRECTLY, THROUGH DNA METHYLATION, HISTONE MODIFICATIONS, MICRO RNAS AND LONG NONCODING RNAS. THIS REPRESENTS AN OPEN FIELD OF INVESTIGATION, WHICH MAY LEAD TO IMPORTANT CLINICAL IMPLICATIONS SUCH AS THE DEVELOPMENT OF EPIGENETIC DRUGS FOR THE TREATMENT OF ENDOMETRIOSIS AND THE IDENTIFICATION OF SPECIFIC AND EARLY BIOMARKERS FOR THE DISEASE. 2023