1 2829 71 FLUSHING OUT CARCINOID SYNDROME: BENEFICIAL EFFECT OF THE ANTICANCER EPIGENETIC AGENT RRX-001 IN A PATIENT WITH A TREATMENT-REFRACTORY NEUROENDOCRINE TUMOR. NEUROENDOCRINE TUMORS (NET) ARE A HETEROGENEOUS GROUP OF NEOPLASMS DEFINED BY THE PRESENCE OF CELLS WITH SECRETORY GRANULES AND THE POTENTIAL TO PRODUCE AND RELEASE HIGH LEVELS OF VASOACTIVE PEPTIDES INTO THE CIRCULATION, LEADING TO SEVERE FLUSHING AND DIARRHEA, WHICH MAY ADVERSELY AFFECT QUALITY OF LIFE. THIS REPORT PRESENTS THE CASE OF A 64-YEAR-OLD MAN WITH CHRONIC REFRACTORY DIARRHEA DUE TO PULMONARY NET TREATED WITH THE EXPERIMENTAL ANTICANCER AGENT RRX-001 IN A PHASE II TRIAL CALLED TRIPLE THREAT WITH SUBSEQUENT RESOLUTION OF HIS DIARRHEA. 2015 2 3418 19 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 3 2461 15 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 4 461 20 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 5 4198 18 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 6 5447 15 REPOSITIONING LIDOCAINE AS AN ANTICANCER DRUG: THE ROLE BEYOND ANESTHESIA. WHILE CANCER TREATMENT HAS IMPROVED DRAMATICALLY, IT HAS ALSO ENCOUNTERED MANY CRITICAL CHALLENGES, SUCH AS DISEASE RECURRENCE, METASTASIS, AND DRUG RESISTANCE, MAKING NEW DRUGS WITH NOVEL MECHANISMS AN URGENT CLINICAL NEED. THE TERM "DRUG REPOSITIONING," ALSO KNOWN AS OLD DRUGS FOR NEW USES, HAS EMERGED AS ONE PRACTICAL STRATEGY TO DEVELOP NEW ANTICANCER DRUGS. ANESTHETICS HAVE BEEN WIDELY USED IN SURGICAL PROCEDURES TO REDUCE THE EXCRUCIATING PAIN. LIDOCAINE, ONE OF THE MOST-USED LOCAL ANESTHETICS IN CLINICAL SETTINGS, HAS BEEN FOUND TO SHOW MULTI-ACTIVITIES, INCLUDING POTENTIAL IN CANCER TREATMENT. GROWING EVIDENCE SHOWS THAT LIDOCAINE MAY NOT ONLY WORK AS A CHEMOSENSITIZER THAT SENSITIZES OTHER CONVENTIONAL CHEMOTHERAPEUTICS TO CERTAIN RESISTANT CANCER CELLS, BUT ALSO COULD SUPPRESS CANCER CELLS GROWTH BY SINGLE USE AT DIFFERENT DOSES OR CONCENTRATIONS. LIDOCAINE COULD SUPPRESS CANCER CELL GROWTH IN VITRO AND IN VIVO VIA MULTIPLE MECHANISMS, SUCH AS REGULATING EPIGENETIC CHANGES AND PROMOTING PRO-APOPTOSIS PATHWAYS, AS WELL AS REGULATING ABC TRANSPORTERS, METASTASIS, AND ANGIOGENESIS, ETC., PROVIDING VALUABLE INFORMATION FOR ITS FURTHER APPLICATION IN CANCER TREATMENT AND FOR NEW DRUG DISCOVERY. IN ADDITION, LIDOCAINE IS NOW UNDER CLINICAL TRIALS TO TREAT CERTAIN TYPES OF CANCER. IN THE CURRENT REVIEW, WE SUMMARIZE THE RESEARCH AND ANALYZE THE UNDERLYING MECHANISMS, AND ADDRESS KEY ISSUES IN THIS AREA. 2020 7 761 19 CATEGORIZING THE CHARACTERISTICS OF HUMAN CARCINOGENS: A NEED FOR SPECIFICITY. THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) HAS RECENTLY PROPOSED EMPLOYING "TEN KEY CHARACTERISTICS OF HUMAN CARCINOGENS" (TKCS) TO DETERMINE THE POTENTIAL OF AGENTS FOR HARMFUL EFFECTS. THE TKCS SEEM LIKELY TO CONFUSE THE UNSATISFACTORY CORRELATION FROM TESTING REGIMES THAT HAVE IGNORED THE DIFFERENCES EVIDENT WHEN CELLULAR CHANGES ARE COMPARED IN SHORT AND LONG-LIVED SPECIES, WITH THEIR VERY DIFFERENT STEM CELL AND SOMATIC CELL PHYLOGENIES. THE PROPOSED CHARACTERISTICS ARE SO BROAD THAT THEIR USE WILL LEAD TO AN INCREASE IN THE CURRENT UNACCEPTABLY HIGH RATE OF FALSE POSITIVES. IT COULD BE AN INFORMATIVE EXPERIMENT TO TAKE WELL-ESTABLISHED APPROVED THERAPEUTICS WITH WELL-KNOWN HUMAN SAFETY PROFILES AND TEST THEM AGAINST THIS NEW TKC PARADIGM. CANCERS ARE INITIATED AND DRIVEN BY HERITABLE AND TRANSIENT CHANGES IN GENE EXPRESSION, EXPAND CLONALLY, AND PROGRESS VIA ADDITIONAL ASSOCIATED ACQUIRED MUTATIONS AND EPIGENETIC ALTERATIONS THAT PROVIDE CELLS WITH AN EVOLUTIONARY ADVANTAGE. THE GENOTOXICITY TESTING PROTOCOLS CURRENTLY EMPLOYED AND REQUIRED BY REGULATION, EMPHASIZE TESTING FOR THE MUTATIONAL POTENTIAL OF THE TEST AGENT. TWO-YEAR, CHRONIC RODENT CANCER BIOASSAYS ARE INTENDED TO TEST FOR THE ENTIRE SPECTRUM OF CARCINOGENIC TRANSFORMATION. THE USE OF CYTOTOXIC DOSES CAUSING INCREASED, SUSTAINED CELL PROLIFERATION THAT FACILITATES ACCUMULATED GENETIC DAMAGE LEADS TO A HIGH FALSE-POSITIVE RATE OF TUMOR INDUCTION. CURRENT CANCER HAZARD ASSESSMENT PROTOCOLS AND WEIGHT-OF-THE-EVIDENCE ANALYSIS OF AGENT-SPECIFIC CANCER RISK ALIGN POORLY WITH THE PATHOGENESIS OF HUMAN CARCINOMA AND SO NEED MODERNIZATION AND IMPROVEMENT IN WAYS SUGGESTED HERE. 2021 8 2446 17 EPIGENETIC STRATEGIES SYNERGIZE WITH PD-L1/PD-1 TARGETED CANCER IMMUNOTHERAPIES TO ENHANCE ANTITUMOR RESPONSES. IMMUNOTHERAPY STRATEGIES TARGETING THE PROGRAMMED CELL DEATH LIGAND 1 (PD-L1)/PROGRAMMED CELL DEATH 1 (PD-1) PATHWAY IN CLINICAL TREATMENTS HAVE ACHIEVED REMARKABLE SUCCESS IN TREATING MULTIPLE TYPES OF CANCER. HOWEVER, OWING TO THE HETEROGENEITY OF TUMORS AND INDIVIDUAL IMMUNE SYSTEMS, PD-L1/PD-1 BLOCKADE STILL SHOWS SLOW RESPONSE RATES IN CONTROLLING MALIGNANCIES IN MANY PATIENTS. ACCUMULATING EVIDENCE HAS SHOWN THAT AN EFFECTIVE RESPONSE TO ANTI-PD-L1/ANTI-PD-1 THERAPY REQUIRES ESTABLISHING AN INTEGRATED IMMUNE CYCLE. DAMAGE IN ANY STEP OF THE IMMUNE CYCLE IS ONE OF THE MOST IMPORTANT CAUSES OF IMMUNOTHERAPY FAILURE. IMPAIRMENTS IN THE IMMUNE CYCLE CAN BE RESTORED BY EPIGENETIC MODIFICATION, INCLUDING REPROGRAMMING THE ENVIRONMENT OF TUMOR-ASSOCIATED IMMUNITY, ELICITING AN IMMUNE RESPONSE BY INCREASING THE PRESENTATION OF TUMOR ANTIGENS, AND BY REGULATING T CELL TRAFFICKING AND REACTIVATION. THUS, A RATIONAL COMBINATION OF PD-L1/PD-1 BLOCKADE AND EPIGENETIC AGENTS MAY OFFER GREAT POTENTIAL TO RETRAIN THE IMMUNE SYSTEM AND TO IMPROVE CLINICAL OUTCOMES OF CHECKPOINT BLOCKADE THERAPY. 2020 9 5905 13 TACKLING THE HETEROGENEITY OF CVID. PURPOSE OF REVIEW: COMMON VARIABLE IMMUNODEFICIENCY IS CLINICALLY THE MOST RELEVANT PRIMARY IMMUNODEFICIENCY OF THE ADULT. ITS HETEROGENEITY HAS HINDERED PROGRESS IN THE PATHOGENETIC UNDERSTANDING OF THE MAJORITY OF COMMON VARIABLE IMMUNODEFICIENCY PATIENTS. THIS ABSTRACT SUMMARIZES RECENT ASPECTS OF THE FIELD AND EMPHASIZES THE NEED FOR A COMMONLY ACCEPTED APPROACH TO CLASSIFY COMMON VARIABLE IMMUNODEFICIENCY. RECENT FINDINGS: IN THE LAST 2 YEARS, THE FIRST GENETIC DEFECTS UNDERLYING COMMON VARIABLE IMMUNODEFICIENCY, INCLUDING ICOS, TACI, BAFF-R AND CD19, HAVE BEEN IDENTIFIED. THE ANALYSIS OF DENDRITIC CELLS DEMONSTRATED ALTERATIONS IN A MAJORITY OF PATIENTS IN ADDITION TO THE DISTURBED T AND B-CELL FUNCTION. SEVERAL CHANGES OF THE ADAPTIVE IMMUNE SYSTEM MIGHT BE SECONDARY TO AN UNDERLYING CHRONIC INFLAMMATORY SETTING POSSIBLY DUE TO A HHV8 INFECTION IN A SUBGROUP OF PATIENTS WITH GRANULOMATOUS DISEASE, AUTOIMMUNE PHENOMENA AND T-CELL DYSFUNCTION. THE OCCURRENCE OF GRANULOMATOUS INFLAMMATION IS ASSOCIATED WITH A WORSE PROGNOSIS COMPARED WITH COMMON VARIABLE IMMUNODEFICIENCY PATIENTS WITHOUT GRANULOMA. SUMMARY: THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY INCLUDES DISTURBANCES OF THE ADAPTIVE AS WELL AS INNATE IMMUNE SYSTEM. IDENTIFIED MONOGENIC DEFECTS ACCOUNT FOR ABOUT 10% OF CASES, LEAVING THE MAJORITY OF DEFECTS UNDEFINED AND CERTAINLY IN PART EPIGENETIC. TO COMBINE THE KNOWN ASPECTS OF THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY TO A CONCLUSIVE PICTURE, THE CLINICAL AND IMMUNOLOGIC PHENOTYPING OF PATIENTS NEEDS TO BE STANDARDIZED. 2005 10 4399 18 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 11 6595 17 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 12 6141 13 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 13 6137 15 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 14 5288 12 PROSPECTS FOR EPIGENETIC COMPOUNDS IN THE TREATMENT OF AUTOIMMUNE DISEASE. THERE IS GROWING EVIDENCE FOR A ROLE FOR EPIGENETIC MECHANISMS IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN MOST CASES OFAUTOIMMUNE DISEASE THE PRECISE EPIGENETIC MECHANISM INVOLVED REMAINS TO BE RESOLVED, HOWEVER DNA HYPOMETHYLATION ACCOMPANIED BY HYPOACETYLATION OFHISTONE H3/H4 IS COMMONLY OBSERVED. DUE TO THE REVERSIBLE NATURE OF EPIGENETIC MARKS THEIR MAINTENANCE ENZYMES SUCH AS DNA METHYLTRANSFERASES (DNMTS), HISTONE DEACETYLASES (HDACS) AND HISTONE LYSINE METHYLTRANSFERASES (HKMT) ARE ATTRACTIVE DRUG TARGETS. SMALL MOLECULE INHIBITORS OF HISTONE MODIFICATION AND DNA METHYLATION MAINTENANCE ARE INCREASINGLY BECOMING AVAILABLE AND WILL BE USEFUL CHEMICAL BIOLOGICAL TOOLS TO DISSECT EPIGENETIC MECHANISMS IN THESE DISEASES. HOWEVER, ALTHOUGH EPIGENETIC THERAPIES USED IN CANCER TREATMENT ARE A PROMISING STARTING POINT FOR THE EXPLORATION OF AUTOIMMUNE DISEASE TREATMENT, THERE IS A REQUIREMENT FOR MORE SPECIFIC AND LESS TOXIC AGENTS FOR THESE CHRONIC DISEASES OR FOR USE AS CHEMOPREVENTATIVE AGENTS. 2011 15 1260 15 CURRENT VIEWS ON THE INTERPLAY BETWEEN TYROSINE KINASES AND PHOSPHATASES IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY BCR-ABL1 ONCOGENE EXPRESSION. THIS DYSREGULATED PROTEIN-TYROSINE KINASE (PTK) IS KNOWN AS THE PRINCIPAL DRIVER OF THE DISEASE AND IS TARGETED BY TYROSINE KINASE INHIBITORS (TKIS). EXTENSIVE DOCUMENTATION HAS ELUCIDATED HOW THE TRANSFORMATION OF MALIGNANT CELLS IS CHARACTERIZED BY MULTIPLE GENETIC/EPIGENETIC CHANGES LEADING TO THE LOSS OF TUMOR-SUPPRESSOR GENES FUNCTION OR PROTO-ONCOGENES EXPRESSION. THE IMPAIRMENT OF ADEQUATE LEVELS OF SUBSTRATES PHOSPHORYLATION, THUS AFFECTING THE BALANCE PTKS AND PROTEIN PHOSPHATASES (PPS), REPRESENTS A WELL-ESTABLISHED CELLULAR MECHANISM TO ESCAPE FROM SELF-LIMITING SIGNALS. IN THIS REVIEW, WE FOCUS OUR ATTENTION ON THE CHARACTERIZATION OF AND INTERACTIONS BETWEEN PTKS AND PPS, EMPHASIZING THEIR BIOLOGICAL ROLES IN DISEASE EXPANSION, THE REGULATION OF LSCS AND TKI RESISTANCE. WE DECIDED TO SEPARATE THOSE PPS THAT HAVE BEEN VALIDATED IN PRIMARY CELL MODELS OR LEUKEMIA MOUSE MODELS FROM THOSE WHOSE STUDIES HAVE BEEN PERFORMED ONLY IN CELL LINES (AND, THUS, REQUIRE VALIDATION), AS THERE MAY BE DIFFERENCES IN THE MANNER THAT THE ASSOCIATED PATHWAYS ARE MODIFIED UNDER THESE TWO CONDITIONS. THIS REVIEW SUMMARIZES THE ROLES OF DIVERSE PPS, WITH HOPE THAT BETTER KNOWLEDGE OF THE INTERPLAY AMONG PHOSPHATASES AND KINASES WILL EVENTUALLY RESULT IN A BETTER UNDERSTANDING OF THIS DISEASE AND CONTRIBUTE TO ITS ERADICATION. 2021 16 5281 18 PROMOTION AND SELECTION BY SERUM GROWTH FACTORS DRIVE FIELD CANCERIZATION, WHICH IS ANTICIPATED IN VIVO BY TYPE 2 DIABETES AND OBESITY. INDIVIDUALS SUFFERING FROM TYPE 2 DIABETES OR OBESITY EXHIBIT A SIGNIFICANT INCREASE IN THE INCIDENCE OF VARIOUS TYPES OF CANCER. IT IS GENERALLY ACCEPTED THAT THOSE CONDITIONS ARISE FROM OVERNUTRITION AND A SEDENTARY LIFESTYLE, WHICH LEAD TO INSULIN RESISTANCE CHARACTERIZED BY OVERPRODUCTION OF INSULIN ACTING AS A GROWTH FACTOR. THERE IS A CONSENSUS BASED LARGELY ON EPIDEMIOLOGICAL DATA THAT CHRONIC OVERPRODUCTION OF INSULIN IS RESPONSIBLE FOR THE INCREASED INCIDENCE OF CANCER. A MODEL SYSTEM IN CULTURE OF NIH 3T3 CELLS INDUCES THE COLLECTIVE EFFECTS OF SERUM GROWTH FACTORS ON PROGRESSION THROUGH THE STAGES OF FIELD CANCERIZATION. IT SHOWS THAT THE DRIVING FORCE OF PROGRESSION IS PROMOTION OF CELL GROWTH UNDER SELECTION AT HIGH CELL DENSITY, WITH NO REQUIREMENT FOR EXOGENOUS CARCINOGENIC AGENTS. THE EARLY EFFECT IS GRADUAL SELECTION AMONG MANY PREEXISTING, LOW-PENETRANCE PRENEOPLASTIC MUTATIONS OR STABLE EPIGENETIC VARIANTS, FOLLOWED BY SPORADIC, HIGH-PENETRANCE TRANSFORMING VARIANTS, ALL DEPENDENT ON ENDOGENOUS PROCESSES. THE SIGNIFICANCE OF THE RESULTS FOR CANCER IN DIABETIC AND OBESE INDIVIDUALS IS THAT THE INITIAL STAGES OF THE PROCESS INVOLVE MULTIORGAN METABOLIC INTERACTIONS THAT PRODUCE A SYSTEMIC INSULIN RESISTANCE WITH CHRONIC OVERPRODUCTION OF INSULIN AND LOCALIZED FIELD CANCERIZATION. HYPOMAGNESEMIA IS PREVALENT IN THE FOREGOING METABALO/SYSTEMIC DISORDERS, AND MAY ALSO PROVIDE A SELECTIVE MICROENVIRONMENT FOR TUMOR DEVELOPMENT. 2013 17 6334 17 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 18 705 13 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 19 4027 16 LUNG CANCER IN A CF PATIENT: COMBINATION OF BAD LUCK OR IS THERE MORE TO SAY? PATIENTS WITH CYSTIC FIBROSIS HAVE INCREASED RISK FOR GASTROINTESTINAL CANCER, LYMPHOID LEUKEMIA AND TESTICULAR CARCINOMAS. CHRONIC INFLAMMATION DOES NOT SEEM TO BE THE ONLY CONTRIBUTING FACTOR. MUTATIONS AND EPIGENETIC ALTERATIONS IN THE CFTR GENE MAY ALTER SUSCEPTIBILITY TO DEVELOP CANCER. LUNG CANCER IS UP TO NOW NOT FREQUENTLY OBSERVED IN CF PATIENTS. IN LUNG CANCER PATIENTS WITHOUT CF LOW CFTR EXPRESSION IS SIGNIFICANTLY ASSOCIATED WITH ADVANCED STAGING, LYMPH NODE METASTASIS. AS THE MANAGEMENT AND LIFE EXPECTANCY OF PATIENTS WITH CYSTIC FIBROSIS HAVE IMPROVED SUBSTANTIALLY IN RECENT YEARS, WE EXPECT AN INCREASED NUMBER OF THESE PATIENTS DIAGNOSED WITH LUNG CANCER. IN ADDITION, IT IS POSSIBLE THAT THEY, AS A RESULT OF CFTR-DYSFUNCTION, WILL PRESENT WITH MORE AGGRESSIVE LUNG TUMORS. TREATING CANCER IN CF PATIENTS IS A CHALLENGE BECAUSE OF MULTI-ORGAN INVOLVEMENT AND CHRONIC COLONIZATION BY RESISTANT PATHOGENS. THE EFFECTIVENESS AND SAFETY OF IMMUNOTHERAPY IN THIS POPULATION NEEDS TO BE FURTHER EVALUATED. 2021 20 389 13 AN INTEGRATIVE HYPOTHESIS LINKING CANCER, DIABETES AND ATHEROSCLEROSIS: THE ROLE OF MUTATIONS AND EPIGENETIC CHANGES. IT APPEARS THAT THE DISEASE STATES OF CANCER, ALTHEROSCLEROSIS AND DIABETES MIGHT SHARE A COMMON ETIOLOGY. THESE CHRONIC DISEASES APPEAR TO BE MULTI-STAGED IN THEIR PROGRESSION, WITH GENETIC, NUTRITIONAL, PSYCHO-SOCIAL, ENVIRONMENTAL AND VIRAL FACTORS INFLUENCING THEIR APPEARANCE. WE OFFERED A HYPOTHESIS (A "MUTATION THEORY OF DISEASE"), STATING THAT THESE DISEASES CAN BE DESCRIBED BY INITIATION AND PROMOTION PHASES; INITIATION BEING THE RESULT OF THE PRODUCTION OF MUTATED CELLS AFTER UNREPAIRED DAMAGED DNA IS REPLICATED; PROMOTION BEING THE SELECTIVE PROLIFERATION OF THE INITIATED CELLS TO FORM CLONES OF MUTATED CELLS. IT WAS FURTHER POSTULATED THAT PROMOTION AFFECTS CELL PROLIFERATION BY ALTERING A MEMBRANE-CA++ REGULATORY SYSTEM. DEPENDING ON THE NATURE OF THE MUTATION IN THE CLONE OF CELLS, SPECIFIC DISEASE STATES WOULD RESULT. THE ROLES OF RADIATIONS, CHEMICALS, VIRUSES, GENES, NUTRITION AND PSYCHO-SOCIAL STRESS WERE RELATED TO EITHER THE INITIATION (MUTATION PRODUCTION) OR THE PROMOTION (CELL PROLIFERATION) PHASE OF THESE DISEASES. 1980