1 30 180 A BRIEF LOOK AT HASHIMOTO'S DISEASE, ADRENAL INCIDENTALOMAS, OBESITY AND INSULIN RESISTANCE-COULD ENDOCRINE DISRUPTORS BE THE OTHER SIDE OF THE SAME COIN? HASHIMOTO'S DISEASE (HD) IS THE MOST COMMON CAUSE OF HYPOTHYROIDISM IN DEVELOPED COUNTRIES. THE EXACT PATHOMECHANISM BEHIND IT HAS NOT BEEN CLEARLY ESTABLISHED; HOWEVER, AN INTERPLAY OF GENETIC SUSCEPTIBILITY, ENVIRONMENTAL TRIGGERS (INCLUDING DIET) AND EPIGENETIC FACTORS SEEMS TO BE INVOLVED. AMONG THE LATTER, INCREASINGLY MORE ATTENTION HAS BEEN PAID TO SOME HORMONALLY ACTIVE SUBSTANCES, KNOWN AS ENDOCRINE DISRUPTORS, WHICH ARE COMMONLY USED WORLDWIDE. HD HAS BECOME A CONDITION WIDELY REPORTED IN THE MEDIA, ACTING AS A CULPRIT FOR INEXPLICABLE WEIGHT GAIN, CHRONIC FATIGUE OR WEAKNESS. NEVERTHELESS, THE RECOGNITION OF HD IS UNDENIABLY INCREASING AND REPRESENTS A MAJOR PUBLIC HEALTH BURDEN. AT THE SAME TIME, IMPROVING ACCESS TO IMAGING TESTS HAS INCREASED THE NUMBER OF INCIDENTALLY DIAGNOSED ADRENAL TUMORS. ABOVE ALL, THE WIDESPREAD USE OF CHEST COMPUTED TOMOGRAPHY (CT) DUE TO THE COVID-19 PANDEMIC HAS CONTRIBUTED TO FREQUENT INCIDENTAL DETECTION OF ADRENAL LESIONS. FORTUNATELY, A VAST MAJORITY OF THESE FINDINGS ARE ASYMPTOMATIC BENIGN TUMORS WITH NO EXCESSIVE HORMONAL ACTIVITY, AND THEREFORE, THEY ARE DEFINED AS ADRENAL INCIDENTALOMAS (AIS). INTERESTINGLY, RECENT STUDIES HAVE INDICATED THAT PATIENTS WITH AIS ARE MORE PRONE TO OBESITY AND INSULIN RESISTANCE. ALTHOUGH MUTUAL RELATIONSHIPS BETWEEN THE THYROID AND THE ADRENAL GLANDS HAVE BEEN STUDIED WIDELY, STILL, LITTLE IS KNOWN ABOUT THE POSSIBLE PATHOPHYSIOLOGICAL ASSOCIATIONS BETWEEN THYROID AUTOIMMUNITY AND THE OCCURRENCE OF ADRENAL INCIDENTALOMAS. THIS ARTICLE PRESENTS A BRIEF REVIEW OF THE COMMON ENDOCRINE DISORDERS WITH A SPECIAL FOCUS ON THE FREQUENTLY COEXISTING INSULIN RESISTANCE AND/OR OBESITY. FURTHERMORE, IN RESPONSE TO THE RECENT GROWING INTEREST IN ENDOCRINE DISRUPTORS, WITH THEIR TRANSGENERATIONAL EPIGENETIC EFFECTS THAT INFLUENCE HORMONAL SYSTEM FUNCTION, A CONCISE OVERVIEW OF THE TOPIC HAS ALSO BEEN INCLUDED. 2023 2 3934 58 LIVER TUMOR INDUCTION. THE SIGNIFICANCE OF THE DEVELOPMENT OF NODULAR LIVER LESIONS IN RODENTS FOLLOWING THE ADMINISTRATION OF TEST AGENTS RAISES SEVERAL QUESTIONS WHICH COULD BE PLACED IN ONE OF TWO GENERAL CATEGORIES: DIAGNOSTIC AND INTERPRETATIONAL. FROM A DIAGNOSTIC POINT OF VIEW, THE PROPER CLASSIFICATION OF LIVER TUMORS INTO A BENIGN AND MALIGNANT CATEGORY HAS TO BE BASED ON THE DIRECT CORRELATION BETWEEN THE MORPHOLOGY AND THE BIOLOGIC BEHAVIOR OF THE LESIONS. THEREFORE, EXTREME CARE SHOULD BE TAKEN TO SEPARATE THE MALIGNANT TUMORS FROM THE BENIGN AND THE BENIGN NEOPLASIA FROM THE HYPERPLASIA. THE SUBSTITUTION OF THE TERM "NEOPLASTIC NODULE" FOR HYPERPLASTIC NODULE IN RATS IS MISLEADING. MOST OF THESE NODULES, WHEN INDUCED UNDER SPECIAL EXPERIMENTAL CONDITIONS, MAY REGRESS OR REMODEL AND THUS THEY ARE NOT NEOPLASTIC IN NATURE. CHRONIC CARCINOGENICITY BIOASSAYS SHOULD INCLUDE "STOP" TYPE OF TREATMENT LEAVING ENOUGH OF THE OBSERVATIONAL TIME TO ESTABLISH THE FATE OF INDUCED NODULAR LESIONS. THE INDUCTION OF HISTOCHEMICALLY CHANGED FOCI CAN SERVE ONLY AS AN INDICATION OF POTENTIAL HEPATOCARCINOGENICITY AND SHOULD NOT BE EQUATED WITH THE INDUCTION OF BONA FIDE CANCER. THE BIOLOGIC INTERPRETATION OF NODULAR LIVER LESIONS, ESPECIALLY IN MICE, NEEDS FURTHER SCRUTINY BECAUSE THESE LESIONS HAVE A TENDENCY TO DEVELOP SPONTANEOUSLY WITH HIGH INCIDENCE IN SOME STRAINS. THIS CHARACTERISTIC THEN RAISES THE QUESTION AS TO THE MECHANISM BY WHICH VARIOUS AGENTS AUGMENT AND/OR ACCELERATE THE DEVELOPMENT OF SUCH TUMORS. IS THIS ACTION PRIMARILY PROMOTING OR INITIATING IN NATURE OR DOES IT REPRESENT THE INDUCTION OF TUMORS DE NOVO? THE ANSWER TO THIS DILEMMA MAY HAVE A DECISIVE BEARING ON CARCINOGENIC RISK ASSESSMENT AND THE TYPE OF REGULATORY ACTION, SINCE THE PROMOTING AGENTS POSSESS A THRESHOLD EFFECT AND THE PROMOTED CHANGES MAY REGRESS FOLLOWING WITHDRAWAL OF TREATMENT. THE INTERPRETATION OF HEPATOCARCINOGENESIS IS FURTHER COMPLICATED BY THE FACT THAT SEVERAL FACTORS, SUCH AS SEX HORMONAL ENVIRONMENT, INCREASED MITOTIC ACTIVITY FOLLOWING AN EXCESSIVE LOSS OF PARENCHYMAL CELLS, DEGREE OF CALORIC INTAKE, ENZYMATIC COMPLEMENT, AND ANIMALS' AGE AT THE TIME OF THE EXPOSURE TO A TEST AGENT, MAY INFLUENCE THE OUTCOME OF LIVER TUMOR DEVELOPMENT BY MODULATING "INITIATION" AND/OR "PROMOTION" OF CARCINOGENESIS. BROAD FLUCTUATION IN THE HISTORIC INCIDENCE OF LIVER TUMORS FURTHER COMPOUNDS THE COMPLEXITY OF THE PROPER BIOASSAY INTERPRETATION. THE SPECIFICALLY DESIGNED EXPERIMENTS MAY HAVE THE OBJECTIVE TO EXPLORE PREDOMINANTLY THE INITIATING OR PROMOTING EFFECTS OF THE AGENT. SUCH PROTOCOLS SHOULD BE USED WHENEVER NECESSARY TO DIFFERENTIATE BETWEEN THESE TWO MECHANISMS OF ACTION. IN THE CAUCASIANS, THE "SPONTANEOUS" DEVELOPMENT OF THE PRIMARY HEPATOCELLULAR TUMORS IS RARE. THE MAJORITY OF THESE TUMORS ARE MALIGNANT AND RAPIDLY FATAL. ACCORDING TO SOME HUMAN PATHOLOGISTS, THE BENIGN VARIETY OF LIVER TUMORS IS RARE AND IT DOES NOT REPRESENT NECESSARILY A PREMALIGNANT STAGE IN TUMOR DEVELOPMENT. CARCINOMA OF THE LIVER MAY OCCUR IN INFANCY, ESPECIALLY IN MALES BEFORE THE AGE OF 2 YEARS. THIS SUGGESTS A GENETIC CAUSATION OR CARCINOGENIC EXPOSURE IN UTERO. ONE OF THE GEOGRAPHIC FACTORS WHICH SIGNIFICANTLY ENHANCES THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HUMANS IS EXPOSURE TO AFLATOXIN B(1) WHICH IS APPARENTLY POTENTIATED BY CONCURRENT LIVER CIRRHOSIS. BECAUSE MANY MORE AGENTS HAVE BEEN FOUND TO BE HEPATOCARCINOGENIC IN MICE AND RATS THAN IN MEN, A QUESTION ARISES AS TO THE DIRECT RELEVANCE OF RODENT STUDIES TO HUMANS. A BALANCED ASSESSMENT OF THE CARCINOGENICITY OF THE AGENT COULD ONLY BE REACHED IN CONSIDERING BOTH THE PHARMACOKINETICS AND THE DEVELOPMENT OF MALIGNANT NEOPLASIA IN OTHER ORGANS. IN THE CASE OF POSITIVE CARCINOGENICITY ASSESSMENT, THE OUTCOME OF THE MUTAGENICITY BIOASSAYS CAN SUGGEST GENIC (GENOTOXIC) OR PARAGENIC (EPIGENETIC) MODE OF ACTION IN MAMMALIAN SYSTEMS. 1982 3 1701 33 DYNAMIC IMMUNE/INFLAMMATION PRECISION MEDICINE: THE GOOD AND THE BAD INFLAMMATION IN INFECTION AND CANCER. NORMAL OR "GOOD" INFLAMMATION PROCESS STARTS FROM A LOCAL CELLULAR RESPONSE AGAINST INJURY OR ANY INFECTIOUS AGENT, WITH THE ACTIVATION OF NEUTROPHILS, MACROPHAGES, LANGERHANS CELLS, DENDRITIC CELLS, AND INNATE IMMUNE CELLS. CYTOKINES AND CHEMOKINES ARE PRODUCED TO AMPLIFY THE LOCAL INFLAMMATORY PROCESS FOLLOWED BY THE MIGRATION OF IMMUNE CELLS TO THE REGIONAL LYMPH NODES WHERE ADAPTIVE IMMUNE RESPONSE IS INITIATED. SYSTEMIC INFLAMMATION ENHANCES THE BIOLOGICAL RESPONSE TO MOBILIZE ADDITIONAL CELLS FROM CENTRAL AND PERIPHERAL IMMUNE/HEMATOPOIETIC SYSTEM. LOCAL MECHANISMS TO LIMIT INFLAMMATION ARE INITIATED AND LEAD TO HEALING. DURING THE NORMAL INFLAMMATORY PROCESS, THERE IS A BALANCE BETWEEN THE PRODUCTION OF INFLAMMATORY CHEMOKINES/CYTOKINES SUCH AS TUMOR NECROSIS FACTOR (TNF)-ALPHA, INTERLEUKIN (IL)-6 AND IL-1 AND THE PRODUCTION OF COMPOUNDS THAT LIMIT INFLAMMATION AND HAVE AN IMMUNE SUPPRESSIVE EFFECT, SUCH AS IL-10 AND TRANSFORMING FACTOR (TGF) BETA. IL-6 AND IL-6/SOLUBLE IL-6 RECEPTOR (R) COMPLEX STIMULATE LIVER CELLS TO PRODUCE INFLAMMATORY PROTEINS, WHICH REPRESENTS THE SYSTEMIC INFLAMMATION RESPONSE. THE MAGNITUDE AND THE DURATION OF THE SYSTEMIC INFLAMMATORY RESPONSE ARE LINKED TO THE CAUSE, UNDER GENETIC AND EPIGENETIC CONTROL. SIGNIFICANT INFLAMMATION AS SEEN IN SEPTIC SHOCK, IN SEVERE FORMS OF INFECTIONS OR IN CERTAIN ACTIVE CANCERS, REPRESENTS THE "BAD INFLAMMATION", CORRELATED WITH A POOR PROGNOSIS. IN ADDITION, THE PERSISTENCE OF A CHRONIC SMOLDERING INFLAMMATION MAY LEAD TO PATHOLOGICAL SITUATIONS WHICH ARE OBSERVED IN THE MAJORITY OF INFLAMMATORY, DEGENERATIVE, DYSMETABOLIC, OR DYSIMMUNE DISEASES AND CANCER. CHRONIC SMOLDERING INFLAMMATION IS A CROSS BETWEEN DIFFERENT PATHOLOGICAL SITUATIONS POSSIBLY LINKED. IN ADDITION, WITHIN THE TUMOR MICROENVIRONMENT, INFLAMMATORY PROCESS RESULTS FROM DIFFERENT CELLULAR MECHANISMS MODULATED BY METABOLIC AND VASCULAR CHANGES. ON THE CONTRARY, A LIMITED AND BALANCED INFLAMMATION INITIATES THE NORMAL IMMUNE RESPONSE, INCLUDING THE ADAPTIVE RESPONSE WHICH AMPLIFIES ANY IMMUNOTHERAPY, INCLUDING VACCINES. IMMUNE CHECKPOINT INHIBITORS AND CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS ARE ASSOCIATED WITH CYTOKINE RELEASE SYNDROME, A CLINICAL RISK LEADING TO THE USE OF ANTI-CYTOKINE DRUGS. NOWADAYS, IT IS TIME TO MONITOR THE DYNAMIC INFLAMMATORY PROCESS FOR A BETTER IMMUNE PRECISION MEDICINE IN BOTH INFECTIONS AND CANCER. 2021 4 6142 41 THE EVALUATION OF CYTOKINES TO HELP ESTABLISH DIAGNOSIS AND GUIDE TREATMENT OF AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES. OUR KNOWLEDGE OF THE ROLE OF CYTOKINES IN PATHOLOGIC CONDITIONS HAS INCREASED CONSIDERABLY WITH THE EMERGENCE OF MOLECULAR AND GENETIC STUDIES, PARTICULARLY IN THE CASE OF AUTOINFLAMMATORY MONOGENIC DISEASES. MANY RARE DISORDERS, CONSIDERED ORPHAN UNTIL RECENTLY, ARE DIRECTLY RELATED TO ABNORMAL GENE REGULATION, AND THE TREATMENT WITH BIOLOGIC AGENTS (BIOLOGICS) TARGETING CYTOKINE RECEPTORS, INTRACELLULAR SIGNALING OR SPECIFIC CYTOKINES IMPROVE THE SYMPTOMS OF AN INCREASING NUMBER OF CHRONIC INFLAMMATORY DISEASES. AS IT IS CURRENTLY IMPOSSIBLE TO SYSTEMATICALLY CONDUCT GENETIC STUDIES FOR ALL PATIENTS WITH AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES, THE EVALUATION OF CYTOKINES CAN BE SEEN AS A SIMPLE, LESS TIME CONSUMING, AND LESS EXPENSIVE ALTERNATIVE. THIS APPROACH COULD BE ESPECIALLY USEFUL WHEN THE DIAGNOSIS OF SYNDROMES OF DISEASES OF UNKNOWN ETIOLOGY REMAINS PROBLEMATIC. THE EVALUATION OF CYTOKINES COULD ALSO HELP AVOID THE CURRENT TRIAL-AND-ERROR APPROACH, WHICH HAS THE DISADVANTAGES OF EXPOSING PATIENTS TO INEFFECTIVE DRUGS WITH POSSIBLE UNNECESSARY SIDE EFFECTS AND PERMANENT ORGAN DAMAGES. IN THIS REVIEW, WE DISCUSS THE VARIOUS POSSIBILITIES, AS WELL AS THE LIMITATIONS OF EVALUATING THE CYTOKINE PROFILES OF PATIENTS SUFFERING FROM AUTOINFLAMMATORY AND AUTOIMMUNE DISEASES, WITH METHODS SUCH AS DIRECT DETECTION OF CYTOKINES IN THE PLASMA/SERUM OR FOLLOWING EX VIVO STIMULATION OF PBMCS LEADING TO THE PRODUCTION OF THEIR CYTOKINE SECRETOME. THE PATIENTS' SECRETOME, COMBINED WITH BIOMARKERS RANGING FROM GENETIC AND EPIGENETIC ANALYSES TO IMMUNOLOGIC BIOMARKERS, MAY HELP NOT ONLY THE DIAGNOSIS BUT ALSO GUIDE THE CHOICE OF BIOLOGICS FOR MORE EFFICIENT AND RAPID TREATMENTS. 2020 5 5584 29 ROLE OF OBESITY IN FEMALE REPRODUCTION. CONTEMPORARY SCIENTISTS NEED NO "P VALUE" AND "RELATIVE RISK" STATISTICS TO BE EXQUISITELY AWARE OF THE INCREASING PREVALENCE OF OBESITY AND COMPLICATIONS POSED BY OBESITY. IT IS NOW WELL RECOGNIZED THAT OBESITY IS STRONGLY ASSOCIATED WITH TYPE 2 DIABETES, HYPERTENSION, VASCULAR DISEASE, TUMORS AND REPRODUCTIVE DISORDERS. OBESE WOMEN SHOW LOWER LEVELS OF GONADOTROPIN HORMONES, REDUCED FECUNDITY, HIGHER MISCARRIAGE RATES AND POORER OUTCOMES OF IN VITRO FERTILIZATION, REVEALING THAT OBESITY AFFECTS FEMALE REPRODUCTION. IN ADDITION, ADIPOSE TISSUE CONTAINS SPECIAL IMMUNE CELLS AND OBESITY-INDUCED INFLAMMATION IS A CHRONIC, LOW-GRADE INFLAMMATORY RESPONSE. HEREIN, WE MAINLY REVIEW DETRIMENTAL INFLUENCES OF OBESITY IN THE COMPLETE PROCESS OF FEMALE REPRODUCTION, INCLUDING HYPOTHALAMIC-PITUITARY-OVARIAN AXIS, OOCYTE MATURATION, EMBRYO AND FETAL DEVELOPMENT. IN THE LATTER PART, WE VIEW OBESITY-INDUCED INFLAMMATION AND DISCUSS RELATED EPIGENETIC IMPACT ON FEMALE REPRODUCTION. 2023 6 5892 46 SYSTEMS GENETICS VIEW OF ENDOMETRIOSIS: A COMMON COMPLEX DISORDER. ENDOMETRIOSIS IS A CONDITION IN WHICH CELLS DERIVED FROM THE ENDOMETRIUM GROW OUTSIDE THE UTERUS, E.G. IN THE PERITONEUM (EXTERNAL GENITAL ENDOMETRIOSIS). AS THESE CELLS ARE UNDER THE INFLUENCE OF FEMALE HORMONES, MAJOR SYMPTOMS OF ENDOMETRIOSIS ARE PAIN, ESPECIALLY DURING THE CYCLE, AND INFERTILITY. NUMEROUS HYPOTHESES FOR THE FORMATION OF ENDOMETRIOSIS CAN BE FOUND IN THE LITERATURE, BUT THERE IS GROWING EVIDENCE OF SERIOUS GENETIC CONTRIBUTIONS TO ENDOMETRIOSIS SUSCEPTIBILITY. THE INVOLVEMENT OF GENES, STEROID HORMONE METABOLISM, IMMUNOLOGICAL REACTIONS, RECEPTOR FORMATION, INFLAMMATION, PROLIFERATION, APOPTOSIS, INTERCELLULAR ADHESION, CELL INVASION AND ANGIOGENESIS AS WELL AS GENES REGULATING THE ACTIVITY OF AFOREMENTIONED ENZYMES HAVE BEEN SUGGESTED. SOME MORE RECENTLY SUGGESTED CANDIDATE GENES PICKED UP IN GENOME-WIDE ASSOCIATION STUDIES ARE INVOLVED IN ONCOGENESIS, METAPLASIA OF ENDOMETRIUM CELLS AND PATHWAYS OF EMBRYONIC DEVELOPMENT OF THE FEMALE REPRODUCTIVE SYSTEM. HOWEVER, GENE MUTATIONS PROVEN TO BE CAUSATIVE FOR ENDOMETRIOSIS HAVE NOT BEEN IDENTIFIED SO FAR, EVEN THOUGH THE ABNORMAL EXPRESSION OF CANDIDATE GENES FOR ENDOMETRIOSIS COULD BE PROVOKED BY DIFFERENT EPIGENETIC MODIFICATIONS INCLUDING DNA METHYLATION, HETEROCHROMATIZATION OR INTRODUCTION OF REGULATORY MIRNA. WE HYPOTHESIZE THAT ENDOMETRIOSIS IS INDUCED BY A COMBINATION OF ABNORMAL GENETIC AND/OR EPIGENETIC MUTATIONS: THE LATTER PAVE THE WAY FOR PATHOLOGICAL CHANGES WHICH BECOME IRREVERSIBLE, AND ACCORDING TO THE "EPIGENETIC LANDSCAPE" THEORY, THIS PROCEEDS TO THE TYPICAL CLINICAL MANIFESTATIONS. TWO STAGES IN THE ENDOMETRIOSIS PATHWAY ARE SUGGESTED: (1) INDUCTION OF PRIMARY ENDOMETRIAL CELLS TOWARD ENDOMETRIOSIS, AND (2) IMPLANTATION AND PROGRESSION OF THESE CELLS INTO ENDOMETRIOSIS LESIONS. THE MODEL FAVORS ENDOMETRIOSIS AS AN OUTGROWTH OF PRIMARY CELLS DIFFERENT IN THEIR ORIGIN, CANALIZATION OF PATHOLOGICAL PROCESSES, MANIFESTATION DIVERSITY PROVOKED BY UNIQUE GENETIC BACKGROUND AND EPIGENETIC INFLUENCES, WHICH RESULT IN MANY DIFFERENT CLINICAL FORMS OF THE DISEASE. 2015 7 737 45 CANCER STEM CELLS. THERE IS AN INCREASING EVIDENCE SUPPORTING THE CANCER STEM CELL HYPOTHESIS. NORMAL STEM CELLS IN THE ADULT ORGANISM ARE RESPONSIBLE FOR TISSUE RENEWAL AND REPAIR OF AGED OR DAMAGED TISSUE. A SUBSTANTIAL CHARACTERISTIC OF STEM CELLS IS THEIR ABILITY FOR SELF-RENEWAL WITHOUT LOSS OF PROLIFERATION CAPACITY WITH EACH CELL DIVISION. THE STEM CELLS ARE IMMORTAL, AND RATHER RESISTANT TO ACTION OF DRUGS. THEY ARE ABLE TO DIFFERENTIATE AND FORM SPECIFIC TYPES OF TISSUE DUE TO THE INFLUENCE OF MICROENVIRONMENTAL AND SOME OTHER FACTORS. STEM CELLS DIVIDE ASYMMETRICALLY PRODUCING TWO DAUGHTER CELLS -- ONE IS A NEW STEM CELL AND THE SECOND IS PROGENITOR CELL, WHICH HAS THE ABILITY FOR DIFFERENTIATION AND PROLIFERATION, BUT NOT THE CAPABILITY FOR SELF-RENEWAL. CANCER STEM CELLS ARE IN MANY ASPECTS SIMILAR TO THE STEM CELLS. IT HAS BEEN PROVEN THAT TUMOR CELLS ARE HETEROGENEOUS COMPRISING RARE TUMOR INITIATING CELLS AND ABUNDANT NON-TUMOR INITIATING CELLS. TUMOR INITIATING CELLS -- CANCER STEM CELLS HAVE THE ABILITY OF SELF-RENEWAL AND PROLIFERATION, ARE RESISTANT TO DRUGS, AND EXPRESS TYPICAL MARKERS OF STEM CELLS. IT IS NOT CLEAR WHETHER CANCER STEM CELLS ORIGINATE FROM NORMAL STEM CELLS IN CONSEQUENCE OF GENETIC AND EPIGENETIC CHANGES AND/OR BY REDIFFERENTIATION FROM SOMATIC TUMOR CELLS TO THE STEM-LIKE CELLS. PROBABLY BOTH MECHANISMS ARE INVOLVED IN THE ORIGIN OF CANCER STEM CELLS. DYSREGULATION OF STEM CELL SELF-RENEWAL IS A LIKELY REQUIREMENT FOR THE DEVELOPMENT OF CANCER. ISOLATION AND IDENTIFICATION OF CANCER STEM CELLS IN HUMAN TUMORS AND IN TUMOR CELL LINES HAS BEEN SUCCESSFUL. TO DATE, THE EXISTENCE OF CANCER STEM CELLS HAS BEEN PROVEN IN ACUTE AND CHRONIC MYELOID LEUKEMIA, IN BREAST CANCER, IN BRAIN TUMORS, IN LUNG CANCER AND GASTROINTESTINAL TUMORS. CANCER STEM CELL MODEL IS ALSO CONSISTENT WITH SOME CLINICAL OBSERVATIONS. ALTHOUGH STANDARD CHEMOTHERAPY KILLS MOST CELLS IN A TUMOR, CANCER STEM CELLS REMAIN VIABLE. DESPITE THE SMALL NUMBER OF SUCH CELLS, THEY MIGHT BE THE CAUSE OF TUMOR RECURRENCE, SOMETIMES MANY YEARS AFTER THE "SUCCESSFUL" TREATMENT OF PRIMARY TUMOR. GROWTH OF METASTASES IN DISTINCT AREAS OF BODY AND THEIR CELLULAR HETEROGENEITY MIGHT BE CONSEQUENCE OF CANCER STEM CELL DIFFERENTIATION AND/OR DEDIFFERENTIATION AND ASYMMETRIC DIVISION OF CANCER STEM CELLS. FURTHER CHARACTERIZATION OF CANCER STEM CELLS IS NEEDED IN ORDER TO FIND WAYS TO DESTROY THEM, WHICH MIGHT CONTRIBUTE SIGNIFICANTLY TO THE THERAPEUTIC MANAGEMENT OF MALIGNANT TUMORS. 2005 8 4732 37 NOVEL BIOMARKERS FOR INFLAMMATORY BOWEL DISEASE AND COLORECTAL CANCER: AN INTERPLAY BETWEEN METABOLIC DYSREGULATION AND EXCESSIVE INFLAMMATION. PERSISTENT INFLAMMATION CAN TRIGGER ALTERED EPIGENETIC, INFLAMMATORY, AND BIOENERGETIC STATES. INFLAMMATORY BOWEL DISEASE (IBD) IS AN IDIOPATHIC DISEASE CHARACTERIZED BY CHRONIC INFLAMMATION OF THE GASTROINTESTINAL TRACT, WITH EVIDENCE OF SUBSEQUENT METABOLIC SYNDROME DISORDER. STUDIES HAVE DEMONSTRATED THAT AS MANY AS 42% OF PATIENTS WITH ULCERATIVE COLITIS (UC) WHO ARE FOUND TO HAVE HIGH-GRADE DYSPLASIA, EITHER ALREADY HAD COLORECTAL CANCER (CRC) OR DEVELOP IT WITHIN A SHORT TIME. THE PRESENCE OF LOW-GRADE DYSPLASIA IS ALSO PREDICTIVE OF CRC. MANY SIGNALING PATHWAYS ARE SHARED AMONG IBD AND CRC, INCLUDING CELL SURVIVAL, CELL PROLIFERATION, ANGIOGENESIS, AND INFLAMMATORY SIGNALING PATHWAYS. CURRENT IBD THERAPEUTICS TARGET A SMALL SUBSET OF MOLECULAR DRIVERS OF IBD, WITH MANY FOCUSED ON THE INFLAMMATORY ASPECT OF THE PATHWAYS. THUS, THERE IS A GREAT NEED TO IDENTIFY BIOMARKERS OF BOTH IBD AND CRC, THAT CAN BE PREDICTIVE OF THERAPEUTIC EFFICACY, DISEASE SEVERITY, AND PREDISPOSITION TO CRC. IN THIS STUDY, WE EXPLORED THE CHANGES IN BIOMARKERS SPECIFIC FOR INFLAMMATORY, METABOLIC, AND PROLIFERATIVE PATHWAYS, TO HELP DETERMINE THE RELEVANCE TO BOTH IBD AND CRC. OUR ANALYSIS DEMONSTRATED, FOR THE FIRST TIME IN IBD, THE LOSS OF THE TUMOR SUPPRESSOR PROTEIN RAS ASSOCIATED FAMILY PROTEIN 1A (RASSF1A), VIA EPIGENETIC CHANGES, THE HYPERACTIVATION OF THE OBLIGATE KINASE OF THE NOD2 PATHOGEN RECOGNITION RECEPTOR (RECEPTOR INTERACTING PROTEIN KINASE 2 [RIPK2]), THE LOSS OF ACTIVATION OF THE METABOLIC KINASE, AMP ACTIVATED PROTEIN KINASE (AMPKALPHA1), AND, LASTLY, THE ACTIVATION OF THE TRANSCRIPTION FACTOR AND KINASE YES ASSOCIATED PROTEIN (YAP) KINASE, THAT IS INVOLVED IN PROLIFERATION OF CELLS. THE EXPRESSION AND ACTIVATION STATUS OF THESE FOUR ELEMENTS ARE MIRRORED IN IBD, CRC, AND IBD-CRC PATIENTS AND, IMPORTANTLY, IN MATCHED BLOOD AND BIOPSY SAMPLES. THE LATTER WOULD SUGGEST THAT BIOMARKER ANALYSIS CAN BE PERFORMED NON-INVASIVELY, TO UNDERSTAND IBD AND CRC, WITHOUT THE NEED FOR INVASIVE AND COSTLY ENDOSCOPIC ANALYSIS. THIS STUDY, FOR THE FIRST TIME, ILLUSTRATES THE NEED TO UNDERSTAND IBD OR CRC BEYOND AN INFLAMMATORY PERSPECTIVE AND THE VALUE OF THERAPEUTICS DIRECTED TO RESET ALTERED PROLIFERATIVE AND METABOLIC STATES WITHIN THE COLON. THE USE OF SUCH THERAPEUTICS MAY TRULY DRIVE PATIENTS INTO REMISSION. 2023 9 1010 37 CHRONICALLY ELEVATED PROLIFERATION AS A RISK FACTOR FOR NEOPLASIA. CHRONIC DISEASE CONDITIONS THAT ARE ASSOCIATED WITH ELEVATED PROLIFERATION ARE WELL ESTABLISHED AS RISK FACTORS FOR CANCER DEVELOPMENT. THESE MAY BE DUE TO VIRUSES (FOR EXAMPLE, IN THE CASE OF HEPATITIS AND LIVER CANCER), BACTERIAL INFECTIONS, PARASITE INFESTATION OR PHYSICAL TRAUMA. IN ADDITION TO THESE EXOGENOUS AGENTS THERE ARE ALSO METABOLIC ABNORMALITIES THAT CAN CONTRIBUTE, CAUSED BY GENETIC OR EPIGENETIC INFLUENCE. IN THE LATTER CASE, AN INCREASE IN SERUM LEVELS OF THE HORMONES OESTROGEN, TESTOSTERONE AND INSULIN MAY BE OF SPECIAL IMPORTANCE. THE PRESENT REVIEW CONCENTRATES ATTENTION ON FACTORS THAT INDUCE ELEVATED CELL TURNOVER AND FOR WHICH THERE IS EPIDEMIOLOGICAL AND/OR EXPERIMENTAL EVIDENCE OF A LINK WITH NEOPLASIA, WITH PARTICULAR STRESS ON THE INDIVIDUAL ORGAN OR TISSUE LEVEL. 1998 10 3694 44 INFLAMMATORY COMPONENTS OF THE THYROID CANCER MICROENVIRONMENT: AN AVENUE FOR IDENTIFICATION OF NOVEL BIOMARKERS. THE INCIDENCE OF THYROID CANCER IN THE UNITED STATES IS ON THE RISE WITH AN APPRECIABLY HIGH DISEASE RECURRENCE RATE OF 20-30%. ANAPLASTIC THYROID CANCER (ATC), ALTHOUGH RARE IN OCCURRENCE, IS AN AGGRESSIVE FORM OF CANCER WITH LIMITED TREATMENT OPTIONS AND BLEAK CURE RATES. THIS CHAPTER USES DISCUSSIONS OF IN VITRO MODELS THAT ARE REPRESENTATIVE OF PAPILLARY, ANAPLASTIC, AND FOLLICULAR THYROID CANCER TO EVALUATE THE CROSSTALK BETWEEN SPECIFIC CELLS OF THE TUMOR MICROENVIRONMENT (TME), WHICH SERVES AS A HIGHLY HETEROGENEOUS REALM OF SIGNALING CASCADES AND METABOLISM THAT ARE ASSOCIATED WITH TUMORIGENESIS. THE CELLULAR CONSTITUENTS OF THE TME CARRY OUT VARYING CHARACTERISTIC IMMUNOMODULATORY FUNCTIONS THAT ARE DISCUSSED THROUGHOUT THIS CHAPTER. THE AFOREMENTIONED CELL TYPES INCLUDE CANCER-ASSOCIATED FIBROBLASTS (CAFS), ENDOTHELIAL CELLS (ECS), AND CANCER STEM CELLS (CSCS), AS WELL AS SPECIFIC IMMUNE CELLS, INCLUDING NATURAL KILLER (NK) CELLS, DENDRITIC CELLS (DCS), MAST CELLS, T REGULATORY (TREG) CELLS, CD8+ T CELLS, AND TUMOR-ASSOCIATED MACROPHAGES (TAMS). TAM-MEDIATED INFLAMMATION IS ASSOCIATED WITH A POOR PROGNOSIS OF THYROID CANCER, AND THE MOLECULAR BASIS OF THE CELLULAR CROSSTALK BETWEEN MACROPHAGES AND THYROID CANCER CELLS WITH RESPECT TO INDUCING A METASTATIC PHENOTYPE IS NOT YET KNOWN. THE DYNAMIC NATURE OF THE PHYSIOLOGICAL TRANSITION TO PATHOLOGICAL METASTATIC PHENOTYPES WHEN ESTABLISHING THE TME ENCOMPASSES A WIDE RANGE OF CHARACTERISTICS THAT ARE FURTHER EXPLORED WITHIN THIS CHAPTER, INCLUDING THE ROLES OF SOMATIC MUTATIONS AND EPIGENETIC ALTERATIONS THAT DRIVE THE GENETIC HETEROGENEITY OF CANCER CELLS, ALLOWING FOR SELECTIVE ADVANTAGES THAT AID IN THEIR PROLIFERATION. INDUCTION OF THESE PROLIFERATING CELLS IS TYPICALLY ACCOMPLISHED THROUGH INFLAMMATORY INDUCTION, WHEREBY CHRONIC INFLAMMATION SETS UP A CONSTANT PHYSIOLOGICAL STATE OF INFLAMMATORY CELL RECRUITMENT. THE SECRETIONS OF THESE INFLAMMATORY CELLS CAN ALTER THE GENETIC MAKEUP OF PROLIFERATING CELLS, WHICH CAN IN TURN, PROMOTE TUMOR GROWTH.THIS CHAPTER ALSO PRESENTS AN IN-DEPTH ANALYSIS OF MOLECULAR INTERACTIONS WITHIN THE TME, INCLUDING SECRETORY CYTOKINES AND EXOSOMES. SINCE THE EXOSOMAL CARGO OF A CELL IS A REFLECTION AND FINGERPRINT OF THE ORIGINATING PARENTAL CELLS, THE PROFILING OF EXOSOMAL MIRNA DERIVED FROM THYROID CANCER CELLS AND MACROPHAGES IN THE TME MAY SERVE AS AN IMPORTANT STEP IN BIOMARKER DISCOVERY. IDENTIFICATION OF A DISTINCT SET OF TUMOR SUPPRESSIVE MIRNAS DOWNREGULATED IN ATC-SECRETED EXOSOMES INDICATES THEIR ROLE IN THE REGULATION OF TUMOR SUPPRESSIVE GENES THAT MAY INCREASE THE METASTATIC PROPENSITY OF ATC. ADDITIONALLY, THE HIGH EXPRESSION OF PRO-INFLAMMATORY CYTOKINES IN STUDIES LOOKING AT THYROID CANCER AND ACTIVATED MACROPHAGE CONDITIONED MEDIA SUGGESTS THE EXISTENCE OF AN INFLAMMATORY TME IN THYROID CANCER. NEW FINDINGS ARE SUGGESTIVE OF THE PRESENCE OF A METASTATIC NICHE IN ATC TISSUES THAT IS INFLUENCED BY THYROID TUMOR MICROENVIRONMENT SECRETOME-INDUCED EPITHELIAL TO MESENCHYMAL TRANSITION (EMT), MEDIATED BY A RECIPROCAL INTERACTION BETWEEN THE PRO-INFLAMMATORY M1 MACROPHAGES AND THE THYROID CANCER CELLS. THUS, TARGETING THE METASTATIC THYROID CARCINOMA MICROENVIRONMENT COULD OFFER POTENTIAL THERAPEUTIC BENEFITS AND SHOULD BE EXPLORED FURTHER IN PRECLINICAL AND TRANSLATIONAL MODELS OF HUMAN METASTATIC THYROID CANCER. 2021 11 5685 35 SHOULD WE INVEST IN BIOLOGICAL AGE PREDICTORS TO TREAT COLORECTAL CANCER IN OLDER ADULTS? COLORECTAL CANCER (CRC) IS A CHRONIC DISEASE OF THE OLD POPULATION WITH SLOW DEVELOPMENT PROGRESSING INTO CLINICAL SIGNS AND SYMPTOMS. BIOLOGICAL AGING IS CHARACTERIZED BY E.G. MITOCHONDRIAL DYSFUNCTION AND EPIGENETIC ALTERATIONS (E.G. METHYLATION) - MECHANISMS THAT ARE ALSO IMPORTANT IN CANCER DEVELOPMENT. FOR CRC, SPECIFIC TYPES OF TUMORS ARE DISTINGUISHABLE BY THEIR METHYLATION PATTERNS AND SEVERAL DETECTION METHODS USING DIFFERENT EPIGENETIC MARKS HAVE BEEN DEVELOPED AS SIGNATURES FOR THE DISEASE. BIOLOGICAL AGE ASSESSED BY DNA METHYLATION PATTERNS FROM BLOOD, I.E. THE EPIGENETIC CLOCK, IS HIGHER IN CRC PATIENTS COMPARED TO CONTROLS, AND MAY BE A TOOL FOR IDENTIFYING INDIVIDUALS AT INCREASED RISK FOR CRC. OTHER TYPES OF BIOMARKERS OF AGING ARE USEFUL TO CALCULATE BIOLOGICAL AGE, SUCH AS METABOLITES, PROTEIN LEVELS, INFLAMMATORY MARKERS AND CLINICAL BIOMARKERS, WHERE COMPOSITE SCORES OF BIOMARKERS HAVE BEEN USED TO ASSESS THE RISK OF CRC AND COLORECTAL ADENOMAS. CLINICAL ASSESSMENTS OF BIOLOGICAL AGING INCLUDES FRAILTY, WHICH IS A GERIATRIC SYNDROME CHARACTERIZED BY INCREASED VULNERABILITY TO ADVERSE OUTCOMES. MORE THAN HALF OF THE CRC PATIENTS ARE ESTIMATED TO BE FRAIL OR PRE-FRAIL, AND THESE INDIVIDUALS ARE AT INCREASED RISK OF POSTOPERATIVE COMPLICATIONS, POORER PROGNOSIS, TREATMENT INTOLERANCE AND DEATH. HENCE, CONSIDERING FRAILTY AS PART OF BIOLOGICAL AGE IN CRC PATIENTS MAY HELP IDENTIFYING THOSE AT NEED OF CLOSE MONITORING. IN SUMMARY, FUTURE SCREENING PROGRAMS FOR CRC MAY MAKE USE OF BIOLOGICAL AGE ASSESSMENTS, E.G. BY EPIGENETIC CLOCK OR COMPOSITE SCORES. MONITORING DISEASE RELAPSE AND TREATMENT RESPONSE SHOULD BE ENHANCED IN FRAIL INDIVIDUALS FOR BETTER PROGNOSIS. 2020 12 5543 33 ROLE OF ENDOGENOUS GLUCOCORTICOIDS IN CANCER IN THE ELDERLY. ALTHOUGH NOT A DISEASE ITSELF, AGING REPRESENTS A RISK FACTOR FOR MANY AGING-RELATED ILLNESSES, INCLUDING CANCER. NUMEROUS CAUSES UNDERLIE THE INCREASED INCIDENCE OF MALIGNANCIES IN THE ELDERLY, FOR EXAMPLE, GENOMIC INSTABILITY AND EPIGENETIC ALTERATIONS THAT OCCUR AT CELLULAR LEVEL, WHICH ALSO INVOLVE THE IMMUNE CELLS. THE PROGRESSIVE DECLINE OF THE IMMUNE SYSTEM FUNCTIONS THAT OCCURS IN AGING DEFINES IMMUNOSENESCENCE, AND INCLUDES BOTH INNATE AND ADAPTIVE IMMUNITY; THE LATTER UNDERGOES MAJOR ALTERATIONS. AGING AND CHRONIC STRESS SHARE THE ABNORMAL HYPOTHALAMIC(-)PITUITARY(-)ADRENAL AXIS ACTIVATION, WHERE ALTERED PERIPHERAL GLUCOCORTICOIDS (GC) LEVELS AND CHRONIC STRESS HAVE BEEN ASSOCIATED WITH ACCELERATED CELLULAR AGING, PREMATURE IMMUNOSENESCENCE, AND AGING-RELATED DISEASES. CONSEQUENTLY, CHANGES IN GC LEVELS AND SENSITIVITY CONTRIBUTE TO THE SIGNS OF IMMUNOSENESCENCE, NAMELY FEWER NAIVE T CELLS, POOR IMMUNE RESPONSE TO NEW ANTIGENS, DECREASED CELL-MEDIATED IMMUNITY, AND THYMIC INVOLUTION. GC SIGNALING ALTERATIONS ALSO INVOLVE EPIGENETIC ALTERATIONS IN DNA METHYLATION, WITH TRANSCRIPTION MODIFICATIONS THAT MAY CONTRIBUTE TO IMMUNOSENESCENCE. IMMUNE CELL AGING LEADS TO DECREASED LEVELS OF IMMUNOSURVEILLANCE, THEREBY PROVIDING TUMOR CELLS ONE MORE ROUTE FOR IMMUNE SYSTEM ESCAPE. HERE, THE CONTRIBUTION OF GC SECRETION AND SIGNALING DYSREGULATION TO THE INCREASED INCIDENCE OF TUMORIGENESIS IN THE ELDERLY IS REVIEWED. 2018 13 4977 54 PATHOPHYSIOLOGY AND EVOLUTIONARY ASPECTS OF DIETARY FATS AND LONG-CHAIN POLYUNSATURATED FATTY ACIDS ACROSS THE LIFE CYCLE. DIETARY FAT IS OUR SECOND MOST IMPORTANT ENERGY-PRODUCING MACRONUTRIENT. IT ALSO CONTAINS FATTY ACIDS AND VITAMINS ESSENTIAL FOR GROWTH, DEVELOPMENT, AND MAINTENANCE OF GOOD HEALTH. DIETARY FAT QUANTITY AND QUALITY HAVE BEEN SUBJECT TO TREMENDOUS CHANGE OVER THE PAST 10,000 YEARS. THIS HAS, TOGETHER WITH OTHER MAN-MADE CHANGES IN OUR ENVIRONMENT, CAUSED A CONFLICT WITH OUR SLOWLY ADAPTING GENOME THAT IS IMPLICATED IN "TYPICALLY WESTERN" DISEASES. RATHER THAN REDUCING OUR LIFE EXPECTANCY, THESE DISEASES NOTABLY DIMINISH OUR NUMBER OF YEARS IN HEALTH. IMPORTANT CHANGES IN DIETARY FAT QUALITY ARE THE INCREASED INTAKES OF CERTAIN SATURATED FATTY ACIDS (SAFA) AND LINOLEIC ACID (LA), INTRODUCTION OF INDUSTRIALLY PRODUCED TRANS FATTY ACIDS, AND REDUCED INTAKES OF OMEGA3 FATTY ACIDS, NOTABLY ALPHA-LINOLENIC ACID (ALA) FROM VEGETABLE SOURCES AND EICOSAPENTAENOIC ACID (EPA) AND DOCOSAHEXAENOIC ACID (DHA) FROM FISH. THE PATHOPHYSIOLOGICAL EFFECTS OF THESE CHANGES ARE DIVERSE, BUT ARE INCREASINGLY ASCRIBED TO INDUCTION OF A PROINFLAMMATORY STATE THAT PROGRESSES EASILY TO CHRONIC LOW-GRADE INFLAMMATION. THE LATTER MIGHT AFFECT VIRTUALLY ALL ORGANS AND SYSTEMS, POSSIBLY BEGINNING AT CONCEPTION, AND POSSIBLY EVEN PRIOR TO GAMETOGENESIS THROUGH EPIGENETIC ALTERATIONS. LOW-GRADE INFLAMMATION MIGHT BE A COMMON DENOMINATOR OF THE METABOLIC SYNDROME AND ITS SEQUELAE (E.G., CORONARY ARTERY DISEASE (CAD), DIABETES MELLITUS TYPE 2, SOME TYPES OF CANCER, AND PREGNANCY COMPLICATIONS), SOME PSYCHIATRIC DISEASES (E.G., MAJOR AND POSTPARTUM DEPRESSION, SCHIZOPHRENIA, AND AUTISM), AND NEURODEGENERATIVE DISEASES (E.G., ALZHEIMER'S DISEASE, PARKINSON'S DISEASE). THE LONG-CHAIN POLYUNSATURATED FATTY ACIDS (LCPUFA) ARACHIDONIC ACID (AA), EPA, AND DHA ARE INTIMATELY RELATED TO THE INITIATION AND RESOLUTION OF INFLAMMATORY RESPONSES. THE CURRENT BALANCE BETWEEN AA AND EPA + DHA IS HOWEVER DISTURBED BY THE DOMINANCE OF AA, WHICH ORIGINATES FROM THE DIET OR SYNTHESIS FROM LA. LCPUFA ARE TOGETHER WITH THEIR HIGHLY POTENT METABOLITES (PROSTAGLANDINS, THROMBOXANES, LEUKOTRIENES, RESOLVINS, AND (NEURO)PROTECTINS) INVOLVED IN THE FUNCTIONING OF MEMBRANE-BOUND RECEPTORS, TRANSPORTERS, ION CHANNELS, AND ENZYMES, AND ALSO IN SIGNAL TRANSDUCTION AND GENE EXPRESSION. AMONG THEIR MANY TARGETS ARE NUCLEAR RECEPTORS WHICH, UPON LIGATION WITH LCPUFA AND THEIR METABOLITES, FUNCTION AS TRANSCRIPTION FACTORS OF A VARIETY OF GENES FUNCTIONING IN MANY PATHWAYS. FOR INSTANCE, THE TARGETED PEROXISOME PROLIFERATORS-ACTIVATED RECEPTORS (PPARS) ARE STRATEGIC INTERMEDIATES IN THE COORDINATED EXPRESSION OF PROTEINS WITH FUNCTIONS IN, FOR EXAMPLE, LIPID AND GLUCOSE HOMEOSTASIS AND INFLAMMATORY REACTIONS. MANY INTERVENTIONS HAVE BEEN CONDUCTED WITH LCPUFA, ESPECIALLY EPA AND DHA, AIMING AT PRIMARY AND SECONDARY CAD PREVENTIONS, IMPROVEMENT OF FETAL AND NEWBORN (BRAIN) DEVELOPMENT BY SUPPLEMENTATION DURING PREGNANCY OR EARLY POSTNATAL LIFE, AND IN PSYCHIATRIC DISEASES. CONSENSUS HAS BEEN REACHED THAT THOSE IN CAD AND DEPRESSION ARE POSITIVE, ALTHOUGH MORE LARGE-SCALE TRIALS ARE NEEDED. MANY RECOMMENDATIONS FOR THE INTAKES OF SATURATED FAT, TRANS FAT AND EPA + DHA HAVE BEEN ISSUED, NOTABLY FOR CAD PREVENTION, AND ALSO FOR EPA + DHA INTAKES BY PREGNANT WOMEN AND FOR AA, EPA, AND DHA INTAKES BY NEWBORNS. THE ULTIMATE GOAL MIGHT, HOWEVER, BE TO RETURN TO THE FAT QUALITY OF OUR ANCIENT DIET ON WHICH OUR GENES HAVE EVOLVED DURING THE PAST MILLION YEARS OF EVOLUTION, WHILE THIS ACTUALLY APPLIES FOR OUR ENTIRE DIETARY COMPOSITION AND LIFESTYLE, AS TRANSLATED TO THE CULTURE OF THE CURRENT SOCIETY. 2010 14 4041 30 MACROPHAGE PLASTICITY IN DUCHENNE MUSCULAR DYSTROPHY: A NEXUS OF PATHOLOGICAL REMODELLING WITH THERAPEUTIC IMPLICATIONS. DUCHENNE MUSCULAR DYSTROPHY (DMD) IS CHARACTERIZED BY CHRONIC SKELETAL MUSCLE NECROSIS, LEADING TO MUSCLE REGENERATION FAILURE AND FIBROSIS. ALTHOUGH MACROPHAGES (MPS) ARE NORMALLY ESSENTIAL FOR MUSCLE REGENERATION, DYSREGULATED MP FUNCTION PROMOTES PATHOLOGICAL MUSCLE REMODELLING. INFILTRATING MPS CAN BE PREDOMINANTLY PRO-INFLAMMATORY (M1 BIASED), ANTI-INFLAMMATORY (M2 BIASED) OR OF A MIXED PHENOTYPE AND CAN ORIGINATE FROM THE ADULT BONE MARROW (MONOCYTE DEPENDENT) OR EMBRYONIC PRECURSORS (MONOCYTE INDEPENDENT). IN MDX MICE (GENETIC MODEL OF DMD) LACKING EITHER TOLL-LIKE RECEPTOR (TLR) 2 OR TLR4, IT IS FOUND THAT MP INFILTRATION OF DYSTROPHIC MUSCLE IS SIGNIFICANTLY REDUCED AND THAT THE MP PHENOTYPE IS SHIFTED TOWARD A MORE ANTI-INFLAMMATORY PROFILE. THIS IS ACCOMPANIED BY SIGNIFICANT IMPROVEMENTS IN MUSCLE HISTOLOGY AND FORCE PRODUCTION. LACK OF THE CHEMOKINE RECEPTOR CCR2, WHICH IMPEDES MONOCYTE RELEASE FROM THE BONE MARROW, LEADS TO SIMILAR BENEFICIAL EFFECTS IN MDX MICE. EVIDENCE WAS ALSO FOUND FOR TLR4-REGULATED INDUCTION OF TRAINED INNATE IMMUNITY IN MPS CULTURED FROM THE BONE MARROW OF MDX MICE BEFORE THEIR ENTRY INTO THE MUSCLE. THESE MPS EXHIBIT EPIGENETIC AND METABOLIC ALTERATIONS, ACCOMPANIED BY NON-SPECIFIC HYPER-RESPONSIVENESS TO MULTIPLE STIMULI, WHICH IS MANIFESTED BY POTENTIATED UPREGULATION OF BOTH PRO- AND ANTI-INFLAMMATORY GENES. IN SUMMARY, EXAGGERATED RECRUITMENT OF MONOCYTE-DERIVED MPS AND SIGNS OF TRAINED INNATE IMMUNITY AT THE LEVEL OF THE BONE MARROW ARE FEATURES OF THE IMMUNOPHENOTYPE ASSOCIATED WITH DYSTROPHIC MUSCLE DISEASE. THESE PHENOMENA ARE REGULATED BY TOLL-LIKE RECEPTORS THAT BIND ENDOGENOUS DAMAGE-ASSOCIATED MOLECULAR PATTERN (DAMP) MOLECULES, SUGGESTING THAT DAMP RELEASE FROM DYSTROPHIC MUSCLES MODULATES MP PLASTICITY AT THE BONE MARROW LEVEL THROUGH TOLL-LIKE RECEPTOR-DRIVEN MECHANISMS. 2022 15 295 39 AGING INDUCES B CELL DEFECTS AND DECREASED ANTIBODY RESPONSES TO INFLUENZA INFECTION AND VACCINATION. BACKGROUND: AGING IS CHARACTERIZED BY A PROGRESSIVE DECLINE IN THE CAPACITY OF THE IMMUNE SYSTEM TO FIGHT INFLUENZA VIRUS INFECTION AND TO RESPOND TO VACCINATION. AMONG THE SEVERAL FACTORS INVOLVED, IN ADDITION TO INCREASED FRAILTY AND HIGH-RISK CONDITIONS, THE AGE-ASSOCIATED DECREASE IN CELLULAR AND HUMORAL IMMUNE RESPONSES PLAYS A RELEVANT ROLE. THIS IS IN LARGE PART DUE TO INFLAMMAGING, THE CHRONIC LOW-GRADE INFLAMMATORY STATUS OF THE ELDERLY, ASSOCIATED WITH INTRINSIC INFLAMMATION OF THE IMMUNE CELLS AND DECREASED IMMUNE FUNCTION. RESULTS: AGING IS USUALLY ASSOCIATED WITH REDUCED INFLUENZA VIRUS-SPECIFIC AND INFLUENZA VACCINE-SPECIFIC ANTIBODY RESPONSES BUT SOME ELDERLY INDIVIDUALS WITH HIGHER PRE-EXPOSURE ANTIBODY TITERS, DUE TO A PREVIOUS INFECTION OR VACCINATION, HAVE LESS PROBABILITY TO GET INFECTED. EXAMPLES OF THIS EXCEPTION ARE THE ELDERLY INDIVIDUALS INFECTED DURING THE 2009 PANDEMIC SEASON WHO MADE ANTIBODIES WITH BROADER EPITOPE RECOGNITION AND HIGHER AVIDITY THAN THOSE MADE BY YOUNGER INDIVIDUALS. SEVERAL STUDIES HAVE ALLOWED THE IDENTIFICATION OF B CELL INTRINSIC DEFECTS ACCOUNTING FOR SUB-OPTIMAL ANTIBODY RESPONSES OF ELDERLY INDIVIDUALS. THESE DEFECTS INCLUDE 1) REDUCED CLASS SWITCH RECOMBINATION, RESPONSIBLE FOR THE GENERATION OF A SECONDARY RESPONSE OF CLASS SWITCHED ANTIBODIES, 2) REDUCED DE NOVO SOMATIC HYPERMUTATION OF THE ANTIBODY VARIABLE REGION, 3) REDUCED BINDING AND NEUTRALIZATION CAPACITY, AS WELL AS BINDING SPECIFICITY, OF THE SECRETED ANTIBODIES, 4) INCREASED EPIGENETIC MODIFICATIONS THAT ARE ASSOCIATED WITH LOWER ANTIBODY RESPONSES, 5) INCREASED FREQUENCIES OF INFLAMMATORY B CELL SUBSETS, AND 6) SHORTER TELOMERES. CONCLUSIONS: ALTHOUGH INFLUENZA VACCINATION REPRESENTS THE MOST EFFECTIVE WAY TO PREVENT INFLUENZA INFECTION, VACCINES WITH GREATER IMMUNOGENICITY ARE NEEDED TO IMPROVE THE RESPONSE OF ELDERLY INDIVIDUALS. RECENT ADVANCES IN TECHNOLOGY HAVE MADE POSSIBLE A BROAD APPROACH TO BETTER UNDERSTAND THE AGE-ASSOCIATED CHANGES IN IMMUNE CELLS, NEEDED TO DESIGN TAILORED VACCINES AND EFFECTIVE THERAPEUTIC STRATEGIES THAT WILL BE ABLE TO IMPROVE THE IMMUNE RESPONSE OF VULNERABLE INDIVIDUALS. 2020 16 601 35 BETA-GLUCAN "TRAINED IMMUNITY" IMMUNOMODULATORY PROPERTIES POTENTIATE TISSUE WOUND MANAGEMENT AND ACCELERATE FITNESS RECOVER. INTRODUCTION: IT IS WELL ESTABLISHED THAT MODERATE PHYSICAL ACTIVITY CAN IMPROVE THE IMMUNE STATUS, RATHER EXCESS OR HIGH-INTENSITY PHYSICAL EXERCISE CAN CAUSE DAMAGE TO THE IMMUNE SYSTEM. IN ADDITION, MUSCLE INJURIES RESULTING FROM INCREASED FREQUENCY AND INTENSITY OF EXERCISES COMPROMISE INNATE IMMUNE ACTIVITY AND MAY DECREASE TISSUE REGENERATION. THUS, BETA-GLUCANS, A NATURAL COMPOUND, MAY REPRESENT AN IMPORTANT SUBSTANCE WITH STRONG IMMUNOMODULATORY PROPERTIES ACTING AS AN IMMUNOSTIMULANT THERAPY KNOWN AS "TRAINED IMMUNITY". THIS IMMUNE STIMULATING THERAPEUTIC IS AN IMMUNOLOGICAL MEMORY PHENOMENON LINKED TO THE INNATE IMMUNE SYSTEM, TRIGGERING CELLULAR CHANGES AT EPIGENETIC, TRANSCRIPTIONAL, AND FUNCTIONAL LEVELS, TO REGULATE THE IMMUNE SYSTEM AND RECOVER ITS HOMEOSTASIS WITH CLINICAL BENEFITS. CONCLUSION: THIS NARRATIVE REVIEW WORKS WITH THE CURRENT EVIDENCE REGARDING BETA-GLUCANS AS A POSSIBLE ALTERNATIVE THERAPY FOR WOUND HEALING AND ITS SAFETY AND EFFICACY IN THE TREATMENT OF MUSCLE INJURIES AND PHYSICAL RECOVERY INCLUDING OTHER CHRONIC CONDITIONS AND DISEASES. 2022 17 835 37 CHEMICAL CARCINOGEN MECHANISMS OF ACTION AND IMPLICATIONS FOR TESTING METHODOLOGY. CHEMICAL CARCINOGENS ARE OF TWO DISTINCT TYPES, DNA-REACTIVE AND EPIGENETIC. TESTING METHODOLOGY CAN BE DIRECTED TOWARD DETECTING EFFECTS OF BOTH TYPES OF CARCINOGEN. CARCINOGENS OF THE DNA-REACTIVE TYPE ARE DEFINED BY THE FORMATION OF COVALENTLY BOUND DNA ADDUCTS. THESE CHEMICALS HAVE STRUCTURES THAT YIELD ELECTROPHILIC REACTANTS EITHER DIRECTLY OR AFTER BIOACTIVATION. THESE AGENTS CAUSE GENOMIC ALTERATION IN THE STRUCTURE OR FUNCTION OF DNA IN THE TARGET CELL. IN ADDITION, THESE COMPOUNDS CAN EXERT OTHER CELLULAR AND TISSUE EPIGENETIC EFFECTS, SUCH AS CELL PROLIFERATION AND GROWTH PROMOTION. CARCINOGENS OF THE EPIGENETIC (PARAGENETIC) TYPE, IN CONTRAST, DO NOT REACT WITH DNA, BUT RATHER DISPLAY CELLULAR EFFECTS SUCH AS NEOPLASM GROWTH PROMOTION, CYTOTOXICITY, INHIBITION OF TISSUE GROWTH REGULATION, PEROXISOME PROLIFERATION, ENDOCRINE MODIFICATION, IMMUNOSUPPRESSION AND/OR SUSTAINED TISSUE ISCHEMIA THAT CAN BE THE BASIS FOR INCREASES IN NEOPLASIA. THEIR CHEMICAL STRUCTURE IS SUCH THAT THEY DO NOT GIVE RISE TO A REACTIVE ELECTROPHILE. THE TESTING METHODOLOGIES TO IDENTIFY EITHER TYPE FOLLOW A DECISION POINT APPROACH DESIGNED TO IDENTIFY POTENTIAL CARCINOGENICITY AND YIELD MECHANISTIC INFORMATION ON THE PRODUCTION OF EFFECTS THAT UNDERLIE CARCINOGENICITY. IT HAS 5 STAGES FOCUSING ON THE CHEMICAL STRUCTURE, DNA-REACTIVITY, EPIGENETIC EFFECTS, LIMITED BIOASSAYS AND FINALLY THE APPLICATION OF THE ACCELERATED BIOASSAY (ABA). ABA REQUIRES 40 WEEKS AND APPLIES THE USE OF SENSITIVE MARKERS FOR INDUCTION OF NEOPLASIA IN COMPARISON TO POSITIVE CONTROL COMPOUNDS FOR IMPORTANT ORGANS IN HUMAN CARCINOGENESIS. IT ENABLES DATA ACQUISITION OF THE ENTIRE CARCINOGENIC PROCESS DIRECTED TOWARD DEVELOPING MECHANISTIC INFORMATION. THE ABA HAS THE POTENTIAL TO REPLACE THE CHRONIC BIOASSAY IN RODENTS IN SOME CIRCUMSTANCES AND CAN SERVE AS AN ALTERNATIVE TO A CHRONIC BIOASSAY IN A SECOND SPECIES. 1996 18 5119 37 POSSIBLE CONTRIBUTION OF CHRONIC INFLAMMATION IN THE INDUCTION OF CANCER IN RHEUMATIC DISEASES. SEVERAL CHRONIC INFLAMMATORY CONDITIONS AND AUTOIMMUNE DISEASES INVOLVING DIFFERENT ORGANS AND TISSUES HAVE BEEN FOUND AT RISK OF PROGRESSION TO CANCER. A WIDE ARRAY OF PROINFLAMMATORY CYTOKINES, PROSTAGLANDINS, NITRIC OXIDE PRODUCTS, AND MATRICELLULAR PROTEINS ARE CLOSELY INVOLVED IN PREMALIGNANT AND MALIGNANT TRANSITION OF CELLS ALMOST ALWAYS IN A BACKGROUND OF CHRONIC INFLAMMATION. INTERESTINGLY, EPIGENETIC PERTURBATIONS (I.E. MIRNA ABERRATIONS, ALTERED DNA METHYLATION) TOGETHER WITH IMPORTANT STEROID HORMONE METABOLIC CHANGES (I.E. OESTROGENS), OR THE ALTERED VITAMIN D CONCENTRATIONS THAT MAY UNBALANCE THE IMMUNE / INFLAMMATORY RESPONSE, HAVE BEEN FOUND LINKED TO THE RISK AND SEVERITY IN SEVERAL CHRONIC INFLAMMATORY CONDITIONS, AS WELL AS IN CANCER. IN PARTICULAR, IT IS EVIDENT, THAT NOT ONLY THE PARENT OESTROGEN BUT ALSO OESTROGEN METABOLITES SHOULD BE TAKEN INTO ACCOUNT WHEN THIS PROCESS IS EVALUATED, SPECIALLY THE FORMATION OF CATECHOLOESTROGEN METABOLITES, THAT ARE CAPABLE OF FORMING EITHER STABLE OR DEPURINATING DNA ADDUCTS, WHICH CAN CAUSE EXTENSIVE DNA DAMAGE. IT IS INTERESTING THAT TODAY THE SUCCESSFUL TREATMENT OF SEVERAL CHRONIC IMMUNE/INFLAMMATORY RHEUMATIC DISEASES IS OBTAINED ALSO BY USING MEDICATIONS INITIALLY DEVELOPED FOR THEIR USE IN ONCOLOGY. THE CIRCADIAN INCREASE OF GROWTH FACTORS, SPECIALLY DURING THE LATE NIGHT, IN BOTH CHRONIC INFLAMMATION AND IN CANCER PATIENTS, AS WELL AS THE PRESENCE OF OESTROGEN-REGULATED CIRCADIAN MECHANISMS, SUGGESTS FURTHER IMPORTANT LINKS. 2014 19 4594 41 NATURAL HISTORY AND LONG-TERM CLINICAL COURSE OF CROHN'S DISEASE. CROHN'S DISEASE IS A CHRONIC INFLAMMATORY DISEASE PROCESS INVOLVING DIFFERENT SITES IN THE GASTROINTESTINAL TRACT. OCCASIONALLY, SO-CALLED METASTATIC DISEASE OCCURS IN EXTRA-INTESTINAL SITES. GRANULOMATOUS INFLAMMATION MAY BE DETECTED IN ENDOSCOPIC BIOPSIES OR RESECTED TISSUES. GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS APPEAR TO PLAY A ROLE. MULTIPLE SUSCEPTIBILITY GENES HAVE BEEN DESCRIBED IN BOTH FAMILIAL AND NON-FAMILIAL FORMS WHILE THE DISEASE IS PHENOTYPICALLY HETEROGENEOUS WITH A FEMALE PREDOMINANCE. THE DISORDER OCCURS OVER A BROAD AGE SPECTRUM, FROM EARLY CHILDHOOD TO LATE ADULTHOOD. MORE THAN 80% ARE DIAGNOSED BEFORE AGE 40 YEARS USUALLY WITH TERMINAL ILEAL AND COLONIC INVOLVEMENT. PEDIATRIC-ONSET DISEASE IS MORE SEVERE AND MORE EXTENSIVE, USUALLY WITH A HIGHER CHANCE OF UPPER GASTROINTESTINAL TRACT DISEASE, COMPARED TO ADULT-ONSET DISEASE. LONG-TERM STUDIES HAVE SHOWN THAT THE DISORDER MAY EVOLVE WITH TIME INTO MORE COMPLEX DISEASE WITH STRICTURE FORMATION AND PENETRATING DISEASE COMPLICATIONS (I.E., FISTULA, ABSCESS). ALTHOUGH PROLONGED REMISSION MAY OCCUR, DISCRETE PERIODS OF SYMPTOMATIC DISEASE MAY RE-APPEAR OVER MANY DECADES SUGGESTING RECURRENCE OR RE-ACTIVATION OF THIS INFLAMMATORY PROCESS. EVENTUAL DEVELOPMENT OF A CURE WILL LIKELY DEPEND ON IDENTIFICATION OF AN ETIOLOGIC CAUSE AND A FUNDAMENTAL UNDERSTANDING OF ITS PATHOGENESIS. UNTIL NOW, TREATMENT HAS FOCUSED ON REMOVING RISK FACTORS, PARTICULARLY CIGARETTE SMOKING, AND IMPROVING SYMPTOMS. IN CLINICAL TRIALS, CLINICAL REMISSION IS LARGELY DEFINED AS IMPROVED NUMERICAL AND ENDOSCOPIC INDICES FOR "MUCOSAL HEALING". "DEEP REMISSION" IS A CONCEPTUAL, MORE "EXTENDED" GOAL THAT MAY OR MAY NOT ALTER THE LONG-TERM NATURAL HISTORY OF THE DISEASE IN SELECTED PATIENTS, ALBEIT AT A SIGNIFICANT RISK FOR TREATMENT COMPLICATIONS, INCLUDING SERIOUS AND UNUSUAL OPPORTUNISTIC INFECTIONS. 2014 20 2950 25 GENETIC AND EPIGENETIC DAMAGE INDUCED BY REACTIVE NITROGEN SPECIES: IMPLICATIONS IN CARCINOGENESIS. CHRONIC INFECTION AND INFLAMMATION ARE RECOGNIZED RISK FACTORS FOR HUMAN CANCER AT VARIOUS SITES. INFECTION AND INFLAMMATION CAN ACTIVATE AND INDUCE A VARIETY OF OXIDANT-GENERATING ENZYMES, INCLUDING NADPH OXIDASE AND INDUCIBLE NITRIC OXIDE SYNTHASE. REACTIVE OXYGEN AND NITROGEN SPECIES PRODUCED BY SUCH ENZYMES REACT WITH EACH OTHER TO GENERATE NEW AND MORE POTENT REACTIVE SPECIES. THESE OXIDANTS NOT ONLY CAN DAMAGE DNA AND INDUCE MUTATIONS, BUT ALSO CAN ACTIVATE ONCOGENE PRODUCTS AND/OR INACTIVATE TUMOR-SUPPRESSOR PROTEINS, THUS CONTRIBUTING TO MOST PROCESSES OF CARCINOGENESIS. APPROPRIATE TREATMENT OF INFLAMMATION SHOULD BE FURTHER EXPLORED FOR CHEMOPREVENTION OF HUMAN CANCERS, ESPECIALLY THOSE ASSOCIATED WITH CHRONIC INFLAMMATION. 2003