1 3780 156 INTERFERON DRIVES HCV SCARRING OF THE EPIGENOME AND CREATES TARGETABLE VULNERABILITIES FOLLOWING VIRAL CLEARANCE. BACKGROUND AND AIMS: CHRONIC HCV INFECTION IS A LEADING ETIOLOGIC DRIVER OF CIRRHOSIS AND ULTIMATELY HCC. OF THE APPROXIMATELY 71 MILLION INDIVIDUALS CHRONICALLY INFECTED WITH HCV, 10%-20% ARE EXPECTED TO DEVELOP SEVERE LIVER COMPLICATIONS IN THEIR LIFETIME. EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS BECOME PROFOUNDLY DISRUPTED IN DISEASE PROCESSES INCLUDING LIVER DISEASE. APPROACH AND RESULTS: TO UNDERSTAND HOW HCV INFECTION INFLUENCES THE EPIGENOME AND WHETHER THESE EVENTS REMAIN AS "SCARS" FOLLOWING CURE OF CHRONIC HCV INFECTION, WE MAPPED GENOME-WIDE DNA METHYLATION, FOUR KEY REGULATORY HISTONE MODIFICATIONS (H3K4ME3, H3K4ME1, H3K27AC, AND H3K27ME3), AND OPEN CHROMATIN IN PARENTAL AND HCV-INFECTED IMMORTALIZED HEPATOCYTES AND THE HUH7.5 HCC CELL LINE, ALONG WITH DNA METHYLATION AND GENE-EXPRESSION ANALYSES FOLLOWING ELIMINATION OF HCV IN THESE MODELS THROUGH TREATMENT WITH INTERFERON-ALPHA (IFN-ALPHA) OR A DIRECT-ACTING ANTIVIRAL (DAA). OUR DATA DEMONSTRATE THAT HCV INFECTION PROFOUNDLY AFFECTS THE EPIGENOME (PARTICULARLY ENHANCERS); HCV SHARES EPIGENETIC TARGETS WITH INTERFERON-ALPHA TARGETS; AND AN OVERWHELMING MAJORITY OF EPIGENETIC CHANGES INDUCED BY HCV REMAIN AS "SCARS" ON THE EPIGENOME FOLLOWING VIRAL CURE. SIMILAR FINDINGS ARE OBSERVED IN PRIMARY HUMAN PATIENT SAMPLES CURED OF CHRONIC HCV INFECTION. SUPPLEMENTATION OF IFN-ALPHA/DAA ANTIVIRAL REGIMENS WITH DNA METHYLTRANSFERASE INHIBITOR 5-AZA-2'-DEOXYCYTIDINE SYNERGIZES IN REVERTING ABERRANT DNA METHYLATION INDUCED BY HCV. FINALLY, BOTH HCV-INFECTED AND CURED CELLS DISPLAYED A BLUNTED IMMUNE RESPONSE, DEMONSTRATING A FUNCTIONAL EFFECT OF EPIGENETIC SCARRING. CONCLUSIONS: INTEGRATION OF EPIGENETIC AND TRANSCRIPTIONAL DATA ELUCIDATE KEY GENE DEREGULATION EVENTS DRIVEN BY HCV INFECTION AND HOW THIS MAY UNDERPIN THE LONG-TERM ELEVATED RISK FOR HCC IN PATIENTS CURED OF HCV DUE TO EPIGENOME SCARRING. 2022 2 795 35 CELLULAR RESILIENCE. CELLULAR RESILIENCE DESCRIBES THE ABILITY OF A CELL TO COPE WITH ENVIRONMENTAL CHANGES SUCH AS TOXICANT EXPOSURE. IF CELLULAR METABOLISM DOES NOT COLLAPSE DIRECTLY AFTER THE HIT OR END IN PROGRAMMED CELL DEATH, THE ENSUING STRESS RESPONSES PROMOTE A NEW HOMEOSTASIS UNDER STRESS. THE PROCESSES OF REVERTING "BACK TO NORMAL" AND REVERSAL OF APOPTOSIS ("ANASTASIS") HAVE BEEN STUDIED LITTLE AT THE CELLULAR LEVEL. CELL TYPES SHOW ASTONISHINGLY SIMILAR VULNERABILITY TO MOST TOXICANTS, EXCEPT FOR THOSE THAT REQUIRE A VERY SPECIFIC TARGET, METABOLISM OR MECHANISM PRESENT ONLY IN SPECIFIC CELL TYPES. THE MAJORITY OF CHEMICALS TRIGGERS "GENERAL CYTOTOXICITY" IN ANY CELL AT SIMILAR CONCENTRATIONS. WE HYPOTHESIZE THAT CELLS DIFFER LESS IN THEIR VULNERABILITY TO A GIVEN TOXICANT THAN IN THEIR RESILIENCE (COPING WITH THE "HIT"). IN MANY CASES, CELLS DO NOT RETURN TO THE NAIVE STATE AFTER A TOXIC INSULT. THE PHENOMENA OF "PRE-CONDITIONING", "TOLERANCE" AND "HORMESIS" DESCRIBE THIS FOR LOW-DOSE EXPOSURES TO TOXICANTS THAT RENDER THE CELL MORE RESISTANT TO SUBSEQUENT HITS. THE DEFENSE AND RESILIENCE PROGRAMS INCLUDE EPIGENETIC CHANGES THAT LEAVE A "MEMORY/SCAR" - AN ALTERATION AS A CONSEQUENCE OF THE STRESS THE CELL HAS EXPERIENCED. THESE MEMORIES MIGHT HAVE LONG-TERM CONSEQUENCES, BOTH POSITIVE (RESISTANCE) AND NEGATIVE, THAT CONTRIBUTE TO CHRONIC AND DELAYED MANIFESTATIONS OF HAZARD AND, ULTIMATELY, DISEASE. THIS ARTICLE CALLS FOR MORE SYSTEMATIC ANALYSES OF HOW CELLS COPE WITH TOXIC PERTURBATIONS IN THE LONG-TERM AFTER STRESSOR WITHDRAWAL. A TECHNICAL PREREQUISITE FOR THESE ARE STABLE (ORGANOTYPIC) CULTURES AND A CHARACTERIZATION OF STRESS RESPONSE MOLECULAR NETWORKS. 2015 3 2940 40 GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL AND SENSITIVE COPD-DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5). EVEN THOUGH CLINICAL, EPIDEMIOLOGICAL AND TOXICOLOGICAL STUDIES HAVE PROGRESSIVELY PROVIDED A BETTER KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS, FURTHER IN VITRO STUDIES ON RELEVANT CELL SYSTEMS ARE STILL NEEDED. HENCE, AIMING OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS, PRIMARY HUMAN BRONCHIAL EPITHELIAL CELLS DERIVED FROM NORMAL SUBJECTS (NHBE) OR SENSITIVE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED PATIENTS (DHBE) WERE DIFFERENTIATED AT THE AIR-LIQUID INTERFACE. THEREAFTER, THEY WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) TO STUDY THE OCCURRENCE OF SOME RELEVANT GENETIC AND/OR EPIGENETIC ENDPOINTS. CONCENTRATION-, EXPOSURE- AND SEASON-DEPENDENT INCREASES OF OH-B[A]P METABOLITES IN NHBE, AND TO A LESSER EXTENT, COPD-DHBE CELLS WERE REPORTED; HOWEVER, THERE WERE MORE TETRA-OH-B[A]P AND 8-OHDG DNA ADDUCTS IN COPD-DHBE CELLS. NO INCREASE IN PRIMARY DNA STRAND BREAK NOR CHROMOSOMAL ABERRATION WAS OBSERVED IN REPEATEDLY EXPOSED CELLS. TELOMERE LENGTH AND TELOMERASE ACTIVITY WERE MODIFIED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN NHBE AND PARTICULARLY COPD-DHBE CELLS. THERE WERE A GLOBAL DNA HYPOMETHYLATION, A P16 GENE PROMOTER HYPERMETHYLATION, AND A DECREASING DNA METHYLTRANSFERASE ACTIVITY IN NHBE AND NOTABLY COPD-DHBE CELLS REPEATEDLY EXPOSED. CHANGES IN SITE-SPECIFIC METHYLATION, ACETYLATION, AND PHOSPHORYLATION OF HISTONE H3 (I.E., H3K4ME3, H3K9AC, H3K27AC, AND H3S10PH) AND RELATED ENZYME ACTIVITIES OCCURRED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN ALL THE REPEATEDLY EXPOSED CELLS. COLLECTIVELY, THESE RESULTS HIGHLIGHTED THE KEY ROLE PLAYED BY GENETIC AND EVEN EPIGENETIC EVENTS IN NHBE AND PARTICULARLY SENSITIVE COPD-DHBE CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) AND THEIR DIFFERENT RESPONSIVENESS. WHILE THESE SPECIFIC EPIGENETIC CHANGES HAVE BEEN ALREADY DESCRIBED IN COPD AND EVEN LUNG CANCER PHENOTYPES, OUR FINDINGS SUPPORTED THAT, TOGETHER WITH GENETIC EVENTS, THESE EPIGENETIC EVENTS COULD DRAMATICALLY CONTRIBUTE TO THE SHIFT FROM HEALTHY TO DISEASED PHENOTYPES FOLLOWING REPEATED EXPOSURE TO RELATIVELY LOW DOSES OF AIR POLLUTION-DERIVED PM(2.5). 2017 4 4692 40 NEWS FROM THE "5TH INTERNATIONAL MEETING ON INFLAMMATORY BOWEL DISEASES" CAPRI 2010. AT THE "5TH INTERNATIONAL MEETING ON INFLAMMATORY BOWEL DISEASES SELECTED TOPICS OF INFLAMMATORY BOWEL DISEASE (IBD), INCLUDING THE ENVIRONMENT, GENETICS, THE GUT FLORA, THE CELL RESPONSE AND IMMUNOMODULATION WERE DISCUSSED IN ORDER TO BETTER UNDERSTAND SPECIFIC CLINICAL AND THERAPEUTIC ASPECTS. THE INCIDENCE OF IBD CONTINUES TO RISE, BOTH IN LOW AND IN HIGH-INCIDENCE AREAS. IT IS BELIEVED THAT FACTORS ASSOCIATED WITH 'WESTERNIZATION' MAY BE CONDITIONING THE EXPRESSION OF THESE DISORDERS. THE INCREASED INCIDENCE OF IBD AMONG MIGRANTS FROM LOW-INCIDENCE TO HIGH-INCIDENCE AREAS WITHIN THE SAME GENERATION SUGGESTS A STRONG ENVIRONMENTAL INFLUENCE. THE DEVELOPMENT OF GENOME-WIDE ASSOCIATION SCANNING (GWAS) TECHNOLOGIES HAS LEAD TO THE DISCOVERY OF MORE THAN 100 IBD LOCI. SOME, AS THE TH 17 PATHWAY GENES, ARE SHARED BETWEEN CROHN'S DISEASE (CD) AND ULCERATIVE COLITIS (UC), WHILE OTHER ARE IBD SUBTYPE-SPECIFIC (AUTOPHAGY GENES, EPITHELIAL BARRIER GENES). DISEASE-SPECIFIC THERAPIES TARGETING THESE PATHWAYS SHOULD BE DEVELOPED. EPIGENETIC REGULATION OF THE INFLAMMATORY RESPONSE ALSO APPEARS TO PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF IBD. THE IMPORTANCE OF GUT FLORA IN INTESTINAL HOMEOSTASIS AND INFLAMMATION WAS REINFORCED, THE CONCEPTS OF EUBIOSIS AND DYSBIOSIS WERE INTRODUCED, AND SOME STRATEGIES FOR REVERTING DYSBIOSIS TO A HOMEOSTATIC STATE OF EUBIOSIS WERE PROPOSED. THE CURRENT STATUS OF STUDIES ON THE HUMAN GUT MICROBIOTA METAGENOME, METAPROTOME, AND METABOLOME WAS ALSO PRESENTED. THE CELL RESPONSE IN INFLAMMATION, INCLUDING ENDOPLASMIC RETICULUM (ER) STRESS RESPONSES, AUTOPHAGY AND INFLAMMASOME-DEPENDENT EVENTS WERE RELATED TO IBD PATHOGENESIS. IT WAS SUGGESTED THAT INFLAMMATION-ASSOCIATED ER STRESS RESPONSES MAY BE A COMMON TRAIT IN THE PATHOGENESIS OF VARIOUS CHRONIC IMMUNE AND METABOLIC DISEASES. HOW INNATE AND ADAPTIVE IMMUNITY SIGNALING EVENTS CAN PERPETUATE CHRONIC INFLAMMATION WAS DISCUSSED EXTENSIVELY. SIGNAL TRANSDUCTION PATHWAYS PROVIDE INTRACELLULAR MECHANISMS BY WHICH CELLS RESPOND AND ADAPT TO MULTIPLE ENVIRONMENTAL STRESSES. THE IDENTIFICATION OF THESE SIGNALS HAS LED TO A GREATER MECHANISTIC UNDERSTANDING OF IBD PATHOGENESIS AND POINTED TO POTENTIALLY NEW THERAPEUTIC TARGETS. A CRITICAL ANALYSIS OF CLINICAL TRIALS AND OF RISK-BENEFIT OF BIOLOGICAL THERAPY WAS PRESENTED. THE PROBLEM OF EPSTEIN-BARR VIRUS (EBV) AND LYMPHOMA IN IBD WAS EXTENSIVELY DISCUSSED. LYMPHOMAS CAN DEVELOP IN INTESTINAL SEGMENTS AFFECTED BY IBD AND ARE IN MOST CASES ASSOCIATED WITH EBV. THE REASONS OF TREATMENT FAILURE WERE ALSO ANALYZED BOTH FROM BASIC AND CLINICAL POINTS OF VIEW. TWO VERY INTERESTING PRESENTATIONS ON THE INTEGRATION OF RESEARCH AND CLINICAL CARE IN THE NEAR FUTURE CLOSED THE MEETING. THESE PRESENTATIONS WERE FOCUSED ON MACROTRENDS AFFECTING HEALTHCARE DELIVERY AND RESEARCH, AND THE NEED TO INNOVATE TRADITIONAL INFRASTRUCTURES TO DEAL WITH THESE CHANGING TRENDS AS WELL AS NEW OPPORTUNITIES TO ACCELERATE SCIENTIFIC KNOWLEDGE. 2010 5 1948 36 EPIGENETIC ACQUISITION OF INDUCIBILITY OF TYPE III CYTOTOXICITY IN P. AERUGINOSA. BACKGROUND: PSEUDOMONAS AERUGINOSA, AN OPPORTUNISTIC PATHOGEN, IS OFTEN ENCOUNTERED IN CHRONIC LUNG DISEASES SUCH AS CYSTIC FIBROSIS OR CHRONIC OBSTRUCTIVE PNEUMONIA, AS WELL AS ACUTE SETTINGS LIKE MECHANICAL VENTILATION ACQUIRED PNEUMONIA OR NEUTROPENIC PATIENTS. IT IS A MAJOR CAUSE OF MORTALITY AND MORBIDITY IN THESE DISEASES. IN LUNGS, P. AERUGINOSA SETTLES IN A BIOFILM MODE OF GROWTH WITH THE SECRETION OF EXOPOLYSACCHARIDES IN WHICH IT IS ENCAPSULATED, ENHANCING ITS ANTIBIOTIC RESISTANCE AND CONTRIBUTING TO THE RESPIRATORY DEFICIENCY OF PATIENTS. HOWEVER, BACTERIA MUST FIRST MULTIPLY TO A HIGH DENSITY AND DISPLAY A CYTOTOXIC PHENOTYPE TO AVOID THE HOST'S DEFENCES. A VIRULENCE DETERMINANT IMPLICATED IN THIS STEP OF INFECTION IS THE TYPE III SECRETION SYSTEM (TTSS), ALLOWING TOXIN INJECTION DIRECTLY INTO HOST CELLS. AT THE BEGINNING OF THE INFECTION, MOST STRAINS ISOLATED FROM PATIENTS' LUNGS POSSESS AN INDUCIBLE TTSS ALLOWING TOXINS INJECTION OR SECRETION UPON IN VIVO OR IN VITRO ACTIVATION SIGNALS. AS THE INFECTION PERSISTS MOST OF THE BACTERIA PERMANENTLY LOOSE THIS CAPACITY, ALTHOUGH NO MUTATIONS HAVE BEEN EVIDENCED. WE NAME "NON INDUCIBLE" THIS PHENOTYPE. AS SUGGESTED BY THE PRESENCE OF A POSITIVE FEEDBACK CIRCUIT IN THE REGULATORY NETWORK CONTROLLING TTSS EXPRESSION, IT MAY BE DUE TO AN EPIGENETIC SWITCH ALLOWING HERITABLE PHENOTYPIC MODIFICATIONS WITHOUT GENOTYPE'S MUTATIONS. RESULTS: USING THE GENERALISED LOGICAL METHOD, WE DESIGNED A MINIMAL MODEL OF THE TTSS REGULATORY NETWORK THAT COULD SUPPORT THE EPIGENETIC HYPOTHESIS, AND STUDIED ITS DYNAMICS WHICH HELPED TO DEFINE A DISCRIMINATING EXPERIMENTAL SCENARIO SUFFICIENT TO VALIDATE THE EPIGENETIC HYPOTHESIS. A MATHEMATICAL FRAMEWORK BASED ON FORMAL METHODS FROM COMPUTER SCIENCE ALLOWED A RIGOROUS VALIDATION AND CERTIFICATION OF PARAMETERS OF THIS MODEL LEADING TO EPIGENETIC BEHAVIOUR. THEN, WE DEMONSTRATED THAT A NON INDUCIBLE STRAIN OF P. AERUGINOSA CAN STABLY ACQUIRE THE CAPACITY TO BE INDUCED BY CALCIUM DEPLETION FOR THE TTSS AFTER A SHORT PULSE OF A REGULATORY PROTEIN. FINALLY, THE INCREASED CYTOTOXICITY OF A STRAIN AFTER THIS EPIGENETIC SWITCH WAS DEMONSTRATED IN VIVO IN AN ACUTE PULMONARY INFECTION MODEL. CONCLUSION: THESE RESULTS MAY OFFER NEW PERSPECTIVES FOR THERAPEUTIC STRATEGIES TO PREVENT LETHAL INFECTIONS BY P. AERUGINOSA BY REVERTING THE EPIGENETIC INDUCIBILITY OF TYPE III CYTOTOXICITY. 2006 6 5769 35 SPECIFIC EPIGENETIC REGULATORS SERVE AS POTENTIAL THERAPEUTIC TARGETS IN IDIOPATHIC PULMONARY FIBROSIS. IDIOPATHIC PULMONARY FIBROSIS (IPF), A DISORDER OBSERVED MOSTLY IN OLDER HUMAN BEINGS, IS CHARACTERISED BY CHRONIC AND PROGRESSIVE LUNG SCARRING LEADING TO AN IRREVERSIBLE DECLINE IN LUNG FUNCTION. THIS HEALTH CONDITION HAS A DISMAL PROGNOSIS AND THE CURRENTLY AVAILABLE DRUGS ONLY DELAY BUT FAIL TO REVERSE THE PROGRESSION OF LUNG DAMAGE. CONSEQUENTLY, IT BECOMES IMPERATIVE TO DISCOVER IMPROVED THERAPEUTIC COMPOUNDS AND THEIR CELLULAR TARGETS TO CURE IPF. IN THIS REGARD, A NUMBER OF RECENT STUDIES HAVE TARGETED THE EPIGENETIC REGULATION BY HISTONE DEACETYLASES (HDACS) TO DEVELOP AND CATEGORISE ANTIFIBROTIC DRUGS FOR LUNGS. THEREFORE, THIS REVIEW FOCUSES ON HOW ABERRANT EXPRESSION OR ACTIVITY OF CLASSES I, II AND III HDACS ALTER TGF-BETA SIGNALLING TO PROMOTE EVENTS SUCH AS EPITHELIAL-MESENCHYMAL TRANSITION, DIFFERENTIATION OF ACTIVATED FIBROBLASTS INTO MYOFIBROBLASTS, AND EXCESS DEPOSITION OF THE EXTRACELLULAR MATRIX TO PROPEL LUNG FIBROSIS. FURTHER, THIS STUDY DESCRIBES HOW CERTAIN CHEMICAL COMPOUNDS OR DIETARY CHANGES MODULATE DYSREGULATED HDACS TO ATTENUATE FIVE FAULTY TGF-BETA-DEPENDENT PROFIBROTIC PROCESSES, BOTH IN ANIMAL MODELS AND CELL LINES REPLICATING IPF, THEREBY IDENTIFYING PROMISING MEANS TO TREAT THIS LUNG DISORDER. 2022 7 391 36 AN INTRODUCTION TO THE MATHEMATICAL MODELING IN THE STUDY OF CANCER SYSTEMS BIOLOGY. BACKGROUND: FREQUENTLY OCCURRING IN CANCER ARE THE ABERRANT ALTERATIONS OF REGULATORY ONCO-METABOLITES, VARIOUS ONCOGENES/EPIGENETIC STOCHASTICITY, AND SUPPRESSOR GENES, AS WELL AS THE DEFICIENT MISMATCH REPAIR MECHANISM, CHRONIC INFLAMMATION, OR THOSE DEVIATIONS BELONGING TO THE OTHER CANCER CHARACTERISTICS. HOW THESE ABERRATIONS THAT EVOLVE OVERTIME DETERMINE THE GLOBAL PHENOTYPE OF MALIGNANT TUMORS REMAINS TO BE COMPLETELY UNDERSTOOD. DYNAMIC ANALYSIS MAY HAVE POTENTIAL TO REVEAL THE MECHANISM OF CARCINOGENESIS AND CAN OFFER NEW THERAPEUTIC INTERVENTION. AIMS: WE INTRODUCE SIMPLIFIED MATHEMATICAL TOOLS TO MODEL SERIAL QUANTITATIVE DATA OF CANCER BIOMARKERS. WE ALSO HIGHLIGHT AN INTRODUCTORY OVERVIEW OF MATHEMATICAL TOOLS AND MODELS AS THEY APPLY FROM THE VIEWPOINT OF KNOWN CANCER FEATURES. METHODS: MATHEMATICAL MODELING OF POTENTIALLY ACTIONABLE GENOMIC PRODUCTS AND HOW THEY PROCEED OVERTIME DURING TUMORIGENESIS ARE EXPLORED. THIS REPORT IS INTENDED TO BE INSTINCTIVE WITHOUT BEING OVERLY TECHNICAL. RESULTS: TO DATE, MANY MATHEMATICAL MODELS OF THE COMMON FEATURES OF CANCER HAVE BEEN DEVELOPED. HOWEVER, THE DYNAMIC OF INTEGRATED HETEROGENEOUS PROCESSES AND THEIR CROSS TALKS RELATED TO CARCINOGENESIS REMAINS TO BE RESOLVED. CONCLUSIONS: IN CANCER RESEARCH, OUTLINING MATHEMATICAL MODELING OF EXPERIMENTALLY OBTAINED DATA SNAPSHOTS OF MOLECULAR SPECIES MAY PROVIDE INSIGHTS INTO A BETTER UNDERSTANDING OF THE MULTIPLE BIOCHEMICAL CIRCUITS. RECENT DISCOVERIES HAVE PROVIDED SUPPORT FOR THE EXISTENCE OF COMPLEX CANCER PROGRESSION IN DYNAMICS THAT SPAN FROM A SIMPLE 1-DIMENSIONAL DETERMINISTIC SYSTEM TO A STOCHASTIC (IE, PROBABILISTIC) OR TO AN OSCILLATORY AND MULTISTABLE NETWORKS. FURTHER RESEARCH IN MATHEMATICAL MODELING OF CANCER PROGRESSION, BASED ON THE EVOLVING MOLECULAR KINETICS (TIME SERIES), COULD INFORM A SPECIFIC AND A PREDICTIVE BEHAVIOR ABOUT THE GLOBAL SYSTEMS BIOLOGY OF VULNERABLE TUMOR CELLS IN THEIR EARLIER STAGES OF ONCOGENESIS. ON THIS FOOTING, NEW PREVENTIVE MEASURES AND ANTICANCER THERAPY COULD THEN BE CONSTRUCTED. 2018 8 3934 42 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 9 107 34 A REVIEW OF PRE-CLINICAL MODELS FOR GULF WAR ILLNESS. GULF WAR ILLNESS (GWI) IS A CHRONIC MULTISYMPTOMATIC DISORDER THAT AFFLICTS OVER 1/3RD OF THE 1991 GW VETERANS. IT SPANS MULTIPLE BODILY SYSTEMS AND PRESENTS ITSELF AS A SYNDROME EXHIBITING DIVERSE SYMPTOMS INCLUDING FATIGUE, DEPRESSION, MOOD, AND MEMORY AND CONCENTRATION DEFICITS, MUSCULOSKELETAL PAIN AND GASTROINTESTINAL DISTRESS IN GW VETERANS. THE ETIOLOGY OF GWI IS COMPLEX AND MANY FACTORS, INCLUDING CHEMICAL, PHYSIOLOGICAL, AND ENVIRONMENTAL STRESSORS PRESENT IN THE GW ARENA, HAVE BEEN IMPLICATED FOR ITS DEVELOPMENT. IT HAS BEEN OVER 30 YEARS SINCE THE END OF THE GW BUT, GWI HAS BEEN PERSISTENT IN SUFFERING VETERANS WHO ARE ALSO DEALING WITH PAUCITY OF EFFECTIVE TREATMENTS. THE MULTIFACTORIAL ASPECT OF GWI ALONG WITH GENETIC HETEROGENEITY AND LACK OF AVAILABLE DATA SURROUNDING WAR-TIME EXPOSURES HAVE PROVED TO BE CHALLENGING IN DEVELOPING PRE-CLINICAL MODELS OF GWI. DESPITE THIS, OVER A DOZEN GWI ANIMAL MODELS EXIST IN THE LITERATURE. IN THIS ARTICLE, FOLLOWING A BRIEF DISCUSSION OF GW HISTORY, GWI DEFINITIONS, AND PROBABLE CAUSES FOR ITS PATHOGENESIS, WE WILL EXPAND UPON VARIOUS EXPERIMENTAL MODELS USED IN GWI LABORATORY RESEARCH. THESE ANIMAL MODELS WILL BE DISCUSSED IN THE CONTEXT OF THEIR ATTEMPTS AT MIMICKING GW-RELATED EXPOSURES WITH REGARDS TO THE VARIATIONS IN CHEMICAL COMBINATIONS, DOSES, AND FREQUENCY OF EXPOSURES. WE WILL DISCUSS THEIR ADVANTAGES AND LIMITATIONS IN MODELING GWI FOLLOWED BY A DISCUSSION OF BEHAVIORAL AND MOLECULAR FINDINGS IN THESE MODELS. THE MECHANISTIC DATA OBTAINED FROM THESE PRECLINICAL STUDIES HAVE OFFERED MULTIPLE MOLECULAR PATHWAYS INCLUDING CHRONIC INFLAMMATION, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, LIPID DISTURBANCES, CALCIUM HOMEOSTATIC ALTERATIONS, CHANGES IN GUT MICROBIOTA, AND EPIGENETIC MODIFICATIONS, AMONGST OTHERS FOR EXPLAINING GWI DEVELOPMENT AND ITS PERSISTENCE. FINALLY, THESE FINDINGS HAVE ALSO INFORMED US ON NOVEL DRUGGABLE TARGETS IN GWI. WHILE, IT HAS BEEN DIFFICULT TO CONCEIVE A SINGLE PRE-CLINICAL MODEL THAT COULD EXPRESS ALL THE GWI SIGNS AND EXHIBIT BIOLOGICAL COMPLEXITY REFLECTIVE OF THE CLINICAL PRESENTATION IN GWI, ANIMAL MODELS HAVE BEEN CRITICAL FOR IDENTIFYING MOLECULAR UNDERPINNINGS OF GWI AND EVALUATING TREATMENT STRATEGIES FOR GWI. 2021 10 4450 27 MOLECULAR MECHANISMS AND CELLULAR CONTRIBUTION FROM LUNG FIBROSIS TO LUNG CANCER DEVELOPMENT. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE, FIBROSING INTERSTITIAL LUNG DISEASE (ILD) OF UNKNOWN AETIOLOGY, WITH A MEDIAN SURVIVAL OF 2-4 YEARS FROM THE TIME OF DIAGNOSIS. ALTHOUGH IPF HAS UNKNOWN AETIOLOGY BY DEFINITION, THERE HAVE BEEN IDENTIFIED SEVERAL RISKS FACTORS INCREASING THE PROBABILITY OF THE ONSET AND PROGRESSION OF THE DISEASE IN IPF PATIENTS SUCH AS CIGARETTE SMOKING AND ENVIRONMENTAL RISK FACTORS ASSOCIATED WITH DOMESTIC AND OCCUPATIONAL EXPOSURE. AMONG THEM, CIGARETTE SMOKING TOGETHER WITH CONCOMITANT EMPHYSEMA MIGHT PREDISPOSE IPF PATIENTS TO LUNG CANCER (LC), MOSTLY TO NON-SMALL CELL LUNG CANCER (NSCLC), INCREASING THE RISK OF LUNG CANCER DEVELOPMENT. TO THIS PURPOSE, IPF AND LC SHARE SEVERAL CELLULAR AND MOLECULAR PROCESSES DRIVING THE PROGRESSION OF BOTH PATHOLOGIES SUCH AS FIBROBLAST TRANSITION PROLIFERATION AND ACTIVATION, ENDOPLASMIC RETICULUM STRESS, OXIDATIVE STRESS, AND MANY GENETIC AND EPIGENETIC MARKERS THAT PREDISPOSE IPF PATIENTS TO LC DEVELOPMENT. NINTEDANIB, A TYROSINE-KINASE INHIBITOR, WAS FIRSTLY DEVELOPED AS AN ANTICANCER DRUG AND THEN RECOGNIZED AS AN ANTI-FIBROTIC AGENT BASED ON THE COMMON TARGET MOLECULAR PATHWAY. IN THIS REVIEW OUR AIM IS TO DESCRIBE THE UPDATED STUDIES ON COMMON CELLULAR AND MOLECULAR MECHANISMS BETWEEN IPF AND LUNG CANCER, KNOWLEDGE OF WHICH MIGHT HELP TO FIND NOVEL THERAPEUTIC TARGETS FOR THIS DISEASE COMBINATION. 2021 11 3271 37 HEPATOCELLULAR CARCINOMA RISK AFTER VIRAL RESPONSE IN HEPATITIS C VIRUS-ADVANCED FIBROSIS: WHO TO SCREEN AND FOR HOW LONG? HEPATITIS C VIRUS (HCV) CHRONIC INFECTION IS ASSOCIATED WITH FIBROSIS PROGRESSION, END-STAGE LIVER COMPLICATIONS AND HCC. NOT SURPRISINGLY, HCV INFECTION IS A LEADING CAUSE OF LIVER-RELATED MORBIDITY AND MORTALITY WORLDWIDE. AFTER SUSTAINED VIROLOGICAL RESPONSE (SVR), THE RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA IS NOT COMPLETELY ELIMINATED IN PATIENTS WITH ESTABLISHED CIRRHOSIS OR WITH ADVANCED FIBROSIS. THEREFORE, LIFELONG SURVEILLANCE IS CURRENTLY RECOMMENDED. THIS STRATEGY IS LIKELY NOT UNIVERSALLY COST-EFFECTIVE AND HARMLESS, CONSIDERING THAT NOT ALL PATIENTS WITH ADVANCED FIBROSIS HAVE THE SAME RISK OF DEVELOPING HCC. FACTORS RELATED TO THE SEVERITY OF LIVER DISEASE AND ITS POTENTIAL TO IMPROVE AFTER SVR, THE MOLECULAR AND EPIGENETIC CHANGES THAT OCCUR DURING INFECTION AND OTHER ASSOCIATED COMORBIDITIES MIGHT ACCOUNT FOR DIFFERENT RISK LEVELS AND ARE LIKELY ESSENTIAL FOR IDENTIFYING PATIENTS WHO WOULD BENEFIT FROM SCREENING PROGRAMS AFTER SVR. EFFORTS TO DEVELOP PREDICTIVE MODELS AND RISK CALCULATORS, BIOMARKERS AND GENETIC PANELS AND EVEN DEEP LEARNING MODELS TO ESTIMATE THE INDIVIDUAL RISK OF HCC HAVE BEEN MADE IN THE DIRECT-ACTING ANTIVIRAL AGENTS ERA, WHEN THOUSANDS OF PATIENTS WITH ADVANCED FIBROSIS AND CIRRHOSIS HAVE REACHED SVR. THESE TOOLS COULD HELP TO IDENTIFY PATIENTS WITH VERY LOW HCC RISK IN WHOM SURVEILLANCE MIGHT NOT BE JUSTIFIED. IN THIS REVIEW, FACTORS AFFECTING THE PROBABILITY OF HCC DEVELOPMENT AFTER SVR, THE BENEFITS AND RISKS OF SURVEILLANCE, SUGGESTED STRATEGIES TO ESTIMATE INDIVIDUALIZED HCC RISK AND THE CURRENT EVIDENCE TO RECOMMEND LIFELONG SURVEILLANCE ARE DISCUSSED. 2021 12 6742 33 WHITHER THE ETIOPATHOGENESIS (AND SCOLIOGENY) OF ADOLESCENT IDIOPATHIC SCOLIOSIS? ALTHOUGH CONSIDERABLE PROGRESS HAD BEEN MADE IN THE PAST TWO DECADES IN UNDERSTANDING THE ETIOPATHOGENESIS OF ADOLESCENT IDIOPATHIC SCOLIOSIS (AIS), IT STILL LACKS AN AGREED THEORY OF ETIOPATHOGENESIS. ONE PROBLEM MAY BE THAT AIS RESULTS NOT FROM ONE CAUSE, BUT SEVERAL THAT INTERACT WITH VARIOUS GENETIC PREDISPOSING FACTORS. THERE IS A VIEW THERE ARE TWO OTHER PATHOGENIC PROCESSES FOR IDIOPATHIC SCOLIOSIS NAMELY, INITIATING (OR INDUCING), AND THOSE THAT CAUSE CURVE PROGRESSION. TWIN STUDIES AND OBSERVATIONS OF FAMILY AGGREGATION HAVE REVEALED SIGNIFICANT GENETIC CONTRIBUTIONS TO IDIOPATHIC SCOLIOSIS, THAT PLACE AIS AMONG OTHER COMMON DISEASE OR COMPLEX TRAITS WITH A HIGH HERITABILITY INTERPRETED BY THE GENETIC VARIANT HYPOTHESIS OF DISEASE. WE SUMMARIZE ETIOPATHOGENETIC KNOWLEDGE OF AIS AS THEORIES OF PATHOGENESIS INCLUDING RECENT MULTIPLE CONCEPTS, AND BLOOD TESTS FOR AIS BASED ON PREDICTIVE BIOMARKERS AND GENETIC VARIANTS THAT SIGNIFY DISEASE RISK. THERE IS INCREASING EVIDENCE FOR THE POSSIBILITY OF AN UNDERLYING NEUROLOGICAL DISORDER FOR AIS, RESEARCH WHICH HOLDS PROMISE. LIKE BRAIN RESEARCH, MOST AIS WORKERS FOCUS ON THEIR OWN CORNER AND THERE IS A NEED FOR GREATER INTEGRATION OF RESEARCH EFFORT. EPIGENETICS, A RELATIVELY RECENT FIELD, EVALUATES FACTORS CONCERNED WITH GENE EXPRESSION IN RELATION TO ENVIRONMENT, DISEASE, NORMAL DEVELOPMENT AND AGING, WITH A COMPLEX REGULATION ACROSS THE GENOME DURING THE FIRST DECADE OF LIFE. RESEARCH ON THE ROLE OF ENVIRONMENTAL FACTORS, EPIGENETICS AND CHRONIC NON-COMMUNICABLE DISEASES (NCDS) INCLUDING ADIPOSITY, AFTER A SLOW START, HAS EXPLODED IN THE LAST DECADE. NOT SO FOR AIS RESEARCH AND THE ENVIRONMENT WHERE, EXCEPT FOR MONOZYGOTIC TWIN STUDIES, THERE ARE ONLY SPORADIC REPORTS TO SUGGEST THAT ENVIRONMENTAL FACTORS ARE AT WORK IN ETIOLOGY. HERE, WE EXAMINE EPIGENETIC CONCEPTS AS THEY MAY RELATE TO HUMAN DEVELOPMENT, NORMAL LIFE HISTORY PHASES AND AIS PATHOGENESIS. ALTHOUGH AIS IS NOT REGARDED AS AN NCD, LIKE THEM, IT IS ASSOCIATED WITH WHOLE ORGANISM METABOLIC PHENOMENA, INCLUDING LOWER BODY MASS INDEX, LOWER CIRCULATING LEPTIN LEVELS AND OTHER SYSTEMIC DISORDERS. SOME EPIGENETIC RESEARCH APPLIED TO SILVER-RUSSELL SYNDROME AND ADIPOSITY IS EXAMINED, FROM WHICH SUGGESTIONS ARE MADE FOR CONSIDERATION OF AIS EPIGENETIC RESEARCH, CROSS-SECTIONAL AND LONGITUDINAL. THE WORD SCOLIOGENY IS SUGGESTED TO INCLUDE ETIOLOGY, PATHOGENESIS AND PATHOMECHANISM. 2012 13 1443 34 DIFFERENTIAL RESPONSES OF HEALTHY AND CHRONIC OBSTRUCTIVE PULMONARY DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(4). WHILE THE KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS IS STILL INCOMPLETE, DETAILED IN VITRO STUDIES ARE HIGHLY NEEDED. WITH THE AIM OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS AND BETTER INTEGRATING A NUMBER OF FACTORS RELATED TO PRE-EXISTING CHRONIC PULMONARY INFLAMMATORY, WE SOUGHT TO DEVELOP PRIMARY CULTURES OF NORMAL HUMAN BRONCHIAL EPITHELIAL (NHBE) CELLS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED HUMAN BRONCHIAL EPITHELIAL (DHBE) CELLS, GROWN AT THE AIR-LIQUID INTERFACE. PAN-CYTOKERATIN AND MUC5AC IMMUNOSTAINING CONFIRMED THE SPECIFIC CELL-TYPES OF BOTH THESE HEALTHY AND DISEASED CELL MODELS AND SHOWED THEY ARE CLOSED TO HUMAN BRONCHIAL EPITHELIA. THEREAFTER, HEALTHY AND DISEASED CELLS WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(4) AT THE NON-CYTOTOXIC CONCENTRATION OF 5 MUG/CM(2). THE DIFFERENCES BETWEEN THE OXIDATIVE AND INFLAMMATORY STATES IN NON-EXPOSED NHBE AND COPD-DHBE CELLS INDICATED THAT DISEASED CELLS CONSERVED THEIR SPECIFIC PHYSIOPATHOLOGICAL CHARACTERISTICS. INCREASES IN BOTH OXIDATIVE DAMAGE AND CYTOKINE SECRETION WERE REPORTED IN REPEATEDLY EXPOSED NHBE CELLS AND PARTICULARLY IN COPD-DHBE CELLS. DISEASED CELLS REPEATEDLY EXPOSED HAD LOWER CAPACITIES TO METABOLIZE THE ORGANIC CHEMICALS-COATED ONTO THE AIR-POLLUTION-DERIVED PM(4), SUCH AS BENZO[A]PYRENE (B[A]P), BUT SHOWED HIGHER SENSIBILITY TO THE FORMATION OF OH-B[A]P DNA ADDUCTS, BECAUSE THEIR DISEASED STATE POSSIBLY AFFECTED THEIR DEFENSES. DIFFERENTIAL PROFILES OF EPIGENETIC HALLMARKS (I.E., GLOBAL DNA HYPOMETHYLATION, P16 PROMOTER HYPERMETHYLATION, TELOMERE LENGTH SHORTENING, TELOMERASE ACTIVATION, AND HISTONE H3 MODIFICATIONS) OCCURRED IN REPEATEDLY EXPOSED NHBE AND PARTICULARLY IN COPD-DHBE CELLS. TAKEN TOGETHER, THESE RESULTS CLOSELY SUPPORTED THE HIGHEST RESPONSIVENESS OF COPD-DHBE CELLS TO A REPEATED EXPOSURE TO AIR POLLUTION-DERIVED PM(4). THE USE OF THESE INNOVATIVE IN VITRO EXPOSURE SYSTEMS SUCH AS NHBE AND COPD-DHBE CELLS COULD THEREFORE BE CONSIDER AS A VERY USEFUL AND POWERFUL PROMISING TOOL IN THE FIELD OF THE RESPIRATORY TOXICOLOGY, TAKING INTO ACCOUNT SENSITIVE INDIVIDUALS. 2016 14 4663 34 NEW HORIZONS: NOVEL APPROACHES TO ENHANCE HEALTHSPAN THROUGH TARGETING CELLULAR SENESCENCE AND RELATED AGING MECHANISMS. THE ELDERLY POPULATION IS INCREASING FASTER THAN OTHER SEGMENTS OF THE POPULATION THROUGHOUT THE WORLD. AGE IS THE LEADING PREDICTOR FOR MOST CHRONIC DISEASES AND DISORDERS, MULTIMORBIDITY, GERIATRIC SYNDROMES, AND IMPAIRED ABILITY TO RECOVER FROM ACCIDENTS OR ILLNESSES. ENHANCING THE DURATION OF HEALTH AND INDEPENDENCE, TERMED HEALTHSPAN, WOULD BE MORE DESIRABLE THAN EXTENDING LIFESPAN MERELY BY PROLONGING THE PERIOD OF MORBIDITY TOWARD THE END OF LIFE. THE GEROSCIENCE HYPOTHESIS POSITS THAT HEALTHSPAN CAN BE EXTENDED BY TARGETING FUNDAMENTAL AGING MECHANISMS, RATHER THAN ATTEMPTING TO ADDRESS EACH AGE-RELATED DISEASE ONE AT A TIME, ONLY SO THE AFFLICTED INDIVIDUAL SURVIVES DISABLED AND DIES SHORTLY AFTERWARD OF ANOTHER AGE-RELATED DISEASE. THESE FUNDAMENTAL AGING MECHANISMS INCLUDE, AMONG OTHERS, CHRONIC INFLAMMATION, FIBROSIS, STEM CELL/ PROGENITOR DYSFUNCTION, DNA DAMAGE, EPIGENETIC CHANGES, METABOLIC SHIFTS, DESTRUCTIVE METABOLITE GENERATION, MITOCHONDRIAL DYSFUNCTION, MISFOLDED OR AGGREGATED PROTEIN ACCUMULATION, AND CELLULAR SENESCENCE. THESE PROCESSES APPEAR TO BE TIGHTLY INTERLINKED, AS TARGETING ANY ONE APPEARS TO AFFECT MANY OF THE REST, UNDERLYING OUR UNITARY THEORY OF FUNDAMENTAL AGING MECHANISMS. INTERVENTIONS TARGETING MANY FUNDAMENTAL AGING PROCESSES ARE BEING DEVELOPED, INCLUDING DIETARY MANIPULATIONS, METFORMIN, MTOR (MECHANISTIC TARGET OF RAPAMYCIN) INHIBITORS, AND SENOLYTICS, WHICH ARE IN EARLY HUMAN TRIALS. THESE INTERVENTIONS COULD LEAD TO GREATER HEALTHSPAN BENEFITS THAN TREATING AGE-RELATED DISEASES ONE AT A TIME. TO ILLUSTRATE THESE POINTS, WE FOCUS ON CELLULAR SENESCENCE AND THERAPIES IN DEVELOPMENT TO TARGET SENESCENT CELLS. COMBINING INTERVENTIONS TARGETING AGING MECHANISMS WITH DISEASE-SPECIFIC DRUGS COULD RESULT IN MORE THAN ADDITIVE BENEFITS FOR CURRENTLY DIFFICULT-TO-TREAT OR INTRACTABLE DISEASES. MORE RESEARCH ATTENTION NEEDS TO BE DEVOTED TO TARGETING FUNDAMENTAL AGING PROCESSES. 2021 15 5623 28 SECOND-HAND SMOKE AND HUMAN LUNG CANCER. SINCE THE EARLY 1980S, THERE HAS BEEN GROWING CONCERN ABOUT POTENTIAL HEALTH CONSEQUENCES OF EXPOSURE TO SECOND-HAND SMOKE (SHS). DESPITE SHS BEING ESTABLISHED AS A RISK FACTOR FOR LUNG CANCER DEVELOPMENT, THE ESTIMATED RISK HAS REMAINED SMALL YET SOMEHOW DEBATABLE. HUMAN EXPOSURE TO SHS IS COMPLICATED BECAUSE OF TEMPORAL VARIABILITIES IN SOURCE, COMPOSITION, AND CONCENTRATION OF SHS. THE TEMPORALITY OF EXPOSURE TO SHS IS IMPORTANT FOR HUMAN LUNG CARCINOGENESIS WITH A LATENCY OF MANY YEARS. TO EXPLORE THE CAUSAL EFFECT OF SHS IN LUNG CARCINOGENESIS, EXPOSURE ASSESSMENTS SHOULD ESTIMATE CHRONIC EXPOSURE TO SHS ON AN INDIVIDUAL BASIS. HOWEVER, CONVENTIONAL EXPOSURE ASSESSMENT FOR SHS RELIES ON ONE-OFF OR SHORT-TERM MEASUREMENTS OF SHS INDICES. A MORE RELIABLE APPROACH WOULD BE TO USE BIOLOGICAL MARKERS THAT ARE SPECIFIC FOR SHS EXPOSURE AND PERTINENT TO LUNG CANCER. THIS APPROACH REQUIRES AN UNDERSTANDING OF THE UNDERLYING MECHANISMS THROUGH WHICH SHS COULD CONTRIBUTE TO LUNG CARCINOGENESIS. THIS REVIEW IS A SYNOPSIS OF RESEARCH ON SHS AND LUNG CANCER, WITH SPECIAL FOCUS ON HYPOTHETICAL MODES OF ACTION OF SHS FOR CARCINOGENESIS, INCLUDING GENOTOXIC AND EPIGENETIC EFFECTS. 2008 16 5013 36 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AS A THERAPEUTIC TARGET FOR HEPATIC FIBROSIS: FROM BENCH TO BEDSIDE. HEPATIC FIBROSIS IS A DYNAMIC CHRONIC LIVER DISEASE OCCURRING AS A CONSEQUENCE OF WOUND-HEALING RESPONSES TO VARIOUS HEPATIC INJURIES. THIS DISORDER IS ONE OF PRIMARY PREDICTORS FOR LIVER-ASSOCIATED MORBIDITY AND MORTALITY WORLDWIDE. TO DATE, NO PHARMACOLOGICAL AGENT HAS BEEN APPROVED FOR HEPATIC FIBROSIS OR COULD BE RECOMMENDED FOR ROUTINE USE IN CLINICAL CONTEXT. CELLULAR AND MOLECULAR UNDERSTANDING OF HEPATIC FIBROSIS HAS REVEALED THAT PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA), THE FUNCTIONING RECEPTOR FOR ANTIDIABETIC THIAZOLIDINEDIONES, PLAYS A PIVOTAL ROLE IN THE PATHOBIOLOGY OF HEPATIC STELLATE CELLS (HSCS), WHOSE ACTIVATION IS THE CENTRAL EVENT IN THE PATHOGENESIS OF HEPATIC FIBROSIS. ACTIVATION OF PPARGAMMA INHIBITS HSC COLLAGEN PRODUCTION AND MODULATES HSC ADIPOGENIC PHENOTYPE AT TRANSCRIPTIONAL AND EPIGENETIC LEVELS. THESE MOLECULAR INSIGHTS INDICATE PPARGAMMA AS A PROMISING DRUG TARGET FOR ANTIFIBROTIC CHEMOTHERAPY. INTENSIVE ANIMAL STUDIES HAVE DEMONSTRATED THAT STIMULATION OF PPARGAMMA REGULATORY SYSTEM THROUGH GENE THERAPY APPROACHES AND PPARGAMMA LIGANDS HAS THERAPEUTIC PROMISE FOR HEPATIC FIBROSIS INDUCED BY A VARIETY OF ETIOLOGIES. AT THE SAME TIME, THIAZOLIDINEDIONE AGENTS HAVE BEEN INVESTIGATED FOR THEIR CLINICAL BENEFITS PRIMARILY IN PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS, A COMMON METABOLIC LIVER DISORDER WITH HIGH POTENTIAL TO PROGRESS TO FIBROSIS AND LIVER-RELATED DEATH. ALTHOUGH SOME STUDIES HAVE SHOWN INITIAL PROMISE, NONE HAS ESTABLISHED LONG-TERM EFFICACY IN WELL-CONTROLLED RANDOMIZED CLINICAL TRIALS. THIS COMPREHENSIVE REVIEW COVERS THE 10-YEAR DISCOVERIES OF THE MOLECULAR BASIS FOR PPARGAMMA REGULATION OF HSC PATHOPHYSIOLOGY AND THEN FOCUSES ON THE ANIMAL INVESTIGATIONS AND CLINICAL TRIALS OF VARIOUS THERAPEUTIC MODALITIES TARGETING PPARGAMMA FOR HEPATIC FIBROSIS. 2013 17 5026 32 PERSONALIZED MEDICINE IN IDIOPATHIC PULMONARY FIBROSIS: FACTS AND PROMISES. PURPOSE OF REVIEW: IN THIS ARTICLE, WE SUMMARIZE AND DISCUSS THE MOST RECENT LITERATURE ON PERSONALIZED MEDICINE IN IDIOPATHIC PULMONARY FIBROSIS (IPF), A CHRONIC PROGRESSIVE AND ALMOST INVARIABLY LETHAL DISEASE OF UNKNOWN CAUSE. THIS REVIEW IS TIMELY AS MAJOR ADVANCES IN OUR UNDERSTANDING OF DISEASE PATHOBIOLOGY AND IMPROVEMENTS IN MOLECULAR TECHNIQUES HAVE RECENTLY LED TO THE IDENTIFICATION OF POTENTIAL SURROGATES OF DIAGNOSIS, PROGNOSIS AND RESPONSE TO TREATMENT. RECENT FINDINGS: THE MOST PROMISING AND ADVANCED CANDIDATE BIOMARKERS ARE PRESENTED BASED ON THEIR PROPOSED MECHANISTIC PATHWAYS (E.G. ALVEOLAR EPITHELIAL CELL DYSFUNCTION, IMMUNE DYSREGULATION, MICROBIOME, EXTRACELLULAR MATRIX REMODELING AND FIBROPROLIFERATION, EPIGENETIC MARKERS AND METABOLOMICS). RECENT DATA SUGGEST THAT COMPONENTS OF THE IMMUNE SYSTEM MAY CONTRIBUTE TO THE DEVELOPMENT OF IPF. A POTENTIAL ROLE FOR INFECTIONS AS A COFACTOR IN DISEASE DEVELOPMENT AND PROGRESSION OR AS A TRIGGER IN DISEASE EXACERBATION HAS ALSO RECENTLY BEEN PROPOSED. SUMMARY: CLINICAL MANAGEMENT OF IPF IS UNSATISFACTORY BECAUSE OF LIMITED AVAILABILITY OF TRULY EFFECTIVE THERAPIES, LACK OF ACCURATE PREDICTORS OF DISEASE BEHAVIOR AND ABSENCE OF SIMPLE SHORT-TERM MEASURES OF THERAPEUTIC RESPONSE. A NUMBER OF PUTATIVE BIOMARKERS HAVE BEEN IDENTIFIED IN PATIENTS WITH IPF, ALTHOUGH NONE HAS BEEN VALIDATED TO THE STANDARD NECESSARY FOR THEIR USE IN EITHER THERAPEUTIC TRIALS OR CLINICAL PRACTICE. CURRENTLY, ONGOING PROSPECTIVE LONGITUDINAL STUDIES WILL HOPEFULLY PERMIT SUCH VALIDATION. 2015 18 361 29 AMBIENT AIR POLLUTION AND THROMBOSIS. AIR POLLUTION IS A GROWING PUBLIC HEALTH CONCERN OF GLOBAL SIGNIFICANCE. ACUTE AND CHRONIC EXPOSURE IS KNOWN TO IMPAIR CARDIOVASCULAR FUNCTION, EXACERBATE DISEASE AND INCREASE CARDIOVASCULAR MORTALITY. SEVERAL PLAUSIBLE BIOLOGICAL MECHANISMS HAVE BEEN PROPOSED FOR THESE ASSOCIATIONS, HOWEVER, AT PRESENT, THE PATHWAYS ARE INCOMPLETE. A SEMINAL REVIEW BY THE AMERICAN HEART ASSOCIATION (2010) CONCLUDED THAT THE THROMBOTIC EFFECTS OF PARTICULATE AIR POLLUTION LIKELY CONTRIBUTED TO THEIR EFFECTS ON CARDIOVASCULAR MORTALITY AND MORBIDITY. THE AIM OF THE CURRENT REVIEW IS TO APPRAISE THE NEWLY ACCUMULATED SCIENTIFIC EVIDENCE (2009-2016) ON CONTRIBUTION OF HAEMOSTASIS AND THROMBOSIS TOWARDS CARDIOVASCULAR DISEASE INDUCED BY EXPOSURE TO BOTH PARTICULATE AND GASEOUS POLLUTANTS.SEVENTY FOUR PUBLICATIONS WERE REVIEWED IN-DEPTH. THE WEIGHT OF EVIDENCE SUGGESTS THAT ACUTE EXPOSURE TO FINE PARTICULATE MATTER (PM(2.5)) INDUCES A SHIFT IN THE HAEMOSTATIC BALANCE TOWARDS A PRO-THROMBOTIC/PRO-COAGULATIVE STATE. INSUFFICIENT DATA WAS AVAILABLE TO ASCERTAIN IF A SIMILAR RELATIONSHIP EXISTS FOR GASEOUS POLLUTANTS, AND VERY FEW STUDIES HAVE ADDRESSED LONG-TERM EXPOSURE TO AMBIENT AIR POLLUTION. PLATELET ACTIVATION, OXIDATIVE STRESS, INTERPLAY BETWEEN INTERLEUKIN-6 AND TISSUE FACTOR, ALL APPEAR TO BE POTENTIALLY IMPORTANT MECHANISMS IN POLLUTION-MEDIATED THROMBOSIS, TOGETHER WITH AN EMERGING ROLE FOR CIRCULATING MICROVESICLES AND EPIGENETIC CHANGES.OVERALL, THE RECENT LITERATURE SUPPORTS, AND ARGUABLY STRENGTHENS, THE CONTENTION THAT AIR POLLUTION CONTRIBUTES TO CARDIOVASCULAR MORBIDITY BY PROMOTING HAEMOSTASIS. THE VOLUME AND DIVERSITY OF THE EVIDENCE HIGHLIGHTS THE COMPLEXITY OF THE PATHOPHYSIOLOGIC MECHANISMS BY WHICH AIR POLLUTION PROMOTES THROMBOSIS; MULTIPLE PATHWAYS ARE PLAUSIBLE AND IT IS MOST LIKELY THEY ACT IN CONCERT. FUTURE RESEARCH SHOULD ADDRESS THE ROLE GASEOUS POLLUTANTS PLAY IN THE CARDIOVASCULAR EFFECTS OF AIR POLLUTION MIXTURE AND DIRECT COMPARISON OF POTENTIALLY SUSCEPTIBLE GROUPS TO HEALTHY INDIVIDUALS. 2018 19 3513 35 IDIOPATHIC PULMONARY FIBROSIS: PATHOGENESIS AND MANAGEMENT. BACKGROUND: IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE DISEASE CHARACTERIZED BY THE ABERRANT ACCUMULATION OF FIBROTIC TISSUE IN THE LUNGS PARENCHYMA, ASSOCIATED WITH SIGNIFICANT MORBIDITY AND POOR PROGNOSIS. THIS REVIEW WILL PRESENT THE SUBSTANTIAL ADVANCES ACHIEVED IN THE UNDERSTANDING OF IPF PATHOGENESIS AND IN THE THERAPEUTIC OPTIONS THAT CAN BE OFFERED TO PATIENTS, AND WILL ADDRESS THE ISSUES REGARDING DIAGNOSIS AND MANAGEMENT THAT ARE STILL OPEN. MAIN BODY: OVER THE LAST TWO DECADES MUCH HAS BEEN CLARIFIED ABOUT THE PATHOGENIC PATHWAYS UNDERLYING THE DEVELOPMENT AND PROGRESSION OF THE LUNG SCARRING IN IPF. SUSTAINED ALVEOLAR EPITHELIAL MICRO-INJURY AND ACTIVATION HAS BEEN RECOGNISED AS THE TRIGGER OF SEVERAL BIOLOGICAL EVENTS OF DISORDERED REPAIR OCCURRING IN GENETICALLY SUSCEPTIBLE AGEING INDIVIDUALS. DESPITE MULTIDISCIPLINARY TEAM DISCUSSION HAS DEMONSTRATED TO INCREASE DIAGNOSTIC ACCURACY, PATIENTS CAN STILL REMAIN UNCLASSIFIED WHEN THE CURRENT DIAGNOSTIC CRITERIA ARE STRICTLY APPLIED, REQUIRING THE IDENTIFICATION OF A USUAL INTERSTITIAL PATTERN EITHER ON HIGH-RESOLUTION COMPUTED TOMOGRAPHY SCAN OR LUNG BIOPSY. OUTSTANDING ACHIEVEMENTS HAVE BEEN MADE IN THE MANAGEMENT OF THESE PATIENTS, AS NINTEDANIB AND PIRFENIDONE CONSISTENTLY PROVED TO REDUCE THE RATE OF PROGRESSION OF THE FIBROTIC PROCESS. HOWEVER, MANY UNCERTAINTIES STILL LIE IN THE CORRECT USE OF THESE DRUGS, RANGING FROM THE INITIAL CHOICE OF THE DRUG, THE APPROPRIATE TIMING FOR TREATMENT AND THE BENEFIT-RISK RATIO OF A COMBINED TREATMENT REGIMEN. SEVERAL NOVEL COMPOUNDS ARE BEING DEVELOPED IN THE PERSPECTIVE OF A MORE TARGETED THERAPEUTIC APPROACH; IN THE MEANTIME, THE SUPPORTIVE CARE OF THESE PATIENTS AND THEIR CARERS SHOULD BE APPROPRIATELY PRIORITIZED, AND GREATER EFFORTS SHOULD BE MADE TOWARD THE PROMPT IDENTIFICATION AND MANAGEMENT OF RELEVANT COMORBIDITIES. CONCLUSIONS: BUILDING ON THE ADVANCES IN THE UNDERSTANDING OF IPF PATHOBIOLOGY, THE FURTHER INVESTIGATION OF THE ROLE OF GENE VARIANTS, EPIGENETIC ALTERATIONS AND OTHER MOLECULAR BIOMARKERS REFLECTING DISEASE ACTIVITY AND BEHAVIOUR WILL HOPEFULLY ENABLE EARLIER AND MORE CONFIDENT DIAGNOSIS, IMPROVE DISEASE PHENOTYPING AND SUPPORT THE DEVELOPMENT OF NOVEL AGENTS FOR PERSONALIZED TREATMENT OF IPF. 2018 20 1253 31 CURRENT PROBLEMS AND FUTURE DIRECTIONS OF TRANSFUSION-INDUCED ALLOIMMUNIZATION: SUMMARY OF AN NHLBI WORKING GROUP. IN APRIL 2010, A WORKING GROUP SPONSORED BY THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE WAS ASSEMBLED TO IDENTIFY RESEARCH STRATEGIES TO IMPROVE OUR UNDERSTANDING OF ALLOIMMUNIZATION CAUSED BY THE TRANSFUSION OF ALLOGENEIC BLOOD COMPONENTS AND TO EVALUATE POTENTIAL APPROACHES TO BOTH REDUCE ITS OCCURRENCE AND MANAGE ITS EFFECTS. SIGNIFICANT SEQUELAE OF ALLOIMMUNIZATION WERE DISCUSSED AND IDENTIFIED, INCLUDING DIFFICULTIES IN MAINTAINING CHRONIC TRANSFUSION OF RED BLOOD CELLS AND PLATELETS, HEMOLYTIC DISEASE OF THE NEWBORN, NEONATAL ALLOIMMUNE THROMBOCYTOPENIA, AND REJECTION OF TRANSPLANTED CELLS AND TISSUES. THE DISCUSSIONS RESULTED IN A CONSENSUS THAT IDENTIFIED KEY AREAS OF FUTURE RESEARCH AND DEVELOPMENTAL AREAS, INCLUDING GENETIC AND EPIGENETIC RECIPIENT FACTORS THAT REGULATE ALLOIMMUNIZATION, BIOCHEMICAL SPECIFICS OF TRANSFUSED PRODUCTS THAT AFFECT ALLOIMMUNIZATION, AND NOVEL TECHNOLOGIES FOR HIGH-THROUGHPUT GENOTYPING TO FACILITATE EXTENSIVE AND EFFICIENT ANTIGEN MATCHING BETWEEN DONOR AND RECIPIENT. ADDITIONAL AREAS OF IMPORTANCE INCLUDED ANALYSIS OF UNAPPRECIATED MEDICAL SEQUELAE OF ALLOIMMUNIZATION, SUCH AS CELLULAR IMMUNITY AND ITS EFFECT UPON TRANSPLANT AND AUTOIMMUNITY. IN ADDITION, SUPPORT FOR RESEARCH INFRASTRUCTURE WAS DISCUSSED, WITH AN EMPHASIS ON ENCOURAGING COLLABORATION AND SYNERGY OF ANIMAL MODELS BIOLOGY AND HUMAN CLINICAL RESEARCH. FINALLY, TRAINING FUTURE INVESTIGATORS WAS IDENTIFIED AS AN AREA OF IMPORTANCE. IN AGGREGATE, THIS COMMUNICATION PROVIDES A SYNOPSIS OF THE OPINIONS OF THE WORKING GROUP ON THE ABOVE ISSUES AND PRESENTS BOTH A LIST OF SUGGESTED PRIORITIES AND THE RATIONALE FOR THE TOPICS OF FOCUS. THE AREAS OF RESEARCH IDENTIFIED IN THIS REPORT REPRESENT POTENTIAL FERTILE GROUND FOR THE MEDICAL ADVANCEMENT OF PREVENTING AND MANAGING ALLOIMMUNIZATION IN ITS DIFFERENT FORMS AND MITIGATING THE CLINICAL PROBLEMS IT PRESENTS TO MULTIPLE PATIENT POPULATIONS. 2011