1 2106 169 EPIGENETIC EVOLUTION AND LINEAGE HISTORIES OF CHRONIC LYMPHOCYTIC LEUKAEMIA. GENETIC AND EPIGENETIC INTRA-TUMORAL HETEROGENEITY COOPERATE TO SHAPE THE EVOLUTIONARY COURSE OF CANCER(1). CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IS A HIGHLY INFORMATIVE MODEL FOR CANCER EVOLUTION AS IT UNDERGOES SUBSTANTIAL GENETIC DIVERSIFICATION AND EVOLUTION AFTER THERAPY(2,3). THE CLL EPIGENOME IS ALSO AN IMPORTANT DISEASE-DEFINING FEATURE(4,5), AND GROWING POPULATIONS OF CELLS IN CLL DIVERSIFY BY STOCHASTIC CHANGES IN DNA METHYLATION KNOWN AS EPIMUTATIONS(6). HOWEVER, PREVIOUS STUDIES USING BULK SEQUENCING METHODS TO ANALYSE THE PATTERNS OF DNA METHYLATION WERE UNABLE TO DETERMINE WHETHER EPIMUTATIONS AFFECT CLL POPULATIONS HOMOGENEOUSLY. HERE, TO MEASURE THE EPIMUTATION RATE AT SINGLE-CELL RESOLUTION, WE APPLIED MULTIPLEXED SINGLE-CELL REDUCED-REPRESENTATION BISULFITE SEQUENCING TO B CELLS FROM HEALTHY DONORS AND PATIENTS WITH CLL. WE OBSERVED THAT THE COMMON CLONAL ORIGIN OF CLL RESULTS IN A CONSISTENTLY INCREASED EPIMUTATION RATE, WITH LOW VARIABILITY IN THE CELL-TO-CELL EPIMUTATION RATE. BY CONTRAST, VARIABLE EPIMUTATION RATES ACROSS HEALTHY B CELLS REFLECT DIVERSE EVOLUTIONARY AGES ACROSS THE TRAJECTORY OF B CELL DIFFERENTIATION, CONSISTENT WITH EPIMUTATIONS SERVING AS A MOLECULAR CLOCK. HERITABLE EPIMUTATION INFORMATION ALLOWED US TO RECONSTRUCT LINEAGES AT HIGH-RESOLUTION WITH SINGLE-CELL DATA, AND TO APPLY THIS DIRECTLY TO PATIENT SAMPLES. THE CLL LINEAGE TREE SHAPE REVEALED EARLIER BRANCHING AND LONGER BRANCH LENGTHS THAN IN NORMAL B CELLS, REFLECTING RAPID DRIFT AFTER THE INITIAL MALIGNANT TRANSFORMATION AND A GREATER PROLIFERATIVE HISTORY. INTEGRATION OF SINGLE-CELL BISULFITE SEQUENCING ANALYSIS WITH SINGLE-CELL TRANSCRIPTOMES AND GENOTYPING CONFIRMED THAT GENETIC SUBCLONES MAPPED TO DISTINCT CLADES, AS INFERRED SOLELY ON THE BASIS OF EPIMUTATION INFORMATION. FINALLY, TO EXAMINE POTENTIAL LINEAGE BIASES DURING THERAPY, WE PROFILED SERIAL SAMPLES DURING IBRUTINIB-ASSOCIATED LYMPHOCYTOSIS, AND IDENTIFIED CLADES OF CELLS THAT WERE PREFERENTIALLY EXPELLED FROM THE LYMPH NODE AFTER TREATMENT, MARKED BY DISTINCT TRANSCRIPTIONAL PROFILES. THE SINGLE-CELL INTEGRATION OF GENETIC, EPIGENETIC AND TRANSCRIPTIONAL INFORMATION THUS CHARTS THE LINEAGE HISTORY OF CLL AND ITS EVOLUTION WITH THERAPY. 2019 2 6571 26 TRANSPOSABLE ELEMENTS CROSS KINGDOM BOUNDARIES AND CONTRIBUTE TO INFLAMMATION AND AGEING: SOMATIC ACQUISITION OF FOREIGN TRANSPOSABLE ELEMENTS AS A CATALYST OF GENOME INSTABILITY, EPIGENETIC DYSREGULATION, INFLAMMATION, SENESCENCE, AND AGEING. THE DE-REPRESSION OF TRANSPOSABLE ELEMENTS (TES) IN MAMMALIAN GENOMES IS THOUGHT TO CONTRIBUTE TO GENOME INSTABILITY, INFLAMMATION, AND AGEING, YET IS VIEWED AS A CELL-AUTONOMOUS EVENT. IN CONTRAST TO MAMMALIAN CELLS, PROKARYOTES CONSTANTLY EXCHANGE GENETIC MATERIAL THROUGH TES, CROSSING BOTH CELL AND SPECIES BARRIERS, CONTRIBUTING TO RAPID MICROBIAL EVOLUTION AND DIVERSITY IN COMPLEX COMMUNITIES SUCH AS THE MAMMALIAN GUT. HERE, IT IS PROPOSED THAT TES RELEASED FROM PROKARYOTES IN THE MICROBIOME OR FROM PATHOGENIC INFECTIONS REGULARLY CROSS THE KINGDOM BARRIER TO THE SOMATIC CELLS OF THEIR EUKARYOTIC HOSTS. IT IS PROPOSED THIS HORIZONTAL TRANSFER OF TES FROM MICROBE TO HOST IS A STOCHASTIC, ONGOING CATALYST OF GENOME DESTABILIZATION, RESULTING IN STRUCTURAL AND EPIGENETIC VARIATIONS, AND ACTIVATION OF WELL-EVOLVED HOST DEFENSE MECHANISMS CONTRIBUTING TO INFLAMMATION, SENESCENCE, AND BIOLOGICAL AGEING. IT IS PROPOSED THAT INNATE IMMUNITY PATHWAYS DEFEND AGAINST THE HORIZONTAL ACQUISITION OF MICROBIAL TES, AND THAT ACTIVATION OF THIS PATHWAY DURING HORIZONTAL TRANSPOSON TRANSFER PROMOTES CHRONIC INFLAMMATION DURING AGEING. FINALLY, IT IS SUGGESTED THAT HORIZONTAL ACQUISITION OF PROKARYOTIC TES INTO MAMMALIAN GENOMES HAS BEEN MASKED AND SUBSEQUENTLY UNDER-REPORTED DUE TO FLAWS IN CURRENT SEQUENCING PIPELINES, AND NEW STRATEGIES TO UNCOVER THESE EVENTS ARE PROPOSED. 2020 3 6588 35 TUMOR HETEROGENEITY IN LYMPHOMAS: A DIFFERENT BREED. THE FACTS THAT CANCER REPRESENTS TISSUES CONSISTING OF HETEROGENEOUS NEOPLASTIC, AS WELL AS REACTIVE, CELL POPULATIONS AND THAT CANCERS OF THE SAME HISTOTYPE MAY SHOW PROFOUND DIFFERENCES IN CLINICAL BEHAVIOR HAVE LONG BEEN RECOGNIZED. WITH THE ADVENT OF NEW TECHNOLOGIES AND THE DEMANDS OF PRECISION MEDICINE, THE INVESTIGATION OF TUMOR HETEROGENEITY HAS GAINED MUCH INTEREST. AN UNDERSTANDING OF INTERTUMORAL HETEROGENEITY IN PATIENTS WITH THE SAME DISEASE ENTITY IS NECESSARY TO OPTIMALLY GUIDE PERSONALIZED TREATMENT. IN ADDITION, INCREASING EVIDENCE INDICATES THAT DIFFERENT TUMOR AREAS OR PRIMARY TUMORS AND METASTASES IN AN INDIVIDUAL PATIENT CAN SHOW SIGNIFICANT INTRATUMORAL HETEROGENEITY ON DIFFERENT LEVELS. THIS PHENOMENON CAN BE DRIVEN BY GENOMIC INSTABILITY, EPIGENETIC EVENTS, THE TUMOR MICROENVIRONMENT, AND STOCHASTIC VARIATIONS IN CELLULAR FUNCTION AND ANTITUMORAL THERAPIES. THESE MECHANISMS MAY LEAD TO BRANCHED SUBCLONAL EVOLUTION FROM A COMMON PROGENITOR CLONE, RESULTING IN SPATIAL VARIATION BETWEEN DIFFERENT TUMOR SITES, DISEASE PROGRESSION, AND TREATMENT RESISTANCE. THIS REVIEW ADDRESSES TUMOR HETEROGENEITY IN LYMPHOMAS FROM A PATHOLOGIST'S VIEWPOINT. THE RELATIONSHIP BETWEEN MORPHOLOGIC, IMMUNOPHENOTYPIC, AND GENETIC HETEROGENEITY IS EXEMPLIFIED IN DIFFERENT LYMPHOMA ENTITIES AND REVIEWED IN THE CONTEXT OF HIGH-GRADE TRANSFORMATION AND TRANSDIFFERENTIATION. IN ADDITION, FACTORS DRIVING HETEROGENEITY, AS WELL AS CLINICAL AND THERAPEUTIC IMPLICATIONS OF LYMPHOMA HETEROGENEITY, WILL BE DISCUSSED. 2018 4 391 42 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 5 6157 32 THE GENETICS AND EPIGENETICS OF ALTERED PROLIFERATIVE HOMEOSTASIS IN AGEING AND CANCER. AGEING MAMMALS ARE SUBJECT TO AN AMAZING ARRAY OF ABERRATIONS IN PROLIFERATIVE HOMEOSTASIS. THESE ARE OF TWO BASIC TYPES: THE POST-MATURATIONAL FAILURE TO ADEQUATELY REPLACE EFFETE SOMATIC CELLS (ATROPHIES) AND EXCESSIVE PROLIFERATIONS OF SOMATIC CELLS (HYPERPLASIAS). TO A SURPRISING DEGREE, THESE OCCUR SIDE BY SIDE WITHIN THE SAME TISSUES AND ARE FEATURES OF NUMEROUS MAMMALIAN GERIATRIC DISORDERS. ATROPHY IS THE LIKELY USUAL INITIAL EVENT, THE PROLIFERATIVE RESPONSE PERHAPS DEVELOPING AS A SECONDARY, COMPENSATORY, INITIALLY ADAPTIVE REACTION. WE HAVE LITTLE UNDERSTANDING OF WHY THIS PUTATIVE COMPENSATORY REACTION SO OFTEN FAILS TO BE APPROPRIATELY REGULATED IN AGEING MAMMALS, LEADING TO SUCH PATHOLOGIES AS CHRONIC INFLAMMATION, FIBROSIS, METAPLASIA AND NEOPLASIA. ADVANCES IN FORMAL GENETIC ANALYSIS, MUTAGENESIS, STEM CELL BIOLOGY AND EPIGENETICS ARE LIKELY TO PROVIDE MAJOR NEW UNDERSTANDING. STOCHASTIC EPIGENETIC SHIFTS IN GENE EXPRESSION ARE OF GROWING INTEREST, PARTICULARLY IN EXPLAINING INTRA-SPECIFIC VARIATIONS ON RATES AND PATTERNS OF AGEING. NATURE MAY WELL HAVE EVOLVED SUCH RANDOM FLUCTUATIONS IN GENE EXPRESSION AS A TYPE OF GROUP-SELECTIONIST ADAPTIVE STRATEGY TO COPE WITH DIVERSE STOCHASTIC ENVIRONMENTAL CHALLENGES. ALTERNATIVELY, SUCH BACKGROUND "NOISE" IN TRANSCRIPTION AND TRANSLATION MAY SIMPLY REFLECT A TYPE OF INFORMATIONAL ENTROPY. 2007 6 384 38 AN EVOLUTIONARY PERSPECTIVE ON CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) SHARES WITH OTHER MYELOID DISEASES A NUMBER OF SOMATIC GENE MUTATIONS. THESE MUTATIONS CAN NOW BE INTEGRATED WITHIN THE FRAMEWORK OF EVOLUTION THEORY TO ADDRESS THE MECHANISMS OF THE DISEASE. SEVERAL EVIDENCES INDICATE THAT THE DISEASE EMERGES IN ADULT HEMATOPOIETIC STEM CELLS (HSC) THROUGH THE AGE-DEPENDENT ACCUMULATION OF DNA DAMAGE, LEADING STOCHASTICALLY TO A DRIVER MUTATION THAT CONFERS A COMPETITIVE ADVANTAGE TO THE CELL. A MUTATION IN TET2 GENE COULD BE ONE OF THESE DRIVER MUTATIONS PROVOKING THE EMERGENCE OF CLONALITY. AFTER A LONG LATENCY, SECONDARY LESIONS, SUCH AS MUTATIONS IN THE SRSF2 GENE, CONTRIBUTE TO PROGRESSION TO FULL-BLOWN MALIGNANCY, WITH ABNORMAL DIFFERENTIATION. ADDITIONAL MUTATIONS ACCUMULATE AND BRANCHING ARISING MOSTLY THROUGH MITOTIC RECOMBINATION GENERATES CLONAL HETEROGENEITY. MODIFICATIONS IN THE MICROENVIRONMENT PROBABLY AFFECT THIS CLONAL DYNAMICS, WHEREAS EPIGENETIC ALTERATIONS, SUCH AS HYPERMETHYLATION OF THE TIF1GAMMA GENE PROMOTER, MAY GENERATE PHENOTYPIC DIVERSIFICATION OF OTHERWISE CLONAL POPULATIONS. THE PRESERVED ALTHOUGH DEREGULATED MYELOID DIFFERENTIATION THAT CHARACTERIZES CMML, WITH GRANULOMONOCYTE EXPANSION AND VARIOUS CYTOPENIAS, MAY DEPEND ON EARLY CLONAL DOMINANCE IN THE HEMATOPIETIC CELL HIERARCHY. PROGRESSION TO ACUTE MYELOID LEUKEMIA OBSERVED IN 25-30% OF THE PATIENTS MAY ARISE FROM THE MASSIVE EXPANSION OF A CLONE WITH NOVEL GENETIC LESIONS, PROVIDING A HIGH FITNESS TO PREVIOUSLY MINOR SUBCLONES WHEN IN CHRONIC PHASE OF THE DISEASE. THIS REVIEW DISCUSSES THE VARIOUS MODELS OF DISEASE EMERGENCE AND PROGRESSION AND HOW THIS RECENT KNOWLEDGE COULD DRIVE RATIONAL THERAPEUTIC STRATEGIES. 2013 7 3811 29 INTRATUMORAL HETEROGENEITY: CLONAL COOPERATION IN EPITHELIAL-TO-MESENCHYMAL TRANSITION AND METASTASIS. ALTHOUGH PHENOTYPIC INTRATUMORAL HETEROGENEITY WAS FIRST DESCRIBED MANY DECADES AGO, THE ADVENT OF NEXT-GENERATION SEQUENCING HAS PROVIDED CONCLUSIVE EVIDENCE THAT IN ADDITION TO PHENOTYPIC DIVERSITY, SIGNIFICANT GENOTYPIC DIVERSITY EXISTS WITHIN TUMORS. TUMOR HETEROGENEITY LIKELY ARISES BOTH FROM CLONAL EXPANSIONS, AS WELL AS FROM DIFFERENTIATION HIERARCHIES EXISTENT IN THE TUMOR, SUCH AS THAT ESTABLISHED BY CANCER STEM CELLS (CSCS) AND NON-CSCS. THESE DIFFERENTIATION HIERARCHIES MAY ARISE DUE TO GENETIC MUTATIONS, EPIGENETIC ALTERATIONS, OR MICROENVIRONMENTAL INFLUENCES. AN ADDITIONAL DIFFERENTIATION HIERARCHY WITHIN EPITHELIAL TUMORS MAY ARISE WHEN ONLY A FEW TUMOR CELLS TRANS-DIFFERENTIATE INTO MESENCHYMAL-LIKE CELLS, A PROCESS KNOWN AS EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT). AGAIN, THIS PROCESS CAN BE INFLUENCED BY BOTH GENETIC AND NON-GENETIC FACTORS. IN THIS REVIEW WE DISCUSS THE EVIDENCE FOR CLONAL INTERACTION AND COOPERATION FOR TUMOR MAINTENANCE AND PROGRESSION, PARTICULARLY WITH RESPECT TO EMT, AND FURTHER ADDRESS THE FAR-REACHING EFFECTS THAT TUMOR HETEROGENEITY MAY HAVE ON CANCER THERAPY. 2015 8 3110 36 GENOTYPE- OR PHENOTYPE-TARGETING ANTICANCER THERAPIES? LESSONS FROM TUMOR EVOLUTIONARY BIOLOGY. DESPITE THE EFFICACY OF MOST CANCER THERAPIES, DRUG RESISTANCE REMAINS A MAJOR PROBLEM IN THE CLINIC. THE ERADICATION OF THE ENTIRE TUMOR AND THE CURE OF THE PATIENT BY CHEMOTHERAPY ALONE ARE RARE, IN PARTICULAR FOR ADVANCED DISEASE. FROM AN EVOLUTIONARY PERSPECTIVE, THE SELECTIVE PRESSURE EXERTED BY CHEMOTHERAPY LEADS TO THE EMERGENCE OF RESISTANT CLONES WHERE RESISTANCE CAN BE ASSOCIATED WITH MANY DIFFERENT FUNCTIONAL MECHANISMS AT THE SINGLE CELL LEVEL OR CAN INVOLVE CHANGES IN THE TUMOR MICRO-ENVIRONMENT. IN THE LAST DECADE, TUMOR GENOMICS HAS CONTRIBUTED TO THE IMPROVEMENT OF OUR UNDERSTANDING OF TUMORIGENESIS AND HAS LED TO THE IDENTIFICATION OF NUMEROUS CELLULAR TARGETS FOR THE DEVELOPMENT OF NOVEL THERAPIES. HOWEVER, SINCE TUMORS ARE BY NATURE EXTREMELY HETEROGENEOUS, THE DRUG EFFICACY AND ECONOMICAL SUSTAINABILITY OF THIS APPROACH IS NOW DEBATABLE. IMPORTANTLY, TUMOR CELL HETEROGENEITY DEPENDS NOT ONLY ON GENETIC MODIFICATIONS BUT ALSO ON NON-GENETIC PROCESSES INVOLVING EITHER STOCHASTIC EVENTS OR EPIGENETIC MODIFICATIONS MAKING GENETIC BIOMARKERS OF UNCERTAIN UTILITY. IN THIS REVIEW, WE WISH TO HIGHLIGHT HOW EVOLUTIONARY BIOLOGY CAN IMPACT OUR UNDERSTANDING OF CARCINOGENESIS AND RESISTANCE TO THERAPIES. WE WILL DISCUSS NEW APPROACHES BASED ON APPLIED ECOLOGY AND EVOLUTION DYNAMICS THAT CAN BE USED TO CONVERT THE CANCER INTO A CHRONIC DISEASE WHERE THE DRUGS WOULD CONTROL TUMOR GROWTH. FINALLY, WE WILL DISCUSS THE WAY METABOLIC DYSFUNCTION OR PHENOTYPIC CHANGES CAN HELP DEVELOPING NEW DELIVERY SYSTEMS OR PHENOTYPETARGETED DRUGS AND HOW EXPLORING NEW SOURCES OF ACTIVE COMPOUNDS CAN CONDUCT TO THE DEVELOPMENT OF DRUGS WITH ORIGINAL MECHANISMS OF ACTION. 2016 9 5631 33 SENESCENCE-INFLAMMATORY REGULATION OF REPARATIVE CELLULAR REPROGRAMMING IN AGING AND CANCER. THE INABILITY OF ADULT TISSUES TO TRANSITORILY GENERATE CELLS WITH FUNCTIONAL STEM CELL-LIKE PROPERTIES IS A MAJOR OBSTACLE TO TISSUE SELF-REPAIR. NUCLEAR REPROGRAMMING-LIKE PHENOMENA THAT INDUCE A TRANSIENT ACQUISITION OF EPIGENETIC PLASTICITY AND PHENOTYPE MALLEABILITY MAY CONSTITUTE A REPARATIVE ROUTE THROUGH WHICH HUMAN TISSUES RESPOND TO INJURY, STRESS, AND DISEASE. HOWEVER, TISSUE REJUVENATION SHOULD INVOLVE NOT ONLY THE TRANSIENT EPIGENETIC REPROGRAMMING OF DIFFERENTIATED CELLS, BUT ALSO THE COMMITTED RE-ACQUISITION OF THE ORIGINAL OR ALTERNATIVE COMMITTED CELL FATE. CHRONIC OR UNRESTRAINED EPIGENETIC PLASTICITY WOULD DRIVE AGING PHENOTYPES BY IMPAIRING THE REPAIR OR THE REPLACEMENT OF DAMAGED CELLS; SUCH UNCONTROLLED PHENOMENA OF IN VIVO REPROGRAMMING MIGHT ALSO GENERATE CANCER-LIKE CELLULAR STATES. WE HEREIN PROPOSE THAT THE ABILITY OF SENESCENCE-ASSOCIATED INFLAMMATORY SIGNALING TO REGULATE IN VIVO REPROGRAMMING CYCLES OF TISSUE REPAIR OUTLINES A THRESHOLD MODEL OF AGING AND CANCER. THE DEGREE OF SENESCENCE/INFLAMMATION-ASSOCIATED DEVIATION FROM THE HOMEOSTATIC STATE MAY DELINEATE A TYPE OF THRESHOLDING ALGORITHM DISTINGUISHING BENEFICIAL FROM DELETERIOUS EFFECTS OF IN VIVO REPROGRAMMING. FIRST, TRANSIENT ACTIVATION OF NF-KAPPAB-RELATED INNATE IMMUNITY AND SENESCENCE-ASSOCIATED INFLAMMATORY COMPONENTS (E.G., IL-6) MIGHT FACILITATE REPARATIVE CELLULAR REPROGRAMMING IN RESPONSE TO ACUTE INFLAMMATORY EVENTS. SECOND, PARA-INFLAMMATION SWITCHES MIGHT PROMOTE LONG-LASTING BUT REVERSIBLE REFRACTORINESS TO REPARATIVE CELLULAR REPROGRAMMING. THIRD, CHRONIC SENESCENCE-ASSOCIATED INFLAMMATORY SIGNALING MIGHT LOCK CELLS IN HIGHLY PLASTIC EPIGENETIC STATES DISABLED FOR REPARATIVE DIFFERENTIATION. THE CONSIDERATION OF A CELLULAR REPROGRAMMING-CENTERED VIEW OF EPIGENETIC PLASTICITY AS A FUNDAMENTAL ELEMENT OF A TISSUE'S CAPACITY TO UNDERGO SUCCESSFUL REPAIR, AGING DEGENERATION OR MALIGNANT TRANSFORMATION SHOULD PROVIDE CHALLENGING STOCHASTIC INSIGHTS INTO THE CURRENT DETERMINISTIC GENETIC PARADIGM FOR MOST CHRONIC DISEASES, THEREBY INCREASING THE SPECTRUM OF THERAPEUTIC APPROACHES FOR PHYSIOLOGICAL AGING AND CANCER. 2017 10 1918 33 ENVIRONMENTAL CARCINOGENESIS AND TRANSGENERATIONAL TRANSMISSION OF CARCINOGENIC RISK: FROM GENETICS TO EPIGENETICS. THE DOMINANT PATHOGENIC MODEL, SOMATIC MUTATION THEORY (SMT), CONSIDERS CARCINOGENESIS AS A 'GENETIC ACCIDENT' DUE TO THE ACCUMULATION OF 'STOCHASTIC' DNA MUTATIONS. THIS MODEL WAS PROPOSED AND ACCEPTED BY THE SCIENTIFIC COMMUNITY WHEN CANCER MAINLY AFFECTED THE ELDERLY, BUT IT DOES NOT EXPLAIN THE EPIDEMIOLOGICAL OBSERVATION OF THE CONTINUOUS INCREASE IN CANCER INCIDENCE AMONG CHILDREN AND YOUNG ADULTS. SOMATIC MUTATION THEORY HAS BEEN PROPOSED FOR A REVISION BASED ON THE EMERGING EXPERIMENTAL EVIDENCE, AS IT DOES NOT FULLY ADDRESS SOME ISSUES THAT HAVE PROVEN TO BE CRUCIAL FOR CARCINOGENESIS, NAMELY: THE INFLAMMATORY CONTEXT OF CANCER; THE KEY ROLE PLAYED BY THE STROMA, MICROENVIRONMENT, ENDOTHELIAL CELLS, ACTIVATED MACROPHAGES, AND SURROUNDING TISSUES; AND THE DISTORTED DEVELOPMENTAL COURSE FOLLOWED BY THE NEOPLASTIC TISSUE. FURTHERMORE, SMT IS OFTEN NOT ABLE TO CONSIDER EITHER THE EXISTENCE OF SPECIFIC MUTATIONS RESULTING IN A WELL-DEFINED CANCER TYPE, OR A CLEAR RELATIONSHIP BETWEEN MUTATIONS AND TUMOR PROGRESSION. MOREOVER, IT DOES NOT EXPLAIN THE MECHANISM OF ACTION OF THE NON-MUTAGENIC AND ENVIRONMENTAL CARCINOGENS. IN THE LAST DECADE, CANCER RESEARCH HAS HIGHLIGHTED THE PROMINENT ROLE OF AN ALTERED REGULATION OF GENE EXPRESSION, SUGGESTING THAT CANCER SHOULD BE CONSIDERED AS A RESULT OF A POLYCLONAL EPIGENETIC DISRUPTION OF STEM/PROGENITOR CELLS, MEDIATED BY TUMOUR-INDUCING GENES. THE MATERNAL AND FETAL EXPOSURE TO A WIDE RANGE OF CHEMICALS AND ENVIRONMENTAL CONTAMINANTS IS RAISING THE ATTENTION OF THE SCIENTIFIC COMMUNITY. INDEED, THE MOST POWERFUL PROCARCINOGENIC MECHANISMS OF ENDOCRINE DISRUPTORS AND OTHER POLLUTANTS IS LINKED TO THEIR POTENTIAL TO INTERFERE EPIGENETICALLY WITH THE EMBRYO-FETAL PROGRAMMING OF TISSUES AND ORGANS, ALTERING THE REGULATION OF THE GENES INVOLVED IN THE CELL CYCLE, CELL PROLIFERATION, APOPTOSIS, AND OTHER KEY SIGNALING PATHWAYS. THE EMBRYO-FETAL EXPOSURE TO ENVIRONMENTAL, STRESSFUL, AND PROINFLAMMATORY TRIGGERS (FIRST HIT), SEEMS TO ACT AS A 'DISEASE PRIMER', MAKING FETAL CELLS AND TISSUES MORE SUSCEPTIBLE TO THE SUBSEQUENT ENVIRONMENTAL EXPOSURES (SECOND HIT), TRIGGERING THE CARCINOGENIC PATHWAYS. FURTHERMORE, EVEN AT THE MOLECULAR LEVEL, IN CARCINOGENESIS, 'EPIGENETICS PRECEDES GENETICS' AS GLOBAL DNA HYPOMETHYLATION, AND THE HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES ARE COMMON BOTH IN CANCEROUS AND IN PRECANCEROUS CELLS, AND GENERALLY PRECEDE MUTATIONS. THESE EPIGENETIC MODELS MAY BETTER EXPLAIN THE INCREASE OF CANCER AND CHRONIC/DEGENERATIVE DISEASES IN THE LAST DECADES AND COULD BE USEFUL TO ADOPT APPROPRIATE PRIMARY PREVENTION MEASURES, ESSENTIALLY BASED ON THE REDUCTION OF MATERNAL-FETAL AND CHILD EXPOSURE TO SEVERAL PROCARCINOGENIC AGENTS AND FACTORS DISPERSED IN THE ENVIRONMENT AND IN THE FOOD-CHAINS, AS RECENTLY SUGGESTED BY THE WORLD HEALTH ORGANIZATION. 2018 11 3773 26 INTERACTION OF CERVICAL MICROBIOME WITH EPIGENOME OF EPITHELIAL CELLS: SIGNIFICANCE OF INFLAMMATION TO PRIMARY HEALTHCARE. ONE PILLAR OF THE PREDICTIVE, PREVENTIVE, AND PERSONALIZED MEDICINE FRAMEWORK STRATEGIES IS THE FEMALE HEALTH. THE EVALUATION OF WOMEN'S LIFESTYLE AND DIETARY HABITS IN CONTEXT WITH GENETIC AND MODIFIABLE RISK FACTORS MAY REFLECT THE PREVENTION OF CERVICAL CANCER BEFORE THE OCCURRENCE OF CLINICAL SYMPTOMS AND PREDICTION OF CERVICAL LESION BEHAVIOR. THE MAIN AIM OF THIS REVIEW IS TO ANALYZE PUBLICATIONS IN THE FIELD OF PRECISION MEDICINE THAT ALLOW THE USE OF RESEARCH KNOWLEDGE OF CERVICAL MICROBIOME, EPIGENETIC MODIFICATIONS, AND INFLAMMATION IN POTENTIAL APPLICATION IN CLINICAL PRACTICE. PERSONALIZED APPROACH IN EVALUATING PATIENT'S RISK OF FUTURE DEVELOPMENT OF CERVICAL ABNORMALITY SHOULD CONSIDER THE BIOMARKERS OF THE LOCAL MICROENVIRONMENT CHARACTERIZED BY THE MICROBIAL COMPOSITION, EPIGENETIC PATTERN OF CERVICAL EPITHELIUM, AND PRESENCE OF CHRONIC INFLAMMATION. NOVEL SEQUENCING TECHNIQUES ENABLE A MORE DETAILED CHARACTERIZATION OF ACTUAL STATE IN CERVICAL EPITHELIUM. BETTER UNDERSTANDING OF ALL CHANGES IN MULTIOMICS LEVEL ENABLES A BETTER ASSESSMENT OF DISEASE PROGNOSIS AND SELECTS THE ELIGIBLE TARGETED THERAPY IN PERSONALIZED MEDICINE. RESTORING OF HEALTHY VAGINAL MICROFLORA AND REVERSING THE OUTBREAK OF CERVICAL ABNORMALITY CAN BE ALSO ACHIEVED BY DIETARY HABITS AS WELL AS UPTAKE OF PREBIOTICS, PROBIOTICS, SYNBIOTICS, MICROBIAL TRANSPLANTATION, AND OTHERS. 2022 12 5341 26 RADIATION-HORMESIS PHENOTYPES, THE RELATED MECHANISMS AND IMPLICATIONS FOR DISEASE PREVENTION AND THERAPY. HUMANS ARE CONTINUOUSLY EXPOSED TO IONIZING RADIATION THROUGHOUT LIFE FROM NATURAL SOURCES THAT INCLUDE COSMIC, SOLAR, AND TERRESTRIAL. MUCH HARSHER NATURAL RADIATION AND CHEMICAL ENVIRONMENTS EXISTED DURING OUR PLANET'S EARLY YEARS. MAMMALS SURVIVED THE HARSHER ENVIRONMENTS VIA EVOLUTIONARILY-CONSERVED GIFTS ? A CONTINUOUSLY EVOLVING SYSTEM OF STRESS-INDUCED NATURAL PROTECTIVE MEASURES (I.E., ACTIVATED NATURAL PROTECTION [ANP]). THE CURRENT PROTECTIVE SYSTEM IS DIFFERENTIALLY ACTIVATED BY STOCHASTIC (I.E., VARIABLE) LOW-RADIATION-DOSE THRESHOLDS AND WHEN OPTIMALLY ACTIVATED IN MAMMALS INCLUDES ANTIOXIDANTS, DNA DAMAGE REPAIR, P53-RELATED APOPTOSIS OF SEVERELY-DAMAGED CELLS, REACTIVE-OXYGEN-SPECIES (ROS)/REACTIVE-NITROGEN-SPECIES (RNS)- AND CYTOKINE-REGULATED AUXILIARY APOPTOSIS THAT SELECTIVELY REMOVES ABERRANT CELLS (E.G., PRECANCEROUS CELLS), SUPPRESSION OF DISEASE PROMOTING INFLAMMATION, AND IMMUNITY AGAINST CANCER CELLS. THE INTERCELLULAR-SIGNALING-BASED PROTECTIVE SYSTEM IS REGULATED AT LEAST IN PART VIA EPIGENETIC REPROGRAMMING OF ADAPTIVE-RESPONSE GENES. WHEN THE SYSTEM IS OPTIMALLY ACTIVATED, IT PROTECTS AGAINST CANCER AND SOME OTHER DISEASES, THEREBY LEADING TO HORMETIC PHENOTYPES (E.G., REDUCED DISEASE INCIDENCE TO BELOW THE BASELINE LEVEL; REDUCED PAIN FROM INFLAMMATION-RELATED PROBLEMS). HERE, SOME EXPRESSED RADIATION HORMESIS PHENOTYPES AND RELATED MECHANISMS ARE DISCUSSED ALONG WITH THEIR IMPLICATIONS FOR DISEASE PREVENTION AND THERAPY. 2014 13 77 23 A NEW ERA OF LOW-DOSE RADIATION EPIDEMIOLOGY. THE LAST DECADE HAS INTRODUCED A NEW ERA OF EPIDEMIOLOGIC STUDIES OF LOW-DOSE RADIATION FACILITATED BY ELECTRONIC RECORD LINKAGE AND POOLING OF COHORTS THAT ALLOW FOR MORE DIRECT AND POWERFUL ASSESSMENTS OF CANCER AND OTHER STOCHASTIC EFFECTS AT DOSES BELOW 100 MGY. SUCH STUDIES HAVE PROVIDED ADDITIONAL EVIDENCE REGARDING THE RISKS OF CANCER, PARTICULARLY LEUKEMIA, ASSOCIATED WITH LOWER-DOSE RADIATION EXPOSURES FROM MEDICAL, ENVIRONMENTAL, AND OCCUPATIONAL RADIATION SOURCES, AND HAVE QUESTIONED THE PREVIOUS FINDINGS WITH REGARD TO POSSIBLE THRESHOLDS FOR CARDIOVASCULAR DISEASE AND CATARACTS. INTEGRATED ANALYSIS OF NEXT GENERATION GENOMIC AND EPIGENETIC SEQUENCING OF GERMLINE AND SOMATIC TISSUES COULD SOON PROPEL OUR UNDERSTANDING FURTHER REGARDING DISEASE RISK THRESHOLDS, RADIOSENSITIVITY OF POPULATION SUBGROUPS AND INDIVIDUALS, AND THE MECHANISMS OF RADIATION CARCINOGENESIS. THESE ADVANCES IN LOW-DOSE RADIATION EPIDEMIOLOGY ARE CRITICAL TO OUR UNDERSTANDING OF CHRONIC DISEASE RISKS FROM THE BURGEONING USE OF NEWER AND EMERGING MEDICAL IMAGING TECHNOLOGIES, AND THE CONTINUED POTENTIAL THREAT OF NUCLEAR POWER PLANT ACCIDENTS OR OTHER RADIOLOGICAL EMERGENCIES. 2015 14 940 36 CHRONIC LYMPHOCYTIC LEUKEMIA AND MANTLE CELL LYMPHOMA: CROSSROADS OF GENETIC AND MICROENVIRONMENT INTERACTIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND MANTLE CELL LYMPHOMA (MCL) ARE 2 WELL-DEFINED ENTITIES THAT DIVERGE IN THEIR BASIC PATHOGENIC MECHANISMS AND CLINICAL EVOLUTION BUT THEY SHARE EPIDEMIOLOGICAL CHARACTERISTICS, CELLS OF ORIGIN, MOLECULAR ALTERATIONS, AND CLINICAL FEATURES THAT DIFFER FROM OTHER LYMPHOID NEOPLASMS. CLL AND MCL ARE CLASSICALLY CONSIDERED INDOLENT AND AGGRESSIVE NEOPLASMS, RESPECTIVELY. HOWEVER, THE CLINICAL EVOLUTION OF BOTH TUMORS IS VERY HETEROGENEOUS, WITH SUBSETS OF PATIENTS HAVING STABLE DISEASE FOR A LONG TIME WHEREAS OTHERS REQUIRE IMMEDIATE INTERVENTION. BOTH CLL AND MCL INCLUDE 2 MAJOR MOLECULAR SUBTYPES THAT SEEM TO DERIVE FROM ANTIGEN-EXPERIENCED CD5(+) B CELLS THAT RETAIN A NAIVE OR MEMORY-LIKE EPIGENETIC SIGNATURE AND CARRY A VARIABLE LOAD OF IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE REGION SOMATIC MUTATIONS FROM TRULY UNMUTATED TO HIGHLY MUTATED, RESPECTIVELY. THESE 2 SUBTYPES OF TUMORS DIFFER IN THEIR MOLECULAR PATHWAYS, GENOMIC ALTERATIONS, AND CLINICAL BEHAVIOR, BEING MORE AGGRESSIVE IN NAIVE-LIKE THAN MEMORY-LIKE-DERIVED TUMORS IN BOTH CLL AND MCL. THE PATHOGENESIS OF THE 2 ENTITIES INTEGRATES THE RELEVANT INFLUENCE OF B-CELL RECEPTOR SIGNALING, TUMOR CELL MICROENVIRONMENT INTERACTIONS, GENOMIC ALTERATIONS, AND EPIGENOME MODIFICATIONS THAT CONFIGURE THE EVOLUTION OF THE TUMORS AND OFFER NEW POSSIBILITIES FOR THERAPEUTIC INTERVENTION. THIS REVIEW WILL FOCUS ON THE SIMILARITIES AND DIFFERENCES OF THESE 2 TUMORS BASED ON RECENT STUDIES THAT ARE ENHANCING THE UNDERSTANDING OF THEIR PATHOGENESIS AND CREATING SOLID BASES FOR NEW MANAGEMENT STRATEGIES. 2018 15 5025 31 PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS. PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS (CVD), ALSO REFERRED TO AS PERSONALIZED OR PRECISION CARDIOLOGY IN ACCORDANCE WITH GENERAL PRINCIPLES OF PERSONALIZED MEDICINE, IS SELECTION OF THE BEST TREATMENT FOR AN INDIVIDUAL PATIENT. IT INVOLVES THE INTEGRATION OF VARIOUS "OMICS" TECHNOLOGIES SUCH AS GENOMICS AND PROTEOMICS AS WELL AS OTHER NEW TECHNOLOGIES SUCH AS NANOBIOTECHNOLOGY. MOLECULAR DIAGNOSTICS AND BIOMARKERS ARE IMPORTANT FOR LINKING DIAGNOSIS WITH THERAPY AND MONITORING THERAPY. BECAUSE CVD INVOLVE PERTURBATIONS OF LARGE COMPLEX BIOLOGICAL NETWORKS, A SYSTEMS BIOLOGY APPROACH TO CVD RISK STRATIFICATION MAY BE USED FOR IMPROVING RISK-ESTIMATING ALGORITHMS, AND MODELING OF PERSONALIZED BENEFIT OF TREATMENT MAY BE HELPFUL FOR GUIDING THE CHOICE OF INTERVENTION. BIOINFORMATICS TOOLS ARE HELPFUL IN ANALYZING AND INTEGRATING LARGE AMOUNTS OF DATA FROM VARIOUS SOURCES. PERSONALIZED THERAPY IS CONSIDERED DURING DRUG DEVELOPMENT, INCLUDING METHODS OF TARGETED DRUG DELIVERY AND CLINICAL TRIALS. INDIVIDUALIZED RECOMMENDATIONS CONSIDER MULTIPLE FACTORS - GENETIC AS WELL AS EPIGENETIC - FOR PATIENTS' RISK OF HEART DISEASE. EXAMPLES OF PERSONALIZED TREATMENT ARE THOSE OF CHRONIC MYOCARDIAL ISCHEMIA, HEART FAILURE, AND HYPERTENSION. SIMILAR APPROACHES CAN BE USED FOR THE MANAGEMENT OF ATRIAL FIBRILLATION AND HYPERCHOLESTEROLEMIA, AS WELL AS THE USE OF ANTICOAGULANTS. PERSONALIZED MANAGEMENT INCLUDES PHARMACOTHERAPY, SURGERY, LIFESTYLE MODIFICATIONS, AND COMBINATIONS THEREOF. FURTHER PROGRESS IN UNDERSTANDING THE PATHOMECHANISM OF COMPLEX CARDIOVASCULAR DISEASES AND IDENTIFICATION OF CAUSATIVE FACTORS AT THE INDIVIDUAL PATIENT LEVEL WILL PROVIDE OPPORTUNITIES FOR THE DEVELOPMENT OF PERSONALIZED CARDIOLOGY. APPLICATION OF PRINCIPLES OF PERSONALIZED MEDICINE WILL IMPROVE THE CARE OF THE PATIENTS WITH CVD. 2017 16 4515 31 MULTI-OMICS APPROACHES FOR PRECISION OBESITY MANAGEMENT : POTENTIALS AND LIMITATIONS OF OMICS IN PRECISION PREVENTION, TREATMENT AND RISK REDUCTION OF OBESITY. INTRODUCTION: OBESITY IS A MULTIFACTORIAL CHRONIC DISEASE THAT CANNOT BE ADDRESSED BY SIMPLY PROMOTING BETTER DIETS AND MORE PHYSICAL ACTIVITY. TO DATE, NOT A SINGLE COUNTRY HAS SUCCESSFULLY BEEN ABLE TO CURB THE ACCUMULATING BURDEN OF OBESITY. ONE EXPLANATION FOR THE LACK OF PROGRESS IS THAT LIFESTYLE INTERVENTION PROGRAMS ARE TRADITIONALLY IMPLEMENTED WITHOUT A COMPREHENSIVE EVALUATION OF AN INDIVIDUAL'S DIAGNOSTIC BIOMARKERS. EVIDENCE FROM GENOME-WIDE ASSOCIATION STUDIES HIGHLIGHT THE IMPORTANCE OF GENETIC AND EPIGENETIC FACTORS IN THE DEVELOPMENT OF OBESITY AND HOW THEY IN TURN AFFECT THE TRANSCRIPTOME, METABOLITES, MICROBIOMES, AND PROTEOMES. OBJECTIVE: THE PURPOSE OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE DIFFERENT TYPES OF OMICS DATA: GENOMICS, EPIGENOMICS, TRANSCRIPTOMICS, PROTEOMICS, METABOLOMICS AND ILLUSTRATE HOW A MULTI-OMICS APPROACH CAN BE FUNDAMENTAL FOR THE IMPLEMENTATION OF PRECISION OBESITY MANAGEMENT. RESULTS: THE DIFFERENT TYPES OF OMICS DESIGNS ARE GROUPED INTO TWO CATEGORIES, THE GENOTYPE APPROACH AND THE PHENOTYPE APPROACH. WHEN APPLIED TO OBESITY PREVENTION AND MANAGEMENT, EACH OMICS TYPE COULD POTENTIALLY HELP TO DETECT SPECIFIC BIOMARKERS IN PEOPLE WITH RISK PROFILES AND GUIDE HEALTHCARE PROFESSIONALS AND DECISION MAKERS IN DEVELOPING INDIVIDUALIZED TREATMENT PLANS ACCORDING TO THE NEEDS OF THE INDIVIDUAL BEFORE THE ONSET OF OBESITY. CONCLUSION: INTEGRATING MULTI-OMICS APPROACHES WILL ENABLE A PARADIGM SHIFT FROM THE ONE SIZE FITS ALL APPROACH TOWARDS PRECISION OBESITY MANAGEMENT, I.E. (1) PRECISION PREVENTION OF THE ONSET OF OBESITY, (2) PRECISION MEDICINE AND TAILORED TREATMENT OF OBESITY, AND (3) PRECISION RISK REDUCTION AND PREVENTION OF SECONDARY DISEASES RELATED TO OBESITY. 2023 17 937 24 CHRONIC LYMPHOCYTIC LEUKAEMIA GENOMICS AND THE PRECISION MEDICINE ERA. MASSIVE GENOMIC ANALYSES HAVE UNDERSCORED THE DIVERSITY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) BETWEEN PATIENTS. GENETIC HETEROGENEITY OF TUMOUR CLONES WITHIN A PATIENT MAY FUEL TUMOUR EVOLUTION. SEVERAL RECURRENTLY DEREGULATED INTRA-CELLULAR PATHWAYS ARE CANDIDATES FOR TARGETED THERAPIES THAT ARE VERY PROMISING AND ARE DRAMATICALLY CHANGING CLINICAL PATIENTS' PERSPECTIVES. IN THIS REVIEW WE PRESENT AN OVERVIEW OF THE GENETIC AND EPIGENETIC FEATURES OF CLL AND THEIR CLINICAL AND BIOLOGICAL IMPLICATIONS. 2017 18 734 33 CANCER HEALTHCARE DISPARITIES AMONG AFRICAN AMERICANS IN THE UNITED STATES. A NEED EXISTS TO EXAMINE RACIAL DISPARITIES IN THE HEALTHCARE ARENA AND THE IMPACT ON PATIENTS WITH CANCER. DESPITE ONGOING EFFORTS TO INCREASE EQUITY IN PRIMARY HEALTHCARE ACCESS, RACIAL AND SOCIOECONOMIC DISPARITIES PERSIST, THUS CONTRIBUTING TO DISPROPORTIONATE TREATMENT OUTCOMES AND SURVIVORSHIP AMONG MINORITY AND LOW-INCOME PATIENTS. SUCH DISPARITIES HAVE BEEN REVEALED IN TREATMENT COHORTS OF PATIENTS WITH MULTIPLE FORMS OF CANCER, INCLUDING BREAST, CERVICAL, OVARIAN, ENDOMETRIAL, PROSTATE, LUNG, COLORECTAL, GASTROINTESTINAL, AND HEPATOCELLULAR, AND HAVE BEEN ATTRIBUTED TO A RANGE OF CO-OCCURRING BEHAVIORAL, SOCIAL DETERMINANTS OF HEALTH, UNDERLYING GENETIC FACTORS, AS WELL AS ACCESS TO EDUCATIONAL OPPORTUNITIES THAT LIMIT THE QUALITY OF INFORMED HEALTHCARE. THESE VARIOUS INTERRELATED FACTORS WIDEN CANCER HEALTHCARE DISPARITIES SYNERGISTICALLY THROUGHOUT UNDERSERVED COMMUNITIES, AND THEIR INFLUENCE HAS BEEN AMPLIFIED BY THE CORONAVIRUS DISEASE 2019 (COVID-19) PANDEMIC. FUNDAMENTALLY, A LACK OF BASIC AND CLINICAL RESEARCH EXISTS THAT FAILS TO ADEQUATELY REFLECT DIVERSITY AND MINORITY INVOLVEMENT IN DRUG DEVELOPMENT. ALTHOUGH OVERCOMING THE OBSTACLES RESPONSIBLE FOR CHRONIC TREATMENT DISPARITIES IS A FORMIDABLE TASK, PROMISING MEANS OF ACHIEVING MORE UNIFORM QUALITY HEALTHCARE ARE BECOMING MORE CLEARLY ELUCIDATED. TO REDUCE DISEASE PROGRESSION, INCREASE OVERALL SURVIVAL, AND IMPROVE THE HEALTH OF VULNERABLE POPULATIONS, IT IS NECESSARY TO IDENTIFY AND FULLY DISCLOSE ENVIRONMENTAL, BIOLOGICAL, AND ANCESTRAL FACTORS THAT IMPACT THE RISK FOR CANCER; HEAL HISTORICAL FRACTURES WITHIN COMMUNITIES; AND INCREASE PARTICIPATION OF RACIAL AND ETHNIC MINORITIES IN SCREENING EFFORTS AND RESEARCH STUDIES. THIS REQUIRES DEVELOPING A SYSTEM OF JUSTICE AND TRUST BASED ON SPECIFIC, SOLUTION-ORIENTED GRASSROOTS COMMUNITY EFFORTS WORKING IN TANDEM WITH MEDICAL AND PHARMACEUTICAL LEADERS. BY FULLY EXPLORING AND PINPOINTING THE UNDERLYING CAUSES OF HEALTHCARE DISPARITIES, IT SHOULD BE POSSIBLE TO DEFINE STRATEGIES AND INTERVENTIONS MOST LIKELY TO TRANSFORM CANCER CARE. THE ULTIMATE GOAL IS UNDERSTANDING INDIVIDUAL, CULTURAL, AND BIOLOGICAL VULNERABILITIES, INCLUDING ENVIRONMENTAL AND EPIGENETIC LIABILITIES, TO OPTIMIZE CANCER PREVENTION, DIAGNOSIS, AND TREATMENT. 2022 19 4663 29 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 20 737 39 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