1 3599 155 IMPORTANCE OF EPIGENETIC CHANGES IN CANCER ETIOLOGY, PATHOGENESIS, CLINICAL PROFILING, AND TREATMENT: WHAT CAN BE LEARNED FROM HEMATOLOGIC MALIGNANCIES? EPIGENETIC ALTERATIONS REPRESENT A KEY CANCER HALLMARK, EVEN IN HEMATOLOGIC MALIGNANCIES (HMS) OR BLOOD CANCERS, WHOSE CLINICAL FEATURES DISPLAY A HIGH INTER-INDIVIDUAL VARIABILITY. EVIDENCE ACCUMULATED IN RECENT YEARS INDICATES THAT INACTIVATING DNA HYPERMETHYLATION PREFERENTIALLY TARGETS THE SUBSET OF POLYCOMB GROUP (PCG) GENES THAT ARE REGULATORS OF DEVELOPMENTAL PROCESSES. CONVERSELY, ACTIVATING DNA HYPOMETHYLATION TARGETS ONCOGENIC SIGNALING PATHWAY GENES, BUT OUTCOMES OF BOTH EVENTS LEAD IN THE OVEREXPRESSION OF ONCOGENIC SIGNALING PATHWAYS THAT CONTRIBUTE TO THE STEM-LIKE STATE OF CANCER CELLS. ON THE BASIS OF RECENT EVIDENCE FROM POPULATION-BASED, CLINICAL AND EXPERIMENTAL STUDIES, WE HYPOTHESIZE THAT FACTORS ASSOCIATED WITH RISK FOR DEVELOPING A HM, SUCH AS METABOLIC SYNDROME AND CHRONIC INFLAMMATION, TRIGGER EPIGENETIC MECHANISMS TO INCREASE THE TRANSCRIPTIONAL EXPRESSION OF ONCOGENES AND ACTIVATE ONCOGENIC SIGNALING PATHWAYS. AMONG OTHERS, SIGNALING PATHWAYS ASSOCIATED WITH SUCH RISK FACTORS INCLUDE PRO-INFLAMMATORY NUCLEAR FACTOR KAPPAB (NF-KAPPAB), AND MITOGENIC, GROWTH, AND SURVIVAL JANUS KINASE (JAK) INTRACELLULAR NON-RECEPTOR TYROSINE KINASE-TRIGGERED PATHWAYS, WHICH INCLUDE SIGNALING PATHWAYS SUCH AS TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT), RAS GTPASES/MITOGEN-ACTIVATED PROTEIN KINASES (MAPKS)/EXTRACELLULAR SIGNAL-RELATED KINASES (ERKS), PHOSPHATIDYLINOSITOL 3-KINASE (PI3K)/AKT/MAMMALIAN TARGET OF RAPAMYCIN (MTOR), AND BETA-CATENIN PATHWAYS. RECENT FINDINGS ON EPIGENETIC MECHANISMS AT WORK IN HMS AND THEIR IMPORTANCE IN THE ETIOLOGY AND PATHOGENESIS OF THESE DISEASES ARE HEREIN SUMMARIZED AND DISCUSSED. FURTHERMORE, THE ROLE OF EPIGENETIC PROCESSES IN THE DETERMINATION OF BIOLOGICAL IDENTITY, THE CONSEQUENCES FOR INTERINDIVIDUAL VARIABILITY IN DISEASE CLINICAL PROFILE, AND THE POTENTIAL OF EPIGENETIC DRUGS IN HMS ARE ALSO CONSIDERED. 2013 2 6906 31 [THE ROLE OF GLYCANS IN CANCER DEVELOPMENT AND PROGRESSION. CLINICAL APPLICATIONS]. CHANGES IN GLYCOSYLATION PATTERN OF CELL SURFACE, BODY FLUIDS AND EXTRACELLULAR MATRIX GLYCOCONJUGATES IS A CHARACTERISTIC FEATURE OF TUMOR CELL MALIGNANCY. THESE CHANGES ARE THE RESULT OF MUTATIONS OF TUMOR-ASSOCIATED GENES AS WELL AS EPIGENETIC CHANGES IN THE TUMOR ENVIRONMENT, INCLUDING NUTRIENT INFLUX, HYPOXIA, CYTOKINE EXPRESSION AND STIMULATION OF CHRONIC INFLAMMATION. THE UNIQUE SET OF CELL SURFACE GLYCOANTIGENS ON NEOPLASTIC CELLS IS RECOGNIZED BY ENDOGENOUS LECTINS LOCATED IN THE EXTRACELLULAR MATRIX, VASCULAR ENDOTHELIUM, ON LEUKOCYTES OR PLATELETS, AND HAS AN IMPACT ON DISRUPTING BASIC CELLULAR PROCESSES, SUCH AS INTERCELLULAR RECOGNITION, CELL-CELL ADHESION OR CELL-ECM INTERACTION. THESE CHANGES HAVE A CRITICAL IMPACT ON THE MIGRATION, INVASIVE AND METASTATIC POTENTIAL OF NEOPLASTIC CELLS AND MODULATE THE IMMUNE RESPONSE. THIS UNIQUE PATTERN OF SUGAR ANTIGENS ON THE CANCER CELLS CAN BE A VAULABLE MARKER TO IDENTIFY THEM, DETERMINE THE STAGE OF THE DISEASE AS WELL AS BE A TARGET OF ANTI-CANCER THERAPY. 2021 3 6263 44 THE MULTIPLE WAYS WNT SIGNALING CONTRIBUTES TO ACUTE LEUKEMIA PATHOGENESIS. WNT PROTEINS CONSTITUTE A VERY CONSERVED FAMILY OF SECRETED GLYCOPROTEINS THAT ACT AS SHORT-RANGE LIGANDS FOR SIGNALING WITH CRITICAL ROLES IN HEMATOPOIESIS, EMBRYONIC DEVELOPMENT, AND TISSUE HOMEOSTASIS. THESE PROTEINS TRANSDUCE SIGNALS VIA THE CANONICAL PATHWAY, WHICH IS BETA-CATENIN-MEDIATED AND BETTER-CHARACTERIZED, OR VIA MORE DIVERSE NONCANONICAL PATHWAYS THAT ARE BETA-CATENIN INDEPENDENT AND COMPRISE THE PLANAR CELL POLARITY (PCP) PATHWAY AND THE WNT/CA(++) PATHWAYS. SEVERAL PROTEINS REGULATE WNT SIGNALING THROUGH A VARIETY OF SOPHISTICATED MECHANISMS. DISORDERS WITHIN THE PATHWAY CAN CONTRIBUTE TO VARIOUS HUMAN DISEASES, AND THE DYSREGULATION OF WNT PATHWAYS BY DIFFERENT MOLECULAR MECHANISMS IS IMPLICATED IN THE PATHOGENESIS OF MANY TYPES OF CANCER, INCLUDING THE HEMATOLOGICAL MALIGNANCIES. THE TYPES OF LEUKEMIA DIFFER CONSIDERABLY AND CAN BE SUBDIVIDED INTO CHRONIC, MYELOID OR LYMPHOCYTIC, AND ACUTE, MYELOID OR LYMPHOCYTIC, LEUKEMIA, ACCORDING TO THE DIFFERENTIATION STAGE OF THE PREDOMINANT CELLS, THE PROGENITOR LINEAGE, THE DIAGNOSTIC AGE STRATA, AND THE SPECIFIC MOLECULAR DRIVERS BEHIND THEIR DEVELOPMENT. HERE, WE REVIEW THE ROLE OF WNT SIGNALING IN NORMAL HEMATOPOIESIS AND DISCUSS IN DETAIL THE MULTIPLE WAYS CANONICAL WNT SIGNALING CAN BE DYSREGULATED IN ACUTE LEUKEMIA, INCLUDING ALTERATIONS IN GENE EXPRESSION AND PROTEIN LEVELS, EPIGENETIC REGULATION, AND MUTATIONS. FURTHERMORE, WE HIGHLIGHT THE DIFFERENT IMPACTS OF THESE ALTERATIONS, CONSIDERING THE DISTINCT FORMS OF THE DISEASE, AND THE THERAPEUTIC POTENTIAL OF TARGETING WNT SIGNALING. 2020 4 389 29 AN INTEGRATIVE HYPOTHESIS LINKING CANCER, DIABETES AND ATHEROSCLEROSIS: THE ROLE OF MUTATIONS AND EPIGENETIC CHANGES. IT APPEARS THAT THE DISEASE STATES OF CANCER, ALTHEROSCLEROSIS AND DIABETES MIGHT SHARE A COMMON ETIOLOGY. THESE CHRONIC DISEASES APPEAR TO BE MULTI-STAGED IN THEIR PROGRESSION, WITH GENETIC, NUTRITIONAL, PSYCHO-SOCIAL, ENVIRONMENTAL AND VIRAL FACTORS INFLUENCING THEIR APPEARANCE. WE OFFERED A HYPOTHESIS (A "MUTATION THEORY OF DISEASE"), STATING THAT THESE DISEASES CAN BE DESCRIBED BY INITIATION AND PROMOTION PHASES; INITIATION BEING THE RESULT OF THE PRODUCTION OF MUTATED CELLS AFTER UNREPAIRED DAMAGED DNA IS REPLICATED; PROMOTION BEING THE SELECTIVE PROLIFERATION OF THE INITIATED CELLS TO FORM CLONES OF MUTATED CELLS. IT WAS FURTHER POSTULATED THAT PROMOTION AFFECTS CELL PROLIFERATION BY ALTERING A MEMBRANE-CA++ REGULATORY SYSTEM. DEPENDING ON THE NATURE OF THE MUTATION IN THE CLONE OF CELLS, SPECIFIC DISEASE STATES WOULD RESULT. THE ROLES OF RADIATIONS, CHEMICALS, VIRUSES, GENES, NUTRITION AND PSYCHO-SOCIAL STRESS WERE RELATED TO EITHER THE INITIATION (MUTATION PRODUCTION) OR THE PROMOTION (CELL PROLIFERATION) PHASE OF THESE DISEASES. 1980 5 2338 35 EPIGENETIC REGULATION OF INFLAMMATORY SIGNALING AND INFLAMMATION-INDUCED CANCER. EPIGENETICS COMPRISE A DIVERSE ARRAY OF REVERSIBLE AND DYNAMIC MODIFICATIONS TO THE CELL'S GENOME WITHOUT IMPLICATING ANY DNA SEQUENCE ALTERATIONS. BOTH THE EXTERNAL ENVIRONMENT SURROUNDING THE ORGANISM, AS WELL AS THE INTERNAL MICROENVIRONMENT OF CELLS AND TISSUES, CONTRIBUTE TO THESE EPIGENETIC PROCESSES THAT PLAY CRITICAL ROLES IN CELL FATE SPECIFICATION AND ORGANISMAL DEVELOPMENT. ON THE OTHER HAND, DYSREGULATION OF EPIGENETIC ACTIVITIES CAN INITIATE AND SUSTAIN CARCINOGENESIS, WHICH IS OFTEN AUGMENTED BY INFLAMMATION. CHRONIC INFLAMMATION, ONE OF THE MAJOR HALLMARKS OF CANCER, STEMS FROM PROINFLAMMATORY CYTOKINES THAT ARE SECRETED BY TUMOR AND TUMOR-ASSOCIATED CELLS IN THE TUMOR MICROENVIRONMENT. AT THE SAME TIME, INFLAMMATORY SIGNALING CAN ESTABLISH POSITIVE AND NEGATIVE FEEDBACK CIRCUITS WITH CHROMATIN TO MODULATE CHANGES IN THE GLOBAL EPIGENETIC LANDSCAPE. IN THIS REVIEW, WE PROVIDE AN IN-DEPTH DISCUSSION OF THE INTERCONNECTED CROSSTALK BETWEEN EPIGENETICS AND INFLAMMATION, SPECIFICALLY HOW EPIGENETIC MECHANISMS AT DIFFERENT HIERARCHICAL LEVELS OF THE GENOME CONTROL INFLAMMATORY GENE TRANSCRIPTION, WHICH IN TURN ENACT CHANGES WITHIN THE CELL'S EPIGENOMIC PROFILE, ESPECIALLY IN THE CONTEXT OF INFLAMMATION-INDUCED CANCER. 2022 6 4558 39 MUTATIONS IN THE NF-KAPPAB SIGNALING PATHWAY: IMPLICATIONS FOR HUMAN DISEASE. THE NUCLEAR FACTOR-KAPPA B (NF-KAPPAB) SIGNALING PATHWAY IS A MULTI-COMPONENT PATHWAY THAT REGULATES THE EXPRESSION OF HUNDREDS OF GENES THAT ARE INVOLVED IN DIVERSE AND KEY CELLULAR AND ORGANISMAL PROCESSES, INCLUDING CELL PROLIFERATION, CELL SURVIVAL, THE CELLULAR STRESS RESPONSE, INNATE IMMUNITY AND INFLAMMATION. NOT SURPRISINGLY, MIS-REGULATION OF THE NF-KAPPAB PATHWAY, EITHER BY MUTATION OR EPIGENETIC MECHANISMS, IS INVOLVED IN MANY HUMAN AND ANIMAL DISEASES, ESPECIALLY ONES ASSOCIATED WITH CHRONIC INFLAMMATION, IMMUNODEFICIENCY OR CANCER. THIS REVIEW DESCRIBES HUMAN DISEASES IN WHICH MUTATIONS IN THE COMPONENTS OF THE CORE NF-KAPPAB SIGNALING PATHWAY HAVE BEEN IMPLICATED AND DISCUSSES THE MOLECULAR MECHANISMS BY WHICH THESE ALTERATIONS IN NF-KAPPAB SIGNALING ARE LIKELY TO CONTRIBUTE TO THE DISEASE PATHOLOGY. THESE MUTATIONS CAN BE GERMLINE OR SOMATIC AND INCLUDE GENE AMPLIFICATION (E.G., REL), POINT MUTATIONS AND DELETIONS (REL, NFKB2, IKBA, CYLD, NEMO) AND CHROMOSOMAL TRANSLOCATIONS (BCL-3). IN ADDITION, HUMAN GENETIC DISEASES ARE BRIEFLY DESCRIBED WHEREIN MUTATIONS AFFECT PROTEIN MODIFIERS OR TRANSDUCERS OF NF-KAPPAB SIGNALING OR DISRUPT NF-KAPPAB-BINDING SITES IN PROMOTERS/ENHANCERS. 2006 7 208 40 ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID) LINKING IMMUNITY, CHRONIC INFLAMMATION, AND CANCER. ACTIVATION-INDUCED CYTIDINE DEAMINASE (AID) IS CRITICALLY INVOLVED IN CLASS SWITCH RECOMBINATION AND SOMATIC HYPERMUTATION OF IG LOCI RESULTING IN DIVERSIFICATION OF ANTIBODIES REPERTOIRE AND PRODUCTION OF HIGH-AFFINITY ANTIBODIES AND AS SUCH REPRESENTS A PHYSIOLOGICAL TOOL TO INTRODUCE DNA ALTERATIONS. THESE PROCESSES TAKE PLACE WITHIN GERMINAL CENTERS OF SECONDARY LYMPHOID ORGANS. UNDER PHYSIOLOGICAL CONDITIONS, AID IS EXPRESSED PREDOMINANTLY IN ACTIVATED B LYMPHOCYTES. BECAUSE OF THE MUTAGENIC AND RECOMBINOGENIC POTENTIAL OF AID, ITS EXPRESSION AND ACTIVITY IS TIGHTLY REGULATED ON DIFFERENT LEVELS TO MINIMIZE THE RISK OF UNWANTED DNA DAMAGE. HOWEVER, CHRONIC INFLAMMATION AND, PROBABLY, COMBINATION OF OTHER NOT-YET-IDENTIFIED FACTORS ARE ABLE TO CREATE A MICROENVIRONMENT SUFFICIENT FOR TRIGGERING AN ABERRANT AID EXPRESSION IN B CELLS AND, IMPORTANTLY, IN NON-B-CELL BACKGROUND. UNDER THESE CIRCUMSTANCES, AID MAY TARGET ALSO NON-IG GENES, INCLUDING CANCER-RELATED GENES AS ONCOGENES, TUMOR SUPPRESSOR GENES, AND GENOMIC STABILITY GENES, AND MODULATE BOTH GENETIC AND EPIGENETIC INFORMATION. DESPITE ONGOING PROGRESS, THE COMPLETE UNDERSTANDING OF FUNDAMENTAL ASPECTS IS STILL LACKING AS (1) WHAT ARE THE CRUCIAL FACTORS TRIGGERING AN ABERRANT AID EXPRESSION/ACTIVITY INCLUDING THE IMPACT OF TH2-DRIVEN INFLAMMATION AND (2) TO WHAT EXTENT MAY ABERRANT AID IN HUMAN NON-B CELLS LEAD TO ABNORMAL CELL STATE ASSOCIATED WITH AN INCREASED RATE OF GENOMIC ALTERATIONS AS POINT MUTATIONS, SMALL INSERTIONS OR DELETIONS, AND/OR RECURRENT CHROMOSOMAL TRANSLOCATIONS DURING SOLID TUMOR DEVELOPMENT AND PROGRESSION. 2012 8 3950 31 LNFLAMMATION-INDUCED EPIGENETIC SWITCHES IN CANCER. THE LINK BETWEEN INFLAMMATION AND CANCER IS WELL ESTABLISHED. CHRONIC INFLAMMATION PROMOTES CANCER INITIATION AND PROGRESSION. VARIOUS STUDIES SHOWED THAT THE UNDERLYING MECHANISMS INVOLVE EPIGENETIC ALTERATIONS. THESE EPIGENETIC ALTERATIONS MIGHT CULMINATE INTO AN EPIGENETIC SWITCH THAT TRANSFORMS PREMALIGNANT CELLS INTO TUMOR CELLS OR NON-INVASIVE INTO INVASIVE TUMOR CELLS, THEREBY PROMOTING METASTASIS. EPIGENETIC SWITCHES REQUIRE AN INITIATING EVENT, WHICH CAN BE INFLAMMATION, WHEREAS THE RESULTING PHENOTYPE IS INHERITED WITHOUT THE INITIATING SIGNAL. EPIGENETIC SWITCHES ARE INDUCED AND MAINTAINED BY DNA METHYLATION, HISTONE MODIFICATIONS, POLYCOMB GROUP (PCG)/TRITHORAX GROUP (TRXG) PROTEINS, AND FEEDBACK LOOPS CONSISTING OF TRANSCRIPTION FACTORS AND MICRORNAS. SINCE EPIGENETIC SWITCHES ARE REVERSIBLE, THEY MIGHT REPRESENT AN IMPORTANT BASIS FOR THE DESIGN OF NOVEL ANTICANCER THERAPEUTICS. THIS REVIEW SUMMARIZES PUBLISHED EVIDENCE OF EPIGENETIC SWITCHES IN CANCER DEVELOPMENT THAT ARE INDUCED BY INFLAMMATION. 2016 9 5130 34 POSTTRANSCRIPTIONAL GENE REGULATION: NOVEL PATHWAYS FOR GLUCOCORTICOIDS' ANTI-INFLAMMATORY ACTION. POSTTRANSCRIPTIONAL GENE REGULATION (PTR) IS A FUNDAMENTAL BIOLOGICAL PROCESS THAT INTEGRATES WITH THE MASTER TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION, IN WAYS THAT ONLY IN THE LAST DECADE HAVE BEEN INCREASINGLY UNDERSTOOD [1, 2]. WHILE EPIGENETIC AND TRANSCRIPTIONAL EVENTS SHAPE CELL RESPONSE QUALITATIVELY, DECIDING THE PATTERN OF GENE EXPRESSION TO 'SWITCH ON OR OFF' IN RESPONSE TO ENDOGENOUS OR ENVIRONMENTAL TRIGGERS, THE KEY TASK OF PTR IS TO ACT AS A 'RHEOSTAT' AND RAPIDLY ADAPT THE CELLULAR RESPONSE BY PROVIDING THE APPROPRIATE AMPLITUDE AND TIMING TO THE PROTEIN EXPRESSION PATTERNS [3, 4]. THE PIVOTAL ROLE OF THIS MECHANISM COMES TO THE FOREFRONT IN INFLAMMATORY AND IMMUNE RESPONSE, WHERE THE CHANGES IN AMPLITUDE AND DURATION IN THE EXPRESSION OF DANGEROUS AND PROTECTIVE GENES ARE IN DELICATE BALANCE, AND ARE CRITICAL IN DETERMINING EITHER THE SUCCESSFUL RESOLUTION OF THE IMMUNE RESPONSE OR ITS CHRONIC OVEREXPRESSION [5]. THIS BRIEF REVIEW INTRODUCES MEMBERS OF THE MAIN CLASSES OF MOLECULES MEDIATING THE CYTOPLASMIC ARM OF GENE REGULATION, NAMELY RNA-BINDING PROTEINS AND MICRO-RNA (MIRNA), AND SUMMARIZES EXPERIMENTAL DATA THAT UNDERSCORE THE ROLE OF THESE MOLECULES IN THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATION, AS WELL AS THEIR PROMISING VALUE AS MECHANISMS CONVEYING THE ANTI-INFLAMMATORY EFFECT OF SYNTHETIC GLUCOCORTICOIDS. 2012 10 5491 38 REVIEW ARTICLE: INFLAMMATION-RELATED PROMOTION OF GASTROINTESTINAL CARCINOGENESIS--A PERIGENETIC PATHWAY. CHRONIC INFLAMMATION HAS BEEN REPORTED TO ACCELERATE NEOPLASMAS IN GASTROINTESTINAL TRACT. CERTAIN BACTERIA INCLUDING HELICOBACTER PYLORI DIRECTLY INTERACT WITH HOST CELLS, INDUCE PROINFLAMMATORY CYTOKINES AND STIMULATE PRODUCTION OF FREE RADICALS. FREE RADICALS CAUSE MUTATIONS IN TARGET CELLS SO THAT NEOPLASTIC CLONES ARE ESTABLISHED. ACCUMULATION OF SUCH GENETIC ALTERATIONS MAY CAUSE MALIGNANT TRANSFORMATION OF SOME ESTABLISHED CLONES. IN ADDITION, INFLAMMATORY ALTERATIONS MAY PROMOTE GROWTH, EXPANSION AND INVASION OF GASTROINTESTINAL EPITHELIAL CELLS. THE LATTER CHANGES CAUSED BY INFLAMMATION MAY OCCUR EVEN WITHOUT FURTHER GENETIC MUTATIONS OR EPIGENETIC ALTERATIONS, AND THEREFORE MAY BE CATEGORIZED AS 'PERIGENETIC ALTERATIONS' OF NEOPLASTIC CELLS. FOR AN EXAMPLE, TUMOUR NECROSIS FACTOR ALPHA (TNF-ALPHA) PLAYS PIVOTAL ROLES NOT ONLY IN THE REDUCTION BUT ALSO IN THE GROWTH, INVASION AND METASTASES OF CERTAIN NEOPLASMAS. OUR STUDIES SHOW THAT TNF-ALPHA INCREASES INTRACELLULAR RADICAL PRODUCTION, DEGRADATES E-CADHERIN / BETA-CATENIN COMPLEX AND PROMOTES DISPERSION AND MIGRATION IN EPITHELIAL CELLS TRANSFORMED WITH AN ACTIVATED SRC ONCOGENE (V-SRC). THESE DATA INDICATE THAT AN INFLAMMATORY CYTOKINE INDUCES THE MALIGNANT POTENTIAL OF SRC-ACTIVATED NEOPLASTIC CELLS. INTERESTINGLY, TNF-ALPHA ALSO INDUCED THESE PHENOTYPIC CHANGES IN NONMUTATED CELLS WHOSE C-SRC WAS ACTIVATED BY TGF-ALPHA, SUGGESTING THAT THE INVASIVE PROPERTIES OF THE CELL WERE NOT NECESSARILY RELATED TO GENE MUTATION. FURTHERMORE, CERTAIN RADICAL SCAVENGERS SUPPRESSED THE INVASIVE PHENOTYPE OF THE CELLS. THESE RESULTS INDICATE THAT PERIGENETIC ALTERATIONS ARE AN IMPORTANT TARGET OF PHARMACOLOGICAL INTERVENTION OF CARCINOGENESIS. 2003 11 3418 32 HUMAN HEALTH CONSEQUENCES OF ENVIRONMENTALLY-MODULATED GENE EXPRESSION: POTENTIAL ROLES OF ELF-EMF INDUCED EPIGENETIC VERSUS MUTAGENIC MECHANISMS OF DISEASE. IN ORDER TO DETERMINE IF THERE MIGHT BE BIOLOGICAL AND HEALTH CONSEQUENCES AFTER EXPOSURES TO EXTREMELY-LOW FREQUENCY ELECTROMAGNETIC FIELDS (ELF-EMF), EITHER EXPERIMENTALLY OR EPIDEMIOLOGICALLY, MECHANISTIC UNDERSTANDING OF THE POTENTIAL MEANS BY WHICH ANY ENVIRONMENTAL AGENT CAN AFFECT CELLS IN A MULTICELLULAR ORGANISM HAS TO BE REVIEWED. THE GOAL OF THIS LIMITED REVIEW IS TO DEMONSTRATE THAT, WHILE THE PREVAILING PARADIGM OF THE ENVIRONMENTALLY-INDUCED ACUTE AND CHRONIC DISEASES INVOLVES EITHER CELL KILLING (CYTOTOXICITY) OR GENE/CHROMOSOME MUTATIONS (GENOTOXICITY), ALTERATION OF THE EXPRESSION OF GENETIC INFORMATION AT THE TRANSCRIPTIONAL (TURNING GENES "ON" OR "OFF"), TRANSLATIONAL (STABILIZING OR DE-STABILIZING THE GENETIC MESSAGE), OR POSTTRANSLATIONAL (ALTERING THE GENE PRODUCT OR PROTEIN) LEVELS HAS THE POTENTIAL TO CONTRIBUTE TO VARIOUS DISEASES. THIS LATTER MECHANISM, "EPIGENETIC" TOXICITY, UNLIKE THE FORMER TWO WHICH ARE IRREVERSIBLE, IS CHARACTERIZED BY THRESHOLD-LIKE ACTION, MULTIPLE BIOCHEMICAL PATHWAYS AND CHRONIC, REGULAR EXPOSURES TO BE EFFECTIVE. ULTIMATELY, EPIGENETIC TOXICANTS AFFECT ONE OF FOUR POTENTIAL CELL STATES, NAMELY ALTERATION OF CELL PROLIFERATION, CELL DIFFERENTIATION, PROGRAMMED CELL DEATH (APOPTOSIS) OR ADAPTIVE RESPONSES OF DIFFERENTIATED CELLS. 2000 12 376 25 AN EPI(C)GENETIC WAR: PATHOGENS, CANCER AND HUMAN GENOME. CANCER IS CHARACTERIZED BY INTER- AND INTRA-TUMOR HETEROGENEITY AND THIS IS ALSO OBSERVED IN THE CONTEXT OF CANCERS CAUSED BY PATHOGENS. NEARLY 20% OF ALL CANCERS ARE ATTRIBUTABLE TO PATHOGENIC ORGANISMS. PATHOGENIC INFECTIONS RESULT IN DEREGULATION OF GENE EXPRESSION BOTH BY GENETIC AND EPIGENETIC MECHANISMS, THEREBY CAUSING MALIGNANT TRANSFORMATION. ANOTHER CHARACTERISTIC OF PATHOGEN-INDUCED CANCERS IS THE OCCURRENCE OF CHRONIC INFLAMMATION DUE TO ACTIVATION OF THE INNATE AND ADAPTIVE ARMS OF THE IMMUNE SYSTEM. THIS REVIEW FOCUSES ON THE EPIGENETIC CHANGES INDUCED BY ONCOVIRUSES, PARASITES, CANCER-CAUSING BACTERIA AND 'ENDOGENOUS PATHOGENS' TO TRIGGER HOST CELL PROLIFERATION INDEFINITELY AS WELL AS THE INFLAMMATION ASSOCIATED WITH PATHOGEN-INDUCED CANCERS. THE OPPORTUNITY OF TARGETING COMPONENTS OF BOTH PATHOGEN AND HOST EPIGENETIC MACHINERY TO LIMIT TUMOR PROGRESSION IS ALSO DISCUSSED. 2018 13 6896 29 [TARGETED EPIGENETIC THERAPY OF CANCER. ACHIEVEMENTS AND PERSPECTIVES]. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL EPIGENETIC CHANGES OF NORMAL CELLS AND CANCER CELLS, AND EMPHASIZE THE ACHIEVEMENTS AND THE PERSPECTIVES OF CANCER EPIGENETIC THERAPY. CANCER EPIGENETIC ALTERATIONS CORRESPOND FOREMOST TO HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES PROMOTORS, GLOBAL DNA HYPOMETHYLATION, AND OVEREXPRESSION AND ACTIVITY OF HISTONE DEACETYLASES. THE PURPOSE OF EPIGENETIC THERAPY IS TO REVERT THE EPIGENETIC ALTERATIONS IN CANCER CELLS AND OBTAIN THE "NORMAL EPIGENOME" RESTORATION. EPIGENETIC TARGETS IN CANCER THERAPY HAVE FOCUSED ON HDACS AND DNMTS INHIBITION. THE AZACITIDINE AND THE DECITABINE, THE VORINOSTAT AND THE ROMIDEPSIN WERE APPROVED BY US-FDA FOR TREATMENT OF MYELODYSPLASTIC SYNDROME, AND CUTANEOUS T-CELL LYMPHOMA, RESPECTIVELY. EPIGENETIC AND EPIGENOMIC CHANGES IN SINGLE OR MULTIPLE GENES HAVE SHOWED POTENTIAL IMPACT IN CANCER AS EARLY DETECTION, PROGNOSIS AND PREDICTIVE MARKS. THE EPIGENETIC REVOLUTION HAS ARRIVED FOR BIOLOGY. THE SIGNIFICANT PROGRESS IN EPIGENETIC STUDIES HAVE ALLOWED US, TO UNDERSTAND NEW LOOKS IN THE PHYSIOLOGY AND PATHOPHYSIOLOGY OF EMBRYONIC DEVELOPMENT, CANCER AND OTHER CHRONIC DISEASES. SPECIFIC MOLECULAR EPIGENETIC ALTERATIONS IN DIFFERENT CANCER TYPES, GIVE US NEW STRATEGIES TO DESIGN IMPROVED CANCER THERAPY. THE CHALLENGE FOR EPIGENETIC INVESTIGATORS IS DESIGN MORE SPECIFIC EPIDRUGS WITH LESSER SIDE EFFECTS. 2012 14 1900 41 ENERGY SENSING PATHWAYS: BRIDGING TYPE 2 DIABETES AND COLORECTAL CANCER? THE RECENTLY RAPID INCREASE OF OBESITY AND TYPE 2 DIABETES MELLITUS HAS CAUSED GREAT BURDEN TO OUR SOCIETY. A POSITIVE ASSOCIATION BETWEEN TYPE 2 DIABETES AND RISK OF COLORECTAL CANCER HAS BEEN REPORTED BY INCREASING EPIDEMIOLOGICAL STUDIES. THE MOLECULAR MECHANISM OF THIS CONNECTION REMAINS ELUSIVE. HOWEVER, TYPE 2 DIABETES MAY RESULT IN ABNORMAL CARBOHYDRATE AND LIPID METABOLISM, HIGH LEVELS OF CIRCULATING INSULIN, INSULIN GROWTH FACTOR-1, AND ADIPOCYTOKINES, AS WELL AS CHRONIC INFLAMMATION. ALL THESE FACTORS COULD LEAD TO THE ALTERATION OF ENERGY SENSING PATHWAYS SUCH AS THE AMP ACTIVATED KINASE (PRKA), MECHANISTIC (MAMMALIAN) TARGET OF RAPAMYCIN (MTOR), SIRT1, AND AUTOPHAGY SIGNALING PATHWAYS. THE RESULTED IMPAIRED SIRT1 AND AUTOPHAGY SIGNALING PATHWAY COULD INCREASE THE RISK OF GENE MUTATION AND CANCER GENESIS BY DECREASING GENETIC STABILITY AND DNA MISMATCH REPAIR. THE DYSREGULATED MTOR AND PRKA PATHWAY COULD REMODEL CELL METABOLISM DURING THE GROWTH AND METASTASIS OF CANCER IN ORDER FOR THE CANCER CELL TO SURVIVE THE UNFAVORABLE MICROENVIRONMENT SUCH AS HYPOXIA AND LOW BLOOD SUPPLY. MOREOVER, THESE PATHWAYS MAY BE COUPLING METABOLIC AND EPIGENETIC ALTERATIONS THAT ARE CENTRAL TO ONCOGENIC TRANSFORMATION. FURTHER RESEARCHES INCLUDING MOLECULAR PATHOLOGIC EPIDEMIOLOGIC STUDIES ARE WARRANTED TO BETTER ADDRESS THE PRECISE LINKS BETWEEN THESE TWO IMPORTANT DISEASES. 2017 15 1232 39 CROSSTALK BETWEEN INFLAMMATORY SIGNALING AND METHYLATION IN CANCER. INFLAMMATION IS AN INTRICATE IMMUNE RESPONSE AGAINST INFECTION AND TISSUE DAMAGE. WHILE THE INITIAL IMMUNE RESPONSE IS IMPORTANT FOR PREVENTING TUMORIGENESIS, CHRONIC INFLAMMATION IS IMPLICATED IN CANCER PATHOGENESIS. IT HAS BEEN LINKED TO VARIOUS STAGES OF TUMOR DEVELOPMENT INCLUDING TRANSFORMATION, PROLIFERATION, ANGIOGENESIS, AND METASTASIS. IMMUNE CELLS, THROUGH THE PRODUCTION OF INFLAMMATORY MEDIATORS SUCH AS CYTOKINES, CHEMOKINES, TRANSFORMING GROWTH FACTORS, AND ADHESION MOLECULES CONTRIBUTE TO THE SURVIVAL, GROWTH, AND PROGRESSION OF THE TUMOR IN ITS MICROENVIRONMENT. THE ABERRANT EXPRESSION AND SECRETION OF PRO-INFLAMMATORY AND GROWTH FACTORS BY THE TUMOR CELLS RESULT IN THE RECRUITMENT OF IMMUNE CELLS, THUS CREATING A MUTUAL CROSSTALK. THE RECIPROCAL SIGNALING BETWEEN THE TUMOR CELLS AND THE IMMUNE CELLS CREATES AND MAINTAINS A SUCCESSFUL TUMOR NICHE. MANY INFLAMMATORY FACTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. IN PARTICULAR, DNA AND HISTONE METHYLATION ARE CRUCIAL FORMS OF TRANSCRIPTIONAL REGULATION AND ABERRANT METHYLATION HAS BEEN ASSOCIATED WITH DEREGULATED GENE EXPRESSION IN ONCOGENESIS. SUCH DEREGULATIONS HAVE BEEN REPORTED IN BOTH SOLID TUMORS AND HEMATOLOGICAL MALIGNANCIES. WITH TECHNOLOGICAL ADVANCEMENTS TO STUDY GENOME-WIDE EPIGENETIC LANDSCAPES, IT IS NOW POSSIBLE TO IDENTIFY MOLECULAR MECHANISMS UNDERLYING ALTERED INFLAMMATORY PROFILES IN CANCER. IN THIS REVIEW, WE DISCUSS THE ROLE OF DNA AND HISTONE METHYLATION IN REGULATION OF INFLAMMATORY PATHWAYS IN HUMAN CANCERS AND REVIEW THE MERITS AND CHALLENGES OF TARGETING INFLAMMATORY MEDIATORS AS WELL AS EPIGENETIC REGULATORS IN CANCER. 2021 16 45 30 A COMPREHENSIVE REVIEW ON RNA INTERFERENCE-MEDIATED TARGETING OF INTERLEUKINS AND ITS POTENTIAL THERAPEUTIC IMPLICATIONS IN COLON CANCER. COLON CANCER IS THE WORLD'S FOURTH LEADING CAUSE OF DEATH. IT IS CANCER OF THE LATTER PART OF THE LARGE INTESTINE, I.E. THE COLON. CHRONIC INFLAMMATION OVER A LONG PERIOD ALSO LEADS TO THE DEVELOPMENT OF CANCER. CANCER IN THE COLON REGION IS ARDUOUS TO DIAGNOSE AND IS DETECTED AT A LATER STAGE WHEN IT METASTASIZES TO OTHER PARTS OF THE BODY LIKE THE LIVER, LUNGS, PERITONEUM, ETC. COLON CANCER IS A GREAT EXAMPLE OF SOLID TUMOURS ASSOCIATED WITH CHRONIC INFLAMMATION. ALTHOUGH CONVENTIONAL THERAPIES ARE EFFECTIVE, THEY LOSE THEIR EFFECTIVENESS BEYOND A CERTAIN POINT. RELAPSE OF THE DISEASE OCCURS FREQUENTLY. RNA INTERFERENCE (RNAI) IS EMERGING AS A GREAT TOOL TO SPECIFICALLY ATTACK THE CANCER CELLS OF A TARGET SITE LIKE THE COLON. RNAI DEALS WITH EPIGENETIC CHANGES MADE IN THE DEFECTIVE CELLS WHICH ULTIMATELY LEADS TO THEIR DEATH WITHOUT HARMING THE HEALTHY CELLS. IN THIS REVIEW, TWO TYPES OF EPIGENETIC MODULATORS HAVE BEEN CONSIDERED, NAMELY SIRNA AND MIRNA, AND THEIR EFFECT ON INTERLEUKINS. INTERLEUKINS, A CLASS OF CYTOKINES, ARE MAJOR INFLAMMATORY RESPONSES OF THE BODY THAT ARE RELEASED BY IMMUNE CELLS LIKE LEUKOCYTES AND MACROPHAGES. SOME OF THESE INTERLEUKINS ARE PRO-INFLAMMATORY, THEREBY PROMOTING INFLAMMATION WHICH EVENTUALLY CAUSES CANCER. RNAI CAN PREVENT COLON CANCER BY INHIBITING PRO-INFLAMMATORY INTERLEUKINS. 2023 17 209 31 ACTIVATION-INDUCED CYTIDINE DEAMINASE: IN SICKNESS AND IN HEALTH. ACTIVATION INDUCED CYTIDINE DEAMINASE (AID) IS AN ESSENTIAL ENZYME OF THE ADAPTIVE IMMUNE SYSTEM. ITS CANONICAL ACTIVITY IS RESTRICTED TO B LYMPHOCYTES, PLAYING AN ESSENTIAL ROLE IN THE DIVERSIFICATION OF ANTIBODIES BY ENHANCING SPECIFICITY AND CHANGING AFFINITY. THIS IS POSSIBLE THROUGH ITS DNA DEAMINASE FUNCTION, LEADING TO MUTATIONS IN DNA. IN THE LAST DECADE, AID HAS BEEN ASSIGNED AN ADDITIONAL FUNCTION: THAT OF A POWERFUL DNA DEMETHYLATOR. ADVERSE CELLULAR CONDITIONS SUCH AS CHRONIC INFLAMMATION CAN LEAD TO ITS DEREGULATION AND OVEREXPRESSION. IT IS AN IMPORTANT DRIVER OF B-CELL LYMPHOMA DUE TO ITS NATURAL ABILITY TO MODIFY DNA THROUGH DEAMINATION, LEADING TO MUTATIONS AND EPIGENETIC CHANGES. HOWEVER, THE DEREGULATION OF AID IS NOT RESTRICTED TO LYMPHOID CELLS. RECENT FINDINGS HAVE PROVIDED NEW INSIGHTS INTO THE ROLE THAT THIS PROTEIN PLAYS IN THE DEVELOPMENT OF NON-LYMPHOID CANCERS, WITH SOME RESEARCH SHEDDING LIGHT ON NOVEL AID-DRIVEN MECHANISMS OF CELLULAR TRANSFORMATION. IN THIS REVIEW, WE PROVIDE AN UPDATED NARRATIVE OF THE NORMAL PHYSIOLOGICAL FUNCTIONS OF AID. ADDITIONALLY, WE REVIEW AND DISCUSS THE RECENT RESEARCH STUDIES THAT HAVE IMPLICATED AID IN CARCINOGENESIS IN VARYING TISSUE TYPES INCLUDING LYMPHOID AND NON-LYMPHOID CANCERS. WE REVIEW THE MECHANISMS, WHEREBY AID PROMOTES CARCINOGENESIS AND HIGHLIGHT IMPORTANT AREAS OF FUTURE RESEARCH. 2020 18 2991 32 GENETIC INSTABILITY IN INHERITED AND SPORADIC LEUKEMIAS. GENETIC INSTABILITY DUE TO INCREASED DNA DAMAGE AND ALTERED DNA REPAIR IS OF CENTRAL SIGNIFICANCE IN THE INITIATION AND PROGRESSION OF INHERITED AND SPORADIC HUMAN LEUKEMIAS. ALTHOUGH VERY RARE, SOME INHERITED DNA REPAIR INSUFFICIENCY SYNDROMES (E.G., FANCONI ANEMIA, BLOOM'S SYNDROME) HAVE ADDED SUBSTANTIALLY TO OUR UNDERSTANDING OF CRUCIAL MECHANISMS OF LEUKEMOGENESIS IN RECENT YEARS. CONVERSELY, SPORADIC LEUKEMIAS ACCOUNT FOR THE MAIN PROPORTION OF LEUKEMIAS AND HERE DNA DAMAGING REACTIVE OXYGEN SPECIES (ROS) PLAY A CENTRAL ROLE. ALTHOUGH THE EXACT MECHANISMS OF INCREASED ROS PRODUCTION REMAIN LARGELY UNKNOWN AND NO SINGLE PATHWAY HAS BEEN DETECTED THUS FAR, SOME ONCOGENIC PROTEINS (E.G., THE ACTIVATED TYROSINE KINASES BCR-ABL1 AND FLT3-ITD) SEEM TO PLAY A KEY ROLE IN DRIVING GENETIC INSTABILITY BY INCREASED ROS GENERATION WHICH INFLUENCES THE DISEASE COURSE (E.G., BLAST CRISIS IN CHRONIC MYELOID LEUKEMIA OR RELAPSE IN FLT3-ITD POSITIVE ACUTE MYELOID LEUKEMIA). OF COURSE OTHER MECHANISMS, WHICH PROMOTE GENETIC INSTABILITY IN LEUKEMIA ALSO EXIST. A NEWLY EMERGING MECHANISM IS THE GENOME-WIDE ALTERATION OF EPIGENETIC MARKS (E.G., HYPOMETHYLATION OF HISTONE H3K79), WHICH PROMOTES CHROMOSOMAL INSTABILITY. TAKEN TOGETHER GENETIC INSTABILITY PLAYS A CRITICAL ROLE BOTH IN INHERITED AND SPORADIC LEUKEMIAS AND EMERGES AS A COMMON THEME IN BOTH INHERITED AND SPORADIC LEUKEMIAS. BEYOND ITS THEORETICAL IMPACT, THE ANALYSIS OF GENETIC INSTABILITY MAY LEAD THE WAY TO THE DEVELOPMENT OF INNOVATIVE THERAPY STRATEGIES. 2010 19 4524 38 MULTIFACETED CONTROL OF DNA REPAIR PATHWAYS BY THE HYPOXIC TUMOR MICROENVIRONMENT. HYPOXIA, AS A PERVASIVE FEATURE IN THE MICROENVIRONMENT OF SOLID TUMORS, PLAYS A SIGNIFICANT ROLE IN CANCER PROGRESSION, METASTASIS, AND ULTIMATELY CLINICAL OUTCOME. ONE KEY CELLULAR CONSEQUENCE OF HYPOXIC STRESS IS THE REGULATION OF DNA REPAIR PATHWAYS, WHICH CONTRIBUTES TO THE GENOMIC INSTABILITY AND MUTATOR PHENOTYPE OBSERVED IN HUMAN CANCERS. TUMOR HYPOXIA CAN VARY IN SEVERITY AND DURATION, RANGING FROM ACUTE FLUCTUATING HYPOXIA ARISING FROM TEMPORARY BLOCKAGES IN THE IMMATURE MICROVASCULATURE, TO CHRONIC MODERATE HYPOXIA DUE TO SPARSE VASCULATURE, TO COMPLETE ANOXIA AT DISTANCES MORE THAN 150 MUM FROM THE NEAREST BLOOD VESSEL. PARALLELING THE INTRA-TUMOR HETEROGENEITY OF HYPOXIA, THE EFFECTS OF HYPOXIA ON DNA REPAIR OCCUR THROUGH DIVERSE MECHANISMS. ACUTELY, HYPOXIA ACTIVATES DNA DAMAGE SIGNALING PATHWAYS, PRIMARILY VIA POST-TRANSLATIONAL MODIFICATIONS. ON A LONGER TIMESCALE, HYPOXIA LEADS TO TRANSCRIPTIONAL AND/OR TRANSLATIONAL DOWNREGULATION OF MOST DNA REPAIR PATHWAYS INCLUDING DNA DOUBLE-STRAND BREAK REPAIR, MISMATCH REPAIR, AND NUCLEOTIDE EXCISION REPAIR. FURTHERMORE, EXTENDED HYPOXIA CAN LEAD TO LONG-TERM PERSISTENT SILENCING OF CERTAIN DNA REPAIR GENES, INCLUDING BRCA1 AND MLH1, REVEALING A MECHANISM BY WHICH TUMOR SUPPRESSOR GENES CAN BE INACTIVATED. THE DISCOVERIES OF THE HYPOXIC MODULATION OF DNA REPAIR PATHWAYS HAVE HIGHLIGHTED MANY POTENTIAL WAYS TO TARGET SUSCEPTIBILITIES OF HYPOXIC CANCER CELLS. IN THIS REVIEW, WE WILL DISCUSS THE MULTIFACETED HYPOXIC CONTROL OF DNA REPAIR AT THE TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND EPIGENETIC LEVELS, AND WE WILL OFFER PERSPECTIVE ON THE FUTURE OF ITS CLINICAL IMPLICATIONS. 2015 20 1260 42 CURRENT VIEWS ON THE INTERPLAY BETWEEN TYROSINE KINASES AND PHOSPHATASES IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY BCR-ABL1 ONCOGENE EXPRESSION. THIS DYSREGULATED PROTEIN-TYROSINE KINASE (PTK) IS KNOWN AS THE PRINCIPAL DRIVER OF THE DISEASE AND IS TARGETED BY TYROSINE KINASE INHIBITORS (TKIS). EXTENSIVE DOCUMENTATION HAS ELUCIDATED HOW THE TRANSFORMATION OF MALIGNANT CELLS IS CHARACTERIZED BY MULTIPLE GENETIC/EPIGENETIC CHANGES LEADING TO THE LOSS OF TUMOR-SUPPRESSOR GENES FUNCTION OR PROTO-ONCOGENES EXPRESSION. THE IMPAIRMENT OF ADEQUATE LEVELS OF SUBSTRATES PHOSPHORYLATION, THUS AFFECTING THE BALANCE PTKS AND PROTEIN PHOSPHATASES (PPS), REPRESENTS A WELL-ESTABLISHED CELLULAR MECHANISM TO ESCAPE FROM SELF-LIMITING SIGNALS. IN THIS REVIEW, WE FOCUS OUR ATTENTION ON THE CHARACTERIZATION OF AND INTERACTIONS BETWEEN PTKS AND PPS, EMPHASIZING THEIR BIOLOGICAL ROLES IN DISEASE EXPANSION, THE REGULATION OF LSCS AND TKI RESISTANCE. WE DECIDED TO SEPARATE THOSE PPS THAT HAVE BEEN VALIDATED IN PRIMARY CELL MODELS OR LEUKEMIA MOUSE MODELS FROM THOSE WHOSE STUDIES HAVE BEEN PERFORMED ONLY IN CELL LINES (AND, THUS, REQUIRE VALIDATION), AS THERE MAY BE DIFFERENCES IN THE MANNER THAT THE ASSOCIATED PATHWAYS ARE MODIFIED UNDER THESE TWO CONDITIONS. THIS REVIEW SUMMARIZES THE ROLES OF DIVERSE PPS, WITH HOPE THAT BETTER KNOWLEDGE OF THE INTERPLAY AMONG PHOSPHATASES AND KINASES WILL EVENTUALLY RESULT IN A BETTER UNDERSTANDING OF THIS DISEASE AND CONTRIBUTE TO ITS ERADICATION. 2021