1 6623 109 UNDERSTANDING KELOID PATHOBIOLOGY FROM A QUASI-NEOPLASTIC PERSPECTIVE: LESS OF A SCAR AND MORE OF A CHRONIC INFLAMMATORY DISEASE WITH CANCER-LIKE TENDENCIES. KELOIDS ARE CONSIDERED AS BENIGN FIBROPROLIFERATIVE SKIN TUMORS GROWING BEYOND THE SITE OF THE ORIGINAL DERMAL INJURY. ALTHOUGH TRADITIONALLY VIEWED AS A FORM OF SKIN SCARRING, KELOIDS DISPLAY MANY CANCER-LIKE CHARACTERISTICS SUCH AS PROGRESSIVE UNCONTROLLED GROWTH, LACK OF SPONTANEOUS REGRESSION AND EXTREMELY HIGH RATES OF RECURRENCE. PHENOTYPICALLY, KELOIDS ARE CONSISTENT WITH NON-MALIGNANT DERMAL TUMORS THAT ARE DUE TO THE EXCESSIVE OVERPRODUCTION OF COLLAGEN WHICH NEVER METASTASIZE. WITHIN THE REMIT OF KELOID PATHOBIOLOGY, THERE IS INCREASING EVIDENCE FOR THE VARIOUS INTERPLAY OF NEOPLASTIC-PROMOTING AND SUPPRESSING FACTORS, WHICH MAY EXPLAIN ITS AGGRESSIVE CLINICAL BEHAVIOR. AMONGST THE MOST COMPELLING PARALLELS BETWEEN KELOIDS AND CANCER ARE THEIR SHARED CELLULAR BIOENERGETICS, EPIGENETIC METHYLATION PROFILES AND EPITHELIAL-TO-MESENCHYMAL TRANSITION AMONGST OTHER DISEASE BIOLOGICAL (GENOTYPIC AND PHENOTYPIC) BEHAVIORS. THIS REVIEW EXPLORES THE QUASI-NEOPLASTIC OR CANCER-LIKE PROPERTIES OF KELOIDS AND HIGHLIGHTS AREAS FOR FUTURE STUDY. 2019 2 4053 29 MANAGING KELOID SCARS: FROM RADIATION THERAPY TO ACTUAL AND POTENTIAL DRUG DELIVERIES. THE AETIOLOGY OF KELOIDS IS BECOMING CLEARER, BUT MANY QUESTIONS REMAIN, INCLUDING ABOUT THE MOST OPTIMAL TREATMENT. CURRENT THERAPIES INCLUDE SURGICAL EXCISION, RADIOTHERAPY, AND VARIOUS PHARMACEUTICAL DRUGS. HOWEVER, NONE OF THESE DRUGS ARE KELOID-SPECIFIC. MOREOVER, ALL CURRENT INTERVENTIONS ARE ASSOCIATED WITH HIGH RECURRENCE RATES. HERE, WE REVIEW THE PHARMACEUTICAL INTERVENTIONS THAT ARE CURRENTLY AVAILABLE. ALL ARE BASED ON THE FACT THAT KELOIDS ARE AN EXPANDING SOLID MASS WITH INTENSE CHRONIC INFLAMMATION AT ITS ADVANCING EDGES. CONSEQUENTLY, CURRENT PHARMACEUTICALS AIM TO REDUCE THE MASS AND/OR SYMPTOMS OF KELOIDS, SIMILAR TO SURGERY AND RADIOTHERAPY. THEY INCLUDE CHEMOTHERAPIES, IMMUNOTHERAPIES, VOLUME-REDUCING THERAPIES, AND ANTI-INFLAMMATORY THERAPIES. WE ALSO DESCRIBE NEW ADVANCES IN KELOID PHARMACEUTICALS. THEY INCLUDE DRUGS THAT WERE DESIGNED TO TREAT SYSTEMIC DISEASES SUCH AS HYPERTENSION OR BREAST CANCER BUT WERE FOUND TO ALSO TREAT KELOIDS. FURTHERMORE, RECENT PROGRESS IN GENETIC, EPIGENETIC, AND STEM CELL THERAPIES SUGGESTS THAT THEY COULD BECOME USEFUL IN THE KELOID FIELD. THIS REVIEW OF PHARMACEUTICAL ADVANCES WILL HOPEFULLY PROMOTE ADDITIONAL RESEARCH AND THE DEVELOPMENT OF EFFECTIVE AND SPECIFIC PHARMACEUTICALS FOR KELOIDS. 2019 3 6655 25 UPDATE ON THE MOLECULAR PATHOLOGY OF CUTANEOUS SQUAMOUS CELL CARCINOMA. CUTANEOUS SQUAMOUS CELL CARCINOMA (CSCC) IS THE SECOND MOST COMMON SKIN CANCER, ORIGINATING FROM KERATINOCYTES OF THE SPINOUS LAYER. NUMEROUS RISK FACTORS HAVE BEEN DISCOVERED FOR THE INITIATION AND GROWTH OF THIS TYPE OF CANCER, SUCH AS EXPOSURE TO UV AND IONIZING RADIATION, CHEMICAL CARCINOGENS, THE PRESENCE OF IMMUNOSUPPRESSION STATES, CHRONIC INFLAMMATION, INFECTIONS WITH HIGH-RISK VIRAL STRAINS, AND, LAST BUT NOT LEAST, THE PRESENCE OF DISEASES ASSOCIATED WITH GENETIC ALTERATIONS. THE IMPORTANT SOCIO-ECONOMIC IMPACT, AS WELL AS THE DIFFICULTY ASSOCIATED WITH THERAPY FOR ADVANCED FORMS, HAS MADE THE MOLECULAR MECHANISMS UNDERLYING THIS NEOPLASIA MORE AND MORE INTENSIVELY STUDIED, WITH THE INTENTION OF ACHIEVING A BETTER UNDERSTANDING AND ADVANCING THE TREATMENT OF THIS PATHOLOGY. THIS REVIEW AIMS TO PROVIDE A BRIEF FORAY INTO THE MOLECULAR, GENETIC, AND EPIGENETIC ASPECTS OF THIS CANCER, AS WELL AS THE TREATMENT METHODS, RANGING FROM THE FIRST USED TO THE LATEST TARGETED THERAPIES. 2023 4 3958 31 LONG NON-CODING RNAS IN BONE METASTASIS: PROGRESSES AND PERSPECTIVES AS POTENTIAL DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. IN A PRECISION MEDICINE PERSPECTIVE, AMONG THE BIOMARKERS POTENTIALLY USEFUL FOR EARLY DIAGNOSIS OF CANCERS, AS WELL AS TO DEFINE THEIR PROGNOSIS AND EVENTUALLY TO IDENTIFY NOVEL AND MORE EFFECTIVE THERAPEUTIC TARGETS, THERE ARE THE LONG NON-CODING RNAS (LNCRNAS). THE TERM LNCRNA IDENTIFIES A CLASS OF NON-CODING RNA MOLECULES INVOLVED IN THE REGULATION OF GENE EXPRESSION THAT INTERVENE AT THE TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND EPIGENETIC LEVEL. METASTASIS IS A NATURAL EVOLUTION OF SOME MALIGNANT TUMOURS, FREQUENTLY ENCOUNTERED IN PATIENTS WITH ADVANCED CANCERS. ONSET AND DEVELOPMENT OF METASTASIS REPRESENTS A DETRIMENTAL EVENT THAT WORSEN THE PATIENT'S PROGNOSIS BY PROFOUNDLY INFLUENCING THE QUALITY OF LIFE AND IS RESPONSIBLE FOR THE OMINOUS PROGRESSION OF THE DISEASE. DUE TO THE PECULIAR ENVIRONMENT AND THE BIOMECHANICAL PROPERTIES, BONE IS A PREFERENTIAL SITE FOR THE SECONDARY GROWTH OF BREAST, PROSTATE AND LUNG CANCERS. UNFORTUNATELY, ONLY PALLIATIVE AND PAIN THERAPIES ARE CURRENTLY AVAILABLE FOR PATIENTS WITH BONE METASTASES, WHILE NO EFFECTIVE AND DEFINITIVE TREATMENTS ARE AVAILABLE. THE UNDERSTANDING OF PATHOPHYSIOLOGICAL BASIS OF BONE METASTASIS FORMATION AND PROGRESSION, AS WELL AS THE IMPROVEMENT IN THE CLINICAL MANAGEMENT OF THE PATIENT, ARE CENTRAL BUT CHALLENGING TOPICS IN BASIC RESEARCH AND CLINICAL PRACTICE. THE IDENTIFICATION OF NEW MOLECULAR SPECIES THAT MAY HAVE A ROLE AS EARLY HALLMARKS OF THE METASTATIC PROCESS COULD OPEN THE DOOR TO THE DEFINITION OF NEW, AND MORE EFFECTIVE, THERAPEUTIC AND DIAGNOSTIC APPROACHES. NON-CODING RNAS SPECIES AND, PARTICULARLY, LNCRNAS ARE PROMISING COMPOUNDS IN THIS SETTING, AND THEIR STUDY MAY BRING TO THE IDENTIFICATION OF RELEVANT PROCESSES. IN THIS REVIEW, WE HIGHLIGHT THE ROLE OF LNCRNAS AS EMERGING MOLECULES IN MEDIATING THE FORMATION AND DEVELOPMENT OF BONE METASTASES, AS POSSIBLE BIOMARKERS FOR CANCER DIAGNOSIS AND PROGNOSIS, AND AS THERAPEUTIC TARGETS TO COUNTERACT CANCER SPREAD. 2023 5 928 17 CHRONIC INFLAMMATION, THE TUMOR MICROENVIRONMENT AND CARCINOGENESIS. CHRONIC INFLAMMATION OFTEN PRECEDES OR ACCOMPANIES A SUBSTANTIAL NUMBER OF CANCERS. INDEED, ANTI-INFLAMMATORY THERAPIES HAVE SHOWN EFFICACY IN CANCER PREVENTION AND TREATMENT. THE EXACT MECHANISMS THAT TURN A WOUND HEALING PROCESS INTO A CANCER PRECURSOR ARE TOPICS OF INTENSE RESEARCH. A PATHOGENIC LINK HAS BEEN IDENTIFIED BETWEEN INFLAMMATORY MEDIATORS, INFLAMMATION RELATED GENE POLYMORPHISMS AND CARCINOGENESIS. ANIMAL MODELS OF CANCER HAVE BEEN INSTRUMENTAL IN DEMONSTRATING THE DIVERSITY OF MECHANISMS THROUGH WHICH EVERY TUMOR COMPARTMENT AND TUMOR STAGE MAY BE AFFECTED BY THE UNDERLYING INFLAMMATORY PROCESS. IN THIS REVIEW, WE FOCUS ON THE INTERACTION BETWEEN CHRONIC INFLAMMATION, TUMOR STEM CELLS AND THE TUMOR MICROENVIRONMENT. WE SUMMARIZE THE PROPOSED MECHANISMS THAT LEAD TO THE RECRUITMENT OF BONE MARROW DERIVED CELLS AND EXPLORE THE GENETIC AND EPIGENETIC ALTERATIONS THAT MAY OCCUR IN INFLAMMATION ASSOCIATED CANCERS. 2009 6 5258 32 PROGRESSION OF TUBULOINTERSTITIAL FIBROSIS AND THE CHRONIC KIDNEY DISEASE PHENOTYPE - ROLE OF RISK FACTORS AND EPIGENETICS. ALTHOUGH THE KIDNEY HAS CAPACITY TO REPAIR AFTER MILD INJURY, ONGOING OR SEVERE DAMAGE RESULTS IN SCARRING (FIBROSIS) AND AN ASSOCIATED PROGRESSIVE LOSS OF KIDNEY FUNCTION. HOWEVER, DESPITE ITS UNIVERSAL SIGNIFICANCE, EVIDENCE HIGHLIGHTS A POPULATION BASED HETEROGENEITY IN THE TRAJECTORY OF CHRONIC KIDNEY DISEASE (CKD) IN THESE PATIENTS. TO EXPLAIN THE HETEROGENEITY OF THE CKD PHENOTYPE REQUIRES AN UNDERSTANDING OF THE RELEVANT RISK FACTORS FOR FIBROSIS. THESE FACTORS INCLUDE BOTH THE EXTRINSIC NATURE OF INJURY, AND INTRINSIC FACTORS SUCH AS AGE, GENDER, GENETICS, AND PERPETUAL ACTIVATION OF FIBROBLASTS THROUGH PRIMING. IN MANY CASES AN ADDITIONAL LEVEL OF REGULATION IS PROVIDED BY EPIGENETIC MECHANISMS WHICH INTEGRATE THE VARIOUS PRO-FIBROTIC AND ANTI-FIBROTIC TRIGGERS IN FIBROGENESIS. IN THIS REVIEW WE THEREFORE EXAMINE THE VARIOUS MOLECULAR AND STRUCTURAL CHANGES OF FIBROSIS, AND HOW THEY ARE INFLUENCED BY EXTRINSIC AND INTRINSIC FACTORS. OUR AIM IS TO PROVIDE A UNIFYING HYPOTHESIS TO HELP EXPLAIN THE TRANSITION FROM ACUTE TO CKD. 2017 7 5029 24 PERSPECTIVES ON MICROBES AS ONCOGENIC INFECTIOUS AGENTS AND IMPLICATIONS FOR BREAST CANCER. CANCER MANAGEMENT IS PARTLY BASED ON WEIGHING RISK FACTORS ATTRIBUTED TO NONINFECTIOUS AGENTS, HUMAN GENES AND EPIGENETIC FACTORS. INFECTIOUS DISEASE CAUSATION HAS LARGELY BEEN RESTRICTED TO GENES DIRECTLY RESPONSIBLE FOR CAUSING CANCER AFTER SUSTAINING DAMAGE I.E. ONCOGENES. LATELY, EVIDENCE HAS EMERGED LINKING INFECTIOUS AGENTS TO A NUMBER OF CHRONIC DISEASES. THESE STUDIES HAVE RECOGNIZED THE INFLUENCE THAT ACUTE, ATYPICAL, LATENT AND CHRONIC INFECTIONS MAY PLAY IN TRICKING THE IMMUNE SYSTEM AND AFFECTING DISEASE ETIOLOGY. SIMILAR EVIDENCE IS EMERGING IN MODEL SYSTEMS WITH RESPECT TO THE ROLE OF INFECTIOUS AGENTS IN GASTROINTESTINAL, LIVER AND LUNG CANCERS. ALTHOUGH VIRUSES HAVE BEEN FOUND IN ASSOCIATION WITH BREAST CANCER, SKEPTICISM REMAINS ABOUT A ROLE FOR OTHER INFECTIOUS AGENTS, NOTABLY MICROBES IN THE DISEASE ETIOLOGY. IMPROVED EXPERIMENTAL DESIGNS EMPLOYED IN DIFFERENT CANCER STUDIES AND A LESS RIGID DEFINITION OF INFECTIOUS CAUSATION MAY AID IN CONFIRMING OR REFUTING A MICROBE-BREAST CANCER CONNECTION. CANCER RECURRENCE COULD POTENTIALLY BE MINIMIZED AND TREATMENT OPTIONS FURTHER TAILORED ON A CASE BY CASE BASIS IF MICROBES/MICROBIAL COMPONENTS/STRAIN VARIANTS ASSOCIATED WITH BREAST CANCER ARE IDENTIFIED; PROBIOTICS ARE EMPLOYED TO REDUCE TREATMENT SIDE-EFFECTS AND IF MICROBES COULD EFFECTIVELY BE HARNESSED IN IMMUNOTHERAPY. 2008 8 461 33 ARCHITECTS OF PITUITARY TUMOUR GROWTH. THE PITUITARY IS A MASTER GLAND RESPONSIBLE FOR THE MODULATION OF CRITICAL ENDOCRINE FUNCTIONS. PITUITARY NEUROENDOCRINE TUMOURS (PITNETS) DISPLAY A CONSIDERABLE PREVALENCE OF 1/1106, FREQUENTLY OBSERVED AS BENIGN SOLID TUMOURS. PITNETS STILL REPRESENT A CAUSE OF IMPORTANT MORBIDITY, DUE TO HORMONAL SYSTEMIC DEREGULATION, WITH SURGICAL, RADIOLOGICAL OR CHRONIC TREATMENT REQUIRED FOR ILLNESS MANAGEMENT. THE APPARENT SCARCENESS, UNCOMMON BEHAVIOUR AND MOLECULAR FEATURES OF PITNETS HAVE RESULTED IN A RELATIVELY SLOW PROGRESS IN DEPICTING THEIR PATHOGENESIS. AN APPROPRIATE INTERPRETATION OF DIFFERENT PHENOTYPES OR CELLULAR OUTCOMES DURING TUMOUR GROWTH IS DESIRABLE, SINCE HISTOPATHOLOGICAL CHARACTERIZATION STILL REMAINS THE MAIN OPTION FOR PROGNOSIS ELUCIDATION. IMPROVED KNOWLEDGE OBTAINED IN RECENT DECADES ABOUT PITUITARY TUMORIGENESIS HAS REVEALED THAT THIS PROCESS INVOLVES SEVERAL CELLULAR ROUTES IN ADDITION TO PROLIFERATION AND DEATH, WITH ITS MODULATION DEPENDING ON MANY SIGNALLING PATHWAYS RATHER THAN BEING THE RESULT OF ABNORMALITIES OF A UNIQUE PROLIFERATION PATHWAY, AS SOMETIMES PRESENTED. PITNETS CAN DISPLAY INTRINSIC HETEROGENEITY AND CELL SUBPOPULATIONS WITH DIVERSE BIOLOGICAL, GENETIC AND EPIGENETIC PARTICULARITIES, INCLUDING TUMORIGENIC POTENTIAL. HENCE, TO OBTAIN A BETTER UNDERSTANDING OF PITNET GROWTH NEW APPROACHES ARE REQUIRED AND THE SYSTEMATIZATION OF THE AVAILABLE DATA, WITH THE ROLE OF CELL DEATH PROGRAMS, AUTOPHAGY, STEM CELLS, CELLULAR SENESCENCE, MITOCHONDRIAL FUNCTION, METABOLIC REPROGRAMMING STILL BEING EMERGING FIELDS IN PITUITARY RESEARCH. WE ENVISAGE THAT THROUGH THE COMBINATION OF MOLECULAR, GENETIC AND EPIGENETIC DATA, TOGETHER WITH THE IMPROVED MORPHOLOGICAL, BIOCHEMICAL, PHYSIOLOGICAL AND METABOLICALLY KNOWLEDGE ON PITUITARY NEOPLASTIC POTENTIAL ACCUMULATED IN RECENT DECADES, TUMOUR CLASSIFICATION SCHEMES WILL BECOME MORE ACCURATE REGARDING TUMOUR ORIGIN, BEHAVIOUR AND PLAUSIBLE CLINICAL RESULTS. 2022 9 6466 29 TISSUE STEM CELLS AND CANCER STEM CELLS: POTENTIAL IMPLICATIONS FOR GASTRIC CANCER. GASTRIC CANCER REMAINS THE SECOND LEADING CAUSE OF DEATH IN THE WORLD TODAY, MAKING THE SEARCH FOR ITS MOLECULAR AND CELLULAR BASIS AN IMPORTANT PRIORITY. THOUGH RECOGNITION OF THE TIGHT LINK BETWEEN INFLAMMATION AND TUMORIGENESIS IS CENTURIES OLD, ONLY RECENTLY ARE THE PIECES OF THE ETIOLOGICAL PUZZLE BEGINNING TO FALL TOGETHER. RECENT ADVANCES IN GASTRIC STEM CELL BIOLOGY APPEAR TO BE CENTRAL TO THIS SLOWLY RESOLVING PUZZLE. AT LEAST TWO TYPES OF STEM CELLS MAY BE IMPORTANT. RESIDENT ADULT OR TISSUE STEM CELLS MAY, IN A CHRONICALLY INFLAMED ENVIRONMENT, SLOWLY ACQUIRE A SERIES OF GENETIC AND EPIGENETIC CHANGES THAT LEAD TO THEIR EMERGENCE AS ''CANCER STEM CELLS''. THIS SCENARIO HAS NOT YET BEEN PROVEN EXPERIMENTALLY, ALTHOUGH THE FIRST STEP, PROSPECTIVE RECOGNITION OF A GASTRIC STEM CELL HAS RECENTLY BEEN CONQUERED. ALTERNATIVELY, THE SETTING OF CHRONIC INFLAMMATORY STRESS AND INJURY MAY LEAD TO LOSS OF THE INDIGENOUS GASTRIC STEM CELLS FROM THEIR NICHES; BONE MARROW DERIVED STEM CELLS MAY THEN BE RECRUITED TO AND ENGRAFT INTO THE GASTRIC EPITHELIUM. SUCH RECRUITED CELLS HAVE THE POTENTIAL TO CONTRIBUTE TO THE TUMOR MASS. INDEED, EVIDENCE SUPPORTING THIS SCENARIO HAS BEEN PUBLISHED. HERE, WE REVIEW THESE RECENT FINDINGS AND DISCUSS IMPLICATIONS FOR THE FUTURE. 2008 10 4738 30 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS. 2023 11 3016 23 GENETICS AND EPIGENETICS OF IBD. INFLAMMATORY BOWEL DISEASES (IBD) ARE CHRONIC INTERMITTENT INFLAMMATORY DISORDERS OF THE GASTROINTESTINAL TRACT OF UNKNOWN ETIOLOGY BUT A CLEAR GENETIC PREDISPOSITION. PROMPTED BY THE FIRST INVESTIGATIONS ON IBD FAMILIES AND TWINS, THE GENETIC AND EPIGENETIC STUDIES HAVE PRODUCED AN UNPRECEDENTED AMOUNT OF INFORMATION IN COMPARISON WITH OTHER IMMUNE-MEDIATED OR COMPLEX DISEASES. NEW INFLAMMATORY PATHWAYS AND POSSIBLE MECHANISMS OF ACTION HAVE BEEN DISCLOSED, POTENTIALLY LEADING TO NEW-TARGETED THERAPY. HOWEVER, THE IDENTIFICATION OF GENETIC MARKERS DUE TO THE GREAT DISEASE HETEROGENEITY AND THE OVERWHELMING CONTRIBUTION OF ENVIRONMENTAL RISK FACTORS HAS NOT MODIFIED YET THE DISEASE MANAGEMENT. THE POSSIBILITY FOR THE FUTURE OF A BETTER PREDICTION OF DISEASE COURSE, RESPONSE TO THERAPY AND THERAPY-RELATED ADVERSE EVENTS MAY ALLOW A MORE EFFICIENT AND PERSONALIZED STRATEGY. THIS REVIEW WILL FOCUS ON MORE RECENT DISCOVERIES THAT MAY POTENTIALLY BE OF RELEVANCE IN DAILY CLINICAL PRACTICE. 2020 12 4550 21 MUTATION-PROMOTING MOLECULAR NETWORKS OF UNCONTROLLED INFLAMMATION. MORE AND MORE STUDIES SHOW THAT CHRONIC INFLAMMATION CAN LEAD TO TUMOR FORMATION. THE COMPLEX INTERACTIONS OF INFLAMMATORY CELLS, STROMA AND TUMOR PARENCHYMAL CELL ARE CLOSELY RELATED TO TUMOR FORMATION. UNDER THE STATE OF CHRONIC INFLAMMATORY MICROENVIRONMENT, LONG-TERM INTERACTION OF INFLAMMATORY CELLS AND STROMAL CELLS AS WELL AS THE PARENCHYMAL CELLS MAKES SIGNALING PATHWAY IN PARENCHYMA CELLS DISORDERED. A SERIES OF GENE LEVEL EDITOR MODIFICATION, EPIGENETIC CHANGES, AND THE REGULATION OF TRANSCRIPTION AND TRANSLATION CHANGES WILL HAPPEN BASED ON SIGNALING PATHWAY DISORDER. THE CHANGES ULTIMATELY LEAD TO CELL MUTATIONS AND PHENOTYPIC TRANSFORMATION OCCURRED. RECENT FINDINGS PROVIDE AN OBJECTIVE BASIS FOR CANCER TREATMENT AND PREVENTION. HOWEVER, FURTHER DISCUSSES AT THE CORE OF THE POSSIBLE MOLECULAR IN TUMOR FORMATION PROVIDE A THEORETICAL FOUNDATION FOR FUTURE STUDY OF THE PATHOGENESIS AND MOLECULAR TARGETED THERAPY OF CANCER. THIS REVIEW SUMMARIZES THE RESEARCH IN THE FIELD OF CHRONIC INFLAMMATION AND CANCER IN RECENT YEARS, AND ANALYZE THE MOLECULES NETWORK IN THE PROCESS OF THE CARCINOGENIC INFLAMMATION COMPREHENSIVELY. BEYOND THAT, THIS REVIEW INTENDS TO DESCRIBE POSSIBLE CARCINOGENIC INFLAMMATION CORE MOLECULAR AND PROVIDES A THEORETICAL BASIS FOR FUTURE STUDY OF THE PATHOGENESIS, CHEMOPREVENTION AND MOLECULAR TARGETED THERAPY OF CANCER. 2017 13 3020 26 GENETICS AND EPIGENETICS OF OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGE-RELATED DISEASE THAT AFFECTS THE TISSUES OF THE SYNOVIAL JOINT, LEADING TO LOSS OF FUNCTION AND PAIN. IT IMPACTS ON BOTH PATIENT MORBIDITY AND MORTALITY. IT IS A COMPLEX, POLYGENIC DISEASE THAT LACKS ANY LARGE-EFFECT SUSCEPTIBILITY LOCI. INSTEAD, OA SUSCEPTIBILITY ALLELES INDIVIDUALLY CONTRIBUTE ONLY MODESTLY TO THE OVERALL DISEASE RISK, MAKING THEIR IDENTIFICATION CHALLENGING. DESPITE THIS, BREAKTHROUGHS HAVE OCCURRED WITH COMPELLING ASSOCIATIONS SO FAR REPORTED TO POLYMORPHISMS WITHIN THE GENES GDF5 AND MCF2L AND TO THE GENOMIC REGION 7Q22. THE LATTER TWO HAVE EMERGED FROM GENOME-WIDE ASSOCIATION SCANS, WHICH ARE LIKELY TO YIELD MORE HITS IN THE NEAR FUTURE. AS FOR MANY COMPLEX DISEASES, IT IS NOW APPARENT THAT EPIGENETIC EFFECTS ARE ALSO IMPORTANT MEDIATORS OF DISEASE BIOLOGY, WITH DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS ALL HAVING A ROLE. AT PRESENT, MUCH OF THE EPIGENETIC FOCUS HAS BEEN ON CARTILAGE, THE TISSUE AT THE CENTER OF THE OA DISEASE PROCESS. IF WE ARE TO GET CLOSE TO A QUALITATIVE AND QUANTITATIVE UNDERSTANDING OF THE IMPACT OF EPIGENETICS ON OA, THEN IN FUTURE THE OTHER TISSUES OF THE JOINT WILL ALSO NEED TO BE INVESTIGATED. ONE OF THE MORE EXCITING INSIGHTS TO HAVE EMERGED RECENTLY IS THE FACT THAT EPIGENETIC EFFECTS CAN IMPACT ON OA GENETIC EFFECTS AND THIS MAY BE A PARTICULARLY FRUITFUL AVENUE FOR INTEGRATING BOTH AS WE MOVE TOWARD A CLEARER UNDERSTANDING OF THE PATHOPHYSIOLOGY OF THIS INTRIGUING DISEASE. 2012 14 736 31 CANCER STEM CELLS--NEW APPROACH TO CANCEROGENENSIS AND TREATMENT. RECENTLY, THERE IS AN INCREASING EVIDENCE SUPPORTING THE THEORY OF CANCER STEM CELLS NOT ONLY IN LEUKEMIA BUT ALSO IN SOLID CANCER. 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. THIS REVIEW IS FOCUSING ON THE RECENT DISCOVERY OF STEM CELLS IN LEUKEMIA, HUMAN BRAIN TUMORS AND BREAST CANCER. A SMALL POPULATION OF CELLS IN THE TUMOR (LESS THAN 1%) SHOWS THE POTENTIAL TO GIVE RISE TO THE TUMOR AND ITS GROWTH. THESE CELLS HAVE A SUBSTANTIAL CHARACTERISTIC OF STEM CELLS--ABILITY FOR SELF-RENEWAL WITHOUT LOSS OF PROLIFERATION CAPACITY WITH EACH CELL DIVISION. FURTHERMORE THEY ARE IMMORTAL, RATHER RESISTANT TO TREATMENT AND EXPRESS TYPICAL MARKERS OF STEM CELLS. THE ORIGIN OF THESE RESIDENT CANCER STEM CELLS IS NOT CLEAR. WHETHER THE CANCER STEM CELLS ORIGINATE FROM NORMAL STEM CELLS IN CONSEQUENCE OF GENETIC AND EPIGENETIC CHANGES AND/OR REDIFFERENTIATION FROM SOMATIC TUMOR CELLS TO THE STEM-LIKE CELLS REMAINS TO BE INVESTIGATED. WE PROPOSE THE IDEA OF THE RELATION BETWEEN NORMAL TISSUE STEM CELLS AND CANCER STEM CELLS AND THEIR POPULATIONS--PROGENITOR CELLS. BASED ON THIS WE HIGHLIGHT ONE OF THE MAJOR CHARACTERISTIC OF STEM CELL--PLASTICITY, WHICH IS EQUALLY IMPORTANT IN THE PHYSIOLOGICAL REGENERATION PROCESS AS WELL AS CARCINOGENESIS. FURTHERMORE, WE CONSIDER THE MICROENVIRONMENT AS A LIMITING FACTOR FOR TUMOR GENESIS IN AML, BREAST CANCER AND BRAIN TUMORS. THUS THE BIOLOGICAL PROPERTIES OF CANCER STEM CELLS ARE JUST BEGINNING TO BE REVEALED, THE CONTINUATION OF THESE STUDIES SHOULD LEAD TO THE DEVELOPMENT OF CANCER STEM CELLS TARGET THERAPIES FOR CANCER TREATMENT. 2008 15 389 17 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 16 45 26 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 6131 27 THE EPIGENETIC REGULATION OF WOUND HEALING. SIGNIFICANCE: EPIGENETIC REGULATORY MECHANISMS ARE ESSENTIAL FOR EPIDERMAL HOMEOSTASIS AND CONTRIBUTE TO THE PATHOGENESIS OF MANY SKIN DISEASES, INCLUDING SKIN CANCER AND PSORIASIS. HOWEVER, WHILE THE EPIGENETIC REGULATION OF EPIDERMAL HOMEOSTASIS IS NOW BECOMING ACTIVE AREA OF RESEARCH, THE EPIGENETIC MECHANISMS CONTROLLING THE WOUND HEALING RESPONSE REMAIN RELATIVELY UNTOUCHED. RECENT ADVANCES: SUBSTANTIAL PROGRESS ACHIEVED WITHIN THE LAST TWO DECADES IN UNDERSTANDING EPIGENETIC MECHANISMS CONTROLLING GENE EXPRESSION ALLOWED DEFINING SEVERAL LEVELS, INCLUDING COVALENT DNA AND HISTONE MODIFICATIONS, ATP-DEPENDENT AND HIGHER-ORDER CHROMATIN CHROMATIN REMODELING, AS WELL AS NONCODING RNA- AND MICRORNA-DEPENDENT REGULATION. RESEARCH PERTAINED OVER THE LAST FEW YEARS SUGGESTS THAT EPIGENETIC REGULATORY MECHANISMS PLAY A PIVOTAL ROLE IN THE REGULATION OF SKIN REGENERATION AND CONTROL AN EXECUTION OF REPARATIVE GENE EXPRESSION PROGRAMS IN BOTH SKIN EPITHELIUM AND MESENCHYME. CRITICAL ISSUES: EPIGENETIC REGULATORS APPEAR TO BE INHERENTLY INVOLVED IN THE PROCESSES OF SKIN REPAIR, AND ARE ABLE TO DYNAMICALLY REGULATE KERATINOCYTE PROLIFERATION, DIFFERENTIATION, AND MIGRATION, TOGETHER WITH INFLUENCING DERMAL REGENERATION AND NEOANGIOGENESIS. THIS IS ACHIEVED THROUGH A SERIES OF COMPLEX REGULATORY MECHANISMS THAT ARE ABLE TO BOTH STIMULATE AND REPRESS GENE ACTIVATION TO TRANSIENTLY ALTER CELLULAR PHENOTYPE AND BEHAVIOR, AND INTERACT WITH GROWTH FACTOR ACTIVITY. FUTURE DIRECTIONS: UNDERSTANDING THE MOLECULAR BASIS OF EPIGENETIC REGULATION IS A PRIORITY AS IT REPRESENTS POTENTIAL THERAPEUTIC TARGETS FOR THE TREATMENT OF BOTH ACUTE AND CHRONIC SKIN CONDITIONS. FUTURE RESEARCH IS, THEREFORE, IMPERATIVE TO HELP DISTINGUISH EPIGENETIC MODULATING DRUGS THAT CAN BE USED TO IMPROVE WOUND HEALING. 2014 18 6359 27 THE ROLE OF INFLAMMATION IN THE PATHOGENESIS OF LUNG CANCER. INTRODUCTION: IT IS REPORTED THAT CANCER MAY ARISE IN CHRONICALLY INFLAMED TISSUE. THERE IS MOUNTING EVIDENCE SUGGESTING THAT THE CONNECTION BETWEEN INFLAMMATION AND LUNG CANCER IS NOT COINCIDENTAL BUT MAY INDEED BE CAUSAL. THE INFLAMMATORY MOLECULES MAY BE RESPONSIBLE FOR AUGMENTED MACROPHAGE RECRUITMENT, DELAYED NEUTROPHIL CLEARANCE AND AN INCREASE IN REACTIVE OXYGEN SPECIES. THE CYTOKINES AND GROWTH FACTORS UNUSUALLY PRODUCED IN CHRONIC PULMONARY DISORDERS HAVE BEEN FOUND TO HAVE HARMFUL PROPERTIES THAT PAVE THE WAY FOR EPITHELIAL-TO-MESENCHYMAL TRANSITION AND TUMOR MICROENVIRONMENT. HOWEVER, THE ROLE OF INFLAMMATION IN LUNG CANCER IS NOT YET FULLY UNDERSTOOD. AREAS COVERED: THE ROLE OF CHRONIC INFLAMMATION IN THE PATHOGENESIS OF LUNG CANCER AND SOME OF THE POSSIBLE MECHANISMS INVOLVED, WITH PARTICULAR FOCUS ON INFLAMMATORY MEDIATORS, GENETIC AND EPIGENETIC ALTERATIONS, INFLAMMATORY MARKERS, TUMOR MICROENVIRONMENT AND ANTI-INFLAMMATORY DRUGS ARE DISCUSSED. A FRAMEWORK FOR UNDERSTANDING THE CONNECTION BETWEEN INFLAMMATION AND LUNG CANCER IS PROVIDED, WHICH MAY AFFORD THE OPPORTUNITY TO INTERCEDE IN SPECIFIC INFLAMMATORY DAMAGE MEDIATING LUNG CARCINOGENESIS AND THERAPEUTIC RESISTANCE. EXPERT OPINION: ADVANCES IN TUMOR IMMUNOLOGY SUPPORT THE CLINICAL IMPLEMENTATION OF IMMUNOTHERAPIES FOR LUNG CANCER. ALONG WITH THERAPEUTIC BENEFITS, IMMUNOTHERAPY PRESENTS THE CHALLENGES OF DRUG-RELATED TOXICITIES. GENE MODIFICATION OF IMMUNOCYTOKINE MAY LOWER THE ASSOCIATED TOXIC EFFECTS. 2011 19 3682 16 INFLAMMATION, FIBROSIS AND CANCER: MECHANISMS, THERAPEUTIC OPTIONS AND CHALLENGES. UNCONTROLLED INFLAMMATION IS A SALIENT FACTOR IN MULTIPLE CHRONIC INFLAMMATORY DISEASES AND CANCERS. IN THIS REVIEW, WE PROVIDED AN IN-DEPTH ANALYSIS OF THE RELATIONSHIPS AND DISTINCTIONS BETWEEN UNCONTROLLED INFLAMMATION, FIBROSIS AND CANCERS, WHILE EMPHASIZING THE CHALLENGES AND OPPORTUNITIES OF DEVELOPING NOVEL THERAPIES FOR THE TREATMENT AND/OR MANAGEMENT OF THESE DISEASES. WE DESCRIBED HOW DRUG DELIVERY SYSTEMS, COMBINATION THERAPY AND THE INTEGRATION OF TISSUE-TARGETED AND/OR PATHWAYS SELECTIVE STRATEGIES COULD OVERCOME THE CHALLENGES OF CURRENT AGENTS FOR MANAGING AND/OR TREATING CHRONIC INFLAMMATORY DISEASES AND CANCERS. WE ALSO RECOGNIZED THE VALUE OF THE RE-EVALUATION OF THE DISEASE-SPECIFIC ROLES OF MULTIPLE PATHWAYS IMPLICATED IN THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATORY DISEASES AND CANCERS-AS WELL AS THE APPLICATION OF DATA FROM SINGLE-CELL RNA SEQUENCING IN THE SUCCESS OF FUTURE DRUG DISCOVERY ENDEAVORS. 2022 20 82 26 A NON-GENETIC BASIS FOR CANCER PROGRESSION AND METASTASIS: SELF-ORGANIZING ATTRACTORS IN CELL REGULATORY NETWORKS. IT IS COMMONLY ASSUMED THAT SOMATIC EVOLUTION DRIVES THE MULTI-STEP PROCESS THAT PRODUCES METASTATIC CANCER. BUT IT IS DIFFICULT TO RECONCILE THE INEXORABLE PROGRESSION TOWARDS METASTASIS IN VIRTUALLY ALL CARCINOMAS AND THE ASSOCIATED COMPLEX CHANGE OF CANCER CELL PHENOTYPE, CHARACTERIZED BY AN EPITHELIAL-TO-MESENCHYMAL TRANSITION, WITH THE RANDOM NATURE OF GENE MUTATIONS. GIVEN THEIR IRREVERSIBLE NATURE, IT IS ALSO DIFFICULT TO EXPLAIN WHY CERTAIN METASTATIC CARCINOMAS CAN REFORM NORMAL TISSUE BOUNDARIES AND REMAIN DORMANT FOR YEARS AT DISTANT SITES. HERE WE PROPOSE AN ENCOMPASSING CONCEPTUAL FRAMEWORK BASED ON SYSTEM-LEVEL DYNAMICS OF GENE REGULATORY NETWORKS THAT MAY HELP RECONCILE THESE INCONSISTENCIES. THE CONCEPTS OF GENE EXPRESSION STATE SPACE AND ATTRACTORS ARE INTRODUCED WHICH PROVIDE A MATHEMATICAL AND MOLECULAR BASIS FOR AN "EPIGENETIC LANDSCAPE". WE THEN DESCRIBE HOW CANCER CELLS ARE TRAPPED IN "EMBRYONIC ATTRACTORS" BECAUSE OF DISTORTIONS OF THIS LANDSCAPE CAUSED BY MUTATIONAL REWIRING OF THE REGULATORY NETWORK. THE IMPLICATIONS OF THIS CONCEPT FOR A NEW INTEGRATIVE UNDERSTANDING OF TUMOR FORMATION AND METASTATIC PROGRESSION ARE DISCUSSED. THIS FORMAL FRAMEWORK OF CANCER PROGRESSION UNITES MAINSTREAM GENETIC DETERMINISM WITH ALTERNATIVE IDEAS THAT EMPHASIZE NON-GENETIC INFLUENCES, INCLUDING CHRONIC GROWTH STIMULATION,EXTRACELLULAR MATRIX REMODELING, ALTERATION OF CELL MECHANICS AND DISRUPTION OF TISSUE ARCHITECTURE. 2006