1 1874 121 EMERGING ROLE OF NF-KAPPAB SIGNALING IN THE INDUCTION OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). THE MAJOR HALLMARK OF CELLULAR SENESCENCE IS AN IRREVERSIBLE CELL CYCLE ARREST AND THUS IT IS A POTENT TUMOR SUPPRESSOR MECHANISM. GENOTOXIC INSULTS, E.G. OXIDATIVE STRESS, ARE IMPORTANT INDUCERS OF THE SENESCENT PHENOTYPE WHICH IS CHARACTERIZED BY AN ACCUMULATION OF SENESCENCE-ASSOCIATED HETEROCHROMATIC FOCI (SAHF) AND DNA SEGMENTS WITH CHROMATIN ALTERATIONS REINFORCING SENESCENCE (DNA-SCARS). INTERESTINGLY, SENESCENT CELLS SECRETE PRO-INFLAMMATORY FACTORS AND THUS THE CONDITION HAS BEEN CALLED THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). EMERGING DATA HAS REVEALED THAT NF-KAPPAB SIGNALING IS THE MAJOR SIGNALING PATHWAY WHICH STIMULATES THE APPEARANCE OF SASP. IT IS KNOWN THAT DNA DAMAGE PROVOKES NF-KAPPAB SIGNALING VIA A VARIETY OF SIGNALING COMPLEXES CONTAINING NEMO PROTEIN, AN NF-KAPPAB ESSENTIAL MODIFIER, AS WELL AS VIA THE ACTIVATION OF SIGNALING PATHWAYS OF P38MAPK AND RIG-1, RETINOIC ACID INDUCIBLE GENE-1. GENOMIC INSTABILITY EVOKED BY CELLULAR STRESS TRIGGERS EPIGENETIC CHANGES, E.G. RELEASE OF HMGB1 PROTEINS WHICH ARE ALSO POTENT ENHANCERS OF INFLAMMATORY RESPONSES. MOREOVER, ENVIRONMENTAL STRESS AND CHRONIC INFLAMMATION CAN STIMULATE P38MAPK AND CERAMIDE SIGNALING AND INDUCE CELLULAR SENESCENCE WITH PRO-INFLAMMATORY RESPONSES. ON THE OTHER HAND, TWO CYCLIN-DEPENDENT KINASE INHIBITORS, P16INK4A AND P14ARF, ARE EFFECTIVE INHIBITORS OF NF-KAPPAB SIGNALING. WE WILL REVIEW IN DETAIL THE SIGNALING PATHWAYS WHICH ACTIVATE NF-KAPPAB SIGNALING AND TRIGGER SASP IN SENESCENT CELLS. 2012 2 5140 37 POTENTIAL REGULATORS OF THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE DURING SENESCENCE AND AGING. SENESCENT CELLS EXPRESS AND SECRETE A VARIETY OF EXTRACELLULAR MODULATORS THAT INCLUDE CYTOKINES, CHEMOKINES, PROTEASES, GROWTH FACTORS, AND SOME ENZYMES ASSOCIATED WITH EXTRACELLULAR MATRIX REMODELING, DEFINED AS THE SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). SASP REINFORCES SENESCENT CELL CYCLE ARREST, STIMULATES AND RECRUITS IMMUNE CELLS FOR IMMUNE-MEDIATED CLEARANCE OF POTENTIALLY TUMORIGENIC CELLS, LIMITS OR INDUCES FIBROSIS, AND PROMOTES WOUND HEALING AND TISSUE REGENERATION. ON THE OTHER HAND, SASP MEDIATES CHRONIC INFLAMMATION LEADING TO THE DESTRUCTION OF TISSUE STRUCTURE AND FUNCTION AND STIMULATING THE GROWTH AND SURVIVAL OF TUMOR CELLS. SASP IS HIGHLY HETEROGENEOUS AND THE ROLE OF SASP DEPENDS ON THE CONTEXT. THE REGULATION OF SASP OCCURS AT MULTIPLE LEVELS INCLUDING CHROMATIN REMODELING, TRANSCRIPTION, MRNA TRANSLATION, INTRACELLULAR TRAFFICKING, AND SECRETION. SEVERAL SASP MODULATORS HAVE ALREADY BEEN IDENTIFIED SETTING THE STAGE FOR FUTURE RESEARCH ON THEIR CLINICAL APPLICATIONS. IN THIS REVIEW, WE SUMMARIZE IN DETAIL THE POTENTIAL SIGNALING PATHWAYS THAT TRIGGER AND REGULATE SASP PRODUCTION DURING AGING AND SENESCENCE. 2022 3 6590 37 TUMOR SUPPRESSOR INACTIVATION IN THE PATHOGENESIS OF ADULT T-CELL LEUKEMIA. TUMOR SUPPRESSOR FUNCTIONS ARE ESSENTIAL TO CONTROL CELLULAR PROLIFERATION, TO ACTIVATE THE APOPTOSIS OR SENESCENCE PATHWAY TO ELIMINATE UNWANTED CELLS, TO LINK DNA DAMAGE SIGNALS TO CELL CYCLE ARREST CHECKPOINTS, TO ACTIVATE APPROPRIATE DNA REPAIR PATHWAYS, AND TO PREVENT THE LOSS OF ADHESION TO INHIBIT INITIATION OF METASTASES. THEREFORE, TUMOR SUPPRESSOR GENES ARE INDISPENSABLE TO MAINTAINING GENETIC AND GENOMIC INTEGRITY. CONSEQUENTLY, INACTIVATION OF TUMOR SUPPRESSORS BY SOMATIC MUTATIONS OR EPIGENETIC MECHANISMS IS FREQUENTLY ASSOCIATED WITH TUMOR INITIATION AND DEVELOPMENT. IN CONTRAST, REACTIVATION OF TUMOR SUPPRESSOR FUNCTIONS CAN EFFECTIVELY REVERSE THE TRANSFORMED PHENOTYPE AND LEAD TO CELL CYCLE ARREST OR DEATH OF CANCEROUS CELLS AND BE USED AS A THERAPEUTIC STRATEGY. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATLL) IS AN AGGRESSIVE LYMPHOPROLIFERATIVE DISEASE ASSOCIATED WITH INFECTION OF CD4 T CELLS BY THE HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 (HTLV-I). HTLV-I-ASSOCIATED T-CELL TRANSFORMATION IS THE RESULT OF A MULTISTEP ONCOGENIC PROCESS IN WHICH THE VIRUS INITIALLY INDUCES CHRONIC T-CELL PROLIFERATION AND ALTERS CELLULAR PATHWAYS RESULTING IN THE ACCUMULATION OF GENETIC DEFECTS AND THE DEREGULATED GROWTH OF VIRALLY INFECTED CELLS. THIS REVIEW WILL FOCUS ON THE CURRENT KNOWLEDGE OF THE GENETIC AND EPIGENETIC MECHANISMS REGULATING THE INACTIVATION OF TUMOR SUPPRESSORS IN THE PATHOGENESIS OF HTLV-I. 2015 4 3688 40 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 5 2800 35 FEEDBACK REGULATORS OF HYPOXIA-INDUCIBLE FACTORS AND THEIR ROLE IN CANCER BIOLOGY. MALIGNANT TUMORS ARE CHARACTERIZED BY REGIONS OF LOW OXYGEN CONCENTRATION (HYPOXIA). THE HYPOXIC TUMOR MICROENVIRONMENT CONTRIBUTES TO TUMOR PROGRESSION BY ACTIVATING A SET OF ADAPTIVE RESPONSES VIA THE KEY TRANSCRIPTIONAL REGULATORS HIF-1ALPHA AND HIF-2ALPHA. THESE FACTORS HAVE BEEN TRADITIONALLY LINKED TO AN AGGRESSIVE TUMOR PHENOTYPE BY PROMOTING PROCESSES ESSENTIAL FOR TUMOR GROWTH, SUCH AS ANGIOGENESIS, GLYCOLYSIS, METASTASIS AND INVASION, AS WELL AS DIFFERENTIATION AND SELF RENEWAL. NOTABLY, THE COMPLEX HIF PATHWAY ALSO INITIATES ANTI-TUMORIGENIC MECHANISMS THAT LEAD TO CELL CYCLE ARREST OR CELL DEATH, INDICATING THE NEED FOR A STRINGENT CONTROL OF THE EXTENT AND THE DIRECTION OF THE HYPOXIA RESPONSE. THE IMPORTANCE OF THIS CONTROL FOR TUMOR CELL SURVIVAL IS ILLUSTRATED BY THE INTRICATE REGULATION OF HIF ACTIVITY AT THE MRNA, PROTEIN AND EPIGENETIC LEVEL BY A COMPLEX NETWORK OF POSITIVE AND NEGATIVE FEEDBACK REGULATORS. WE PROPOSE THAT THESE FEEDBACK REGULATORS HELP TO FLEXIBLY ADJUST AND ADAPT HIF ACTIVATED RESPONSES TO THE FLUCTUATING OXYGEN CONCENTRATIONS WITHIN TUMORS DURING ACUTE AND CHRONIC HYPOXIA AND TO CURTAIL THE TUMOR-SUPPRESSING COMPONENTS OF THE HIF PATHWAY. MOREOVER, FEEDBACK REGULATION OF HIF INDUCES A SWITCH FROM HIF-1ALPHA TO HIF-2ALPHA DRIVEN RESPONSES UNDER CHRONIC HYPOXIA WHICH MAY HAVE ESSENTIAL FUNCTIONS IN THE REGULATION OF TUMOR CELL DIFFERENTIATION AND TUMOR STEM CELL MAINTENANCE. GIVEN THEIR CENTRAL ROLE IN CANCER BIOLOGY, HIF FEEDBACK REGULATORS MAY REPRESENT AN ATTRACTIVE AND NOVEL ANTI-TUMOR THERAPY TARGET TO OVERCOME CELL DEATH RESISTANCE IN TUMORS. 2010 6 6910 20 [TRANSFORMING GROWTH FACTOR-BETA AND RENAL FIBROSIS]. TRANSFORMING GROWTH FACTOR-BETA (TGF-BETA) IS A DRIVING FORCE OF RENAL FIBROSIS, WHICH MAY LEAD TO CHRONIC KIDNEY DISEASES AND EVEN END STAGE RENAL DISEASES. BY ACTIVATING CANONICAL AND NON-CANONICAL SIGNALING PATHWAYS, TGF-BETA PROMOTES THE SYNTHESIS OF EXTRACELLULAR MATRIX WHILE PREVENTING THEIR DEGRADATION. IN THE INJURED KIDNEY, TGF-BETA INDUCES APOPTOSIS, PROLIFERATION AND FIBROTIC RESPONSE OF RENAL CELLS INCLUDING EPITHELIAL CELLS, ENDOTHELIAL CELLS, PODOCYTES, FIBROBLASTS, PERICYTES AND MACROPHAGES, AND IT ALSO PROMOTES TRANSDIFFERENTIATION, ACTIVATION AND PROLIFERATION OF MYOFIBROBLASTS. ADDITIONALLY, TGF-BETA EXERTS PROFIBROTIC EFFECTS BY INTERPLAYING WITH OTHER SIGNALING PATHWAYS LIKE BMP-7, WNT/BETA-CATENIN AND MAP KINASE. SMAD3 IS THE CENTRAL PATHOLOGICAL GENE IN RENAL FIBROSIS, AND EPIGENETIC REGULATION OF TGF-BETA/SMAD3 IS A HOT TOPIC IN KIDNEY FIELD. ALTHOUGH DIRECT TARGETING TGF-BETA MAY CAUSE SIDE EFFECTS INCLUDING TUMORIGENESIS AND IMMUNE DISEASES, THE THERAPEUTIC STRATEGIES TARGETING THE BALANCE OF DOWNSTREAM SMAD3 AND SMAD7 MAY PREVENT OR DELAY THE PROGRESSION OF FIBROTIC KIDNEY DISEASE. 2018 7 5632 38 SENESCENT CELLS: SASPECTED DRIVERS OF AGE-RELATED PATHOLOGIES. THE PROGRESSION OF PHYSIOLOGICAL AGEING IS DRIVEN BY INTRACELLULAR ABERRATIONS INCLUDING TELOMERE ATTRITION, GENOMIC INSTABILITY, EPIGENETIC ALTERATIONS AND LOSS OF PROTEOSTASIS. THESE IN TURN DAMAGE CELLS AND COMPROMISE THEIR FUNCTIONALITY. CELLULAR SENESCENCE, A STABLE IRREVERSIBLE CELL-CYCLE ARREST, IS ELICITED IN DAMAGED CELLS AND PREVENTS THEIR PROPAGATION IN THE ORGANISM. UNDER NORMAL CONDITIONS, SENESCENT CELLS RECRUIT THE IMMUNE SYSTEM WHICH FACILITATES THEIR REMOVAL FROM TISSUES. NEVERTHELESS, DURING AGEING, TISSUE-RESIDING SENESCENT CELLS TEND TO ACCUMULATE, AND MIGHT NEGATIVELY IMPACT THEIR MICROENVIRONMENT VIA PROFOUND SECRETORY PHENOTYPE WITH PRO-INFLAMMATORY CHARACTERISTICS, TERMED SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP). INDEED, SENESCENT CELLS ARE MOSTLY ABUNDANT AT SITES OF AGE-RELATED PATHOLOGIES, INCLUDING DEGENERATIVE DISORDERS AND MALIGNANCIES. INTERESTINGLY, STUDIES ON PROGEROID MICE INDICATE THAT SELECTIVE ELIMINATION OF SENESCENT CELLS CAN DELAY AGE-RELATED DETERIORATION. THIS SUGGESTS THAT CHRONIC INFLAMMATION INDUCED BY SENESCENT CELLS MIGHT BE A MAIN DRIVER OF THESE PATHOLOGIES. IMPORTANTLY, SENESCENT CELLS ACCUMULATE AS A RESULT OF DEFICIENT IMMUNE SURVEILLANCE, AND THEIR REMOVAL IS INCREASED UPON THE USE OF IMMUNE STIMULATORY AGENTS. INSIGHTS INTO MECHANISMS OF SENESCENCE SURVEILLANCE COULD BE COMBINED WITH CURRENT APPROACHES FOR CANCER IMMUNOTHERAPY TO PROPOSE NEW PREVENTIVE AND THERAPEUTIC STRATEGIES FOR AGE-RELATED DISEASES. 2014 8 798 43 CELLULAR SENESCENCE, SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE, AND CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS INCREASINGLY BEING ACCEPTED AS A TYPE OF RENAL AGEING. THE KIDNEY UNDERGOES AGE-RELATED ALTERATIONS IN BOTH STRUCTURE AND FUNCTION. TO DATE, A COMPREHENSIVE ANALYSIS OF CELLULAR SENESCENCE AND SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP) IN CKD IS LACKING. HENCE, THIS REVIEW MAINLY DISCUSSES THE RELATIONSHIP BETWEEN THE TWO PHENOMENA TO SHOW THE STRIKING SIMILARITIES BETWEEN SASP AND CKD-ASSOCIATED SECRETORY PHENOTYPE (CASP). IT HAS BEEN REPORTED THAT REPLICATIVE SENESCENCE, STRESS-INDUCED PREMATURE AGEING, AND EPIGENETIC ABNORMALITIES PARTICIPATE IN THE OCCURRENCE AND DEVELOPMENT OF CKD. GENOMIC DAMAGE AND EXTERNAL ENVIRONMENTAL STIMULI CAUSE INCREASED LEVELS OF OXIDATIVE STRESS AND A CHRONIC INFLAMMATORY STATE AS A RESULT OF IRREVERSIBLE CELL CYCLE ARREST AND LOW DOSES OF SASP. SIMILAR TO SASP, CASP FACTORS ACTIVATE TISSUE REPAIR BY MULTIPLE MECHANISMS. ONCE TISSUE REPAIR FAILS, THE ACCUMULATED SASP OR CASP SPECIES AGGRAVATE DNA DAMAGE RESPONSE (DDR) AND CAUSE THE SENESCENT CELLS TO SECRETE MORE SASP FACTORS, ACCELERATING THE PROCESS OF CELLULAR AGEING AND EVENTUALLY LEADING TO VARIOUS AGEING-RELATED CHANGES. IT IS CONCLUDED THAT CELLULAR SENESCENCE AND SASP PARTICIPATE IN THE PATHOLOGICAL PROCESS OF CKD, AND CORRESPONDINGLY CKD ACCELERATED THE PROGRESSION OF CELL SENESCENCE AND THE SECRETION OF SASP. THESE RESULTS WILL FACILITATE THE INTEGRATION OF THESE MECHANISMS INTO THE CARE AND MANAGEMENT OF CKD AND OTHER AGE-RELATED DISEASES. 2017 9 1944 24 EPIGALLOCATECHIN-3-GALLATE AND BIX-01294 HAVE DIFFERENT IMPACT ON EPIGENETICS AND SENESCENCE MODULATION IN ACUTE AND CHRONIC MYELOID LEUKEMIA CELLS. MYELOID LEUKEMIA TREATMENT IS QUITE SUCCESSFUL NOWADAYS; NEVERTHELESS THE DEVELOPMENT OF NEW THERAPIES IS STILL NECESSARY. IN THE PRESENT STUDY, WE INVESTIGATED THE POTENTIAL OF EPIGENETIC MODULATORS EGCG (EPIGALLOCATECHIN-3-GALLATE) AND BIX-01294 (N-(1-BENZYLPIPERIDIN-4-YL)-6,7-DIMETHOXY-2-(4-METHYL-1,4-DIAZEPAN-1-YL)QUINAZOLIN-4-AMINE) TO ALTER EPIGENETIC STATE AND CAUSE CELLULAR SENESCENCE IN ACUTE AND CHRONIC MYELOID LEUKEMIA NB4 AND K562 CELLS. WE HAVE SHOWN THAT AFTER LEUKEMIA CELL TREATMENT WITH EGCG AND BIX-01294 THE PROLIFERATION AND SURVIVAL WERE INHIBITED OF BOTH CELL LINES; HOWEVER, ONLY NB4 CELLS UNDERWENT APOPTOSIS. BOTH EPIGENETIC MODULATORS CAUSED CELL CYCLE ARREST IN G0/G1 PHASE AS ASSESSED BY RT-QPCR (P53, P21, RB) AND FLOW CYTOMETRY ANALYSIS. INCREASED LEVELS OF ATM, HMGA2, PHOSPHORYLATED ATM, AND SA-BETA-GALACTOSIDASE STAINING INDICATED THAT EGCG CAUSED CELLULAR SENESCENCE, WHEREAS BIX-01294 DID NOT. IMMUNOBLOT ANALYSIS OF EPIGENETIC PLAYERS DNMT1, HP1ALPHA, H3K9ME3, EZH2, AND SUZ12 DEMONSTRATED BENEFICIAL EPIGENETIC MODULATION BY BOTH AGENTS WITH EXCEPTION OF MAINLY NO EPIGENETIC CHANGES CAUSED IN K562 CELLS BY EGCG. THEREFORE, WE SUGGEST EGCG AS A PROMISING EPIGENETIC MODULATOR FOR ACUTE PROMYELOCYTIC LEUKEMIA THERAPY AND AS A POTENTIAL CELLULAR SENESCENCE INDUCER IN BOTH ACUTE AND CHRONIC MYELOID LEUKEMIA TREATMENT, WHEREAS BIX-01294 COULD BE BENEFICIAL AS AN EPIGENETIC MODIFIER FOR BOTH MYELOID LEUKEMIAS TREATMENT. 2018 10 3550 46 IMMUNOSENESCENCE IN ATHEROSCLEROSIS: A ROLE FOR CHRONIC VIRAL INFECTIONS. IMMUNE SYSTEM IS A VERSATILE AND DYNAMIC BODY ORGAN WHICH OFFERS SURVIVAL AND ENDURANCE OF HUMAN BEINGS IN THEIR HOSTILE LIVING ENVIRONMENT. HOWEVER, SIMILAR TO OTHER CELLS, IMMUNE CELLS ARE HIJACKED BY SENESCENCE. THE AGEING IMMUNE CELLS LOSE THEIR BENEFICIAL FUNCTIONS BUT CONTINUE TO PRODUCE INFLAMMATORY MEDIATORS WHICH DRAW OTHER IMMUNE AND NON-IMMUNE CELLS TO THE SENESCENCE LOOP. IMMUNOSENESCENCE HAS BEEN SHOWN TO BE ASSOCIATED WITH DIFFERENT PATHOLOGICAL CONDITIONS AND DISEASES, AMONG WHICH ATHEROSCLEROSIS HAS RECENTLY COME TO LIGHT. THERE ARE COMMON DRIVERS OF BOTH IMMUNOSENESCENCE AND ATHEROSCLEROSIS; E.G. INFLAMMATION, REACTIVE OXYGEN SPECIES (ROS), CHRONIC VIRAL INFECTIONS, GENOMIC DAMAGE, OXIDIZED-LDL, HYPERTENSION, CIGARETTE SMOKE, HYPERGLYCAEMIA, AND MITOCHONDRIAL FAILURE. CHRONIC VIRAL INFECTIONS INDUCE INFLAMMAGING, SUSTAINED CYTOKINE SIGNALING, ROS GENERATION AND DNA DAMAGE WHICH ARE ASSOCIATED WITH ATHEROGENESIS. ACCUMULATING EVIDENCE SHOWS THAT SEVERAL DNA AND RNA VIRUSES ARE STIMULATORS OF IMMUNOSENESCENCE AND ATHEROSCLEROSIS IN AN INTERRELATED NETWORK. DNA VIRUSES SUCH AS CMV, EBV AND HBV UPREGULATE P16, P21 AND P53 SENESCENCE-ASSOCIATED MOLECULES; INDUCE INFLAMMAGING, METABOLIC REPROGRAMMING OF INFECTED CELLS, REPLICATIVE SENESCENCE AND TELOMERE SHORTENING. RNA VIRUSES SUCH AS HCV AND HIV INDUCE ROS GENERATION, DNA DAMAGE, INDUCTION OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP), METABOLIC REPROGRAMMING OF INFECTED CELLS, G1 CELL CYCLE ARREST, TELOMERE SHORTENING, AS WELL AS EPIGENETIC MODIFICATIONS OF DNA AND HISTONES. THE NEWLY EMERGED SARS-COV-2 VIRUS IS ALSO A POTENT INDUCER OF CYTOKINE STORM AND SASP. THE SPIKE PROTEIN OF SARS-COV-2 PROMOTES SENESCENCE PHENOTYPE IN ENDOTHELIAL CELLS BY AUGMENTING P16, P21, SENESCENCE-ASSOCIATED BETA-GALACTOSIDASE (SA-BETA-GAL) AND ADHESION MOLECULES EXPRESSION. THE IMPACT OF SARS-COV-2 MEGA-INFLAMMATION ON ATHEROGENESIS, HOWEVER, REMAINS TO BE INVESTIGATED. IN THIS REVIEW WE FOCUS ON THE COMMON PROCESSES IN IMMUNOSENESCENCE AND ATHEROGENESIS CAUSED BY CHRONIC VIRAL INFECTIONS AND DISCUSS THE CURRENT KNOWLEDGE ON THIS TOPIC. 2022 11 306 23 AKT TARGETING AS A STRATEGY TO BOOST CHEMOTHERAPY EFFICACY IN NON-SMALL CELL LUNG CANCER THROUGH METABOLISM SUPPRESSION. METABOLIC REPROGRAMMING IS A HALLMARK OF CANCER DEVELOPMENT, MEDIATED BY GENETIC AND EPIGENETIC ALTERATIONS THAT MAY BE PHARMACOLOGICALLY TARGETED. AMONG ONCOGENES, THE KINASE AKT IS COMMONLY OVEREXPRESSED IN TUMORS AND FAVORS GLYCOLYSIS, PROVIDING A RATIONALE FOR USING AKT INHIBITORS. HERE, WE ADDRESSED THE QUESTION OF WHETHER AND HOW INHIBITING AKT ACTIVITY COULD IMPROVE THERAPY OF NON-SMALL CELL LUNG CANCER (NSCLC) THAT REPRESENTS MORE THAN 80% OF ALL LUNG CANCER CASES. FIRST, WE DEMONSTRATED THAT AKT INHIBITORS INTERACTED SYNERGISTICALLY WITH MICROTUBULE-TARGETING AGENTS (MTAS) AND SPECIFICALLY IN CANCER CELL LINES, INCLUDING THOSE RESISTANT TO CHEMOTHERAPY AGENTS AND ANTI-EGFR TARGETED THERAPIES. IN VIVO, WE FURTHER REVEALED THAT THE CHRONIC ADMINISTRATION OF LOW-DOSES OF PACLITAXEL - I.E. METRONOMIC SCHEDULING - AND THE ANTI-AKT PERIFOSINE WAS THE MOST EFFICIENT AND THE BEST TOLERATED TREATMENT AGAINST NSCLC. REGARDING DRUG MECHANISM OF ACTION, PERIFOSINE POTENTIATED THE PRO-APOPTOTIC EFFECTS OF PACLITAXEL, INDEPENDENTLY OF CELL CYCLE ARREST, AND COMBINING PACLITAXEL/PERIFOSINE RESULTED IN A SUSTAINED SUPPRESSION OF GLYCOLYTIC AND MITOCHONDRIAL METABOLISM. THIS STUDY POINTS OUT THAT TARGETING CANCER CELL BIOENERGETICS MAY REPRESENT A NOVEL THERAPEUTIC AVENUE IN NSCLC, AND PROVIDES A STRONG FOUNDATION FOR FUTURE CLINICAL TRIALS OF METRONOMIC MTAS COMBINED WITH AKT INHIBITORS. 2017 12 3466 23 HYPOXIA AS A KEY PLAYER IN THE AKI-TO-CKD TRANSITION. RECENT CLINICAL AND ANIMAL STUDIES HAVE SHOWN THAT ACUTE KIDNEY INJURY (AKI), EVEN IF FOLLOWED BY COMPLETE RECOVERY OF RENAL FUNCTION, CAN EVENTUALLY RESULT IN CHRONIC KIDNEY DISEASE (CKD). RENAL HYPOXIA IS EMERGING AS A KEY PLAYER IN THE PATHOPHYSIOLOGY OF THE AKI-TO-CKD TRANSITION. CAPILLARY RAREFACTION AFTER AKI EPISODES INDUCES RENAL HYPOXIA, WHICH CAN IN TURN PROFOUNDLY AFFECT TUBULAR EPITHELIAL CELLS, (MYO)FIBROBLASTS, AND INFLAMMATORY CELLS, CULMINATING IN TUBULOINTERSTITIAL FIBROSIS, I.E., PROGRESSION TO CKD. DAMAGED TUBULAR EPITHELIAL CELLS THAT FAIL TO REDIFFERENTIATE MIGHT SUPPLY A DECREASED AMOUNT OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND CONTRIBUTE TO CAPILLARY RAREFACTION, THUS AGGRAVATING HYPOXIA AND FORMING A VICIOUS CYCLE. MOUNTING EVIDENCE ALSO SHOWS THAT EPIGENETIC CHANGES ARE CLOSELY RELATED TO RENAL HYPOXIA IN THE PATHOPHYSIOLOGY OF CKD PROGRESSION. ANIMAL EXPERIMENTS SUGGEST THAT TARGETING HYPOXIA IS A PROMISING STRATEGY TO BLOCK THE TRANSITION FROM AKI TO CKD. HOWEVER, THE PRECISE MECHANISMS BY WHICH HYPOXIA INDUCES THE AKI-TO-CKD TRANSITION AND BY WHICH HYPOXIA-INDUCIBLE FACTOR ACTIVATION CAN EXERT A PROTECTIVE EFFECT IN THIS CONTEXT SHOULD BE CLARIFIED IN FURTHER STUDIES. 2014 13 4381 35 MITOCHONDRIAL DYSFUNCTION AND THE AKI-TO-CKD TRANSITION. ACUTE KIDNEY INJURY (AKI) HAS BEEN WIDELY RECOGNIZED AS AN IMPORTANT RISK FACTOR FOR THE OCCURRENCE AND DEVELOPMENT OF CHRONIC KIDNEY DISEASE (CKD). EVEN MILDER AKI HAS ADVERSE CONSEQUENCES AND COULD PROGRESS TO RENAL FIBROSIS, WHICH IS THE ULTIMATE COMMON PATHWAY FOR VARIOUS TERMINAL KIDNEY DISEASES. THUS, IT IS URGENT TO DEVELOP A STRATEGY TO HINDER THE TRANSITION FROM AKI TO CKD. SOME MECHANISMS OF THE AKI-TO-CKD TRANSITION HAVE BEEN REVEALED, SUCH AS NEPHRON LOSS, CELL CYCLE ARREST, PERSISTENT INFLAMMATION, ENDOTHELIAL INJURY WITH VASCULAR RAREFACTION, AND EPIGENETIC CHANGES. PREVIOUS STUDIES HAVE ELUCIDATED THE PIVOTAL ROLE OF MITOCHONDRIA IN ACUTE INJURIES AND DEMONSTRATED THAT THE FITNESS OF THIS ORGANELLE IS A MAJOR DETERMINANT IN BOTH THE PATHOGENESIS AND RECOVERY OF ORGAN FUNCTION. RECENT RESEARCH HAS SUGGESTED THAT DAMAGE TO MITOCHONDRIAL FUNCTION IN EARLY AKI IS A CRUCIAL FACTOR LEADING TO TUBULAR INJURY AND PERSISTENT RENAL INSUFFICIENCY. DYSREGULATION OF MITOCHONDRIAL HOMEOSTASIS, ALTERATIONS IN BIOENERGETICS, AND ORGANELLE STRESS CROSS TALK CONTRIBUTE TO THE AKI-TO-CKD TRANSITION. IN THIS REVIEW, WE FOCUS ON THE PATHOPHYSIOLOGY OF MITOCHONDRIA IN RENAL RECOVERY AFTER AKI AND PROGRESSION TO CKD, CONFIRMING THAT TARGETING MITOCHONDRIA REPRESENTS A POTENTIALLY EFFECTIVE THERAPEUTIC STRATEGY FOR THE PROGRESSION OF AKI TO CKD. 2020 14 4674 31 NEW INSIGHTS INTO THE ROLE AND MECHANISM OF PARTIAL EPITHELIAL-MESENCHYMAL TRANSITION IN KIDNEY FIBROSIS. EPITHELIAL-MESENCHYMAL TRANSITION (EMT) IS DESCRIBED AS THE PROCESS IN WHICH INJURED RENAL TUBULAR EPITHELIAL CELLS UNDERGO A PHENOTYPE CHANGE, ACQUIRING MESENCHYMAL CHARACTERISTICS AND MORPHING INTO FIBROBLASTS. INITIALLY, IT WAS WIDELY THOUGHT OF AS A CRITICAL MECHANISM OF FIBROGENESIS UNDERLYING CHRONIC KIDNEY DISEASE. HOWEVER, EVIDENCE THAT RENAL TUBULAR EPITHELIAL CELLS CAN CROSS THE BASEMENT MEMBRANE AND BECOME FIBROBLASTS IN THE RENAL INTERSTITIUM IS RARE, LEADING TO DEBATE ABOUT THE EXISTENCE OF EMT. RECENT RESEARCH HAS DEMONSTRATED THAT AFTER INJURY, RENAL TUBULAR EPITHELIAL CELLS ACQUIRE MESENCHYMAL CHARACTERISTICS AND THE ABILITY TO PRODUCE A VARIETY OF PROFIBROTIC FACTORS AND CYTOKINES, BUT REMAIN ATTACHED TO THE BASEMENT MEMBRANE. ON THIS BASIS, A NEW CONCEPT OF "PARTIAL EPITHELIAL-MESENCHYMAL TRANSITION (PEMT)" WAS PROPOSED TO EXPLAIN THE CONTRIBUTION OF RENAL EPITHELIAL CELLS TO RENAL FIBROGENESIS. IN THIS REVIEW, WE DISCUSS THE CONCEPT OF PEMT AND THE MOST RECENT FINDINGS RELATED TO THIS PROCESS, INCLUDING CELL CYCLE ARREST, METABOLIC ALTERNATION OF EPITHELIAL CELLS, INFILTRATION OF IMMUNE CELLS, EPIGENETIC REGULATION AS WELL AS THE NOVEL SIGNALING PATHWAYS THAT MEDIATE THIS DISTURBED EPITHELIAL-MESENCHYMAL COMMUNICATION. A DEEPER UNDERSTANDING OF THE ROLE AND THE MECHANISM OF PEMT MAY HELP IN DEVELOPING NOVEL THERAPIES TO PREVENT AND HALT FIBROSIS IN KIDNEY DISEASE. 2020 15 6444 41 THERAPEUTIC ASPECTS OF C-MYC SIGNALING IN INFLAMMATORY AND CANCEROUS COLONIC DISEASES. COLONIC INFLAMMATION IS REQUIRED TO HEAL INFECTIONS, WOUNDS, AND MAINTAIN TISSUE HOMEOSTASIS. AS THE SEVENTH HALLMARK OF CANCER, HOWEVER, IT MAY AFFECT ALL PHASES OF TUMOR DEVELOPMENT, INCLUDING TUMOR INITIATION, PROMOTION, INVASION AND METASTATIC DISSEMINATION, AND ALSO EVASION IMMUNE SURVEILLANCE. INFLAMMATION ACTS AS A CELLULAR STRESSOR AND MAY TRIGGER DNA DAMAGE OR GENETIC INSTABILITY, AND, FURTHER, CHRONIC INFLAMMATION CAN PROVOKE GENETIC MUTATIONS AND EPIGENETIC MECHANISMS THAT PROMOTE MALIGNANT CELL TRANSFORMATION. BOTH SPORADICAL AND COLITIS-ASSOCIATED COLORECTAL CARCINOGENESIS ARE MULTI-STEP, COMPLEX PROCESSES ARISING FROM THE UNCONTROLLED PROLIFERATION AND SPREADING OF MALIGNANTLY TRANSFORMED CELL CLONES WITH THE OBVIOUS ABILITY TO EVADE THE HOST'S PROTECTIVE IMMUNITY. IN CELLS UPON DNA DAMAGE SEVERAL PROTO-ONCOGENES, INCLUDING C-MYC ARE ACTIVATED IN PARELELL WITH THE INACTIVATION OF TUMOR SUPPRESSOR GENES. THE TARGET GENES OF THE C-MYC PROTEIN PARTICIPATE IN DIFFERENT CELLULAR FUNCTIONS, INCLUDING CELL CYCLE, SURVIVAL, PROTEIN SYNTHESIS, CELL ADHESION, AND MICRO-RNA EXPRESSION. THE TRANSCRIPTIONAL PROGRAM REGULATED BY C-MYC IS CONTEXT DEPENDENT, THEREFORE THE FINAL CELLULAR RESPONSE TO ELEVATED C-MYC LEVELS MAY RANGE FROM INCREASED PROLIFERATION TO AUGMENTED APOPTOSIS. CONSIDERING PHYSIOLOGICAL INTESTINAL HOMEOSTASIS, C-MYC DISPLAYS A FUNDAMENTAL ROLE IN THE REGULATION OF CELL PROLIFERATION AND CRYPT CELL NUMBER. HOWEVER, C-MYC GENE IS FREQUENTLY DEREGULATED IN INFLAMMATION, AND OVEREXPRESSED IN BOTH SPORADIC AND COLITIS-ASSOCIATED COLON ADENOCARCINOMAS. RECENT RESULTS DEMONSTRATED THAT ENDOGENOUS C-MYC IS ESSENTIAL FOR EFFICIENT INDUCTION OF P53-DEPENDENT APOPTOSIS FOLLOWING DNA DAMAGE, BUT C-MYC FUNCTION IS ALSO INVOLVED IN AND REGULATED BY AUTOPHAGY-RELATED MECHANISMS, WHILE ITS EXPRESSION IS AFFECTED BY DNA-METHYLATION, OR HISTONE ACETYLATION. MOLECULES DIRECTLY TARGETING C-MYC, OR AGENTS ACTING ON OTHER GENES INVOLVED IN THE C-MYC PATHWAY COULD BE SELECTED FOR COMBINED REGIMENTS. HOWEVER, DUE TO ITS CONTEXT-DEPENDENT CELLULAR FUNCTION, IT IS CLINICALLY ESSENTIAL TO CONSIDER WHICH CYTOTOXIC DRUGS ARE USED IN COMBINATION WITH C-MYC TARGETED AGENTS IN VARIOUS TISSUES. INCREASING OUR KNOWLEDGE ABOUT MYC-DEPENDENT PATHWAYS MIGHT PROVIDE DIRECTION TO NOVEL ANTI-INFLAMMATORY AND COLORECTAL CANCER THERAPIES. 2016 16 4605 27 NEGATIVE REGULATORS OF TGF-BETA1 SIGNALING IN RENAL FIBROSIS; PATHOLOGICAL MECHANISMS AND NOVEL THERAPEUTIC OPPORTUNITIES. ELEVATED EXPRESSION OF THE MULTIFUNCTIONAL CYTOKINE TRANSFORMING GROWTH FACTOR BETA1 (TGF-BETA1) IS CAUSATIVELY LINKED TO KIDNEY FIBROSIS PROGRESSION INITIATED BY DIABETIC, HYPERTENSIVE, OBSTRUCTIVE, ISCHEMIC AND TOXIN-INDUCED INJURY. THERAPEUTICALLY RELEVANT APPROACHES TO DIRECTLY TARGET THE TGF-BETA1 PATHWAY (E.G., NEUTRALIZING ANTIBODIES AGAINST TGF-BETA1), HOWEVER, REMAIN ELUSIVE IN HUMANS. TGF-BETA1 SIGNALING IS SUBJECTED TO EXTENSIVE NEGATIVE CONTROL AT THE LEVEL OF TGF-BETA1 RECEPTOR, SMAD2/3 ACTIVATION, COMPLEX ASSEMBLY AND PROMOTER ENGAGEMENT DUE TO ITS CRITICAL ROLE IN TISSUE HOMEOSTASIS AND NUMEROUS PATHOLOGIES. PROGRESSIVE KIDNEY INJURY IS ACCOMPANIED BY THE DEREGULATION (LOSS OR GAIN OF EXPRESSION) OF SEVERAL NEGATIVE REGULATORS OF THE TGF-BETA1 SIGNALING CASCADE BY MECHANISMS INVOLVING PROTEIN AND MRNA STABILITY OR EPIGENETIC SILENCING, FURTHER AMPLIFYING TGF-BETA1/SMAD3 SIGNALING AND FIBROSIS. EXPRESSION OF BONE MORPHOGENETIC PROTEINS 6 AND 7 (BMP6/7), SMAD7, SLOAN-KETTERING INSTITUTE PROTO-ONCOGENE (SKI) AND SKI-RELATED NOVEL GENE (SNON), PHOSPHATE TENSIN HOMOLOG ON CHROMOSOME 10 (PTEN), PROTEIN PHOSPHATASE MAGNESIUM/MANGANESE DEPENDENT 1A (PPM1A) AND KLOTHO ARE DRAMATICALLY DECREASED IN VARIOUS NEPHROPATHIES IN ANIMALS AND HUMANS ALBEIT WITH DIFFERENT KINETICS WHILE THE EXPRESSION OF SMURF1/2 E3 LIGASES ARE INCREASED. SUCH DEREGULATIONS FREQUENTLY INITIATE MALADAPTIVE RENAL REPAIR INCLUDING RENAL EPITHELIAL CELL DEDIFFERENTIATION AND GROWTH ARREST, FIBROTIC FACTOR (CONNECTIVE TISSUE GROWTH FACTOR (CTGF/CCN2), PLASMINOGEN ACTIVATOR INHIBITOR TYPE-1 (PAI-1), TGF-BETA1) SYNTHESIS/SECRETION, FIBROPROLIFERATIVE RESPONSES AND INFLAMMATION. THIS REVIEW ADDRESSES HOW LOSS OF THESE NEGATIVE REGULATORS OF TGF-BETA1 PATHWAY EXACERBATES RENAL LESION FORMATION AND DISCUSSES THE THERAPEUTIC VALUE IN RESTORING THE EXPRESSION OF THESE MOLECULES IN AMELIORATING FIBROSIS, THUS, PRESENTING NOVEL APPROACHES TO SUPPRESS TGF-BETA1 HYPERACTIVATION DURING CHRONIC KIDNEY DISEASE (CKD) PROGRESSION. 2021 17 3289 29 HIF-1ALPHA MEDIATES TUMOR HYPOXIA TO CONFER A PERPETUAL MESENCHYMAL PHENOTYPE FOR MALIGNANT PROGRESSION. ALTHOUGH TUMOR PROGRESSION INVOLVES GENETIC AND EPIGENETIC ALTERATIONS TO NORMAL CELLULAR BIOLOGY, THE UNDERLYING MECHANISMS OF THESE CHANGES REMAIN OBSCURE. NUMEROUS STUDIES HAVE SHOWN THAT HYPOXIA-INDUCIBLE FACTOR 1ALPHA (HIF-1ALPHA) IS OVEREXPRESSED IN MANY HUMAN CANCERS AND UP-REGULATES A HOST OF HYPOXIA-RESPONSIVE GENES FOR CANCER GROWTH AND SURVIVAL. WE RECENTLY IDENTIFIED AN ALTERNATIVE MECHANISM OF HIF-1ALPHA FUNCTION THAT INDUCES GENETIC ALTERATIONS BY SUPPRESSING DNA REPAIR. HERE, WE SHOW THAT LONG-TERM HYPOXIA, WHICH MIMICS THE TUMOR MICROENVIRONMENT, DRIVES A PERPETUAL EPITHELIAL-MESENCHYMAL TRANSITION (EMT) THROUGH UP-REGULATION OF THE ZINC FINGER E-BOX BINDING HOMEOBOX PROTEIN ZEB2, WHEREAS SHORT-TERM HYPOXIA INDUCES A REVERSIBLE EMT THAT REQUIRES THE TRANSCRIPTION FACTOR TWIST1. MOREOVER, WE SHOW THAT THE PERPETUAL EMT DRIVEN BY CHRONIC HYPOXIA DEPENDS ON HIF-1ALPHA INDUCTION OF GENETIC ALTERATIONS RATHER THAN ITS CANONICAL TRANSCRIPTIONAL ACTIVATOR FUNCTION. THESE MESENCHYMAL TUMOR CELLS NOT ONLY ACQUIRE TUMORIGENICITY BUT ALSO DISPLAY CHARACTERISTICS OF ADVANCED CANCERS, INCLUDING NECROSIS, AGGRESSIVE INVASION, AND METASTASIS. HENCE, THESE RESULTS REVEAL A MECHANISM BY WHICH HIF-1ALPHA PROMOTES A PERPETUAL MESENCHYMAL PHENOTYPE, THEREBY ADVANCING TUMOR PROGRESSION. 2011 18 450 28 APOPTOSIS AND AGING: INCREASED RESISTANCE TO APOPTOSIS ENHANCES THE AGING PROCESS. APOPTOSIS IS A VITAL COMPONENT IN THE EVOLUTIONARILY CONSERVED HOST DEFENSE SYSTEM. APOPTOSIS IS THE GUARDIAN OF TISSUE INTEGRITY BY REMOVING UNFIT AND INJURED CELLS WITHOUT EVOKING INFLAMMATION. HOWEVER, APOPTOSIS SEEMS TO BE A DOUBLE-EDGED SWORD SINCE DURING LOW-LEVEL CHRONIC STRESS, SUCH AS IN AGING, INCREASED RESISTANCE TO APOPTOSIS CAN LEAD TO THE SURVIVAL OF FUNCTIONALLY DEFICIENT, POST-MITOTIC CELLS WITH DAMAGED HOUSEKEEPING FUNCTIONS. SENESCENT CELLS ARE REMARKABLY RESISTANT TO APOPTOSIS, AND SEVERAL STUDIES INDICATE THAT HOST DEFENSE MECHANISMS CAN ENHANCE ANTI-APOPTOTIC SIGNALING, WHICH SUBSEQUENTLY INDUCES A SENESCENT, PRO-INFLAMMATORY PHENOTYPE DURING THE AGING PROCESS. AT THE MOLECULAR LEVEL, AGE-RELATED RESISTANCE TO APOPTOSIS INVOLVES (1) FUNCTIONAL DEFICIENCY IN P53 NETWORK, (2) INCREASED ACTIVITY IN THE NF-KAPPAB-IAP/JNK AXIS, AND (3) CHANGES IN MOLECULAR CHAPERONES, MICRORNAS, AND EPIGENETIC REGULATION. WE WILL DISCUSS THE MOLECULAR BASIS OF AGE-RELATED RESISTANCE TO APOPTOSIS AND EMPHASIZE THAT INCREASED RESISTANCE COULD ENHANCE THE AGING PROCESS. 2011 19 570 38 BCR-ABL INDEPENDENT MECHANISMS OF RESISTANCE IN CHRONIC MYELOID LEUKEMIA. NOT ALL CHRONIC MYELOID LEUKEMIA (CML) PATIENTS ARE CURED WITH TYROSINE KINASE INHIBITORS (TKIS), AND A PROPORTION OF THEM DEVELOP RESISTANCE. RECENTLY, CONTINUOUS BCR-ABL GENE EXPRESSION HAS BEEN FOUND IN RESISTANT CELLS WITH UNDETECTABLE BCR-ABL PROTEIN EXPRESSION, INDICATING THAT RESISTANCE MAY OCCUR THROUGH KINASE INDEPENDENT MECHANISMS, MAINLY DUE TO THE PERSISTENCE OF LEUKEMIA STEM CELLS (LSCS). LSCS RESIDE IN THE BONE MARROW NICHE IN A QUIESCENT STATE, AND ARE CHARACTERIZED BY A HIGH HETEROGENEITY IN GENETIC, EPIGENETIC, AND TRANSCRIPTIONAL MECHANISMS. NEW APPROACHES BASED ON SINGLE CELL GENOMICS HAVE OFFERED THE OPPORTUNITY TO IDENTIFY DISTINCT SUBPOPULATIONS OF LSCS AT DIAGNOSIS AND DURING TREATMENT. IN THE ONE HAND, TKIS ARE NOT ABLE TO EFFICIENTLY KILL CML-LSCS, BUT THEY MAY BE RESPONSIBLE FOR THE MODIFICATION OF SOME LSCS CHARACTERISTICS, THUS CONTRIBUTING TO HETEROGENEITY WITHIN THE TUMOR. IN THE OTHER HAND, THE BONE MARROW NICHE IS RESPONSIBLE FOR THE INTERACTIONS BETWEEN SURROUNDING STROMAL CELLS AND LSCS, RESULTING IN THE GENERATION OF SPECIFIC SIGNALS WHICH COULD FAVOR LSCS CELL CYCLE ARREST AND ALLOW THEM TO PERSIST DURING TREATMENT WITH TKIS. ADDITIONALLY, LSCS MAY THEMSELVES ALTER THE NICHE BY EXPRESSING VARIOUS COSTIMULATORY MOLECULES AND SECRETING SUPPRESSIVE CYTOKINES, ABLE TO TARGET METABOLIC PATHWAYS, CREATE AN ANTI-APOPTOTIC ENVIRONMENT, AND ALTER IMMUNE SYSTEM FUNCTIONS. ACCORDINGLY, THE PRODUCTION OF AN IMMUNOSUPPRESSANT MILIEU MAY FACILITATE TUMOR ESCAPE FROM IMMUNE SURVEILLANCE AND INDUCE CHEMO-RESISTANCE. IN THIS REVIEW WE WILL FOCUS ON BCR-ABL-INDEPENDENT MECHANISMS, ANALYZING ESPECIALLY THOSE WITH A POTENTIAL CLINICAL IMPACT IN THE MANAGEMENT OF CML PATIENTS. 2019 20 3670 38 INFLAMMAGING AND COMPLEMENT SYSTEM: A LINK BETWEEN ACUTE KIDNEY INJURY AND CHRONIC GRAFT DAMAGE. THE ABERRANT ACTIVATION OF COMPLEMENT SYSTEM IN SEVERAL KIDNEY DISEASES SUGGESTS THAT THIS PILLAR OF INNATE IMMUNITY HAS A CRITICAL ROLE IN THE PATHOPHYSIOLOGY OF RENAL DAMAGE OF DIFFERENT ETIOLOGIES. A GROWING BODY OF EXPERIMENTAL EVIDENCE INDICATES THAT COMPLEMENT ACTIVATION CONTRIBUTES TO THE PATHOGENESIS OF ACUTE KIDNEY INJURY (AKI) SUCH AS DELAYED GRAFT FUNCTION (DGF) IN TRANSPLANT PATIENTS. AKI IS CHARACTERIZED BY THE RAPID LOSS OF THE KIDNEY'S EXCRETORY FUNCTION AND IS A COMPLEX SYNDROME CURRENTLY LACKING A SPECIFIC MEDICAL TREATMENT TO ARREST OR ATTENUATE PROGRESSION IN CHRONIC KIDNEY DISEASE (CKD). RECENT EVIDENCE SUGGESTS THAT INDEPENDENTLY FROM THE INITIAL TRIGGER (I.E., SEPSIS OR ISCHEMIA/REPERFUSIONS INJURY), AN EPISODE OF AKI IS STRONGLY ASSOCIATED WITH AN INCREASED RISK OF SUBSEQUENT CKD. THE AKI-TO-CKD TRANSITION MAY INVOLVE A WIDE RANGE OF MECHANISMS INCLUDING SCAR-FORMING MYOFIBROBLASTS GENERATED FROM DIFFERENT SOURCES, MICROVASCULAR RAREFACTION, MITOCHONDRIAL DYSFUNCTION, OR CELL CYCLE ARREST BY THE INVOLVEMENT OF EPIGENETIC, GENE, AND PROTEIN ALTERATIONS LEADING TO COMMON FINAL SIGNALING PATHWAYS [I.E., TRANSFORMING GROWTH FACTOR BETA (TGF-BETA), P16 (INK4A) , WNT/BETA-CATENIN PATHWAY] INVOLVED IN RENAL AGING. RESEARCH IN RECENT YEARS HAS REVEALED THAT SEVERAL STRESSORS OR COMPLICATIONS SUCH AS REJECTION AFTER RENAL TRANSPLANTATION CAN LEAD TO ACCELERATED RENAL AGING WITH DETRIMENTAL EFFECTS WITH THE ESTABLISHMENT OF CHRONIC PROINFLAMMATORY CELLULAR PHENOTYPES WITHIN THE KIDNEY. DESPITE A GREATER UNDERSTANDING OF THESE MECHANISMS, THE ROLE OF COMPLEMENT SYSTEM IN THE CONTEXT OF THE AKI-TO-CKD TRANSITION AND RENAL INFLAMMAGING IS STILL POORLY EXPLORED. THE PURPOSE OF THIS REVIEW IS TO SUMMARIZE RECENT FINDINGS DESCRIBING THE ROLE OF COMPLEMENT IN AKI-TO-CKD TRANSITION. WE WILL ALSO ADDRESS HOW AND WHEN COMPLEMENT INHIBITORS MIGHT BE USED TO PREVENT AKI AND CKD PROGRESSION, THEREFORE IMPROVING GRAFT FUNCTION. 2020