1  3486 124 IDENTIFICATION OF COMMON MICRORNA BETWEEN COPD AND NON-SMALL CELL LUNG CANCER THROUGH PATHWAY ENRICHMENT ANALYSIS. BACKGROUND: DIFFERENT FACTORS HAVE BEEN INTRODUCED WHICH INFLUENCE THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND NON-SMALL CELL LUNG CANCER (NSCLC). COPD AS AN INDEPENDENT FACTOR IS INVOLVED IN THE DEVELOPMENT OF LUNG CANCER. MOREOVER, THERE ARE CERTAIN RESEMBLANCES BETWEEN NSCLC AND COPD, SUCH AS GROWTH FACTORS, ACTIVATION OF INTRACELLULAR PATHWAYS, AS WELL AS EPIGENETIC FACTORS. ONE OF THE BEST APPROACHES TO UNDERSTAND THE POSSIBLE SHARED PATHOGENESIS ROUTES BETWEEN COPD AND NSCLC IS TO STUDY THE BIOLOGICAL PATHWAYS THAT ARE ACTIVATED. MICRORNAS (MIRNAS) ARE CRITICAL BIOMOLECULES THAT IMPLICATE THE REGULATION OF SEVERAL BIOLOGICAL AND CELLULAR PROCESSES. AS SUCH, THE MAIN GOAL OF THIS STUDY WAS TO USE A SYSTEMS BIOLOGY APPROACH TO DISCOVER COMMON DYSREGULATED MIRNAS BETWEEN COPD AND NSCLC, ONE THAT TARGETS MOST GENES WITHIN COMMON ENRICHED PATHWAYS. RESULTS: TO RECONSTRUCT THE MIRNA-PATHWAYS FOR EACH DISEASE, WE USED THE MICROARRAY MIRNA EXPRESSION DATA. THEN, WE EMPLOYED "MIRNA SET ENRICHMENT ANALYSIS" (MIRSEA) TO IDENTIFY THE MOST SIGNIFICANT JOINT MIRNAS BETWEEN COPD AND NSCLC BASED ON THE ENRICHMENT SCORES. OVERALL, OUR STUDY REVEALED THE INVOLVEMENT OF THE TARGETS OF MIRNAS (SUCH AS HAS-MIR-15B, HSA-MIR-106A, HAS-MIR-17, HAS-MIR-103, AND HAS-MIR-107) IN THE MOST IMPORTANT COMMON BIOLOGICAL PATHWAYS. CONCLUSIONS: ACCORDING TO THE PROMISING RESULTS OF THE PATHWAY ANALYSIS, THE IDENTIFIED MIRNAS CAN BE UTILIZED AS THE NEW POTENTIAL SIGNATURES FOR THERAPY THROUGH UNDERSTANDING THE MOLECULAR MECHANISMS OF BOTH DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2  3831  49 INVOLVEMENT OF INFLAMMATORY CYTOKINES AND EPIGENETIC MODIFICATION OF THE MTTFA COMPLEX IN T-HELPER CELLS OF PATIENTS' SUFFERING FROM NON-SMALL CELL LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. DYSREGULATED INFLAMMATORY RESPONSE PLAYS A CRUCIAL ROLE IN THE PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND NON-SMALL CELL LUNG CANCER (NSCLC). HENCE, THE PURPOSE OF THIS RESEARCH IS TO UNCOVER THE LINK BETWEEN ALTERATIONS IN INFLAMMATORY CYTOKINE LEVELS AND DISEASE PROGRESSION IN CD4(+)T CELLS OF PATIENTS SUFFERING FROM COPD AND LUNG CANCER. WE ALSO INVESTIGATED THE EPIGENETIC REGULATION OF MTTFA TO DELINEATE THE ROLE OF OXIDATIVE STRESS-MEDIATED INFLAMMATION IN LUNG CANCER AND COPD. THE RT(2) PROFILER PCR ARRAY WAS USED TO EXAMINE THE DIFFERENTIAL EXPRESSION PATTERN OF INFLAMMATORY GENES IN CD4(+) T HELPER (TH) CELLS FROM COPD, NSCLC, AND CONTROL SUBJECTS. CANDIDATE INFLAMMATORY GENE LOCI WERE SELECTED AND THE ENRICHMENT OF TRANSCRIPTIONAL FACTOR AND HISTONE MODIFIERS WAS ANALYSED USING CHIP-QPCR. IN COMPARISON TO CONTROL SUBJECTS, A SET OF GENES (E.G., BMP2, CCL2, IL5, VEGFA, ETC.) ARE OVER-EXPRESSED WHEREAS ANOTHER SET OF GENES (E.G., AIMP1, IFNG, LTA, LTB, TNF, ETC.) ARE UNDER-EXPRESSED IN BOTH COPD AND NSCLC PATIENTS. THE INCREASED PERCENT ENRICHMENT OF INFLAMMATION-ASSOCIATED TRANSCRIPTION FACTORS INCLUDING NF-KB, CREB, HIF1, AND MYC AT THE LOCI OF INFLAMMATORY GENES WAS REVEALED BY OUR CHROMATIN IMMUNOPRECIPITATION (CHIP) DATA. H3K4ME3, H3K9ME3, H3K14AC, HDAC1, 2, 3, 6 ALL SHOWED DYSREGULATED ENRICHMENT AT THE VEGFA GENE LOCUS. ONE OF THE EPIGENETIC MODIFICATIONS, HISTONE METHYLATION, WAS FOUND TO BE ABNORMAL IN THE MTTFA COMPLEX IN COPD AND NSCLC PATIENTS IN COMPARISON TO CONTROLS. ALTHOUGH THERE IS MOUNTING EVIDENCE OF SEVERAL LINKS BETWEEN THESE DISORDERS, THERAPEUTIC OPTIONS REMAIN INADEQUATE. OUR FINDINGS CONTRIBUTE TO THE BODY OF KNOWLEDGE ABOUT THERAPEUTIC TECHNIQUES THAT USE INFLAMMATORY CYTOKINES AS A PROGNOSTIC MARKER AND HIGHLIGHT THE NEED FOR EPIGENETIC THERAPY FOR THESE DEBILITATING LUNG DISEASES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
3   740  43 CANCER/TESTIS ANTIGENS: EXPRESSION, REGULATION, TUMOR INVASION, AND USE IN IMMUNOTHERAPY OF CANCERS. CANCER/TESTIS ANTIGENS (CTAS) ARE NAMED BASED ON THEIR EXPRESSION PATTERN THAT IS RESTRICTED IN A NUMBER OF NORMAL AND ABNORMAL TISSUES. TUMOR CELLS FREQUENTLY EXPRESS ANTIGENS WHOSE EXPRESSION IS TYPICALLY RESTRICTED TO GERM CELLS. THEIR UNIQUE EXPRESSION PATTERN IS GUARANTEED BY PRECISE EPIGENETIC REGULATORY MECHANISMS. BECAUSE OF THEIR TUMOR-LIMITED, HIGH IMMUNOGENICITY, AND BIASED EXPRESSION, DISCOVERY OF THESE MOLECULES PROVIDES UNPRECEDENTED OPPORTUNITIES FOR FURTHER RESEARCH AND CLINICAL DEVELOPMENT IN THE FIELD OF CANCER DIAGNOSIS AND IMMUNOTHERAPY. EVOLVING EVIDENCE REVEALS THAT A NUMBER OF CTAS STIMULATE EPITHELIAL MESENCHYMAL TRANSITION (EMT) AND GENERATION OF CANCER STEM-LIKE CELLS, INTENSIFYING METASTASIS, INVASION, AND TUMORIGENESIS. BASED ON THESE FEATURES, CTAS ATTRACT ATTENTION TO BE CONSIDERED AS IDEAL TARGETS FOR DEVELOPING SEVERAL CLINICAL TRIALS, MANY OF THEM CONCENTRATING ON CTA VACCINE THERAPY. ACCORDING TO RECENT PRACTICAL CLINICAL INTEREST, MORE CHARACTERIZATIONS OF CTA REGULATION ARE IDENTIFIED. CTA EXPRESSION HAS BEEN DEMONSTRATED IN A VARIETY OF HUMAN CANCER TISSUES, AND SOME OF THEM HAVE BEEN FOUND TO ELICIT HUMORAL AND/OR CELLULAR IMMUNE RESPONSES IN CANCER PATIENTS. CTAS ARE BRILLIANT TARGETS FOR ANTICANCER DRUG DISCOVERY, TARGETED TUMOR THERAPY, AND DIAGNOSTIC BIOMARKERS, FURTHERMORE, VALUED GENES IN THE STUDY OF IMMUNOTHERAPY, PROMOTING TUMORIGENESIS, AND MALIGNANT PROGRESSION. THIS REVIEW OUTLINES AND CATEGORIZES OUR CURRENT UNDERSTANDING OF THE COMPLEX AND BIASED PROCESS OF CTAS MRNA AND PROTEIN EXPRESSION IN CANCER, AND SUPPLIES THE MOST RECENT INFORMATION ON THEIR REGULATION AND FUNCTION. BESIDES, A CONCISE SYNOPSIS OF THE MAJOR CLINICAL TRIALS INVOLVING CTAS, AS THERAPEUTIC AVENUES, IS DISCUSSED. ABBREVIATIONS: AIRE: AUTOIMMUNE REGULATOR; CAMP: CYCLIC ADENOSINE 3',5'-CYCLIC MONOPHOSPHATE; CEA: CARCINOEMBRYONIC ANTIGEN; CML: CHRONIC MYELOID LEUKEMIA; CREB: CYCLICAMP RESPONSE ELEMENT BINDING; CSCS: CANCER STEM CELLS; CTAS: CANCER/TESTIS ANTIGENS; CTL: CYTOTOXIC T LYMPHOCYTE; DCS: DENDRITIC CELLS; EMT: EPITHELIAL-MESENCHYMAL TRANSITION; ERK: EXTRACELLULAR SIGNAL-REGULATED KINASE; ESCC: ESOPHAGEAL SQUAMOUS CELL CARCINOMA; ETS: E26 TRANSFORMATION-SPECIFIC; HIS: HISTIDINE; HLA: HUMAN LEUKOCYTE ANTIGEN; HNSCC: HEAD AND NECK SQUAMOUS CELL CARCINOMA; IFN-GAMMA: INTERFERON-GAMMA; IHC: IMMUNOHISTOCHEMISTRY; IL-7: INTERLEUKIN7; MHC: MAJOR HISTOCOMPATIBILITY COMPLEX; MMP2: MATRIX METALLOPROTEINASE 2; MTECS: MEDULLARY THYMUS EPITHELIAL CELLS; MUC1: MUCIN 1; NSCLC: NON-SMALL CELL LUNG CANCER; PRAME: PREFERENTIALLY EXPRESSED ANTIGEN IN MELANOMA; RDA: REPRESENTATIONAL DIFFERENCE ANALYSIS; SEREX: SEROLOGICAL ANALYSIS OF CDNA EXPRESSION; SSX: SYNOVIAL SARCOMA X CHROMOSOME; TAAS: TUMOR-ASSOCIATED ANTIGENS; TCR: T-CELL RECEPTOR; TCGA: THE CANCER GENOME ATLAS; TGF-BETA: TRANSFORMING GROWTH FACTOR-BETA.	2016	

4  2659  43 EPITHELIAL-TO-MESENCHYMAL TRANSITION IN THE CONTEXT OF EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITION IN NON-SMALL-CELL LUNG CANCER. THE IDENTIFICATION OF ONCOGENIC DRIVER MUTATIONS IN NON-SMALL-CELL LUNG CANCER (NSCLC) HAS LED TO THE DEVELOPMENT OF TARGETED DRUGS. TYROSINE KINASE INHIBITORS (TKIS) DIRECTED AGAINST THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) TARGET LUNG TUMOURS BEARING EGFR-ACTIVATING MUTATIONS. THIS NEW THERAPEUTIC STRATEGY HAS GREATLY IMPROVED TUMOUR RESPONSE RATES. HOWEVER, DRUG RESISTANCE INVARIABLY OCCURS DURING TKI-BASED TREATMENT. EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) IS ONE OF THE RESISTANCE MECHANISMS IDENTIFIED IN EGFR-MUTATED NSCLC TREATED WITH TKIS. IN THIS REVIEW WE GATHER TOGETHER THE MOST IMPORTANT FINDINGS ON THIS PHENOMENON IN RELATION TO CANCER STEM CELLS AND CANCER EPIGENETICS. WE ALSO OUTLINE THE CORRELATION BETWEEN THE EFFECTS OF STROMAL FACTORS FROM THE MICROENVIRONMENT, THE TRANSCRIPTION FACTORS ACTIVATED, THE EPIGENETIC CHANGES IN CHROMATIN, AND THE EVOLUTION OF CELLULAR BEHAVIOUR. NOTABLY, EMT HAS ALREADY BEEN SHOWN TO BE THE LINK BETWEEN BENIGN LUNG DISEASES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG CARCINOGENESIS. THE VARIOUS MECHANISMS OF ACQUIRED RESISTANCE TO EGFR-TKIS ARE ALSO BRIEFLY DESCRIBED TO PROVIDE BACKGROUND INFORMATION ON EMT. OUR EXTENSIVE REVIEW OF THE SCIENTIFIC LITERATURE SERVES TO HIGHLIGHT THE CELLULAR AND MOLECULAR EVENTS THAT LEAD TO THE ONSET OF EMT IN NSCLC CELLS TREATED WITH EGFR-TKIS. FINALLY, WE PUT FORWARD A HYPOTHESIS TO EXPLAIN WHY, IN SOME CASES, EMT RATHER THAN OTHER KNOWN MECHANISMS IS INVOLVED IN RESISTANCE TO TKIS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  3447  29 HYPERMETHYLATION OF MITOCHONDRIAL TRANSCRIPTION FACTOR A INDUCED BY CIGARETTE SMOKE IS ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. PURPOSE OF THE STUDY: CIGARETTE SMOKING IS A LEADING ENVIRONMENTAL CONTRIBUTOR TO CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), BUT ITS EPIGENETIC REGULATION OF MTTFA GENE REMAINS ELUSIVE. THIS STUDY AIMS TO EXPLORE THE RELATIONSHIP OF DNA METHYLATION OF MTTFA AND CIGARETTE SMOKING IN COPD. MATERIALS AND METHODS: WE ANALYZED DNA METHYLATION ON MTTFA PROMOTERS IN CLINICAL SAMPLES FROM COPD PATIENTS AND SUBJECTS WITH NORMAL PULMONARY FUNCTION. EXPRESSION OF MTTFA MRNA IN THE CLINICAL SAMPLES AND MTTFA MRNA AND PROTEIN IN HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS(HUVECS) TREATED WITH CIGARETTE SMOKE EXTRACT (CSE) WAS EVALUATED. MTTFA MRNA AND PROTEIN LEVELS WERE MEASURED TO DETERMINE EFFECTS OF DEMETHYLATION AGENTS ON CSE-TREATED HUVECS. RESULTS: THE DNA METHYLATION LEVEL OF THE MTTFA PROMOTER WAS SIGNIFICANTLY INCREASED IN COPD GROUP. EXPRESSION OF MTTFA MRNA WAS DOWNREGULATED IN THE LUNGS AS A CONSEQUENCE OF HYPERMETHYLATION OF MTTFA PROMOTER. EXPRESSION OF MTTFA MRNA AND PROTEIN WAS DOWNREGULATED IN CSE-TREATED HUVECS AS A CONSEQUENCE OF HYPERMETHYLATION OF THE MTTFA PROMOTER. MTTFA EXPRESSION IN CSE-TREATED HUVECS WAS RESTORED BY THE METHYLATION INHIBITOR, 5-AZA-2'-DEOXYCYTIDINE(AZA). CONCLUSIONS: CIGARETTE SMOKE-INDUCED HYPERMETHYLATION OF THE MTTFA PROMOTER IS RELATED TO THE INITIATION AND PROGRESSION OF COPD. OUR FINDING MAY PROVIDE A NEW STRATEGY FOR THE INTERVENTION OF COPD BY DEVELOPING DEMETHYLATION AGENTS TARGETING MTTFA HYPERMETHYLATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
6   306  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  3193  44 HDAC INHIBITION REGULATES OXIDATIVE STRESS IN CD4(+)THELPER CELLS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND NON-SMALL CELL LUNG CANCER PATIENTS VIA MITOCHONDRIAL TRANSCRIPTION FACTOR A (MTTFA) MODULATING NF-KAPPAB/HIF1ALPHA AXIS. HISTONE DEACETYLASES (HDACS) PLAY A CRUCIAL ROLE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION BY REMODELLING CHROMATIN. ISOENZYMES OF THE HDAC FAMILY EXHIBIT ABERRANT REGULATION IN A WIDE VARIETY OF CANCERS AS WELL AS SEVERAL INFLAMMATORY LUNG DISORDERS LIKE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). INHIBITION OF HDACS IS A POTENTIAL THERAPEUTIC STRATEGY THAT COULD BE USED TO REVERSE EPIGENETIC MODIFICATION. TRICHOSTATIN A (TSA), A POWERFUL HISTONE DEACETYLASE (HDAC) INHIBITOR, HAS ANTI-CANCER EFFECTS IN NUMEROUS CANCER TYPES. HOWEVER, IT IS NOT YET APPARENT HOW HDAC INHIBITORS AFFECT HUMAN NON-SMALL CELL LUNG CANCER CELLS (NSCLC) AND COPD. THIS STUDY AIMS TO INVESTIGATE TSA'S ROLE IN RESTORING MITOCHONDRIAL DYSFUNCTION AND ITS EFFECT ON HYPOXIA AND INFLAMMATION IN CD4(+)T CELLS OBTAINED FROM PATIENTS WITH COPD AND LUNG CANCER. AS A RESULT OF TREATMENT WITH TSA, THERE IS A REDUCTION IN THE EXPRESSION OF INFLAMMATORY CYTOKINES AND A DECREASED ENRICHMENT OF TRANSCRIPTIONAL FACTORS ASSOCIATED WITH INFLAMMATION AT VEGFA GENE LOCI. WE HAVE SEEN A SUBSTANTIAL DECREASE IN THE EXPRESSION OF NF-KAPPAB AND HIF1ALPHA, WHICH ARE THE CRITICAL MEDIATORS OF INFLAMMATION AND HYPOXIA, RESPECTIVELY. FOLLOWING TSA TREATMENT, MTTFA EXPRESSION WAS INCREASED, FACILITATING PATIENTS WITH COPD AND NSCLC IN THE RECOVERY OF THEIR DYSFUNCTIONAL MITOCHONDRIA. FURTHERMORE, WE HAVE DISCOVERED THAT TSA TREATMENT IN PATIENTS WITH COPD AND NSCLC MAY LEAD TO IMMUNOPROTECTIVE NESS BY INDUCING TH1NESS. OUR FINDING GIVES A NEW INSIGHT INTO THE EXISTING BODY OF KNOWLEDGE REGARDING TSA-BASED THERAPEUTIC METHODS AND HIGHLIGHTS THE NECESSITY OF EPIGENETIC THERAPY FOR THESE DEVASTATING LUNG DISORDERS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
8  2822  41 FIRST-IN-HUMAN STUDY OF INHALED AZACITIDINE IN PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER. BACKGROUND: AEROSOLIZED AZACITIDINE HAS BEEN SHOWN TO INHIBIT ORTHOTOPIC LUNG CANCER GROWTH AND INDUCE RE-EXPRESSION OF METHYLATED TUMOR SUPPRESSOR GENES IN MURINE MODELS. WE HYPOTHESIZED THAT INHALED AZACITIDINE IS SAFE AND EFFECTIVE IN REVERSING EPIGENETIC CHANGES IN THE BRONCHIAL EPITHELIUM SECONDARY TO CHRONIC SMOKING. PATIENTS AND METHODS: WE REPORT THE FIRST IN HUMAN STUDY OF INHALED AZACITIDINE. AZACITIDINE IN AQUEOUS SOLUTION WAS USED TO GENERATE AN AEROSOL SUSPENSION OF 0.25-5 MUM PARTICLE SIZE. MAIN INCLUSION CRITERIA: STAGE IV OR RECURRENT NSCLC WITH PREDOMINANTLY LUNG INVOLVEMENT, >/=1 PRIOR SYSTEMIC THERAPY, ECOG PS 0-1, AND ADEQUATE PULMONARY FUNCTION. PATIENTS RECEIVED INHALED AZACITIDINE DAILY ON DAYS 1-5 AND 15-19 OF 28-DAY CYCLES, AT 3 ESCALATING DOSES (15, 30 AND 45 MG/M(2) DAILY). THE PRIMARY OBJECTIVE WAS TO DETERMINE THE FEASIBILITY AND TOLERABILITY OF THIS NEW THERAPEUTIC MODALITY. THE KEY SECONDARY OBJECTIVES INCLUDED PHARMACOKINETICS, METHYLATION PROFILES AND EFFICACY. RESULTS: FROM 3/2015 TO 2/2018, EIGHT PATIENTS RECEIVED A MEDIAN NUMBER OF 2 (IQR = 1) CYCLES OF INHALED AZACITIDINE. NO CLINICALLY SIGNIFICANT ADVERSE EVENTS WERE OBSERVED, EXCEPT ONE PATIENT TREATED AT THE HIGHEST DOSE DEVELOPED AN ASYMPTOMATIC GRADE 2 DECREASED DLCO WHICH RESOLVED SPONTANEOUSLY. ONE PATIENT RECEIVING 12 CYCLES OF THERAPY HAD AN OBJECTIVE AND DURABLE PARTIAL RESPONSE, AND TWO PATIENTS HAD STABLE DISEASE. PLASMA AZACITIDINE WAS ONLY BRIEFLY DETECTABLE IN PATIENTS TREATED AT THE HIGHER DOSES. MOREOVER, IN 2 OF 3 PARTICIPANTS WHO AGREED AND UNDERWENT PRE- AND POST-TREATMENT BRONCHOSCOPY, THE GLOBAL DNA METHYLATION IN THE BRONCHIAL EPITHELIUM DECREASED BY 24 % AND 79 % POST-THERAPY, RESPECTIVELY. THE INTERVAL BETWEEN LAST INHALED TREATMENT AND BRONCHOSCOPY WAS 3 DAYS. CONCLUSIONS: INHALED AZACITIDINE RESULTED IN NEGLIGIBLE PLASMA LEVELS COMPARED TO THE PREVIOUSLY REPORTED SUBCUTANEOUS ADMINISTRATION AND WAS WELL-TOLERATED. THE RESULTS JUSTIFY THE CONTINUED DEVELOPMENT OF INHALED AZACITIDINE AT NON-CYTOTOXIC DOSES FOR PATIENTS WITH LUNG-CONFINED MALIGNANT AND/OR PREMALIGNANT LESIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9  4450  45 MOLECULAR MECHANISMS AND CELLULAR CONTRIBUTION FROM LUNG FIBROSIS TO LUNG CANCER DEVELOPMENT. IDIOPATHIC PULMONARY FIBROSIS (IPF) IS A CHRONIC, PROGRESSIVE, FIBROSING INTERSTITIAL LUNG DISEASE (ILD) OF UNKNOWN AETIOLOGY, WITH A MEDIAN SURVIVAL OF 2-4 YEARS FROM THE TIME OF DIAGNOSIS. ALTHOUGH IPF HAS UNKNOWN AETIOLOGY BY DEFINITION, THERE HAVE BEEN IDENTIFIED SEVERAL RISKS FACTORS INCREASING THE PROBABILITY OF THE ONSET AND PROGRESSION OF THE DISEASE IN IPF PATIENTS SUCH AS CIGARETTE SMOKING AND ENVIRONMENTAL RISK FACTORS ASSOCIATED WITH DOMESTIC AND OCCUPATIONAL EXPOSURE. AMONG THEM, CIGARETTE SMOKING TOGETHER WITH CONCOMITANT EMPHYSEMA MIGHT PREDISPOSE IPF PATIENTS TO LUNG CANCER (LC), MOSTLY TO NON-SMALL CELL LUNG CANCER (NSCLC), INCREASING THE RISK OF LUNG CANCER DEVELOPMENT. TO THIS PURPOSE, IPF AND LC SHARE SEVERAL CELLULAR AND MOLECULAR PROCESSES DRIVING THE PROGRESSION OF BOTH PATHOLOGIES SUCH AS FIBROBLAST TRANSITION PROLIFERATION AND ACTIVATION, ENDOPLASMIC RETICULUM STRESS, OXIDATIVE STRESS, AND MANY GENETIC AND EPIGENETIC MARKERS THAT PREDISPOSE IPF PATIENTS TO LC DEVELOPMENT. NINTEDANIB, A TYROSINE-KINASE INHIBITOR, WAS FIRSTLY DEVELOPED AS AN ANTICANCER DRUG AND THEN RECOGNIZED AS AN ANTI-FIBROTIC AGENT BASED ON THE COMMON TARGET MOLECULAR PATHWAY. IN THIS REVIEW OUR AIM IS TO DESCRIBE THE UPDATED STUDIES ON COMMON CELLULAR AND MOLECULAR MECHANISMS BETWEEN IPF AND LUNG CANCER, KNOWLEDGE OF WHICH MIGHT HELP TO FIND NOVEL THERAPEUTIC TARGETS FOR THIS DISEASE COMBINATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  4028  36 LUNG TUMORS, COPD AND IMMUNE RESPONSE: IS EPIGENETICS THE BOTTOM LINE? NSCLC IS A HETEROGENEOUS DISORDER CONSISTING OF DISTINCT MOLECULAR SUBTYPES WHICH CAN BE TREATED BY USING SPECIFIC DRUGS TARGETED TO DISTINCT GENETIC LESIONS. IT IS WELL KNOWN THAT NSCLS INCIDENCE IS HIGHER IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS BECAUSE THEY SHARE A COMMON RISK FACTOR (CIGARETTE SMOKING) AND IT IS BELIEVED THAT THE TYPICAL INFLAMMATORY MICROENVIRONMENT OBSERVED IN COPD MAY INFLUENCE THE MOLECULAR MECHANISMS RESPONSIBLE OF CARCINOGENESIS. IN THE LAST YEARS, THE ROLE OF EPIGENETIC PROCESSES IN CELL BIOLOGY AND TISSUE PATHOLOGY HAS BEEN EXTENSIVELY STUDIED BOTH IN COPD AND NSCLC. THE RECENT PAPER BY WAUTERS ET AL. SHOWED A SPECIFIC PATTERN OF DRIVER MUTATIONS AND MOLECULAR FEATURES IN NSCLC RAISING IN THE CONTEXT OF COPD. ALL THESE FINDINGS HAVE SHOWN FOR THE FIRST TIME THAT LUNG TUMORS FOUND IN COPD PATIENTS DIFFER FROM THOSE OBSERVED IN PATIENT WITHOUT COPD DUE TO THE PRESENCE OF A SPECIFIC TUMOR MICROENVIRONMENT WHICH IS CHARACTERIZED BY REDUCED CD4+ TREG CELLS. ON THIS BASIS, THE PRESENT WORK AIMS AT DISCUSSING AND ANALYZING THE CONTEXT-SPECIFIC MECHANISMS OF CLONAL SELECTION AND EVOLUTION MAINLY FOCUSING ON THE EPIGENETIC ALTERATIONS AND AT POINTING OUT THE POTENTIAL THERAPEUTIC IMPLICATIONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11  5227  33 PRMT6 MEDIATES INFLAMMATION VIA ACTIVATION OF THE NF-KAPPAB/P65 PATHWAY ON A CIGARETTE SMOKE EXTRACT-INDUCED MURINE EMPHYSEMA MODEL. INTRODUCTION: SMOKE-DRIVEN LUNG INFLAMMATION IS CONSIDERED TO BE THE MAJOR PATHOPHYSIOLOGY MECHANISM OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)/EMPHYSEMA. PROTEIN ARGININE METHYLTRANSFERASE 6 (PRMT6) IS A KEY EPIGENETIC ENZYME, WHICH IS RELATED TO PROTECTING THE TRI-METHYLATION OF H3K4 (H3K4ME3). WE HYPOTHESIZED THAT PTMT6 PROTECTS LUNG INFLAMMATION THROUGH THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY. METHODS: MICE WERE INJECTED WITH CIGARETTE SMOKE EXTRACT (CSE) OR PBS TO ESTABLISH A MICE MODEL, INTRATRACHEALLY INSTILLED WITH OVEREXPRESSED PRMT6 OR NEGATIVE CONTROL VECTOR. MORPHOMETRY OF LUNG SLIDES AND LUNG FUNCTION WERE MEASURED. WE DETERMINED THE PROTEIN EXPRESSION OF PRMT6 AND ITS RELATED HISTONE TARGETS, THE ACTIVATION OF NF-KAPPAB PATHWAY, THE LEVEL OF TUMOR NECROSIS FACTOR ALPHA (TNFALPHA) AND INTERLEUKIN-1BETA (IL-1BETA). RESULTS: AFTER PRMT6 OVEREXPRESSION, THE MORPHOMETRY INDEXES AND LUNG FUNCTION WERE IMPROVED. ALSO, THE EXPRESSION OF H3K4ME3 WAS DECREASED. OVEREXPRESSED PRMT6 COULD SUPPRESS CSE-INDUCED NF-KAPPAB ACTIVATION AND PRO-INFLAMMATION GENES EXPRESSION. CONCLUSIONS: THE OVEREXPRESSED PRMT6 COULD SERVE AS AN INFLAMMATION INHIBITOR, POTENTIALLY THROUGH BLOCKING THE NF-KAPPAB/P65 PATHWAY IN THE MURINE EMPHYSEMA MODEL.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  2326  28 EPIGENETIC REGULATION OF HOTAIR IN ADVANCED CHRONIC MYELOID LEUKEMIA. PURPOSE: CHRONIC MYELOID LEUKEMIA (CML) ACCOUNTS FOR ~10% OF LEUKEMIA CASES, AND ITS PROGRESSION INVOLVES EPIGENETIC GENE REGULATION. THIS STUDY INVESTIGATED EPIGENETIC REGULATION OF HOTAIR AND ITS TARGET MICRORNA, MIR-143, IN ADVANCED CML. PATIENTS AND METHODS: WE FIRST ISOLATED BONE MARROW MONONUCLEAR CELLS FROM 70 PATIENTS WITH DIFFERENT PHASES OF CML AND FROM HEALTHY DONORS AS NORMAL CONTROL; WE ALSO CULTURED K562 AND KCL22 CELLS, TREATED WITH DEMETHYLATION DRUG; MTT ASSAY, FLOW CYTOMETRY, QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR), METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), WESTERN BLOT, LUCIFERASE ASSAY, RNA PULL-DOWN ASSAY AND RNA-BINDING PROTEIN IMMUNOPRECIPITATION (RIP) ASSAY WERE PERFORMED. RESULT: AS MEASURED BY QPCR, HOTAIR EXPRESSION IN K562 CELLS, KCL22 CELLS, AND SAMPLES FROM CASES OF ADVANCED-STAGE CML INCREASED WITH LEVELS OF SEVERAL DNA METHYLTRANSFERASES AND HISTONE DEACETYLATES, INCLUDING DNMT1, DNMT3A, HDAC1, EZH2, AND LSD1, AND MIR-143 LEVELS WERE DECREASED AND HOTAIR LEVELS WERE INCREASED. TREATMENT WITH 5-AZACYTIDINE, A DNA METHYLATION INHIBITOR, DECREASED DNMT1, DNMT3A, HDAC1, EZH2, LSD1 MRNA, PROTEIN LEVELS, AND HOTAIR MRNA LEVELS BUT INCREASED MIR-143 LEVELS. HOTAIR KNOCKDOWN AND MIR-143 OVEREXPRESSION BOTH INHIBITED PROLIFERATION AND PROMOTED APOPTOSIS IN KCL22 AND K562 CELLS THROUGH THE PI3K/AKT PATHWAY. RNA PULL-DOWN, MASS SPECTROMETRY, AND RIP ASSAYS SHOWED THAT HOTAIR INTERACTED WITH EZH2 AND LSD1. A DUAL-LUCIFERASE ASSAY DEMONSTRATED THAT HOTAIR INTERACTED WITH MIR-143. CONCLUSION: OUR FINDINGS DEMONSTRATE THE KEY EPIGENETIC INTERACTIONS OF HOTAIR RELATED TO CML PROGRESSION AND SUGGEST HOTAIR AS A POTENTIAL THERAPEUTIC TARGET FOR ADVANCED CML. FURTHERMORE, OUR RESULTS SUPPORT THE USE OF DEMETHYLATION DRUGS AS A CML TREATMENT STRATEGY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13  3873  24 K-RAS AND P16(INK4A)ALTERATIONS IN SPUTUM OF NSCLC PATIENTS AND IN HEAVY ASYMPTOMATIC CHRONIC SMOKERS. NSCLC RATES AMONG THE MOST FREQUENT AND LETHAL NEOPLASM WORLD-WIDE AND A SIGNIFICANT DECREASE IN MORBIDITY AND MORTALITY RELIES ONLY UPON EFFECTIVE EARLY DIAGNOSTIC STRATEGIES. WE INVESTIGATED K-RAS MUTATIONS AND P16(INK4A) HYPERMETHYLATION IN TUMOR TISSUE AND SPUTUM OF 50 PATIENTS WITH NSCLC AND CORRELATED THEM WITH SPUTUM CYTOLOGY AND WITH TUMOR STAGING, GRADING AND LOCATION, TO ASCERTAIN, IN SPUTUM, THEIR POTENTIAL DIAGNOSTIC IMPACT. THE SAME GENETIC/EPIGENETIC ABNORMALITIES AND CYTOLOGICAL FEATURES WERE ALSO EVALUATED IN SPUTUM FROM 100 CHRONIC HEAVY SMOKERS. GENETIC ANALYSIS IDENTIFIED MOLECULAR ABNORMALITIES IN 64% TUMORS (14/50 K-RAS MUTATIONS AND 24/50 P16(INK4A) HYPERMETHYLATION) AND IN 48% SPUTUM (11/50 K-RAS MUTATIONS AND 16/50 P16(INK4A) HYPERMETHYLATION). IN TUMORS K-RAS MUTATIONS AND P16(INK4A) HYPERMETHYLATION WERE MOSTLY MUTUALLY EXCLUSIVE, BEING FOUND IN THE SAME PATIENTS IN 3 CASES ONLY. GENETIC ABNORMALITIES IN SPUTUM WERE DETECTED ONLY IN MOLECULAR ABNORMAL TUMORS. MOLECULAR CHANGES IN SPUTUM HAD RATES OF DETECTION SIMILAR TO CYTOLOGY (42%) BUT THE CYTO-MOLECULAR COMBINATION INCREASED THE DIAGNOSTIC YIELD UP TO 60%. INTERESTINGLY, THE RATE OF DETECTION OF GENETIC CHANGES IN SPUTUM OF TUMORS AT EARLY STAGE (T1) WAS NOT SIGNIFICANTLY DIFFERENT FROM THAT OF TUMORS AT MORE ADVANCED STAGE (T2-T4). IN FACT K-RAS POINT MUTATIONS WERE FREQUENTLY RECOGNISED IN TUMORS AT EARLY STAGE WHILE P16(INK4A) INACTIVATION PREVAILED IN TUMORS AT ADVANCED STAGE ( P=0.0063). AS EXPECTED, DIAGNOSTIC CYTOLOGICAL FINDINGS WERE MORE FREQUENTLY FOUND IN TUMORS AT ADVANCED STAGE (P=0.004). NO CORRELATION WAS FOUND BETWEEN TUMOR GRADING AND LOCATION (CENTRAL VERSUS PERIPHERAL) AND MOLECULAR CHANGES. P16(INK4A) HYPERMETHYLATION, BUT NOT K-RAS MUTATIONS, WAS DOCUMENTED IN SPORADIC CASES OF ASYMPTOMATIC HEAVY SMOKERS (4%) WHERE IT WAS UNCOUPLED FROM CYTOLOGICAL ABNORMALITIES. IN CONCLUSION THE CYTO-MOLECULAR DIAGNOSTIC STRATEGY ADOPTED IN THIS STUDY WAS ABLE TO DETECT THE MAJORITY OF TUMORS BUT IN ORDER TO BE PROPOSED AS EFFECTIVE AND EARLY DIAGNOSTIC TOOL, THIS MOLECULAR PANEL NEEDS TO BE TESTED IN PROSPECTIVE STUDIES WITH ADEQUATE FOLLOW-UP.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
14  2765  28 EXPRESSION, EPIGENETIC REGULATION, AND HUMORAL IMMUNOGENICITY OF CANCER-TESTIS ANTIGENS IN CHRONIC MYELOID LEUKEMIA. OBJECTIVE: CANCER-TESTIS (CT) ANTIGENS REPRESENT ATTRACTIVE TARGETS FOR TUMOR IMMUNOTHERAPY BASED ON THEIR TUMOR-RESTRICTED EXPRESSION AND IMMUNOGENICITY. HOWEVER, A BROAD PICTURE OF THE EXPRESSION OF CT ANTIGENS AND ASSOCIATED HUMORAL IMMUNE RESPONSES IN CHRONIC MYELOID LEUKEMIA (CML) IS STILL MISSING. METHODS: WE SCREENED CML CELL LINES AND BONE MARROW (BM) SAMPLES FROM HEALTHY DONORS BY RT-PCR FOR THE EXPRESSION OF 31 CT ANTIGENS BEFORE AND AFTER TREATMENT WITH EPIGENETIC AGENTS. EXPRESSION OF TUMOR-RESTRICTED ANTIGENS WAS FURTHER EXAMINED IN 60 CML PATIENTS AND HUMORAL IMMUNE RESPONSES AGAINST 15 CT ANTIGENS WERE SCREENED BY ELISA. RESULTS: IN UNTREATED CELL LINES WE DETECTED THE EXPRESSION OF 17 CT ANTIGENS THAT WERE ABSENT FROM NORMAL BM. EXPRESSION OF MOST ANTIGENS INCREASED FOLLOWING DEMETHYLATING TREATMENT WITH 5'-AZA-2'-DEOXYCYTIDINE. IN THESE SAMPLES, ONLY PRAME WAS REPEATEDLY DETECTED AND EXPRESSION CORRELATED WITH SEVERAL CLINICOPATHOLOGICAL PARAMETERS AND DECREASED OVERALL SURVIVAL. WE FURTHER SHOW THAT A LOWER FREQUENCY OF PRAME-POSITIVE SAMPLES DURING IMATINIB TREATMENT WAS NOT CAUSED BY GENE-SPECIFIC DOWNREGULATION. ANALYZING THE PATIENTS' ANTIBODY RESPONSES WE FOUND THAT THE VAST MAJORITY OF PATIENTS LACKED SPONTANEOUS IMMUNITY AGAINST CT ANTIGENS INCLUDING PRAME. CONCLUSIONS: CT ANTIGEN EXPRESSION CAN BE INCREASED BY THE APPLICATION OF EPIGENETIC AGENTS AND THE EXPRESSION OF PRAME CORRELATES WITH CLINICOPATHOLOGICAL PARAMETERS AND OVERALL SURVIVAL IN PATIENTS WITH CML, BUT DOES NOT LEAD TO HUMORAL IMMUNE RESPONSES. PRAME-SPECIFIC IMMUNOTHERAPY MIGHT REPRESENT A PROMISING APPROACH FOR THE ERADICATION OF RESIDUAL THERAPY-RESISTANT LEUKEMIC CELLS DUE TO ITS FREQUENT EXPRESSION AND STABILITY UNDER IMATINIB TREATMENT.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
15  1484  38 DLEU2: A MEANINGFUL LONG NONCODING RNA IN ONCOGENESIS. BACKGROUND: LONG NON-CODING RNA (LNCRNA) WITH LITTLE OR NO CODING ABILITY HAS SHOWN A VARIETY OF BIOLOGICAL FUNCTIONS IN CANCER, INCLUDING EPIGENETIC REGULATION, DNA DAMAGE, REGULATION OF MICRORNAS, AND PARTICIPATION IN SIGNAL TRANSDUCTION PATHWAYS. LNCRNA CAN BE USED AS AN ONCOGENE AND TUMOR SUPPRESSOR GENE THROUGH TRANSCRIPTIONAL REGULATION IN CANCER. FOR EXAMPLE, THE OVER-EXPRESSED LNCRNA DLEU2 PROMOTES THE OCCURRENCE OF LARYNGEAL CANCER, LUNG CANCER, HEPATOCELLULAR CARCINOMA, ETC., AND INHIBITS THE PROGRESSION OF CHRONIC LYMPHOCYTIC LEUKEMIA. DELETED IN LYMPHOCYTIC LEUKEMIA 2 (DLEU2), AS ONE OF THE LONG NON-CODING RNAS, WAS FIRST FOUND IN CHRONIC LYMPHOBLASTIC LEUKEMIA AND DRAWN INTO THE PROGRESS OF INNUMERABLE CANCERS. THE MOLECULAR MECHANISM OF DLEU2 IN MULTIPLE TUMORS WILL BE REVEALED. METHODS: IN THIS REVIEW, CURRENT STUDIES ON THE BIOLOGICAL FUNCTIONS AND MECHANISMS OF DLEU2 IN TUMORS ARE SUMMARIZED AND ANALYZED; RELATED RESEARCHES ARE SYSTEMATICALLY RETRIEVED AND COLLECTED THROUGH PUBMED. RESULTS: DLEU2, A NOVEL CANCER-RELATED LNCRNA, HAS BEEN DEMONSTRATED TO BE ABNORMALLY EXPRESSED IN VARIOUS MALIGNANT TUMORS, INCLUDING LEUKEMIA, ESOPHAGEAL CANCER, LUNG CANCER, GLIOMA, HEPATOCELLULAR CARCINOMA, MALIGNANT PLEURAL MESOTHELIOMA, BLADDER CANCER, PANCREATIC CANCER, PHARYNX AND THROAT CANCER, RENAL CLEAR CELL CARCINOMA, BREAST CANCER, OSTEOSARCOMA. BESIDES, LNCRNA DLEU2 HAS BEEN SHOWN TO BE INVOLVED IN THE PROCESS OF PROLIFERATION, MIGRATION, INVASION AND INHIBITION OF APOPTOSIS OF CANCER CELLS. CONCLUSION: DUE TO THE BIOLOGICAL FUNCTIONS AND MECHANISMS INVOLVED IN DLEU2, IT MAY REPRESENT AN AVAILABLE BIOMARKER OR POTENTIAL THERAPEUTIC TARGET IN A VARIETY OF MALIGNANT TUMORS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
16  3767  34 INTEGRATIVE EPIGENOMIC ANALYSIS IN DIFFERENTIATED HUMAN PRIMARY BRONCHIAL EPITHELIAL CELLS EXPOSED TO CIGARETTE SMOKE. CIGARETTE SMOKE (CS) IS ONE OF THE MAJOR RISK FACTORS FOR MANY PULMONARY DISEASES, INCLUDING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER. THE FIRST LINE OF DEFENSE FOR CS EXPOSURE IS THE BRONCHIAL EPITHELIAL CELLS. ELUCIDATION OF THE EPIGENETIC CHANGES DURING CS EXPOSURE IS KEY TO GAINING A MECHANISTIC UNDERSTANDING INTO HOW MATURE AND DIFFERENTIATED BRONCHIAL EPITHELIAL CELLS RESPOND TO CS. THEREFORE, WE PERFORMED EPIGENOMIC PROFILING IN CONJUNCTION WITH TRANSCRIPTIONAL PROFILING IN WELL-DIFFERENTIATED HUMAN BRONCHIAL EPITHELIAL (HBE) CELLS CULTURED IN AIR-LIQUID INTERFACE (ALI) EXPOSED TO THE VAPOR PHASE OF CS. THE GENOME-WIDE ENRICHMENT OF HISTONE 3 LYSINE 27 ACETYLATION WAS DETECTED BY CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY NEXT GENERATION SEQUENCING (CHIP-SEQ) IN HBE CELLS AND SUGGESTED THE PLAUSIBLE BINDING OF SPECIFIC TRANSCRIPTION FACTORS RELATED TO CS EXPOSURE. ADDITIONALLY, INTERROGATION OF CHIP-SEQ DATA WITH GENE EXPRESSION PROFILING OF HBE CELLS AFTER CS EXPOSURE FOR DIFFERENT DURATIONS (3 HOURS, 2 DAYS, 4 DAYS) SUGGESTED THAT EARLIER EPIGENETIC CHANGES (3 HOURS AFTER CS EXPOSURE) MAY BE ASSOCIATED WITH LATER GENE EXPRESSION CHANGES INDUCED BY CS EXPOSURE (4 DAYS). THE INTEGRATION OF EPIGENETICS AND GENE EXPRESSION DATA REVEALED SIGNALING PATHWAYS RELATED TO CS-INDUCED EPIGENETIC CHANGES IN HBE CELLS THAT MAY IDENTIFY NOVEL REGULATORY PATHWAYS RELATED TO CS-INDUCED COPD.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17   922  26 CHRONIC IL-1BETA-INDUCED INFLAMMATION REGULATES EPITHELIAL-TO-MESENCHYMAL TRANSITION MEMORY PHENOTYPES VIA EPIGENETIC MODIFICATIONS IN NON-SMALL CELL LUNG CANCER. CHRONIC INFLAMMATION FACILITATES TUMOR PROGRESSION. WE DISCOVERED THAT A SUBSET OF NON-SMALL CELL LUNG CANCER CELLS UNDERWENT A GRADUALLY PROGRESSING EPITHELIAL-TO-MESENCHYMAL (EMT) PHENOTYPE FOLLOWING A 21-DAY EXPOSURE TO IL-1BETA, AN ABUNDANT PROINFLAMMATORY CYTOKINE IN THE AT-RISK FOR LUNG CANCER PULMONARY AND THE LUNG TUMOR MICROENVIRONMENTS. PATHWAY ANALYSIS OF THE GENE EXPRESSION PROFILE AND IN VITRO FUNCTIONAL STUDIES REVEALED THAT THE EMT AND EMT-ASSOCIATED PHENOTYPES, INCLUDING ENHANCED CELL INVASION, PD-L1 UPREGULATION, AND CHEMORESISTANCE, WERE SUSTAINED IN THE ABSENCE OF CONTINUOUS IL-1BETA EXPOSURE. WE REFERRED TO THIS PHENOMENON AS EMT MEMORY. UTILIZING A DOXYCYCLINE-CONTROLLED SLUG EXPRESSION SYSTEM, WE FOUND THAT HIGH EXPRESSION OF THE TRANSCRIPTION FACTOR SLUG WAS INDISPENSABLE FOR THE ESTABLISHMENT OF EMT MEMORY. HIGH SLUG EXPRESSION IN TUMORS OF LUNG CANCER PATIENTS WAS ASSOCIATED WITH POOR SURVIVAL. CHEMICAL OR GENETIC INHIBITION OF SLUG UPREGULATION PREVENTED EMT FOLLOWING THE ACUTE IL-1BETA EXPOSURE BUT DID NOT REVERSE EMT MEMORY. CHROMATIN IMMUNOPRECIPITATION AND METHYLATION-SPECIFIC PCR FURTHER REVEALED A SLUG-MEDIATED TEMPORAL REGULATION OF EPIGENETIC MODIFICATIONS, INCLUDING ACCUMULATION OF H3K27, H3K9, AND DNA METHYLATION, IN THE CDH1 (E-CADHERIN) PROMOTER FOLLOWING THE CHRONIC IL-1BETA EXPOSURE. CHEMICAL INHIBITION OF DNA METHYLATION NOT ONLY RESTORED E-CADHERIN EXPRESSION IN EMT MEMORY, BUT ALSO PRIMED CELLS FOR CHEMOTHERAPY-INDUCED APOPTOSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
18  3939  26 LNC-IL7R ALLEVIATES PM(2.5)-MEDIATED CELLULAR SENESCENCE AND APOPTOSIS THROUGH EZH2 RECRUITMENT IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: LONG-TERM EXPOSURE TO PM(2.5) (PARTICULATE MATTER WITH AN AERODYNAMIC DIAMETER OF </= 2.5 MUM) IS ASSOCIATED WITH PULMONARY INJURY AND EMPHYSEMA IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE INVESTIGATED MECHANISMS THROUGH WHICH THE LONG NONCODING RNA LNC-IL7R CONTRIBUTES TO CELLULAR DAMAGE BY INDUCING OXIDATIVE STRESS IN COPD PATIENTS EXPOSED TO PM(2.5). METHODS: ASSOCIATIONS OF SERUM LNC-IL7R LEVELS WITH LUNG FUNCTION, EMPHYSEMA, AND PREVIOUS PM(2.5) EXPOSURE IN COPD PATIENTS WERE ANALYZED. REACTIVE OXYGEN SPECIES AND LNC-IL7R LEVELS WERE MEASURED IN PM(2.5)-TREATED CELLS. THE LEVELS OF LNC-IL7R AND CELLULAR SENESCENCE-ASSOCIATED GENES, NAMELY P16(INK4A) AND P21(CIP1/WAF1), WERE DETERMINED THROUGH LUNG TISSUE SECTION STAINING. THE EFFECTS OF P16(INK4A) OR P21(CIP1/WAF1) REGULATION WERE EXAMINED BY PERFORMING LNC-IL7R OVEREXPRESSION AND KNOCKDOWN ASSAYS. THE FUNCTIONS OF LNC-IL7R-MEDIATED CELL PROLIFERATION, CELL CYCLE, SENESCENCE, COLONY FORMATION, AND APOPTOSIS WERE EXAMINED IN CELLS TREATED WITH PM(2.5). CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE CONDUCTED TO INVESTIGATE THE EPIGENETIC REGULATION OF P21(CIP1/WAF1). RESULTS: LNC-IL7R LEVELS DECREASED IN COPD PATIENTS AND WERE NEGATIVELY CORRELATED WITH EMPHYSEMA OR PM(2.5) EXPOSURE. LNC-IL7R LEVELS WERE UPREGULATED IN NORMAL LUNG EPITHELIAL CELLS BUT NOT IN COPD CELLS EXPOSED TO PM(2.5). LOWER LNC-IL7R EXPRESSION IN PM(2.5)-TREATED CELLS INDUCED P16(INK4A) AND P21(CIP1/WAF1) EXPRESSION BY INCREASING OXIDATIVE STRESS. HIGHER LNC-IL7R EXPRESSION PROTECTED AGAINST CELLULAR SENESCENCE AND APOPTOSIS, WHEREAS LOWER LNC-IL7R EXPRESSION AUGMENTED INJURY IN PM(2.5)-TREATED CELLS. LNC-IL7R AND THE ENHANCER OF ZESTE HOMOLOG 2 (EZH2) SYNERGISTICALLY SUPPRESSED P21(CIP1/WAF1) EXPRESSION THROUGH EPIGENETIC MODULATION. CONCLUSION: LNC-IL7R ATTENUATES PM(2.5)-MEDIATED P21(CIP1/WAF1) EXPRESSION THROUGH EZH2 RECRUITMENT, AND ITS DYSFUNCTION MAY AUGMENT CELLULAR INJURY IN COPD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19  4899  30 OXIDATIVE STRESS MEDIATES THE APOPTOSIS AND EPIGENETIC MODIFICATION OF THE BCL-2 PROMOTER VIA DNMT1 IN A CIGARETTE SMOKE-INDUCED EMPHYSEMA MODEL. BACKGROUND: EMPHYSEMA IS A CRUCIAL PATHOLOGICAL CHARACTERISTIC OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). OXIDATIVE STRESS, APOPTOSIS AND EPIGENETIC MECHANISMS CONTRIBUTE TO THE PATHOGENESIS OF EMPHYSEMA. HOWEVER, AN ATTEMPT TO ACCURATELY IDENTIFY WHETHER THESE MECHANISMS INTERACT WITH EACH OTHER AND HOW THEY ARE TRIGGERED HAS NEVER BEEN CONDUCTED. METHOD: THE TOTAL REACTIVE OXYGEN SPECIES (ROS) LEVEL, PULMONARY APOPTOSIS AND B-CELL LYMPHOMA/LEUKEMIA-2 (BCL-2) EXPRESSION, AN APOPTOSIS REGULATOR, WERE DETECTED IN SAMPLES FROM COPD PATIENTS. BISULFITE SEQUENCING PCR (BSP) WAS CONDUCTED TO OBSERVE THE ALTERATIONS IN THE METHYLATION OF THE BCL-2 PROMOTER IN SPECIMENS. THE DYSREGULATION OF DNA METHYLTRANSFERASE ENZYME 1 (DNMT1), A VITAL DNA METHYLTRANSFERASE ENZYME, IN THE LUNGS OF PATIENTS WAS CONFIRMED THROUGH WESTERN BLOTTING. TO FIND OUT INTERACTIONS BETWEEN OXIDATIVE STRESS AND DNA METHYLATION IN EMPHYSEMA, MOUSE MODELS WERE BUILT WITH ANTIOXIDANT TREATMENT AND DNMT1 SILENCING, AND WERE EXAMINED WITH THE PULMONARY APOPTOSIS, BCL-2 AND DNMT1 LEVELS, AND EPIGENETIC ALTERATIONS OF BCL-2. RESULTS: HIGHER ROS LEVELS AND PULMONARY APOPTOSIS WERE OBSERVED IN COPD PATIENTS THAN IN HEALTHY CONTROLS. DOWNREGULATED BCL-2 EXPRESSION WITH INCREASED PROMOTER METHYLATION AND DNMT1 PROTEIN EXPRESSION WAS FOUND IN COPD PATIENTS. ANTIOXIDANT TREATMENT REDUCED THE LEVEL OF ROS, DNMT1 PROTEIN AND EMPHYSEMATOUS PROGRESSION IN THE SMOKING MODELS. FOLLOWING DNMT1 BLOCKADE, SMOKING MODELS SHOWED IMPROVED LUNG FUNCTION, PULMONARY APOPTOSIS, EMPHYSEMATOUS PROGRESSION, AND INCREASED BCL-2 PROTEIN LEVEL WITH LESS PROMOTER METHYLATION THAN EMPHYSEMA MICE. CONCLUSION: CIGARETTE-INDUCED OXIDATIVE STRESS MEDIATES PULMONARY APOPTOSIS AND HYPERMETHYLATION OF THE BCL-2 PROMOTER IN EMPHYSEMA MODELS THROUGH DNMT1.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
20  2782  29 EZH2 INHIBITION CONFERS PIK3CA-DRIVEN LUNG TUMORS ENHANCED SENSITIVITY TO PI3K INHIBITION. MEMBERS OF THE PI3K SIGNALING PATHWAY, ESPECIALLY PIK3CA, THE GENE ENCODING THE CATALYTIC SUBUNIT OF THE PI3K COMPLEX, ARE HIGHLY MUTATED AND AMPLIFIED IN VARIOUS CANCER TYPES, INCLUDING NON-SMALL CELL LUNG CANCER. ALTHOUGH PI3K INHIBITORS HAVE BEEN USED IN CLINICS FOR FOLLICULAR LYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA, NO AGENTS TARGETING PI3K ABERRATIONS IN LUNG CANCER HAVE BEEN APPROVED BY THE FDA SO FAR. IN THIS STUDY, WE OBSERVED THAT PIK3CA-E545K, THE MOST COMMON MUTATION IN LUNG CANCER, HARBORED A MODEST INDUCTION OF STEM-LIKE PROPERTIES IN LUNG EPITHELIAL CELLS, AND DROVE DEVELOPMENT OF ADENOCARCINOMA AUTOCHTHONOUSLY WHEN PAIRED WITH P53 LOSS IN A MURINE MOUSE MODEL. WE ALSO FOUND THAT PIK3CA-MUTANT OF AMPLIFIED LUNG CANCER CELLS WERE SENSITIVE TO EZH2 INHIBITION. EZH2 INHIBITION SYNERGIZED WITH PI3K INHIBITION IN HUMAN CANCER CELLS IN VITRO AND WORKED TOGETHER EFFICIENTLY IN VIVO. MECHANISTICALLY, EZH2 INHIBITION COOPERATED WITH PI3K INHIBITION TO PRODUCE A MORE POTENT SUPPRESSION OF PHOSPHO-AKT DOWNSTREAM OF PI3K. THIS STUDY SUGGESTS A PROMISING COMBINATION THERAPY TO COMBAT LUNG CANCERS WITH PIK3CA MUTATION OR AMPLIFICATION. BOTH COPANLISIB, THE PI3K INHIBITOR, AND TAZEMETOSTAT, THE EZH2 INHIBITOR, ARE FDA-APPROVED, WHICH SHOULD ENHANCE THE CLINICAL TRANSLATION OF THIS WORK.	2022