1   740 236 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2  4660  52 NEW APPROACHES TO THE TREATMENT OF MYELODYSPLASIA. THE THERAPEUTIC DILEMMA THAT CONFRONTS THE MANAGEMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) IS ILLUSTRATED BY THE ABSENCE OF A FOOD AND DRUG ADMINISTRATION-APPROVED AGENT WITH AN INDICATION FOR THIS DISEASE. CLINICAL HETEROGENEITY AND INADEQUATE UNDERSTANDING OF THE DISEASE PATHOBIOLOGY HAVE LIMITED PROGRESS IN THE DEVELOPMENT OF NOVEL THERAPEUTICS. PRECLINICAL INVESTIGATIONS INDICATE THAT RECIPROCAL INTERACTION BETWEEN THE MALIGNANT CLONE AND THE MICROENVIRONMENT SERVE TO CREATE A HOSTILE MILIEU THAT REINFORCES INEFFECTIVE BLOOD CELL PRODUCTION. INEFFECTIVE HEMATOPOIESIS, THE HALLMARK OF MDS, ARISES FROM IMPAIRED PROGENITOR RESPONSIVENESS TO NORMAL TROPHIC SIGNALS AND EXCESS LOCAL GENERATION OF INHIBITORY CYTOKINES, WHICH PROMOTE ACCELERATED APOPTOTIC LOSS OF PROGENITORS AND THEIR PROGENY. EVIDENCE TO SUPPORT THIS MODEL DERIVES FROM CYTOKINE NEUTRALIZATION STUDIES AND THE DIRECT RELATIONSHIP BETWEEN PLASMA TUMOR NECROSIS FACTOR-ALPHA CONCENTRATION AND DNA OXIDATION AND GLUTATHIONE DEPLETION IN MALIGNANT CD34+ PROGENITORS. RECENT INVESTIGATIONS INDICATE THAT ANGIOGENIC MOLECULES GENERATED BY MALIGNANT MYELOMONOCYTIC PRECURSORS REPRESENT INTEGRAL DIFFUSABLE SIGNALS THAT REINFORCE LEUKEMIA PROGENITOR SELF-RENEWAL WHILE PROMOTING THE GENERATION OF PROAPOPTOTIC CYTOKINES AND MEDULLARY ANGIOGENIC RESPONSE. THE POTENTIAL FOR LEUKEMIA EVOLUTION IS COMPOUNDED BY EPIGENETIC EVENTS INCLUDING METHYLATION SILENCING OF THE P15 PROTO-ONCOGENE OR ACTIVATING RAS POINT MUTATIONS. DELINEATION OF SUCH BIOLOGIC FEATURES THAT ARE CENTRAL TO THE PATHOBIOLOGY OF MDS PROVIDES A RELIABLE FRAMEWORK FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS. ANTIANGIOGENIC AGENTS IN CLINICAL TESTING INCLUDE VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) RECEPTOR TYROSINE KINASE INHIBITORS, THALIDOMIDE AND RELATED ANALOGUES, AND THE RECOMBINANT VEGF NEUTRALIZING ANTIBODY, BEVACIZUMAB. AGENTS WHOSE ACTIONS MAY RESTORE DIFFERENTIATION PROGRAMS, SUCH AS THE DNA METHYLTRANSFERASE INHIBITORS OR HISTONE DEACETYLASE INHIBITORS, OFFER THE PROSPECT TO PROMOTE EFFECTIVE HEMATOPOIESIS WHILE IMPACTING THE POTENTIAL FOR LEUKEMIA EVOLUTION. RAS FARNESYL TRANSFERASE INHIBITORS HAVE SHOWN ENCOURAGING PRELIMINARY RESULTS IN ACUTE MYELOID LEUKEMIA AND ARE CURRENTLY UNDER INVESTIGATION IN ADVANCED MDS AND CHRONIC MYELOMONOCYTIC LEUKEMIA. ARSENIC TRIOXIDE (ATO) INTERACTS WITH A SPECTRUM OF BIOLOGIC TARGETS THAT MAY BE UNIQUELY SUITED TO MDS. ATO IS A POTENT INDUCER OF APOPTOSIS IN THIOL-DEPLETED MALIGNANT PROGENITORS AND NEOVASCULAR ENDOTHELIUM, WHILE PROMOTING DIFFERENTIATION THROUGH HISTONE ACETYLATION AND INACTIVATION OF TRANSCRIPTIONAL COREPRESSORS. THE IDENTIFICATION OF RELEVANT BIOLOGIC TARGETS IN MDS HAS RAISED EXPECTATIONS FOR THE DEVELOPMENT OF DISEASE-SPECIFIC THERAPIES FOR MDS IN THE YEARS THAT FOLLOW.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3  2355  39 EPIGENETIC REGULATION OF PRAME GENE IN CHRONIC MYELOID LEUKEMIA. TUMOR ASSOCIATED ANTIGENS (TAA) PROVIDE ATTRACTIVE TARGETS FOR CANCER-SPECIFIC IMMUNOTHERAPY. PRAME IS A TAA GENE UP-REGULATED IN ADVANCED PHASES OF CHRONIC MYELOID LEUKEMIA (CML). TO DATE, MOLECULAR MECHANISMS FOR THE EXPRESSION OF PRAME HAVE NEVER BEEN STUDIED. WE FOUND THAT SOME PH'-POSITIVE CELL LINES DID NOT EXPRESS PRAME. THE EXPRESSION OF PRAME WAS RESTORED IN THESE CELL LINES BY TREATMENT WITH 5'-AZA-2'-DEOXYCYTIDINE, SUGGESTING THAT THE EXPRESSION OF PRAME IS MAINLY SUPPRESSED BY HYPERMETHYLATION. BISULFITE SEQUENCING ANALYSIS OF THE CPG SITES OF THE PRAME EXON 2 IN THESE CANCER CELL LINES REVEALED A CLOSE RELATIONSHIP BETWEEN THE METHYLATION STATUS OF THE PRAME GENE AND ITS EXPRESSION. A METHYLATION-SPECIFIC PCR ANALYSIS DEMONSTRATED THAT HYPOMETHYLATION OF PRAME WAS SIGNIFICANTLY MORE FREQUENT IN CML BLAST CRISIS (70%) THAN IN CHRONIC PHASE (36%) (P=0.01) AND WAS CORRELATED WITH HIGH EXPRESSION LEVELS OF PRAME TRANSCRIPTS (P<0.0001). THESE RESULTS SUGGEST THAT HYPOMETHYLATION OF PRAME UP-REGULATES ITS EXPRESSION IN CML AND MIGHT PLAY A SIGNIFICANT ROLE IN THE PROGRESSION OF THE DISEASE.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4   150  45 ABERRANT HYPOMETHYLATION OF THE CANCER-TESTIS ANTIGEN PRAME CORRELATES WITH PRAME EXPRESSION IN ACUTE MYELOID LEUKEMIA. PRAME IS A TUMOR-ASSOCIATED ANTIGEN, WHICH BELONGS TO THE FAMILY OF CANCER-TESTIS ANTIGENS (CTA). THE EXPRESSION OF CTA IS MAINLY RESTRICTED TO THE TESTIS AND VARIOUS TUMORS. IN CONTRAST TO OTHER CTA, PRAME EXPRESSION IS ALSO FREQUENTLY DETECTED IN ACUTE AND CHRONIC LEUKEMIAS. DUE TO THIS EXPRESSION PATTERN, PRAME HAS ATTRACTED GREAT INTEREST AS A PROGNOSTIC TUMOR MARKER THAT CAN BE USED FOR THE DETECTION OF MINIMAL RESIDUAL DISEASE AND AS A POTENTIAL TARGET FOR IMMUNOTHERAPY. IN ACUTE MYELOID LEUKEMIA (AML), PRAME EXPRESSION HAS BEEN OBSERVED IN 30-64% OF CASES. TO EVALUATE WHETHER EPIGENETIC MECHANISMS CONTRIBUTE TO PRAME ACTIVATION IN AML, WE STUDIED DNA METHYLATION OF 15 CPG DINUCLEOTIDES WITHIN A CPG-RICH REGION LOCATED IN THE INTRON 1 OF THE PRAME GENE. DNA METHYLATION WAS DETERMINED BY SEQUENCE ANALYSIS OF CLONED PCR PRODUCTS GENERATED FROM BISULFITE-TREATED GENOMIC DNA. METHYLATION PATTERNS WERE CORRELATED WITH PRAME MRNA LEVELS AS DETERMINED BY MICROARRAY ANALYSIS AND REAL-TIME PCR. WE FOUND ALMOST COMPLETE METHYLATION IN MONONUCLEAR BLOOD CELLS FROM TWO HEALTHY DONORS AND IN BONE MARROW CELLS OF FOUR PRAME-NEGATIVE AML PATIENTS. IN CONTRAST, THE DEGREE OF PRAME METHYLATION WAS CLEARLY REDUCED IN FOUR PRAME-POSITIVE AML BONE MARROW SAMPLES. IN PARTICULAR, THESE SAMPLES WERE CHARACTERIZED BY THE PRESENCE OF CLONES, WHICH WERE COMPLETELY DEVOID OF METHYLATION. THE SIGNIFICANT INVERSE CORRELATION BETWEEN THE DEGREE OF METHYLATION AND PRAME EXPRESSION SUGGESTS A CAUSAL ROLE OF DNA METHYLATION IN PRAME REGULATION. SUCH A ROLE IS FURTHER SUPPORTED BY THE OBSERVATION THAT TREATMENT OF PRAME-NEGATIVE CELL LINES U-937 AND THP-1 WITH THE DEMETHYLATING AGENT 5'-AZA-2'DC RESULTED IN A DOSE-RELATED UPREGULATION OF PRAME EXPRESSION.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  4821  34 OCHRATOXIN A: 13-WEEK ORAL TOXICITY AND CELL PROLIFERATION IN MALE F344/N RATS. OCHRATOXIN A (OTA) IS NEPHROTOXIC AND A POTENT RENAL CARCINOGEN. MALE RATS ARE MOST SUSCEPTIBLE TO OTA TOXICITY, AND CHRONIC ADMINISTRATION OF OTA (70 AND 210 MICROG/KG BW) FOR 2 YEARS HAS BEEN SHOWN TO INDUCE HIGH INCIDENCES OF ADENOMAS AND CARCINOMAS ARISING FROM THE STRAIGHT SEGMENT OF THE PROXIMAL TUBULE EPITHELIUM. IN CONTRAST, TREATMENT WITH A LOWER DOSE OF 21 MICROG/KG BW DID NOT RESULT IN INCREASED TUMOR RATES, SUGGESTING A NONLINEAR DOSE RESPONSE FOR RENAL TUMOR FORMATION BY OTA. SINCE THE MECHANISM OF OTA CARCINOGENICITY IS STILL LARGELY UNKNOWN, THIS STUDY WAS CONDUCTED TO INVESTIGATE EARLY FUNCTIONAL AND PATHOLOGICAL EFFECTS OF OTA AND TO DETERMINE IF SUSTAINED STIMULATION OF RENAL CELL PROLIFERATION PLAYS A ROLE. MALE F344/N RATS WERE TREATED WITH OTA FOR UP TO 13 WEEKS UNDER CONDITIONS OF THE NATIONAL TOXICOLOGY PROGRAM (NTP) BIOASSAY. CELL PROLIFERATION IN THE RENAL CORTEX AND OUTER STRIPE OF THE OUTER MEDULLA (OSOM) WAS DETERMINED USING BROMODEOXYURIDINE INCORPORATION AND IMMUNOHISTOCHEMISTRY. HISTOPATHOLOGICAL EXAMINATION SHOWED RENAL ALTERATIONS IN MID- AND HIGH-DOSE-TREATED ANIMALS INVOLVING SINGLE-CELL DEATH AND PROMINENT NUCLEAR ENLARGEMENT WITHIN THE STRAIGHT PROXIMAL TUBULES. TREATMENT WITH OTA AT DOSES OF 70 AND 210 MICROG/KG BW LED TO A MARKED DOSE- AND TIME-DEPENDENT INCREASE IN RENAL CELL PROLIFERATION, EXTENDING FROM THE MEDULLARY RAYS INTO THE OSOM. NO EFFECTS WERE EVIDENT IN KIDNEYS OF LOW-DOSE-TREATED ANIMALS OR IN THE LIVER, WHICH IS NOT A TARGET FOR OTA CARCINOGENICITY. A NO OBSERVED EFFECT LEVEL IN THIS STUDY WAS ESTABLISHED AT 21 MICROG/KG BW, CORRELATING WITH THE DOSE IN THE NTP 2-YEAR BIOASSAY THAT DID NOT PRODUCE RENAL TUMORS. THE APPARENT CORRELATION BETWEEN ENHANCED CELL TURNOVER AND TUMOR FORMATION INDUCED BY OTA INDICATES THAT STIMULATION OF CELL PROLIFERATION MAY PLAY AN IMPORTANT ROLE IN OTA CARCINOGENICITY AND PROVIDES FURTHER EVIDENCE FOR AN EPIGENETIC, THRESHOLDED MECHANISM.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  2765  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
7  2326  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8   791  30 CELLULAR AND MOLECULAR NETWORKS IN CHRONIC MYELOID LEUKEMIA: THE LEUKEMIC STEM, PROGENITOR AND STROMAL CELL INTERPLAY. THE USE OF IMATINIB, SECOND AND THIRD GENERATION ABL TYROSINE KINASE INHIBITORS (TKI) (I.E. DASATINIB, NILOTINIB, BOSUTINIB AND PONATINIB) MADE CML A CLINICALLY MANAGEABLE AND, IN A SMALL PERCENTAGE OF CASES, A CURED DISEASE. TKI THERAPY ALSO TURNED CML BLASTIC TRANSFORMATION INTO A RARE EVENT; HOWEVER, DISEASE PROGRESSION STILL OCCURS IN THOSE PATIENTS WHO ARE REFRACTORY, NOT COMPLIANT WITH TKI THERAPY OR DEVELOP RESISTANCE TO MULTIPLE TKIS. IN THE PAST FEW YEARS, IT BECAME CLEAR THAT THE BCRABL1 ONCOGENE DOES NOT OPERATE ALONE TO DRIVE DISEASE EMERGENCE, MAINTENANCE AND PROGRESSION. INDEED, IT SEEMS THAT BONE MARROW (BM) MICROENVIRONMENT-GENERATED SIGNALS AND CELL AUTONOMOUS BCRABL1 KINASE-INDEPENDENT GENETIC AND EPIGENETIC ALTERATIONS ALL CONTRIBUTE TO: I. PERSISTENCE OF A QUIESCENT LEUKEMIC STEM CELL (LSC) RESERVOIR, II. INNATE OR ACQUIRED RESISTANCE TO TKIS, AND III. PROGRESSION INTO THE FATAL BLAST CRISIS STAGE. HEREIN, WE REVIEW THE INTRICATE LEUKEMIC NETWORK IN WHICH ABERRANT, BUT FINELY TUNED, SURVIVAL, MITOGENIC AND SELF-RENEWAL SIGNALS ARE GENERATED BY LEUKEMIC PROGENITORS, STROMAL CELLS, IMMUNE CELLS AND METABOLIC MICROENVIRONMENTAL CONDITIONS (E.G. HYPOXIA) TO PROMOTE LSC MAINTENANCE AND BLASTIC TRANSFORMATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9  6881  36 [RESEARCH PROGRESS OF M6A METHYLATION MODIFICATION IN HEMATOLOGICAL TUMORS--REVIEW]. N6-METHYLADENOSINE (M6A) IS ONE OF THE MOST COMMON EPIGENETIC MODIFICATIONS OF EUKARYOTIC MRNAS, WHICH IS INVOLVED IN THE REGULATION OF GENE EXPRESSIONS AND BIOLOGICAL PROCESSES IN A VARIETY OF CELLS WITH DYNAMIC AND REVERSIBLE METHYLATION PROCESSES. IN RECENT YEARS, MANY STUDIES HAVE SHOWN THAT M6A METHYLATION MODIFICATION NOT ONLY ACTS ON THE GROWTH, PROLIFERATION, AND MEDULLARY DIFFERENTIATION OF ACUTE MYELOID LEUKEMIA CELLS, BUT ALSO PARTICIPATES IN THE REGULATION OF THE PROLIFERATION AND APOPTOSIS OF OTHER HEMATOLOGICAL TUMOR CELLS SUCH AS CHRONIC MYELOID LEUKEMIA AND DIFFUSE LARGE B-CELL LYMPHOMA, AND IT CAN EVEN WEAKEN THE EFFICACY OF ANTI-HEMATOLOGICAL TUMOR IMMUNOTHERAPY AND INDUCE IMMUNE ESCAPE LEADING TO TUMOR RESISTANCE. WITH THE SUCCESSIVE DEVELOPMENT OF A VARIETY OF M6A METHYLATION-RELATED ENZYME INHIBITORS, IT WILL PROVIDE NEW THERAPEUTIC IDEAS FOR PATIENTS WITH RELAPSED AND REFRACTORY HEMATOLOGICAL TUMORS. IN THIS PAPER, WE REVIEW THE RESEARCH PROGRESS ON THE MECHANISM OF M6A METHYLATION ON THE OCCURRENCE, DEVELOPMENT, AND TUMOR IMMUNITY OF VARIOUS HEMATOLOGICAL TUMORS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10  1046  37 CLINICAL DEVELOPMENT OF DECITABINE AS A PROTOTYPE FOR AN EPIGENETIC DRUG PROGRAM. THIS REVIEW HIGHLIGHTS DECITABINE AS A PROTOTYPE EPIGENETIC MODIFYING DRUG TO SHOW HOW THE CLINICAL DEVELOPMENT OF EPIGENETIC AGENTS DIFFERS FROM THAT OF TRADITIONAL CYTOTOXIC CHEMOTHERAPIES. DECITABINE, A CYTOSINE ANALOGUE, IS CYTOTOXIC AT HIGH DOSES BUT HAS SELECTIVE DNA DEMETHYLATING ACTIVITY AT LOW DOSES. THE FOCUS OF CURRENT DECITABINE INVESTIGATIONS IS TWOFOLD: TO ELUCIDATE ALL OF THE MECHANISMS OF ACTION AND TO DETERMINE THE OPTIMAL DOSE, SCHEDULE, AND CONCOMITANT THERAPIES. NEW PHASE I TRIALS HAVE IDENTIFIED A "BIOLOGICALLY EFFECTIVE DOSE," WHICH IS 1 TO 2 LOGS LOWER THAN THE CYTOTOXIC DOSE. A CLINICAL DEVELOPMENT PROGRAM WITH LOW-DOSE DECITABINE IN MALIGNANT DISEASES IS FOCUSED ON MYELODYSPLASTIC SYNDROME (MDS), ACUTE MYELOGENOUS LEUKEMIA (AML), AND CHRONIC MYELOGENOUS LEUKEMIA (CML). A PHASE III TRIAL IN MDS SHOWED OBJECTIVE RESPONSES (COMPLETE [CR] PLUS PARTIAL [PR] REMISSION) AND LONGER MEDIAN TIME TO PROGRESSION TO AML OR DEATH WITH DECITABINE THAN WITH SUPPORTIVE CARE ALONE. THE OPTIMAL USE OF DECITABINE MAY BE IN COMBINATION WITH OTHER AGENTS THAT PROMOTE GENE EXPRESSION, NAMELY, HISTONE DEACETYLASE (HDAC) INHIBITORS. OPTIMIZED DECITABINE DOSES AND COMBINATIONS WITH OTHER EPIGENETIC THERAPIES THAT CAN BE USED AT MINIMALLY TOXIC DOSES PROVIDE POTENTIALLY SAFER THERAPEUTIC OPTIONS AND INTRODUCE NOVEL COMBINATION THERAPIES.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
11  4491  38 MONOSOMY 7 MYELOPROLIFERATIVE DISEASE IN CHILDREN WITH NEUROFIBROMATOSIS, TYPE 1: EPIDEMIOLOGY AND MOLECULAR ANALYSIS. LOSS OF CONSTITUTIONAL HETEROZYGOSITY IS A COMMON MOLECULAR FEATURE OF CANCERS IN WHICH INACTIVATION OF ONE OR MORE TUMOR SUPPRESSOR GENES IS THOUGHT TO CONTRIBUTE TO TUMORIGENESIS. RECENT EVIDENCE SUGGESTS THAT THE GENE RESPONSIBLE FOR NEUROFIBROMATOSIS, TYPE 1 (NF-1), BELONGS TO THIS CLASS OF HERITABLE CANCER GENES. CHILDREN WITH NF-1 SHOW AN INCREASED INCIDENCE OF MYELOID LEUKEMIA, INCLUDING JUVENILE CHRONIC MYELOGENOUS LEUKEMIA (JCML) AND, PERHAPS, THE MYELOPROLIFERATIVE SYNDROME (MPS) ASSOCIATED WITH BONE MARROW MONOSOMY 7 (MO 7). WE HAVE INVESTIGATED FIVE CHILDREN WITH MO 7: THREE WITH NF-1 AND TWO OTHERS WITH SUGGESTIVE EVIDENCE OF NF-1. SOUTHERN BLOTTING EXPERIMENTS PERFORMED IN FOUR PATIENTS SHOWED NO LOSS OF HETEROZYGOSITY IN BONE MARROW SPECIMENS USING PROBES LINKED TO THE NF-1 LOCUS ON THE LONG ARM OF CHROMOSOME 17. BOTH OF OUR PATIENTS WITH FAMILIAL NF-1 INHERITED THE DISEASE FROM THEIR MOTHERS, AS DID 14 OF 19 OTHER CASES OF MYELOID LEUKEMIA IN CHILDREN WITH FAMILIAL NF-1. SEVENTEEN OF THESE 21 CHILDREN WERE BOYS. MYELOID LEUKEMIA DEVELOPED IN 12 BOYS AND FOUR GIRLS WHO INHERITED NF-1 FROM THEIR MOTHERS, AND IN FIVE BOYS WHO INHERITED THE DISEASE FROM THEIR FATHERS. FATHER-TO-DAUGHTER TRANSMISSION WAS NOT OBSERVED. TAKEN TOGETHER, THE PRESENCE OF CHROMOSOME 7 DELETIONS IN THE LEUKEMIAS OF CHILDREN WITH NF-1, A PATTERN OF INHERITANCE FAVORING MATERNAL TRANSMISSION OF NF-1, AND THE MARKED PREDILECTION FOR BOYS TO DEVELOP JCML AND MO 7 SUGGEST A MULTISTEP MECHANISM OF ONCOGENESIS IN WHICH EPIGENETIC FACTORS MIGHT PLAY A ROLE. FURTHER INVESTIGATION IS REQUIRED TO DETERMINE IF THE NF-1 GENES IN THE LEUKEMIC BONE MARROWS OF THESE PATIENTS HAVE ACQUIRED POINT MUTATIONS OR SMALL DELETIONS.	1992	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
12  4533  42 MULTIPLE GENE KNOCKDOWN STRATEGIES FOR INVESTIGATING THE PROPERTIES OF HUMAN LEUKEMIA STEM CELLS AND EXPLORING NEW THERAPIES. THE PAST TWO DECADES HAVE WITNESSED SIGNIFICANT STRIDES IN LEUKEMIA THERAPIES THROUGH APPROVAL OF THERAPEUTIC INHIBITORS TARGETING ONCOGENE-DRIVING DYSREGULATED TYROSINE KINASE ACTIVITIES AND KEY EPIGENETIC AND APOPTOSIS REGULATORS. ALTHOUGH THESE DRUGS HAVE BROUGHT ABOUT COMPLETE REMISSION IN THE MAJORITY OF PATIENTS, MANY PATIENTS FACE RELAPSE OR HAVE REFRACTORY DISEASE. THE MAIN FACTOR CONTRIBUTING TO RELAPSE IS THE PRESENCE OF A SMALL SUBPOPULATION OF DORMANT DRUG-RESISTANT LEUKEMIA CELLS THAT POSSESS STEM CELL FEATURES (TERMED AS LEUKEMIA STEM CELLS OR LSCS). THUS, OVERCOMING DRUG RESISTANCE AND TARGETING LSCS REMAIN MAJOR CHALLENGES FOR CURATIVE TREATMENT OF HUMAN LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A GOOD EXAMPLE, WITH RARE, PROPAGATING LSCS AND DRUG-RESISTANT CELLS THAT CANNOT BE ERADICATED BY BCR-ABL-DIRECTED TYROSINE KINASE INHIBITOR (TKI) MONOTHERAPY AND THAT ARE RESPONSIBLE FOR DISEASE RELAPSE/PROGRESSION. THEREFORE, IT IS IMPERATIVE TO IDENTIFY KEY PLAYERS IN REGULATING BCR-ABL1-DEPENDENT AND INDEPENDENT DRUG-RESISTANCE MECHANISMS, AND THEIR KEY PATHWAYS, SO THAT CML LSCS CAN BE SELECTIVELY TARGETED OR SENSITIZED TO TKIS. HERE, WE DESCRIBE SEVERAL EASILY ADAPTABLE GENE KNOCKDOWN APPROACHES IN CD34(+) CML STEM/PROGENITOR CELLS THAT CAN BE USED TO INVESTIGATE THE BIOLOGICAL PROPERTIES OF LSCS AND MOLECULAR EFFECTS OF GENES OF INTEREST (GOI), WHICH CAN BE FURTHER EXPLORED AS THERAPEUTIC MODALITIES AGAINST LSCS IN THE CONTEXT OF HUMAN LEUKEMIA.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
13   837  52 CHEMICALLY INDUCED RENAL TUBULE TUMORS IN THE LABORATORY RAT AND MOUSE: REVIEW OF THE NCI/NTP DATABASE AND CATEGORIZATION OF RENAL CARCINOGENS BASED ON MECHANISTIC INFORMATION. THE INCIDENCE OF RENAL TUBULE CARCINOGENESIS IN MALE AND FEMALE RATS OR MICE WITH 69 CHEMICALS FROM THE 513 BIOASSAYS CONDUCTED TO DATE BY THE NCI/NTP HAS BEEN COLLATED, THE CHEMICALS CATEGORIZED, AND THE RELATIONSHIP BETWEEN CARCINOGENESIS AND RENAL TUBULE HYPERPLASIA AND EXACERBATION OF THE SPONTANEOUS, AGE-RELATED RODENT DISEASE CHRONIC PROGRESSIVE NEPHROPATHY (CPN) EXAMINED. WHERE INFORMATION ON MECHANISM OR MODE OF ACTION EXISTS, THE CHEMICALS HAVE BEEN CATEGORIZED BASED ON THEIR ABILITY TO DIRECTLY OR INDIRECTLY INTERACT WITH RENAL DNA, OR ON THEIR ACTIVITY VIA EPIGENETIC PATHWAYS INVOLVING EITHER DIRECT OR INDIRECT CYTOTOXICITY WITH REGENERATIVE HYPERPLASIA, OR EXACERBATION OF CPN. NINE CHEMICALS WERE IDENTIFIED AS DIRECTLY INTERACTING WITH DNA, WITH SIX OF THESE PRODUCING RENAL TUBULE TUMORS AT HIGH INCIDENCE IN RATS OF BOTH SEXES, AND IN SOME CASES ALSO IN MICE. OCHRATOXIN A WAS THE MOST POTENT COMPOUND IN THIS GROUP, PRODUCING A HIGH TUMOR INCIDENCE AT VERY LOW DOSES, OFTEN WITH METASTASIS. THREE CHEMICALS WERE DISCUSSED IN THE CONTEXT OF INDIRECT DNA DAMAGE MEDIATED BY AN OXIDATIVE FREE RADICAL MECHANISM, ONE OF THESE BEING FROM THE NTP DATABASE. A THIRD CATEGORY INCLUDED FOUR CHEMICALS THAT HAD THE POTENTIAL TO CAUSE DNA DAMAGE FOLLOWING CONJUGATION WITH GLUTATHIONE AND SUBSEQUENT ENZYMATIC ACTIVATION TO A REACTIVE SPECIES, USUALLY A THIOL-CONTAINING ENTITY. TWO CHEMICALS WERE ALLOCATED INTO THE CATEGORY INVOLVING A DIRECT CYTOTOXIC ACTION ON THE RENAL TUBULE FOLLOWED BY SUSTAINED COMPENSATORY CELL PROLIFERATION, WHILE NINE WERE INCLUDED IN A GROUP WHERE THE CELL LOSS AND SUSTAINED INCREASE IN RENAL TUBULE CELL TURNOVER WERE DEPENDENT ON LYSOSOMAL ACCUMULATION OF THE MALE RAT-SPECIFIC PROTEIN, ALPHA2MU-GLOBULIN. IN A SIXTH CATEGORY, MORPHOLOGIC EVIDENCE ON TWO CHEMICALS INDICATED THAT THE RENAL TUMORS WERE A CONSEQUENCE OF EXACERBATED CPN. FOR THE REMAINING CHEMICALS, THERE WERE NO PERTINENT DATA ENABLING ASSIGNMENT TO A MECHANISTIC CATEGORY. ACCORDINGLY, THESE CHEMICALS, ACTING THROUGH AN AS YET UNKNOWN MECHANISM, WERE GROUPED AS EITHER BEING ASSOCIATED WITH AN ENHANCEMENT OF CPN (CATEGORY 7, 16 CHEMICALS), OR NOT ASSOCIATED WITH ENHANCED CPN (CATEGORY 8, 4 CHEMICALS). A NINTH CATEGORY DEALT WITH 11 CHEMICALS THAT WERE REGARDED AS PRODUCING INCREASES IN RENAL TUBULE TUMORS THAT DID NOT REACH STATISTICAL SIGNIFICANCE. A 10TH CATEGORY DISCUSSED 6 CHEMICALS THAT INDUCED RENAL TUMORS IN MICE BUT NOT IN RATS, PLUS 8 CHEMICALS THAT PRODUCED A LOW INCIDENCE OF RENAL TUBULE TUMORS IN MICE THAT DID NOT REACH STATISTICAL SIGNIFICANCE. AS MORE MECHANISTIC DATA ARE GENERATED, SOME CHEMICALS WILL INEVITABLY BE PLACED IN DIFFERENT GROUPS, PARTICULARLY THOSE FROM CATEGORIES 7 AND 8. A LARGE NUMBER OF CHEMICALS IN THE SERIES EXACERBATED CPN, BUT THOSE IN CATEGORY 7 ESPECIALLY MAY BE CANDIDATES FOR INCLUSION IN CATEGORY 6 WHEN FURTHER INFORMATION IS GLEANED FROM THE RELEVANT NTP STUDIES. ALSO, NEW DATA ON SPECIFIC CHEMICALS WILL PROBABLY EXPAND CATEGORY 5 AS CYTOTOXICITY AND CELL REGENERATION ARE IDENTIFIED AS OBLIGATORY STEPS IN RENAL CARCINOGENESIS IN MORE CASES. ADDITIONAL CONFIRMATORY OUTCOMES ARISING FROM THIS REVIEW ARE THAT METASTASES FROM RENAL TUBULE TUMORS, WHILE ENCOUNTERED WITH CHEMICALS CAUSING DNA DAMAGE, ARE RARE WITH THOSE ACTING THROUGH AN EPIGENETIC PATHWAY, WITH THE EXCEPTION BEING FUMONISIN B1; THAT MALE RATS AND MICE ARE GENERALLY MORE SUSCEPTIBLE THAN FEMALE RATS AND MICE TO CHEMICAL INDUCTION OF RENAL TUBULE TUMORS; AND THAT A BACKGROUND OF ATYPICAL TUBULE HYPERPLASIA IS A USEFUL INDICATOR REFLECTING A CHEMICALLY ASSOCIATED RENAL TUBULE TUMOR RESPONSE. WITH RESPECT TO RENAL TUBULE TUMORS AND HUMAN RISK ASSESSMENT, CHEMICALS IN CATEGORIES 1 AND 2, AND POSSIBLY 3, WOULD CURRENTLY BE JUDGED BY LINEAR DEFAULT METHODS; CHEMICALS IN CATEGORY 4 (AND PROBABLY SOME IN CATEGORY 3) AS EXHIBITING A THRESHOLD OF ACTIVITY WARRANTING THE BENCHMARK APPROACH; AND THOSE IN CATEGORIES 5 AND 6 AS REPRESENTING MECHANISMS THAT HAVE NO RELEVANCE FOR EXTRAPOLATION TO HUMANS.	2004	

14   709  42 C-MYC ONCOPROTEIN DICTATES TRANSCRIPTIONAL PROFILES OF ATP-BINDING CASSETTE TRANSPORTER GENES IN CHRONIC MYELOGENOUS LEUKEMIA CD34+ HEMATOPOIETIC PROGENITOR CELLS. RESISTANCE TO CHEMOTHERAPEUTIC AGENTS REMAINS ONE OF THE MAJOR IMPEDIMENTS TO A SUCCESSFUL TREATMENT OF CHRONIC MYELOID LEUKEMIA (CML). MISREGULATION OF THE ACTIVITY OF A SPECIFIC GROUP OF ATP-BINDING CASSETTE TRANSPORTERS (ABC) IS RESPONSIBLE FOR REDUCING THE INTRACELLULAR CONCENTRATION OF DRUGS IN LEUKEMIC CELLS. MOREOVER, A CONSISTENT BODY OF EVIDENCE ALSO SUGGESTS THAT ABC TRANSPORTERS PLAY A ROLE IN CANCER PROGRESSION BEYOND THE EFFLUX OF CYTOTOXIC DRUGS. DESPITE A LARGE NUMBER OF STUDIES THAT INVESTIGATED THE FUNCTION OF THE ABC TRANSPORTERS, LITTLE IS KNOWN ABOUT THE TRANSCRIPTIONAL REGULATION OF THE ABC GENES. HERE, WE PRESENT DATA SHOWING THAT THE ONCOPROTEIN C-MYC IS A DIRECT TRANSCRIPTIONAL REGULATOR OF A LARGE SET OF ABC TRANSPORTERS IN CML. FURTHERMORE, MOLECULAR ANALYSIS CARRIED OUT IN CD34+ HEMATOPOIETIC CELL PRECURSORS OF 21 CML PATIENTS REVEALS THAT THE OVEREXPRESSION OF ABC TRANSPORTERS DRIVEN BY C-MYC IS A PECULIAR CHARACTERISTIC OF THE CD34+ POPULATION IN CML AND WAS NOT FOUND EITHER IN THE POPULATION OF MONONUCLEAR CELLS FROM WHICH THEY HAD BEEN PURIFIED NOR IN CD34+ CELLS ISOLATED FROM HEALTHY DONORS. FINALLY, WE DESCRIBE HOW THE METHYLATION STATE OF CPG ISLANDS MAY REGULATE THE ACCESS OF C-MYC TO ABCG2 GENE PROMOTER, A WELL-STUDIED GENE ASSOCIATED WITH MULTIDRUG RESISTANCE IN CML, HENCE, AFFECTING ITS EXPRESSION. TAKEN TOGETHER, OUR FINDINGS SUPPORT A MODEL IN WHICH C-MYC-DRIVEN TRANSCRIPTIONAL EVENTS, COMBINED WITH EPIGENETIC MECHANISMS, DIRECT AND REGULATE THE EXPRESSION OF ABC GENES WITH POSSIBLE IMPLICATIONS IN TUMOR MALIGNANCY AND DRUG EFFLUX IN CML.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15  3934  50 LIVER TUMOR INDUCTION. THE SIGNIFICANCE OF THE DEVELOPMENT OF NODULAR LIVER LESIONS IN RODENTS FOLLOWING THE ADMINISTRATION OF TEST AGENTS RAISES SEVERAL QUESTIONS WHICH COULD BE PLACED IN ONE OF TWO GENERAL CATEGORIES: DIAGNOSTIC AND INTERPRETATIONAL. FROM A DIAGNOSTIC POINT OF VIEW, THE PROPER CLASSIFICATION OF LIVER TUMORS INTO A BENIGN AND MALIGNANT CATEGORY HAS TO BE BASED ON THE DIRECT CORRELATION BETWEEN THE MORPHOLOGY AND THE BIOLOGIC BEHAVIOR OF THE LESIONS. THEREFORE, EXTREME CARE SHOULD BE TAKEN TO SEPARATE THE MALIGNANT TUMORS FROM THE BENIGN AND THE BENIGN NEOPLASIA FROM THE HYPERPLASIA. THE SUBSTITUTION OF THE TERM "NEOPLASTIC NODULE" FOR HYPERPLASTIC NODULE IN RATS IS MISLEADING. MOST OF THESE NODULES, WHEN INDUCED UNDER SPECIAL EXPERIMENTAL CONDITIONS, MAY REGRESS OR REMODEL AND THUS THEY ARE NOT NEOPLASTIC IN NATURE. CHRONIC CARCINOGENICITY BIOASSAYS SHOULD INCLUDE "STOP" TYPE OF TREATMENT LEAVING ENOUGH OF THE OBSERVATIONAL TIME TO ESTABLISH THE FATE OF INDUCED NODULAR LESIONS. THE INDUCTION OF HISTOCHEMICALLY CHANGED FOCI CAN SERVE ONLY AS AN INDICATION OF POTENTIAL HEPATOCARCINOGENICITY AND SHOULD NOT BE EQUATED WITH THE INDUCTION OF BONA FIDE CANCER. THE BIOLOGIC INTERPRETATION OF NODULAR LIVER LESIONS, ESPECIALLY IN MICE, NEEDS FURTHER SCRUTINY BECAUSE THESE LESIONS HAVE A TENDENCY TO DEVELOP SPONTANEOUSLY WITH HIGH INCIDENCE IN SOME STRAINS. THIS CHARACTERISTIC THEN RAISES THE QUESTION AS TO THE MECHANISM BY WHICH VARIOUS AGENTS AUGMENT AND/OR ACCELERATE THE DEVELOPMENT OF SUCH TUMORS. IS THIS ACTION PRIMARILY PROMOTING OR INITIATING IN NATURE OR DOES IT REPRESENT THE INDUCTION OF TUMORS DE NOVO? THE ANSWER TO THIS DILEMMA MAY HAVE A DECISIVE BEARING ON CARCINOGENIC RISK ASSESSMENT AND THE TYPE OF REGULATORY ACTION, SINCE THE PROMOTING AGENTS POSSESS A THRESHOLD EFFECT AND THE PROMOTED CHANGES MAY REGRESS FOLLOWING WITHDRAWAL OF TREATMENT. THE INTERPRETATION OF HEPATOCARCINOGENESIS IS FURTHER COMPLICATED BY THE FACT THAT SEVERAL FACTORS, SUCH AS SEX HORMONAL ENVIRONMENT, INCREASED MITOTIC ACTIVITY FOLLOWING AN EXCESSIVE LOSS OF PARENCHYMAL CELLS, DEGREE OF CALORIC INTAKE, ENZYMATIC COMPLEMENT, AND ANIMALS' AGE AT THE TIME OF THE EXPOSURE TO A TEST AGENT, MAY INFLUENCE THE OUTCOME OF LIVER TUMOR DEVELOPMENT BY MODULATING "INITIATION" AND/OR "PROMOTION" OF CARCINOGENESIS. BROAD FLUCTUATION IN THE HISTORIC INCIDENCE OF LIVER TUMORS FURTHER COMPOUNDS THE COMPLEXITY OF THE PROPER BIOASSAY INTERPRETATION. THE SPECIFICALLY DESIGNED EXPERIMENTS MAY HAVE THE OBJECTIVE TO EXPLORE PREDOMINANTLY THE INITIATING OR PROMOTING EFFECTS OF THE AGENT. SUCH PROTOCOLS SHOULD BE USED WHENEVER NECESSARY TO DIFFERENTIATE BETWEEN THESE TWO MECHANISMS OF ACTION. IN THE CAUCASIANS, THE "SPONTANEOUS" DEVELOPMENT OF THE PRIMARY HEPATOCELLULAR TUMORS IS RARE. THE MAJORITY OF THESE TUMORS ARE MALIGNANT AND RAPIDLY FATAL. ACCORDING TO SOME HUMAN PATHOLOGISTS, THE BENIGN VARIETY OF LIVER TUMORS IS RARE AND IT DOES NOT REPRESENT NECESSARILY A PREMALIGNANT STAGE IN TUMOR DEVELOPMENT. CARCINOMA OF THE LIVER MAY OCCUR IN INFANCY, ESPECIALLY IN MALES BEFORE THE AGE OF 2 YEARS. THIS SUGGESTS A GENETIC CAUSATION OR CARCINOGENIC EXPOSURE IN UTERO. ONE OF THE GEOGRAPHIC FACTORS WHICH SIGNIFICANTLY ENHANCES THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HUMANS IS EXPOSURE TO AFLATOXIN B(1) WHICH IS APPARENTLY POTENTIATED BY CONCURRENT LIVER CIRRHOSIS. BECAUSE MANY MORE AGENTS HAVE BEEN FOUND TO BE HEPATOCARCINOGENIC IN MICE AND RATS THAN IN MEN, A QUESTION ARISES AS TO THE DIRECT RELEVANCE OF RODENT STUDIES TO HUMANS. A BALANCED ASSESSMENT OF THE CARCINOGENICITY OF THE AGENT COULD ONLY BE REACHED IN CONSIDERING BOTH THE PHARMACOKINETICS AND THE DEVELOPMENT OF MALIGNANT NEOPLASIA IN OTHER ORGANS. IN THE CASE OF POSITIVE CARCINOGENICITY ASSESSMENT, THE OUTCOME OF THE MUTAGENICITY BIOASSAYS CAN SUGGEST GENIC (GENOTOXIC) OR PARAGENIC (EPIGENETIC) MODE OF ACTION IN MAMMALIAN SYSTEMS.	1982	
                                                                                                                                                                                                                                                                                                    
16  5613  31 SAFETY AND EFFICACY OF ABEXINOSTAT, A PAN-HISTONE DEACETYLASE INHIBITOR, IN NON-HODGKIN LYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA: RESULTS OF A PHASE II STUDY. HISTONE DEACETYLASE INHIBITORS ARE MEMBERS OF A CLASS OF EPIGENETIC DRUGS THAT HAVE PROVEN ACTIVITY IN T-CELL MALIGNANCIES, BUT LITTLE IS KNOWN ABOUT THEIR EFFICACY IN B-CELL LYMPHOMAS. ABEXINOSTAT IS AN ORALLY AVAILABLE HYDROXAMATE-CONTAINING HISTONE DEACETYLASE INHIBITOR THAT DIFFERS FROM APPROVED INHIBITORS; ITS UNIQUE PHARMACOKINETIC PROFILE AND ORAL DOSING SCHEDULE, TWICE DAILY FOUR HOURS APART, ALLOWS FOR CONTINUOUS EXPOSURE AT CONCENTRATIONS REQUIRED TO EFFICIENTLY KILL TUMOR CELLS. IN THIS PHASE II STUDY, PATIENTS WITH RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA OR CHRONIC LYMPHOCYTIC LEUKEMIA RECEIVED ORAL ABEXINOSTAT AT 80 MG BID FOR 14 DAYS OF A 21-DAY CYCLE AND CONTINUED UNTIL PROGRESSIVE DISEASE OR UNACCEPTABLE TOXICITY. A TOTAL OF 100 PATIENTS WITH B-CELL MALIGNANCIES AND T-CELL LYMPHOMAS WERE ENROLLED BETWEEN OCTOBER 2011 AND JULY 2014. ALL PATIENTS RECEIVED AT LEAST ONE DOSE OF STUDY DRUG. PRIMARY REASONS FOR DISCONTINUATION INCLUDED PROGRESSIVE DISEASE (56%) AND ADVERSE EVENTS (25%). GRADE 3 OR OVER ADVERSE EVENTS AND ANY SERIOUS ADVERSE EVENTS WERE REPORTED IN 88% AND 73% OF PATIENTS, RESPECTIVELY. THE MOST FREQUENTLY REPORTED GRADE 3 OR OVER TREATMENT-EMERGENT RELATED ADVERSE EVENTS WERE THROMBOCYTOPENIA (80%), NEUTROPENIA (27%), AND ANEMIA (12%). AMONG THE 87 PATIENTS EVALUABLE FOR EFFICACY, OVERALL RESPONSE RATE WAS 28% (COMPLETE RESPONSE 5%), WITH HIGHEST RESPONSES OBSERVED IN PATIENTS WITH FOLLICULAR LYMPHOMA (OVERALL RESPONSE RATE 56%), T-CELL LYMPHOMA (OVERALL RESPONSE RATE 40%), AND DIFFUSE LARGE B-CELL LYMPHOMA (OVERALL RESPONSE RATE 31%). FURTHER INVESTIGATION OF THE SAFETY AND EFFICACY OF ABEXINOSTAT IN FOLLICULAR LYMPHOMA, T-CELL LYMPHOMA, AND DIFFUSE LARGE B-CELL LYMPHOMA IMPLEMENTING A LESS DOSE-INTENSE WEEK-ON-WEEK-OFF SCHEDULE IS WARRANTED. (TRIAL REGISTERED AT: EUDRACT-2009-013691-47).	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
17  4820  30 OCHRATOXIN A AS A POTENTIAL ETIOLOGIC FACTOR IN ENDEMIC NEPHROPATHY: LESSONS FROM TOXICITY STUDIES IN RATS. VARIOUS REPORTS SUGGEST THAT CHRONIC DIETARY EXPOSURE TO OCHRATOXIN A (OTA), A MYCOTOXIN FREQUENTLY DETECTED IN VARIOUS FOOD ITEMS MAY BE LINKED TO THE PATHOGENESIS OF ENDEMIC NEPHROPATHY, A CHRONIC TUBULOINTERSTITIAL KIDNEY DISEASE WHICH OCCURS IN GEOGRAPHICALLY LIMITED AREAS OF THE BALKAN REGION. OTA IS A POTENT NEPHROTOXIN AND RENAL CARCINOGEN. HOWEVER, THE PATHOLOGICAL LESIONS OBSERVED IN KIDNEYS OF RATS TREATED WITH OTA APPEAR BE RATHER DIFFERENT FROM THE CLINICAL AND PATHOLOGICAL CHARACTERISTICS OF ENDEMIC NEPHROPATHY. MOREOVER, INCREASING EVIDENCE SUGGESTS THAT OTA DOES NOT BIND TO DNA BUT INDUCES TUMORS BY AN EPIGENETIC, THRESHOLDED MECHANISM. THIS IMPLIES THAT THERE IS A DOSE BELOW WHICH NO ADVERSE HEALTH EFFECTS ARE EXPECTED TO OCCUR. BASED ON FOOD CONSUMPTION DATA AND OTA SERUM CONCENTRATIONS, IT APPEARS THAT HUMAN EXPOSURE - EVEN IN AREAS WITH RELATIVELY HIGH DIETARY EXPOSURE TO OTA SUCH AS ENDEMIC VILLAGES - IS SEVERAL ORDERS OF MAGNITUDE BELOW DOSES KNOWN TO CAUSE NEPHROTOXICITY AND TUMOR FORMATION IN LABORATORY ANIMALS. WHILE IT IS UNDOUBTEDLY IMPORTANT TO ENCOURAGE PREVENTION OF FOOD CONTAMINATION BY OTA AND OTHER MYCOTOXINS, THESE OBSERVATIONS SUGGEST THAT OTA IS NOT LIKELY TO BE AN ETIOLOGICAL FACTOR INVOLVED IN BEN AND INDICATE A NEED TO SEARCH FOR NEW CLUES FOR THE ETIOLOGY OF THIS ENDEMIC KIDNEY DISEASE.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  5212  32 PRESERVATION OF QUIESCENT CHRONIC MYELOGENOUS LEUKEMIA STEM CELLS BY THE BONE MARROW MICROENVIRONMENT. THE MAJORITY OF LEUKEMIA PATIENTS ACHIEVING REMISSION ULTIMATELY RELAPSE. PERSISTENCE OF LEUKEMIA STEM CELLS (LSC) CAPABLE OF REGENERATING LEUKEMIA IS A MAJOR CAUSE OF RELAPSE. THERE IS A PRESSING NEED TO BETTER UNDERSTAND MECHANISMS OF LSC REGULATION AND THEIR RESISTANCE TO THERAPY IN ORDER TO IMPROVE OUTCOMES FOR LEUKEMIA. CHRONIC MYELOGENOUS LEUKEMIA (CML) IS A LETHAL MYELOPROLIFERATIVE DISORDER THAT THAT IS CAUSED BY HEMATOPOIETIC STEM CELL (HSC) TRANSFORMATION BY THE BCR-ABL TYROSINE KINASE. TREATMENT WITH TYROSINE KINASE INHIBITORS (TKI) HAS REVOLUTIONIZED CML TREATMENT, BUT FAILS TO ELIMINATE LSC RESPONSIBLE FOR PROPAGATING AND REGENERATING LEUKEMIA. THEREFORE, PATIENTS REQUIRE CONTINUED TREATMENT TO PREVENT RELAPSE. LEUKEMIC AND NORMAL STEM CELLS SHARE PROPERTIES OF QUIESCENCE AND SELF-RENEWAL, THAT ARE SUPPORTED BY BONE MARROW NICHES. PERSISTENCE OF LSC AFTER TKI TREATMENT IS RELATED TO TYROSINE KINASE INDEPENDENT MECHANISMS WHICH INCLUDE INTRINSIC PROPERTIES OF LSCS DETERMINED BY EPIGENETIC ALTERATIONS, ALTERED TRANSCRIPTIONAL REGULATORY NETWORKS OR MITOCHONDRIAL/METABOLIC CHANGES. IN ADDITION TO CELL INTRINSIC CHANGES, SIGNALS FROM THE BONE MARROW MICROENVIRONMENT (BMM) PLAY A CRITICAL ROLE IN PROTECTING LSC FROM TKI TREATMENT. EACH TYPE OF ALTERATION MAY OFFER POTENTIAL POINTS OF INTERVENTION FOR THERAPEUTIC TARGETING OF LSC.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19   826  38 CHARACTERIZATION OF K562 CELLS: UNCOVERING NOVEL CHROMOSOMES, ASSESSING TRANSFERRIN RECEPTOR EXPRESSION, AND PROBING PHARMACOLOGICAL THERAPIES. HUMAN ERYTHROLEUKEMIC K562 CELLS REPRESENT THE PROTOTYPICAL CELL CULTURE MODEL OF CHRONIC MYELOID LEUKEMIA (CML). THE CELLS ARE PSEUDO-TRIPLOID AND POSITIVE FOR THE PHILADELPHIA CHROMOSOME. THEREFORE, K562 CELLS HAVE BEEN WIDELY USED FOR INVESTIGATING THE BCR/ABL1 ONCOGENE AND THE TYROSINE KINASE INHIBITOR, IMATINIB-MESYLATE. FURTHER, K562 CELLS OVEREXPRESS TRANSFERRIN RECEPTORS (TFR) AND HAVE BEEN USED AS A MODEL FOR TARGETING CYTOTOXIC THERAPIES, VIA RECEPTOR-MEDIATED ENDOCYTOSIS. HERE, WE HAVE CHARACTERIZED K562 CELLS FOCUSING ON THE KARYOTYPE OF CELLS IN PROLONGED CULTURE, REGULATION OF EXPRESSION OF TFR IN WILDTYPE (WT) AND DOXORUBICIN-RESISTANT CELLS, AND RESPONSES TO HISTONE DEACETYLASE INHIBITION (HDACI). KARYOTYPE ANALYSIS INDICATES NOVEL CHROMOSOMES AND GENE EXPRESSION ANALYSIS SUGGESTS A SHIFT OF CULTURED K562 CELLS AWAY FROM PATIENT-DERIVED LEUKEMIC CELLS. WE CONFIRM THE HIGH EXPRESSION OF TFR ON K562 CELLS USING IMMUNOFLUORESCENCE AND CELL-SURFACE RECEPTOR BINDING RADIOASSAYS. IMPORTANTLY, HIGH TFR EXPRESSION IS OBSERVED IN PATIENT-DERIVED CELLS, AND WE HIGHLIGHT THE PERSISTENT EXPRESSION OF TFR FOLLOWING DOXORUBICIN ACQUIRED RESISTANCE. EPIGENETIC ANALYSIS INDICATES THAT PERMISSIVE HISTONE ACETYLATION AND METHYLATION AT THE PROMOTER REGION REGULATES THE TRANSCRIPTION OF TFR IN K562 CELLS. FINALLY, WE SHOW RELATIVELY HIGH EXPRESSION OF HDAC ENZYMES IN K562 CELLS AND DEMONSTRATE THE CHEMOTOXIC EFFECTS OF HDACI, USING THE FDA-APPROVED HYDROXAMIC ACID, VORINOSTAT. TOGETHER WITH A DESCRIPTION OF MORPHOLOGY, INFRARED SPECTRAL ANALYSIS, AND EXAMINATION OF METABOLIC PROPERTIES, WE PROVIDE A COMPREHENSIVE CHARACTERIZATION OF K562 CELLS. OVERALL, K562 CELL CULTURE SYSTEMS REMAIN WIDELY USED FOR THE INVESTIGATION OF NOVEL THERAPEUTICS FOR CML, WHICH IS PARTICULARLY IMPORTANT IN CASES OF IMATINIB-MESYLATE RESISTANCE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20  3614  35 IN VITRO CELL TRANSFORMATION ASSAYS: A VALUABLE APPROACH FOR CARCINOGENIC POTENTIALITY ASSESSMENT OF NANOMATERIALS. THIS REVIEW EXPLORES THE APPLICATION OF IN VITRO CELL TRANSFORMATION ASSAYS (CTAS) AS A SCREENING PLATFORM TO ASSESS THE CARCINOGENIC POTENTIAL OF NANOMATERIALS (NMS) RESULTING FROM CONTINUOUSLY GROWING INDUSTRIAL PRODUCTION AND USE. THE WIDESPREAD APPLICATION OF NMS IN VARIOUS FIELDS HAS RAISED CONCERNS ABOUT THEIR POTENTIAL ADVERSE EFFECTS, NECESSITATING SAFETY EVALUATIONS, PARTICULARLY IN LONG-TERM CONTINUOUS EXPOSURE SCENARIOS. CTAS PRESENT A REALISTIC SCREENING PLATFORM FOR KNOWN AND EMERGING NMS BY EXAMINING THEIR RESEMBLANCE TO THE HALLMARK OF MALIGNANCY, INCLUDING HIGH PROLIFERATION RATES, LOSS OF CONTACT INHIBITION, THE GAIN OF ANCHORAGE-INDEPENDENT GROWTH, CELLULAR INVASION, DYSREGULATION OF THE CELL CYCLE, APOPTOSIS RESISTANCE, AND ABILITY TO FORM TUMORS IN EXPERIMENTAL ANIMALS. THROUGH THE DELIBERATE TRANSFORMATION OF CELLS VIA CHRONIC NM EXPOSURE, RESEARCHERS CAN INVESTIGATE THE TUMORIGENIC PROPERTIES OF NMS AND THE UNDERLYING MECHANISMS OF CANCER DEVELOPMENT. THIS ARTICLE EXAMINES NM-INDUCED CELL TRANSFORMATION STUDIES, FOCUSING ON IDENTIFYING EXISTING KNOWLEDGE GAPS. SPECIFICALLY, IT EXPLORES THE PHYSICOCHEMICAL PROPERTIES OF NMS, EXPERIMENTAL MODELS, ASSAYS, DOSE AND TIME REQUIREMENTS FOR CELL TRANSFORMATION, AND THE UNDERLYING MECHANISMS OF MALIGNANCY. OUR REVIEW AIMS TO ADVANCE UNDERSTANDING IN THIS FIELD AND IDENTIFY AREAS FOR FURTHER INVESTIGATION.	2023