1  5609 121 S-ADENOSYLMETHIONINE DECREASES THE PEAK BLOOD ALCOHOL LEVELS 3 H AFTER AN ACUTE BOLUS OF ETHANOL BY INDUCING ALCOHOL METABOLIZING ENZYMES IN THE LIVER. INTRODUCTION: AN ALCOHOL BOLUS CAUSES THE BLOOD ALCOHOL LEVEL (BAL) TO PEAK AT 1-2 H POST INGESTION. THE ETHANOL ELIMINATION RATE IS REGULATED BY ALCOHOL METABOLIZING ENZYMES, PRIMARILY ALCOHOL DEHYDROGENASE (ADH1), ACETALDEHYDE DEHYDROGENASE (ALDH), AND CYTOCHROME P450 (CYP2E1). RECENTLY, S-ADENOSYLMETHIONINE (SAME) WAS FOUND TO REDUCE ACUTE BALS 3 H AFTER AN ALCOHOL BOLUS. THE QUESTION, THEN, WAS: WHAT IS THE MECHANISM INVOLVED IN THIS REDUCTION OF BAL BY FEEDING SAME? TO ANSWER THIS QUESTION, WE INVESTIGATED THE CHANGES IN ETHANOL METABOLIZING ENZYMES AND THE EPIGENETIC CHANGES THAT REGULATE THE EXPRESSION OF THESE ENZYMES DURING ACUTE BINGE DRINKING AND CHRONIC DRINKING. METHODS: RATS WERE FED A BOLUS OF ETHANOL WITH OR WITHOUT SAME, AND WERE SACRIFICED AT 3 H OR 12 H AFTER THE BOLUS. RESULTS: RT-PCR AND WESTERN BLOT ANALYSES SHOWED THAT SAME SIGNIFICANTLY INDUCED ADH1 LEVELS IN THE 3 H LIVER SAMPLES. HOWEVER, SAME DID NOT AFFECT THE CHANGES IN ADH1 PROTEIN LEVELS 12 H POST BOLUS. SINCE SAME IS A METHYL DONOR, IT WAS POSTULATED THAT THE ADH1 GENE EXPRESSION UP REGULATION AT 3 H WAS DUE TO A HISTONE MODIFICATION INDUCED BY METHYLATION FROM METHYL TRANSFERASES. DIMETHYLATED HISTONE 3 LYSINE 4 (H3K4ME2), A MODIFICATION RESPONSIBLE FOR GENE EXPRESSION ACTIVATION, WAS FOUND TO BE SIGNIFICANTLY INCREASED BY SAME AT 3 H POST BOLUS. CONCLUSION: THESE RESULTS CORRELATED WITH THE LOW BAL FOUND AT 3 H POST BOLUS, AND SUPPORT THE CONCEPT THAT SAME INCREASED THE GENE EXPRESSION TO INCREASE THE ELIMINATION RATE OF ETHANOL IN BINGE DRINKING BY INCREASING H3K4ME2.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
2  2907  60 GENE EXPRESSION MODIFICATIONS IN THE LIVER CAUSED BY BINGE DRINKING AND S-ADENOSYLMETHIONINE FEEDING. THE ROLE OF EPIGENETIC CHANGES. CHRONIC ETHANOL INGESTION, ACHIEVED BY FEEDING ETHANOL AT A CONSTANT RATE USING INTRAGASTRIC TUBE FEEDING, ALTERS THE EXPRESSION OF GENES IN THE LIVER. THIS IS DONE BY EPIGENETIC MECHANISMS, WHICH DEPEND ON THE BLOOD ALCOHOL LEVELS AT THE TIME OF KILLING. HOWEVER, ACUTE BOLUS FEEDING OF ETHANOL CHANGES GENE EXPRESSION WITHOUT LASTING EPIGENETIC CHANGES. THIS OCCURS WITH HISTONE 3 METHYLATION AND ACETYLATION MODIFICATIONS. THE GENE EXPRESSION RESPONSE TO AN ACUTE BOLUS OF ETHANOL MIGHT BE MODIFIED BY FEEDING S-ADENOSYLMETHIONINE (SAME), A METHYL DONOR. IN THE PRESENT STUDY, RATS WERE GIVEN A BOLUS OF ETHANOL (6 G/KG BODY WEIGHT (BW), SAME (1 G/KG BW), ETHANOL + SAME, OR ISOCALORIC GLUCOSE. THE GROUP OF RATS (N = 3) WERE KILLED AT 3 AND 12 H POST BOLUS, AND GENE MICROARRAY ANALYSIS WAS PERFORMED ON THEIR LIVER CELLS. SAME REDUCED THE 3 H BLOOD ETHANOL LEVELS AND INCREASED THE ALT LEVELS AT 3 H. VENN DIAGRAMS SHOWED THAT ALCOHOL CHANGED THE EXPRESSION OF 646 GENES AT 3 H POST BOLUS AND 586 GENES AT 12 H. SAME CHANGED THE EXPRESSION OF 1,012 GENES WHEN FED WITH ETHANOL 3 H POST ETHANOL BOLUS AND 554 GENES AT 12 H POST ETHANOL BOLUS. SAME ALONE CHANGED THE EXPRESSION OF 1,751 GENES AT 3 H AND 1,398 AT 12 H. THERE WERE MORE CHANGES IN GENE EXPRESSION AT 3 H THAN AT 12 H POST ETHANOL WHEN ETHANOL ALONE WAS COMPARED TO THE DEXTROSE CONTROL. THE SAME WAS TRUE WHEN SAME WAS COMPARED TO SAME + ETHANOL. ETHANOL UP REGULATED GENE EXPRESSION IN MOST FUNCTIONAL PATHWAYS AT 3 H. HOWEVER, WHEN SAME WAS FED WITH ETHANOL AT 3 H, MOST PATHWAYS WERE DOWN REGULATED. AT 12 H, HOWEVER, WHEN ETHANOL WAS FED, THE PATHWAYS WERE HALF UP REGULATED AND HALF DOWN REGULATED. THE SAME WAS TRUE WHEN SAME + ETHANOL WAS FED. THE EXPRESSION OF EPIGENETICALLY IMPORTANT GENES, SUCH AS BHMT AND FOXN3, WAS UP REGULATED 3 H POST ALCOHOL BOLUS. AT 3 H, SAME DOWN REGULATED THE EXPRESSION OF GENES, SUCH AS BHMT, MAT2A, JUN, TNFRS9, AHCY 1, TGFBR1 AND 2, AND PCAF. AT 12 H, THE INSULIN SIGNALING PATHWAYS WERE HALF DOWN REGULATED BY ETHANOL, WHICH WAS PARTLY PREVENTED BY SAME. THE MAPK PATHWAY WAS UP REGULATED BY ETHANOL, BUT SAME DID NOT PREVENT THIS. IN CONCLUSION, PROFOUND CHANGES IN GENE EXPRESSION EVOLVED BETWEEN 3 H AND 12 POST ETHANOL BOLUS. SAME DOWN REGULATED THESE CHANGES IN GENE EXPRESSION AT 3 H, AND LESS SO AT 12 H.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3    88  34 A PHASE I BIOLOGICAL STUDY OF MG98, AN OLIGODEOXYNUCLEOTIDE ANTISENSE TO DNA METHYLTRANSFERASE 1, IN PATIENTS WITH HIGH-RISK MYELODYSPLASIA AND ACUTE MYELOID LEUKEMIA. PURPOSE: EPIGENETIC SILENCING VIA ABERRANT PROMOTER DNA HYPERMETHYLATION OF NORMAL GENES HAS BEEN DESCRIBED AS A LEUKEMOGENIC MECHANISM IN MYELODYSPLASTIC SYNDROMES (MDS) AND ACUTE MYELOID LEUKEMIAS (AML). WE HYPOTHESIZED THAT MG98, AN OLIGONUCLEOTIDE ANTISENSE TO DNA METHYLTRANSFERASE 1 (DNMT1), COULD REVERSE MALIGNANT PHENOTYPES BY DOWN-REGULATING DNMT1 AND INDUCING REEXPRESSION OF HYPERMETHYLATED GENES. THIS PHASE I STUDY WAS CONDUCTED TO DETERMINE A BIOLOGICALLY EFFECTIVE DOSE AND DESCRIBE THE SAFETY OF MG98 IN MDS/AML. EXPERIMENTAL DESIGN: TWENTY-THREE PATIENTS WITH MDS (N = 11) AND AML (N = 12) WERE ENROLLED. BIOLOGICALLY EFFECTIVE DOSE WAS DEFINED AS THE DOSE AT WHICH > OR =50% OF PATIENTS EXPERIENCED >50% REDUCTION IN DNMT1 EXPRESSION WITH ACCEPTABLE TOXICITY. ESCALATING DOSES OF MG98 WERE ADMINISTERED ACCORDING TO TWO SCHEDULES (2-HOUR I.V. BOLUS FOLLOWED BY 5-DAY CONTINUOUS I.V. INFUSION EVERY 14 DAYS, OR 14-DAY CONTINUOUS I.V. INFUSION EVERY 21 DAYS). RESULTS: DNMT1 DOWN-REGULATION WAS OBSERVED IN 8 PATIENTS. HOWEVER, BIOLOGICALLY EFFECTIVE DOSE WAS NOT REACHED. REEXPRESSION OF TARGET GENES (P15, WIT1, AND ER) WAS OBSERVED IN 12 PATIENTS BUT DID NOT CORRELATE WITH DNMT1 DOWN-REGULATION. ESCALATION WAS STOPPED DUE TO DOSE-LIMITING TOXICITIES (BONE PAIN, NAUSEA, AND FEVER). NO OBJECTIVE CLINICAL RESPONSE WAS OBSERVED. DISEASE STABILIZATION OCCURRED IN 6 (26%) PATIENTS. CONCLUSIONS: NO PHARMACODYNAMIC OR CLINICAL ACTIVITY WAS OBSERVED AT MG98 DOSES AND SCHEDULES ADMINISTERED. DESPITE THIS, PURSUING DNMT1 DOWN-REGULATION REMAINS A SOUND APPROACH FOR TARGETING ABERRANT EPIGENETICS IN AML/MDS. FUTURE STUDIES WITH DIFFERENT FORMULATION AND/OR DOSES AND SCHEDULES WILL BE REQUIRED TO ENSURE EFFICIENT MG98 INTRACELLULAR UPTAKE AND FULLY EVALUATE ITS THERAPEUTIC POTENTIAL.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4  5478  32 RESULTS OF A RANDOMIZED STUDY OF 3 SCHEDULES OF LOW-DOSE DECITABINE IN HIGHER-RISK MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA. EPIGENETIC THERAPY WITH HYPOMETHYLATING DRUGS IS NOW THE STANDARD OF CARE IN MYELODYSPLASTIC SYNDROME (MDS). RESPONSE RATES REMAIN LOW, AND MECHANISM-BASED DOSE OPTIMIZATION HAS NOT BEEN REPORTED. WE INVESTIGATED THE CLINICAL AND PHARMACODYNAMIC RESULTS OF DIFFERENT DOSE SCHEDULES OF DECITABINE. ADULTS WITH ADVANCED MDS OR CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) WERE RANDOMIZED TO 1 OF 3 DECITABINE SCHEDULES: (1) 20 MG/M2 INTRAVENOUSLY DAILY FOR 5 DAYS; (2) 20 MG/M2 SUBCUTANEOUSLY DAILY FOR 5 DAYS; AND (3) 10 MG/M2 INTRAVENOUSLY DAILY FOR 10 DAYS. RANDOMIZATION FOLLOWED A BAYESIAN ADAPTIVE DESIGN. NINETY-FIVE PATIENTS WERE TREATED (77 WITH MDS, AND 18 WITH CMML). OVERALL, 32 PATIENTS (34%) ACHIEVED A COMPLETE RESPONSE (CR), AND 69 (73%) HAD AN OBJECTIVE RESPONSE BY THE NEW MODIFIED INTERNATIONAL WORKING GROUP CRITERIA. THE 5-DAY INTRAVENOUS SCHEDULE, WHICH HAD THE HIGHEST DOSE-INTENSITY, WAS SELECTED AS OPTIMAL; THE CR RATE IN THAT ARM WAS 39%, COMPARED WITH 21% IN THE 5-DAY SUBCUTANEOUS ARM AND 24% IN THE 10-DAY INTRAVENOUS ARM (P < .05). THE HIGH DOSE-INTENSITY ARM WAS ALSO SUPERIOR AT INDUCING HYPOMETHYLATION AT DAY 5 AND AT ACTIVATING P15 EXPRESSION AT DAYS 12 OR 28 AFTER THERAPY. WE CONCLUDE THAT A LOW-DOSE, DOSE-INTENSITY SCHEDULE OF DECITABINE OPTIMIZES EPIGENETIC MODULATION AND CLINICAL RESPONSES IN MDS.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5  2120  45 EPIGENETIC HISTONE MODIFICATIONS IN A CLINICALLY RELEVANT RAT MODEL OF CHRONIC ETHANOL-BINGE-MEDIATED LIVER INJURY. PURPOSE: ETHANOL BINGE AUGMENTS LIVER INJURY AFTER CHRONIC ETHANOL CONSUMPTION IN HUMANS, BUT THE MECHANISM BEHIND THE ENHANCED LIVER INJURY BY ETHANOL BINGE IS NOT KNOWN. IN THIS STUDY WE USED A CLINICALLY RELEVANT RAT MODEL IN WHICH LIVER INJURY IS AMPLIFIED BY BINGE AFTER CHRONIC ETHANOL TREATMENT AND INVESTIGATED THE IMPORTANCE OF HISTONE MODIFICATIONS. METHODS: EIGHT-WEEK-OLD SPRAGUE-DAWLEY RATS WERE FED ETHANOL IN A LIQUID DIET FOR 4 WEEKS. CONTROL RATS WERE FED AN ISOCALORIC LIQUID DIET. THIS WAS FOLLOWED BY THREE BINGE ADMINISTRATIONS OF ETHANOL (INTRAGASTRIC 5 G/KG BODY WEIGHT, 12 H APART). IN THE CONTROL, ETHANOL WAS REPLACED BY WATER. FOUR HOURS AFTER THE LAST BINGE ADMINISTRATION, LIVER SAMPLES WERE ANALYZED FOR HISTONE MODIFICATIONS AND PARAMETERS OF LIVER INJURY. RESULTS: CHRONIC ETHANOL ADMINISTRATION ALONE CAUSED AN INCREASE IN HISTONE H3 SER10 AND SER28 (H3S10 OR S28) PHOSPHORYLATION, AND BINGE ETHANOL REDUCED THEIR LEVELS. LEVELS OF DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10) INCREASED AFTER ACUTE BINGE ETHANOL AND REMAINED SAME AFTER CHRONIC ETHANOL BINGE. IN CONTRAST, HISTONE H3 LYSINE-9 ACETYLATION (H3ACK9) WAS NOT INCREASED AFTER CHRONIC ETHANOL BUT INCREASED SIGNIFICANTLY AFTER ACUTE BINGE AND CHRONIC ETHANOL BINGE. INCREASE IN HISTONE ACETYLATION WAS ACCOMPANIED BY INCREASED PHOSPHO-ERK1/2 IN THE NUCLEAR EXTRACTS. INCREASED ACETYLATION AFTER CHRONIC ETHANOL BINGE WAS ALSO ACCOMPANIED BY INCREASED PROTEIN LEVELS OF GCN5 HISTONE ACETYL TRANSFERASE AND A MODEST INCREASE IN HDAC3 IN THE NUCLEUS. HISTONE LYSINE-9 DIMETHYLATION WAS SIGNIFICANTLY INCREASED AFTER CHRONIC ETHANOL BINGE. CHRONIC ETHANOL BINGE ALSO RESULTED IN A DECREASE IN THE SAM:SAH RATIO WITH A RELATIVE DECREASE OF SAM LEVELS AND A CORRESPONDING INCREASE IN SAH LEVELS. CONCLUSIONS: ETHANOL BINGE AFTER CHRONIC ETHANOL ALTERED THE PROFILE OF SITE-SPECIFIC HISTONE MODIFICATIONS AND MAY UNDERLIE THE MECHANISM OF AUGMENTED LIVER INJURY BY CHRONIC-ETHANOL-BINGE-TREATED RATS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6  3619  44 IN VIVO ACUTE ON CHRONIC ETHANOL EFFECTS IN LIVER: A MOUSE MODEL EXHIBITING EXACERBATED INJURY, ALTERED METABOLIC AND EPIGENETIC RESPONSES. CHRONIC ALCOHOLICS WHO ALSO BINGE DRINK (I.E., ACUTE ON CHRONIC) ARE PRONE TO AN EXACERBATED LIVER INJURY BUT ITS MECHANISM IS NOT UNDERSTOOD. WE THEREFORE INVESTIGATED THE IN VIVO EFFECTS OF CHRONIC AND BINGE ETHANOL INGESTION AND COMPARED TO CHRONIC ETHANOL FOLLOWED BY THREE REPEAT BINGE ETHANOL ON THE LIVER OF MALE C57/BL6 MICE FED ETHANOL IN LIQUID DIET (4%) FOR FOUR WEEKS FOLLOWED BY BINGE ETHANOL (INTRAGASTRIC ADMINISTRATION, 3.5 G/KG BODY WEIGHT, THREE DOSES, 12H APART). CHRONIC FOLLOWED BY BINGE ETHANOL EXACERBATED FAT ACCUMULATION, NECROSIS, DECREASE IN HEPATIC SAM AND SAM:SAH RATIO, INCREASE IN ADENOSINE LEVELS, AND ELEVATED CYP2E1 LEVELS. HISTONE H3 LYSINE ACETYLATION (H3ACK9), DUALLY MODIFIED PHOSPHOACETYLATED HISTONE H3 (H3ACK9/PS10), AND PHOSPHORYLATED H2AX INCREASED AFTER BINGE WHEREAS PHOSPHORYLATION OF HISTONE H3 SER 10 (H3S10) AND H3 SER 28 (H3S28) INCREASED AFTER CHRONIC ETHANOL-BINGE. HISTONE H3 LYSINE 4 AND 9 DIMETHYLATION INCREASED WITH A MARKED DIMETHYLATION IN H3K9 IN CHRONIC ETHANOL BINGE GROUP. TRIMETHYLATED HISTONE H3 LEVELS DID NOT CHANGE. NUCLEAR LEVELS OF HISTONE ACETYL TRANSFERASE GCN5 AND HISTONE DEACETYLASE HDAC3 WERE ELEVATED WHEREAS PHOSPHO-CREB DECREASED IN A DISTINCTIVE MANNER. TAKEN TOGETHER, ACUTE ON CHRONIC ETHANOL INGESTION CAUSED AMPLIFICATION OF LIVER INJURY AND ELICITED CHARACTERISTIC PROFILES OF HISTONE MODIFICATIONS, METABOLIC ALTERATIONS, AND CHANGES IN NUCLEAR PROTEIN LEVELS. THESE FINDINGS DEMONSTRATE THAT CHRONIC ETHANOL EXPOSURE RENDERS LIVER MORE SUSCEPTIBLE TO REPEAT ACUTE/BINGE ETHANOL INDUCED ACCELERATION OF ALCOHOLIC LIVER DISEASE.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
7   872  41 CHRONIC ALCOHOL EXPOSURE DIFFERENTIALLY ALTERS ONE-CARBON METABOLISM IN RAT LIVER AND BRAIN. BACKGROUND: EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION PLAY AN IMPORTANT ROLE IN REGULATING THE PATHOPHYSIOLOGY OF ALCOHOLISM. CHRONIC ALCOHOL EXPOSURE LEADS TO BEHAVIORAL CHANGES AS WELL AS DECREASED EXPRESSION OF GENES ASSOCIATED WITH SYNAPTIC PLASTICITY. IN THE LIVER, IT HAS BEEN DOCUMENTED THAT CHRONIC ALCOHOL EXPOSURE IMPAIRS METHIONINE SYNTHASE (MS) ACTIVITY LEADING TO A DECREASE IN S-ADENOSYL METHIONINE/S-ADENOSYL HOMOCYSTEINE (SAM/SAH) RATIO WHICH RESULTS IN DNA HYPOMETHYLATION; HOWEVER, IT IS NOT KNOWN WHETHER SIMILAR ALTERATIONS OF SAM AND SAH LEVELS ARE ALSO PRODUCED IN BRAIN. METHODS: MALE ADULT SPRAGUE DAWLEY RATS WERE FED CHRONICALLY WITH LIEBER-DECARLI ETHANOL (ETOH) (9% V/V) OR CONTROL DIET. THE ETOH-DIET-FED RATS WERE WITHDRAWN FOR 0 AND 24 HOURS. THE CEREBELLUM AND LIVER TISSUES WERE DISSECTED AND USED TO INVESTIGATE CHANGES IN ONE-CARBON METABOLISM, SAM, AND SAH LEVELS. RESULTS: WE FOUND THAT CHRONIC ETOH EXPOSURE DECREASED SAM LEVELS, SAM/SAH RATIO, MS, METHYLENE TETRAHYDROFOLATE REDUCTASE, AND BETAINE HOMOCYSTEINE METHYLTRANSFERASE (BHMT) EXPRESSION AND INCREASED METHIONINE ADENOSYLTRANSFERASE-2B (MAT2B) BUT NOT MAT2A EXPRESSION IN THE LIVER. IN CONTRAST, CHRONIC ETOH EXPOSURE DECREASED SAH LEVELS, INCREASED SAM/SAH RATIO AND THE EXPRESSION OF MAT2A AND S-ADENOSYL HOMOCYSTEINE HYDROLASE, WHILE THE LEVELS OF SAM OR BHMT EXPRESSION IN CEREBELLUM REMAINED UNALTERED. HOWEVER, IN BOTH LIVER AND CEREBELLUM, CHRONIC ETOH EXPOSURE DECREASED THE EXPRESSION OF MS AND INCREASED MAT2B EXPRESSION. ALL CHRONIC ETOH-INDUCED CHANGES OF ONE-CARBON METABOLISM IN CEREBELLUM, BUT NOT LIVER, RETURNED TO NEAR-NORMAL LEVELS DURING ETOH WITHDRAWAL. CONCLUSIONS: THESE RESULTS INDICATE A DECREASED "METHYLATION INDEX" IN LIVER AND AN INCREASED "METHYLATION INDEX" IN CEREBELLUM. THE OPPOSING CHANGES OF THE "METHYLATION INDEX" SUGGEST ALTERED DNA METHYLATION IN LIVER AND CEREBELLUM, THUS IMPLICATING ONE-CARBON METABOLISM IN THE PATHOPHYSIOLOGY OF ALCOHOLISM.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8   894  48 CHRONIC ETHANOL FEEDING ALTERS HEPATOCYTE MEMORY WHICH IS NOT ALTERED BY ACUTE FEEDING. BACKGROUND: GENE EXPRESSION CHANGES IN THE LIVER AFTER ACUTE BINGE DRINKING MAY DIFFER FROM THE CHANGES SEEN IN CHRONIC ETHANOL FEEDING IN THE RAT. THE CHANGES IN GENE EXPRESSION AFTER CHRONIC ETHANOL FEEDING MAY SENSITIZE THE LIVER TO ALCOHOL-INDUCED LIVER DAMAGE, WHICH IS NOT SEEN AFTER ACUTE BINGE DRINKING. METHODS: TO TEST THIS HYPOTHESIS, GENE MICROARRAY ANALYSIS WAS PERFORMED ON THE LIVERS OF RATS (N = 3) FED AN ACUTE BINGE DOSE OF ETHANOL (6 G/KG BODY WT) AND KILLED AT 3 AND 12 HOURS AFTER ETHANOL BY GAVAGE. THE GENE MICROARRAYS WERE COMPARED WITH THOSE MADE ON THE LIVER OF RATS FROM A PREVIOUS STUDY, IN WHICH THE RATS WERE FED ETHANOL BY INTRAGASTRIC TUBE FOR 1 MONTH (36% OF CALORIES DERIVED FROM ETHANOL). RESULTS: MICROARRAY ANALYSIS DATA VARIED BETWEEN THE ACUTE AND CHRONIC MODELS IN SEVERAL IMPORTANT RESPECTS. GROWTH FACTORS INCREASED MAINLY IN THE CHRONIC ALCOHOL FED RAT. CHANGES IN ENZYMES INVOLVED IN OXIDATIVE STRESS WERE NOTED ONLY WITH CHRONIC ETHANOL FEEDING. GENE EXPRESSION OF FAT METABOLISM WAS INCREASED ONLY WITH CHRONIC ETHANOL FEEDING. MOST IMPORTANTLY, EPIGENETIC RELATED ENZYMES AND ACETYLATION AND METHYLATION OF HISTONES CHANGED ONLY AFTER CHRONIC ETHANOL FEEDING. CONCLUSIONS: THE RESULTS SUPPORT THE CONCEPT THAT CHRONIC ETHANOL INGESTION INDUCES ALTERED GENE EXPRESSION AS A RESULT OF CHANGES IN EPIGENETIC MECHANISMS, WHERE ACETYLATION AND METHYLATION OF HISTONES WERE ALTERED.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9  5056  24 PHASE I TRIAL OF LOW DOSE DECITABINE TARGETING DNA HYPERMETHYLATION IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKAEMIA AND NON-HODGKIN LYMPHOMA: DOSE-LIMITING MYELOSUPPRESSION WITHOUT EVIDENCE OF DNA HYPOMETHYLATION. TARGETING ABERRANT DNA HYPERMETHYLATION IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) AND NON-HODGKIN LYMPHOMA (NHL) WITH DECITABINE MAY REVERSE EPIGENETIC SILENCING IN B-CELL MALIGNANCIES. TWENTY PATIENTS WERE ENROLLED IN TWO PHASE I TRIALS TO DETERMINE THE MINIMUM EFFECTIVE PHARMACOLOGICAL DOSE OF DECITABINE IN PATIENTS WITH RELAPSED/REFRACTORY CLL (N = 16) AND NHL (N = 4). PATIENTS RECEIVED 1-3 CYCLES OF DECITABINE. DOSE-LIMITING TOXICITY (DLT) WAS OBSERVED IN 2 OF 4 CLL AND 2 OF 2 NHL PATIENTS RECEIVING DECITABINE AT 15 MG/M(2) PER D DAYS 1-10, CONSISTING OF GRADE 3-4 THROMBOCYTOPENIA AND HYPERBILIRUBINAEMIA. SIX PATIENTS WITH CLL RECEIVED DECITABINE AT 10 MG/M(2) PER D DAYS 1-10 WITHOUT DLT; HOWEVER, RE-EXPRESSION OF METHYLATED GENES OR CHANGES IN GLOBAL DNA METHYLATION WERE NOT OBSERVED. THEREFORE, A 5-DAY DECITABINE SCHEDULE WAS EXAMINED. WITH 15 MG/M(2) PER D DECITABINE DAYS 1-5, DLT OCCURRED IN 2 OF 6 CLL AND 2 OF 2 NHL PATIENTS, CONSISTING OF GRADE 3-4 NEUTROPENIA, THROMBOCYTOPENIA, AND FEBRILE NEUTROPENIA. EIGHT PATIENTS HAD STABLE DISEASE. IN 17 PATIENTS, THERE WERE NO SIGNIFICANT CHANGES IN GENOME-WIDE METHYLATION OR IN TARGET GENE RE-EXPRESSION. IN CONCLUSION, DOSE-LIMITING MYELOSUPPRESSION AND INFECTIOUS COMPLICATIONS PREVENTED DOSE ESCALATION OF DECITABINE TO LEVELS ASSOCIATED WITH CHANGES IN GLOBAL METHYLATION OR GENE RE-EXPRESSION IN CLL AND NHL.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10  5044  31 PHARMACOKINETICS AND PHARMACODYNAMICS WITH EXTENDED DOSING OF CC-486 IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES. CC-486 (ORAL AZACITIDINE) IS AN EPIGENETIC MODIFIER IN DEVELOPMENT FOR PATIENTS WITH MYELODYSPLASTIC SYNDROMES AND ACUTE MYELOID LEUKEMIA. IN PART 1 OF THIS TWO-PART STUDY, A 7-DAY CC-486 DOSING SCHEDULE SHOWED CLINICAL ACTIVITY, WAS GENERALLY WELL TOLERATED, AND REDUCED DNA METHYLATION. EXTENDING DOSING OF CC-486 BEYOND 7 DAYS WOULD INCREASE DURATION OF AZACITIDINE EXPOSURE. WE HYPOTHESIZED THAT EXTENDED DOSING WOULD THEREFORE PROVIDE MORE SUSTAINED EPIGENETIC ACTIVITY. REPORTED HERE ARE THE PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) PROFILES OF CC-486 EXTENDED DOSING SCHEDULES IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) OR ACUTE MYELOID LEUKEMIA (AML) FROM PART 2 OF THIS STUDY. PK AND/OR PD DATA WERE AVAILABLE FOR 59 PATIENTS WHO WERE SEQUENTIALLY ASSIGNED TO 1 OF 4 EXTENDED CC-486 DOSING SCHEDULES: 300MG ONCE-DAILY OR 200MG TWICE-DAILY FOR 14 OR 21 DAYS PER 28-DAY CYCLE. BOTH 300MG ONCE-DAILY SCHEDULES AND THE 200MG TWICE-DAILY 21-DAY SCHEDULE SIGNIFICANTLY (ALL P < .05) REDUCED GLOBAL DNA METHYLATION IN WHOLE BLOOD AT ALL MEASURED TIME POINTS (DAYS 15, 22, AND 28 OF THE TREATMENT CYCLE), WITH SUSTAINED HYPOMETHYLATION AT CYCLE END COMPARED WITH BASELINE. CC-486 EXPOSURES AND REDUCED DNA METHYLATION WERE SIGNIFICANTLY CORRELATED. PATIENTS WHO HAD A HEMATOLOGIC RESPONSE HAD SIGNIFICANTLY GREATER METHYLATION REDUCTIONS THAN NON-RESPONDING PATIENTS. THESE DATA DEMONSTRATE THAT EXTENDED DOSING OF CC-486 SUSTAINS EPIGENETIC EFFECTS THROUGH THE TREATMENT CYCLE. TRIAL REGISTRATION: CLINICALTRIALS.GOV NCT00528983.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11   765  27 CC-486 MAINTENANCE AFTER STEM CELL TRANSPLANTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA OR MYELODYSPLASTIC SYNDROMES. RELAPSE IS THE MAIN CAUSE OF TREATMENT FAILURE AFTER ALLOGENEIC STEM CELL TRANSPLANT (ALLOSCT) IN ACUTE MYELOID LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROMES (MDS). INJECTABLE AZACITIDINE CAN IMPROVE POST-TRANSPLANT OUTCOMES BUT PRESENTS CHALLENGES WITH EXPOSURE AND COMPLIANCE. ORAL CC-486 ALLOWS EXTENDED DOSING TO PROLONG AZACITIDINE ACTIVITY. WE INVESTIGATED USE OF CC-486 MAINTENANCE THERAPY AFTER ALLOSCT. ADULTS WITH MDS OR AML IN MORPHOLOGIC COMPLETE REMISSION AT CC-486 INITIATION (42 TO 84 DAYS AFTER ALLOSCT) WERE INCLUDED. PATIENTS RECEIVED 1 OF 4 CC-486 DOSING SCHEDULES PER 28-DAY CYCLE FOR UP TO 12 CYCLES. ENDPOINTS INCLUDED SAFETY, PHARMACOKINETICS, GRAFT-VERSUS-HOST DISEASE (GVHD) INCIDENCE, RELAPSE/PROGRESSION RATE, AND SURVIVAL. OF 30 PATIENTS, 7 RECEIVED CC-486 ONCE DAILY FOR 7 DAYS PER CYCLE (200 MG, N = 3; 300 MG, N = 4) AND 23 FOR 14 DAYS PER CYCLE (150 MG, N = 4; 200 MG, N = 19 [EXPANSION COHORT]). GRADES 3 TO 4 ADVERSE EVENTS WERE INFREQUENT AND OCCURRED WITH SIMILAR FREQUENCY ACROSS REGIMENS. STANDARD CONCOMITANT MEDICATIONS DID NOT ALTER CC-486 PHARMACOKINETIC PARAMETERS. THREE PATIENTS (10%) EXPERIENCED GRADE III ACUTE GVHD AND 9 EXPERIENCED CHRONIC GVHD. OF 28 EVALUABLE PATIENTS, 6 (21%) RELAPSED OR HAD PROGRESSIVE DISEASE: 3 OF 7 PATIENTS (43%) WHO HAD RECEIVED 7-DAY DOSING AND 3 OF 23 (13%) WHO HAD RECEIVED 14-DAY DOSING. TRANSPLANT-RELATED MORTALITY WAS 3%. AT 19 MONTHS OF FOLLOW-UP, MEDIAN OVERALL SURVIVAL WAS NOT REACHED. ESTIMATED 1-YEAR SURVIVAL RATES WERE 86% AND 81% IN THE 7-DAY AND 14-DAY DOSING COHORTS, RESPECTIVELY. CC-486 MAINTENANCE WAS GENERALLY WELL TOLERATED, WITH LOW RATES OF RELAPSE, DISEASE PROGRESSION, AND GVHD. CC-486 MAINTENANCE MAY PERMIT EPIGENETIC MANIPULATION OF THE ALLOREACTIVE RESPONSE POSTALLOGRAFT. FINDINGS REQUIRE CONFIRMATION IN RANDOMIZED TRIALS. (CLINICALTRIALS.GOV NCT01835587.).	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12  2769  26 EXTENDED DOSING WITH CC-486 (ORAL AZACITIDINE) IN PATIENTS WITH MYELOID MALIGNANCIES. CC-486 (ORAL AZACITIDINE) IS AN EPIGENETIC MODIFIER IN CLINICAL DEVELOPMENT FOR TREATMENT OF HEMATOLOGICAL CANCERS. THIS STUDY OF EXTENDED CC-486 DOSING INCLUDED PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDSS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), OR ACUTE MYELOID LEUKEMIA (AML). AFTER A PHARMACOKINETIC ASSESSMENT PERIOD, 31 PATIENTS (MDS N = 18, CMML N = 4, AND AML N = 9) ENTERED A CLINICAL PHASE IN WHICH THEY RECEIVED CC-486 300 MG ONCE-DAILY FOR 21 DAYS OF REPEATED 28-DAY CYCLES. MEDIAN AGE WAS 71 YEARS (RANGE: 53-93); 42% OF PATIENTS WERE AGED >/=75 YEARS. A TOTAL OF 5 PATIENTS WITH AML (63%) HAD PRIOR MDS. MEDIAN NUMBER OF CC-486 TREATMENT CYCLES WAS 4 (RANGE: 1-32). THE MOST COMMON TREATMENT-EMERGENT ADVERSE EVENTS (TEAES) WERE GASTROINTESTINAL (84% OF PATIENTS) AND HEMATOLOGIC (81%). MOST COMMON GRADE 3-4 TEAES WERE NEUTROPENIA (N = 13, 42%) AND ANEMIA (N = 9, 29%). TEN PATIENTS EXPERIENCED GRADE 4 NEUTROPENIA. INFREQUENTLY, CC-486 DOSE WAS INTERRUPTED OR REDUCED DUE TO GASTROINTESTINAL (N = 5, 16%) OR HEMATOLOGIC (N = 6, 19%) TEAES. OVERALL RESPONSE RATE (COMPLETE REMISSION [CR], CR WITH INCOMPLETE HEMATOLOGICAL RECOVERY [CRI], PARTIAL REMISSION [PR], MARROW CR) IN THE MDS/CMML SUBGROUPS WAS 32% AND IN THE AML SUBGROUP (CR/CRI/PR) WAS 22%. RED BLOOD CELL TRANSFUSION INDEPENDENCE RATES IN THE MDS/CMML AND AML SUBGROUPS WERE 33% AND 25%, RESPECTIVELY, AND 2 MDS/CMML PATIENTS ATTAINED HEMATOLOGIC IMPROVEMENT AS A BEST RESPONSE ON-STUDY. NO BASELINE GENE MUTATION WAS PREDICTIVE OF RESPONSE/NONRESPONSE. CC-486 ALLOWS FLEXIBLE DOSING AND SCHEDULES TO IMPROVE TOLERABILITY OR RESPONSE. NEUTROPENIA IN EARLY TREATMENT CYCLES DESERVES SCRUTINY AND MAY WARRANT INITIATION OF PROPHYLACTIC ANTIBIOTICS. KEY POINTS: THE SAFETY PROFILE OF ORAL CC-486 WAS COMPARABLE TO THAT OF INJECTABLE AZACITIDINE; MOST ADVERSE EVENTS WERE HEMATOLOGICAL AND GASTROINTESTINAL. EXTENDED (21-DAY/CYCLE) CC-486 DOSING INDUCED RESPONSES IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES, MANY OF WHOM HAD PRIOR DNMTI FAILURE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
13  1800  29 EFFECT OF HISTONE DEACETYLASE INHIBITOR ON ETHANOL WITHDRAWAL-INDUCED HYPERALGESIA IN RATS. BACKGROUND: INCREASED PAIN SENSITIVITY IS OBSERVED FOLLOWING ALCOHOL WITHDRAWAL, AND ATTEMPTS TO ALLEVIATE THIS HYPERALGESIA CAN CONTRIBUTE TO THE CYCLE OF ADDICTION. THE AIM OF THIS STUDY WAS TO DETERMINE IF ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA WAS OBSERVED IN A CHRONIC ETHANOL EXPOSURE MODEL AND IF THIS PAIN WAS AFFECTED BY HISTONE DEACETYLASE INHIBITORS, THUS REVEALING AN EPIGENETIC MECHANISM. METHODS: ADULT MALE SPRAGUE DAWLEY RATS RECEIVED LIEBER-DECARLI LIQUID CONTROL OR ETHANOL (9% V/V) DIET FOR 15 DAYS. MECHANICAL SENSITIVITY WAS MEASURED WITH VON FREY HAIR STIMULATION OF THE HINDPAW DURING ETHANOL ADMINISTRATION AND 24- AND 72-HOUR WITHDRAWAL. RESULTS: ETHANOL WITHDRAWAL PRODUCED SEVERE AND SUSTAINED MECHANICAL HYPERALGESIA, AN EFFECT NOT OBSERVED IN THE CONTROL OR ETHANOL-MAINTAINED GROUPS. FURTHERMORE, THIS HYPERALGESIA WAS ATTENUATED BY THE HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID TREATMENT. CONCLUSIONS: HEIGHTENED PAIN SENSITIVITY WAS OBSERVED FOLLOWING WITHDRAWAL FROM CHRONIC ETHANOL EXPOSURE, AND HISTONE DEACETYLASE INHIBITORS COULD BE NOVEL TREATMENTS FOR THIS ALCOHOL WITHDRAWAL-INDUCED HYPERALGESIA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14  4581  31 N-METHYL-D-ASPARTATE 2B RECEPTOR SUBTYPE (NR2B) PROMOTER METHYLATION IN PATIENTS DURING ALCOHOL WITHDRAWAL. NMDA RECEPTORS AND ESPECIALLY THE NR2B RECEPTOR SUBTYPE PLAY A CRUCIAL ROLE DURING CHRONIC ETHANOL CONSUMPTION AND ALCOHOL WITHDRAWAL. THEREFORE, THE NR2B RECEPTOR SUBTYPE EXPRESSION IN PERIPHERAL BLOOD CELLS OF 32 MALE PATIENTS SUFFERING FROM ALCOHOL DEPENDENCY WERE ASSESSED THROUGH QUANTITATIVE RT-PCR AND TO EXPLORE REGULATING EPIGENETIC MECHANISMS, A METHYLATION ANALYSIS WAS CONDUCTED USING BISULFITE SEQUENCING OF A FRAGMENT OF THE NR2B PROMOTER REGION. THE EXPRESSION OF THE NR2B RECEPTOR INCREASED SIGNIFICANTLY DURING THE FIRST 24 H OF WITHDRAWAL TREATMENT (DAY 1; T = 4.1, P = 0.001), AND ALSO ON AND DAY 3 (T = 2.4; P = 0.029). THE SEVERITY OF ALCOHOL DRINKING PATTERN, MEASURED BY LIFETIME DRINKING AND DAILY ETHANOL INTAKE, WAS NEGATIVELY CORRELATED WITH THE METHYLATION OF A DEFINED CLUSTER OF FIVE CPG-SITES WITHIN THE NR2B PROMOTER (LIFETIME DRINKING: SPEARMAN'S RHO = -0.55; P = 0.013; DAILY ETHANOL INTAKE: RHO = -0.46; P = 0.043). THESE FINDINGS MIGHT EXPLAIN THE OBSERVATION OF AN IMPACT OF ALCOHOL CONSUMPTION PATTERNS ON THE GRAVITY OF WITHDRAWAL SYMPTOMS.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15  3841  42 IRON SUPPLEMENTATION REVERSES THE REDUCTION OF HYDROXYMETHYLCYTOSINE IN HEPATIC DNA ASSOCIATED WITH CHRONIC ALCOHOL CONSUMPTION IN RATS. BACKGROUND: ALCOHOL IS KNOWN TO AFFECT TWO EPIGENETIC PHENOMENA, DNA METHYLATION AND DNA HYDROXYMETHYLATION, AND IRON IS A COFACTOR OF TEN-ELEVEN TRANSLOCATION (TET) ENZYMES THAT CATALYZE THE CONVERSION FROM METHYLCYTOSINE TO HYDROXYMETHYLCYTOSINE. IN THE PRESENT STUDY WE AIMED TO DETERMINE THE EFFECTS OF ALCOHOL ON DNA HYDROXYMETHYLATION AND FURTHER EFFECTS OF IRON ON ALCOHOL ASSOCIATED EPIGENETIC CHANGES. METHODS: TWENTY-FOUR MALE SPRAGUE-DAWLEY RATS WERE FED EITHER LIEBER-DECARLI ALCOHOL DIET (36% CALORIES FROM ETHANOL) OR LIEBER-DECARLI CONTROL DIET ALONG WITH OR WITHOUT IRON SUPPLEMENTATION (0.6% CARBONYL IRON) FOR 8 WEEKS. HEPATIC NON-HEME IRON CONCENTRATIONS WERE MEASURED BY COLORIMETRIC ASSAYS. PROTEIN LEVELS OF HEPATIC FERRITIN AND TRANSFERRIN RECEPTOR WERE DETERMINED BY WESTERN BLOTTING. METHYLCYTOSINE, HYDROXYMETHYLCYTOSINE AND UNMODIFIED CYTOSINE IN DNA WERE SIMULTANEOUSLY MEASURED BY LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY METHOD. RESULTS: IRON SUPPLEMENTATION SIGNIFICANTLY INCREASED HEPATIC NON-HEME IRON CONTENTS (P < 0.05) BUT ALCOHOL ALONE DID NOT. HOWEVER, BOTH ALCOHOL AND IRON SIGNIFICANTLY INCREASED HEPATIC FERRITIN LEVELS AND DECREASED HEPATIC TRANSFERRIN RECEPTOR LEVELS (P < 0.05). ALCOHOL REDUCED HEPATIC DNA HYDROXYMETHYLATION (0.21% +/- 0.04% VS. 0.33% +/- 0.04%, P = 0.01) COMPARED TO CONTROL, WHILE IRON SUPPLEMENTATION TO ALCOHOL DIET DID NOT CHANGE DNA HYDROXYMETHYLATION. THERE WAS NO SIGNIFICANT DIFFERENCE IN METHYLCYTOSINE LEVELS, WHILE UNMODIFIED CYTOSINE LEVELS WERE SIGNIFICANTLY INCREASED IN ALCOHOL-FED GROUPS COMPARED TO CONTROL (95.61% +/- 0.08% VS. 95.26% +/- 0.12%, P = 0.03), SUGGESTING THAT ALCOHOL FURTHER INCREASES THE CONVERSION FROM HYDROXYMETHYLCYTOSINE TO UNMODIFIED CYTOSINE. CONCLUSIONS: CHRONIC ALCOHOL CONSUMPTION ALTERS GLOBAL DNA HYDROXYMETHYLATION IN THE LIVER BUT IRON SUPPLEMENTATION REVERSES THE EPIGENETIC EFFECT OF ALCOHOL.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16  5612  34 SAFETY AND ACTIVITY OF RRX-001 IN PATIENTS WITH ADVANCED CANCER: A FIRST-IN-HUMAN, OPEN-LABEL, DOSE-ESCALATION PHASE 1 STUDY. BACKGROUND: EPIGENETIC ALTERATIONS HAVE BEEN STRONGLY ASSOCIATED WITH TUMOUR FORMATION AND RESISTANCE TO CHEMOTHERAPEUTIC DRUGS, AND EPIGENETIC MODIFICATIONS ARE AN ATTRACTIVE TARGET IN CANCER RESEARCH. RRX-001 IS ACTIVATED BY HYPOXIA AND INDUCES THE GENERATION OF REACTIVE OXYGEN AND NITROGEN SPECIES THAT CAN EPIGENETICALLY MODULATE DNA METHYLATION, HISTONE DEACETYLATION, AND LYSINE DEMETHYLATION. THE AIM OF THIS PHASE 1 STUDY WAS TO ASSESS THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF RRX-001. METHODS: IN THIS OPEN-LABEL, DOSE-ESCALATION, PHASE 1 STUDY, WE RECRUITED ADULT PATIENTS (AGED >18 YEARS) WITH HISTOLOGICALLY OR CYTOLOGICALLY CONFIRMED DIAGNOSIS OF ADVANCED, MALIGNANT, INCURABLE SOLID TUMOURS FROM UNIVERSITY OF CALIFORNIA AT SAN DIEGO, CA, USA, AND SARAH CANNON RESEARCH INSTITUTE, NASHVILLE, TN, USA. KEY ELIGIBILITY CRITERIA INCLUDED EVALUABLE DISEASE, EASTERN COOPERATIVE GROUP PERFORMANCE STATUS OF 2 OR LESS, AN ESTIMATED LIFE EXPECTANCY OF AT LEAST 12 WEEKS, ADEQUATE LABORATORY PARAMETERS, DISCONTINUATION OF ALL PREVIOUS ANTINEOPLASTIC THERAPIES AT LEAST 6 WEEKS BEFORE INTERVENTION, AND NO RESIDUAL SIDE-EFFECTS FROM PREVIOUS THERAPIES. PATIENTS WERE ASSIGNED TO RECEIVE INTRAVENOUS INFUSIONS OF RRX-001 AT INCREASING DOSES (10 MG/M(2), 16.7 MG/M(2), 24.6 MG/M(2), 33 MG/M(2), 55 MG/M(2), AND 83 MG/M(2)) EITHER ONCE OR TWICE-WEEKLY FOR AT LEAST 4 WEEKS, WITH AT LEAST THREE PATIENTS PER DOSE COHORT AND ALLOWING A 2-WEEK OBSERVATION PERIOD BEFORE DOSE ESCALATION. SAMPLES FOR SAFETY AND PHARMACOKINETICS ANALYSIS, INCLUDING STANDARD CHEMISTRY AND HAEMATOLOGICAL PANELS, WERE TAKEN ON EACH TREATMENT DAY. THE PRIMARY OBJECTIVE WAS TO ASSESS SAFETY, TOLERABILITY, AND DOSE-LIMITING TOXIC EFFECTS OF RRX-001, TO DETERMINE SINGLE-DOSE PHARMACOKINETICS, AND TO IDENTIFY A RECOMMENDED DOSE FOR PHASE 2 TRIALS. ALL ANALYSES WERE DONE PER PROTOCOL. ACCRUAL IS COMPLETE AND FOLLOW-UP IS STILL ON-GOING. THIS TRIAL IS REGISTERED WITH CLINICALTRIALS.GOV, NUMBER NCT01359982. FINDINGS: BETWEEN OCT 10, 2011, AND MARCH 18, 2013, WE ENROLLED 25 PATIENTS AND TREATED SIX PATIENTS IN THE 10 MG/M(2) COHORT, THREE PATIENTS IN THE 16.7 MG/M(2) COHORT, THREE PATIENTS IN THE 24.6 MG/M(2) COHORT, FOUR PATIENTS IN THE 33 MG/M(2) COHORT, THREE PATIENTS IN THE 55 MG/M(2), AND SIX PATIENTS IN THE 83 MG/M(2) COHORT. PAIN AT THE INJECTION SITE, MOSTLY GRADE 1 AND GRADE 2, WAS THE MOST COMMON ADVERSE EVENT RELATED TO TREATMENT, EXPERIENCED BY 21 (84%) PATIENTS. OTHER COMMON DRUG-RELATED ADVERSE EVENTS INCLUDED ARM SWELLING OR OEDEMA (EIGHT [32%] PATIENTS), AND VEIN HARDENING (SEVEN [28%] PATIENTS). NO DOSE-LIMITING TOXICITIES WERE OBSERVED. TIME CONSTRAINTS RELATED TO MANAGEMENT OF INFUSION PAIN FROM RRX-001 RESULTED IN A MAXIMALLY FEASIBLE DOSE OF 83 MG/M(2). OF THE 21 EVALUABLE PATIENTS, ONE (5%) PATIENT HAD A PARTIAL RESPONSE, 14 (67%) PATIENTS HAD STABLE DISEASE, AND SIX (29%) PATIENTS HAD PROGRESSIVE DISEASE; ALL RESPONSES WERE ACROSS A VARIETY OF TUMOUR TYPES. FOUR PATIENTS WHO HAD RECEIVED RRX-001 WERE SUBSEQUENTLY RECHALLENGED WITH A TREATMENT THAT THEY HAD BECOME REFRACTORY TO; ALL FOUR RESPONDED TO THE RECHALLENGE. INTERPRETATION: RRX-001 IS A WELL-TOLERATED NOVEL COMPOUND WITHOUT CLINICALLY SIGNIFICANT TOXIC EFFECTS AT THE TESTED DOSES. PRELIMINARY EVIDENCE OF ACTIVITY IS PROMISING AND, ON THE BASIS OF ALL FINDINGS, A DOSE OF 16.7 MG/M(2) WAS RECOMMENDED AS THE TARGETED DOSE FOR PHASE 2 TRIALS. FUNDING: EPICENTRX (FORMERLY RADIORX).	2015	

17  4397  43 MODULATION OF DNA METHYLATION AND GENE EXPRESSION IN RODENT CORTICAL NEUROPLASTICITY PATHWAYS EXERTS RAPID ANTIDEPRESSANT-LIKE EFFECTS. BACKGROUND: STRESS INCREASES DNA METHYLATION, PRIMARILY A SUPPRESSIVE EPIGENETIC MECHANISM CATALYZED BY DNA METHYLTRANSFERASES (DNMT), AND DECREASES THE EXPRESSION OF GENES INVOLVED IN NEURONAL PLASTICITY AND MOOD REGULATION. DESPITE CHRONIC ANTIDEPRESSANT TREATMENT DECREASES STRESS-INDUCED DNA METHYLATION, IT IS NOT KNOWN WHETHER INHIBITION OF DNMT WOULD CONVEY RAPID ANTIDEPRESSANT-LIKE EFFECTS. AIM: THIS WORK TESTED SUCH A HYPOTHESIS AND EVALUATED WHETHER A BEHAVIORAL EFFECT INDUCED BY DNMT INHIBITORS (DNMTI) CORRESPONDS WITH CHANGES IN DNA METHYLATION AND TRANSCRIPT LEVELS IN GENES CONSISTENTLY ASSOCIATED WITH THE NEUROBIOLOGY OF DEPRESSION AND SYNAPTIC PLASTICITY (BDNF, TRKB, 5-HT(1A), NMDA, AND AMPA). METHODS: MALE WISTAR RATS RECEIVED INTRAPERITONEAL (I.P.) INJECTION OF TWO PHARMACOLOGICALLY DIFFERENT DNMTI (5-AZAD 0.2 AND 0.6 MG/KG OR RG108 0.6 MG/KG) OR VEHICLE (1 ML/KG), 1 H OR 7 DAYS BEFORE THE LEARNED HELPLESSNESS TEST (LH). DNA METHYLATION IN TARGET GENES AND THE CORRESPONDENT TRANSCRIPT LEVELS WERE MEASURED IN THE HIPPOCAMPUS (HPC) AND PREFRONTAL CORTEX (PFC) USING MEDIP-QPCR. IN PARALLEL SEPARATE GROUPS, THE ANTIDEPRESSANT-LIKE EFFECT OF 5-AZAD AND RG108 WAS INVESTIGATED IN THE FORCED SWIMMING TEST (FST). THE INVOLVEMENT OF CORTICAL BDNF-TRKB-MTOR PATHWAYS WAS ASSESSED BY INTRA-VENTRAL MEDIAL PFC (VMPFC) INJECTIONS OF RAPAMYCIN (MTOR INHIBITOR), K252A (TRKB RECEPTOR ANTAGONIST), OR VEHICLE (0.2 MUL/SIDE). RESULTS: WE FOUND THAT BOTH 5-AZAD AND RG108 ACUTELY AND 7 DAYS BEFORE THE TEST DECREASED ESCAPE FAILURES IN THE LH. LH STRESS INCREASED DNA METHYLATION AND DECREASED TRANSCRIPT LEVELS OF BDNF IV AND TRKB IN THE PFC, EFFECTS THAT WERE NOT SIGNIFICANTLY ATTENUATED BY RG108 TREATMENT. THE SYSTEMIC ADMINISTRATION OF 5-AZAD (0.2 MG/KG) AND RG108 (0.2 MG/KG) INDUCED AN ANTIDEPRESSANT-LIKE EFFECT IN FST, WHICH WAS, HOWEVER, ATTENUATED BY TRKB AND MTOR INHIBITION INTO THE VMPFC. CONCLUSION: THESE FINDINGS SUGGEST THAT ACUTE INHIBITION OF STRESS-INDUCED DNA METHYLATION PROMOTES RAPID AND SUSTAINED ANTIDEPRESSANT EFFECTS ASSOCIATED WITH INCREASED BDNF-TRKB-MTOR SIGNALING IN THE PFC.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  3331  39 HISTONE DEACETYLASE INHIBITOR SUBERANILOHYDROXAMIC ACID TREATMENT REVERSES HYPOSENSITIVITY TO GAMMA-AMINOBUTYRIC ACID IN THE VENTRAL TEGMENTAL AREA DURING ETHANOL WITHDRAWAL. BACKGROUND: THE VENTRAL TEGMENTAL AREA (VTA) IS IMPORTANT FOR ALCOHOL-RELATED REWARD AND REINFORCEMENT. MOUSE VTA NEURONS ARE HYPOSENSITIVE TO GAMMA-AMINOBUTYRIC ACID (GABA) DURING ETHANOL (ETOH) WITHDRAWAL, AND GABA RESPONSIVENESS IS NORMALIZED BY IN VITRO TREATMENT WITH HISTONE DEACETYLASE INHIBITORS (HDACI). THE PRESENT STUDY EXAMINED THE EFFECT OF A SYSTEMICALLY ADMINISTERED HDACI, SUBERANILOHYDROXAMIC ACID (SAHA) ON GABA SENSITIVITY, AND RELATED MOLECULAR CHANGES IN VTA NEURONS DURING WITHDRAWAL AFTER CHRONIC ETOH INTAKE IN RATS. METHODS: SPRAGUE DAWLEY MALE ADULT RATS WERE FED WITH LIEBER-DECARLI DIET (9% ETOH OR CONTROL DIET) FOR 16 DAYS. EXPERIMENTAL GROUPS INCLUDED CONTROL DIET-FED AND ETOH DIET-FED (0- OR 24-HOUR WITHDRAWAL) RATS TREATED WITH EITHER SAHA OR VEHICLE INJECTION. SINGLE-UNIT RECORDINGS WERE USED TO MEASURE THE RESPONSE OF VTA NEURONS TO GABA. IMMUNOHISTOCHEMISTRY WAS PERFORMED TO EXAMINE LEVELS OF HDAC2, ACETYLATED HISTONE H3 LYSINE 9 (ACH3K9), AND GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS IN THE VTA; QUANTITATIVE POLYMERASE CHAIN REACTION WAS PERFORMED TO EXAMINE THE MRNA LEVELS OF HDAC2 AND GABA(A) RECEPTOR SUBUNITS. RESULTS: VTA NEURONS FROM THE WITHDRAWAL GROUP EXHIBITED GABA HYPOSENSITIVITY. IN VIVO SAHA TREATMENT 2 HOURS BEFORE SACRIFICE NORMALIZED THE SENSITIVITY OF VTA NEURONS TO GABA. ETOH WITHDRAWAL WAS ASSOCIATED WITH INCREASED HDAC2 AND DECREASED ACH3K9 PROTEIN LEVELS; SAHA TREATMENT NORMALIZED ACH3K9 LEVELS. INTERESTINGLY, NO SIGNIFICANT CHANGE WAS OBSERVED IN THE MRNA LEVELS OF HDAC2. THE MRNA LEVELS, BUT NOT PROTEIN LEVELS, OF GABA(A) RECEPTOR ALPHA1 AND ALPHA5 SUBUNITS WERE INCREASED DURING WITHDRAWAL. CONCLUSIONS: WITHDRAWAL FROM CHRONIC ETOH EXPOSURE RESULTS IN A DECREASE IN GABA-MEDIATED INHIBITION, AND THIS GABA HYPOSENSITIVITY IS NORMALIZED BY IN VIVO SAHA TREATMENT. DISRUPTION OF SIGNALING IN THE VTA PRODUCED BY ALTERATION OF GABA NEUROTRANSMISSION COULD BE 1 NEUROADAPTIVE PHYSIOLOGICAL PROCESS LEADING TO CRAVING AND RELAPSE. THESE RESULTS SUGGEST THAT HDACI PHARMACOTHERAPY WITH AGENTS LIKE SAHA MIGHT BE AN EFFECTIVE TREATMENT FOR ALCOHOLISM.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19  2750  41 EXPRESSION LEVELS OF THE TYROSINE HYDROXYLASE GENE AND HISTONE MODIFICATIONS AROUND ITS PROMOTER IN THE LOCUS COERULEUS AND VENTRAL TEGMENTAL AREA OF RATS DURING FORCED ABSTINENCE FROM MORPHINE. BACKGROUND: EPIGENETIC MECHANISMS SUCH AS HISTONE MODIFICATIONS MAY BE INVOLVED IN THE STRUCTURAL AND BEHAVIORAL CHANGES ASSOCIATED WITH ADDICTION. WE STUDIED WHETHER MORPHINE-INDUCED CHANGES IN MRNA LEVELS OF THE CATECHOLAMINE BIOSYNTHESIS ENZYME, TYROSINE HYDROXYLASE (TH), ARE ASSOCIATED WITH HISTONE MODIFICATIONS AROUND THE PROMOTER OF THIS GENE IN THE LOCUS COERULEUS (LC) AND VENTRAL TEGMENTAL AREA (VTA) OF RATS. METHODS: DEPENDENCE WAS INDUCED IN RATS BY INTRAPERITONEAL INJECTIONS OF MORPHINE FOR 11 DAYS. THE ANIMALS WERE KILLED 2 H (CHRONIC MORPHINE), 24 H AND 7 DAYS (SPONTANEOUS WITHDRAWAL) AFTER THE LAST INJECTION OF MORPHINE. RESULTS: ANALYSIS OF OUR REAL-TIME QUANTITATIVE REVERSE TRANSCRIPTION PCR RESULTS BY 1-WAY ANOVA SHOWED SIGNIFICANT UPREGULATION (5.13 +/- 0.39 FOLDS) OF LC LEVELS OF THE TH TRANSCRIPT 24 H AFTER THE LAST INJECTION OF MORPHINE TO RATS, WHEN COMPARED WITH 2 H AND 7 DAYS TIME POINTS. CHRONIC MORPHINE AND MORPHINE ABSTINENCE FAILED TO CAUSE ANY SIGNIFICANT CHANGES IN THE LEVELS OF TH MRNA IN THE VTA AFTER CESSATION OF MORPHINE. CONSISTENTLY, CHROMATIN IMMUNOPRECIPITATION REAL-TIME QUANTITATIVE PCR ASSAYS REVEALED THAT 24 H AFTER THE LAST INJECTION OF MORPHINE, LEVELS OF H3 ACETYLATION WERE SIGNIFICANTLY INCREASED (4.12 +/- 0.38 FOLDS) AT THE PROMOTER OF THE TH GENE IN THE LC BUT NOT IN THE VTA. OUR DATA ALSO SHOWED THAT HISTONE H3 TRIMETHYLATION FAILED TO CHANGE AROUND THE TH GENE PROMOTER EITHER IN THE VTA OR IN THE LC AFTER MORPHINE ABSTINENCE. CONCLUSIONS: RESULTS OF THE PRESENT STUDY, FOR THE FIRST TIME, DEMONSTRATE THE INVOLVEMENT OF HISTONE H3 ACETYLATION IN THE REGULATION OF TH GENE EXPRESSION IN THE LC OF RATS DURING FORCED ABSTINENCE FROM MORPHINE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20  2347  41 EPIGENETIC REGULATION OF MIR-124 UNDER ETHANOL DEPENDENCE AND WITHDRAWAL. WITHDRAWAL FROM CHRONIC ALCOHOL CAUSE THE PERSISTENT MOLECULAR ALTERATION, SUCH AS CHANGES IN THE RELEASE OF NEUROTRANSMITTER AND GENE EXPRESSION. THE ALTERATIONS ARE THOUGHT TO INCREASE IN THE RISK OF RELAPSE. RECENT STUDIES SUGGEST THAT THE GENE EXPRESSION REGULATED BY HISTONE ACETYLATION MAY PLAY AN IMPORTANT ROLE IN THE DEPENDENCE OF ABUSED DRUGS, INCLUDING OF ETHANOL. FURTHERMORE, MIRNA, ANOTHER REGULATOR OF GENE EXPRESSION, ARE ALSO IMPORTANT MOLECULES FOR THE DEPENDENCE. HOWEVER, CHANGES IN THE MOLECULES UNDER ETHANOL WITHDRAWAL AND ITS RELATIONSHIP ARE POORLY UNDERSTOOD. IN THE PRESENT STUDY, WE INVESTIGATED THE EXPRESSION OF ACETYLATED HISTONE H3 AND MIR-124 IN MOUSE BRAIN AT 3 DAYS AFTER ETHANOL WITHDRAWAL. 6-WEEK AGES OF C57BL/6J MICE WERE TREATED WITH LIQUID DIET CONTAINING ETHANOL FOR 10 DAYS. USING THE ESCALATING ETHANOL DOSAGE SCHEDULE, THE MICE WERE FED THE ETHANOL DIET AS FOLLOWS: 1ST DAY: 1 W/V%: 2ND AND 3RD DAY: 3 W/V%; 4TH AND 5TH DAY: 4 W/V% AND FROM THE 6TH TO 10TH DAY: 5 W/V% ETHANOL DIET, RESPECTIVELY. THE PAIR-FED CONTROL MICE WERE GIVEN THE SAME VOLUME OF ETHANOL-FREE LIQUID DIET WITH GLUCOSE SUBSTITUTED IN ISOCALORIC QUANTITIES FOR ETHANOL. AFTER FEEDING ALCOHOL LIQUID DIET, THE MICE SHOWED SEVERE WITHDRAWAL SIGNS. THE EXPRESSION OF ACETYLATED HISTONE H3 WAS SIGNIFICANTLY DECREASED IN LIMBIC FOREBRAIN AT 3 DAYS AFTER WITHDRAWAL. WE FOUND THAT MIR-124 ALSO DECREASED IN THE LIMBIC FOREBRAIN. IT HAS BEEN REPORTED THAT CDC42 REGULATES NEURONAL DEVELOPMENT AS A TARGET OF MIR-124. WE FOUND THAT CDC42 PROTEIN MARKEDLY INCREASED IN BOTH BRAIN REGIONS AT 3 DAYS AFTER WITHDRAWAL. OUR FINDINGS SUGGEST THAT CHANGES IN THE EXPRESSION OF MIR-124 VIA HISTONE ACETYLATION LEADS TO CHANGE THE CDC42 EXPRESSION UNDER ETHANOL WITHDRAWAL.	2012