1  5613 155 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2    73  29 A MULTI-GENERATIONAL STUDY ON LOW-DOSE BPA EXPOSURE IN WISTAR RATS: EFFECTS ON MATERNAL BEHAVIOR, FLAVOR INTAKE AND DEVELOPMENT. BISPHENOL A (BPA) IS A COMMON ENDOCRINE DISRUPTOR FOUND AS AN ENVIRONMENTAL AND FOOD CONTAMINANT. IT EXERTS BOTH DEVELOPMENTAL AND BEHAVIORAL EFFECTS, MAINLY WHEN EXPOSURE OCCURS IN EARLY LIFE. THE AIM OF THIS STUDY WAS TO DETERMINE THE MULTI-GENERATIONAL EFFECTS OF CHRONIC, HUMAN-RELEVANT LOW-DOSE EXPOSURE TO BPA ON DEVELOPMENT, MATERNAL BEHAVIOR AND FLAVOR PREFERENCE IN WISTAR RATS. BPA WAS ORALLY ADMINISTERED AT A DAILY DOSE OF 5 MUG/KG BODY WEIGHT TO F0 PREGNANT DAMS FROM THE FIRST DAY OF GESTATION (GD 1) UNTIL THE LAST DAY OF LACTATION (LD 21), AND THEN TO F1 OFFSPRING FROM WEANING (PND 21) TO ADULTHOOD (PND 100). F2 OFFSPRING WERE NOT EXPOSED. DEVELOPMENT AND CLINICAL SIGNS OF TOXICITY WERE ASSESSED DAILY. MATERNAL BEHAVIOR WAS EVALUATED BY OBSERVING NURSING AND PUP-CARING ACTIONS, AS WELL AS "NON-MATERNAL" BEHAVIORS IN F0 AND F1 DAMS FROM PARTURITION UNTIL LD 8. THE FLAVOR PREFERENCES OF F1 AND F2 OFFSPRING WERE EVALUATED BASED ON THE INTAKE OF SWEET, SALT AND FAT SOLUTIONS USING THE TWO-BOTTLE CHOICE TEST ON PND 21-34 AND PND 86-99. BPA EXPOSURE: 1) DECREASED MATERNAL BEHAVIOR IN F1 DAMS, 2) CAUSED DEVELOPMENTAL DEFECTS IN BOTH F1 AND F2 OFFSPRING, WITH A NOTICEABLE DECREASE IN ANOGENITAL DISTANCE IN MALE RATS, AND 3) DID NOT AFFECT FLAVORED SOLUTION INTAKE IN F1, BUT INDUCED CHANGES IN SWEET PREFERENCE IN F2 JUVENILES AND IN SALT AND FAT SOLUTION INTAKES IN F2 ADULTS, AND 4) INDUCED A BODY WEIGHT INCREASE IN THE F2 GENERATION ONLY, WHEREAS FOOD INTAKE AND WATER CONSUMPTION DID NOT CHANGE. TAKEN AS A WHOLE, OUR FINDINGS SHOWED THAT BOTH GESTATIONAL (F0) AND LIFELONG (F1) EXPOSURES TO A HUMAN-RELEVANT DOSE OF BPA COULD INDUCE MULTI-GENERATIONAL EFFECTS ON BOTH DEVELOPMENT AND BEHAVIOR. THESE RESULTS SUGGEST POSSIBLE SELECTIVE NEUROENDOCRINE DEFECTS AND/OR EPIGENETIC CHANGES CAUSED BY BPA EXPOSURE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3   392  31 AN ORALLY BIOAVAILABLE CHEMICAL PROBE OF THE LYSINE METHYLTRANSFERASES EZH2 AND EZH1. EZH2 OR EZH1 IS THE CATALYTIC SUBUNIT OF THE POLYCOMB REPRESSIVE COMPLEX 2 THAT CATALYZES METHYLATION OF HISTONE H3 LYSINE 27 (H3K27). THE TRIMETHYLATION OF H3K27 (H3K27ME3) IS A TRANSCRIPTIONALLY REPRESSIVE POST-TRANSLATIONAL MODIFICATION. OVEREXPRESSION OF EZH2 AND HYPERTRIMETHYLATION OF H3K27 HAVE BEEN IMPLICATED IN A NUMBER OF CANCERS. SEVERAL SELECTIVE INHIBITORS OF EZH2 HAVE BEEN REPORTED RECENTLY. HEREIN WE DISCLOSE UNC1999, THE FIRST ORALLY BIOAVAILABLE INHIBITOR THAT HAS HIGH IN VITRO POTENCY FOR WILD-TYPE AND MUTANT EZH2 AS WELL AS EZH1, A CLOSELY RELATED H3K27 METHYLTRANSFERASE THAT SHARES 96% SEQUENCE IDENTITY WITH EZH2 IN THEIR RESPECTIVE CATALYTIC DOMAINS. UNC1999 WAS HIGHLY SELECTIVE FOR EZH2 AND EZH1 OVER A BROAD RANGE OF EPIGENETIC AND NON-EPIGENETIC TARGETS, COMPETITIVE WITH THE COFACTOR SAM AND NON-COMPETITIVE WITH THE PEPTIDE SUBSTRATE. THIS INHIBITOR POTENTLY REDUCED H3K27ME3 LEVELS IN CELLS AND SELECTIVELY KILLED DIFFUSED LARGE B CELL LYMPHOMA CELL LINES HARBORING THE EZH2(Y641N) MUTANT. IMPORTANTLY, UNC1999 WAS ORALLY BIOAVAILABLE IN MICE, MAKING THIS INHIBITOR A VALUABLE TOOL FOR INVESTIGATING THE ROLE OF EZH2 AND EZH1 IN CHRONIC ANIMAL STUDIES. WE ALSO DESIGNED AND SYNTHESIZED UNC2400, A CLOSE ANALOGUE OF UNC1999 WITH POTENCY >1,000-FOLD LOWER THAN THAT OF UNC1999 AS A NEGATIVE CONTROL FOR CELL-BASED STUDIES. FINALLY, WE CREATED A BIOTIN-TAGGED UNC1999 (UNC2399), WHICH ENRICHED EZH2 IN PULL-DOWN STUDIES, AND A UNC1999-DYE CONJUGATE (UNC2239) FOR CO-LOCALIZATION STUDIES WITH EZH2 IN LIVE CELLS. TAKEN TOGETHER, THESE COMPOUNDS REPRESENT A SET OF USEFUL TOOLS FOR THE BIOMEDICAL COMMUNITY TO INVESTIGATE THE ROLE OF EZH2 AND EZH1 IN HEALTH AND DISEASE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4  5478  40 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   765  49 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6  5044  41 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
7  6445  22 THERAPEUTIC BENEFITS OF THE METHYL DONOR S-ADENOSYLMETHIONINE ON NERVE INJURY-INDUCED MECHANICAL HYPERSENSITIVITY AND COGNITIVE IMPAIRMENT IN MICE. DESPITE CONSIDERABLE ADVANCES IN UNDERSTANDING MECHANISMS INVOLVED IN CHRONIC PAIN, EFFECTIVE TREATMENT REMAINS ELUSIVE. COMORBID CONDITIONS INCLUDING ANXIETY, DEPRESSION, AND COGNITIVE IMPAIRMENT FURTHER IMPACT QUALITY OF LIFE. CHRONIC PAIN IS ASSOCIATED WITH REVERSIBLE CHANGES IN BRAIN ANATOMY AND FUNCTION AND WITH LONG-TERM CHANGES IN GENE EXPRESSION. EPIGENETIC MECHANISMS, INCLUDING DNA METHYLATION, CONTRIBUTE TO WIDE-SPREAD AND LONG-LASTING REPROGRAMMING OF GENE EXPRESSION. WE PREVIOUSLY REPORTED DECREASES IN GLOBAL DNA METHYLATION IN THE MOUSE FRONTAL CORTEX 6 MONTHS AFTER INDUCTION OF NEUROPATHIC PAIN USING THE SPARED NERVE INJURY (SNI) MODEL. HERE, WE EXAMINED THE THERAPEUTIC EFFECT OF INCREASING DNA METHYLATION USING THE METHYL DONOR S-ADENOSYLMETHIONINE (SAM). S-ADENOSYLMETHIONINE IS MARKETED AS A NUTRITIONAL SUPPLEMENT FOR A RANGE OF CONDITIONS INCLUDING LIVER DISEASE, DEPRESSION, OSTEOARTHRITIS, FIBROMYALGIA, AND DEMENTIA. THREE MONTHS AFTER SNI OR SHAM SURGERY, ANIMALS WERE TREATED WITH SAM (20 MG/KG, 3X/WEEK) OR SALINE ORALLY FOR 4 MONTHS, AND THE IMPACT ON SENSORY, MOTOR, MOTIVATIONAL, AND COGNITIVE INDICES WAS MEASURED. S-ADENOSYLMETHIONINE ATTENUATED SNI-INDUCED MECHANICAL HYPERSENSITIVITY AND REDUCED ACTIVE AVOIDANCE OF MECHANICAL STIMULI BUT HAD NO EFFECT ON COLD SENSITIVITY OR MOTOR CAPACITY. S-ADENOSYLMETHIONINE COMPLETELY BLOCKED NERVE INJURY-INDUCED COGNITIVE IMPAIRMENT AND ATTENUATED SNI-INDUCED DECREASES IN GLOBAL DNA METHYLATION IN THE FRONTAL CORTEX. IN SUMMARY, CHRONIC ORAL ADMINISTRATION OF THE METHYL DONOR, SAM, ATTENUATED SENSORY AND COGNITIVE SYMPTOMS ASSOCIATED WITH NERVE INJURY IN MICE. THESE EFFECTS MAY BE MEDIATED, IN PART, THROUGH MODULATION OF DNA METHYLATION IN THE CENTRAL NERVOUS SYSTEM BY SYSTEMIC ADMINISTRATION OF THE METHYL DONOR SAM.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8  1004  33 CHRONIC TREATMENT WITH HORMONAL CONTRACEPTIVES ALTERS HIPPOCAMPAL BDNF AND HISTONE H3 POST-TRANSLATIONAL MODIFICATIONS BUT NOT LEARNING AND MEMORY IN FEMALE RATS. HORMONAL CONTRACEPTIVES PREVENT OVULATION WITH SUBSEQUENT REDUCTION IN ENDOGENOUS LEVELS OF ESTRADIOL, PROGESTERONE AND ITS NEUROACTIVE METABOLITE ALLOPREGNANOLONE. THESE NEUROSTEROIDS MODULATE SEVERAL BRAIN FUNCTIONS, INCLUDING NEURONAL PLASTICITY, COGNITION AND MEMORY. WE HYPOTHESIZED THAT HORMONAL CONTRACEPTIVES MIGHT AFFECT SYNAPTIC PLASTICITY, LEARNING AND MEMORY, AS A CONSEQUENCE OF SUPPRESSED ENDOGENOUS HORMONES LEVELS. FEMALE RATS WERE ORALLY TREATED WITH A COMBINATION OF ETHINYL ESTRADIOL (EE, 0.020 MG) AND LEVONORGESTREL (LNG, 0.060 MG) ONCE DAILY FOR FOUR WEEKS. DECREASED HIPPOCAMPAL BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS AND ALTERED HISTONE H3 POST-TRANSLATIONAL MODIFICATIONS (PTMS) WERE OBSERVED 14 DAYS AFTER DISCONTINUATION FROM CHRONIC EE-LNG TREATMENT. THESE EFFECTS WERE NOT ACCOMPANIED BY ALTERATIONS IN LONG-TERM PLASTICITY AT GLUTAMATERGIC SYNAPSES, RECOGNITION MEMORY IN THE NOVEL OBJECT AND NOVEL PLACE LOCATION TESTS, OR SPATIAL LEARNING, MEMORY, AND BEHAVIORAL FLEXIBILITY IN THE MORRIS WATER MAZE TEST. THUS, DECREASED BDNF CONTENT DOES NOT AFFECT SYNAPTIC PLASTICITY AND COGNITIVE PERFORMANCE; RATHER IT MIGHT BE RELEVANT FOR THE OCCURRENCE OF CERTAIN PSYCHIATRIC SYMPTOMS, REPORTED BY SOME WOMEN USING HORMONAL CONTRACEPTIVES. THESE RESULTS PROVIDE THE FIRST EVIDENCE OF HIPPOCAMPAL EPIGENETIC CHANGES INDUCED BY HORMONAL CONTRACEPTIVES AND COMPLEMENT PREVIOUS STUDIES ON THE NEUROBIOLOGICAL ACTIONS OF HORMONAL CONTRACEPTIVES; THE FINDING THAT EFFECTS OF CHRONIC EE-LNG TREATMENT ON BDNF CONTENT AND HISTONE PTMS ARE OBSERVED 14 DAYS AFTER DRUG DISCONTINUATION WARRANTS FURTHER INVESTIGATION TO BETTER UNDERSTAND THE IMPLICATIONS OF SUCH LONG-TERM CONSEQUENCES FOR WOMEN'S HEALTH.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9  3785  22 INTERGENERATIONAL EFFECTS OF PRE-PREGNANCY CHRONIC LIPOPOLYSACCHARIDE FROM PORPHYROMONAS GINGIVALIS ON THE LEARNING, MEMORY AND SEIZURE SUSCEPTIBILITY OF OFFSPRING. OBJECTIVE: THE AIM OF THIS STUDY WAS TO INVESTIGATE THE EFFECTS OF PRE-PREGNANCY CHRONIC EXPOSURE TO PORPHYROMONAS GINGIVALIS LPS (PG LPS) ON THE LEARNING, MEMORY, AND SEIZURE SUSCEPTIBILITY OF THE OFFSPRING. DESIGN: TO ACHIEVE PERIODONTITIS, PG LPS (5 MUG/KG) WAS INJECTED INTO THE GINGIVAL OF FIVE FEMALE RATS EVERY 48 H FOR THREE WEEKS. FIVE CONTROL FEMALE RATS RECEIVED SALINE (0.9 %) AND FIVE FEMALE WERE KEPT INTACT. THE CONCENTRATIONS OF TNF-ALPHA AND IL-6 WERE MEASURED IN THE BLOOD SAMPLES. ONE WEEK AFTER THE FINAL INJECTION, FEMALES WERE MATED WITH INTACT MALES. FOLLOWING BIRTH AND WEANING, TWO MALE AND TWO FEMALE OFFSPRING WERE RANDOMLY SELECTED FROM EACH MOTHER, AND NEW GROUPS OF MALE AND FEMALE OFFSPRING WERE DEFINED FOR BEHAVIORAL ASSESSMENTS. MORRIS WATER MAZE WAS USED TO EVALUATE SPATIAL MEMORY, SHUTTLE BOX WAS USED TO INVESTIGATE AVOIDANCE MEMORY AND A PENTYLENETETRAZOLE-INDUCED SEIZURE WAS USED TO EVALUATE SEIZURE SUSCEPTIBILITY IN THE OFFSPRING. RESULTS: SPATIAL LEARNING AND AVOIDANCE MEMORY SIGNIFICANTLY DECREASED IN BOTH MALE AND FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE RATS, COMPARED TO THE CONTROL OFFSPRING. LATENCY TO REACH SEIZURE STAGES 1 AND 2 SIGNIFICANTLY INCREASED IN THE MALE OFFSPRING, BUT NOT THE FEMALE OFFSPRING OF PG LPS-EXPOSED FEMALE, COMPARED TO THE CONTROL OFFSPRING. HOWEVER, NO SIGNIFICANT DIFFERENCE WAS FOUND IN LATENCY TO REACH STAGES 3-5. CONCLUSION: PRE-PREGNANCY EXPOSURE TO PG LPS COULD AFFECT SOME BEHAVIORAL FUNCTIONS IN BOTH MALE AND FEMALE OFFSPRING INTERGENERATIONALLY.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10  6612  23 ULTRA-LOW-DOSE NALOXONE ENHANCES THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN PTX-TREATED RATS: REGULATION ON GLOBAL HISTONE METHYLATION. OBJECTIVE: EPIGENETIC REPROGRAMMING MAY HAVE A POSSIBLE ROLE IN NEUROPATHIC PAIN DEVELOPMENT; THE PRESENT STUDY EXAMINED THE GLOBAL PATTERNS OF LYSINE HISTONE MODIFICATION. IN THIS SERIAL STUDY WE ANALYZED THE LEVELS OF HISTONE 3 LYSINE 4 MONOMETHYLATION, HISTONE 3 LYSINE 4 DIMETHYLATION, AND HISTONE 3 LYSINE 9 TRIMETHYLATION IN PERTUSSIS TOXIN (PTX)-INDUCED THERMAL HYPERALGESIC RAT SPINAL CORDS. METHODS: MALE WISTAR RATS IMPLANTED WITH AN INTRATHECAL CATHETER RECEIVED A SINGLE INTRATHECAL PTX (1 MUG IN 5 MUL SALINE) INJECTION. FOUR DAYS LATER, THEY WERE RANDOMLY ASSIGNED TO RECEIVE EITHER A SINGLE INJECTION OF SALINE, OR ULTRA-LOW-DOSE NALOXONE (15 NG IN 5 MUL SALINE), FOLLOWED BY MORPHINE (10 MUG IN 5 MUL SALINE) INJECTION 30 MINUTES LATER. RESULTS: THE RESULTS SHOWED THAT PTX INJECTION INDUCED THERMAL HYPERALGESIA AND SIGNIFICANT INCREASE OF GLOBAL HISTONE METHYLATION IN THE SPINAL CORDS. INTRATHECAL MORPHINE ALONE DID NOT AFFECT THE THERMAL HYPERALGESIA AND GLOBAL HISTONE METHYLATION. IN CONTRAST, INTRATHECAL ADMINISTRATION OF ULTRA-LOW-DOSE NALOXONE PLUS MORPHINE SIGNIFICANTLY ATTENUATED THE PTX-INDUCED THERMAL HYPERALGESIA AND DOWN-REGULATED THE GLOBAL HISTONE METHYLATION. CONCLUSION: THE RESULTS SUGGEST THAT ULTRA-LOW-DOSE NALOXONE MIGHT BE CLINICAL VALUABLE FOR NEUROPATHIC PAIN MANAGEMENT VIA REGULATING GLOBAL HISTONE MODIFICATION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11  2769  50 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
12  5056  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  5283  37 PROPHYLACTIC OR PREEMPTIVE LOW-DOSE AZACITIDINE AND DONOR LYMPHOCYTE INFUSION TO PREVENT DISEASE RELAPSE FOLLOWING ALLOGENEIC TRANSPLANTATION IN PATIENTS WITH HIGH-RISK ACUTE MYELOGENOUS LEUKEMIA OR MYELODYSPLASTIC SYNDROME. BECAUSE OF THE PERSISTENTLY HIGH RATES OF RELAPSE OF PATIENTS WITH HIGH-RISK ACUTE MYELOGENOUS LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROME (MDS) FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT), POST-TRANSPLANTATION MAINTENANCE THERAPY HAS BEEN PROPOSED. WE PREVIOUSLY INITIATED A PHASE II TRIAL IN WHICH EPIGENETIC THERAPY WAS COMBINED WITH IMMUNOTHERAPY IN AN ATTEMPT TO REDUCE DISEASE RELAPSE. IN THAT STUDY, LOW-DOSE AZACITIDINE (AZA) AND ESCALATING DOSES OF DONOR LYMPHOCYTE INFUSION (DLI) WERE GIVEN AS POST-ALLO-HSCT MAINTENANCE TREATMENT. IN THE PRESENT STUDY, WE RETROSPECTIVELY ANALYZE A LARGER COHORT OF PATIENTS RECEIVING POST-TRANSPLANTATION MAINTENANCE THERAPY AND PROVIDE UPDATES ON SOME PATIENTS OF THE EARLIER STUDY. THE OBJECTIVES OF THE PRESENT STUDY WERE TO ANALYZE THE CUMULATIVE INCIDENCE OF RELAPSE (CIR), OVERALL SURVIVAL (OS), AND PROGRESSION-FREE SURVIVAL (PFS) AND THE INCIDENCE OF ACUTE AND CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD) OF PATIENTS WITH HIGH-RISK AML OR MDS RECEIVING POST-TRANSPLANTATION MAINTENANCE TREATMENT WITH AZA WITH OR WITHOUT DLI. WE RETROSPECTIVELY ANALYZED 77 PATIENTS (54 WITH AML, 23 WITH MDS) CONSIDERED AT HIGH RISK BASED ON EITHER THEIR GENOMIC OR CLINICAL STATUS AT TRANSPLANTATION. FOLLOWING ALLOGENEIC TRANSPLANTATION, THEY RECEIVED AT LEAST 1 CYCLE OF PROPHYLACTIC OR PREEMPTIVE LOW-DOSE AZA WITH OR WITHOUT ESCALATING DOSES OF DLI TO PREVENT DISEASE RELAPSE. ALMOST ONE-HALF OF THE PATIENTS (47%) WERE ABLE TO RECEIVE THE FULL 12 CYCLES OF SCHEDULED AZA, AND A MAJORITY (79%) RECEIVED AT LEAST 1 DLI. WITH A MEDIAN FOLLOW-UP OF 24 MONTHS, 19 PATIENTS (25%; 16 WITH AML, 3 WITH MDS) RELAPSED, AT A MEDIAN OF 9.8 MONTHS (RANGE, 4 TO 58.6 MONTHS), GIVING A 22% CIR AT 24 MONTHS. OS AND PFS AT 24 MONTHS WERE 70.8% AND 68.3%, RESPECTIVELY. THE CUMULATIVE INCIDENCES OF GRADE II-IV ACUTE GVHD AND CHRONIC GVHD WERE 27.4% AND 45%, RESPECTIVELY. ONLY A MINORITY OF PATIENTS (11%) REQUIRED DELAYED ADMINISTRATION OF AZA. THESE FINDINGS CONFIRM THAT AZA-DLI MAINTENANCE IS BOTH TOLERABLE AND EFFECTIVE IN REDUCING THE RISK OF POST-TRANSPLANTATION RELAPSE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  4913  34 PAIN MODULATION IN WAG/RIJ EPILEPTIC RATS (A GENETIC MODEL OF ABSENCE EPILEPSY): EFFECTS OF BIOLOGICAL AND PHARMACOLOGICAL HISTONE DEACETYLASE INHIBITORS. EPIGENETIC MECHANISMS ARE INVOLVED IN EPILEPSY AND CHRONIC PAIN DEVELOPMENT. ABOUT THAT, WE STUDIED THE EFFECTS OF THE NATURAL HISTONE DEACETYLASE (HDAC) INHIBITOR SODIUM BUTYRATE (BUT) IN COMPARISON WITH VALPROIC ACID (VPA) IN A VALIDATED GENETIC MODEL OF GENERALIZED ABSENCE EPILEPSY AND EPILEPTOGENESIS. WAG/RIJ RATS WERE TREATED WITH BUT (30 MG/KG), VPA (300 MG/KG), AND THEIR COMBINATION (BUT + VPA) DAILY PER OS FOR 6 MONTHS. RATS WERE SUBJECTED AT RANDALL-SELITTO, VON FREY, HOT PLATE, AND TAIL FLICK TESTS AFTER 1, 3, AND 6 MONTHS OF TREATMENT TO EVALUATE HYPERSENSITIVITY TO NOXIOUS AND NON-NOXIUOUS STIMULI. MOREOVER, PPAR-GAMMA (G3335 1 MG/KG), GABA-B (CGP35348 80 MG/KG), AND OPIOID (NALOXONE 1 MG/KG) RECEPTOR ANTAGONISTS WERE ADMINISTRATED TO INVESTIGATE THE POSSIBLE MECHANISMS INVOLVED IN ANALGESIC ACTIVITY. THE EXPRESSION OF NFKB, GLUTATHIONE REDUCTASE, AND PROTEIN OXIDATION (CARBONYLATION) WAS ALSO EVALUATED BY WESTERN BLOT ANALYSIS. WAG/RIJ RATS SHOWED AN ALTERED PAIN THRESHOLD THROUGHOUT THE STUDY (P < 0.001). BUT AND BUT + VPA TREATMENT REDUCED HYPERSENSITIVITY (P < 0.01). VPA WAS SIGNIFICANTLY EFFECTIVE ONLY AFTER 1 MONTH (P < 0.01). ALL THE THREE RECEPTORS ARE INVOLVED IN BUT + VPA EFFECTS (P < 0.001). BUT AND BUT + VPA DECREASED THE EXPRESSION OF NFKB AND ENHANCED GLUTATHIONE REDUCTASE (P < 0.01); PROTEIN OXIDATION (CARBONYLATION) WAS REDUCED (P < 0.01). NO EFFECT WAS REPORTED WITH VPA. IN CONCLUSION BUT, ALONE OR IN COADMINISTRATION WITH VPA, IS A VALUABLE CANDIDATE FOR MANAGING THE EPILEPSY-RELATED PERSISTENT PAIN.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  5480  27 RESVERATROL REVERSES MORPHINE-INDUCED NEUROINFLAMMATION IN MORPHINE-TOLERANT RATS BY REVERSAL HDAC1 EXPRESSION. BACKGROUND/PURPOSE: WE PREVIOUSLY SHOWED THAT SUBSEQUENT INTRATHECAL (I.T.) INJECTION OF RESVERATROL (30 MUG) SIGNIFICANTLY REVERSES MORPHINE-EVOKED NEUROINFLAMMATION IN MORPHINE-TOLERANT RATS. THE PRESENT STUDY EXAMINED THE UNDERLYING MECHANISM. METHODS: MALE WISTAR RATS WERE IMPLANTED WITH TWO I.T. CATHETERS, ONE OF WHICH WAS CONNECTED TO A MINIOSMOTIC PUMP AND USED FOR MORPHINE (15 MUG/H) OR SALINE INFUSION FOR 120 HOURS. TO EXAMINE THE EFFECTS ON SPINAL CORD EXPRESSION OF HISTONE DEACETYLASE 1 (HDAC1), THE INFLAMMATORY CYTOKINE TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), AND TNF RECEPTOR (TNFR) 1 AND TNFR2 DURING TOLERANCE INDUCTION, A TAIL-FLICK TEST WAS PERFORMED PRIOR TO INFUSION AND AFTER 24 HOURS, 48 HOURS, 72 HOURS, 96 HOURS, AND 120 HOURS OF INFUSION. RESULTS: RESVERATROL TREATMENT PRIOR TO MORPHINE CHALLENGE RESTORED THE ANTINOCICEPTIVE EFFECT OF MORPHINE IN MORPHINE-TOLERANT RATS AND REVERSED THE MORPHINE INFUSION-INDUCED INCREASE IN HDAC1, TNF-ALPHA, AND TNFR1 EXPRESSION. MOREOVER, CHRONIC MORPHINE INFUSION INCREASED TNFR1-SPECIFIC EXPRESSION IN NEURON IN MORPHINE-TOLERANT RAT SPINAL CORDS, AND THIS EFFECT WAS ALMOST COMPLETELY INHIBITED BY RESVERATROL TREATMENT PRIOR TO MORPHINE CHALLENGE. CONCLUSION: RESVERATROL RESTORES THE ANTINOCICEPTIVE EFFECT OF MORPHINE BY REVERSING MORPHINE INFUSION-INDUCED SPINAL CORD NEUROINFLAMMATION AND INCREASE IN TNFR1 EXPRESSION. THE REVERSAL OF THE MORPHINE-INDUCED INCREASE IN TNFR1 EXPRESSION BY RESVERATROL IS PARTIALLY DUE TO REVERSAL OF THE MORPHINE INFUSION-INDUCED INCREASE IN HDAC1 EXPRESSION. RESVERATROL PRETREATMENT CAN BE USED AS AN ADJUVANT IN CLINICAL PAIN MANAGEMENT FOR PATIENTS WHO NEED LONG-TERM MORPHINE TREATMENT OR WITH NEUROPATHIC PAIN.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16  1833  21 EFFECTS OF METHYL DONOR DIETS ON INCISIONAL PAIN IN MICE. BACKGROUND: DIETARY SUPPLEMENTATION WITH METHYL DONORS CAN INFLUENCE THE PROGRAMMING OF EPIGENETIC PATTERNS RESULTING IN PERSISTENT ALTERATIONS IN DISEASE SUSCEPTIBILITY AND BEHAVIOR. HOWEVER, THE DIETARY EFFECTS OF METHYL DONORS ON PAIN HAVE NOT BEEN EXPLORED. IN THIS STUDY, WE EVALUATED THE EFFECTS OF DIETARY METHYL DONOR CONTENT ON PAIN RESPONSES IN MICE. METHODS: MALE AND FEMALE C57BL/6J MICE WERE TREATED WITH HIGH OR LOW METHYL DONOR DIETS EITHER IN THE PERINATAL PERIOD OR AFTER WEANING. MECHANICAL AND THERMAL NOCICEPTIVE SENSITIVITY WERE MEASURED BEFORE AND AFTER INCISION. RESULTS: MICE FED HIGH OR LOW METHYL DONOR DIETS DISPLAYED EQUAL WEIGHT GAIN OVER THE COURSE OF THE EXPERIMENTS. WHEN EXPOSED TO THESE DIETARY MANIPULATIONS IN THE PERINATAL PERIOD, ONLY MALE OFFSPRING OF DAMS FED A HIGH METHYL DONOR DIET DISPLAYED INCREASED MECHANICAL ALLODYNIA. HINDPAW INCISION IN THESE ANIMALS CAUSED ENHANCED NOCICEPTIVE SENSITIZATION, BUT DIETARY HISTORY DID NOT AFFECT THE DURATION OF SENSITIZATION. FOR MICE EXPOSED TO HIGH OR LOW METHYL DONOR DIETS AFTER WEANING, NO SIGNIFICANT DIFFERENCES WERE OBSERVED IN MECHANICAL OR THERMAL NOCICEPTIVE SENSITIVITY EITHER AT BASELINE OR IN RESPONSE TO HINDPAW INCISION. CONCLUSIONS: PERINATAL DIETARY FACTORS SUCH AS METHYL DONOR CONTENT MAY IMPACT PAIN EXPERIENCES IN LATER LIFE. THESE EFFECTS, HOWEVER, MAY BE SPECIFIC TO SEX AND PAIN MODALITY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17  5612  62 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	

18  4397  24 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  2822  47 FIRST-IN-HUMAN STUDY OF INHALED AZACITIDINE IN PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER. BACKGROUND: AEROSOLIZED AZACITIDINE HAS BEEN SHOWN TO INHIBIT ORTHOTOPIC LUNG CANCER GROWTH AND INDUCE RE-EXPRESSION OF METHYLATED TUMOR SUPPRESSOR GENES IN MURINE MODELS. WE HYPOTHESIZED THAT INHALED AZACITIDINE IS SAFE AND EFFECTIVE IN REVERSING EPIGENETIC CHANGES IN THE BRONCHIAL EPITHELIUM SECONDARY TO CHRONIC SMOKING. PATIENTS AND METHODS: WE REPORT THE FIRST IN HUMAN STUDY OF INHALED AZACITIDINE. AZACITIDINE IN AQUEOUS SOLUTION WAS USED TO GENERATE AN AEROSOL SUSPENSION OF 0.25-5 MUM PARTICLE SIZE. MAIN INCLUSION CRITERIA: STAGE IV OR RECURRENT NSCLC WITH PREDOMINANTLY LUNG INVOLVEMENT, >/=1 PRIOR SYSTEMIC THERAPY, ECOG PS 0-1, AND ADEQUATE PULMONARY FUNCTION. PATIENTS RECEIVED INHALED AZACITIDINE DAILY ON DAYS 1-5 AND 15-19 OF 28-DAY CYCLES, AT 3 ESCALATING DOSES (15, 30 AND 45 MG/M(2) DAILY). THE PRIMARY OBJECTIVE WAS TO DETERMINE THE FEASIBILITY AND TOLERABILITY OF THIS NEW THERAPEUTIC MODALITY. THE KEY SECONDARY OBJECTIVES INCLUDED PHARMACOKINETICS, METHYLATION PROFILES AND EFFICACY. RESULTS: FROM 3/2015 TO 2/2018, EIGHT PATIENTS RECEIVED A MEDIAN NUMBER OF 2 (IQR = 1) CYCLES OF INHALED AZACITIDINE. NO CLINICALLY SIGNIFICANT ADVERSE EVENTS WERE OBSERVED, EXCEPT ONE PATIENT TREATED AT THE HIGHEST DOSE DEVELOPED AN ASYMPTOMATIC GRADE 2 DECREASED DLCO WHICH RESOLVED SPONTANEOUSLY. ONE PATIENT RECEIVING 12 CYCLES OF THERAPY HAD AN OBJECTIVE AND DURABLE PARTIAL RESPONSE, AND TWO PATIENTS HAD STABLE DISEASE. PLASMA AZACITIDINE WAS ONLY BRIEFLY DETECTABLE IN PATIENTS TREATED AT THE HIGHER DOSES. MOREOVER, IN 2 OF 3 PARTICIPANTS WHO AGREED AND UNDERWENT PRE- AND POST-TREATMENT BRONCHOSCOPY, THE GLOBAL DNA METHYLATION IN THE BRONCHIAL EPITHELIUM DECREASED BY 24 % AND 79 % POST-THERAPY, RESPECTIVELY. THE INTERVAL BETWEEN LAST INHALED TREATMENT AND BRONCHOSCOPY WAS 3 DAYS. CONCLUSIONS: INHALED AZACITIDINE RESULTED IN NEGLIGIBLE PLASMA LEVELS COMPARED TO THE PREVIOUSLY REPORTED SUBCUTANEOUS ADMINISTRATION AND WAS WELL-TOLERATED. THE RESULTS JUSTIFY THE CONTINUED DEVELOPMENT OF INHALED AZACITIDINE AT NON-CYTOTOXIC DOSES FOR PATIENTS WITH LUNG-CONFINED MALIGNANT AND/OR PREMALIGNANT LESIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20  2827  25 FLUOXETINE INCREASES HIPPOCAMPAL NEUROGENESIS AND INDUCES EPIGENETIC FACTORS BUT DOES NOT IMPROVE FUNCTIONAL RECOVERY AFTER TRAUMATIC BRAIN INJURY. THE SELECTIVE SEROTONIN REUPTAKE INHIBITOR FLUOXETINE INDUCES HIPPOCAMPAL NEUROGENESIS, STIMULATES MATURATION AND SYNAPTIC PLASTICITY OF ADULT HIPPOCAMPAL NEURONS, AND REDUCES MOTOR/SENSORY AND MEMORY IMPAIRMENTS IN SEVERAL CNS DISORDERS. IN THE SETTING OF TRAUMATIC BRAIN INJURY (TBI), ITS EFFECTS ON NEUROPLASTICITY AND FUNCTION HAVE YET TO BE THOROUGHLY INVESTIGATED. HERE WE EXAMINED THE EFFICACY OF FLUOXETINE AFTER A MODERATE TO SEVERE TBI, PRODUCED BY A CONTROLLED CORTICAL IMPACT. THREE DAYS AFTER TBI OR SHAM SURGERY, MICE WERE TREATED WITH FLUOXETINE (10 MG/KG/D) OR VEHICLE FOR 4 WEEKS. TO EVALUATE THE EFFECTS OF FLUOXETINE ON NEUROPLASTICITY, HIPPOCAMPAL NEUROGENESIS AND EPIGENETIC MODIFICATION WERE STUDIED. STEREOLOGIC ANALYSIS OF THE DENTATE GYRUS REVEALED A SIGNIFICANT INCREASE IN DOUBLECORTIN-POSITIVE CELLS IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE RELATIVE TO CONTROLS, A FINDING CONSISTENT WITH ENHANCED HIPPOCAMPAL NEUROGENESIS. EPIGENETIC MODIFICATIONS, INCLUDING AN INCREASE IN HISTONE 3 ACETYLATION AND INDUCTION OF METHYL-CPG-BINDING PROTEIN, A TRANSCRIPTION FACTOR INVOLVED IN DNA METHYLATION, WERE LIKEWISE SEEN BY IMMUNOHISTOCHEMISTRY AND QUANTITATIVE WESTERN IMMUNOBLOTS, RESPECTIVELY, IN BRAIN-INJURED ANIMALS TREATED WITH FLUOXETINE. TO DETERMINE IF FLUOXETINE IMPROVES NEUROLOGICAL OUTCOMES AFTER TBI, GAIT FUNCTION AND SPATIAL LEARNING AND MEMORY WERE ASSESSED BY THE CATWALK-ASSISTED GAIT TEST AND BARNES MAZE TEST, RESPECTIVELY. NO DIFFERENCES IN THESE PARAMETERS WERE SEEN BETWEEN FLUOXETINE- AND VEHICLE-TREATED ANIMALS. THUS WHILE FLUOXETINE ENHANCED NEUROPLASTICITY IN THE HIPPOCAMPUS AFTER TBI, ITS CHRONIC ADMINISTRATION DID NOT RESTORE LOCOMOTOR FUNCTION OR AMELIORATE MEMORY DEFICITS.	2011