1  1118 155 COMPARATIVE GENOTYPING AND PHENOTYPING OF ASPERGILLUS FUMIGATUS ISOLATES FROM HUMANS, DOGS AND THE ENVIRONMENT. BACKGROUND: ASPERGILLUS FUMIGATUS IS A UBIQUITOUS SAPROTROPHIC FUNGUS AND AN OPPORTUNISTIC PATHOGEN OF HUMANS AND ANIMALS. HUMANS AND ANIMALS CAN INHALE HUNDREDS OF A. FUMIGATUS SPORES DAILY. NORMALLY THIS IS HARMLESS FOR HUMANS, BUT IN CASE OF IMMUNODEFICIENCY, INVASIVE PULMONARY ASPERGILLOSIS (IPA) CAN DEVELOP WITH A HIGH MORTALITY RATE. A. FUMIGATUS ALSO CAUSES NON-INVASIVE MYCOSES LIKE SINO-NASAL ASPERGILLOSIS (SNA) IN DOGS. RESULTS: IN THIS STUDY WE COMPARED A. FUMIGATUS ISOLATES FROM HUMANS WITH SUSPECTED IPA, DOGS WITH SNA, AND A SET OF ENVIRONMENTAL ISOLATES. PHYLOGENETIC INFERENCE BASED ON CALMODULIN (CAM) AND BETA-TUBULIN (BENA) SEQUENCES DID NOT REVEAL A. FUMIGATUS SUB-GROUPS LINKED TO THE ORIGIN OF THE ISOLATES. GENOTYPING AND MICROSATELLITE ANALYSIS SHOWED THAT EACH DOG WAS INFECTED BY ONE A. FUMIGATUS GENOTYPE, WHEREAS HUMAN PATIENTS HAD MIXED INFECTIONS. AZOLE RESISTANCE WAS DETERMINED BY ANTIFUNGAL SUSCEPTIBILITY TESTING AND SEQUENCING OF THE CYP51A GENE. A TOTAL OF 12 OUT OF 29 HUMAN ISOLATES AND 1 OUT OF 27 ENVIRONMENTAL ISOLATES WERE AZOLE RESISTANT. OF THE AZOLE RESISTANT STRAINS, 11 HUMAN ISOLATES SHOWED TR(34)/L98H (N = 6) OR TR46/Y121F/T289A (N = 5). PHENOTYPICALLY, ISOLATES FROM DOGS WERE MORE VARIABLE IN GROWTH SPEED AND MORPHOLOGY WHEN COMPARED TO THOSE ISOLATED FROM HUMAN AND THE ENVIRONMENT. CONCLUSIONS: 1. A. FUMIGATUS FROM DOGS WITH SNA ARE PHENOTYPICALLY VERY DIVERSE IN CONTRAST TO THEIR ENVIRONMENTAL AND HUMAN COUNTERPARTS. 2. PHENOTYPIC VARIABILITY CAN BE INDUCED DURING THE CHRONIC INFECTION PROCESS IN THE SINUS OF THE DOGS. THE BASIS OF THIS HETEROGENEITY MIGHT BE DUE TO GENOMIC DIFFERENCES AND/OR EPIGENETIC VARIATIONS. 3. DIFFERENCES IN DOGS IS A COULD BE A RESULT OF WITHIN-HOST ADAPTION AND MIGHT BE TRIGGERED BY ENVIRONMENTAL FACTORS IN THE SINUS, HOWEVER THIS HYPOTHESIS STILL NEEDS TO BE TESTED.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  1053  33 CLINICAL IMPLICATIONS OF INTERFERON-GAMMA GENETIC AND EPIGENETIC VARIANTS. INTERFERON-GAMMA (IFN-GAMMA) IS AN INTEGRAL AND CRITICAL MOLECULE OF THE IMMUNE SYSTEM, WITH MULTIPLE FUNCTIONS, MOSTLY RELATED TO THE T HELPER TYPE 1 (TH1) RESPONSE TO INFECTION. IT IS CRITICAL FOR DEFENCE AGAINST MYCOBACTERIAL INFECTION AND IS OF INCREASING INTEREST IN DEFENCE AGAINST FUNGI. IN THIS ARTICLE, WE REVIEW THE GENETIC AND EPIGENETIC VARIANTS AFFECTING IFN-GAMMA EXPRESSION AND INVESTIGATE ITS ROLE IN DISEASE, WITH AN EMPHASIS ON FUNGAL DISEASES SUCH AS INVASIVE AND CHRONIC PULMONARY ASPERGILLOSIS. OVER 347 IFN-GAMMA GENE VARIANTS HAVE BEEN DESCRIBED, IN MULTIPLE ETHNIC POPULATIONS. MANY APPEAR TO CONFER A SUSCEPTIBILITY TO DISEASE, ESPECIALLY TUBERCULOSIS (TB) AND HEPATITIS, BUT ALSO SOME NON-INFECTIOUS CONDITIONS SUCH AS APLASTIC ANAEMIA, CERVICAL CANCER AND PSORIASIS. SEVERAL EPIGENETIC MODIFICATIONS ARE ALSO DESCRIBED, INCREASING IFN-GAMMA EXPRESSION IN TH1 LYMPHOCYTES AND REDUCING IFN-GAMMA EXPRESSION IN TH2 LYMPHOCYTES. RECOMBINANT IFN-GAMMA ADMINISTRATION IS LICENSED FOR THE PROPHYLAXIS OF INFECTION (BACTERIAL AND FUNGAL) IN PATIENTS WITH THE PHAGOCYTE FUNCTIONAL DEFICIENCY SYNDROME CHRONIC GRANULOMATOUS DISEASE, ALTHOUGH THE BENEFITS APPEAR LIMITED. INTERFERON-GAMMA THERAPY IS GIVEN TO PATIENTS WITH PROFOUND DEFECTS IN IFN-GAMMA AND INTERLEUKIN-12 PRODUCTION AND APPEARS TO BE BENEFICIAL FOR PATIENTS WITH INVASIVE ASPERGILLOSIS AND CRYPTOCOCCAL MENINGITIS, BUT THE STUDIES ARE NOT DEFINITIVE. A HIGH PROPORTION OF PATIENTS WITH CHRONIC PULMONARY ASPERGILLOSIS ARE POOR PRODUCERS OF IFN-GAMMA IN RESPONSE TO MULTIPLE STIMULI AND COULD ALSO BENEFIT FROM IFN-GAMMA ADMINISTRATION. THE INVESTIGATION AND MANAGEMENT OF PATIENTS WITH POSSIBLE OR DEMONSTRATED IFN-GAMMA DEFICIENCY IN ADULTHOOD IS POORLY STUDIED AND COULD BE GREATLY ENHANCED WITH THE INTEGRATION OF GENETIC DATA.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
3  2977  42 GENETIC AND PHENOTYPIC CHARACTERIZATION OF IN-HOST DEVELOPED AZOLE-RESISTANT ASPERGILLUS FLAVUS ISOLATES. ASPERGILLUS FLAVUS IS A PATHOGENIC FUNGAL SPECIES THAT CAN CAUSE PULMONARY ASPERGILLOSIS, AND TRIAZOLE COMPOUNDS ARE USED FOR THE TREATMENT OF THESE INFECTIONS. PROLONGED EXPOSURE TO AZOLES MAY SELECT FOR COMPENSATORY MUTATIONS IN THE A. FLAVUS GENOME, RESULTING IN AZOLE RESISTANCE. HERE, WE CHARACTERIZE A SERIES OF 11 ISOGENIC A. FLAVUS STRAINS ISOLATED FROM A PATIENT WITH PULMONARY ASPERGILLOSIS. OVER A PERIOD OF THREE MONTHS, THE INITIALLY AZOLE-SUSCEPTIBLE STRAIN DEVELOPED ITRACONAZOLE AND VORICONAZOLE RESISTANCE. SHORT TANDEM REPEAT ANALYSIS AND WHOLE-GENOME SEQUENCING REVEALED THE HIGH GENETIC RELATEDNESS OF ALL ISOLATES, INDICATING AN INFECTION WITH ONE SINGLE ISOLATE. IN CONTRAST, THE ISOLATES WERE MACROSCOPICALLY HIGHLY DIVERSE, SUGGESTING AN ADAPTATION TO THE ENVIRONMENT DUE TO (EPI)GENETIC CHANGES. THE WHOLE-GENOME SEQUENCING OF SUSCEPTIBLE AND AZOLE-RESISTANT STRAINS SHOWED A NUMBER OF MUTATIONS THAT MIGHT BE ASSOCIATED WITH AZOLE RESISTANCE. THE MAJORITY OF RESISTANT STRAINS CONTAIN A Y119F MUTATION IN THE CYP51A GENE, WHICH CORRESPONDS TO THE Y121F MUTATION FOUND IN A. FUMIGATUS. ONE AZOLE-RESISTANT STRAIN DEMONSTRATED A DIVERGENT SET OF MUTATIONS, INCLUDING A V99A MUTATION IN A MAJOR FACILITATOR SUPERFAMILY (MSF) MULTIDRUG TRANSPORTER (AFLA 083950).	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
4   537  18 ASYMPTOMATIC HYPERURICEMIA: IS IT REALLY ASYMPTOMATIC? PURPOSE OF REVIEW: HYPERURICEMIA IS HIGHLY PREVALENT, AFFECTING APPROXIMATELY 38 MILLION INDIVIDUALS IN THE UNITED STATES. HOWEVER, THE SIGNIFICANCE OF ASYMPTOMATIC HYPERURICEMIA - HYPERURICEMIA IN THE ABSENCE OF GOUT - CONTINUES TO BE DEBATED. RECENT FINDINGS: ASYMPTOMATIC HYPERURICEMIA RESULTS IN MONOSODIUM URATE CRYSTAL DEPOSITION IN TISSUES, WHICH MAY PROMOTE CHRONIC INFLAMMATION. INTRACELLULARLY, HYPERURICEMIA INHIBITS THE MASTER REGULATOR ADENOSINE MONOPHOSPHATE (AMP)-ASSOCIATED PROTEIN KINASE AND MAY CONDITION INNATE IMMUNE RESPONSES THROUGH DURABLE EPIGENETIC MODIFICATIONS. AT THE POPULATION LEVEL, ASYMPTOMATIC HYPERURICEMIA IS ASSOCIATED WITH MULTIPLE COMORBIDITIES, INCLUDING HYPERTENSION, CHRONIC KIDNEY DISEASE, CORONARY ARTERY DISEASE, AND DIABETES; LIMITATIONS OF THESE STUDIES INCLUDE THAT MOST ARE RETROSPECTIVE AND SOME DO NOT RIGOROUSLY DISTINGUISH BETWEEN ASYMPTOMATIC HYPERURICEMIA AND GOUT. TREATMENT STUDIES SUGGEST THAT URATE LOWERING MAY REDUCE THE RISK OF INCIDENCE OR PROGRESSION OF SOME OF THESE COMORBIDITIES; UNFORTUNATELY, MANY OF THESE TREATMENT STUDIES ARE SMALL OR FLAWED, AND NOT ALL STUDY RESULTS ARE CONSISTENT. SUMMARY: ACCUMULATING EVIDENCE SUGGESTS THAT ASYMPTOMATIC HYPERURICEMIA CONTRIBUTES TO THE COMORBIDITIES WITH WHICH IT ASSOCIATES AND THAT PROPER ASYMPTOMATIC HYPERURICEMIA TREATMENT MAY REDUCE FUTURE RISK. ADDITIONAL PROSPECTIVE TRIALS ARE NEEDED TO DEFINITELY ESTABLISH CAUSALITY AND SUPPORT DECISION-MAKING AS TO WHETHER, AND WHICH PATIENTS WITH ASYMPTOMATIC HYPERURICEMIA WOULD WARRANT URATE-LOWERING TREATMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5  3635  26 INCREASED DNA METHYLATION, CELLULAR SENESCENCE AND PREMATURE EPIGENETIC AGING IN GUINEA PIGS AND HUMANS WITH TUBERCULOSIS. BACKGROUND: TUBERCULOSIS (TB) IS THE ARCHETYPICAL CHRONIC INFECTION, WITH PATIENTS HAVING MONTHS OF SYMPTOMS BEFORE DIAGNOSIS. IN THE TWO YEARS AFTER SUCCESSFUL THERAPY, SURVIVORS OF TB HAVE A THREE-FOLD INCREASED RISK OF DEATH. METHODS: GUINEA PIGS WERE INFECTED WITH MYCOBACTERIUM TUBERCULOSIS (MTB) FOR 45 DAYS, FOLLOWED BY RRBS DNA METHYLATION ANALYSIS. IN HUMANS, NETWORK ANALYSIS OF DIFFERENTIALLY EXPRESSED GENES ACROSS THREE TB COHORTS WERE VISUALIZED AT THE PATHWAY-LEVEL. SERUM LEVELS OF INFLAMMATION WERE MEASURED BY ELISA. HORVATH (DNA METHYLATION) AND RNA-SEQ BIOLOGICAL CLOCKS WERE USED TO INVESTIGATE SHIFTS IN CHRONOLOGICAL AGE AMONG HUMANS WITH TB. RESULTS: GUINEA PIGS WITH TB DEMONSTRATED DNA HYPERMETHYLATION AND SHOWED SYSTEM-LEVEL SIMILARITY TO HUMANS WITH TB (P-VALUE = 0.002). THE TRANSCRIPTOME IN TB IN MULTIPLE COHORTS WAS ENRICHED FOR DNA METHYLATION AND CELLULAR SENESCENCE. SENESCENCE ASSOCIATED PROTEINS CXCL9, CXCL10, AND TNF WERE ELEVATED IN TB PATIENTS COMPARED TO HEALTHY CONTROLS. HUMANS WITH TB DEMONSTRATE 12.7 YEARS (95% CI: 7.5, 21.9) AND 14.38 YEARS (95% CI: 10.23-18.53) OF CELLULAR AGING AS MEASURED BY EPIGENETIC AND GENE EXPRESSION BASED CELLULAR CLOCKS, RESPECTIVELY. CONCLUSIONS: IN BOTH GUINEA PIGS AND HUMANS, TB PERTURBS EPIGENETIC PROCESSES, PROMOTING PREMATURE CELLULAR AGING AND INFLAMMATION, A PLAUSIBLE MEANS TO EXPLAIN THE LONG-TERM DETRIMENTAL HEALTH OUTCOMES AFTER TB.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
6  3037  43 GENOME AND METHYLOME VARIATION IN HELICOBACTER PYLORI WITH A CAG PATHOGENICITY ISLAND DURING EARLY STAGES OF HUMAN INFECTION. BACKGROUND & AIMS: HELICOBACTER PYLORI IS REMARKABLE FOR ITS GENETIC VARIATION; YET, LITTLE IS KNOWN ABOUT ITS GENETIC CHANGES DURING EARLY STAGES OF HUMAN INFECTION, AS THE BACTERIA ADAPT TO THEIR NEW ENVIRONMENT. WE ANALYZED GENOME AND METHYLOME VARIATIONS IN A FULLY VIRULENT STRAIN OF H PYLORI DURING EXPERIMENTAL INFECTION. METHODS: WE PERFORMED A RANDOMIZED PHASE I/II, OBSERVER-BLIND, PLACEBO-CONTROLLED STUDY OF 12 HEALTHY, H PYLORI-NEGATIVE ADULTS IN GERMANY FROM OCTOBER 2008 THROUGH MARCH 2010. THE VOLUNTEERS WERE GIVEN A PROPHYLACTIC VACCINE CANDIDATE (N = 7) OR PLACEBO (N = 5) AND THEN CHALLENGED WITH H PYLORI STRAIN BCM-300. BIOPSY SAMPLES WERE COLLECTED AND H PYLORI WERE ISOLATED. GENOMES OF THE CHALLENGE STRAIN AND 12 REISOLATES, OBTAINED 12 WEEKS AFTER (OR IN 1 CASE, 62 WEEKS AFTER) INFECTION WERE SEQUENCED BY SINGLE-MOLECULE, REAL-TIME TECHNOLOGY, WHICH, IN PARALLEL, PERMITTED DETERMINATION OF GENOME-WIDE METHYLATION PATTERNS FOR ALL STRAINS. FUNCTIONAL EFFECTS OF GENETIC CHANGES OBSERVED IN H PYLORI STRAINS DURING HUMAN INFECTION WERE ASSESSED BY MEASURING RELEASE OF INTERLEUKIN 8 FROM AGS CELLS (TO DETECT CAG PATHOGENICITY ISLAND FUNCTION), NEUTRAL RED UPTAKE (TO DETECT VACUOLATING CYTOTOXIN ACTIVITY), AND ADHESION ASSAYS. RESULTS: THE OBSERVED MUTATION RATE WAS IN AGREEMENT WITH RATES PREVIOUSLY DETERMINED FROM PATIENTS WITH CHRONIC H PYLORI INFECTIONS, WITHOUT EVIDENCE OF A MUTATION BURST. A LOSS OF CAG PATHOGENICITY ISLAND FUNCTION WAS OBSERVED IN 3 REISOLATES. IN ADDITION, 3 REISOLATES FROM THE VACCINE GROUP ACQUIRED MUTATIONS IN THE VACUOLATING CYTOTOXIN GENE VACA, RESULTING IN LOSS OF VACUOLIZATION ACTIVITY. WE OBSERVED INTERSTRAIN VARIATION IN METHYLOMES DUE TO PHASE VARIATION IN GENES ENCODING METHYLTRANSFERASES. CONCLUSIONS: WE ANALYZED ADAPTATION OF A FULLY VIRULENT STRAIN OF H PYLORI TO 12 DIFFERENT VOLUNTEERS TO OBTAIN A ROBUST ESTIMATE OF THE FREQUENCY OF GENETIC AND EPIGENETIC CHANGES IN THE ABSENCE OF INTERSTRAIN RECOMBINATION. OUR FINDINGS INDICATE THAT THE LARGE AMOUNT OF GENETIC VARIATION IN H PYLORI POSES A CHALLENGE TO VACCINE DEVELOPMENT. CLINICALTRIALS.GOV NO: NCT00736476.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7   414  33 ANALYSIS OF PROMOTER METHYLATION IN STOOL: A NOVEL METHOD FOR THE DETECTION OF COLORECTAL CANCER. BACKGROUND & AIMS: DETECTION OF TUMOR-DERIVED DNA ALTERATIONS IN STOOL IS AN INTRIGUING NEW APPROACH WITH HIGH POTENTIAL FOR THE NONINVASIVE DETECTION OF COLORECTAL CANCER (CRC). BECAUSE OF HETEROGENEITY OF TUMORS, USUALLY MULTIPLE MARKERS DISTRIBUTED THROUGHOUT THE HUMAN GENOME NEED TO BE ANALYZED. THIS IS LABOR INTENSIVE AND DOES NOT ALLOW FOR HIGH THROUGH-PUT SCREENING. THEREFORE, MARKERS WITH HIGH SENSITIVITY AND GOOD SPECIFICITY ARE NEEDED. WE EXPLORED THE POTENTIAL OF A SINGLE EPIGENETIC MARKER IN COMPARISON WITH FECAL OCCULT BLOOD TESTING (FOBT) FOR THE DISCRIMINATION OF PATIENTS WITH CRCS AND ADENOMAS FROM THOSE WITHOUT. METHODS: METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) WAS PERFORMED TO ANALYZE HYPERMETHYLATED IN CANCER 1 (HIC1) PROMOTER METHYLATION STATUS IN A BLINDED FASHION IN STOOL SAMPLES FROM 26 PATIENTS WITH CRC, 13 WITH ADENOMA > OR =1 CM, 9 WITH HYPERPLASTIC POLYPS, 9 WITH CHRONIC INFLAMMATORY BOWEL DISEASE, AND 32 WITH ENDOSCOPICALLY NORMAL COLON. RESULTS: NINETY-SEVEN PERCENT OF THE STOOL SAMPLES CONTAINED AMPLIFIABLE DNA. FORTY-TWO PERCENT OF THE SAMPLES FROM PATIENTS WITH CRC AND 31% OF THE SAMPLES FROM PATIENTS WITH COLORECTAL ADENOMA > OR =1 CM WERE POSITIVE FOR HIC1 PROMOTER METHYLATION. NO METHYLATED HIC1 PROMOTER DNA WAS DETECTED IN THE FECAL DNA FROM PATIENTS WITH ENDOSCOPICALLY NORMAL COLON OR HYPERPLASTIC POLYPS. CONCLUSIONS: THE EPIGENETIC MARKER HIC1 PROMOTER METHYLATION CARRIES HIGH POTENTIAL FOR THE REMOTE DETECTION OF CRCS. WE POSTULATE THAT A PANEL OF MERELY A FEW GENETIC AND EPIGENETIC MARKERS WILL BE REQUIRED FOR THE HIGHLY SENSITIVE AND SPECIFIC DETECTION OF CRCS AND ADENOMAS IN FECAL SAMPLES FROM AFFECTED PATIENTS.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
8  3850  25 IS GENDER A FACTOR AFFECTING LONG-TERM HETEROTOPIC OSSIFICATION INCIDENCE AFTER SINGLE-LEVEL CERVICAL DISC ARTHROPLASTY? BACKGROUND: CERVICAL DISC DISEASES HAVE BEEN TREATED BY CERVICAL DISC ARTHROPLASTY (CDA). NEVERTHELESS, SOME PATIENTS WILL EXPERIENCE A MOBILITY FAILURE IN THEIR CERVICAL PROSTHESES OVER TIME BECAUSE OF HETEROTOPIC OSSIFICATION. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ROLE OF GENDER IN LONG-TERM OUTCOMES AFTER CDA. METHODS: A RETROSPECTIVE, SINGLE-CENTER STUDY OF PATIENTS WHO UNDERWENT SINGLE-LEVEL CDA WITH A BRYAN CERVICAL DISC PROSTHESIS WAS PERFORMED, INCLUDING A NARRATIVE REVIEW ABOUT GENDER DIFFERENCES IN BOTH STRUCTURAL AND BIOMECHANICAL FEATURES OF THE CERVICAL SPINE. RESULTS: STUDY PATIENTS (14 MEN, 30 WOMEN) HAD AN AVERAGE FOLLOW-UP OF 9.8 +/- 3.2 YEARS. SIGNIFICANT DIFFERENCES EMERGED BETWEEN GENDERS FOR SPECIFIC ITEMS IN NECK DISABILITY INDEX PREOPERATIVE EVALUATION, WITH WOMEN REPORTING WORSE PAIN SCORES (P = 0.05). AFTER STRATIFICATION BY AGE, WE FOUND A HIGHER PREOPERATIVE OVERALL NECK DISABILITY INDEX SCORE FOR FEMALE PATIENTS <36 YEARS OF AGE (P = 0.03). IN AN INTERGENDER, BODY MASS INDEX-SPECIFIC COMPARISON, WE ALSO FOUND A SIGNIFICANT DIFFERENCE IN NECK DISABILITY INDEX PREOPERATIVE SCORE WITH NORMAL-WEIGHT MALE PATIENTS FARING WORSE THAN OVERWEIGHT MALE PATIENTS (P = 0.05). AT A RADIOLOGICAL LEVEL, WE FOUND A TENDENCY TOWARD A HIGHER HETEROTOPIC OSSIFICATION INCIDENCE IN MALE PATIENTS (62% IN MEN, 17% IN WOMEN, P = 0.06). THE FEMALE CERVICAL SPINE HAS DISTINCTIVE FEATURES, INCLUDING BONE STRUCTURE, MUSCULAR ACTION, SOFT TISSUE RESPONSE, AND GENETIC AND EPIGENETIC RESPONSE TO OSTEOARTHRITIS. CONCLUSIONS: THE INCIDENCE OF MOBILITY FAILURE IN OUR SERIES OF SINGLE-LEVEL CDA WAS LOWER IN FEMALE PATIENTS. SEVERAL GENDER-SPECIFIC FACTORS BOTH IN STATIC AND IN DYNAMIC FEATURES MAY PLAY A SIGNIFICANT ROLE IN SPINAL PATHOLOGY AND CDA LONG-TERM RADIOLOGICAL OUTCOME.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9  4363  36 MIRNA AS MARKERS FOR THE DIAGNOSTIC SCREENING OF COLON CANCER. EARLY SCREENING FOR COLON CANCER (CC) ALLOWS FOR EARLY STAGE DIAGNOSIS OF THE MALIGNANCY AND POTENTIALLY REDUCES DISEASE MORTALITY AS THE CANCER IS MOST LIKELY CURABLE AT ITS EARLIEST STAGES. EARLY DETECTION WOULD BE DESIRABLE IF ACCURATE, PRACTICAL AND COST-EFFECTIVE DIAGNOSTIC MEASURES FOR THIS CANCER WERE AVAILABLE. MORTALITY AND MORBIDITY FROM CC REPRESENT A MAJOR HEALTH PROBLEM INVOLVING A MALIGNANT DISEASE THAT IS THEORETICALLY PREVENTABLE THROUGH SCREENING. CURRENT SCREENING METHODS (E.G., THE CONVENIENT AND INEXPENSIVE IMMUNOLOGICAL FECAL OCCULT BLOOD TEST, FOBTI, OBTAINED FROM PATIENTS' MEDICAL RECORDS) EITHER LACK SENSITIVITY AND REQUIRE DIETARY RESTRICTION, WHICH IMPEDES COMPLIANCE AND USE; ARE COSTLY (E.G., COLONOSCOPY), WHICH DECREASES COMPLIANCE; OR COULD RESULT IN MORTALITY. IN COMPARISON WITH THE FOBT TEST, A NON-INVASIVE SENSITIVE SCREEN FOR WHICH THERE IS NO REQUIREMENT FOR DIETARY RESTRICTION WOULD BE A MORE CONVENIENT TEST. COLORECTAL CANCER IS THE ONLY CANCER FOR WHICH COLONOSCOPY IS RECOMMENDED AS A SCREENING METHOD. ALTHOUGH COLONOSCOPY IS A RELIABLE SCREENING TOOL, THE INVASIVE NATURE, ABDOMINAL PAIN, POTENTIAL COMPLICATIONS AND HIGH COST HAVE HAMPERED THE APPLICATION OF THIS PROCEDURE WORLDWIDE. A SCREENING APPROACH USING THE STABLE MIRNA MOLECULES, WHICH ARE RELATIVELY NON-DEGRADABLE WHEN EXTRACTED FROM NON-INVASIVE STOOL AND SEMI-INVASIVE BLOOD SAMPLES BY COMMERCIALLY AVAILABLE KITS AND MANIPULATED THEREAFTER, WOULD BE PREFERABLE TO A TRANSCRIPTOMIC MRNA-, A MUTATION DNA-, AN EPIGENETIC- OR A PROTEOMIC-BASED TEST. THE APPROACH USES REVERSE TRANSCRIPTASE, MODIFIED REAL-TIME QUANTITATIVE PCR. ALTHOUGH EXOSOMAL RNA WOULD BE MISSED, USING A RESTRICTED EXTRACTION OF TOTAL RNA FROM STOOL OR BLOOD, A PARALLEL TEST COULD ALSO BE CARRIED OUT ON RNA OBTAINED FROM STOOL OR PLASMA SAMPLES, AND APPROPRIATE CORRECTIONS FOR EXSOSOMAL LOSS CAN BE MADE FOR ACCURATE AND QUANTITATIVE TEST RESULT. EVENTUALLY, A CHIP CAN BE DEVELOPED TO FACILITATE DIAGNOSIS, AS HAS BEEN DONE FOR THE QUANTIFICATION OF GENETICALLY MODIFIED ORGANISMS IN FOODS. THE GOLD STANDARD TO WHICH THE MOLECULAR MIRNA TEST IS COMPARED IS COLONOSCOPY, WHICH CAN BE OBTAINED FROM PATIENTS' MEDICAL RECORDS. IF PERFORMANCE CRITERIA ARE MET, AS DETAILED HEREIN, A MIRNA TEST IN HUMAN STOOL OR BLOOD SAMPLES BASED ON HIGH-THROUGHPUT AUTOMATED TECHNOLOGIES AND QUANTITATIVE EXPRESSION MEASUREMENTS COMMONLY USED IN THE DIAGNOSTIC CLINICAL LABORATORY SHOULD BE ADVANCED TO THE CLINICAL SETTING, WHICH WILL MAKE A SIGNIFICANT IMPACT ON CC PREVENTION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
10  4227  33 METHYLATION OF FREE-FLOATING DEOXYRIBONUCLEIC ACID FRAGMENTS IN THE BRONCHOALVEOLAR LAVAGE FLUID OF DOGS WITH CHRONIC BRONCHITIS EXPOSED TO ENVIRONMENTAL TOBACCO SMOKE. BACKGROUND: THE ETIOLOGY OF CANINE CHRONIC BRONCHITIS (CB) IS NOT COMPLETELY UNDERSTOOD, ALTHOUGH EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE (ETS) AFFECTS THE AIRWAY INFLAMMATORY RESPONSES IN SOME DOGS WITH CB. THE MECHANISM BY WHICH THIS OCCURS IS UNKNOWN. FINDINGS: WE INVESTIGATED THE CONCENTRATIONS AND METHYLATION RATES OF FREE-FLOATING DNA FRAGMENTS IN BRONCHOALVEOLAR LAVAGE FLUID (BALF) FROM DOGS WITH CHRONIC BRONCHITIS. BASED ON SERUM COTININE LEVELS, DOGS WITH CB WERE DIVIDED INTO 2 GROUPS: DOGS THAT EITHER HAD OR HAD NOT BEEN EXPOSED TO ETS. OUR RESULTS DEMONSTRATED THAT THE TOTAL NUCLEATED CELL AND MACROPHAGE NUMBERS INCREASED IN BALF OF ETS-EXPOSED DOGS WITH CB. THERE WERE NO SIGNIFICANT DIFFERENCES IN DNA CONCENTRATIONS AND METHYLATION RATES IN BALF BETWEEN THE 2 GROUPS. HOWEVER, 3 OUT OF 8 DOGS EXPOSED TO ETS HAD HIGH DNA METHYLATION RATES IN THEIR BALF SAMPLES. CONCLUSION: OUR RESULTS SUGGEST THAT ETS EXPOSURE LEADS TO EPIGENETIC MODIFICATIONS OF CELLULAR COMPONENTS IN BALF IN DOGS DIAGNOSED WITH CB.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11  6368  36 THE ROLE OF MICRORNAS IN CHRONIC PSEUDOMONAS LUNG INFECTION IN CYSTIC FIBROSIS. BACKGROUND: CYSTIC FIBROSIS (CF) IS THE MOST COMMON LIFE LIMITING GENETIC DISORDER, CHARACTERIZED BY CHRONIC RESPIRATORY FAILURE SECONDARY TO INFLAMMATION AND CHRONIC BACTERIAL LUNG INFECTION. PSEUDOMONAS AERUGINOSA LUNG INFECTION IS ASSOCIATED WITH MORE SEVERE LUNG DISEASE AND RAPID PROGRESSION OF RESPIRATORY FAILURE WHEN COMPARED TO STAPHYLOCOCCUS AUREUS INFECTION. WE HYPOTHESIZED THAT A SPECIFIC SIGNATURE OF EPIGENETIC FACTORS TARGETING SPECIFIC GENE TRANSCRIPTS CONTRIBUTES TO THE INCREASED MORBIDITY SEEN IN CF PATIENTS WITH CHRONIC PSEUDOMONAS INFECTION. METHODS: WE COLLECTED EXHALED BREATH CONDENSATE (EBC) FROM 27 SUBJECTS AND EVALUATED MIRNA SIGNATURES IN THESE SAMPLES USING COMMERCIAL PCR ARRAY. WE IDENTIFIED PREDICTED MRNA TARGETS AND ASSOCIATED SIGNALING PATHWAYS USING INGENUITY PATHWAY ANALYSIS. RESULTS: WE FOUND 11 DIFFERENTIALLY EXPRESSED MIRNAS IN EBC OF PATIENTS INFECTED WITH PSEUDOMONAS AERUGINOSA COMPARED TO EBC FROM CF PATIENTS WHO WERE NOT CHRONICALLY INFECTED WITH PSEUDOMONAS AERUGINOSA (P < 0.05). SIX OF THESE MIRNAS (HSA-MIRNA-1247, HSA-MIRNA-1276, HSA-MIRNA-449C, HSA-MIRNA-3170, HSA-MIRNA-432-5P AND HSA-MIR-548) WERE SIGNIFICANTLY DIFFERENT IN THE CF PSEUDOMONAS POSITIVE GROUP WHEN COMPARED TO BOTH THE CF PSEUDOMONAS NEGATIVE GROUP AND HEALTHY CONTROL GROUP. INGENUITY PATHWAY ANALYSIS (IPA) REVEALED ORGANISMAL INJURY AND ABNORMALITIES, REPRODUCTIVE SYSTEM DISEASE AND CANCER AS THE TOP DISEASES AND BIO FUNCTIONS ASSOCIATED WITH THESE MIRNAS. IPA ALSO DETECTED RELA, JUN, TNF, IL-10, CTNNB1, IL-13, SERPINB8, CALM1, STARD3NL, SFI1, CD55, RPS6KA4, TTC36 AND HIST1H3D AS THE TOP TARGET GENES FOR THESE MIRNAS. CONCLUSION: OUR STUDY IDENTIFIED 6 MIRNAS AS EPIGENETIC FACTORS SPECIFICALLY ASSOCIATED WITH CHRONIC PSEUDOMONAS INFECTION IN PATIENTS WITH CF.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
12  1140  31 CONCENTRATION OF FOLIC ACID (FA) IN SERUM OF JAPANESE PREGNANT WOMEN. OBJECTIVES EXPOSURE TO INORGANIC ARSENIC (IAS) IS A WORLD-WIDE HEALTH CONCERN. WE REPORTED THAT JAPANESE CHILDREN AND PREGNANT WOMEN ARE EXPOSED TO MODERATE LEVELS OF IAS THROUGH FOOD. REDUCING IAS CONTAMINATION FROM FOODS OF HIGH IAS IS AN IMPORTANT ISSUE UNIQUE IN JAPAN. INTEGRATED IAS IS METHYLATED TO LESS TOXIC ORGANIC FORMS, AND S-ADENOSYL-L-METHYONINE (SAM), A COMMON METHYL-DONOR OF DNA AND HISTONES, IS UTILIZED IN THIS PROCESS. CHRONIC CONSUMPTION OF SAM BY IAS METABOLISM DUE TO EXPOSURE TO IAS MIGHT ALTER THE EPIGENETIC MODIFICATION OF GENOME. THE SAM BIOSYNTHESIS PATHWAY IS DEPENDENT ON FOLATE CYCLE, AND IT IS POSSIBLE THAT INGESTION OF SUFFICIENT FOLIC ACID (FA) IS PROTECTIVE TO IAS INDUCED TOXICITY. METHODS IN THE COURSE OF OUR CROSS-SECTIONAL BODY BURDEN ANALYSES OF PB AND IAS IN JAPANESE CHILDREN AND PREGNANT WOMEN, TERMED "PBAS STUDY", FA CONCENTRATION IN SERUM OF 104 PREGNANT WOMEN WAS MEASURED. RESULTS MEAN (+/-SEM) OF SERUM FA CONCENTRATION WAS 15.8 +/- 1.3 (NG/ML). THERE ARE SIGNIFICANT NUMBER OF PEOPLE SHOWING VERY HIGH FA (>30 NG/ ML), AND LARGE FRACTION OF THEM WERE TAKING SUPPLEMENTS DAILY. CONCLUSIONS THESE RESULTS SUGGESTED THAT LEVEL OF FA INGESTION OF JAPANESE PREGNANT WOMEN IS HIGH FOR SUPPORTING NORMAL FETAL DEVELOPMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13  5612  40 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	

14  1061  36 CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS IS CHARACTERIZED BY AN UPREGULATION OF PERIPHERAL T-REGULATORY CELL POLARIZED TOWARDS T-BET AND TIGIT. BACKGROUND: NON-INFECTIOUS UVEITIS CAN CAUSE CHRONIC RELAPSING AND REMITTING OCULAR INFLAMMATION, WHICH MAY REQUIRE HIGH DOSE SYSTEMIC IMMUNOSUPPRESSION TO PREVENT SEVERE SIGHT LOSS. IT HAS BEEN CLASSICALLY DESCRIBED AS AN AUTOIMMUNE DISEASE, MEDIATED BY PRO-INFLAMMATORY TH1 AND TH17 T-CELL SUBSETS. STUDIES SUGGEST THAT NATURAL IMMUNOSUPPRESSIVE CD4(+)CD25(+)FOXP3(+) T-REGULATORY CELLS (TREGS) ARE INVOLVED IN RESOLUTION OF INFLAMMATION AND MAY BE INVOLVED IN THE MAINTENANCE OF CLINICAL REMISSION. OBJECTIVE: TO INVESTIGATE WHETHER THERE IS A PERIPHERAL BLOOD IMMUNOREGULATORY PHENOTYPE ASSOCIATED WITH CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS BY COMPARING PERIPHERAL BLOOD LEVELS OF TREG, TH1, AND TH17, AND ASSOCIATED DNA METHYLATION AND CYTOKINE LEVELS IN PATIENTS WITH ACTIVE UVEITIC DISEASE, CONTROL SUBJECTS AND PATIENTS (WITH PREVIOUSLY ACTIVE DISEASE) IN CLINICAL REMISSION INDUCED BY IMMUNOSUPPRESSIVE DRUGS. METHODS: ISOLATED PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) FROM PERIPHERAL BLOOD SAMPLES FROM PROSPECTIVELY RECRUITED SUBJECTS WERE ANALYZED BY FLOW CYTOMETRY FOR CD3, CD4, FOXP3, TIGIT, T-BET, AND RELATED ORPHAN RECEPTOR GAMMAT. EPIGENETIC DNA METHYLATION LEVELS OF FOXP3 TREG-SPECIFIC DEMETHYLATED REGION (TSDR), FOXP3 PROMOTER, TBX21, RORC2, AND TIGIT LOCI WERE DETERMINED IN CRYOPRESERVED PBMC USING A NEXT-GENERATION SEQUENCING APPROACH. RELATED CYTOKINES WERE MEASURED IN BLOOD SERA. FUNCTIONAL SUPPRESSIVE CAPACITY OF TREG WAS ASSESSED USING T-CELL PROLIFERATION ASSAYS. RESULTS: FIFTY PATIENTS WITH UVEITIS (INTERMEDIATE, POSTERIOR, AND PANUVEITIS) AND 10 CONTROL SUBJECTS WERE RECRUITED. THE FREQUENCY OF CD4(+)CD25(+)FOXP3(+) TREG, TIGIT(+) TREG, AND T-BET(+) TREG AND THE RATIO OF TREG TO TH1 WERE SIGNIFICANTLY HIGHER IN REMISSION PATIENTS COMPARED WITH PATIENTS WITH ACTIVE UVEITIC DISEASE; AND TIGIT(+) TREGS WERE A SIGNIFICANT PREDICTOR OF CLINICAL REMISSION. TREG FROM PATIENTS IN CLINICAL REMISSION DEMONSTRATED A HIGH LEVEL OF IN VITRO SUPPRESSIVE FUNCTION COMPARED WITH TREG FROM CONTROL SUBJECTS AND FROM PATIENTS WITH UNTREATED ACTIVE DISEASE. PBMC FROM PATIENTS IN CLINICAL REMISSION HAD SIGNIFICANTLY LOWER METHYLATION LEVELS AT THE FOXP3 TSDR, FOXP3 PROMOTER, AND TIGIT LOCI AND HIGHER LEVELS AT RORC LOCI THAN THOSE WITH ACTIVE DISEASE. CLINICAL REMISSION WAS ALSO ASSOCIATED WITH SIGNIFICANTLY HIGHER SERUM LEVELS OF TRANSFORMING GROWTH FACTOR BETA AND IL-10, WHICH POSITIVELY CORRELATED WITH TREG LEVELS, AND LOWER SERUM LEVELS OF IFNGAMMA, IL-17A, AND IL-22 COMPARED WITH PATIENTS WITH ACTIVE DISEASE. CONCLUSION: CLINICAL REMISSION OF SIGHT-THREATENING NON-INFECTIOUS UVEITIS HAS AN IMMUNOREGULATORY PHENOTYPE CHARACTERIZED BY UPREGULATION OF PERIPHERAL TREG, POLARIZED TOWARD T-BET AND TIGIT. THESE FINDINGS MAY ASSIST WITH INDIVIDUALIZED THERAPY OF UVEITIS, BY INFORMING WHETHER DRUG THERAPY HAS INDUCED PHENOTYPICALLY STABLE TREG ASSOCIATED WITH LONG-TERM CLINICAL REMISSION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  3553  35 IMMUNOTOLERANCE OF DAIRY HEIFERS IN RESPONSE TO REPEATED EXPOSURE TO BACTERIAL LIPOPOLYSACCHARIDE ENDOTOXIN. DAIRY CATTLE FACE A VARIETY OF STRESSFUL EVENTS ON A DAILY BASIS. MORE SPECIFICALLY, CLIMATE CHANGE HAS RESULTED IN MORE FREQUENT HEAT STRESS EVENTS THAT INCREASE THE INCIDENCE OF CHRONIC BACTERIAL INFECTIONS BY INDUCING CONDITIONS LIKE LEAKY GUT SYNDROME, WHEREBY THE INTEGRITY OF THE INTESTINAL EPITHELIUM IS COMPROMISED ALLOWING FOR LUMINAL BACTERIAL LIPOPOLYSACCHARIDE (LPS) ENDOTOXIN TO INFILTRATE THE HOST'S BLOODSTREAM RESULTING IN ACUTE OR CHRONIC SYSTEMIC STIMULATION OF THE INNATE IMMUNE SYSTEM. REPEATED EXPOSURE TO LPS OVER A SHORT PERIOD OF TIME IS REPORTED TO INDUCE IMMUNOTOLERANCE WITHIN THE HOST. THIS LPS TOLERANCE IS AN ESSENTIAL IMMUNOHOMEOSTATIC RESPONSE THAT CAN PROTECT AGAINST OVER ACTIVATION OF THE INFLAMMATORY RESPONSE DURING SUBSEQUENT EXPOSURE TO LPS. IN THE PRESENT STUDY, HOLSTEIN CALVES (N = 20) WERE INITIALLY STRESS CHALLENGED WITH EITHER SALINE, OR 100, 200 OR 400 NG/KG OF LPS ADMINISTERED INTRAMUSCULAR, AND AGAIN RE-CHALLENGED WITH 200 NG/KG OF LPS 2-WEEKS LATER. SERUM WAS COLLECTED EVERY 2 HR FOR 6 HR TO PROFILE CHANGES IN CIRCULATORY STRESS BIOMARKERS AFTER THE REPEATED LPS EXPOSURES. HEIFERS THAT WERE INITIALLY CHALLENGED WITH 100, 200 AND 400 NG/KG OF LPS DEMONSTRATED SIGNIFICANTLY ATTENUATED CORTISOL RESPONSES IN THE SECOND CHALLENGE (P < 0.01, 0.01 AND 0.05, RESPECTIVELY), WHEREAS CONTROL ANIMALS WHO PREVIOUSLY RECEIVED SALINE DEMONSTRATED A STRONG CORTISOL RESPONSE AT 2 HR AFTER RECEIVING 200 NG/KG OF LPS (P < 0.05). THE CYTOKINE/CHEMOKINE (IL-6, CCL2, CCL3 AND CCL4) RESPONSES WERE ALSO ATTENUATED DURING THE LPS RECHALLENGE (P < 0.05). FINALLY, MICRORNA EXPRESSION PROFILES WERE DETERMINED TO ASSESS THE EPIGENETIC RESPONSE TO REPEATED LPS EXPOSURE. INTERESTINGLY, MIR-31 AND MIR-223 WERE DOWNREGULATED IN RESPONSE TO THE SECOND LPS CHALLENGE. THE PRESENT STUDY DEMONSTRATES THE DYNAMIC NATURE OF THE STRESS RESPONSE IN DAIRY CATTLE AS IT RELATES TO THE DEVELOPMENT OF LPS TOLERANCE. UNDERSTANDING THE ROLES OF VARIOUS STRESS BIOMARKERS IN THE CONTEXT OF INNATE IMMUNE CELL TOLERANCE IS ESSENTIAL FOR EVALUATING THEIR IMPACT ON IMMUNE SYSTEM HOMEOSTASIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16   846  35 CHILDHOOD EXPOSURE TO AMBIENT POLYCYCLIC AROMATIC HYDROCARBONS IS LINKED TO EPIGENETIC MODIFICATIONS AND IMPAIRED SYSTEMIC IMMUNITY IN T CELLS. BACKGROUND: EVIDENCE SUGGESTS THAT EXPOSURE TO POLYCYCLIC AROMATIC HYDROCARBONS (PAHS) INCREASES ATOPY; IT IS UNCLEAR HOW PAH EXPOSURE IS LINKED TO INCREASED SEVERITY OF ATOPIC DISEASES. OBJECTIVE: WE HYPOTHESIZED THAT AMBIENT PAH EXPOSURE IS LINKED TO IMPAIRMENT OF IMMUNITY IN ATOPIC CHILDREN (DEFINED AS CHILDREN WITH ASTHMA AND/OR ALLERGIC RHINITIS) FROM FRESNO, CALIFORNIA, AN AREA WITH ELEVATED AMBIENT PAHS. METHODS: WE RECRUITED 256 SUBJECTS FROM FRESNO, CA. AMBIENT PAH CONCENTRATIONS (NG/M(3) ) WERE MEASURED USING A SPATIAL-TEMPORAL REGRESSION MODEL OVER MULTIPLE TIME PERIODS. ASTHMA DIAGNOSIS WAS DETERMINED BY CURRENT NHLBI CRITERIA. PHENOTYPING AND FUNCTIONAL IMMUNE MEASUREMENTS WERE PERFORMED FROM ISOLATED CELLS. FOR EPIGENETIC MEASUREMENTS, DNA WAS ISOLATED AND PYROSEQUENCED. RESULTS: WE SHOW THAT HIGHER AVERAGE PAH EXPOSURE WAS SIGNIFICANTLY ASSOCIATED WITH IMPAIRED TREG FUNCTION AND INCREASED METHYLATION IN THE FORKHEAD BOX PROTEIN 3 (FOXP3) LOCUS (P < 0.05), CONDITIONAL ON ATOPIC STATUS. THESE EPIGENETIC MODIFICATIONS WERE SIGNIFICANTLY LINKED TO DIFFERENTIAL PROTEIN EXPRESSION OF FOXP3 (P < 0.001). METHYLATION WAS ASSOCIATED WITH CELLULAR FUNCTIONAL CHANGES, SPECIFICALLY TREG DYSFUNCTION, AND AN INCREASE IN TOTAL PLASMA IGE LEVELS. PROTEIN EXPRESSION OF IL-10 DECREASED AND IFN-GAMMA INCREASED AS THE EXTENT OF PAH EXPOSURE INCREASED. THE STRENGTH OF THE ASSOCIATIONS GENERALLY INCREASED AS THE TIME WINDOW FOR AVERAGE PAH EXPOSURE INCREASED FROM 24 HR TO 1 YEAR, SUGGESTING MORE OF A CHRONIC RESPONSE. SIGNIFICANT ASSOCIATIONS WITH CHRONIC PAH EXPOSURE AND IMMUNE OUTCOMES WERE ALSO OBSERVED IN SUBJECTS WITH ALLERGIC RHINITIS. CONCLUSIONS AND CLINICAL RELEVANCE: COLLECTIVELY, THESE RESULTS DEMONSTRATE THAT INCREASED AMBIENT PAH EXPOSURE IS ASSOCIATED WITH IMPAIRED SYSTEMIC IMMUNITY AND EPIGENETIC MODIFICATIONS IN A KEY LOCUS INVOLVED IN ATOPY: FOXP3, WITH A HIGHER IMPACT ON ATOPIC CHILDREN. THE RESULTS SUGGEST THAT INCREASED ATOPIC CLINICAL SYMPTOMS IN CHILDREN COULD BE LINKED TO INCREASED PAH EXPOSURE IN AIR POLLUTION.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17  5016  38 PERSISTENT BACTERIAL COINFECTION OF A COVID-19 PATIENT CAUSED BY A GENETICALLY ADAPTED PSEUDOMONAS AERUGINOSA CHRONIC COLONIZER. PSEUDOMONAS AERUGINOSA IS A BIOFILM-FORMING OPPORTUNISTIC PATHOGEN WHICH CAUSES CHRONIC INFECTIONS IN IMMUNOCOMPROMISED PATIENTS AND LEADS TO HIGH MORTALITY RATE. IT IS IDENTIFIED AS A COMMON COINFECTING PATHOGEN IN COVID-19 PATIENTS CAUSING EXACERBATION OF ILLNESS. IN OUR HOSPITAL, P. AERUGINOSA IS ONE OF THE TOP COINFECTING BACTERIA IDENTIFIED AMONG COVID-19 PATIENTS. WE COLLECTED A STRONG BIOFILM-FORMING P. AERUGINOSA STRAIN DISPLAYING SMALL COLONY VARIANT MORPHOLOGY FROM A SEVERE COVID-19 PATIENT. GENOMIC AND TRANSCRIPTOMIC SEQUENCING ANALYSES WERE PERFORMED WITH PHENOTYPIC VALIDATION TO INVESTIGATE ITS ADAPTATION IN SARS-COV-2 INFECTED ENVIRONMENT. GENOMIC CHARACTERIZATION PREDICTED SPECIFIC GENOMIC ISLANDS HIGHLY ASSOCIATED WITH VIRULENCE, TRANSCRIPTIONAL REGULATION, AND DNA RESTRICTION-MODIFICATION SYSTEMS. EPIGENETIC ANALYSIS REVEALED A SPECIFIC N(6)-METHYL ADENINE (M(6)A) METHYLATING PATTERN INCLUDING METHYLATION OF ALGINATE, FLAGELLAR AND QUORUM SENSING ASSOCIATED GENES. DIFFERENTIAL GENE EXPRESSION ANALYSIS INDICATED THAT THIS ISOLATE FORMED EXCESSIVE BIOFILM BY REDUCING FLAGELLAR FORMATION (7.4 TO 1,624.1 FOLDS) AND OVERPRODUCING EXTRACELLULAR MATRIX COMPONENTS INCLUDING CDRA (4.4 FOLDS), ALGINATE (5.2 TO 29.1 FOLDS) AND PEL (4.8-5.5 FOLDS). IN SUMMARY, WE DEMONSTRATED THAT P. AEUGINOSA CLINICAL ISOLATES WITH NOVEL EPIGENETIC MARKERS COULD FORM EXCESSIVE BIOFILM, WHICH MIGHT ENHANCE ITS ANTIBIOTIC RESISTANCE AND IN VIVO COLONIZATION IN COVID-19 PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18  4015  31 LOW-DOSE EXPOSURE TO BISPHENOLS A, F AND S OF HUMAN PRIMARY ADIPOCYTE IMPACTS CODING AND NON-CODING RNA PROFILES. BISPHENOL A (BPA) EXPOSURE HAS BEEN SUSPECTED TO BE ASSOCIATED WITH DELETERIOUS EFFECTS ON HEALTH INCLUDING OBESITY AND METABOLICALLY-LINKED DISEASES. ALTHOUGH BISPHENOLS F (BPF) AND S (BPS) ARE BPA STRUCTURAL ANALOGS COMMONLY USED IN MANY MARKETED PRODUCTS AS A REPLACEMENT FOR BPA, ONLY SPARSE TOXICOLOGICAL DATA ARE AVAILABLE YET. OUR OBJECTIVE WAS TO COMPREHENSIVELY CHARACTERIZE BISPHENOLS GENE TARGETS IN A HUMAN PRIMARY ADIPOCYTE MODEL, IN ORDER TO DETERMINE WHETHER THEY MAY INDUCE CELLULAR DYSFUNCTION, USING CHRONIC EXPOSURE AT TWO CONCENTRATIONS: A "LOW-DOSE" SIMILAR TO THE DOSE USUALLY ENCOUNTERED IN HUMAN BIOLOGICAL FLUIDS AND A HIGHER DOSE. THEREFORE, BPA, BPF AND BPS HAVE BEEN ADDED AT 10 NM OR 10 MUM DURING THE DIFFERENTIATION OF HUMAN PRIMARY ADIPOCYTES FROM SUBCUTANEOUS FAT OF THREE NON-DIABETIC CAUCASIAN FEMALE PATIENTS. GENE EXPRESSION (MRNA/LNCRNA) ARRAYS AND MICRORNA ARRAYS, HAVE BEEN USED TO ASSESS CODING AND NON-CODING RNA CHANGES. WE DETECTED SIGNIFICANTLY DEREGULATED MRNA/LNCRNA AND MIRNA AT LOW AND HIGH DOSES. ENRICHMENT IN "CANCER" AND "ORGANISMAL INJURY AND ABNORMALITIES" RELATED PATHWAYS WAS FOUND IN RESPONSE TO THE THREE PRODUCTS. SOME LONG INTERGENIC NON-CODING RNAS AND SMALL NUCLEOLAR RNAS WERE DIFFERENTIALLY EXPRESSED SUGGESTING THAT BISPHENOLS MAY ALSO ACTIVATE MULTIPLE CELLULAR PROCESSES AND EPIGENETIC MODIFICATIONS. THE ANALYSIS OF UPSTREAM REGULATORS OF DEREGULATED GENES HIGHLIGHTED HORMONES OR HORMONE-LIKE CHEMICALS SUGGESTING THAT BPS AND BPF CAN BE SUSPECTED TO INTERFERE, JUST LIKE BPA, WITH HORMONAL REGULATION AND HAVE TO BE CONSIDERED AS ENDOCRINE DISRUPTORS. ALL THESE RESULTS SUGGEST THAT AS BPA, ITS SUBSTITUTES BPS AND BPF SHOULD BE USED WITH THE SAME RESTRICTIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19  3179  41 HAIR CORTISOL AS A HYPOTHALAMIC-PITUITARY-ADRENAL AXIS BIOMARKER IN PREGNANT WOMEN WITH ASTHMA: A RETROSPECTIVE OBSERVATIONAL STUDY. BACKGROUND: CORTISOL IS A HORMONE INVOLVED IN MANY PHYSIOLOGICAL FUNCTIONS INCLUDING FETAL MATURATION AND EPIGENETIC PROGRAMMING DURING PREGNANCY. THIS STUDY AIMED TO USE HAIR CORTISOL AS A BIOMARKER OF CHRONIC INHALED CORTICOSTEROID (ICS) EXPOSURE AND ASSESS THE POTENTIAL EFFECTS OF ASTHMA ON THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN PREGNANT WOMEN. WE HYPOTHESIZED THAT PREGNANT WOMEN WITH ASTHMA TREATED WITH ICS WOULD EXHIBIT LOWER HAIR CORTISOL CONCENTRATIONS, INDICATIVE OF ADRENAL SUPPRESSION, COMPARED TO WOMEN WITH ASTHMA NOT USING ICS AND WOMEN WHO DO NOT HAVE ASTHMA. METHODS: WE PERFORMED AN OBSERVATIONAL RETROSPECTIVE COHORT STUDY. HAIR SAMPLES WERE ANALYZED FROM PREGNANT WOMEN WITH ASTHMA, WITH (N = 56) AND WITHOUT (N = 31) ICS TREATMENT, AND PREGNANT WOMEN WITHOUT ASTHMA (N = 31). HAIR SAMPLES WERE SEGMENTED BASED ON THE GROWTH RATE OF 1 CM/MONTH AND ANALYZED BY ENZYME IMMUNOASSAY TO PROVIDE CORTISOL CONCENTRATIONS CORRESPONDING TO PRECONCEPTION, TRIMESTERS 1-3, AND POSTPARTUM. HAIR CORTISOL CONCENTRATIONS WERE COMPARED WITHIN AND AMONG THE GROUPS USING NON-PARAMETRIC STATISTICAL TESTS. RESULTS: HAIR CORTISOL CONCENTRATIONS INCREASED ACROSS TRIMESTERS FOR ALL THREE GROUPS, BUT THIS INCREASE WAS DAMPENED IN WOMEN WITH ASTHMA (P = 0.03 FOR CONTROLS VS. ICS TREATED AND CONTROLS VS. NO ICS). ICS TREATED WOMEN TAKING MORE THAN FIVE DOSES PER WEEK HAD HAIR CORTISOL CONCENTRATIONS 47 % LOWER IN THIRD TRIMESTER THAN CONTROLS. LINEAR REGRESSION OF THE THIRD TRIMESTER HAIR CORTISOL RESULTS IDENTIFIED ASTHMA AS A SIGNIFICANT FACTOR WHEN COMPARING CONSISTENT ICS USE OR ASTHMA AS THE PREDICTOR (F(1, 25) = 9.7, P = 0.005, R(2) ADJ = 0.257). CONCLUSIONS: HAIR CORTISOL SUCCESSFULLY SHOWED THE EXPECTED CHANGE IN CORTISOL OVER THE COURSE OF PREGNANCY AND MAY BE A USEFUL BIOMARKER OF HPA AXIS FUNCTION IN PREGNANT WOMEN WITH ASTHMA. THE POTENTIAL IMPACT OF DECREASED MATERNAL CORTISOL IN WOMEN WITH ASTHMA ON PERINATAL OUTCOMES REMAINS TO BE DETERMINED.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  5760  34 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION.	2016