1  3383 161 HNF1B NEPHROPATHY HAS A SLOW-PROGRESSIVE PHENOTYPE IN CHILDHOOD-WITH THE EXCEPTION OF VERY EARLY ONSET CASES: RESULTS OF THE GERMAN MULTICENTER HNF1B CHILDHOOD REGISTRY. BACKGROUND: HNF1B GENE MUTATIONS ARE AN IMPORTANT CAUSE OF BILATERAL (CYSTIC) DYSPLASIA IN CHILDREN, COMPLICATED BY CHRONIC RENAL INSUFFICIENCY. THE CLINICAL VARIABILITY, THE ABSENCE OF GENOTYPE-PHENOTYPE CORRELATIONS, AND LIMITED LONG-TERM DATA RENDER COUNSELING OF AFFECTED FAMILIES DIFFICULT. METHODS: LONGITUDINAL DATA OF 62 CHILDREN PROBANDS WITH GENETICALLY PROVEN HNF1B NEPHROPATHY WAS OBTAINED IN A MULTICENTER APPROACH. GENETIC FAMILY CASCADE SCREENING WAS PERFORMED IN 30/62 CASES. RESULTS: EIGHTY-SEVEN PERCENT OF PATIENTS HAD BILATERAL DYSPLASIA, 74% VISIBLE BILATERAL, AND 16% UNILATERAL RENAL CYSTS AT THE END OF OBSERVATION. CYST DEVELOPMENT WAS NON-PROGRESSIVE IN 72% WITH A MEAN GLOMERULAR FILTRATION RATE (GFR) LOSS OF - 0.33 ML/MIN/1.73M(2) PER YEAR (+/- 8.9). IN PATIENTS WITH AN INCREASE IN CYST NUMBER, THE ANNUAL GFR REDUCTION WAS - 2.8 ML/MIN/1.73M(2) (+/- 13.2), IN THE TOTAL COHORT - 1.0 ML/MIN/1.73M(2) (+/-10.3). A SUBSET OF HNF1B PATIENTS DIFFERS FROM THIS GROUP AND DEVELOPS END STAGE RENAL DISEASE (ESRD) AT VERY EARLY AGES < 2 YEARS. HYPERURICEMIA (37%) WAS A FREQUENT FINDING AT YOUNG AGE (MEDIAN 1 YEAR), WHEREAS HYPOMAGNESEMIA (24%), ELEVATED LIVER ENZYMES (21%), AND HYPERGLYCEMIA (8%) SHOWED AN INCREASED INCIDENCE IN THE TEENAGED CHILD. GENETIC ANALYSIS REVEALED NO GENOTYPE-PHENOTYPE CORRELATIONS BUT A SIGNIFICANT PARENT-OF-ORIGIN EFFECT WITH A PREPONDERANCE OF 81% OF MATERNAL INHERITANCE IN DOMINANT CASES. CONCLUSIONS: IN MOST CHILDREN, HNF1B NEPHROPATHY HAS A NON-PROGRESSIVE COURSE OF CYST DEVELOPMENT AND A SLOW-PROGRESSIVE COURSE OF KIDNEY FUNCTION. A SUBGROUP OF PATIENTS DEVELOPED ESRD AT VERY YOUNG AGE < 2 YEARS REQUIRING SPECIAL MEDICAL ATTENTION. THE PARENT-OF-ORIGIN EFFECT SUGGESTS AN INFLUENCE OF EPIGENETIC MODIFIERS IN HNF1B DISEASE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
2  5329  26 PURINERGIC SIGNALING IN THE LUMEN OF A NORMAL NEPHRON AND IN REMODELED PKD ENCAPSULATED CYSTS. THE NEPHRON IS THE FUNCTIONAL UNIT OF THE KIDNEY. BLOOD AND PLASMA ARE CONTINUALLY FILTERED WITHIN THE GLOMERULI THAT BEGIN EACH NEPHRON. ADENOSINE 5' TRIPHOSPHATE (ATP) AND ITS METABOLITES ARE FREELY FILTERED BY EACH GLOMERULUS AND ENTER THE LUMEN OF EACH NEPHRON BEGINNING AT THE PROXIMAL CONVOLUTED TUBULE (PCT). FLOW RATE, OSMOLALITY, AND OTHER MECHANICAL OR CHEMICAL STIMULI FOR ATP SECRETION ARE PRESENT IN EACH NEPHRON SEGMENT. THESE ATP-RELEASE STIMULI ARE ALSO DIFFERENT IN EACH NEPHRON SEGMENT DUE TO WATER OR SALT PERMEABILITY OR IMPERMEABILITY ALONG DIFFERENT LUMINAL MEMBRANES OF THE CELLS THAT LINE EACH NEPHRON SEGMENT. EACH OF THE ABOVE STIMULI CAN TRIGGER ADDITIONAL ATP RELEASE INTO THE LUMEN OF A NEPHRON SEGMENT. EACH NEPHRON-LINING EPITHELIAL CELL IS A POTENTIAL SOURCE OF SECRETED ATP. TOGETHER WITH FILTERED ATP AND ITS METABOLITES DERIVED FROM THE GLOMERULUS, SECRETED ATP AND ADENOSINE DERIVED FROM CELLS ALONG THE NEPHRON ARE LIKELY THE PRINCIPAL TWO OF SEVERAL NUCLEOTIDE AND NUCLEOSIDE CANDIDATES FOR RENAL AUTOCRINE AND PARACRINE LIGANDS WITHIN THE TUBULAR FLUID OF THE NEPHRON. THIS MINIREVIEW DISCUSSES THE FIRST PRINCIPLES OF PURINERGIC SIGNALING AS THEY RELATE TO THE NEPHRON AND THE URINARY BLADDER. THE REVIEW DISCUSSES HOW THE LUMEN OF A RENAL TUBULE PRESENTS AN IDEAL PURINERGIC SIGNALING MICROENVIRONMENT. THE REVIEW ALSO ILLUSTRATES HOW REMODELED AND ENCAPSULATED CYSTS IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) AND REMODELED PSEUDOCYSTS IN AUTOSOMAL RECESSIVE PKD (ARPKD) OF THE RENAL COLLECTING DUCT LIKELY CREATE AN EVEN MORE IDEAL MICROENVIRONMENT FOR PURINERGIC SIGNALING. ONCE TRAPPED IN THESE CLOSED MICROENVIRONMENTS, PURINERGIC SIGNALING BECOMES CHRONIC AND LIKELY PLAYS A SIGNIFICANT EPIGENETIC AND DETRIMENTAL ROLE IN THE SECONDARY PROGRESSION OF PKD, ONCE THE REMODELING OF THE RENAL TISSUE HAS BEGUN. IN PKD CYSTIC MICROENVIRONMENTS, WE ARGUE THAT NORMAL PURINERGIC SIGNALING WITHIN THE LUMEN OF THE NEPHRON PROVIDES DETRIMENTAL ACCELERATION OF ADPKD ONCE REMODELING IS COMPLETE.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  3478  20 IDENTIFICATION OF ADPKD-RELATED GENES AND PATHWAYS IN CELLS OVEREXPRESSING PKD2. CONSISTENT WITH THE GENE DOSAGE EFFECT HYPOTHESIS, RENAL CYSTS CAN ARISE IN TRANSGENIC MURINE MODELS OVEREXPRESSING EITHER PKD1 OR PKD2, WHICH ARE CAUSAL GENES FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD). TO DETERMINE WHETHER PKD GENE OVEREXPRESSION IS A UNIVERSAL MECHANISM DRIVING CYSTOGENESIS OR IS MERELY RESTRICTED TO RODENTS, OTHER ANIMAL MODELS ARE REQUIRED. PREVIOUSLY, WE FAILED TO OBSERVE ANY RENAL CYSTS IN A TRANSGENIC PORCINE MODEL OF PKD2 OVEREXPRESSION PARTIALLY DUE TO EPIGENETIC SILENCING OF THE TRANSGENE. THUS, TO EXPLORE THE FEASIBILITY OF PORCINE MODELS AND IDENTIFY POTENTIAL GENES/PATHWAYS AFFECTED IN ADPKD, LLC-PK1 CELLS WITH HIGH PKD2 EXPRESSION WERE GENERATED. MRNA SEQUENCING (RNA-SEQ) WAS PERFORMED, AND MYC, IER3, AND ADM WERE FOUND TO BE UPREGULATED GENES COMMON TO THE DIFFERENT PKD2 OVEREXPRESSION CELL MODELS. MYC IS A WELL-CHARACTERIZED FACTOR CONTRIBUTING TO CYSTOGENESIS, AND ADM IS A BIOMARKER FOR CHRONIC KIDNEY DISEASE. THUS, THESE GENES MIGHT BE INDICATORS OF DISEASE PROGRESSION. ADDITIONALLY, SOME ADPKD-ASSOCIATED PATHWAYS, E.G., THE MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) PATHWAY, WERE ENRICHED IN THE CELLS. MOREOVER, GENE ONTOLOGY (GO) ANALYSIS DEMONSTRATED THAT PROLIFERATION, APOPTOSIS, AND CELL CYCLE REGULATION, WHICH ARE HALLMARKS OF ADPKD, WERE ALTERED. THEREFORE, OUR EXPERIMENT IDENTIFIED SOME BIOMARKERS OR INDICATORS OF ADPKD, INDICATING THAT HIGH PKD2 EXPRESSION WOULD LIKELY DRIVE CYSTOGENESIS IN FUTURE PORCINE MODELS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4  1477  29 DIVERSE PHENOTYPIC EXPRESSION OF NPHP4 MUTATIONS IN FOUR SIBLINGS. NEPHRONOPHTHISIS (NPHP) IS AN AUTOSOMAL RECESSIVE DISEASE CHARACTERIZED BY RENAL TUBULAR BASEMENT MEMBRANE DISRUPTION, INTERSTITIAL FIBROSIS AND TUBULAR CYSTS THAT PROGRESSES TO END-STAGE KIDNEY DISEASE (ESKD). THERE ARE ALSO CHARACTERISTIC EXTRARENAL MANIFESTATIONS. MUTATIONS OF MORE THAN THIRTEEN GENES THAT CAN CAUSE NPHP HAVE BEEN IDENTIFIED. WE HEREIN REPORT FOUR SIBLINGS FROM A CONSANGUINEOUS FAMILY, WHO CARRIED THE SAME NPHP4 MUTATIONS BUT PRESENTED WITH DIFFERENT DISEASE PHENOTYPES RANGING FROM ENURESIS NOCTURNA TO ESKD. DILUTED URINE AND ECHOGENIC KIDNEYS IN ULTRASOUND EXAMINATION WERE CONSISTENT, WHICH IS TYPICAL FOR 100% OF THE NPHP CASES THAT HAVE BEEN DESCRIBED. CHRONIC KIDNEY DISEASE DEVELOPED IN THE OLDER TWO BROTHERS. THE OBSERVED PHENOTYPIC DIFFERENCES ARE LIKELY TO BE RELATED TO ENVIRONMENTAL AND EPIGENETIC FACTORS, OLIGOGENIC INHERITANCE AND MODIFIER GENES AFFECTING THE AGE OF PRESENTATION OF SIGNS AND SYMPTOMS. NPHP SHOULD BE CONSIDERED AS AN IMPORTANT CAUSE OF CKD IN CHILDREN, WHICH INSIDIOUSLY PROGRESSES TO ESKD, WITH NO SPECIFIC THERAPY AVAILABLE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5  4963  32 PATHOGENESIS OF THYROID NODULES: HISTOLOGICAL CLASSIFICATION? THYROID NODULE GENESIS MAY BE CONSIDERED AS AN AMPLIFICATION OF THYROID HETEROGENEITY DUE TO GENETIC AND/OR EPIGENETIC MECHANISMS. WE CLASSIFIED THE THYROID NODULES IN FIVE TYPES WITH DISTINCT HISTOLOGICAL FEATURES: HYPERPLASTIC, NEOPLASTIC, COLLOID, CYSTIC AND THYROIDITIC NODULES. HYPERPLASTIC: THYROCYTE PROLIFERATION IS UNDER THE CONTROL OF TSH BUT SEVERAL OTHER PARACRINE AND AUTOCRINE FACTORS ARE SECRETED BY FOLLICULAR CELLS, THE STROMAL APPARATUS AND THE LYMPHOCYTES, WHICH ARE IMPLICATED IN INITIATION AND PERPETUATION OF THYROID HYPERPLASIA. GROWTH OCCURS MAINLY THROUGH TSHR, CAMP AND PKA. CONSTITUTIVE CAMP OVERPRODUCTION HAS BEEN SHOWN TO BE DUE TO POINT MUTATION OF THE TSHR OR GS PROTEIN, PRODUCING OVERGROWTH AND HYPERFUNCTION. NEOPLASTIC: SEVERAL ACTIVATED ONCOGENES HAVE BEEN IDENTIFIED IN THYROID MALIGNANCIES. ONCOGENES RELEVANT TO THE THYROID CARCINOGENESIS ARE: MUTATED TSHR AND GSP (CONSTITUTIVE ACTIVATION OF CAMP); TRK (RECEPTOR FOR NGF); RET/PTC (PHOSPHORYLATION OF TYROSINE KINASE RECEPTOR)--AN ISOFORM OF THIS ONCOGENE IS INDUCED BY RADIATION: RAS (IT ENCODES GS PROTEINS TRANSDUCING MITOGENIC SIGNALS); AND C-MET (RECEPTOR FOR HEPATOCYTE GROWTH FACTOR). THE EVOLUTION OF A DIFFERENTIATED THYROID CANCER TOWARDS AN UNDIFFERENTIATED CANCER IS DUE TO A MUTATION OF A FAMILY OF PROTEINS (I.E., P53), WHICH ACTS AS A BRAKE, PREVENTING THE GENOMIC INSTABILITY OF CANCER. IT IS SUGGESTED THAT A TUMOR INITIATES BY RET OR RAS AND POSSIBLY PROGRESSES--AS A RESULT OF ADDITIONAL MUTATIONS AND BY P53 MUTATION--TO ANAPLASTIC CARCINOMA. COLLOID: FLATTENING OF THE EPITHELIUM AND DILATATION OF FOLLICLES CONTAINING VISCOUS MATERIAL--MADE UP BY A CONCENTRATED SOLUTION OF THYROGLOBULIN (HTG)--IS THE CHARACTERISTIC OF THE COLLOID NODULE. A DEFECT OF INTRALUMINAL REABSORPTION OF HTG HAS BEEN SUGGESTED BUT NOT PROVEN. EXPERIMENTALLY, A LOAD OF IODINE IS ABLE TO CHANGE THYROID HYPERPLASIA TO A COLLOID FEATURE; HOWEVER, A LOAD OF IODINE IS RARELY FOUND IN THE CLINICAL HISTORY OF PATIENTS. A NEW CLUE TO THE PATHOGENESIS COMES FROM THE FINDING THAT A RELEVANT PART OF THE COLLOID (10-20%) IS MADE UP OF INSOLUBLE GLOBULES, WHERE HTG IS COMPACTED IN A POLYMERIC FORM. IT IS SUGGESTED THAT STOCKING HTG INTO GLOBULES IS DEFECTIVE IN COLLOID NODULES, LEADING TO ENORMOUS ENLARGEMENT OF THE FOLLICLE. CYSTIC: IT IS ESTIMATED THAT BETWEEN 15 AND 40% OF THYROID NODULES ARE PARTLY OR ENTIRELY CYSTIC. THE 'TRUE CYST' IS RARE; MOST OF THE SO-CALLED CYSTIC NODULES ARE 'PSEUDOCYSTS', WHICH FOLLOW NECROSIS AND COLLIQUATION. NECROSIS ISSUES AS AN IMBALANCE BETWEEN GROWTH AND THE PRECISELY REGULATED PROCESS OF ANGIOGENESIS. MORE RECENTLY, THE VEGF/VPF HAS BEEN FOUND TO BE AT THE ORIGIN OF RECENT AND RECURRENT CYSTS. IMMUNOTOXIC AND APOPTOTIC MECHANISMS HAVE ALSO BEEN SUGGESTED. CHEMICAL ANALYSIS OF CYSTIC FLUID SHOWED A 'DENATURED' AND 'SERUM-LIKE' PATTERN SUGGESTING DIFFERENT MECHANISMS IN THE PATHOGENESIS OF THE PSEUDOCYSTIC THYROID NODULES. THYROIDITIC: NODULAR LYMPHOCYTIC THYROIDITIS (NLT) INCLUDES TWO DIFFERENT ENTITIES: 1) LYMPHOCYTE THYROIDITIS GROWING AS A NODULE IN A HYPERPLASTIC OR NORMAL GLAND, AND 2) LYMPHOCYTE THYROIDITIS ASSOCIATED IN THE SAME NODULE WITH OTHER NODULAR DISEASES OF THE THYROID: PAPILLARY THYROID CARCINOMA AND LYMPHOMA HAVE BEEN FOUND TO BE ASSOCIATED TO CHRONIC LYMPHOCYTIC THYROIDITIS.	2001	

6  1129  24 COMPREHENSIVE ANALYSIS OF MRNA-LNCRNA CO-EXPRESSION PROFILES IN MOUSE BRAIN DURING INFECTION WITH TOXOPLASMA GONDII. TOXOPLASMA GONDII IS AN OBLIGATE INTRACELLULAR PROTOZOAN PARASITE WHICH SERIOUSLY THREATENS THE HEALTH OF DOMESTIC ANIMALS AND HUMANS. LONG NON-CODING RNAS (LNCRNAS) ARE NON-PROTEIN-CODING TRANSCRIPTS GREATER THAN 200 NUCLEOTIDES, WHICH ARE WIDELY INVOLVED IN TRANSCRIPTIONAL AND EPIGENETIC REGULATIONS. HOWEVER, LITTLE IS KNOWN ABOUT THE ROLES OF HOST LNCRNAS IN THE RESPONSE TO T. GONDII INFECTIONS. IN THIS STUDY, USING ILLUMINA SEQUENCING TECHNOLOGY, WE ANALYZED THE EXPRESSION PROFILES OF MRNAS AND LNCRNAS IN BALB/C MOUSE BRAIN FOLLOWING INFECTION BY T. GONDII PRU STRAIN (TYPE II GENOTYPE) CYSTS. THE IDENTIFIED DIFFERENTIALLY EXPRESSED (DE) RNAS WERE SUBJECTED TO BIOINFORMATICS ANALYSIS. A TOTAL OF 2,090 ANNOTATED LNCRNAS ALONG WITH 3,577 NOVEL LNCRNAS WERE IDENTIFIED. IN THE ACUTELY INFECTED MOUSE BRAIN, A TOTAL OF 330 MRNAS AND 19 LNCRNAS WERE DYS-REGULATED, WHEREAS 136 DE MRNAS AND 9 DE LNCRNAS WERE IDENTIFIED IN CHRONICALLY INFECTED MOUSE BRAIN. GO ANALYSIS REVEALED THAT THESE DE MRNAS IDENTIFIED AT ACUTE INFECTION STAGE WERE INVOLVED IN IMMUNE RESPONSE, WHEREAS DE MRNAS FOUND AT CHRONIC INFECTION STAGE WERE MOSTLY ENRICHED IN RESPONSE TO PROTOZOAN. KEGG ANALYSIS SHOWED THAT DE MRNAS WERE SIGNIFICANTLY ENRICHED IN DISEASE RELATED PATHWAYS. IN ADDITION, THE PUTATIVE MRNA-LNCRNA CO-EXPRESSION NETWORK WAS CONSTRUCTED, AND SEVERAL HUB REGULATORY RNAS WERE IDENTIFIED BASED ON THE TRANSCRIPTOME DATA. THIS STUDY FIRSTLY CHARACTERIZED THE CO-EXPRESSION PROFILE OF MRNAS AND LNCRNAS IN MOUSE BRAIN INFECTED WITH T. GONDII AND PROVIDED A FRAMEWORK FOR FURTHER STUDIES OF THE ROLES OF LNCRNAS IN HOST NEUROPATHOLOGY DURING TOXOPLASMOSIS PROGRESSION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7  6116  22 THE EPIGENETIC CORRELATION AMONG OVARIAN CANCER, ENDOMETRIOSIS AND PCOS: A REVIEW. OVARIAN CANCER IS A FREQUENT MALIGNANCY THAT AFFECTS A LARGE PERCENTAGE OF WOMEN. ENDOMETRIOSIS IS A CHRONIC CONDITION, WHERE THERE IS A PRODUCTION OF BENIGN LESIONS WERE OBSERVED IN THE UTERINE ENVIRONMENT. PCOS IS A METABOLIC DISORDER CHARACTERIZED BY THE PRESENCE OF NUMEROUS CYSTS IN THE OVARIES. THE RELATION BETWEEN OVARIAN MALIGNANCIES AND PCOS, BY AN INCREASED RATIO OF OVARIAN STROMAL TISSUES IN PCOS PATIENTS. THE DIRECT CORRELATION IS NOT YET CONFIRMED AMONG THE THREE DISORDERS, BUT IT IS OFTEN NOTED THAT THEY SHARE RISK FACTORS, SUCH AS OBESITY, HORMONAL IMBALANCES. EPIGENETIC FACTORS HAVE SHOWN TO BE AN IMPORTANT REASON FOR CANCER PROGRESSION. OUR FINDINGS AT THE EPIGENETIC LEVEL INCLUDES A COMPARATIVE ANALYSIS, POINT MUTATIONS IN GENES, OVERACTIVATION OF SIGNALING PATHWAYS. THIS REVIEW PAPER, HIGHLIGHT THE POSSIBLE CORRELATION BETWEEN THE THREE DISORDERS IN TERMS OF GENETIC AND EPIGENETIC FACTORS AND HOW IT COULD TOGETHER TRIGGER THE CANCER PROGRESSION AND METASTASIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
8  6368  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
9  4825  34 OCULAR FUNDUS ABNORMALITIES IN PATIENTS WITH BALKAN ENDEMIC NEPHROPATHY AND OTHER CHRONIC KIDNEY DISEASES. AIM: THE AIM OF THIS STUDY WAS TO EXAMINE THE OCULAR FUNDUS PATHOLOGY IN PATIENTS WITH BALKAN ENDEMIC NEPHROPATHY (BN) AND CHRONIC KIDNEY DISEASES (CKD). METHODS: THE STUDY INCLUDED 51 PATIENTS WITH BN FROM THE SOUTH MORAVA RIVER REGION IN SERBIA, AND 102 SUBJECTS WITH DIFFERENT STAGES OF CHRONIC RENAL DISEASES, MATCHED ACCORDING TO AGE AND GENDER, OBTAINED FROM A DATABASE USED IN A RECENTLY PUBLISHED STUDY. ALL PATIENTS HAD VISITED OUTPATIENT DEPARTMENT OF THE CLINIC OF NEPHROLOGY, CLINICAL CENTER NIS. ALL PATIENTS UNDERWENT ROUTINE OPHTHALMIC EXAMINATIONS. RESULTS: THERE WERE SIGNIFICANTLY MORE (P < 0.001) PATIENTS WITH AGE-RELATED MACULAR DEGENERATION (AMD) IN THE GROUP WITH BN (31.37 %) THAN IN THOSE WITH CKD (5.88 %). MULTIVARIATE LOGISTIC REGRESSION ANALYSIS CONFIRMED THAT THE SIGNIFICANT FACTORS RELATED TO AMD IN THE GROUP WITH BN WERE ALBUMINURIA (P < 0.05) AND PROTEINURIA (P < 0.05); IN CKD PATIENTS, THE LEVEL OF HDL (P < 0.05), WHILE NEGATIVE CORRELATION WITH THE LEVEL OF TRIGLYCERIDE WAS REGISTERED (P < 0.05). THERE WAS NO ASSOCIATION BETWEEN ESTIMATED GLOMERULAR FILTRATION RATE AND AMD. THE SIGNIFICANT FACTORS RELATED TO RETINOPATHY IN THE GROUP WITH BN ARE AGE (P < 0.05) AND SERUM CREATININE VALUES (P < 0.05), IN PATIENTS WITH CKD INCREASING AGE (P < 0.001) AND DM (P < 0.05). CONCLUSION: OCULAR FUNDUS PATHOLOGY IN PATIENTS WITH BN IS SIMILAR TO THE PATHOLOGY OF OTHER CKD, BUT WITH SIGNIFICANTLY MORE AMD (ABOUT FOUR TIMES), PROBABLY RELATED TO THE GENETIC/EPIGENETIC FACTORS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10  5790  31 SRSF2-P95 HOTSPOT MUTATION IS HIGHLY ASSOCIATED WITH ADVANCED FORMS OF MASTOCYTOSIS AND MUTATIONS IN EPIGENETIC REGULATOR GENES. MASTOCYTOSIS IS A RARE AND CHRONIC DISEASE WITH PHENOTYPES RANGING FROM INDOLENT TO SEVERE. PROGNOSIS FOR THIS DISEASE IS VARIABLE AND VERY FEW BIOMARKERS TO PREDICT DISEASE EVOLUTION OR OUTCOME ARE CURRENTLY KNOWN. WE HAVE PERFORMED COMPREHENSIVE SCREENING IN OUR LARGE COHORT OF MASTOCYTOSIS PATIENTS FOR MUTATIONS PREVIOUSLY FOUND IN OTHER MYELOID DISEASES AND THAT COULD SERVE AS PROGNOSTIC INDICATORS. KIT, SRSF2-P95 AND TET2 MUTATIONS WERE BY FAR THE MOST FREQUENT, DETECTED IN 81%, 24% AND 21% OF PATIENTS, RESPECTIVELY. WHERE TET2 AND SRSF2-P95 MUTATION BOTH CORRELATED WITH ADVANCED DISEASE PHENOTYPES, SRSF2-P95 HOTSPOT MUTATION WAS FOUND ALMOST EXCLUSIVELY IN PATIENTS DIAGNOSED WITH ASSOCIATED CLONAL HEMATOLOGIC NON-MAST CELL DISEASE. STATISTICALLY, TET2 AND SRSF2-P95 MUTATIONS WERE HIGHLY ASSOCIATED, SUGGESTING A MECHANISTIC LINK BETWEEN THESE TWO FACTORS. FINALLY, ANALYSIS OF BOTH CLONAL AND SORTED CELL POPULATIONS FROM PATIENTS CONFIRMS THE PRESENCE OF THESE MUTATIONS IN THE MAST CELL COMPONENT OF THE DISEASE, SUGGESTS AN ONTOLOGICAL MUTATION HIERARCHY AND PROVIDES EVIDENCE FOR THE EXPANSION OF MULTIPLE CLONES. THIS HIGHLIGHTS THE PROGNOSTIC POTENTIAL OF SUCH APPROACHES, IF APPLIED SYSTEMATICALLY, FOR DELINEATING THE ROLES OF SPECIFIC MUTATIONS IN PREDISPOSING AND/OR DRIVING DISTINCT DISEASE PHENOTYPES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
11  4052  26 MALIGNANT TRANSFORMATION OF A DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR (DNET) CHARACTERIZED BY GENOME-WIDE METHYLATION ANALYSIS. DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS (DNET) ARE CONSIDERED TO BE RARE, BENIGN, AND ASSOCIATED WITH CHRONIC EPILEPSY. WE PRESENT THE CASE OF A 28-YEAR-OLD MAN WITH A HISTORY OF EPILEPSY SINCE AGE 12. SURGERY OF AN OCCIPITAL CORTICAL LESION IN 2009 REVEALED A DNET. FIVE YEARS LATER, A RECURRENT TUMOR AT THE EDGE OF THE RESECTION CAVITY WAS REMOVED, AND THE TISSUE UNDERWENT AN INTENSIVE DIAGNOSTIC WORKUP. THE FIRST TUMOR WAS UNEQUIVOCALLY CHARACTERIZED AS A DNET, BUT NEUROPATHOLOGICAL DIAGNOSTICS OF THE RECURRENT TUMOR REVEALED A GLIOBLASTOMA. AFTER 6 MONTHS, ANOTHER RECURRENT TUMOR WAS DETECTED NEXT TO THE LOCATION OF THE ORIGINAL TUMOR, AND THIS WAS ALSO RESECTED. AN ILLUMINA 450 K BEADCHIP METHYLATION ARRAY WAS PERFORMED TO CHARACTERIZE ALL OF THE TUMORS. THE METHYLATION PROFILE OF THESE TUMORS SIGNIFICANTLY DIFFERED FROM OTHER GLIOBLASTOMA AND EPILEPSY-ASSOCIATED TUMOR PROFILES AND REVEALED A DNET-LIKE METHYLATION PROFILE. THUS, MOLECULAR CHARACTERIZATION OF THESE RECURRENT TUMORS SUGGESTS MALIGNANT TRANSFORMATION OF A PREVIOUSLY BENIGN DNET. WE FOUND INCREASED COPY NUMBER CHANGES IN THE RECURRENT DNET TUMORS AFTER MALIGNANT TRANSFORMATION. MODERN HIGH-THROUGHPUT ANALYSIS ADDS ESSENTIAL MOLECULAR INFORMATION IN ADDITION TO STANDARD HISTOPATHOLOGY FOR PROPER IDENTIFICATION OF RARE BRAIN TUMORS THAT PRESENT WITH AN UNUSUAL CLINICAL COURSE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12   414  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  5173  31 PREDICTING PROGRESSION OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE BY CHANGES IN THE TELOMERIC EPIGENOME. AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) IS THE MOST COMMON INHERITED CAUSE OF CHRONIC KIDNEY DISEASE WITH POLYCYSTIN&NBSP;(PKD) 1 AND 2 GENE MUTATION. HOWEVER, THE INTRA-FAMILIAL VARIABILITY IN SYMPTOMS FURTHER SUGGESTS A NON-MENDELIAN CONTRIBUTION TO THE DISEASE. OUR GOAL WAS TO FIND A MARKER TO TRACK THE EPIGENETIC CHANGES COMMON TO RAPIDLY PROGRESSING FORMS OF THE DISEASE. THE RISK OF ADPKD INCREASES WITH AGE, AND AGING SHORTENS THE TELOMERE LENGTH (TL). TELOMERES ARE A NUCLEOPROTEIN STRUCTURE COMPOSED MAINLY OF THREE COMPLEXES, SHELTERIN, CST AND RNA-CONTAINING TELOMERE REPEAT(TERRA), WHICH PROTECTS THE ENDS OF CHROMOSOMES FROM DEGRADATION AND FUSION, AND PLAYS A ROLE IN MAINTAINING CELLULAR STABILITY AND IN THE REPAIR OF TELOMERIC DAMAGE. TERRAS ARE TRANSCRIBED FROM TELOMERIC REGIONS AND A PART OF THEM IS ENGAGED IN A DNA/RNA HYBRID (R-LOOP) AT EACH CHROMOSOME END. WE TRACKED TL AND TERRA LEVELS IN BLOOD SAMPLES OF 78 PATIENTS AND 20 HEALTHY CONTROL. OUR STUDY DEMONSTRATES THAT TL WAS SHORTENED AND TERRA EXPRESSION LEVELS IN THE DNA-ATTACHED FRACTION INCREASED IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY PATIENTS WITH MUTATIONS IN PKD1 AND PKD2 COMPARED TO THE CONTROL GROUP. MOREOVER, IT WAS OBSERVED THAT THE EXPRESSION OF TERRA ENGAGED IN THE R-LOOP WAS HIGHER AND THE LENGTH OF TELOMERES SHORTER IN PATIENTS WITH ADPKD WHO SHOWED RAPID DISEASE PROGRESSION. INTRAFAMILIAL VARIATION IN TL AND TERRA LEVELS WITH THE SAME MUTATION WOULD INDICATE RELIABLE EPIGENETIC POTENTIAL BIOMARKERS IN DISEASE MONITORING.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14  2205  28 EPIGENETIC MODIFICATION OF THE X CHROMOSOME INFLUENCES SUSCEPTIBILITY TO POLYCYSTIC OVARY SYNDROME. CONTEXT: THE CAUSE OF POLYCYSTIC OVARY SYNDROME (PCOS) IS UNKNOWN, ALTHOUGH GENETIC AND ENVIRONMENTAL INFLUENCES ARE CLEARLY IMPLICATED. SOME GENETIC STUDIES HAVE SUGGESTED THE INVOLVEMENT OF X-LINKED GENES IN PCOS, BUT THE INFLUENCE OF X CHROMOSOME INACTIVATION (XCI) ON MANIFESTATION OF THIS DISORDER HAS NOT PREVIOUSLY BEEN EXAMINED. OBJECTIVE: THE OBJECTIVE OF THE STUDY WAS TO TEST THE NULL HYPOTHESIS THAT XCI HAS NO INFLUENCE ON CLINICAL PRESENTATION OF PCOS. DESIGN: WE EXAMINED PATTERNS OF XCI BETWEEN SISTER PAIRS WITH THE SAME GENOTYPE AT A POLYMORPHIC LOCUS ON THE X CHROMOSOME IN FAMILIES WITH PCOS. SETTING: THE STUDY WAS CONDUCTED AT A PRIVATE PRACTICE. PARTICIPANTS: PCOS WAS DEFINED AS HYPERANDROGENEMIA WITH CHRONIC ANOVULATION. FORTY FAMILIES WERE STUDIED IN WHICH DNA WAS OBTAINED FROM AT LEAST ONE PARENT, THE PROBAND, AND ONE SISTER THAT COULD BE ACCURATELY DIAGNOSED AS BEING AFFECTED OR UNAFFECTED. MAIN OUTCOME MEASURE(S): RELATIVE EXPRESSION OF TWO X-LINKED ALLELES WAS DETERMINED, AND THE RATIO OF ONE TO THE OTHER REPRESENTED THE PATTERN OF XCI. RESULTS: THE STATISTICAL ODDS ON A DIFFERENT CLINICAL PRESENTATION BETWEEN SISTERS WAS APPROXIMATELY 29 TIMES HIGHER IN SISTER PAIRS WITH DIFFERENT PATTERNS OF XCI, COMPARED WITH SISTER PAIRS WITH THE SAME PATTERN OF XCI (ODDS RATIO 28.9; 95% CONFIDENCE INTERVAL 4.0-206; P = 0.0008). CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE TO REFUTE THE NULL HYPOTHESIS AND PROPOSE A CLOSER INSPECTION OF X-LINKED GENES IN PCOS, ONE IN WHICH BOTH GENOTYPE AND EPIGENOTYPE ARE CONSIDERED. ENVIRONMENTAL DETERMINANTS OF PCOS MAY ALTER CLINICAL PRESENTATION VIA EPIGENETIC MODIFICATIONS, WHICH CURRENTLY REMAIN UNDETECTED IN TRADITIONAL GENETIC ANALYSES.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
15   537  20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16  5435  30 RELATIVE ROLE OF METHYLATOR AND TUMOR SUPPRESSOR PATHWAYS IN ULCERATIVE COLITIS-ASSOCIATED COLON CANCER. BACKGROUND: CHRONIC ULCERATIVE COLITIS (UC) IS ASSOCIATED WITH AN INCREASED COLORECTAL CANCER RISK WHICH MAY BE SECONDARY TO REPETITIVE MUCOSAL INJURY. BOTH EPIGENETIC METHYLATION AND THE CLASSIC ADENOMA-TO-CARCINOMA SEQUENCE HAVE BEEN IMPLICATED IN THIS MALIGNANT TRANSFORMATION, BUT THE UNDERLYING MOLECULAR MECHANISMS REMAIN POORLY DEFINED. THIS STUDY COMPARES THE MOLECULAR CHARACTERISTICS OF COLITIS-ASSOCIATED AND COMMON COLORECTAL CANCERS. METHODS: NINETEEN PATIENTS WITH COLORECTAL ADENOCARCINOMAS ARISING WITHIN UC WERE MATCHED FOR AGE AND CANCER SITE WITH 54 PATIENTS WITH SPORADIC ADENOCARCINOMAS. TUMOR TISSUE WAS EXAMINED FOR BRAF MUTATIONS, CPG ISLAND METHYLATOR PHENOTYPE (CIMP), AND MLH1 PROMOTER METHYLATION. MUTATIONS OF KRAS AND P53 WERE ASSESSED BY SEQUENCING. RESULTS: PATIENT DEMOGRAPHICS WERE SIMILAR FOR THE TWO GROUPS. CIMP WAS OBSERVED IN 22% OF SPORADIC COLORECTAL CANCERS AND IN 5% OF UC CANCERS (P = 0.162). RATES OF BRAF MUTATION (4% VS 5%, P = 1.0), MLH1 METHYLATION (9% VERSUS 5%, P = 0.682), AND KRAS MUTATIONS (24% VERSUS 32%, P = 0.552) WERE SIMILAR BETWEEN THE GROUPS. HOWEVER, COLITIS-ASSOCIATED COLORECTAL CANCERS WERE MORE LIKELY TO HAVE A P53 MUTATION COMPARED TO SPORADIC ADENOCARCINOMAS (95% VERSUS 53%, P = 0.001). THE DOMINANT MUTATION FOR COLITIS-ASSOCIATED CANCERS WAS A MUTATION IN CODON 4, REPRESENTING HALF OF THE MUTATIONS. FURTHERMORE, COLITIS-ASSOCIATED CANCERS HAD A HIGHER RATE OF MUTATION IN CODON 8 (48% VERSUS 6%, P < 0.001) THAN SPORADIC COUNTERPARTS. CONCLUSIONS: UNLIKE OTHER INFLAMMATORY GASTROINTESTINAL CANCERS, COLITIS-ASSOCIATED COLORECTAL CANCERS DO NOT PREFERENTIALLY ARISE VIA A METHYLATOR PATHWAY WHEN COMPARED TO SPORADIC COLORECTAL CANCERS. CHROMOSOMAL INSTABILITY REMAINS AN IMPORTANT ETIOLOGY, BUT WITH A UNIQUE P53 FREQUENCY AND MUTATION PATTERN.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
17  4363  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  1577  23 DNA METHYLATION PROFILE IN CHRONIC MYELOMONOCYTIC LEUKEMIA ASSOCIATES WITH DISTINCT CLINICAL, BIOLOGICAL AND GENETIC FEATURES. CHROMOSOMAL ABNORMALITIES ARE DETECTED IN 20-30% OF PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND CORRELATE WITH PROGNOSIS. ON THE MUTATION LEVEL, DISRUPTIVE ALTERATIONS ARE PARTICULARLY FREQUENT IN CHROMATIN REGULATORY GENES. HOWEVER, LITTLE IS KNOWN ABOUT THE CONSEQUENTIAL ALTERATIONS IN THE EPIGENETIC MARKING OF THE GENOME. HERE, WE REPORT THE ANALYSIS OF GENOMIC DNA METHYLATION PATTERNS OF 64 CMML PATIENTS AND 10 HEALTHY CONTROLS, USING A DNA METHYLATION MICROARRAY FOCUSED ON PROMOTER REGIONS. DIFFERENTIAL METHYLATION ANALYSIS BETWEEN PATIENTS AND CONTROLS ALLOWED US TO IDENTIFY ABNORMALITIES IN DNA METHYLATION, INCLUDING HYPERMETHYLATION OF SPECIFIC GENES AND LARGE GENOME REGIONS WITH ABERRANT DNA METHYLATION. UNSUPERVISED HIERARCHICAL CLUSTER ANALYSIS IDENTIFIED TWO MAIN CLUSTERS THAT ASSOCIATED WITH THE CLINICAL, BIOLOGICAL, AND GENETIC FEATURES OF PATIENTS. GROUP 1 WAS ENRICHED IN PATIENTS WITH ADVERSE CLINICAL AND BIOLOGICAL CHARACTERISTICS AND POORER OVERALL AND PROGRESSION-FREE SURVIVAL. IN ADDITION, SIGNIFICANT DIFFERENCES IN DNA METHYLATION WERE OBSERVED BETWEEN PATIENTS WITH LOW RISK AND INTERMEDIATE/HIGH RISK KARYOTYPES AND BETWEEN TET2 MUTANT AND WILD TYPE PATIENTS. TAKEN TOGETHER, OUR RESULTS DEMONSTRATE THAT ALTERED DNA METHYLATION PATTERNS REFLECT THE CMML DISEASE STATE AND ALLOW TO IDENTIFY PATIENT GROUPS WITH DISTINCT CLINICAL FEATURES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19  4820  27 OCHRATOXIN A AS A POTENTIAL ETIOLOGIC FACTOR IN ENDEMIC NEPHROPATHY: LESSONS FROM TOXICITY STUDIES IN RATS. VARIOUS REPORTS SUGGEST THAT CHRONIC DIETARY EXPOSURE TO OCHRATOXIN A (OTA), A MYCOTOXIN FREQUENTLY DETECTED IN VARIOUS FOOD ITEMS MAY BE LINKED TO THE PATHOGENESIS OF ENDEMIC NEPHROPATHY, A CHRONIC TUBULOINTERSTITIAL KIDNEY DISEASE WHICH OCCURS IN GEOGRAPHICALLY LIMITED AREAS OF THE BALKAN REGION. OTA IS A POTENT NEPHROTOXIN AND RENAL CARCINOGEN. HOWEVER, THE PATHOLOGICAL LESIONS OBSERVED IN KIDNEYS OF RATS TREATED WITH OTA APPEAR BE RATHER DIFFERENT FROM THE CLINICAL AND PATHOLOGICAL CHARACTERISTICS OF ENDEMIC NEPHROPATHY. MOREOVER, INCREASING EVIDENCE SUGGESTS THAT OTA DOES NOT BIND TO DNA BUT INDUCES TUMORS BY AN EPIGENETIC, THRESHOLDED MECHANISM. THIS IMPLIES THAT THERE IS A DOSE BELOW WHICH NO ADVERSE HEALTH EFFECTS ARE EXPECTED TO OCCUR. BASED ON FOOD CONSUMPTION DATA AND OTA SERUM CONCENTRATIONS, IT APPEARS THAT HUMAN EXPOSURE - EVEN IN AREAS WITH RELATIVELY HIGH DIETARY EXPOSURE TO OTA SUCH AS ENDEMIC VILLAGES - IS SEVERAL ORDERS OF MAGNITUDE BELOW DOSES KNOWN TO CAUSE NEPHROTOXICITY AND TUMOR FORMATION IN LABORATORY ANIMALS. WHILE IT IS UNDOUBTEDLY IMPORTANT TO ENCOURAGE PREVENTION OF FOOD CONTAMINATION BY OTA AND OTHER MYCOTOXINS, THESE OBSERVATIONS SUGGEST THAT OTA IS NOT LIKELY TO BE AN ETIOLOGICAL FACTOR INVOLVED IN BEN AND INDICATE A NEED TO SEARCH FOR NEW CLUES FOR THE ETIOLOGY OF THIS ENDEMIC KIDNEY DISEASE.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
20  1585  27 DNA METHYLATION PROFILING IDENTIFIES EPIGENETIC DIFFERENCES BETWEEN DIABETES PATIENTS WITH ESRD AND DIABETES PATIENTS WITHOUT NEPHROPATHY. WE IDENTIFIED POTENTIAL EPIGENETIC BIOMARKERS FOR CHRONIC KIDNEY DISEASE PROGRESSION BY COMPARING SITE-SPECIFIC DNA METHYLATION LEVELS IN MORE THAN 14,000 GENES BETWEEN AFRICAN AMERICAN AND HISPANIC DIABETES PATIENTS WITH END STAGE RENAL DISEASE (ESRD) AND DIABETES PATIENTS WITHOUT NEPHROPATHY. WE IDENTIFIED 187 GENES THAT ARE DIFFERENTIALLY METHYLATED BETWEEN THE TWO GROUPS ON AT LEAST TWO CPG SITES IN EACH GENE IN DNA EXTRACTED FROM SALIVA. OF THE 187 GENES WHOSE MEAN METHYLATION LEVELS DIFFERED BETWEEN THE TWO GROUPS, 39 GENES, OR CLOSELY RELATED GENE FAMILY MEMBERS, HAVE BEEN REPORTED TO BE INVOLVED IN KIDNEY DEVELOPMENT OR DIABETIC NEPHROPATHY, PER SE, OR HAVE BEEN ASSOCIATED WITH DIALYSIS-INDUCED CHANGES IN GENE EXPRESSION IN PERIPHERAL BLOOD CELLS. THE FACT THAT SUCH A SUBSTANTIAL FRACTION (21%) OF THE 187 CANDIDATE GENES HAVE BEEN IMPLICATED PREVIOUSLY THROUGH GENOME ASSOCIATION OR TRANSCRIPTION PROFILING STUDIES SUGGESTS STRONGLY THAT THE DNA METHYLATION DIFFERENCES WE OBSERVE ARE ASSOCIATED WITH DISEASE PREDISPOSITION AND/OR TREATMENT. THE FACT THAT THESE NEPHROPATHY AND/OR DIALYSIS-ASSOCIATED DIFFERENCES BETWEEN PATIENTS WERE IDENTIFIED IN DNA EXTRACTED FROM SALIVA OFFERS PROOF-OF-PRINCIPLE THAT INTER-INDIVIDUAL EPIGENETIC DIFFERENCES MAY PROVE USEFUL AS PREDICTIVE BIOMARKERS OF DISEASE SUSCEPTIBILITY.	2011