1  4363 196 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	
                                                                                                                                               
2   414  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  1031  48 CIRCULATING TUMOR DNA DETECTION AND ITS APPLICATION STATUS IN GASTRIC CANCER: A NARRATIVE REVIEW. CIRCULATING TUMOR DNA (CTDNA) IS THE SMALL GENOMIC FRAGMENT RELEASED BY TUMOR CELLS INTO THE CIRCULATING SYSTEM, WHICH CARRIES THE GENE VARIATION FEATURES, SUCH AS MUTATION, INSERTION, DELETION, REARRANGEMENT, COPY NUMBER VARIATION (CNV) AND METHYLATION, RENDERING IT AN IMPORTANT BIOMARKER. IT CAN BE USED NOT ONLY TO DIAGNOSE CERTAIN TYPES OF SOLID TUMORS, BUT ALSO TO MONITOR THE THERAPEUTIC RESPONSE AND EXPLORE THE MINIMAL RESIDUAL DISEASE (MRD) AND RESISTANT MUTATION OF TARGETED THERAPY. THEREFORE, CTDNA DETECTION MAY BECOME THE PREFERRED NON-INVASIVE TUMOR SCREENING METHOD. FOR PATIENTS WHO CANNOT RECEIVE FURTHER GENE DETECTION DUE TO INSUFFICIENT OR RESTRICTED SAMPLE COLLECTION WITH THE DEFINED PATHOLOGICAL DIAGNOSIS, CTDNA DETECTION CAN BE CARRIED OUT TO DETERMINE THE GENE MUTATION TYPE, WITH NO NEED FOR REPEATED SAMPLING. GASTRIC CANCER (GC) IS A MALIGNANCY WITH EXTREMELY HIGH MORBIDITY AND MORTALITY, AND ITS GENESIS AND DEVELOPMENT ARE THE CONSEQUENCE OF INTERACTIONS OF MULTIPLE FACTORS, INCLUDING ENVIRONMENT, DIET, HEREDITY, HELICOBACTER PYLORI INFECTION, CHRONIC INFLAMMATORY INFILTRATION, AND PRECANCEROUS LESION. AS THE RESEARCH ON GC MOVES FORWARD, THE EXISTING RESEARCH MAINLY FOCUSES ON GENETIC AND EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, NON-CODING RNA CHANGES, GENE MUTATION, GENE HETEROZYGOSITY LOSS AND MICROSATELLITE INSTABILITY. THIS PAPER AIMED TO SUMMARIZE THE CONTENTS OF CTDNA DETECTION, ITS APPLICATION STATUS IN GC AND CLINICAL SIGNIFICANCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4  5787  43 SPUTUM ANALYSIS: NON-INVASIVE EARLY LUNG CANCER DETECTION. LUNG CANCER IS THE LEADING CAUSE OF CANCER-RELATED DEATHS OVER THE WORLD, CHARACTERIZED BY A VERY HIGH MORTALITY RATE. MOLECULAR TECHNIQUE DEVELOPMENT TRIES TO FOCUS ON EARLY DETECTION OF CANCERS BY STUDYING MOLECULAR ALTERATIONS THAT CHARACTERIZE CANCER CELLS. WORLDWIDE LUNG CANCER RESEARCH HAS FOCUSED ON AN EVER-INCREASING NUMBER OF MOLECULAR ELEMENTS OF CARCINOGENESIS AT GENETIC, EPIGENETIC AND PROTEIN LEVELS. THE NON-INVASIVENESS IS THE CHARACTERISTIC THAT ALL CLINICAL TRIALS ON CANCER DETECTION SHOULD HAVE. ABNORMAL CHEST IMAGING AND/OR NON-SPECIFIC SYMPTOMS ARE INITIAL SIGNALS OF LUNG CANCER THAT APPEAR IN AN ADVANCED STAGE OF DISEASE. THIS FACT REPRESENTS THE CAUSE OF THE LOW 5-YEAR SURVIVAL RATE: OVER 90% OF PATIENTS DYING WITHIN 5 YEARS OF DIAGNOSIS. SINCE SMOKERS HAVE HIGHER QUANTITY OF SPUTUM CONTAINING EXFOLIATED CELLS FROM THE BRONCHIAL TREE, AND THE SPUTUM REPRESENTS THE MOST EASILY ACCESSIBLE BIOLOGICAL FLUID AND ITS COLLECTION IS NON-INVASIVE, ANALYSIS OF THIS SAMPLE REPRESENTS A GOOD AREA OF RESEARCH IN EARLY LUNG CANCER DIAGNOSIS. CONTINUED CIGARETTE SMOKING IS THE CAUSE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), WITH AN ESTIMATED ATTRIBUTABLE RISK FACTOR EXCEEDING 80% IN SMOKING AFFECTED INDIVIDUALS. LUNG CANCER IS FOUND IN 40-70% OF PATIENTS WITH COPD, PARTICULARLY IN SEVERE DISEASE, AND IT IS A COMMON CAUSE OF DEATH IN THESE PATIENTS. A LARGE PROSPECTIVE TRIAL OF ALMOST HALF A MILLION NON-SMOKERS SHOWED AS LUNG CANCER IS ALSO COMMON IN PATIENTS WITH COPD WHO HAVE NEVER SMOKED. THIS REVIEW DESCRIBES ISSUES RELATED TO EARLY LUNG CANCER SCREENING USING NON-INVASIVE METHODS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5  3271  39 HEPATOCELLULAR CARCINOMA RISK AFTER VIRAL RESPONSE IN HEPATITIS C VIRUS-ADVANCED FIBROSIS: WHO TO SCREEN AND FOR HOW LONG? HEPATITIS C VIRUS (HCV) CHRONIC INFECTION IS ASSOCIATED WITH FIBROSIS PROGRESSION, END-STAGE LIVER COMPLICATIONS AND HCC. NOT SURPRISINGLY, HCV INFECTION IS A LEADING CAUSE OF LIVER-RELATED MORBIDITY AND MORTALITY WORLDWIDE. AFTER SUSTAINED VIROLOGICAL RESPONSE (SVR), THE RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA IS NOT COMPLETELY ELIMINATED IN PATIENTS WITH ESTABLISHED CIRRHOSIS OR WITH ADVANCED FIBROSIS. THEREFORE, LIFELONG SURVEILLANCE IS CURRENTLY RECOMMENDED. THIS STRATEGY IS LIKELY NOT UNIVERSALLY COST-EFFECTIVE AND HARMLESS, CONSIDERING THAT NOT ALL PATIENTS WITH ADVANCED FIBROSIS HAVE THE SAME RISK OF DEVELOPING HCC. FACTORS RELATED TO THE SEVERITY OF LIVER DISEASE AND ITS POTENTIAL TO IMPROVE AFTER SVR, THE MOLECULAR AND EPIGENETIC CHANGES THAT OCCUR DURING INFECTION AND OTHER ASSOCIATED COMORBIDITIES MIGHT ACCOUNT FOR DIFFERENT RISK LEVELS AND ARE LIKELY ESSENTIAL FOR IDENTIFYING PATIENTS WHO WOULD BENEFIT FROM SCREENING PROGRAMS AFTER SVR. EFFORTS TO DEVELOP PREDICTIVE MODELS AND RISK CALCULATORS, BIOMARKERS AND GENETIC PANELS AND EVEN DEEP LEARNING MODELS TO ESTIMATE THE INDIVIDUAL RISK OF HCC HAVE BEEN MADE IN THE DIRECT-ACTING ANTIVIRAL AGENTS ERA, WHEN THOUSANDS OF PATIENTS WITH ADVANCED FIBROSIS AND CIRRHOSIS HAVE REACHED SVR. THESE TOOLS COULD HELP TO IDENTIFY PATIENTS WITH VERY LOW HCC RISK IN WHOM SURVEILLANCE MIGHT NOT BE JUSTIFIED. IN THIS REVIEW, FACTORS AFFECTING THE PROBABILITY OF HCC DEVELOPMENT AFTER SVR, THE BENEFITS AND RISKS OF SURVEILLANCE, SUGGESTED STRATEGIES TO ESTIMATE INDIVIDUALIZED HCC RISK AND THE CURRENT EVIDENCE TO RECOMMEND LIFELONG SURVEILLANCE ARE DISCUSSED.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
6   778  49 CELL-FREE DNA METHYLATION: THE NEW FRONTIERS OF PANCREATIC CANCER BIOMARKERS' DISCOVERY. PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS AMONG THE MOST LETHAL CANCER TYPES WORLD-WIDE. ITS HIGH MORTALITY IS RELATED TO THE DIFFICULTY IN THE DIAGNOSIS, WHICH OFTEN OCCURS WHEN THE DISEASE IS ALREADY ADVANCED. AS OF TODAY, NO EARLY DIAGNOSTIC TESTS ARE AVAILABLE, WHILE ONLY A LIMITED NUMBER OF PROGNOSTIC TESTS HAVE REACHED CLINICAL PRACTICE. THE MAIN REASON IS THE LACK OF RELIABLE BIOMARKERS THAT ARE ABLE TO CAPTURE THE EARLY DEVELOPMENT OR THE PROGRESSION OF THE DISEASE. HENCE, THE DISCOVERY OF BIOMARKERS FOR EARLY DIAGNOSIS OR PROGNOSIS OF PDAC REMAINS, DE FACTO, AN UNMET NEED. AN INCREASING NUMBER OF STUDIES HAS SHOWN THAT CELL-FREE DNA (CFDNA) METHYLATION ANALYSIS REPRESENTS A PROMISING NON-INVASIVE APPROACH FOR THE DISCOVERY OF BIOMARKERS WITH DIAGNOSTIC OR PROGNOSTIC POTENTIAL. IN PARTICULAR, CFDNA METHYLATION COULD BE UTILIZED FOR THE IDENTIFICATION OF DISEASE-SPECIFIC SIGNATURES IN PRE-NEOPLASTIC LESIONS OR CHRONIC PANCREATITIS (CP), REPRESENTING A SENSITIVE AND NON-INVASIVE METHOD OF EARLY DIAGNOSIS OF PDAC. IN THIS REVIEW, WE WILL DISCUSS THE ADVANTAGES AND PITFALLS OF CFDNA METHYLATION STUDIES. FURTHER, WE WILL PRESENT THE CURRENT ADVANCES IN THE DISCOVERY OF PANCREATIC CANCER BIOMARKERS WITH EARLY DIAGNOSTIC OR PROGNOSTIC POTENTIAL, FOCUSING ON PANCREAS-SPECIFIC (E.G., CUX2 OR REG1A) OR ABNORMAL (E.G., ADAMTS1 OR BNC1) CFDNA METHYLATION SIGNATURES IN HIGH RISK PRE-NEOPLASTIC CONDITIONS AND PDAC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
7  5685  44 SHOULD WE INVEST IN BIOLOGICAL AGE PREDICTORS TO TREAT COLORECTAL CANCER IN OLDER ADULTS? COLORECTAL CANCER (CRC) IS A CHRONIC DISEASE OF THE OLD POPULATION WITH SLOW DEVELOPMENT PROGRESSING INTO CLINICAL SIGNS AND SYMPTOMS. BIOLOGICAL AGING IS CHARACTERIZED BY E.G. MITOCHONDRIAL DYSFUNCTION AND EPIGENETIC ALTERATIONS (E.G. METHYLATION) - MECHANISMS THAT ARE ALSO IMPORTANT IN CANCER DEVELOPMENT. FOR CRC, SPECIFIC TYPES OF TUMORS ARE DISTINGUISHABLE BY THEIR METHYLATION PATTERNS AND SEVERAL DETECTION METHODS USING DIFFERENT EPIGENETIC MARKS HAVE BEEN DEVELOPED AS SIGNATURES FOR THE DISEASE. BIOLOGICAL AGE ASSESSED BY DNA METHYLATION PATTERNS FROM BLOOD, I.E. THE EPIGENETIC CLOCK, IS HIGHER IN CRC PATIENTS COMPARED TO CONTROLS, AND MAY BE A TOOL FOR IDENTIFYING INDIVIDUALS AT INCREASED RISK FOR CRC. OTHER TYPES OF BIOMARKERS OF AGING ARE USEFUL TO CALCULATE BIOLOGICAL AGE, SUCH AS METABOLITES, PROTEIN LEVELS, INFLAMMATORY MARKERS AND CLINICAL BIOMARKERS, WHERE COMPOSITE SCORES OF BIOMARKERS HAVE BEEN USED TO ASSESS THE RISK OF CRC AND COLORECTAL ADENOMAS. CLINICAL ASSESSMENTS OF BIOLOGICAL AGING INCLUDES FRAILTY, WHICH IS A GERIATRIC SYNDROME CHARACTERIZED BY INCREASED VULNERABILITY TO ADVERSE OUTCOMES. MORE THAN HALF OF THE CRC PATIENTS ARE ESTIMATED TO BE FRAIL OR PRE-FRAIL, AND THESE INDIVIDUALS ARE AT INCREASED RISK OF POSTOPERATIVE COMPLICATIONS, POORER PROGNOSIS, TREATMENT INTOLERANCE AND DEATH. HENCE, CONSIDERING FRAILTY AS PART OF BIOLOGICAL AGE IN CRC PATIENTS MAY HELP IDENTIFYING THOSE AT NEED OF CLOSE MONITORING. IN SUMMARY, FUTURE SCREENING PROGRAMS FOR CRC MAY MAKE USE OF BIOLOGICAL AGE ASSESSMENTS, E.G. BY EPIGENETIC CLOCK OR COMPOSITE SCORES. MONITORING DISEASE RELAPSE AND TREATMENT RESPONSE SHOULD BE ENHANCED IN FRAIL INDIVIDUALS FOR BETTER PROGNOSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8   777  37 CELL-FREE CIRCULATING EPIGENOMIC SIGNATURES: NON-INVASIVE BIOMARKER FOR CARDIOVASCULAR AND OTHER AGE-RELATED CHRONIC DISEASES. THE BURDEN OF CARDIO-VASCULAR AND OTHER AGE-RELATED NON-COMMUNICABLE DISEASES ARE RAPIDLY INCREASING WORLDWIDE. MAJORITY OF THESE CHRONIC AILMENTS ARE CURABLE, IF DIAGNOSED AT EARLY STAGES. CANDIDATE BIOMARKERS OF EARLY DETECTION ARE THEREFORE ESSENTIAL FOR IDENTIFICATION OF HIGH-RISK INDIVIDUALS, PROMPT AND ACCURATE DISEASE DIAGNOSIS, AND TO MONITOR THERAPEUTIC RESPONSE. THE FUNCTIONAL SIGNIFICANCE OF CIRCULATING NUCLEIC ACIDS THAT RECAPITULATE SPECIFIC DISEASE PROFILES IS NOW WELL ESTABLISHED. BUT SUBTLE CHANGES IN DNA SEQUENCE MAY NOT SOLELY REFLECT THE DIFFERENTIATION OF GENE EXPRESSION PATTERNS OBSERVED IN DIVERSE SET OF DISEASES AS EPIGENETIC PHENOMENA PLAY A LARGER ROLE IN AETIOLOGY AND PATHO-PHYSIOLOGY. UNLIKE GENETIC MARKERS, KNOWLEDGE ABOUT THE DIAGNOSTIC UTILITY OF CIRCULATING EPIGENETIC SIGNATURES: METHYLATED DNA; MICRO RNA AND MODIFIED HISTONES ARE DEFICIENT. CHARACTERIZATION OF THESE NOVEL ENTITIES THROUGH OMICS-BASED MOLECULAR TECHNOLOGIES MIGHT PROMPT DEVELOPMENT OF A RANGE OF LABORATORY-BASED STRATEGIES, THEREBY ACCELERATING THEIR BROADER TRANSLATIONAL PURPOSE FOR EARLY DISEASE DIAGNOSIS, MONITORING THERAPEUTIC RESPONSE AND DRUG RESISTANCE. HOWEVER, LARGEST OPPORTUNITY FOR INNOVATION LIES IN DEVELOPING POINT-OF-CARE TESTS WITH ACCURATE DIAGNOSTIC AND HIGHER PROGNOSTIC SCORE THAT IS APPLICABLE FOR SCREENING OF HIGH-RISK POPULATIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9  3925  39 LIQUID BIOPSIES BASED ON DNA METHYLATION AS BIOMARKERS FOR THE DETECTION AND PROGNOSIS OF LUNG CANCER. LUNG CANCER (LC) IS THE MAIN CAUSE OF CANCER-RELATED MORTALITY. MOST LC PATIENTS ARE DIAGNOSED IN AN ADVANCED STAGE WHEN THE SYMPTOMS ARE OBVIOUS, AND THE PROGNOSIS IS QUITE POOR. ALTHOUGH LOW-DOSE COMPUTED TOMOGRAPHY (LDCT) IS A ROUTINE CLINICAL EXAMINATION FOR EARLY DETECTION OF LC, THE FALSE-POSITIVE RATE IS OVER 90%. AS ONE OF THE INTENSELY STUDIED EPIGENETIC MODIFICATIONS, DNA METHYLATION PLAYS A KEY ROLE IN VARIOUS DISEASES, INCLUDING CANCER AND OTHER DISEASES. HYPERMETHYLATION IN TUMOR SUPPRESSOR GENES OR HYPOMETHYLATION IN ONCOGENES IS AN IMPORTANT EVENT IN TUMORIGENESIS. REMARKABLY, DNA METHYLATION USUALLY OCCURS IN THE VERY EARLY STAGE OF MALIGNANT TUMORS. THUS, DNA METHYLATION ANALYSIS MAY PROVIDE SOME USEFUL INFORMATION ABOUT THE EARLY DETECTION OF LC. IN RECENT YEARS, LIQUID BIOPSY HAS DEVELOPED RAPIDLY. LIQUID BIOPSY CAN DETECT AND MONITOR BOTH PRIMARY AND METASTATIC MALIGNANT TUMORS AND CAN REFLECT TUMOR HETEROGENEITY. MOREOVER, IT IS A MINIMALLY INVASIVE PROCEDURE, AND IT CAUSES LESS PAIN FOR PATIENTS. THIS REVIEW SUMMARIZED VARIOUS LIQUID BIOPSIES BASED ON DNA METHYLATION FOR LC. AT FIRST, WE BRIEFLY DISCUSSED SOME EMERGING TECHNOLOGIES FOR DNA METHYLATION ANALYSIS. SUBSEQUENTLY, WE OUTLINED CELL-FREE DNA (CFDNA), SPUTUM, BRONCHOALVEOLAR LAVAGE FLUID, BRONCHIAL ASPIRATES, AND BRONCHIAL WASHINGS DNA METHYLATION-BASED LIQUID BIOPSY FOR THE EARLY DETECTION OF LC. FINALLY, THE PROGNOSTIC VALUE OF DNA METHYLATION IN CFDNA AND SPUTUM AND THE DIAGNOSTIC VALUE OF OTHER DNA METHYLATION-BASED LIQUID BIOPSIES FOR LC WERE ALSO ANALYZED.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
10    22  34 5-HYDROXYMETHYLCYTOSINE AS A CLINICAL BIOMARKER: FLUORESCENCE-BASED ASSAY FOR HIGH-THROUGHPUT EPIGENETIC QUANTIFICATION IN HUMAN TISSUES. EPIGENETIC TRANSFORMATIONS MAY PROVIDE EARLY INDICATORS FOR CANCER AND OTHER DISEASE. SPECIFICALLY, THE AMOUNT OF GENOMIC 5-HYDROXYMETHYLCYTOSINE (5-HMC) WAS SHOWN TO BE GLOBALLY REDUCED IN A WIDE RANGE OF CANCERS. THE INTEGRATION OF THIS GLOBAL BIOMARKER INTO DIAGNOSTIC WORKFLOWS IS HAMPERED BY THE LIMITATIONS OF CURRENT 5-HMC QUANTIFICATION METHODS. HERE WE PRESENT AND VALIDATE A FLUORESCENCE-BASED PLATFORM FOR HIGH-THROUGHPUT AND COST-EFFECTIVE QUANTIFICATION OF GLOBAL GENOMIC 5-HMC LEVELS. WE UTILIZED THE ASSAY TO CHARACTERIZE CANCEROUS TISSUES BASED ON THEIR 5-HMC CONTENT, AND OBSERVED A PRONOUNCED REDUCTION IN 5-HMC LEVEL IN VARIOUS CANCER TYPES. WE PRESENT DATA FOR GLIOBLASTOMA, COLORECTAL CANCER, MULTIPLE MYELOMA, CHRONIC LYMPHOCYTIC LEUKEMIA AND PANCREATIC CANCER, COMPARED TO CORRESPONDING CONTROLS. POTENTIALLY, THE TECHNIQUE COULD ALSO BE USED TO FOLLOW RESPONSE TO TREATMENT FOR PERSONALIZED TREATMENT SELECTION. WE PRESENT INITIAL PROOF-OF-CONCEPT DATA FOR TREATMENT OF FAMILIAL ADENOMATOUS POLYPOSIS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  3140  47 GLOBAL EPIGENETIC SCREENING TECHNOLOGIES: A NOVEL TOOL TO ADDRESS CANCER HEALTH DISPARITIES IN HIGH-RISK POPULATION GROUPS. RACIAL, ETHNIC AND CLASS DISPARITIES IN CANCER INCIDENCE AND MORTALITY HAVE BEEN WELL DOCUMENTED. DISPARITIES IN THE UTILIZATION OF PREVENTIVE, CURATIVE AND TREATMENT SERVICES AMONG ETHNIC MINORITIES HAVE BEEN REPORTED. SCREENING CAN BE EFFECTIVE AT DETECTING CANCER AT TREATABLE STAGES, BUT A LARGE PROPORTION OF PEOPLE AT RISK HAVE NOT BEEN SCREENED OR ARE NOT REGULARLY SCREENED, AS RECOMMENDED BY THE AMERICAN CANCER SOCIETY'S NATIONAL GUIDELINES. EARLY DETECTION TECHNOLOGIES HAVE THE POTENTIAL OF BOTH INFLUENCING MORTALITY FROM CANCER, AS WELL AS ENHANCING PRIMARY PREVENTION THROUGH DETECTION AND REMOVAL OF LESIONS THAT COULD POTENTIALLY DEVELOP INTO CANCER. CANCER IS AN EPIGENETIC DISEASE CHARACTERIZED BY THE BREAKDOWN OF DNA METHYLATION AND HISTONES MODIFICATION PATTERNS. EPIGENETIC APPROACHES MAY CONTRIBUTE TO A REDUCTION IN CANCER HEALTH DISPARITIES IMPACTING EARLY DETECTION AND INCREASING CANCER TREATMENT OPTIONS. EPIGENETIC EVENTS REPRESENT IMPORTANT MECHANISM(S) BY WHICH GENE FUNCTION IS SELECTIVELY ACTIVATED OR INACTIVATED, THROUGH GENETIC AND NON-GENETIC MANIFESTATIONS. EMERGING EVIDENCE INDICATES THAT VARIOUS EPIGENETIC ALTERATIONS, SUCH AS GLOBAL HISTONES MODIFICATIONS AND DNA HYPOMETHYLATION, COMMON TO MOST TYPES OF CANCER, ARE MODIFIED BY ENVIRONMENTAL EXPOSURES THROUGHOUT THE LIFE COURSE. A SIMPLE, EASILY EXPLAINED AND EASY TO UNDERSTAND NON-INVASIVE TEST, SUCH AS THE DNA METHYLATION INDEX, THAT MAY SCREEN FOR SEVERAL CANCER SITES AT ONCE, MAY REMOVE SOME OF THE EXISTING BARRIERS TO CANCER SCREENING UTILIZATION, AND CONTRIBUTE TO THE REDUCTION OF CANCER DISPARITIES. EPIGENETIC APPROACHES MAY ALSO PROVE TO BE USEFUL IN IDENTIFYING ENVIRONMENTAL AND LIFESTYLE FACTORS THAT CONTRIBUTE TO THE PREVALENCE OF OTHER CHRONIC CONDITIONS IN HIGH RISK POPULATIONS, SUCH AS PUERTO RICAN POPULATIONS IN THE UNITED STATES AND PUERTO RICO.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
12  2015  40 EPIGENETIC BIOMARKERS IN ESOPHAGEAL CANCER. THE ABERRANT DNA METHYLATION OF TUMOR SUPPRESSOR GENES IS WELL DOCUMENTED IN ESOPHAGEAL CANCER, INCLUDING ADENOCARCINOMA (EAC) AND SQUAMOUS CELL CARCINOMA (ESCC) AS WELL AS IN BARRETT'S ESOPHAGUS (BE), A PRE-MALIGNANT CONDITION THAT IS ASSOCIATED WITH CHRONIC ACID REFLUX. BE IS A WELL-RECOGNIZED RISK FACTOR FOR THE DEVELOPMENT OF EAC, AND CONSEQUENTLY THE STANDARD OF CARE IS FOR INDIVIDUALS WITH BE TO BE PLACED IN ENDOSCOPIC SURVEILLANCE PROGRAMS AIMED AT DETECTING EARLY HISTOLOGIC CHANGES THAT ASSOCIATE WITH AN INCREASED RISK OF DEVELOPING EAC. YET BECAUSE THE ABSOLUTE RISK OF EAC IN INDIVIDUALS WITH BE IS MINIMAL, A CLINICAL NEED IN THE MANAGEMENT OF BE IS THE IDENTIFICATION OF ADDITIONAL RISK MARKERS THAT WILL INDICATE INDIVIDUALS WHO ARE AT A SIGNIFICANT ABSOLUTE RISK OF EAC SO THAT THEY MAY BE SUBJECTED TO MORE INTENSIVE SURVEILLANCE. THE BEST CURRENTLY AVAILABLE RISK MARKER IS THE DEGREE OF DYSPLASIA IN ENDOSCOPIC BIOPSIES FROM THE ESOPHAGUS; HOWEVER, THIS MARKER IS SUBOPTIMAL FOR A VARIETY OF REASONS. TO DATE, THERE ARE NO MOLECULAR BIOMARKERS THAT HAVE BEEN TRANSLATED TO WIDESPREAD CLINICAL PRACTICE. THE SEARCH FOR BIOMARKERS, INCLUDING HYPERMETHYLATED GENES, FOR EITHER THE DIAGNOSIS OF BE, EAC, OR ESCC OR FOR RISK STRATIFICATION FOR THE DEVELOPMENT OF EAC IN THOSE WITH BE IS CURRENTLY AN AREA OF ACTIVE RESEARCH. IN THIS REVIEW, WE SUMMARIZE THE STATUS OF IDENTIFIED CANDIDATE EPIGENETIC BIOMARKERS FOR BE, EAC, AND ESCC. MOST OF THESE ABERRANTLY METHYLATED GENES HAVE BEEN DESCRIBED IN THE CONTEXT OF EARLY DETECTION OR DIAGNOSTIC MARKERS; OTHERS MIGHT PROVE USEFUL FOR ESTIMATING PROGNOSIS OR PREDICTING RESPONSE TO TREATMENT. FINALLY, SPECIAL ATTENTION WILL BE PAID TO SOME OF THE CHALLENGES THAT MUST BE OVERCOME IN ORDER TO DEVELOP CLINICALLY USEFUL ESOPHAGEAL CANCER BIOMARKERS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  5706  51 SINGLE-MOLECULE QUANTIFICATION OF 5-HYDROXYMETHYLCYTOSINE FOR DIAGNOSIS OF BLOOD AND COLON CANCERS. BACKGROUND: THE DNA MODIFICATION 5-HYDROXYMETHYLCYTOSINE (5HMC) IS NOW REFERRED TO AS THE SIXTH BASE OF DNA WITH EVIDENCE OF TISSUE-SPECIFIC PATTERNS AND CORRELATION WITH GENE REGULATION AND EXPRESSION. THIS EPIGENETIC MARK WAS RECENTLY REPORTED AS A POTENTIAL BIOMARKER FOR MULTIPLE TYPES OF CANCER, BUT ITS APPLICATION IN THE CLINIC IS LIMITED BY THE UTILITY OF RECENT 5HMC QUANTIFICATION ASSAYS. WE USE A RECENTLY DEVELOPED, ULTRA-SENSITIVE, FLUORESCENCE-BASED SINGLE-MOLECULE METHOD FOR GLOBAL QUANTIFICATION OF 5HMC IN GENOMIC DNA. THE HIGH SENSITIVITY OF THE METHOD GIVES ACCESS TO PRECISE QUANTIFICATION OF EXTREMELY LOW 5HMC LEVELS COMMON IN MANY CANCERS. METHODS: WE ASSESSED 5HMC LEVELS IN DNA EXTRACTED FROM A SET OF COLON AND BLOOD CANCER SAMPLES AND COMPARED 5HMC LEVELS WITH HEALTHY CONTROLS, IN A SINGLE-MOLECULE APPROACH. RESULTS: USING OUR METHOD, WE OBSERVED A SIGNIFICANTLY REDUCED LEVEL OF 5HMC IN BLOOD AND COLON CANCERS AND COULD DISTINGUISH BETWEEN COLON TUMOR AND COLON TISSUE ADJACENT TO THE TUMOR BASED ON THE GLOBAL LEVELS OF THIS MOLECULAR BIOMARKER. CONCLUSIONS: SINGLE-MOLECULE DETECTION OF 5HMC ALLOWS DISTINGUISHING BETWEEN MALIGNANT AND HEALTHY TISSUE IN CLINICALLY RELEVANT AND ACCESSIBLE TISSUE SUCH AS BLOOD AND COLON. THE PRESENTED METHOD OUTPERFORMS CURRENT COMMERCIALLY AVAILABLE QUANTIFICATION KITS AND MAY POTENTIALLY BE DEVELOPED INTO A WIDELY USED, 5HMC QUANTIFICATION ASSAY FOR RESEARCH AND CLINICAL DIAGNOSTICS. FURTHERMORE, USING THIS METHOD, WE CONFIRM THAT 5HMC IS A GOOD MOLECULAR BIOMARKER FOR DIAGNOSING COLON AND VARIOUS TYPES OF BLOOD CANCER.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
14   250  44 ADVANCED GLYCATION END PRODUCTS (AGES): BIOCHEMISTRY, SIGNALING, ANALYTICAL METHODS, AND EPIGENETIC EFFECTS. THE ADVANCED GLYCATION END PRODUCTS (AGES) ARE ORGANIC MOLECULES FORMED IN ANY LIVING ORGANISMS WITH A GREAT VARIETY OF STRUCTURAL AND FUNCTIONAL PROPERTIES. THEY ARE CONSIDERED ORGANIC MARKERS OF THE GLYCATION PROCESS. DUE TO THEIR GREAT HETEROGENEITY, THERE IS NO SPECIFIC TEST FOR THEIR OPERATIONAL MEASUREMENT. IN THIS REVIEW, WE HAVE UPDATED THE MOST COMMON CHROMATOGRAPHIC, COLORIMETRIC, SPECTROSCOPIC, MASS SPECTROMETRIC, AND SEROLOGICAL METHODS, TYPICALLY USED FOR THE DETERMINATION OF AGES IN BIOLOGICAL SAMPLES. WE HAVE DESCRIBED THEIR SIGNALING AND SIGNAL TRANSDUCTION MECHANISMS AND CELL EPIGENETIC EFFECTS. ALTHOUGH MASS SPECTROMETRIC ANALYSIS IS NOT WIDESPREAD IN THE DETECTION OF AGES AT THE CLINICAL LEVEL, THIS TECHNIQUE IS HIGHLY PROMISING FOR THE EARLY DIAGNOSIS AND THERAPEUTICS OF DISEASES CAUSED BY AGES. PROTOCOLS ARE AVAILABLE FOR HIGH-RESOLUTION MASS SPECTROMETRY OF GLYCATED PROTEINS ALTHOUGH THEY ARE CHARACTERIZED BY COMPLEX MACHINE MANAGEMENT. SIMPLER PROCEDURES ARE AVAILABLE ALTHOUGH MUCH LESS PRECISE THAN MASS SPECTROMETRY. AMONG THEM, IMMUNOCHEMICAL TESTS ARE VERY COMMON SINCE THEY ARE ABLE TO DETECT AGES IN A SIMPLE AND IMMEDIATE WAY. IN THESE YEARS, NEW METHODOLOGIES HAVE BEEN DEVELOPED USING AN IN VIVO NOVEL AND NONINVASIVE SPECTROSCOPIC METHODS. THESE METHODS ARE BASED ON THE MEASUREMENT OF AUTOFLUORESCENCE OF AGES. ANOTHER METHOD CONSISTS OF DETECTING AGES IN THE HUMAN SKIN TO DETECT CHRONIC EXPOSURE, WITHOUT THE INCONVENIENCE OF INVASIVE METHODS. THE AIM OF THIS REVIEW IS TO COMPARE THE DIFFERENT APPROACHES OF MEASURING AGES AT A CLINICAL PERSPECTIVE DUE TO THEIR STRICT ASSOCIATION WITH OXIDATIVE STRESS AND INFLAMMATION.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
15  5486  44 REVERSE INFLAMMAGING: LONG-TERM EFFECTS OF HCV CURE ON BIOLOGICAL AGE. BACKGROUND & AIMS: CHRONIC HEPATITIS C VIRUS (HCV) INFECTION CAN BE CURED WITH DIRECT-ACTING ANTIVIRALS (DAAS). HOWEVER, NOT ALL SEQUELAE OF CHRONIC HEPATITIS C APPEAR TO BE COMPLETELY REVERSIBLE AFTER SUSTAINED VIROLOGIC RESPONSE (SVR). RECENTLY, CHRONIC VIRAL INFECTIONS HAVE BEEN SHOWN TO BE ASSOCIATED WITH BIOLOGICAL AGE ACCELERATION DEFINED BY THE EPIGENETIC CLOCK. THE AIM OF THIS STUDY WAS TO INVESTIGATE WHETHER CHRONIC HCV INFECTION IS ASSOCIATED WITH EPIGENETIC CHANGES AND BIOLOGICAL AGE ACCELERATION AND WHETHER THIS IS REVERSIBLE AFTER SVR. METHODS: WE INCLUDED 54 WELL-CHARACTERIZED INDIVIDUALS WITH CHRONIC HEPATITIS C WHO ACHIEVED SVR AFTER DAA THERAPY AT THREE TIME POINTS: DAA TREATMENT INITIATION, END OF TREATMENT, AND LONG-TERM FOLLOW-UP (MEDIAN 96 WEEKS AFTER END OF TREATMENT). GENOME-WIDE DNA METHYLATION STATUS WAS DETERMINED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND USED TO CALCULATE EPIGENETIC AGE ACCELERATION (EAA) USING HORVATH'S CLOCK. RESULTS: INDIVIDUALS WITH HCV HAD AN OVERALL SIGNIFICANT EAA OF 3.12 YEARS AT BASELINE COMPARED WITH -2.61 YEARS IN THE AGE- AND SEX-MATCHED REFERENCE GROUP (P <0.00003). HCV ELIMINATION RESULTED IN A SIGNIFICANT LONG-TERM INCREASE IN DNA METHYLATION DOMINATED BY HYPERMETHYLATED CPGS IN ALL PATIENT GROUPS. ACCORDINGLY, EAA DECREASED TO 1.37 YEARS AT LONG-TERM FOLLOW-UP. THE DECREASE IN EAA WAS SIGNIFICANT ONLY BETWEEN THE END OF TREATMENT AND FOLLOW-UP (P = 0.01). INTERESTINGLY, EIGHT INDIVIDUALS WHO DEVELOPED HEPATOCELLULAR CARCINOMA AFTER SVR HAD THE HIGHEST EAA AND SHOWED NO EVIDENCE OF REVERSAL AFTER SVR. CONCLUSIONS: OUR DATA CONTRIBUTE TO THE UNDERSTANDING OF THE BIOLOGICAL IMPACT OF HCV ELIMINATION AFTER DAA THERAPY AND DEMONSTRATE THAT HCV ELIMINATION CAN LEAD TO "REVERSE INFLAMMAGING". IN ADDITION, OUR DATA SUPPORT THE POTENTIAL USE OF BIOLOGICAL AGE AS A BIOMARKER FOR HCV SEQUELAE AFTER SVR. IMPACT AND IMPLICATIONS: CHRONIC HEPATITIS C VIRUS INFECTION IS NOW CURABLE WITH DIRECT-ACTING ANTIVIRALS, BUT IT REMAINS UNCLEAR WHETHER HEPATITIS C SEQUELAE ARE FULLY REVERSIBLE AFTER VIRAL ELIMINATION. OUR RESULTS SUGGEST THAT EPIGENETIC CHANGES OR ACCELERATION OF BIOLOGICAL AGE ARE REVERSIBLE IN PRINCIPLE, BUT THIS REQUIRES TIME, WHILE A LACK OF REVERSIBILITY APPEARS TO BE ASSOCIATED WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. WHILE MOST CLINICAL RISK SCORES NOW TAKE CHRONOLOGICAL AGE INTO ACCOUNT, IT MAY BE WORTHWHILE TO EXPLORE HOW BIOLOGICAL AGE MIGHT IMPROVE THESE SCORES IN THE FUTURE. BIOLOGICAL AGE MAY BE A CORNERSTONE FOR THE INDIVIDUALIZED CLINICAL ASSESSMENT OF PATIENTS IN THE FUTURE, AS IT BETTER REFLECTS PATIENTS' LIFESTYLE AND ENVIRONMENTAL EXPOSURES OVER DECADES.	2023	

16  5025  34 PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS. PERSONALIZED MANAGEMENT OF CARDIOVASCULAR DISORDERS (CVD), ALSO REFERRED TO AS PERSONALIZED OR PRECISION CARDIOLOGY IN ACCORDANCE WITH GENERAL PRINCIPLES OF PERSONALIZED MEDICINE, IS SELECTION OF THE BEST TREATMENT FOR AN INDIVIDUAL PATIENT. IT INVOLVES THE INTEGRATION OF VARIOUS "OMICS" TECHNOLOGIES SUCH AS GENOMICS AND PROTEOMICS AS WELL AS OTHER NEW TECHNOLOGIES SUCH AS NANOBIOTECHNOLOGY. MOLECULAR DIAGNOSTICS AND BIOMARKERS ARE IMPORTANT FOR LINKING DIAGNOSIS WITH THERAPY AND MONITORING THERAPY. BECAUSE CVD INVOLVE PERTURBATIONS OF LARGE COMPLEX BIOLOGICAL NETWORKS, A SYSTEMS BIOLOGY APPROACH TO CVD RISK STRATIFICATION MAY BE USED FOR IMPROVING RISK-ESTIMATING ALGORITHMS, AND MODELING OF PERSONALIZED BENEFIT OF TREATMENT MAY BE HELPFUL FOR GUIDING THE CHOICE OF INTERVENTION. BIOINFORMATICS TOOLS ARE HELPFUL IN ANALYZING AND INTEGRATING LARGE AMOUNTS OF DATA FROM VARIOUS SOURCES. PERSONALIZED THERAPY IS CONSIDERED DURING DRUG DEVELOPMENT, INCLUDING METHODS OF TARGETED DRUG DELIVERY AND CLINICAL TRIALS. INDIVIDUALIZED RECOMMENDATIONS CONSIDER MULTIPLE FACTORS - GENETIC AS WELL AS EPIGENETIC - FOR PATIENTS' RISK OF HEART DISEASE. EXAMPLES OF PERSONALIZED TREATMENT ARE THOSE OF CHRONIC MYOCARDIAL ISCHEMIA, HEART FAILURE, AND HYPERTENSION. SIMILAR APPROACHES CAN BE USED FOR THE MANAGEMENT OF ATRIAL FIBRILLATION AND HYPERCHOLESTEROLEMIA, AS WELL AS THE USE OF ANTICOAGULANTS. PERSONALIZED MANAGEMENT INCLUDES PHARMACOTHERAPY, SURGERY, LIFESTYLE MODIFICATIONS, AND COMBINATIONS THEREOF. FURTHER PROGRESS IN UNDERSTANDING THE PATHOMECHANISM OF COMPLEX CARDIOVASCULAR DISEASES AND IDENTIFICATION OF CAUSATIVE FACTORS AT THE INDIVIDUAL PATIENT LEVEL WILL PROVIDE OPPORTUNITIES FOR THE DEVELOPMENT OF PERSONALIZED CARDIOLOGY. APPLICATION OF PRINCIPLES OF PERSONALIZED MEDICINE WILL IMPROVE THE CARE OF THE PATIENTS WITH CVD.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
17    70  32 A METHOD TO DETECT DIFFERENTIALLY METHYLATED LOCI WITH NEXT-GENERATION SEQUENCING. EPIGENETIC CHANGES, ESPECIALLY DNA METHYLATION AT CPG LOCI HAVE IMPORTANT IMPLICATIONS IN CANCER AND OTHER COMPLEX DISEASES. WITH THE DEVELOPMENT OF NEXT-GENERATION SEQUENCING (NGS), IT IS FEASIBLE TO GENERATE DATA TO INTERROGATE THE DIFFERENCE IN METHYLATION STATUS FOR GENOME-WIDE LOCI USING CASE-CONTROL DESIGN. HOWEVER, A PROPER AND EFFICIENT STATISTICAL TEST IS LACKING. THERE ARE SEVERAL CHALLENGES. FIRST, UNLIKE METHYLATION EXPERIMENTS USING MICROARRAYS, WHERE THERE IS ONE MEASURE OF METHYLATION FOR ONE INDIVIDUAL AT A PARTICULAR CPG SITE, HERE WE HAVE THE COUNTS OF METHYLATION ALLELE AND UNMETHYLATION ALLELE FOR EACH INDIVIDUAL. SECOND, DUE TO THE NATURE OF SAMPLE PREPARATION, THE MEASURED METHYLATION REFLECTS THE METHYLATION STATUS OF A MIXTURE OF CELLS INVOLVED IN SAMPLE PREPARATION. THEREFORE, THE UNDERLYING DISTRIBUTION OF THE MEASURED METHYLATION LEVEL IS UNKNOWN, AND A ROBUST TEST IS MORE DESIRABLE THAN PARAMETRIC APPROACH. THIRD, CURRENTLY NGS MEASURES METHYLATION AT OVER 2 MILLION CPG SITES. ANY STATISTICAL TESTS HAVE TO BE COMPUTATIONALLY EFFICIENT IN ORDER TO BE APPLIED TO THE NGS DATA. TAKING THESE CHALLENGES INTO ACCOUNT, WE PROPOSE A TEST FOR DIFFERENTIAL METHYLATION BASED ON CLUSTERED DATA ANALYSIS BY MODELING THE METHYLATION COUNTS. WE PERFORMED SIMULATIONS TO SHOW THAT IT IS ROBUST UNDER SEVERAL DISTRIBUTIONS FOR THE MEASURED METHYLATION LEVELS. IT HAS GOOD POWER AND IS COMPUTATIONALLY EFFICIENT. FINALLY, WE APPLY THE TEST TO OUR NGS DATA ON CHRONIC LYMPHOCYTIC LEUKEMIA. THE RESULTS INDICATE THAT IT IS A PROMISING AND PRACTICAL TEST.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
18  3849  30 IS ERADICATION OF HELICOBACTER PYLORI THE FEASIBLE WAY TO PREVENT GASTRIC CANCER? NEW EVIDENCE AND PROGRESS, BUT STILL A LONG WAY TO GO. EPIDEMIOLOGICAL, ANIMAL AND BIOLOGICAL STUDIES PROVIDE COMPELLING EVIDENCE FOR THE ROLE OF HELICOBACTER PYLORI INFECTION IN GASTRIC CARCINOGENESIS. THE FINDING THAT H. PYLORI-INDUCED CHRONIC ATROPHIC GASTRITIS IS THE MAJOR CAUSE OF GASTRIC CANCER SUGGESTS THAT ERADICATION OF THE BACTERIUM MAY PREVENT THIS MALIGNANCY. COMPUTER-SIMULATION STUDIES HAVE CONFIRMED THE COST-EFFECTIVENESS OF ERADICATION IN HIGH-RISK SUBJECTS; HOWEVER, UNRESOLVED ISSUES COMPLICATE ACTIVE TESTING FOR AND TREATMENT OF H. PYLORI INFECTION AMONG ASYMPTOMATIC CARRIERS. CONCERNS INCLUDE THE ENORMOUS COSTS FOR DEVELOPING COUNTRIES TO IMPLEMENT STRATEGIES, THE INCONCLUSIVENESS OF DATA FROM RANDOMIZED CONTROLLED STUDIES, THE POTENTIAL INDUCTION OF ANTIMICROBIAL RESISTANCE, AND THE UNCERTAIN EFFECT OF ELIMINATING THIS ORGANISM ON THE SPECTRUM OF MODERN DISEASE. ALTHOUGH CURRENT EVIDENCE IS INSUFFICIENT TO RECOMMEND UNIVERSAL TESTING AND TREATMENT, IT IS POSSIBLE TO IDENTIFY HIGHLY SUSCEPTIBLE INDIVIDUALS WHO ARE MOST LIKELY TO BENEFIT FROM TREATMENT. NOVEL BIOMARKERS FOR PREDICTING RISK ARE UNDER EXTENSIVE INVESTIGATION, INCLUDING GENETIC, EPIGENETIC AND PROTEINOMIC FACTORS. THE EMERGING EVIDENCE SUGGESTS THAT TREATMENT OF H. PYLORI INFECTION IN ASYMPTOMATIC CARRIERS MAY DECREASE THE BURDEN OF GASTRIC CANCER. HOWEVER, CONFIRMATION OF LONG-TERM BENEFITS REMAINS A LONG WAY OFF.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
19  4751  36 NOVEL RISK MARKERS FOR GASTRIC CANCER SCREENING: PRESENT STATUS AND FUTURE PROSPECTS. INITIAL IDENTIFICATION OF POPULATIONS AT HIGH RISK OF GASTRIC CANCER (GC) IS IMPORTANT FOR ENDOSCOPIC SCREENING OF GC. AS SERUM PEPSINOGEN (PG) TEST-POSITIVE SUBJECTS WITH PROGRESSION OF CHRONIC ATROPHIC GASTRITIS (CAG) SHOW A HIGH LIKELIHOOD OF FUTURE CANCER DEVELOPMENT, THIS POPULATION WARRANTS CAREFUL FOLLOW-UP OBSERVATION AS A HIGH-RISK GC GROUP. BY COMBINING THE PG TEST WITH HELICOBACTER PYLORI (HP) ANTIBODY TITERS, THE HP-RELATED CHRONIC GASTRITIS STAGE CAN BE CLASSIFIED, THUS IDENTIFYING NOT ONLY A GC HIGH-RISK GROUP BUT ALSO A LOW-RISK GROUP. AMONG PG TEST-NEGATIVE PATIENTS WITHOUT CAG, THOSE WITH HIGH SERUM PG II LEVELS AND HP ANTIBODY TITERS ARE THOUGHT TO HAVE SEVERE GASTRIC MUCOSAL INFLAMMATION AND THE RISK OF DIFFUSE-TYPE GC IS ALSO HIGH. MEANWHILE, IN GASTRIC MUCOSAE OBTAINED BY ENDOSCOPIC BIOPSY, HP INFECTION INDUCES ABERRANT DNA METHYLATION IN CPG ISLANDS IN MULTIPLE GENE REGIONS AND THE EXTENT OF METHYLATION CLEARLY CORRELATES WITH GC RISK. BY QUANTIFYING ABERRANT DNA METHYLATION IN SUITABLE GENE MARKERS, WE CAN DETERMINE THE EXTENT OF THE EPIGENETIC FIELD FOR CANCERIZATION. THESE NOVEL CONCEPTS AND RISK MARKERS WILL HAVE MANY CLINICAL APPLICATIONS IN GASTROINTESTINAL ENDOSCOPY, INCLUDING MORE EFFICIENT ENDOSCOPIC GC SCREENING AND A STRATEGIC APPROACH TO METACHRONOUS MULTIPLE GCS AFTER ENDOSCOPIC TREATMENT.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
20  6386  41 THE ROLE OF QUANTITATIVE NPTX2 HYPERMETHYLATION AS A NOVEL SERUM DIAGNOSTIC MARKER IN PANCREATIC CANCER. OBJECTIVES: THE MAJORITY OF PANCREATIC CANCERS ARE FOUND TO BE UNRESECTABLE, AND THE ONLY CHANCE FOR CURE LIES ON EARLY DETECTION AND COMPLETE RESECTION. SEVERAL GENES HAVE BEEN DISCOVERED TO BE ABERRANTLY METHYLATED IN PRIMARY PANCREATIC CANCER TISSUE, AND THIS CANCER DNA CAN BE DETECTED IN THE PLASMA. THE AIMS OF THIS STUDY WERE TO DEVELOP A NOVEL DIAGNOSTIC MARKER BASED ON EPIGENETIC CHARACTERISTICS OF PANCREATIC CANCER. METHODS: WE ENROLLED 104 PATIENTS WITH PANCREATIC CANCER, 60 WITH CHRONIC PANCREATITIS, AND 5 WITH BENIGN BILIARY STONE DISEASES. THE BLOOD SAMPLES WERE COLLECTED BEFORE SURGERY OR ANY KINDS OF TREATMENT MODALITIES. DNA WAS EXTRACTED FROM THE PLASMA OF EACH PATIENT, AND NPTX2 (NEURONAL PENTRAXIN II) CPG ISLAND HYPERMETHYLATION WAS EXAMINED QUANTITATIVELY BY REAL-TIME POLYMERASE CHAIN REACTION. RESULTS: NPTX2 HYPERMETHYLATION LEVELS WERE SIGNIFICANTLY HIGHER COMPARED WITH CHRONIC PANCREATITIS (P = 0.016). THE SENSITIVITY AND SPECIFICITY WERE 80% AND 76%, RESPECTIVELY (CUTOFF = 0.015). NPTX2 GENE HYPERMETHYLATION LEVEL WAS SIGNIFICANTLY ELEVATED IN CORRELATION WITH HIGHER AMERICAN JOINT COMMITTEE ON CANCER STAGES. CONCLUSIONS: THE ABERRANTLY METHYLATED NPTX2 GENE MAY HELP TO DISTINGUISH BETWEEN CHRONIC PANCREATITIS AND PANCREATIC CANCER WITH CONVENTIONAL DIAGNOSTIC TOOLS AND COULD BECOME A VALUABLE DIAGNOSTIC MARKER.	2012