1 1673 148 DRIVER GENE MUTATIONS AND EPIGENETICS IN COLORECTAL CANCER. OBJECTIVE: THE MAJORITY OF PATIENTS WITH COLORECTAL CANCER ARE DIAGNOSED WITH LOCALLY ADVANCED AND/OR DISSEMINATED DISEASE, AND TREATMENT OPTIONS INCLUDE SURGERY IN COMBINATION WITH CYTOTOXIC CHEMOTHERAPY REGIMENS, BIOLOGICS, AND/OR RADIOTHERAPY. THUS, COLORECTAL CANCER REMAINS A HEAVY BURDEN ON SOCIETY AND HEALTH CARE SYSTEMS.MOUNTING EVIDENCE SHOW THAT DRIVER GENE MUTATIONS PLAY ONLY PART OF THE ROLE IN CARCINOGENESIS. EPIGENETICS ARE STRONGLY IMPLICATED IN INITIATION AND PROGRESSION OF COLORECTAL CANCER ALONG WITH MAJOR PLAYERS SUCH AS INTESTINAL MICROBIOTIC DYSBIOSIS AND CHRONIC MUCOSAL INFLAMMATION.TO ASSESS PHENOTYPIC CHANGES IN PROTEINS AND GENE EXPRESSION, MULTIGENE EXPRESSION SIGNATURES BASED ON SEQUENCING TECHNIQUES HAVE BEEN DEVELOPED TO HOPEFULLY IMPROVE PREDICTORS OF THE TUMOR PROFILE, IMMUNE RESPONSE, AND THERAPEUTIC OUTCOMES. OUR OBJECTIVE WAS TO REVIEW CURRENT ADVANCES IN THE FIELD AND TO UPDATE SURGEONS AND ACADEMICS ON DRIVER GENE MUTATIONS AND EPIGENETICS IN COLORECTAL CANCER. BACKGROUND AND METHODS: THIS IS A NARRATIVE REVIEW STUDYING RELEVANT RESEARCH PUBLISHED IN THE PUBMED DATABASE FROM 2012-2018. RESULTS AND CONCLUSION: INCREASED UNDERSTANDING OF THE MOLECULAR BIOLOGY WILL IMPROVE OPTIONS TO CHARACTERIZE COLORECTAL CANCER WITH REGARD TO MUTATIONS AND MOLECULAR PATHWAYS, INCLUDING MICROSATELLITE INSTABILITY, EPIGENETICS, MICROBIOTA, AND MICROENVIRONMENT. RESEARCH WILL INEVITABLY IMPROVE RISK GROUP STRATIFICATION AND TARGETED TREATMENT APPROACHES.EPIGENETIC PROFILING AND EPIGENETIC MODULATING DRUGS WILL INCREASE RISK STRATIFICATION, INCREASE ACCESSIBILITY FOR DNA TARGETING CHEMOTHERAPEUTICS AND REDUCE CYTOTOXIC DRUG RESISTANCE.NEW GENERATION ANTIBIOTICS SUCH AS BIOFILM INHIBITORS AND QUORUM SENSING INHIBITORS ARE BEING DEVELOPED TO TARGET THE CARCINOGENETIC IMPACT OF COLONIC DYSBIOSIS AND INFLAMMATION. 2020 2 1522 45 DNA METHYLATION CHANGE PROFILING OF COLORECTAL DISEASE: SCREENING TOWARDS CLINICAL USE. COLON CANCER REMAINS ONE OF THE LEADING CAUSES OF CANCER-RELATED DEATHS WORLDWIDE. TRANSFORMATION OF COLON EPITHELIAL CELLS INTO INVASIVE ADENOCARCINOMAS HAS BEEN WELL KNOWN TO BE DUE TO THE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC CHANGES. IN THE PAST DECADE, THE ETIOLOGY OF INFLAMMATORY BOWEL DISEASE (IBD) WHICH IS CHARACTERIZED BY CHRONIC INFLAMMATION OF THE INTESTINAL MUCOSA, WAS ONLY PARTIALLY EXPLAINED BY GENETIC STUDIES PROVIDING SUSCEPTIBILITY LOCI, BUT RECENTLY EPIGENETIC STUDIES HAVE PROVIDED CRITICAL EVIDENCES AFFECTING IBD PATHOGENESIS. OVER THE PAST DECADE, A DEEP UNDERSTANDING OF EPIGENETICS ALONG WITH TECHNOLOGICAL ADVANCES HAVE LED TO IDENTIFYING NUMEROUS GENES THAT ARE REGULATED BY PROMOTER DNA HYPERMETHYLATION IN COLORECTAL DISEASES. RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF DNA METHYLATION IN COLORECTAL DISEASES COULD IMPROVE A MULTITUDE OF POWERFUL DNA METHYLATION-BASED BIOMARKERS, PARTICULARLY FOR USE AS DIAGNOSIS, PROGNOSIS, AND PREDICTION FOR THERAPEUTIC APPROACHES. THIS REVIEW FOCUSES ON THE EMERGING POTENTIAL FOR TRANSLATIONAL RESEARCH OF EPIGENETIC ALTERATIONS INTO CLINICAL UTILITY AS MOLECULAR BIOMARKERS. MOREOVER, THIS REVIEW DISCUSSES RECENT PROGRESS REGARDING THE IDENTIFICATION OF UNKNOWN HYPERMETHYLATED GENES IN COLON CANCERS AND IBD, AS WELL AS THEIR POSSIBLE ROLE IN CLINICAL PRACTICE, WHICH WILL HAVE IMPORTANT CLINICAL SIGNIFICANCE, PARTICULARLY IN THE ERA OF THE PERSONALIZED MEDICINE. 2021 3 3697 32 INFLAMMATORY MARKERS IN CANCER: POTENTIAL RESOURCES. CANCER IS A LEADING CAUSE OF DEATH WORLDWIDE AND A MAJOR BURDEN ON DEVELOPING AND LESS DEVELOPED COUNTRIES OF THE WORLD WITH LIMITED RESOURCES FOR PREVENTION AND EFFECTIVE TREATMENT OF CANCER. ALTHOUGH CANCER IS MULTIFACTORIAL IN ORIGIN, VARIOUS EPIDEMIOLOGICAL AND EXPERIMENTAL STUDIES SUGGEST THAT CHRONIC INFLAMMATION HAS AN IMPORTANT ROLE IN ALL STAGES OF CANCER, FROM INITIATION TO PROGRESSION AND EVEN SURVIVAL OF THE PATIENT. INFLAMMATORY PRODUCTS LIKE CYTOKINES, CHEMOKINES, LEUCOCYTES, PROSTAGLANDINS, CYCLOOXYGENASE, REACTIVE OXYGEN AND NITROGEN SPECIES, METALLOPROTEINASE INDUCE GENETIC AND EPIGENETIC CHANGES IN NORMAL CELLS DAMAGING ITS DNA, INHIBITING ITS REPAIR, ALTERING TRANSCRIPTION FACTORS, PREVENTING APOPTOSIS, AND STIMULATING ANGIOGENESIS, AND THUS RESULTING IN CARCINOGENESIS. THUS, THESE INFLAMMATORY MEDIATORS HAVE A POTENTIAL ROLE TO BECOME CANCER BIOMARKERS FOR ALL STAGES OF CANCER AS MANY OF THEM CAN BE MEASURED IN A COST-EFFECTIVE MANNER. HOWEVER, LARGE SCALE PROSPECTIVE TRIALS ARE REQUIRED TO VALIDATE THESE POTENTIAL CANCER BIOMARKERS. NONETHELESS, A TRANSITION FROM POTENTIAL TO PRACTICAL UTILIZATION OF THESE MARKERS WILL BE AN EFFECTIVE TOOL FOR THE AMELIORATION OF CANCER BURDEN AND MORTALITY IN A RESOURCE LIMITED SETTING. 2020 4 4429 36 MOLECULAR BIOLOGY AS A TOOL FOR THE TREATMENT OF CANCER. CANCER IS A GENETIC DISEASE CHARACTERIZED BY UNCONTROLLED CELL GROWTH AND METASTASIS. CANCER CAN HAVE A NUMBER OF CAUSES, SUCH THE ACTIVATION OF ONCOGENES, THE INACTIVATION OF TUMOR-SUPPRESSING GENES, MUTAGENESIS PROVOKED BY EXTERNAL FACTORS, AND EPIGENETIC MODIFICATIONS. THE DEVELOPMENT OF DIAGNOSTIC TOOLS AND TREATMENTS USING A MOLECULAR BIOLOGICAL APPROACH PERMITS THE USE OF SENSITIVE, LOW-COST, NONINVASIVE TESTS FOR CANCER PATIENTS. BIOMARKERS CAN BE USED TO PROVIDE RAPID, PERSONALIZED ONCOLOGY, IN PARTICULAR THE MOLECULAR DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA, AND GASTRIC, COLON, AND BREAST CANCERS. MOLECULAR TESTS BASED ON DNA METHYLATION CAN ALSO BE USED TO DIRECT TREATMENTS OR EVALUATE THE TOXIC EFFECTS OF CHEMOTHERAPY. THE ADEQUATE DIAGNOSIS, PROGNOSIS, AND PREDICTION OF THE RESPONSE OF CANCER PATIENTS TO TREATMENT ARE ESSENTIAL TO ENSURE THE MOST EFFECTIVE THERAPY, REDUCE THE DAMAGING EFFECTS OF TREATMENT, AND DIRECT THE THERAPY TO SPECIFIC TARGETS, AND IN THIS CONTEXT, MOLECULAR BIOLOGY HAS BECOME INCREASINGLY IMPORTANT IN ONCOLOGY. IN THIS BRIEF REVIEW, WE WILL DEMONSTRATE THE FUNDAMENTAL IMPORTANCE OF MOLECULAR BIOLOGY FOR THE TREATMENT OF THREE TYPES OF CANCER-CHRONIC MYELOID LEUKEMIA, HEREDITARY DIFFUSE GASTRIC CANCER, AND ASTROCYTOMAS (SPORADIC TUMORS OF THE CENTRAL NERVOUS SYSTEM). IN EACH OF THESE THREE MODELS, DISTINCT BIOLOGICAL MECHANISMS ARE INVOLVED IN THE TRANSFORMATION OF THE CELLS, BUT IN ALL CASES, MOLECULAR BIOLOGY IS FUNDAMENTAL TO THE DEVELOPMENT OF PERSONALIZED ANALYSES FOR EACH PATIENT AND EACH TYPE OF NEOPLASIA, AND TO GUARANTEE THE SUCCESS OF THE TREATMENT. 2018 5 1168 48 CONTRIBUTION OF EPITHELIAL AND GUT MICROBIOME INFLAMMATORY BIOMARKERS TO THE IMPROVEMENT OF COLORECTAL CANCER PATIENTS' STRATIFICATION. IN ORDER TO ENSURE THAT PRIMARY ENDPOINTS OF CLINICAL STUDIES ARE ATTAINED, THE PATIENTS' STRATIFICATION IS AN IMPORTANT ASPECT. SELECTION CRITERIA INCLUDE AGE, GENDER, AND ALSO SPECIFIC BIOMARKERS, SUCH AS INFLAMMATION SCORES. THESE CRITERIA ARE NOT SUFFICIENT TO ACHIEVE A STRAIGHTFORWARD SELECTION, HOWEVER, IN CASE OF MULTIFACTORIAL DISEASES, WITH UNKNOWN OR PARTIALLY IDENTIFIED MECHANISMS, OCCASIONALLY INCLUDING HOST FACTORS, AND THE MICROBIOME. IN THESE CASES, THE EFFICACY OF INTERVENTIONS IS DIFFICULT TO PREDICT, AND AS A RESULT, THE SELECTION OF SUBJECTS IS OFTEN RANDOM. COLORECTAL CANCER (CRC) IS A HIGHLY HETEROGENEOUS DISEASE, WITH VARIABLE CLINICAL FEATURES, OUTCOMES, AND RESPONSE TO THERAPY; THE CRC ONSET AND PROGRESS INVOLVES MULTIPLE SEQUENTIAL STEPS WITH ACCUMULATION OF GENETIC ALTERATIONS, NAMELY, MUTATIONS, GENE AMPLIFICATION, AND EPIGENETIC CHANGES. THE GUT MICROBES, EITHER EUBIOTIC OR DYSBIOTIC, COULD INFLUENCE THE CRC EVOLUTION THROUGH A COMPLEX AND VERSATILE CROSSTALK WITH THE INTESTINAL AND IMMUNE CELLS, PERMANENTLY CHANGING THE TUMOR MICROENVIRONMENT. THERE HAVE BEEN SIGNIFICANT ADVANCES IN THE DEVELOPMENT OF PERSONALIZED APPROACHES FOR CRC SCREENING, TREATMENT, AND POTENTIAL PREVENTION. ADVANCES IN MOLECULAR TECHNIQUES BRING NEW CRITERIA FOR PATIENTS' STRATIFICATION-MUTATIONAL ANALYSIS AT THE TIME OF DIAGNOSIS TO GUIDE TREATMENT, FOR EXAMPLE. GUT MICROBIOME HAS EMERGED AS THE MAIN TRIGGER OF GUT MUCOSAL HOMEOSTASIS. THIS MAY IMPACT CANCER SUSCEPTIBILITY THROUGH MAINTENANCE OF THE EPITHELIAL/MUCUS BARRIER AND PRODUCTION OF PROTECTIVE METABOLITES, SUCH AS SHORT-CHAIN FATTY ACIDS (SCFAS) VIA INTERACTIONS WITH THE HOSTS' DIET AND METABOLISM. MICROBIOME DYSBIOSIS LEADS TO THE ENRICHMENT OF CANCER-PROMOTING BACTERIAL POPULATIONS, LOSS OF PROTECTIVE POPULATIONS OR MAINTAINING AN INFLAMMATORY CHRONIC STATE, ALL OF WHICH CONTRIBUTE TO THE DEVELOPMENT AND PROGRESSION OF CRC. MEANWHILE, VARIATIONS IN PATIENT RESPONSES TO ANTI-CANCER IMMUNO- AND CHEMOTHERAPIES WERE ALSO LINKED TO INTER-INDIVIDUAL DIFFERENCES IN INTESTINE MICROBIOMES. THE AUTHORS AIM TO HIGHLIGHT THE CONTRIBUTION OF EPITHELIAL AND GUT MICROBIOME INFLAMMATORY BIOMARKERS IN THE IMPROVEMENT OF CRC PATIENTS' STRATIFICATION TOWARDS A PERSONALIZED APPROACH OF EARLY DIAGNOSIS AND TREATMENT. 2021 6 6675 32 USING EPIGENETIC THERAPY TO OVERCOME CHEMOTHERAPY RESISTANCE. IT HAS BEEN KNOWN FOR DECADES THAT AS CANCER PROGRESSES, TUMORS DEVELOP GENETIC ALTERATIONS, MAKING THEM HIGHLY PRONE TO DEVELOPING RESISTANCE TO THERAPIES. CLASSICALLY, IT HAS BEEN THOUGHT THAT THESE ACQUIRED GENETIC CHANGES ARE FIXED. THIS HAS LED TO THE PARADIGM OF MOVING FROM ONE CANCER THERAPY TO THE NEXT WHILE AVOIDING PAST THERAPIES. HOWEVER, EMERGING DATA ON EPIGENETIC CHANGES DURING TUMOR PROGRESSION AND USE OF EPIGENETIC THERAPIES HAVE SHOWN THAT EPIGENETIC MODIFICATIONS LEADING TO CHEMOTHERAPY RESISTANCE HAVE THE POTENTIAL TO BE REVERSIBLE WITH EPIGENETIC THERAPY. IN FACT, PROMISING CLINICAL DATA EXIST THAT TREATMENT WITH EPIGENETIC AGENTS CAN DIMINISH CHEMOTHERAPY RESISTANCE IN A NUMBER OF TUMOR TYPES INCLUDING CHRONIC MYELOGENOUS LEUKEMIA, COLORECTAL, OVARIAN, LUNG AND BREAST CANCER. THE POTENTIAL FOR EPIGENETIC-MODIFYING DRUGS TO ALLOW FOR TREATMENT OF RESISTANT DISEASE IS EXCITING AND CLINICAL TRIALS HAVE JUST BEGUN TO EVALUATE THIS AREA. 2016 7 6325 34 THE ROLE OF ANTI-INFLAMMATORY DRUGS IN COLORECTAL CANCER. A LARGE BODY OF EVIDENCE INDICATES THAT GENETIC MUTATIONS, EPIGENETIC CHANGES, CHRONIC INFLAMMATION, DIET, AND LIFESTYLE ARE KEY RISK FACTORS FOR COLORECTAL CANCER (CRC). PREVENTION OF CRC HAS LONG BEEN CONSIDERED A PLAUSIBLE APPROACH FOR THE POPULATION AND INDIVIDUALS AT HIGH RISK FOR DEVELOPING THIS DISEASE. A SIGNIFICANT EFFORT HAS BEEN MADE IN THE DEVELOPMENT OF NOVEL DRUGS FOR BOTH PREVENTION AND TREATMENT OVER THE PAST TWO DECADES. THIS REVIEW HIGHLIGHTS RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS IN CRC PREVENTION AND ADJUVANT TREATMENT. MOREOVER, WE FOCUS ON THE MOLECULAR MECHANISMS UNDERLYING THE ANTITUMOR EFFECTS OF THESE DRUGS IN CRC. THE KNOWLEDGE OF HOW ANTI-INFLAMMATORY AGENTS INHIBIT CANCER FORMATION AND PROGRESSION MAY PROVIDE A RATIONALE FOR THE DEVELOPMENT OF MORE EFFECTIVE CHEMOPREVENTIVE AND CHEMOTHERAPEUTIC AGENTS WITH LESS TOXICITY. 2013 8 1958 29 EPIGENETIC AGING AND COLORECTAL CANCER: STATE OF THE ART AND PERSPECTIVES FOR FUTURE RESEARCH. ALTHOUGH TRANSLATIONAL RESEARCH HAS IDENTIFIED A LARGE NUMBER OF POTENTIAL BIOMARKERS INVOLVED IN COLORECTAL CANCER (CRC) CARCINOGENESIS, A BETTER UNDERSTANDING OF THE MOLECULAR PATHWAYS ASSOCIATED WITH BIOLOGICAL AGING IN COLORECTAL CELLS AND TISSUES IS NEEDED. HERE, WE AIM TO SUMMARIZE THE STATE OF THE ART ABOUT THE ROLE OF AGE ACCELERATION, DEFINED AS THE DIFFERENCE BETWEEN EPIGENETIC AGE AND CHRONOLOGICAL AGE, IN THE DEVELOPMENT AND PROGRESSION OF CRC. SOME STUDIES HAVE SHOWN THAT ACCELERATED BIOLOGICAL AGING IS POSITIVELY ASSOCIATED WITH THE RISK OF CANCER AND DEATH IN GENERAL. IN LINE WITH THESE FINDINGS, OTHER STUDIES HAVE SHOWN HOW THE ASSESSMENT OF EPIGENETIC AGE IN PEOPLE AT RISK FOR CRC COULD BE HELPFUL FOR MONITORING THE MOLECULAR RESPONSE TO PREVENTIVE INTERVENTIONS. MOREOVER, IT WOULD BE INTERESTING TO INVESTIGATE WHETHER ABERRANT EPIGENETIC AGING COULD HELP IDENTIFY CRC PATIENTS WITH A HIGH RISK OF RECURRENCE AND A WORST PROGNOSIS, AS WELL AS THOSE WHO RESPOND POORLY TO TREATMENT. YET, THE APPLICATION OF THIS NOVEL CONCEPT IS STILL IN ITS INFANCY, AND FURTHER RESEARCH SHOULD BE ENCOURAGED IN ANTICIPATION OF FUTURE APPLICATIONS IN CLINICAL PRACTICE. 2020 9 5913 31 TARGETED THERAPY IN LEUKEMIA. RESEARCH CONDUCTED OVER THE LAST TWO DECADES HAS YIELDED A DETAILED UNDERSTANDING OF THE MOLECULAR LESIONS THAT CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF HEMATOPOIETIC STEM CELLS AND COMMITTED PROGENITORS INTO THE VARIOUS FORMS OF ACUTE AND CHRONIC LEUKEMIA. ALTHOUGH OUR UNDERSTANDING OF THE MOLECULAR PATHOLOGY OF LEUKEMIA REMAINS INCOMPLETE, THE INFORMATION GAINED TO DATE HAS HAD A PROFOUND IMPACT ON THE WAY THESE MALIGNANCIES ARE BOTH DIAGNOSED AND MONITORED DURING THERAPY. MORE RECENTLY, TARGETED THERAPIES HAVE BEEN DEVELOPED AGAINST SOME OF THE IDENTIFIED GENETIC LESIONS. THESE THERAPIES HAVE LED TO SIGNIFICANT IMPROVEMENTS IN PATIENT OUTCOMES WHILE SIMULTANEOUSLY DECREASING THERAPY-RELATED TOXICITY. WITH THE ADVENT OF GENOME-WIDE METHODS TO DEFINE THE TOTAL COMPLEMENT OF GENETIC AND EPIGENETIC LESIONS INVOLVED IN LEUKEMOGENESIS, NEW TARGETED THERAPIES CAN BE ANTICIPATED. THIS REVIEW HIGHLIGHTS SOME OF THE TARGETED THERAPIES THAT ARE PRESENTLY BEING USED TO TREAT HEMATOPOIETIC MALIGNANCIES AND DESCRIBES SOME OF THE RECENT ADVANCES THAT SHOULD HAVE A SIGNIFICANT IMPACT ON THE DEVELOPMENT OF FUTURE TARGET THERAPIES. 2008 10 3683 38 INFLAMMATION, MICROBIOTA, AND PROSTATE CANCER. CONTEXT: CHRONIC INFLAMMATION OF THE PROSTATE HAS BEEN ASSOCIATED WITH PRENEOPLASTIC LESIONS AND CANCER DEVELOPMENT. MULTIPLE CAUSES HAVE BEEN CONSIDERED FOR CHRONIC INFLAMMATION OF THE PROSTATE. INFLAMMATORY CYTOKINES SUCH AS INTERLEUKINS ARE IMPLICATED IN PROSTATE CARCINOGENESIS AND DEVELOPMENT. OBJECTIVE: TO EVALUATE LITERATURE PUBLISHED ON ETIOLOGICAL FACTORS, URINARY MICROBIOTA, MORPHOLOGICAL FEATURES OF PROLIFERATIVE INFLAMMATORY ATROPHY AND HIGH-GRADE PROSTATE INTRAEPITHELIAL NEOPLASIA, GENETIC POLYMORPHISMS, INFLAMMATORY STRESS, AND CYTOKINE SIGNALING. EVIDENCE ACQUISITION: WE SEARCHED LITERATURE FROM PUBMED FROM 2010 AND ALSO INCLUDED THE MOST IMPORTANT PUBLICATIONS FROM THE PREVIOUS PERIOD. EVIDENCE SYNTHESIS: PROSTATE CANCER INFLAMMATION AND PREMALIGNANT LESIONS HAVE BEEN FREQUENTLY DISCUSSED IN SCIENTIFIC LITERATURE. A LIMITED NUMBER OF MODELS ARE AVAILABLE FOR STUDYING INFLAMMATION AND PREMALIGNANT LESIONS. HOWEVER, MORPHOLOGICAL PATHOLOGY COULD BE COMPLEMENTED BY ANALYSIS OF GENE POLYMORPHISMS IN THESE PATIENTS AND APPROPRIATE FUNCTIONAL STUDIES. CONCLUSIONS: PROSTATITIS COULD BE CAUSED BY BACTERIAL OR VIRAL INFECTIONS, DIETARY COMPOUNDS, AND CHANGES IN TESTOSTERONE:ESTRADIOL RATIO. IN SOME CASES, THE MICROBIOTA CAN EXERT DIRECT EFFECTS ON CANCER DEVELOPMENT. PROSTATE INFLAMMATORY ATROPHY OR HIGH GRADE PROSTATE INTRAEPITHELIAL NEOPLASIA HAVE BEEN ASSOCIATED WITH RESPONSE TO CELLULAR STRESS AND HAVE BEEN DISCUSSED IN CONNECTION TO EARLY CANCER DEVELOPMENT. A LARGE NUMBER OF GENETIC POLYMORPHISMS HAVE BEEN IDENTIFIED IN INFLAMMATORY PROSTATE. GENETIC AND EPIGENETIC ALTERATIONS MAY BE A CONSEQUENCE OF THE PROINFLAMMATORY STRESS IN THE PROSTATE. PROINFLAMMATORY CYTOKINES INTERLEUKIN-6 AND -8 CONTRIBUTE TO PROSTATE MALIGNANCY; HOWEVER, THEIR FUNCTION WAS MORE FREQUENTLY INVESTIGATED IN CANCER TISSUE RATHER THAN IN INFLAMMATION. PATIENT SUMMARY: WE PERFORMED A REVIEW OF RECENT LITERATURE RELATED TO PROSTATE INFLAMMATION, MICROBIOTA, AND PROSTATE CANCER. NEW FUNCTIONAL APPROACHES ARE REQUIRED FOR A BETTER UNDERSTANDING OF THE ROLE OF INFLAMMATION AND CANCER DEVELOPMENT. 2016 11 4800 43 OBESITY AND INFLAMMATION: COLORECTAL CANCER ENGINES. THE PREVALENCE OF OBESITY CONTINUES TO INCREASE TO THE EXTENT THAT IT BECAME A WORLDWIDE PANDEMIC. AN ACCUMULATING BODY OF EVIDENCE HAS ASSOCIATED OBESITY WITH THE DEVELOPMENT OF DIFFERENT TYPES OF CANCER, INCLUDING COLORECTAL CANCER, WHICH IS A NOTORIOUS DISEASE WITH A HIGH MORTALITY RATE. AT THE MOLECULAR LEVEL, COLORECTAL CANCER IS A HETEROGENOUS DISEASE CHARACTERIZED BY A MYRIAD OF GENETIC AND EPIGENETIC ALTERATIONS ASSOCIATED WITH VARIOUS FORMS OF GENOMIC INSTABILITY (DETAILED IN SUPPLEMENTARY MATERIALS). RECENTLY, THE MICROENVIRONMENT HAS EMERGED AS A MAJOR FACTOR IN CARCINOGENESIS. OUR AIM IS TO DEFINE THE DIFFERENT MOLECULAR ALTERATIONS LEADING TO THE DEVELOPMENT OF COLORECTAL CANCER IN OBESE PATIENTS WITH A FOCUS ON THE ROLE OF THE MICROENVIRONMENT IN CARCINOGENESIS. WE ALSO HIGHLIGHT ALL EXISTENT MOLECULES IN CLINICAL TRIALS THAT TARGET THE ACTIVATED PATHWAYS IN OBESITY-ASSOCIATED COLORECTAL CANCER, WHETHER USED AS SINGLE TREATMENTS OR IN COMBINATION. OBESITY PREDISPOSES TO COLORECTAL CANCER VIA CREATING A STATE OF CHRONIC INFLAMMATION WITH DYSREGULATED ADIPOKINES, INFLAMMATORY MEDIATORS, AND OTHER FACTORS SUCH AS IMMUNE CELL INFILTRATION. A UNIFYING THEME IN OBESITY-MEDIATED COLORECTAL CANCER IS THE ACTIVATION OF THE PI3K/AKT, MTOR/MAPK, AND STAT3 SIGNALING PATHWAYS. DIFFERENT INHIBITORY MOLECULES TOWARDS THESE PATHWAYS EXIST, INCREASING THE THERAPEUTIC CHOICE OF OBESITY-ASSOCIATED COLON CANCER. HOWEVER, OBESE PATIENTS ARE MORE LIKELY TO SUFFER FROM CHEMOTHERAPY OVERDOSING. PREVENTING OBESITY THROUGH MAINTAINING A HEALTHY AND ACTIVE LIFESTYLE REMAINS TO BE THE BEST REMEDY. 2022 12 2704 26 EXERCISE AND COLORECTAL CANCER: PREVENTION AND MOLECULAR MECHANISMS. EXERCISE AND PHYSICAL ACTIVITY HAVE BEEN SHOWN TO BE STRONGLY ASSOCIATED WITH A DECREASED INCIDENCE RATE OF VARIOUS CHRONIC DISEASES ESPECIALLY NUMEROUS HUMAN MALIGNANCIES. A HUGE NUMBER OF CLINICAL TRIALS AND META-ANALYSIS HAVE DEMONSTRATED THAT EXERCISE IS SIGNIFICANTLY EFFECTIVE IN LOWERING THE RISK OF COLORECTAL CANCER. IN ADDITION, IT IS SUGGESTED AS AN EFFECTIVE THERAPEUTIC MODALITY AGAINST THIS CANCER TYPE. THEREFORE, IN THIS REVIEW, WE WILL REVIEW COMPREHENSIBLY THE EFFECTS OF EXERCISE IN PREVENTING, TREATING, AND ALLEVIATING THE ADVERSE EFFECTS OF CONVENTIONAL THERAPEUTIC OPTIONS IN COLORECTAL CANCER. MOREOVER, THE POSSIBLE MECHANISMS UNDERLYING THE POSITIVE EFFECTS OF EXERCISE AND PHYSICAL ACTIVITY IN COLORECTAL CANCER, INCLUDING REGULATION OF INFLAMMATION, APOPTOSIS, GROWTH FACTOR AXIS, IMMUNITY, EPIGENETIC, ETC. WILL BE ALSO DISCUSSED. 2022 13 5290 21 PROSTATE CANCER PREVENTION: AGENT DEVELOPMENT STRATEGIES. DESPITE ADVANCES IN SURGERY, RADIATION, AND MEDICAL THERAPY OVER THE PAST DECADE AND THE WIDESPREAD ADOPTION OF PSA SCREENING, PROSTATE CANCER CONTINUES TO BE THE SECOND LEADING CAUSE OF CANCER DEATH IN MEN IN THE UNITED STATES. INVASIVE CANCER IS THE END RESULT OF CARCINOGENESIS, A CHRONIC PROCESS OCCURRING OVER MANY YEARS DRIVEN BY GENETIC AND EPIGENETIC ALTERATIONS. THE PROTRACTED NATURE OF THIS TRANSFORMATION TO THE MALIGNANT PHENOTYPE PROVIDES AN OPPORTUNITY TO INTERVENE PHARMACOLOGICALLY TO PREVENT, REVERSE, OR DELAY CARCINOGENESIS, I.E. CHEMOPREVENTION. HEREIN, WE DESCRIBE THE UNIQUE FEATURES OF CANCER PREVENTION, AS OPPOSED TO CANCER TREATMENT, AGENT DEVELOPMENT CLINICAL TRIALS, AND PROVIDE A SUMMARY OF THE ONGOING RESEARCH IN THIS FIELD BEING SUPPORTED BY THE NATIONAL CANCER INSTITUTE. 2014 14 3038 36 GENOME ENGINEERING FOR OSTEOARTHRITIS: FROM DESIGNER CELLS TO DISEASE-MODIFYING DRUGS. BACKGROUND: OSTEOARTHRITIS (OA) IS A HIGHLY PREVALENT DEGENERATIVE JOINT DISEASE INVOLVING JOINT CARTILAGE AND ITS SURROUNDING TISSUES. OA IS THE LEADING CAUSE OF PAIN AND DISABILITY WORLDWIDE. AT PRESENT, THERE ARE NO DISEASE-MODIFYING OA DRUGS, AND THE PRIMARY THERAPIES INCLUDE EXERCISE AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS UNTIL TOTAL JOINT REPLACEMENT AT THE END-STAGE OF THE DISEASE. METHODS: IN THIS REVIEW, WE SUMMARIZED THE CURRENT STATE OF KNOWLEDGE IN GENETIC AND EPIGENETIC ASSOCIATIONS AND RISK FACTORS FOR OA AND THEIR POTENTIAL DIAGNOSTIC AND THERAPEUTIC APPLICATIONS. RESULTS: GENOME-WIDE ASSOCIATION STUDIES AND ANALYSIS OF EPIGENETIC MODIFICATIONS (SUCH AS MIRNA EXPRESSION, DNA METHYLATION AND HISTONE MODIFICATIONS) CONDUCTED ACROSS VARIOUS POPULATIONS SUPPORT THE NOTION THAT THERE IS A GENETIC BASIS FOR CERTAIN SUBSETS OF OA PATHOGENESIS. CONCLUSION: WITH RECENT ADVANCES IN THE DEVELOPMENT OF GENOME EDITING TECHNOLOGIES SUCH AS THE CRISPR-CAS9 SYSTEM, THESE GENETIC AND EPIGENETIC ALTERNATIONS IN OA CAN BE USED AS PLATFORMS FROM WHICH POTENTIAL BIOMARKERS FOR THE DIAGNOSIS, PROGNOSIS, DRUG RESPONSE, AND DEVELOPMENT OF POTENTIAL PERSONALIZED THERAPEUTIC TARGETS FOR OA CAN BE APPROACHED. FURTHERMORE, GENOME EDITING HAS ALLOWED THE DEVELOPMENT OF "DESIGNER" CELLS, WHEREBY THE RECEPTORS, GENE REGULATORY NETWORKS, OR TRANSGENES CAN BE MODIFIED AS A BASIS FOR NEW CELL-BASED THERAPIES. 2019 15 3110 40 GENOTYPE- OR PHENOTYPE-TARGETING ANTICANCER THERAPIES? LESSONS FROM TUMOR EVOLUTIONARY BIOLOGY. DESPITE THE EFFICACY OF MOST CANCER THERAPIES, DRUG RESISTANCE REMAINS A MAJOR PROBLEM IN THE CLINIC. THE ERADICATION OF THE ENTIRE TUMOR AND THE CURE OF THE PATIENT BY CHEMOTHERAPY ALONE ARE RARE, IN PARTICULAR FOR ADVANCED DISEASE. FROM AN EVOLUTIONARY PERSPECTIVE, THE SELECTIVE PRESSURE EXERTED BY CHEMOTHERAPY LEADS TO THE EMERGENCE OF RESISTANT CLONES WHERE RESISTANCE CAN BE ASSOCIATED WITH MANY DIFFERENT FUNCTIONAL MECHANISMS AT THE SINGLE CELL LEVEL OR CAN INVOLVE CHANGES IN THE TUMOR MICRO-ENVIRONMENT. IN THE LAST DECADE, TUMOR GENOMICS HAS CONTRIBUTED TO THE IMPROVEMENT OF OUR UNDERSTANDING OF TUMORIGENESIS AND HAS LED TO THE IDENTIFICATION OF NUMEROUS CELLULAR TARGETS FOR THE DEVELOPMENT OF NOVEL THERAPIES. HOWEVER, SINCE TUMORS ARE BY NATURE EXTREMELY HETEROGENEOUS, THE DRUG EFFICACY AND ECONOMICAL SUSTAINABILITY OF THIS APPROACH IS NOW DEBATABLE. IMPORTANTLY, TUMOR CELL HETEROGENEITY DEPENDS NOT ONLY ON GENETIC MODIFICATIONS BUT ALSO ON NON-GENETIC PROCESSES INVOLVING EITHER STOCHASTIC EVENTS OR EPIGENETIC MODIFICATIONS MAKING GENETIC BIOMARKERS OF UNCERTAIN UTILITY. IN THIS REVIEW, WE WISH TO HIGHLIGHT HOW EVOLUTIONARY BIOLOGY CAN IMPACT OUR UNDERSTANDING OF CARCINOGENESIS AND RESISTANCE TO THERAPIES. WE WILL DISCUSS NEW APPROACHES BASED ON APPLIED ECOLOGY AND EVOLUTION DYNAMICS THAT CAN BE USED TO CONVERT THE CANCER INTO A CHRONIC DISEASE WHERE THE DRUGS WOULD CONTROL TUMOR GROWTH. FINALLY, WE WILL DISCUSS THE WAY METABOLIC DYSFUNCTION OR PHENOTYPIC CHANGES CAN HELP DEVELOPING NEW DELIVERY SYSTEMS OR PHENOTYPETARGETED DRUGS AND HOW EXPLORING NEW SOURCES OF ACTIVE COMPOUNDS CAN CONDUCT TO THE DEVELOPMENT OF DRUGS WITH ORIGINAL MECHANISMS OF ACTION. 2016 16 2832 38 FOCUSING THE SPOTLIGHT ON THE ZEBRAFISH INTESTINE TO ILLUMINATE MECHANISMS OF COLORECTAL CANCER. COLORECTAL CANCER, ENCOMPASSING COLON AND RECTAL CANCER, ARISES FROM THE EPITHELIAL LINING OF THE LARGE BOWEL. IT IS MOST PREVALENT IN WESTERNISED SOCIETIES AND IS INCREASING IN FREQUENCY AS THE WORLD BECOMES MORE INDUSTRIALISED. UNFORTUNATELY, METASTATIC COLORECTAL CANCER IS NOT CURED BY CHEMOTHERAPY AND THE ANNUAL NUMBER OF DEATHS CAUSED BY COLORECTAL CANCER, CURRENTLY 700,000, IS EXPECTED TO RISE. OUR UNDERSTANDING OF THE CONTRIBUTION THAT GENETIC MUTATIONS MAKE TO COLORECTAL CANCER, ALTHOUGH INCOMPLETE, IS REASONABLY WELL ADVANCED. HOWEVER, IT HAS ONLY RECENTLY BECOME WIDELY APPRECIATED THAT IN ADDITION TO THE ONGOING ACCUMULATION OF GENETIC MUTATIONS, CHRONIC INFLAMMATION ALSO PLAYS A CRITICAL ROLE IN THE INITIATION AND PROGRESSION OF THIS DISEASE. WHILE A ROBUST AND TRACTABLE GENETIC MODEL OF COLORECTAL CANCER IN ZEBRAFISH, SUITABLE FOR PRE-CLINICAL STUDIES, IS NOT YET AVAILABLE, THE IDENTIFICATION OF GENES REQUIRED FOR THE RAPID PROLIFERATION OF ZEBRAFISH INTESTINAL EPITHELIAL CELLS DURING DEVELOPMENT HAS HIGHLIGHTED A NUMBER OF ESSENTIAL GENES THAT COULD BE TARGETED TO DISABLE COLORECTAL CANCER CELLS. MOREOVER, APPRECIATION OF THE UTILITY OF ZEBRAFISH TO STUDY INTESTINAL INFLAMMATION IS ON THE RISE. IN PARTICULAR, ZEBRAFISH PROVIDE UNIQUE OPPORTUNITIES TO INVESTIGATE THE IMPACT OF GENETIC AND ENVIRONMENTAL FACTORS ON THE INTEGRITY OF INTESTINAL EPITHELIAL BARRIER FUNCTION. WITH CURRENTLY AVAILABLE TOOLS, THE INTERPLAY BETWEEN EPIGENETIC REGULATORS, INTESTINAL INJURY, MICROBIOTA COMPOSITION AND INNATE IMMUNE CELL MOBILISATION CAN BE ANALYSED IN EXQUISITE DETAIL. THIS PROVIDES EXCELLENT OPPORTUNITIES TO DEFINE CRITICAL EVENTS THAT COULD POTENTIALLY BE TARGETED THERAPEUTICALLY. FURTHER INTO THE FUTURE, THE USE OF ZEBRAFISH LARVAE AS HOSTS FOR XENOGRAFTS OF HUMAN COLORECTAL CANCER TISSUE, WHILE STILL IN ITS INFANCY, HOLDS GREAT PROMISE THAT ZEBRAFISH COULD ONE DAY PROVIDE A PRACTICAL, PRECLINICAL PERSONALIZED MEDICINE PLATFORM FOR THE RAPID ASSESSMENT OF THE METASTATIC POTENTIAL AND DRUG-SENSITIVITY OF PATIENT-DERIVED CANCERS. 2016 17 3958 35 LONG NON-CODING RNAS IN BONE METASTASIS: PROGRESSES AND PERSPECTIVES AS POTENTIAL DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. IN A PRECISION MEDICINE PERSPECTIVE, AMONG THE BIOMARKERS POTENTIALLY USEFUL FOR EARLY DIAGNOSIS OF CANCERS, AS WELL AS TO DEFINE THEIR PROGNOSIS AND EVENTUALLY TO IDENTIFY NOVEL AND MORE EFFECTIVE THERAPEUTIC TARGETS, THERE ARE THE LONG NON-CODING RNAS (LNCRNAS). THE TERM LNCRNA IDENTIFIES A CLASS OF NON-CODING RNA MOLECULES INVOLVED IN THE REGULATION OF GENE EXPRESSION THAT INTERVENE AT THE TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND EPIGENETIC LEVEL. METASTASIS IS A NATURAL EVOLUTION OF SOME MALIGNANT TUMOURS, FREQUENTLY ENCOUNTERED IN PATIENTS WITH ADVANCED CANCERS. ONSET AND DEVELOPMENT OF METASTASIS REPRESENTS A DETRIMENTAL EVENT THAT WORSEN THE PATIENT'S PROGNOSIS BY PROFOUNDLY INFLUENCING THE QUALITY OF LIFE AND IS RESPONSIBLE FOR THE OMINOUS PROGRESSION OF THE DISEASE. DUE TO THE PECULIAR ENVIRONMENT AND THE BIOMECHANICAL PROPERTIES, BONE IS A PREFERENTIAL SITE FOR THE SECONDARY GROWTH OF BREAST, PROSTATE AND LUNG CANCERS. UNFORTUNATELY, ONLY PALLIATIVE AND PAIN THERAPIES ARE CURRENTLY AVAILABLE FOR PATIENTS WITH BONE METASTASES, WHILE NO EFFECTIVE AND DEFINITIVE TREATMENTS ARE AVAILABLE. THE UNDERSTANDING OF PATHOPHYSIOLOGICAL BASIS OF BONE METASTASIS FORMATION AND PROGRESSION, AS WELL AS THE IMPROVEMENT IN THE CLINICAL MANAGEMENT OF THE PATIENT, ARE CENTRAL BUT CHALLENGING TOPICS IN BASIC RESEARCH AND CLINICAL PRACTICE. THE IDENTIFICATION OF NEW MOLECULAR SPECIES THAT MAY HAVE A ROLE AS EARLY HALLMARKS OF THE METASTATIC PROCESS COULD OPEN THE DOOR TO THE DEFINITION OF NEW, AND MORE EFFECTIVE, THERAPEUTIC AND DIAGNOSTIC APPROACHES. NON-CODING RNAS SPECIES AND, PARTICULARLY, LNCRNAS ARE PROMISING COMPOUNDS IN THIS SETTING, AND THEIR STUDY MAY BRING TO THE IDENTIFICATION OF RELEVANT PROCESSES. IN THIS REVIEW, WE HIGHLIGHT THE ROLE OF LNCRNAS AS EMERGING MOLECULES IN MEDIATING THE FORMATION AND DEVELOPMENT OF BONE METASTASES, AS POSSIBLE BIOMARKERS FOR CANCER DIAGNOSIS AND PROGNOSIS, AND AS THERAPEUTIC TARGETS TO COUNTERACT CANCER SPREAD. 2023 18 731 34 CANCER CHEMOPREVENTION: CLASSIC AND EPIGENETIC MECHANISMS INHIBITING TUMORIGENESIS. WHAT HAVE WE LEARNED SO FAR? CANCERS DERIVE FROM STEP BY STEP PROCESSES WHICH ARE DIFFERENTIATED BY THE PROGRESSIVELY ACCUMULATED MUTATIONS. FOR SOME TUMORS THERE IS A CLEAR PROGRESSIVE ADVANCEMENT FROM BENIGN LESIONS TO MALIGNANCY AND FOR THESE, PREVENTIVE SCREENING PROGRAMS EXIST. IN SUCH CASES HAVING THOSE BENIGN LESIONS ARE A CLEAR INDICATOR OF PREDISPOSITION WHILE FOR SOME OTHER CASES, FAMILIAL PATTERNS OF CANCER INCIDENCE AND THE IDENTIFICATION OF MUTATIONS ARE THE MAIN INDICATORS OF HIGHER RISK FOR HAVING THE DISEASE. FOR PATIENTS IDENTIFIED AS HAVING PREDISPOSITION, CHEMOPREVENTION IS A GOAL AND IN SOME CASES A POSSIBILITY. CHEMOPREVENTION IS THE USE OF ANY COMPOUND, EITHER NATURAL OR SYNTHETIC THAT ABROGATES CARCINOGENESIS OR TUMOR PROGRESSION, THROUGH DIFFERENT MECHANISMS, SOME OF WHICH HAVE ALREADY BEEN DESCRIBED. FOR EXAMPLE, THE CLASSIC MECHANISMS MAY INVOLVE ACTIVATION OF FREE RADICAL SCAVENGING ENZYMES, CONTROL OF CHRONIC INFLAMMATION, AND DOWNREGULATION OF SPECIFIC SIGNALING PATHWAYS. MORE RECENTLY, EPIGENETICS ALLOWED FURTHER UNDERSTANDING OF THE CHEMOPREVENTIVE POTENTIAL OF SEVERAL AGENTS, SUCH AS SULFORAPHANE, GREEN TEA DERIVED COMPOUNDS, RESVERATROL, ISOFLAVONES, AND OTHERS WHICH WE EXPLOIT IN THIS REVIEW ARTICLE. THROUGHOUT THE TEXT WE DISCUSS THE PROPERTIES COMPOUNDS SHOULD HAVE IN ORDER TO BE CLASSIFIED AS CHEMOPREVENTIVE ONES AND THE CHALLENGES IN TRANSLATIONAL RESEARCH IN THIS AREA, AS LOTS OF THE SUCCESS ACHIEVED IN VITRO CANNOT BE TRANSLATED INTO THE CLINICAL SETTINGS, DUE TO SEVERAL DIFFERENT DRAWBACKS, WHICH INCLUDE TOXICITY, COST, DOSE DEFINITION, PATIENT ADHERENCE, AND REGIMEN OF USE. 2018 19 4325 41 MICRORNAS IN THE EVALUATION AND POTENTIAL TREATMENT OF LIVER DISEASES. ACUTE AND CHRONIC LIVER DISEASE CONTINUE TO RESULT IN SIGNIFICANT MORBIDITY AND MORTALITY OF PATIENTS, ALONG WITH INCREASING BURDEN ON THEIR FAMILIES, SOCIETY AND THE HEALTH CARE SYSTEM. THIS IN PART IS DUE TO INCREASED INCIDENCE OF LIVER DISEASE ASSOCIATED FACTORS SUCH AS METABOLIC SYNDROME; IMPROVED SURVIVAL OF PATIENTS WITH CHRONIC PREDISPOSING CONDITIONS SUCH AS HIV; AS WELL AS ADVANCES IN THE FIELD OF TRANSPLANTATION AND ASSOCIATED CARE LEADING TO IMPROVED SURVIVAL. THE FACT THAT ONE DISEASE CAN RESULT IN DIFFERENT MANIFESTATIONS AND OUTCOMES HIGHLIGHTS THE NEED FOR IMPROVED UNDERSTANDING OF NOT JUST GENETIC PHENOMENON PREDISPOSING TO A CONDITION, BUT ADDITIONALLY THE ROLE OF EPIGENETIC AND ENVIRONMENTAL FACTORS LEADING TO THE PHENOTYPE OF THE DISEASE. IT IS NOT SURPRISING THAT PROVIDERS CONTINUE TO FACE DAILY CHALLENGES PERTAINING TO DIAGNOSTIC ACCURACY, PROGNOSTICATION OF DISEASE SEVERITY, PROGRESSION, AND RESPONSE TO THERAPIES. A NUMBER OF THESE CHALLENGES CAN BE ADDRESSED BY INCORPORATING A PERSONALIZED APPROACH OF MANAGEMENT TO THE CURRENT PARADIGM OF CARE. RECENT ADVANCES IN THE FIELDS OF MOLECULAR BIOLOGY AND GENETICS HAVE PAVED THE WAY TO MORE ACCURATE, INDIVIDUALIZED AND PRECISE APPROACH TO CARING FOR LIVER DISEASE. THE STUDY OF MICRORNAS AND THEIR ROLE IN BOTH HEALTHY AND DISEASED LIVERS IS ONE EXAMPLE OF SUCH ADVANCES. AS THESE SMALL, NON-CODING RNAS WORK ON FINE-TUNING OF CELLULAR ACTIVITIES AND ORGAN FUNCTION IN A DYNAMIC AND PRECISE FASHION, THEY PROVIDE US A GOLDEN OPPORTUNITY TO ADVANCE THE FIELD OF HEPATOLOGY. THE STUDY OF MICRORNAS IN LIVER DISEASE PROMISES TREMENDOUS IMPROVEMENT IN HEPATOLOGY AND IS LIKELY TO LAY THE FOUNDATION TOWARDS A PERSONALIZED APPROACH IN LIVER DISEASE. 2016 20 6653 38 UPDATE ON PANCREATIC CANCER AND ALCOHOL-ASSOCIATED RISK. DUCTAL ADENOCARCINOMA OF THE PANCREAS IS CHARACTERIZED BY EXTREMELY AGGRESSIVE BEHAVIOR, WITH AN OVERALL 5-YEAR SURVIVAL OF <4%. BECAUSE CONVENTIONAL AND SPECIFICALLY TAILORED THERAPEUTIC REGIMENS HAVE LITTLE IMPACT ON PATIENT SURVIVAL, EPIDEMIOLOGICAL AND MOLECULAR RESEARCH AIMS AT IDENTIFYING AND REDUCING RISK FACTORS. CIGARETTE SMOKING, OBESITY, DIABETES MELLITUS, AND CHRONIC PANCREATITIS ARE AMENABLE TO MEDICAL PREVENTION OR THERAPY. HEAVY ALCOHOL CONSUMPTION IS AN INCONSISTENT SINGLE RISK FACTOR FOR PANCREATIC CANCER BUT MAY PROMOTE CARCINOGENESIS BY INCREASING THE RISK OF DIABETES MELLITUS OR CHRONIC PANCREATITIS. FOR VARIOUS AGENTS, THE KEY CARCINOGENIC EFFECT IS PROBABLY AN INFLAMMATORY RESPONSE IN THE PANCREATIC TISSUE. ON THE MOLECULAR LEVEL, MUTATIONS OF ONCOGENES AND TUMOR SUPPRESSOR GENES, AS WELL AS VARIOUS EPIGENETIC ALTERATIONS, SUCH AS OVEREXPRESSION OF GROWTH FACTORS AND THEIR RECEPTORS, ARE IMPORTANT IN TUMORIGENESIS. COMPLETE AND SAFE SURGICAL RESECTION, TOGETHER WITH ADJUVANT THERAPY, OFFERS PROLONGED SURVIVAL, WITH 5-YEAR SURVIVAL RATES OF APPROXIMATELY 25%. HOWEVER, FOR UNRESECTABLE OR DISSEMINATED DISEASE, WHICH CONSTITUTES THE VAST MAJORITY OF CASES, TREATMENT IS PALLIATIVE. DESPITE INCREASING KNOWLEDGE ABOUT THE MOLECULAR PATHOLOGY OF PANCREATIC CANCER AND DESPITE ADVANCES IN TREATMENT, THE OVERALL COURSE OF THE DISEASE IS DISMAL, AND REINFORCED EFFORTS TO REDUCE INCIDENCE AND IMPROVE OUTCOME ARE NEEDED DESPERATELY. 2006