1 3160 180 GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS: PATHOPHYSIOLOGY-BASED REVIEW ON CURRENT APPROACHES AND FUTURE DIRECTIONS. GRAFT-VERSUS-HOST DISEASE (GVHD) WAS FIRST DESCRIBED IN 1959, SINCE THEN MAJOR EFFORTS HAVE BEEN MADE IN ORDER TO UNDERSTAND ITS PHYSIOPATHOLOGY AND ANIMAL MODELS HAVE PLAYED A KEY ROLE. THREE STEPS, INVOLVING DIFFERENT PATHWAYS, HAVE BEEN RECOGNISED IN EITHER ACUTE AND CHRONIC GVHD, IDENTIFYING THEM AS TWO DISTINCT ENTITIES. IN ORDER TO REDUCE GVHD INCIDENCE AND SEVERITY, PROPHYLACTIC MEASURES WERE ADDED TO TRANSPLANT PROTOCOLS. THE COMBINATION OF A CALCINEURIN INHIBITOR (CNI) PLUS AN ANTIMETABOLITE REMAINS THE STANDARD OF CARE. BETTER KNOWLEDGE OF GVHD PATHOPHYSIOLOGY HAS MOVED THIS FIELD FORWARD AND NOWADAYS DIFFERENT DRUGS ARE BEING USED ON A DAILY BASIS. IMPROVING GVHD PROPHYLAXIS IS A MAJOR GOAL AS IT WOULD TRANSLATE INTO LESS NON-RELAPSE MORTALITY AND BETTER OVERALL SURVIVAL. AS COMPARED TO CNI PLUS METHOTREXATE THE COMBINATION OF CNI PLUS MYCOPHENOLATE MOPHETIL (MMF) ALLOWS US TO OBTAIN SIMILAR RESULTS IN TERMS OF GVHD INCIDENCE BUT A LOWER TOXICITY RATE IN TERMS OF NEUTROPENIA OR MUCOSITIS. THE USE OF ATG HAS BEEN RELATED TO A LOWER RISK OF ACUTE AND CHRONIC GVHD IN PROSPECTIVE RANDOMIZED TRIALS AS WELL AS THE USE OF POSTTRANSPLANT CYCLOPHOSPHAMIDE, WITH NO OR MARGINAL IMPACT ON OVERALL SURVIVAL BUT WITH AN IMPROVEMENT IN GVHD-RELAPSE FREE SURVIVAL (GRFS). THE USE OF SIROLIMUS HAS BEEN RELATED TO A LOWER RISK OF ACUTE GVHD AND SIGNIFICANTLY INFLUENCED OVERALL SURVIVAL IN ONE PROSPECTIVE RANDOMIZED TRIAL. OTHER PROSPECTIVE TRIALS HAVE EVALUATED THE USE OF RECEPTORS SUCH AS CCR5 OR ALPHA4BETA7 TO AVOID T-CELLS TRAFFICKING INTO GVHD TARGET ORGANS, CYTOKINE BLOCKERS OR IMMUNE CHECK POINT AGONISTS. ALSO, EPIGENETIC MODIFIERS HAVE SHOWN PROMISING RESULTS IN PHASE II TRIALS. ATTENTION SHOULD BE PAID TO GRAFT-VERSUS-LEUKEMIA, INFECTIONS AND IMMUNE RECOVERY BEFORE BRINGING NEW PROPHYLACTIC STRATEGIES TO CLINICAL PRACTICE. ALTHOUGH THE LIST OF NOVEL AGENTS FOR GVHD PROPHYLAXIS IS GROWING, RANDOMIZED TRIALS ARE STILL LACKING FOR MANY OF THEM. 2021 2 1048 36 CLINICAL EPIGENETICS AND ACUTE/CHRONIC REJECTION IN SOLID ORGAN TRANSPLANTATION: AN UPDATE. THE LACK OF A PRECISE STRATIFICATION ALGORITHM FOR PREDICTING PATIENTS AT HIGH RISK OF GRAFT REJECTION CHALLENGES THE CURRENT SOLID ORGAN TRANSPLANTATION (SOT) CLINICAL SETTING. IN FACT, THE ESTABLISHED BIOMARKERS FOR TRANSPLANTATION OUTCOMES ARE UNABLE TO ACCURATELY PREDICT THE ONSET TIME AND SEVERITY OF GRAFT REJECTION (ACUTE OR CHRONIC) AS WELL AS THE INDIVIDUAL RESPONSE TO IMMUNOSUPPRESSIVE DRUGS. THUS, IDENTIFYING NOVEL MOLECULAR PATHWAYS UNDERLYING EARLY IMMUNOLOGICAL RESPONSES WHICH CAN DAMAGE TRANSPLANT INTEGRITY IS NEEDED TO REACH PRECISION MEDICINE AND PERSONALIZED THERAPY OF SOT. DIRECT EPIGENETIC-SENSITIVE MECHANISMS, MAINLY DNA METHYLATION AND HISTONE MODIFICATIONS, MAY PLAY A RELEVANT ROLE FOR IMMUNE ACTIVATION AND LONG-TERM EFFECTS (E.G., ACTIVATION OF FIBROTIC PROCESSES) WHICH MAY BE TRANSLATED IN NEW NON-INVASIVE BIOMARKERS AND DRUG TARGETS. IN PARTICULAR, THE MEASURE OF DNA METHYLATION BY USING THE BLOOD-BASED "EPIGENETIC CLOCK" SYSTEM MAY BE AN ADDED VALUE TO THE DONOR ELIGIBILITY CRITERIA PROVIDING AN ESTIMATION OF THE HEART BIOLOGICAL AGE AS WELL AS A PREDICTIVE BIOMARKERS. BESIDES, MONITORING OF DNA METHYLATION CHANGES MAY AID TO PREDICT ACUTE VS CHRONIC GRAFT DAMAGE IN KIDNEY TRANSPLANTATION (KT) PATIENTS. FOR EXAMPLE, HYPERMETHYLATION OF GENES BELONGING TO THE NOTCH AND WNT PATHWAYS SHOWED A HIGHER PREDICTIVE VALUE FOR CHRONIC INJURY OCCURRING AT 12 MONTHS POST-KT WITH RESPECT TO ESTABLISHED CLINICAL PARAMETERS. DETECTING HIGHER CIRCULATING CELL-FREE DNA (CFDNA) FRAGMENTS CARRYING HEPATOCYTE-SPECIFIC UNMETHYLATED LOCI IN THE INTER-ALPHA-TRYPSIN INHIBITOR HEAVY CHAIN 4 (ITIH4), INSULIN LIKE GROWTH FACTOR 2 RECEPTOR (IGF2R), AND VITRONECTIN (VTN) GENES MAY BE USEFUL TO PREDICT ACUTE GRAFT INJURY AFTER LIVER TRANSPLANTATION (LT) IN SERUM SAMPLES. FURTHERMORE, HYPOMETHYLATION IN THE FORKHEAD BOX P3 (FOXP3) GENE MAY SERVE AS A MARKER OF INFILTRATING NATURAL TREG PERCENTAGE IN THE GRAFT PROVIDING THE ABILITY TO PREDICT ACUTE REJECTION EVENTS AFTER HEART TRANSPLANTATION (HTX). WE AIM TO UPDATE ON THE POSSIBLE CLINICAL RELEVANCE OF DNA METHYLATION CHANGES REGULATING IMMUNE-RELATED PATHWAYS UNDERLYING ACUTE OR CHRONIC GRAFT REJECTION IN KT, LT, AND HTX WHICH MIGHT BE USEFUL TO PREVENT, MONITOR, AND TREAT SOLID ORGAN REJECTION AT PERSONALIZED LEVEL. 2021 3 4198 29 METABOLIC PROFILING DISTINGUISHES THREE SUBTYPES OF ALZHEIMER'S DISEASE. THE CAUSE OF ALZHEIMER'S DISEASE IS INCOMPLETELY DEFINED, AND NO TRULY EFFECTIVE THERAPY EXISTS. HOWEVER, MULTIPLE STUDIES HAVE IMPLICATED METABOLIC ABNORMALITIES SUCH AS INSULIN RESISTANCE, HORMONAL DEFICIENCIES, AND HYPERHOMOCYSTEINEMIA. OPTIMIZING METABOLIC PARAMETERS IN A COMPREHENSIVE WAY HAS YIELDED COGNITIVE IMPROVEMENT, BOTH IN SYMPTOMATIC AND ASYMPTOMATIC INDIVIDUALS. THEREFORE, EXPANDING THE STANDARD LABORATORY EVALUATION IN PATIENTS WITH DEMENTIA MAY BE REVEALING. HERE I REPORT THAT METABOLIC PROFILING REVEALS THREE ALZHEIMER'S DISEASE SUBTYPES. THE FIRST IS INFLAMMATORY, IN WHICH MARKERS SUCH AS HS-CRP AND GLOBULIN:ALBUMIN RATIO ARE INCREASED. THE SECOND TYPE IS NON-INFLAMMATORY, IN WHICH THESE MARKERS ARE NOT INCREASED, BUT OTHER METABOLIC ABNORMALITIES ARE PRESENT. THE THIRD TYPE IS A VERY DISTINCTIVE CLINICAL ENTITY THAT AFFECTS RELATIVELY YOUNG INDIVIDUALS, EXTENDS BEYOND THE TYPICAL ALZHEIMER'S DISEASE INITIAL DISTRIBUTION TO AFFECT THE CORTEX WIDELY, IS CHARACTERIZED BY EARLY NON-AMNESTIC FEATURES SUCH AS DYSCALCULIA AND APHASIA, IS OFTEN MISDIAGNOSED OR LABELED ATYPICAL ALZHEIMER'S DISEASE, TYPICALLY AFFECTS APOE4-NEGATIVE INDIVIDUALS, AND IS ASSOCIATED WITH STRIKING ZINC DEFICIENCY. GIVEN THE INVOLVEMENT OF ZINC IN MULTIPLE ALZHEIMER'S-RELATED METABOLIC PROCESSES, SUCH AS INSULIN RESISTANCE, CHRONIC INFLAMMATION, ADAM10 PROTEOLYTIC ACTIVITY, AND HORMONAL SIGNALING, THIS SYNDROME OF ALZHEIMER'S-PLUS WITH LOW ZINC (APLZ) WARRANTS FURTHER METABOLIC, GENETIC, AND EPIGENETIC CHARACTERIZATION. 2015 4 5905 31 TACKLING THE HETEROGENEITY OF CVID. PURPOSE OF REVIEW: COMMON VARIABLE IMMUNODEFICIENCY IS CLINICALLY THE MOST RELEVANT PRIMARY IMMUNODEFICIENCY OF THE ADULT. ITS HETEROGENEITY HAS HINDERED PROGRESS IN THE PATHOGENETIC UNDERSTANDING OF THE MAJORITY OF COMMON VARIABLE IMMUNODEFICIENCY PATIENTS. THIS ABSTRACT SUMMARIZES RECENT ASPECTS OF THE FIELD AND EMPHASIZES THE NEED FOR A COMMONLY ACCEPTED APPROACH TO CLASSIFY COMMON VARIABLE IMMUNODEFICIENCY. RECENT FINDINGS: IN THE LAST 2 YEARS, THE FIRST GENETIC DEFECTS UNDERLYING COMMON VARIABLE IMMUNODEFICIENCY, INCLUDING ICOS, TACI, BAFF-R AND CD19, HAVE BEEN IDENTIFIED. THE ANALYSIS OF DENDRITIC CELLS DEMONSTRATED ALTERATIONS IN A MAJORITY OF PATIENTS IN ADDITION TO THE DISTURBED T AND B-CELL FUNCTION. SEVERAL CHANGES OF THE ADAPTIVE IMMUNE SYSTEM MIGHT BE SECONDARY TO AN UNDERLYING CHRONIC INFLAMMATORY SETTING POSSIBLY DUE TO A HHV8 INFECTION IN A SUBGROUP OF PATIENTS WITH GRANULOMATOUS DISEASE, AUTOIMMUNE PHENOMENA AND T-CELL DYSFUNCTION. THE OCCURRENCE OF GRANULOMATOUS INFLAMMATION IS ASSOCIATED WITH A WORSE PROGNOSIS COMPARED WITH COMMON VARIABLE IMMUNODEFICIENCY PATIENTS WITHOUT GRANULOMA. SUMMARY: THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY INCLUDES DISTURBANCES OF THE ADAPTIVE AS WELL AS INNATE IMMUNE SYSTEM. IDENTIFIED MONOGENIC DEFECTS ACCOUNT FOR ABOUT 10% OF CASES, LEAVING THE MAJORITY OF DEFECTS UNDEFINED AND CERTAINLY IN PART EPIGENETIC. TO COMBINE THE KNOWN ASPECTS OF THE PATHOGENESIS OF COMMON VARIABLE IMMUNODEFICIENCY TO A CONCLUSIVE PICTURE, THE CLINICAL AND IMMUNOLOGIC PHENOTYPING OF PATIENTS NEEDS TO BE STANDARDIZED. 2005 5 761 30 CATEGORIZING THE CHARACTERISTICS OF HUMAN CARCINOGENS: A NEED FOR SPECIFICITY. THE INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) HAS RECENTLY PROPOSED EMPLOYING "TEN KEY CHARACTERISTICS OF HUMAN CARCINOGENS" (TKCS) TO DETERMINE THE POTENTIAL OF AGENTS FOR HARMFUL EFFECTS. THE TKCS SEEM LIKELY TO CONFUSE THE UNSATISFACTORY CORRELATION FROM TESTING REGIMES THAT HAVE IGNORED THE DIFFERENCES EVIDENT WHEN CELLULAR CHANGES ARE COMPARED IN SHORT AND LONG-LIVED SPECIES, WITH THEIR VERY DIFFERENT STEM CELL AND SOMATIC CELL PHYLOGENIES. THE PROPOSED CHARACTERISTICS ARE SO BROAD THAT THEIR USE WILL LEAD TO AN INCREASE IN THE CURRENT UNACCEPTABLY HIGH RATE OF FALSE POSITIVES. IT COULD BE AN INFORMATIVE EXPERIMENT TO TAKE WELL-ESTABLISHED APPROVED THERAPEUTICS WITH WELL-KNOWN HUMAN SAFETY PROFILES AND TEST THEM AGAINST THIS NEW TKC PARADIGM. CANCERS ARE INITIATED AND DRIVEN BY HERITABLE AND TRANSIENT CHANGES IN GENE EXPRESSION, EXPAND CLONALLY, AND PROGRESS VIA ADDITIONAL ASSOCIATED ACQUIRED MUTATIONS AND EPIGENETIC ALTERATIONS THAT PROVIDE CELLS WITH AN EVOLUTIONARY ADVANTAGE. THE GENOTOXICITY TESTING PROTOCOLS CURRENTLY EMPLOYED AND REQUIRED BY REGULATION, EMPHASIZE TESTING FOR THE MUTATIONAL POTENTIAL OF THE TEST AGENT. TWO-YEAR, CHRONIC RODENT CANCER BIOASSAYS ARE INTENDED TO TEST FOR THE ENTIRE SPECTRUM OF CARCINOGENIC TRANSFORMATION. THE USE OF CYTOTOXIC DOSES CAUSING INCREASED, SUSTAINED CELL PROLIFERATION THAT FACILITATES ACCUMULATED GENETIC DAMAGE LEADS TO A HIGH FALSE-POSITIVE RATE OF TUMOR INDUCTION. CURRENT CANCER HAZARD ASSESSMENT PROTOCOLS AND WEIGHT-OF-THE-EVIDENCE ANALYSIS OF AGENT-SPECIFIC CANCER RISK ALIGN POORLY WITH THE PATHOGENESIS OF HUMAN CARCINOMA AND SO NEED MODERNIZATION AND IMPROVEMENT IN WAYS SUGGESTED HERE. 2021 6 943 29 CHRONIC LYMPHOCYTIC LEUKEMIA. PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA CAN BE DIVIDED INTO THREE CATEGORIES: THOSE WHO ARE MINIMALLY AFFECTED BY THE PROBLEM, OFTEN NEVER REQUIRING THERAPY; THOSE THAT INITIALLY FOLLOW AN INDOLENT COURSE BUT SUBSEQUENTLY PROGRESS AND REQUIRE THERAPY; AND THOSE THAT FROM THE POINT OF DIAGNOSIS EXHIBIT AN AGGRESSIVE DISEASE NECESSITATING TREATMENT. LIKEWISE, SUCH PATIENTS PASS THROUGH THREE PHASES: DEVELOPMENT OF THE DISEASE, DIAGNOSIS, AND NEED FOR THERAPY. FINALLY, THE LEUKEMIC CLONES OF ALL PATIENTS APPEAR TO REQUIRE CONTINUOUS INPUT FROM THE EXTERIOR, MOST OFTEN THROUGH MEMBRANE RECEPTORS, TO ALLOW THEM TO SURVIVE AND GROW. THIS REVIEW IS PRESENTED ACCORDING TO THE TEMPORAL COURSE THAT THE DISEASE FOLLOWS, FOCUSING ON THOSE EXTERNAL INFLUENCES FROM THE TISSUE MICROENVIRONMENT (TME) THAT SUPPORT THE TIME LINES AS WELL AS THOSE INTERNAL INFLUENCES THAT ARE INHERITED OR DEVELOP AS GENETIC AND EPIGENETIC CHANGES OCCURRING OVER THE TIME LINE. REGARDING THE FORMER, SPECIAL EMPHASIS IS PLACED ON THE INPUT PROVIDED VIA THE B-CELL RECEPTOR FOR ANTIGEN AND THE C-X-C-MOTIF CHEMOKINE RECEPTOR-4 AND THE THERAPEUTIC AGENTS THAT BLOCK THESE INPUTS. REGARDING THE LATTER, PROMINENCE IS LAID UPON INHERITED SUSCEPTIBILITY GENES AND THE GENETIC AND EPIGENETIC ABNORMALITIES THAT LEAD TO THE DEVELOPMENTAL AND PROGRESSION OF THE DISEASE. 2021 7 6633 37 UNHEALTHY SMOKERS: SCOPES FOR PROPHYLACTIC INTERVENTION AND CLINICAL TREATMENT. BACKGROUND: GLOBALLY, TOBACCO USE CAUSES APPROXIMATELY 6 MILLION DEATHS PER YEAR, AND PREDICTIONS REPORT THAT WITH CURRENT TRENDS; MORE THAN 8 MILLION DEATHS ARE EXPECTED ANNUALLY BY 2030. CIGARETTE SMOKINGS IS CURRENTLY ACCOUNTABLE FOR MORE THAN 480,000 DEATHS EACH YEAR IN UNITED STATES (US) AND IS THE LEADING CAUSE OF PREVENTABLE DEATH IN THE US. ON AVERAGE, SMOKERS DIE 10 YEARS EARLIER THAN NONSMOKERS AND IF SMOKING CONTINUES AT ITS CURRENT PROPORTION AMONG ADOLESCENTS, ONE IN EVERY 13 AMERICANS AGED 17 YEARS OR YOUNGER IS EXPECTED TO DIE PREMATURELY FROM A SMOKING-RELATED ILLNESS. EVEN THOUGH THERE HAS BEEN A MARGINAL SMOKING DECLINE OF AROUND 5% IN RECENT YEARS (2005 VS 2015), SMOKERS STILL ACCOUNT FOR 15% OF THE US ADULT POPULATION. WHAT IS ALSO CONCERNING IS THAT 41,000 OUT OF 480,000 DEATHS RESULTS FROM SECONDHAND SMOKE (SHS) EXPOSURE. HEREIN, WE PROVIDE A DETAILED REVIEW OF HEALTH COMPLICATIONS AND MAJOR PATHOLOGICAL MECHANISMS INCLUDING MUTATION, INFLAMMATION, OXIDATIVE STRESS, AND HEMODYNAMIC AND PLASMA PROTEIN CHANGES ASSOCIATED WITH CHRONIC SMOKING. FURTHER, WE DISCUSS PROPHYLACTIC INTERVENTIONS AND ASSOCIATED BENEFITS AND PROVIDE A RATIONALE FOR THE SCOPE OF CLINICAL TREATMENT. CONCLUSIONS: CONSIDERING THESE PREMISES, IT IS EVIDENT THAT MUCH DETAILED TRANSLATIONAL AND CLINICAL STUDIES ARE NEEDED. FACTORS SUCH AS THE LENGTH OF SMOKING CESSATION FOR EX-SMOKERS, THE LEVEL OF SMOKE EXPOSURE IN CASE OF SHS, PRE-ESTABLISHED HEALTH CONDITIONS, GENETICS (AND EPIGENETICS MODIFICATION CAUSED BY CHRONIC SMOKING) ARE FEW OF THE CRITERIA THAT NEED TO BE EVALUATED TO BEGIN ASSESSING THE PROPHYLACTIC AND/OR THERAPEUTIC IMPACT OF TREATMENTS AIMED AT CHRONIC AND FORMER SMOKERS (ESPECIALLY EARLY STAGE EX-SMOKERS) INCLUDING THOSE FREQUENTLY SUBJECTED TO SECOND HAND TOBACCO SMOKE EXPOSURE. HEREIN, WE PROVIDE A DETAILED REVIEW OF HEALTH COMPLICATIONS AND MAJOR PATHOLOGICAL MECHANISMS INCLUDING MUTATION, INFLAMMATION, OXIDATIVE STRESS, AND HEMODYNAMIC AND PLASMA PROTEIN CHANGES ASSOCIATED WITH CHRONIC SMOKING. FURTHER, WE DISCUSS ABOUT PROPHYLACTIC INTERVENTIONS AND ASSOCIATED BENEFITS AND PROVIDE A RATIONALE AND SCOPE FOR CLINICAL TREATMENT. 2017 8 4852 30 OPPORTUNITIES AND CHALLENGES IN DRUG DEVELOPMENT FOR PEDIATRIC CANCERS. THE USE OF TARGETED SMALL-MOLECULE THERAPEUTICS AND IMMUNOTHERAPEUTICS HAS BEEN LIMITED TO DATE IN PEDIATRIC ONCOLOGY. RECENTLY, THE NUMBER OF PEDIATRIC APPROVALS HAS RISEN, AND REGULATORY INITIATIVES IN THE UNITED STATES AND EUROPE HAVE AIMED TO INCREASE THE STUDY OF NOVEL ANTICANCER THERAPIES IN CHILDREN. CHALLENGES OF DRUG DEVELOPMENT IN CHILDREN INCLUDE THE RARITY OF INDIVIDUAL CANCER DIAGNOSES AND THE HIGH PREVALENCE OF DIFFICULT-TO-DRUG TARGETS, INCLUDING TRANSCRIPTION FACTORS AND EPIGENETIC REGULATORS. ONGOING PEDIATRIC ADAPTATION OF BIOMARKER-DRIVEN TRIAL DESIGNS AND FURTHER EXPLORATION OF AGENTS TARGETING NON-KINASE DRIVERS CONSTITUTE HIGH-PRIORITY OBJECTIVES FOR FUTURE PEDIATRIC ONCOLOGY DRUG DEVELOPMENT. SIGNIFICANCE: INCREASING ATTENTION TO DRUG DEVELOPMENT FOR CHILDREN WITH CANCER BY REGULATORS AND PHARMACEUTICAL COMPANIES HOLDS THE PROMISE OF ACCELERATING THE AVAILABILITY OF NEW THERAPIES FOR CHILDREN WITH CANCER, POTENTIALLY IMPROVING SURVIVAL AND DECREASING THE ACUTE AND CHRONIC TOXICITIES OF THERAPY. HOWEVER, UNIQUE APPROACHES ARE NECESSARY TO STUDY NOVEL THERAPIES IN CHILDREN THAT TAKE INTO ACCOUNT LOW PATIENT NUMBERS, THE PEDIATRIC CANCER GENOMIC LANDSCAPE AND TUMOR MICROENVIRONMENT, AND THE NEED FOR PEDIATRIC FORMULATIONS. IT IS ALSO CRITICAL TO EVALUATE THE POTENTIAL FOR UNIQUE TOXICITIES IN GROWING HOSTS WITHOUT AFFECTING THE PACE OF DISCOVERY FOR CHILDREN WITH THESE LIFE-THREATENING DISEASES. 2021 9 5038 29 PHARMACOGENETICS OF CHRONIC PAIN AND ITS TREATMENT. THIS PAPER REVIEWS THE IMPACT OF GENETIC VARIABILITY OF DRUG METABOLIZING ENZYMES, TRANSPORTERS, RECEPTORS, AND PATHWAYS INVOLVED IN CHRONIC PAIN PERCEPTION ON THE EFFICACY AND SAFETY OF ANALGESICS AND OTHER DRUGS USED FOR CHRONIC PAIN TREATMENT. SEVERAL CANDIDATE GENES HAVE BEEN IDENTIFIED IN THE LITERATURE, WHILE THERE IS USUALLY ONLY LIMITED CLINICAL EVIDENCE SUBSTANTIATING FOR THE PENETRATION OF THE TESTING FOR THESE CANDIDATE BIOMARKERS INTO THE CLINICAL PRACTICE. FURTHER, THE PAIN-PERCEPTION REGULATION AND MODULATION ARE STILL NOT FULLY UNDERSTOOD, AND THUS MORE COMPLEX KNOWLEDGE OF GENETIC AND EPIGENETIC BACKGROUND FOR ANALGESIA WILL BE NEEDED PRIOR TO THE CLINICAL USE OF THE CANDIDATE GENETIC BIOMARKERS. 2013 10 4918 39 PANCREATIC CANCER: FROM BENCH TO 5-YEAR SURVIVAL. PANCREATIC DUCTAL ADENOCARCINOMA IS ONE OF THE MOST AGGRESSIVE HUMAN MALIGNANCIES, WITH AN OVERALL 5-YEAR SURVIVAL RATE OF LESS THAN 4%. ON THE MOLECULAR LEVEL, AN INCREASING NUMBER OF GENETIC AND EPIGENETIC ALTERATIONS HAVE BEEN DISCOVERED, WITH A PARTICULAR FOCUS ON GROWTH FACTORS AND RELATED PATHWAYS. SMALL-MOLECULE TYROSINE KINASE INHIBITORS, ANTIBODIES, AND OTHER APPROACHES HAVE BEEN DEVELOPED IN RECENT YEARS TO TARGET THESE SIGNAL TRANSDUCTION PATHWAYS, AND FIRST CLINICAL TRIALS SHOW ENCOURAGING RESULTS. IN ADDITION, MOLECULAR ALTERATIONS HAVE BEEN IDENTIFIED THAT ENABLE THE CANCER CELLS TO INVADE THE PERINEURIUM AND THE RETROPERITONEAL SPACE, THUS EXPLAINING AT LEAST IN PART THE HIGH RATE OF LOCAL RECURRENCE AND THE SEVERE PAIN SYNDROME. TECHNICALLY, PANCREATIC SURGERY HAS ADVANCED, WITH ACCEPTABLE MORBIDITY AND MORTALITY RATES IN HIGH-VOLUME CENTERS. RANDOMIZED CONTROLLED TRIALS ARE INCREASINGLY CARRIED OUT TO DEFINE THE BEST PALLIATIVE AND ADJUVANT THERAPY FOR THIS DISEASE. TRANSLATIONAL RESEARCH COMBINED WITH CLINICAL TRIALS WILL HOPEFULLY LEAD TO IMPROVED SURVIVAL AND BETTER QUALITY OF LIFE FOR PANCREATIC CANCER PATIENTS IN THE FUTURE. 2006 11 461 38 ARCHITECTS OF PITUITARY TUMOUR GROWTH. THE PITUITARY IS A MASTER GLAND RESPONSIBLE FOR THE MODULATION OF CRITICAL ENDOCRINE FUNCTIONS. PITUITARY NEUROENDOCRINE TUMOURS (PITNETS) DISPLAY A CONSIDERABLE PREVALENCE OF 1/1106, FREQUENTLY OBSERVED AS BENIGN SOLID TUMOURS. PITNETS STILL REPRESENT A CAUSE OF IMPORTANT MORBIDITY, DUE TO HORMONAL SYSTEMIC DEREGULATION, WITH SURGICAL, RADIOLOGICAL OR CHRONIC TREATMENT REQUIRED FOR ILLNESS MANAGEMENT. THE APPARENT SCARCENESS, UNCOMMON BEHAVIOUR AND MOLECULAR FEATURES OF PITNETS HAVE RESULTED IN A RELATIVELY SLOW PROGRESS IN DEPICTING THEIR PATHOGENESIS. AN APPROPRIATE INTERPRETATION OF DIFFERENT PHENOTYPES OR CELLULAR OUTCOMES DURING TUMOUR GROWTH IS DESIRABLE, SINCE HISTOPATHOLOGICAL CHARACTERIZATION STILL REMAINS THE MAIN OPTION FOR PROGNOSIS ELUCIDATION. IMPROVED KNOWLEDGE OBTAINED IN RECENT DECADES ABOUT PITUITARY TUMORIGENESIS HAS REVEALED THAT THIS PROCESS INVOLVES SEVERAL CELLULAR ROUTES IN ADDITION TO PROLIFERATION AND DEATH, WITH ITS MODULATION DEPENDING ON MANY SIGNALLING PATHWAYS RATHER THAN BEING THE RESULT OF ABNORMALITIES OF A UNIQUE PROLIFERATION PATHWAY, AS SOMETIMES PRESENTED. PITNETS CAN DISPLAY INTRINSIC HETEROGENEITY AND CELL SUBPOPULATIONS WITH DIVERSE BIOLOGICAL, GENETIC AND EPIGENETIC PARTICULARITIES, INCLUDING TUMORIGENIC POTENTIAL. HENCE, TO OBTAIN A BETTER UNDERSTANDING OF PITNET GROWTH NEW APPROACHES ARE REQUIRED AND THE SYSTEMATIZATION OF THE AVAILABLE DATA, WITH THE ROLE OF CELL DEATH PROGRAMS, AUTOPHAGY, STEM CELLS, CELLULAR SENESCENCE, MITOCHONDRIAL FUNCTION, METABOLIC REPROGRAMMING STILL BEING EMERGING FIELDS IN PITUITARY RESEARCH. WE ENVISAGE THAT THROUGH THE COMBINATION OF MOLECULAR, GENETIC AND EPIGENETIC DATA, TOGETHER WITH THE IMPROVED MORPHOLOGICAL, BIOCHEMICAL, PHYSIOLOGICAL AND METABOLICALLY KNOWLEDGE ON PITUITARY NEOPLASTIC POTENTIAL ACCUMULATED IN RECENT DECADES, TUMOUR CLASSIFICATION SCHEMES WILL BECOME MORE ACCURATE REGARDING TUMOUR ORIGIN, BEHAVIOUR AND PLAUSIBLE CLINICAL RESULTS. 2022 12 4148 40 MECHANISTIC BASIS OF EX VIVO UMBILICAL CORD BLOOD STEM PROGENITOR CELL EXPANSION. UMBILICAL CORD BLOOD (CB) TRANSPLANTATION HAS BEEN USED SUCCESSFULLY IN HUMANS FOR THREE DECADES DUE TO ITS RAPID AVAILABILITY FOR PATIENTS LACKING A SUITABLE ALLOGENEIC DONOR, LESS STRINGENT HLA MATCHING REQUIREMENTS, AND LOW RATES OF RELAPSE AND CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD). HOWEVER, CB TRANSPLANTATION IS ASSOCIATED WITH COMPLICATIONS, SUCH AS DELAYED HEMATOPOIETIC ENGRAFTMENT, GRAFT FAILURE, WHICH INCREASES INFECTION AND BLEEDING AND CAUSES LONGER HOSPITAL STAYS, AND TRANSPLANT-RELATED MORTALITY. THE MAJORITY OF THESE BIOLOGICAL LIMITATIONS ARE DUE TO THE UNFORESEEABLE FUNCTIONAL POTENCY OF MULTIPOTENT HEMATOPOIETIC STEM CELLS (HSCS), WHICH REDUCE THE PREDICTABILITY OF SUCCESSFUL TRANSPLANTATION; HOWEVER, SEVERAL STRATEGIES HAVE BEEN DEVELOPED TO INCREASE THE NUMBER OF HEMATOPOIETIC STEM PROGENITOR CELLS (HSPCS) INFUSED DURING CB TRANSPLANTATION. THIS REVIEW PRIMARILY ADDRESSES THE METHODS THAT PROMOTE EX VIVO CB EXPANSION WITHIN THE CONTEXT OF SYMMETRICAL AND ASYMMETRICAL HSC DIVISION AND THOSE THAT RELY ON EPIGENETIC MECHANISMS, ALONG WITH THE REPORTEDLY MOST SUCCESSFUL CYTOKINE COMBINATIONS. WE ALSO REVIEW RECENT CLINICAL RESEARCH ON SMALL MOLECULES (STEMREGENIN-1, UM171, AND NICOTINAMIDE) IN EX VIVO EXPANDED CB AND DISCUSS YET UNVALIDATED PRECLINICAL STRATEGIES. EXPANDING AND TRANSPLANTING CB GRAFT ENRICHED IN HSPCS IN A SINGLE CB UNIT IS A PARTICULARLY EXCITING PROSPECT WITH THE POTENTIAL TO IMPROVE THE USE AND AVAILABILITY OF CB GRAFTS. GREATER KNOWLEDGE OF OPTIMAL EX VIVO EXPANSION STRATEGIES, CELL LONGEVITY, AND GRAFT POTENCY WILL EXPAND THE SCOPE OF CELLULAR THERAPIES. ALSO THE DEVELOPMENT OF ADEQUATE EX VIVO HSPC EXPANSION STRATEGIES COULD BRING EXPANDED CORD BLOOD GRAFTS TO THE FOREFRONT OF TRANSPLANT THERAPY AND REGENERATIVE MEDICINE. 2020 13 4926 41 PARKINSON'S DISEASE AND SARS-COV-2 INFECTION: PARTICULARITIES OF MOLECULAR AND CELLULAR MECHANISMS REGARDING PATHOGENESIS AND TREATMENT. ACCUMULATING DATA SUGGEST THAT CHRONIC NEUROINFLAMMATION-MEDIATED NEURODEGENERATION IS A SIGNIFICANT CONTRIBUTING FACTOR FOR PROGRESSIVE NEURONAL AND GLIAL CELL DEATH IN AGE-RELATED NEURODEGENERATIVE PATHOLOGY. FURTHERMORE, IT COULD BE ENCOUNTERED AS LONG-TERM CONSEQUENCES IN SOME VIRAL INFECTIONS, INCLUDING POST-COVID-19 PARKINSONISM-RELATED CHRONIC SEQUELAE. THE CURRENT SYSTEMATIC REVIEW IS FOCUSED ON A RECENT QUESTION AROUSED DURING THE PANDEMIC'S SUCCESSIVE WAVES: ARE THERE POST-SARS-COV-2 IMMUNE-MEDIATED REACTIONS RESPONSIBLE FOR PROMOTING NEURODEGENERATION? DOES THE HOST'S DYSREGULATED IMMUNE COUNTER-OFFENSIVE CONTRIBUTE TO THE PATHOGENESIS OF NEURODEGENERATIVE DISEASES, EMERGING AS PARKINSON'S DISEASE, IN A COMPLEX INTERRELATION BETWEEN GENETIC AND EPIGENETIC RISK FACTORS? A SYNTHETIC AND SYSTEMATIC LITERATURE REVIEW WAS ACCOMPLISHED BASED ON THE "PREFERRED REPORTING ITEMS FOR SYSTEMATIC PRINCIPLES REVIEWS AND META-ANALYSES" (PRISMA) METHODOLOGY, INCLUDING REGISTRATION ON THE SPECIFIC ONLINE PLATFORM: INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS-PROSPERO, NO. 312183. INITIALLY, 1894 ARTICLES WERE DETECTED. AFTER FULFILLING THE FIVE STEPS OF THE SELECTION METHODOLOGY, 104 PAPERS WERE SELECTED FOR THIS SYNTHETIC REVIEW. DOCUMENTATION WAS ENHANCED WITH A SUPPLEMENTARY 47 BIBLIOGRAPHIC RESOURCES IDENTIFIED IN THE LITERATURE WITHIN A NON-STANDARDIZED SEARCH CONNECTED TO THE SUBJECT. AS A FINAL STEP OF THE PRISMA METHOD, WE HAVE FULFILLED A POPULATION-INTERVENTION-COMPARISON-OUTCOME-TIME (PICOT)/POPULATION-INTERVENTION-COMPARISON-OUTCOME-STUDY TYPE (PICOS)-BASED METANALYSIS OF CLINICAL TRIALS IDENTIFIED AS CONNECTED TO OUR SEARCH, TARGETING THE OUTCOMES OF REHABILITATIVE KINESITHERAPEUTIC INTERVENTIONS COMPARED TO CLINICAL APPROACHES LACKING SUCH KIND OF TREATMENT. ACCORDINGLY, WE IDENTIFIED 10 CLINICAL TRIALS RELATED TO OUR ARTICLE. THE MULTI/INTERDISCIPLINARY CONVENTIONAL THERAPY OF PARKINSON'S DISEASE AND NON-CONVENTIONAL MULTITARGET APPROACH TO AN INTEGRATIVE TREATMENT WAS BRIEFLY ANALYZED. THIS ARTICLE SYNTHESIZES THE CURRENT FINDINGS ON THE PATHOGENIC INTERFERENCE BETWEEN THE DYSREGULATED COMPLEX MECHANISMS INVOLVED IN AGING, NEUROINFLAMMATION, AND NEURODEGENERATION, FOCUSING ON PARKINSON'S DISEASE AND THE ACUTE AND CHRONIC REPERCUSSIONS OF COVID-19. TIME WILL TELL WHETHER COVID-19 NEUROINFLAMMATORY EVENTS COULD TRIGGER LONG-TERM NEURODEGENERATIVE EFFECTS AND CONTRIBUTE TO THE WORSENING AND/OR EXPLOSION OF NEW CASES OF PD. THE EXTENT OF THE INTERRELATED NEUROPATHOGENIC PHENOMENON REMAINS OBSCURE, SO FURTHER CLINICAL OBSERVATIONS AND PROSPECTIVE LONGITUDINAL COHORT STUDIES ARE NEEDED. 2022 14 1340 32 DESIGNING SAFER DRUGS: (Q)SAR-BASED IDENTIFICATION OF MUTAGENS AND CARCINOGENS. MUTAGENICITY AND CARCINOGENICITY ARE CHRONIC EFFECTS OF PRIMARY CONCERN FOR HUMAN HEALTH. A UNIFYING APPROACH TO THEIR MECHANISTIC UNDERSTANDING IS THE RECOGNITION THAT MANY CHEMICALS PROVOKE BOTH EFFECTS BY ELECTROPHILIC ATTACK TO THE BIOLOGICAL MACROMOLECULES, AS SUCH OR AFTER METABOLISM (GENOTOXIC CARCINOGENICITY). QSARS OF INDIVIDUAL CLASSES OF GENOTOXIC CARCINOGENS HAVE CONTRIBUTED TO THE ELUCIDATION OF THE CHEMICAL DETERMINANTS OF THIS ACTIVITY. LITTLE WORK HAS BEEN DONE ON THE EPIGENETIC CARCINOGENS, ACTING THROUGH NON-GENOTOXIC, VERY SPECIFIC MECHANISMS. HOWEVER, THE EXISTING QSARS FOR INDIVIDUAL CHEMICAL CLASSES ARE TOO FEW TO BE OF REAL USEFULNESS IN THE SCREENING OF MASSES OF CANDIDATE DRUGS. MODELS FOR PREDICTING THE CARCINOGENICITY OF "ANY TYPE" OF CHEMICALS HAVE BEEN PROPOSED: PROSPECTIVE PREDICTION EXERCISES POINTED TO THE SERIOUS LIMITATIONS OF MOST OF THESE APPROACHES. THE BEST ALTERNATIVE IS PROVIDED BY PANELS OF HUMAN EXPERTS. THE ABOVE PREDICTION EXERCISES CONSIDERED SAMPLES OF GENERAL CHEMICALS, THUS WE SPECIFICALLY ADDRESSED IN THIS PAPER THE ISSUE OF PHARMACEUTICAL DRUGS. WE APPLIED OUR EXPERT KNOWLEDGE TO A DATABASE OF DRUGS WHOSE CARCINOGENICITY/NONCARCINOGENICITY STATUS WAS KNOWN. WHEREAS MOST OF THE NONCARCINOGENS WERE CORRECTLY IDENTIFIED, OUR PREDICTION OF CARCINOGENS WAS LESS SUCCESSFUL THAN WITH THE GENERAL CHEMICALS. SEVERAL CARCINOGENIC DRUGS DID NOT SHOW RECOGNIZED STRUCTURAL ALERTS, AND SUPPOSEDLY ACTED BY EPIGENETIC MECHANISMS. WHEREAS THE CONTRIBUTION OF HUMAN EXPERTS IS HIGHLY VALUABLE IN THIS PHASE (E.G. PRIORITY SETTING), MORE WORK IS NECESSARY ON: A) EPIGENETIC CARCINOGENS; B) EFFICIENT COMPUTERIZED MODELS. 2003 15 6480 33 TOWARDS PRECISION MEDICINE IN GENERALIZED ANXIETY DISORDER: REVIEW OF GENETICS AND PHARMACO(EPI)GENETICS. GENERALIZED ANXIETY DISORDER (GAD) IS A PREVALENT AND CHRONIC MENTAL DISORDER THAT ELICITS WIDESPREAD FUNCTIONAL IMPAIRMENT. GIVEN THE HIGH DEGREE OF NON-RESPONSE/PARTIAL RESPONSE AMONG PATIENTS WITH GAD TO AVAILABLE PHARMACOLOGICAL TREATMENTS, THERE IS A STRONG NEED FOR NOVEL APPROACHES THAT CAN OPTIMIZE OUTCOMES, AND LEAD TO MEDICATIONS THAT ARE SAFER AND MORE EFFECTIVE. ALTHOUGH INVESTIGATIONS HAVE IDENTIFIED INTERESTING TARGETS PREDICTING TREATMENT RESPONSE THROUGH PHARMACOGENETICS (PGX), PHARMACO-EPIGENETICS, AND NEUROIMAGING METHODS, THESE STUDIES ARE OFTEN SOLITARY, NOT REPLICATED, AND CARRY SEVERAL LIMITATIONS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CURRENT STATUS OF GAD GENETICS AND PGX AND PRESENTS POTENTIAL STRATEGIES TO IMPROVE TREATMENT RESPONSE BY COMBINING BETTER PHENOTYPING WITH PGX AND IMPROVED ANALYTICAL METHODS. THESE STRATEGIES CARRY THE DUAL BENEFIT OF DELIVERING DATA ON BIOMARKERS OF TREATMENT RESPONSE AS WELL AS POINTING TO DISEASE MECHANISMS THROUGH THE BIOLOGY OF THE MARKERS ASSOCIATED WITH RESPONSE. OVERALL, THESE EFFORTS CAN SERVE TO IDENTIFY CLINICAL, GENETIC, AND EPIGENETIC FACTORS THAT CAN BE INCORPORATED INTO A PHARMACO(EPI)GENETIC TEST THAT MAY ULTIMATELY IMPROVE TREATMENT RESPONSE AND REDUCE THE SOCIOECONOMIC BURDEN OF GAD. 2019 16 2901 31 GENDER DIFFERENCES IN GERM-CELL MUTAGENESIS AND GENETIC RISK. CURRENT INTERNATIONAL CLASSIFICATION SYSTEMS FOR CHEMICAL MUTAGENS ARE HAZARD-BASED RATHER THAN AIMED AT ASSESSING RISKS QUANTITATIVELY. IN THE PAST, GERM-CELL TESTS HAVE BEEN MAINLY PERFORMED WITH A LIMITED NUMBER OF SOMATIC CELL MUTAGENS, AND RARELY UNDER CONDITIONS AIMED AT COMPARING GENDER-SPECIFIC DIFFERENCES IN SUSCEPTIBILITY TO MUTAGEN EXPOSURES. THERE ARE PROFOUND DIFFERENCES IN THE GENETIC CONSTITUTION, AND IN HORMONAL, STRUCTURAL, AND FUNCTIONAL ASPECTS OF DIFFERENTIATION AND CONTROL OF GAMETOGENESIS BETWEEN THE SEXES. A CRITICAL REVIEW OF THE LITERATURE SUGGESTS THAT THESE DIFFERENCES MAY HAVE A PROFOUND IMPACT ON THE RELATIVE SUSCEPTIBILITY, STAGE OF HIGHEST SENSITIVITY AND THE RELATIVE RISK FOR THE GENESIS OF GENE MUTATION, AS WELL AS STRUCTURAL AND NUMERICAL CHROMOSOMAL ABERRATIONS IN MALE AND FEMALE GERM CELLS. TRANSMISSION OF GERM-CELL MUTATIONS TO THE OFFSPRING MAY ALSO ENCOUNTER GENDER-SPECIFIC INFLUENCES. GENDER DIFFERENCES IN SUSCEPTIBILITY TO CHEMICALLY DERIVED ALTERATIONS IN IMPRINTING PATTERNS MAY POSE A THREAT FOR THE HEALTH OF THE OFFSPRING AND MAY ALSO BE TRANSMITTED TO FUTURE GENERATIONS. RECENT REPORTS ON DIFFERENT GENETIC EFFECTS FROM HIGH ACUTE AND FROM CHRONIC LOW-DOSE EXPOSURES CHALLENGE THE VALIDITY OF CONCLUSIONS DRAWN FROM STANDARD METHODS OF MUTAGENICITY TESTING. IN CONCLUSION, RESEARCH IS URGENTLY NEEDED TO IDENTIFY GENETIC HAZARDS FOR A LARGER RANGE OF CHEMICAL COMPOUNDS, INCLUDING THOSE SUSPECTED TO DISTURB PROPER CHROMOSOME SEGREGATION. ALTERATIONS IN EPIGENETIC PROGRAMMING AND THEIR HEALTH CONSEQUENCES WILL HAVE TO BE INVESTIGATED. MORE ATTENTION SHOULD BE PAID TO GENDER-SPECIFIC GENETIC EFFECTS. FINALLY, THE DATABASE FOR GERM-CELL MUTAGENS SHOULD BE ENLARGED USING MOLECULAR METHODOLOGIES, AND GENETIC EPIDEMIOLOGY STUDIES SHOULD BE PERFORMED WITH THESE TECHNIQUES TO VERIFY HUMAN GENETIC RISK. 2007 17 5447 45 REPOSITIONING LIDOCAINE AS AN ANTICANCER DRUG: THE ROLE BEYOND ANESTHESIA. WHILE CANCER TREATMENT HAS IMPROVED DRAMATICALLY, IT HAS ALSO ENCOUNTERED MANY CRITICAL CHALLENGES, SUCH AS DISEASE RECURRENCE, METASTASIS, AND DRUG RESISTANCE, MAKING NEW DRUGS WITH NOVEL MECHANISMS AN URGENT CLINICAL NEED. THE TERM "DRUG REPOSITIONING," ALSO KNOWN AS OLD DRUGS FOR NEW USES, HAS EMERGED AS ONE PRACTICAL STRATEGY TO DEVELOP NEW ANTICANCER DRUGS. ANESTHETICS HAVE BEEN WIDELY USED IN SURGICAL PROCEDURES TO REDUCE THE EXCRUCIATING PAIN. LIDOCAINE, ONE OF THE MOST-USED LOCAL ANESTHETICS IN CLINICAL SETTINGS, HAS BEEN FOUND TO SHOW MULTI-ACTIVITIES, INCLUDING POTENTIAL IN CANCER TREATMENT. GROWING EVIDENCE SHOWS THAT LIDOCAINE MAY NOT ONLY WORK AS A CHEMOSENSITIZER THAT SENSITIZES OTHER CONVENTIONAL CHEMOTHERAPEUTICS TO CERTAIN RESISTANT CANCER CELLS, BUT ALSO COULD SUPPRESS CANCER CELLS GROWTH BY SINGLE USE AT DIFFERENT DOSES OR CONCENTRATIONS. LIDOCAINE COULD SUPPRESS CANCER CELL GROWTH IN VITRO AND IN VIVO VIA MULTIPLE MECHANISMS, SUCH AS REGULATING EPIGENETIC CHANGES AND PROMOTING PRO-APOPTOSIS PATHWAYS, AS WELL AS REGULATING ABC TRANSPORTERS, METASTASIS, AND ANGIOGENESIS, ETC., PROVIDING VALUABLE INFORMATION FOR ITS FURTHER APPLICATION IN CANCER TREATMENT AND FOR NEW DRUG DISCOVERY. IN ADDITION, LIDOCAINE IS NOW UNDER CLINICAL TRIALS TO TREAT CERTAIN TYPES OF CANCER. IN THE CURRENT REVIEW, WE SUMMARIZE THE RESEARCH AND ANALYZE THE UNDERLYING MECHANISMS, AND ADDRESS KEY ISSUES IN THIS AREA. 2020 18 728 39 CAN WE IDENTIFY PATIENTS WITH HIGH RISK OF OSTEOARTHRITIS PROGRESSION WHO WILL RESPOND TO TREATMENT? A FOCUS ON BIOMARKERS AND FRAILTY. OSTEOARTHRITIS (OA), A DISEASE AFFECTING DIFFERENT PATIENT PHENOTYPES, APPEARS AS AN OPTIMAL CANDIDATE FOR PERSONALIZED HEALTHCARE. THE AIM OF THE DISCUSSIONS OF THE EUROPEAN SOCIETY FOR CLINICAL AND ECONOMIC ASPECTS OF OSTEOPOROSIS AND OSTEOARTHRITIS (ESCEO) WORKING GROUP WAS TO EXPLORE THE VALUE OF MARKERS OF DIFFERENT SOURCES IN DEFINING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. THE ESCEO ORGANIZED A SERIES OF MEETINGS TO EXPLORE THE POSSIBILITY OF IDENTIFYING PATIENTS WHO WOULD MOST BENEFIT FROM TREATMENT FOR OA, ON THE BASIS OF RECENT DATA AND EXPERT OPINION. IN THE FIRST MEETING, PATIENT PHENOTYPES WERE IDENTIFIED ACCORDING TO THE NUMBER OF AFFECTED JOINTS, BIOMECHANICAL FACTORS, AND THE PRESENCE OF LESIONS IN THE SUBCHONDRAL BONE. IN THE SECOND MEETING, SUMMARIZED IN THE PRESENT ARTICLE, THE WORKING GROUP EXPLORED OTHER MARKERS INVOLVED IN OA. PROFILES OF PATIENTS MAY BE DEFINED ACCORDING TO THEIR LEVEL OF PAIN, FUNCTIONAL LIMITATION, AND PRESENCE OF COEXISTENT CHRONIC CONDITIONS INCLUDING FRAILTY STATUS. A CONSIDERABLE AMOUNT OF DATA SUGGESTS THAT MAGNETIC RESONANCE IMAGING MAY ALSO ASSIST IN DELINEATING DIFFERENT PHENOTYPES OF PATIENTS WITH OA. AMONG MULTIPLE BIOCHEMICAL BIOMARKERS IDENTIFIED, NONE IS SUFFICIENTLY VALIDATED AND RECOGNIZED TO IDENTIFY PATIENTS WHO SHOULD BE TREATED. CONSIDERABLE EFFORTS ARE ALSO BEING MADE TO IDENTIFY GENETIC AND EPIGENETIC FACTORS INVOLVED IN OA, BUT RESULTS ARE STILL LIMITED. THE MANY POTENTIAL BIOMARKERS THAT COULD BE USED AS POTENTIAL STRATIFIERS ARE PROMISING, BUT MORE RESEARCH IS NEEDED TO CHARACTERIZE AND QUALIFY THE EXISTING BIOMARKERS AND TO IDENTIFY NEW CANDIDATES. 2015 19 4686 51 NEW THERAPEUTIC TARGETS IN TRANSFUSION-DEPENDENT AND -INDEPENDENT THALASSEMIA. BETA-THALASSEMIAS ARE CHARACTERIZED BY REDUCED PRODUCTION OF BETA-GLOBIN CHAIN, RESULTING IN ALPHA/BETA-CHAIN UNBALANCE AND PRECIPITATION OF ALPHA-GLOBIN-HEME COMPLEXES AND DETERMINING INEFFECTIVE ERYTHROPOIESIS. INEFFECTIVE ERYTHROPOIESIS, CHRONIC HEMOLYTIC ANEMIA, AND COMPENSATORY HEMATOPOIETIC EXPANSION ARE THE DISEASE HALLMARKS, AND THEY ARE RELATED TO THE SEVERITY OF THE CHAIN UNBALANCE. SEVERAL CLINICAL FORMS OF BETA-THALASSEMIA, INCLUDING THE COINHERITANCE OF BETA-THALASSEMIA WITH HEMOGLOBIN E RESULTING IN HEMOGLOBIN E/BETA-THALASSEMIA, HAVE BEEN DESCRIBED. CLINICALLY, BETA-THALASSEMIAS CAN BE CLASSIFIED AS TRANSFUSION-DEPENDENT THALASSEMIA (TDT) AND NON-TRANSFUSION-DEPENDENT THALASSEMIA (NTDT) ACCORDING TO THE SEVERITY OF THE PHENOTYPE, WHICH IS CAUSED BY A WIDE SPECTRUM OF MUTATIONS IN A HOMOZYGOUS OR COMPOUND HETEROZYGOUS STATE. CURRENT TREATMENT OF TDT CONSISTS OF REGULAR TRANSFUSIONS THAT LEAD TO IRON OVERLOAD, REQUIRING IRON CHELATION TO PREVENT IRON-RELATED ORGAN TOXICITY. NTDT PATIENTS DO NOT REQUIRE TRANSFUSIONS OR ONLY OCCASIONALLY REQUIRE THEM; HOWEVER, THEY DEVELOP IRON OVERLOAD AS WELL BECAUSE OF INCREASED INTESTINAL IRON ABSORPTION CAUSED BY CHRONIC ANEMIA. HEMATOPOIETIC STEM CELL ALLOGENIC TRANSPLANT IS THE ONLY APPROVED CURE FOR BETA-THALASSEMIA; HOWEVER, IT IS STILL LIMITED BY CLINICAL CONDITIONS AND THE AVAILABILITY OF MATCHED DONORS AS WELL AS BY POTENTIAL GRAFT-VERSUS-HOST DISEASE (GVHD). GENE THERAPY COULD AVOID THE GVHD RISK, ALTHOUGH HEMATOPOIETIC STEM CELLS MUST BE GENETICALLY MODIFIED EX VIVO. EPIGENETIC MANIPULATION AND GENOMIC EDITING ARE NOVEL EXPERIMENTAL APPROACHES. AN INCREASED UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT CONTROLS THE DISEASE PROCESS PROMPTED US TO EXPLORE ALTERNATIVE THERAPEUTIC APPROACHES THAT ADDRESS THE UNDERLYING CHAIN UNBALANCE, INEFFECTIVE ERYTHROPOIESIS, AND IRON DYSREGULATION. MOLECULES, SUCH AS JAK2 INHIBITORS AND THE ACTIVIN-RECEPTOR LIGAND TRAP THAT TARGET INEFFECTIVE ERYTHROPOIESIS, ARE ALREADY IN CLINICAL TRIALS WITH PROMISING RESULTS. OTHER AGENTS AIMED TO GENERATE IRON-RESTRICTED ERYTHROPOIESIS ARE ALSO UNDER EXPERIMENTAL EVALUATION. 2017 20 1882 32 EMERGING TREATMENTS IN ACUTE MYELOID LEUKAEMIA. ACUTE MYELOID LEUKAEMIA (AML) IS THE MOST COMMON FORM OF LEUKAEMIA IN YOUNG ADULTS. ALTHOUGH 75-85% OF PATIENTS WILL ACHIEVE COMPLETE REMISSION AFTER INDUCTION CHEMOTHERAPY, THE LONG-TERM SURVIVAL IS STILL < 50% AT 5 YEARS. CHEMOTHERAPY HAS INCREASED IN INTENSITY IN RECENT YEARS AND IS PERCEIVED TO HAVE REACHED THE LIMIT OF TOXICITY. ALLOGENEIC BONE MARROW TRANSPLANTATION, WHICH IS UNDOUBTEDLY THE MOST EFFECTIVE WAY TO PREVENT RELAPSE, MAY NOT ADD SUBSTANTIAL SURVIVAL BENEFITS. SEVERAL NEW PHARMACOLOGICAL APPROACHES TO THE TREATMENT OF AML ARE NOW BECOMING AVAILABLE, WITH VARIOUS MOLECULAR TARGETS IDENTIFIED, INCLUDING THE FARNESYLATION OF RAS FAMILY PROTEINS AND TYROSINE KINASES INVOLVED IN SIGNAL TRANSDUCTION AND EPIGENETIC METHYLATION. MORE SELECTIVE DELIVERY OF CHEMOTHERAPEUTIC AGENTS IS ALSO FEASIBLE USING HUMANISED MONOCLONAL ANTIBODIES, WITH THE INTRIGUING POSSIBILITY OF INCREASING TREATMENT DELIVERY WITHOUT INCREASING THE TOXICITY. HOWEVER, DESPITE THE PROGRESS IN THE RATIONAL DESIGN OF DRUGS IN DISORDERS SUCH AS CHRONIC MYELOID LEUKAEMIA, AML LACKS A SINGLE SPECIFIC PATHOGNOMIC GENETIC EVENT TO ACT AS A DRUG TARGET. THIS REVIEW DISCUSSES THE DRUGS PRESENTLY UNDER INVESTIGATION IN PHASE II OR PHASE III TRIALS IN AML. 2004