1 6035 101 THE CHALLENGES OF LONG-TERM TRANSCRIPTIONAL GENE SILENCING BY RNA VIRUSES. SINCE THE PAST FEW DECADES, THE SMALL RNA (SRNA) TECHNOLOGIES INCLUDING SMALL INTERFERING RNA AND MIRNA HAVE BEEN WIDELY EXPLORED FOR THERAPEUTIC DEVELOPMENT. CLASSICALLY, THESE SRNAS TARGET THE CODING REGIONS OF MRNA TO EXERT TEMPORAL GENE SILENCING IN A POST-TRANSCRIPTIONAL MANNER. INTERESTINGLY, SRNAS TARGETING GENE PROMOTERS HAVE BEEN RECENTLY DESCRIBED TO MEDIATE LONG-TERM TRANSCRIPTIONAL GENE SILENCING (TGS) BY EPIGENETIC MODIFICATIONS. THIS HAS FURTHER HARNESSED THE POTENTIAL APPLICATIONS IN GENE THERAPY. HOWEVER, EFFICIENT DELIVERY IS A COMMON HURDLE FOR ALMOST ANY TYPES OF GENE THERAPY APPROACHES. IN A RECENT ISSUE OF TRENDS IN BIOCHEMICAL SCIENCES, BALTUSNIKAS ET AL. HAVE PROPOSED TO USE RNA VIRUSES TO DELIVER SRNA FOR LONG-TERM TGS, SUGGESTING LONG-TERM THERAPY BY A SINGLE ADMINISTRATION APPROACH FOR VARIOUS DISEASES, INCLUDING CHRONIC, INCURABLE, AND FATAL ILLNESSES. BEING A NOVEL AND AMBITIOUS GENE THERAPY STRATEGY, WE HEREBY WOULD LIKE TO EMPHASIZE THREE MAJOR CHALLENGES AND PROPOSE POTENTIAL SOLUTIONS. 2018 2 3938 25 LNC(ING)RNAS TO THE "SHOCK AND KILL" STRATEGY FOR HIV-1 CURE. THE ADVENT OF ANTIRETROVIRAL THERAPY ALMOST 25 YEARS AGO HAS TRANSFORMED HIV-1 INFECTION INTO A MANAGEABLE CHRONIC CONDITION, ALBEIT STILL INCURABLE. THE INABILITY OF THE TREATMENT REGIMEN TO ELIMINATE LATENTLY INFECTED CELLS THAT HARBOR THE VIRUS IN AN EPIGENETICALLY SILENT STATE POSES A MAJOR HURDLE. CURRENT CURE APPROACHES ARE FOCUSED ON A "SHOCK AND KILL" STRATEGY THAT USES LATENCY-REVERSING AGENTS TO CHEMICALLY REVERSE THE PROVIRAL QUIESCENCE IN LATENTLY INFECTED CELLS, FOLLOWED BY IMMUNE-MEDIATED CLEARANCE OF REACTIVATED CELLS. TO DATE, HUNDREDS OF COMPOUNDS HAVE BEEN INVESTIGATED FOR VIRAL REACTIVATION, YET NONE HAS RESULTED IN A FUNCTIONAL CURE. THE INSUFFICIENCY OF THESE LATENCY-REVERSING AGENTS (LRAS) ALONE INDICATES A CRITICAL NEED FOR ADDITIONAL, ALTERNATE APPROACHES SUCH AS GENETIC MANIPULATION. LONG NON-CODING RNAS (LNCRNAS) ARE AN EMERGING CLASS OF REGULATORY RNAS WITH FUNCTIONAL ROLES IN MANY CELLULAR PROCESSES, INCLUDING EPIGENETIC MODULATION. A NUMBER OF LNCRNAS HAVE ALREADY BEEN IMPLICATED TO PLAY IMPORTANT ROLES IN HIV-1 LATENCY AND, AS SUCH, PHARMACOLOGICAL MODULATION OF LNCRNAS CONSTITUTES A RATIONAL ALTERNATIVE APPROACH IN HIV-1 CURE RESEARCH. IN THIS REVIEW, WE DISCUSS THE CURRENT STATE OF KNOWLEDGE OF THE ROLE OF LNCRNAS IN HIV-1 INFECTION AND EXPLORE THE SCOPE FOR A LNCRNA-MEDIATED GENETIC APPROACH WITHIN THE SHOCK AND KILL STRATEGY OF HIV-1 CURE. 2021 3 1101 16 COMBINATION THERAPY USING LHRH AND SOMATOSTATIN ANALOGUES PLUS DEXAMETHASONE IN ANDROGEN ABLATION REFRACTORY PROSTATE CANCER PATIENTS WITH BONE INVOLVEMENT: A BENCH TO BEDSIDE APPROACH. THE DEVELOPMENT OF RESISTANCE TO ANTICANCER THERAPIES IS A MAJOR HURDLE IN PREVENTING LONG-LASTING CLINICAL RESPONSES TO CONVENTIONAL THERAPIES IN HORMONE-REFRACTORY PROSTATE CANCER. HEREIN, THE MOLECULAR EVIDENCE DOCUMENTING THAT BONE METASTASIS MICROENVIRONMENT SURVIVAL FACTORS (MAINLY THE PARACRINE GROWTH HORMONE-INDEPENDENT, UROKINASE-TYPE PLASMINOGEN ACTIVATOR-MEDIATED INCREASE OF IGF-1 AND THE ENDOCRINE PRODUCTION OF GROWTH HORMONE-DEPENDENT IGF-1, MAINLY LIVER-DERIVED IGF-1 PRODUCTION) PRODUCE AN EPIGENETIC FORM OF PROSTATE CANCER CELLS THAT ARE RESISTANT TO PROAPOPTOTIC THERAPIES IS REVIEWED. CONSEQUENTLY, THE AUTHORS PRESENT THE CONCEPTUAL FRAMEWORK OF A NOVEL ANTIBONE MICROENVIRONMENT SURVIVAL FACTOR, MAINLY AN ANTI-IGF-1 HORMONAL MANIPULATION FOR ANDROGEN ABLATION REFRACTORY PROSTATE CANCER (A COMBINATION OF CONVENTIONAL ANDROGEN ABLATION THERAPY [LUTEINISING HORMONE-RELEASING HORMONE AGONIST-A OR ORCHIECTOMY]) WITH DEXAMETHASONE PLUS SOMATOSTATIN ANALOGUE, WHICH YIELDED DURABLE OBJECTIVE RESPONSES AND MAJOR IMPROVEMENT OF BONE PAIN AND PERFORMANCE STATUS IN STAGE D3 PROSTATE CANCER PATIENTS. 2006 4 3906 21 LESSONS LEARNED--RESOLVING THE ENIGMA OF GENETIC FACTORS IN IBS. IBS IS THE MOST PREVALENT FUNCTIONAL GASTROINTESTINAL DISORDER AND PHENOTYPICALLY CHARACTERIZED BY CHRONIC ABDOMINAL DISCOMFORT, PAIN AND ALTERED DEFECATION PATTERNS. THE PATHOPHYSIOLOGY OF IBS IS MULTIFACTORIAL, ALBEIT WITH A SUBSTANTIAL GENETIC COMPONENT. TO DATE, STUDIES USING VARIOUS METHODOLOGIES, RANGING FROM FAMILY AND TWIN STUDIES TO CANDIDATE GENE APPROACHES AND GENOME-WIDE ASSOCIATION STUDIES, HAVE IDENTIFIED SEVERAL GENETIC VARIANTS IN THE CONTEXT OF IBS. YET, DESPITE ENLARGED SAMPLE SIZES, INCREASED STATISTICAL POWER AND META-ANALYSES IN THE PAST 7 YEARS, POSITIVE ASSOCIATIONS ARE STILL SCARCE AND/OR HAVE NOT BEEN REPRODUCED. IN ADDITION, EPIGENETIC AND PHARMACOGENETIC APPROACHES REMAIN IN THEIR INFANCY. A MAJOR HURDLE IS THE LACK OF LARGE HOMOGENIZED CASE-CONTROL COHORTS RECRUITED ACCORDING TO STANDARDIZED AND HARMONIZED CRITERIA. THE COST ACTION BM1106 GENIEUR (GENES IN IRRITABLE BOWEL SYNDROME RESEARCH NETWORK EUROPE) HAS BEEN ESTABLISHED TO ADDRESS THESE OBSTACLES. IN THIS REVIEW, THE (EPI)GENETIC WORKING GROUP OF GENIEUR REPORTS ON THE CURRENT STATE-OF-THE-ART IN THE FIELD, HIGHLIGHTS FUNDAMENTAL FLAWS AND PITFALLS IN CURRENT IBS (EPI)GENETIC RESEARCH AND PROVIDES A VISION ON HOW TO ADDRESS AND IMPROVE (EPI)GENETIC APPROACHES IN THIS COMPLEX DISORDER IN THE FUTURE. 2016 5 5147 31 POTENTIAL ROLES OF LONG NONCODING RNAS AS THERAPEUTIC TARGETS IN ORGAN TRANSPLANTATION. ORGAN TRANSPLANTATION IS THE MOST PREFERRED TREATMENT OPTION FOR END-STAGE ORGAN DISEASES; HOWEVER, ALLOGRAFT REJECTION IS THE MAJOR HURDLE IN SUCCESSFUL LONG-TERM TRANSPLANT SURVIVAL. IN SPITE OF DEVELOPING BETTER HLA MATCHING AND MORE EFFECTIVE IMMUNOSUPPRESSIVE REGIMEN, ONE-YEAR GRAFT SURVIVAL HAS BEEN INCREASED BY NEARLY 90% AND THE INCIDENCE OF ACUTE REJECTION BY ONE-YEAR POST-TRANSPLANTATION HAS BEEN DECREASED BY 12.2% IN THE LAST DECADES, CHRONIC ALLOGRAFT REJECTION HAS REMAINED AS ONE OF THE MAJOR OBSTACLES TO THE LONG-LASTING SURVIVAL OF THE TRANSPLANTED ALLOGRAFT. THEREFORE, SEEMINGLY PREVENTING THE ALLOGRAFT REJECTION AND INDUCING IMMUNOLOGICAL TOLERANCE AGAINST TRANSPLANTED ALLOGRAFTS IS ONE OF THE PRIMARY GOALS IN TRANSPLANTATION RESEARCH TO ENABLE LONG-LASTING GRAFT SURVIVAL. VARIOUS MECHANISMS SUCH AS LONG NONCODING RNAS (LNCRNAS) HAVE BEEN PROPOSED THAT INDUCE IMMUNE TOLERANCE BY MODULATING THE GENE EXPRESSION AND REGULATING INNATE AND ADAPTIVE IMMUNE RESPONSES DURING TRANSPLANTATION. BESIDES, BECAUSE OF INVOLVEMENT IN REGULATING EPIGENETIC, TRANSCRIPTIONAL, AND POST-TRANSLATIONAL MECHANISMS, LNCRNAS COULD AFFECT ALLOGRAFT STATUS. THEREFORE, THESE MOLECULES COULD BE CONSIDERED AS THE POTENTIAL TARGETS FOR PREDICTION, PROGNOSIS, DIAGNOSIS, AND TREATMENT OF GRAFT REJECTION. IT IS SUGGESTED THAT THE NONINVASIVE PREDICTIVE BIOMARKERS HOLD PROMISE TO OVERCOME THE CURRENT LIMITATIONS OF CONVENTIONAL TISSUE BIOPSY IN THE DIAGNOSIS OF REJECTION. HENCE, THIS REVIEW AIMS TO PROVIDE A COMPREHENSIVE OVERVIEW OF LNCRNAS AND THEIR FUNCTION TO FACILITATE DIAGNOSIS, PROGNOSIS, AND PREDICTION OF THE RISK OF GRAFT REJECTION, AND THE SUGGESTIVE THERAPEUTIC CHOICES AFTER TRANSPLANTATION. 2022 6 6439 35 THERAPEUTIC ANTIBODIES: CURRENT STATE AND FUTURE TRENDS--IS A PARADIGM CHANGE COMING SOON? ANTIBODY-BASED THERAPEUTICS CURRENTLY ENJOY UNPRECEDENTED SUCCESS, GROWTH IN RESEARCH AND REVENUES, AND RECOGNITION OF THEIR POTENTIAL. IT APPEARS THAT THE PROMISE OF THE "MAGIC BULLET" HAS LARGELY BEEN REALIZED. THERE ARE CURRENTLY 22 MONOCLONAL ANTIBODIES (MABS) APPROVED BY THE UNITED STATES FOOD AND DRUG ADMINISTRATION (FDA) FOR CLINICAL USE AND HUNDREDS ARE IN CLINICAL TRIALS FOR TREATMENT OF VARIOUS DISEASES INCLUDING CANCERS, IMMUNE DISORDERS, AND INFECTIONS. THE REVENUES FROM THE TOP FIVE THERAPEUTIC ANTIBODIES (RITUXAN, REMICADE, HERCEPTIN, HUMIRA, AND AVASTIN) NEARLY DOUBLED FROM $6.4 BILLION IN 2004 TO $11.7 BILLION IN 2006. DURING THE LAST SEVERAL YEARS MAJOR PHARMACEUTICAL COMPANIES RACED TO ACQUIRE ANTIBODY COMPANIES, WITH A RECENT EXAMPLE OF MEDIMMUNE BEING PURCHASED FOR $15.6 BILLION BY ASTRAZENECA. THESE THERAPEUTIC AND BUSINESS SUCCESSES REFLECT THE MAJOR ADVANCES IN ANTIBODY ENGINEERING WHICH HAVE RESULTED IN THE GENERATION OF SAFE, SPECIFIC, HIGH-AFFINITY, AND NON-IMMUNOGENIC ANTIBODIES DURING THE LAST THREE DECADES. CURRENTLY, SECOND AND THIRD GENERATIONS OF ANTIBODIES ARE UNDER DEVELOPMENT, MOSTLY TO IMPROVE ALREADY EXISTING ANTIBODY SPECIFICITIES. HOWEVER, ALTHOUGH THE REFINEMENT OF ALREADY KNOWN METHODOLOGIES IS CERTAINLY OF GREAT IMPORTANCE FOR POTENTIAL CLINICAL USE, THERE ARE NO CONCEPTUALLY NEW DEVELOPMENTS IN THE LAST DECADE COMPARABLE, FOR EXAMPLE, TO THE DEVELOPMENT OF ANTIBODY LIBRARIES, PHAGE DISPLAY, DOMAIN ANTIBODIES (DABS), AND ANTIBODY HUMANIZATION TO NAME A FEW. A FUNDAMENTAL QUESTION IS THEN WHETHER THERE WILL BE ANOTHER CHANGE IN THE PARADIGM OF RESEARCH AS HAPPENED 1-2 DECADES AGO OR THE CURRENT TREND OF GRADUAL IMPROVEMENT OF ALREADY DEVELOPED METHODOLOGIES AND THERAPEUTIC ANTIBODIES WILL CONTINUE. ALTHOUGH ANY PREDICTION COULD PROVE INCORRECT, IT APPEARS THAT CONCEPTUALLY NEW METHODOLOGIES ARE NEEDED TO OVERCOME THE FUNDAMENTAL PROBLEMS OF DRUG (ANTIBODY) RESISTANCE DUE TO GENETIC OR/AND EPIGENETIC ALTERATIONS IN CANCER AND CHRONIC INFECTIONS, AS WELL AS PROBLEMS RELATED TO ACCESS TO TARGETS AND COMPLEXITY OF BIOLOGICAL SYSTEMS. IF NEW METHODOLOGIES ARE NOT DEVELOPED, IT IS LIKELY THAT GRADUAL SATURATION WILL OCCUR IN THE PIPELINE OF CONCEPTUALLY NEW ANTIBODY THERAPEUTICS. IN THIS SCENARIO WE WILL WITNESS AN INCREASE IN COMBINATION OF TARGETS AND ANTIBODIES, AND FURTHER ATTEMPTS TO PERSONALIZE TARGETED TREATMENTS BY USING APPROPRIATE BIOMARKERS AS WELL AS TO DEVELOP NOVEL SCAFFOLDS WITH PROPERTIES THAT ARE SUPERIOR TO THOSE OF THE ANTIBODIES NOW IN CLINICAL USE. 2009 7 5154 23 PRAKRITI-BASED MEDICINE: A STEP TOWARDS PERSONALIZED MEDICINE. THE CONCEPT OF PERSONALIZED MEDICINE HAS BEEN AROUND FOR AS LONG AS PEOPLE HAVE BEEN PRACTICING MEDICINE. FROM CHARAKA TO HIPPOCRATES, ALL HAVE PRACTICED THE PERSONALIZED APPROACH FOR TREATING A DISEASE. IN THE 21(ST) CENTURY, PERSONALIZED MEDICINE IS ALL ABOUT DNA. WHEREAS THE SINGLE NUCLEOTIDE POLYMORPHISM (SNP) AND EPIGENETIC FACTORS INFLUENCE DRUG RESPONSE AND FORM THE BASIS OF PERSONALIZED MEDICINE, THE TRIDOSHA THEORY FORMS THE BASIS OF PRAKRITI-BASED MEDICINE. IT IS WELL ESTABLISHED BY NOW THAT WESTERN ALLOPATHIC MEDICINE IS EXCELLENT IN HANDLING ACUTE MEDICAL CRISES, WHEREAS AYURVEDA HAS SUCCESSFULLY DEMONSTRATED AN ABILITY TO MANAGE CHRONIC DISORDERS THAT WESTERN MEDICINE HAS BEEN UNABLE TO CURE. WITH EFFECTIVE INTEGRATION OF 'OMICS' PRAKRITI-BASED MEDICINE CAN PLAY A VITAL ROLE IN THIS CHANGING SCENARIO OF GLOBAL HEALTH WISDOM AS AYURVEDA OFFERS ITS MODALITIES BY WAY OF AHARA (DIET), VIHARA (LIFESTYLE), AND AUSHADHI (MEDICATION), WHICH ARE THE THREE PILLARS OF PRAKRITI-BASED MEDICINE MAKING IT A HOLISTIC SCIENCE. PRAKRITI-BASED MEDICINE AND OTHER TRADITIONAL MEDICINE SYSTEMS HAVE THE POTENTIAL TO OFFER REMEDIES TO THE CHALLENGING HEALTH ISSUES LIKE ADVERSE DRUG REACTIONS, DRUG WITHDRAWALS, AND ECONOMIC DISPARITIES AMONG FEW. AN INTEGRATIVE GLOBAL APPROACH COULD DO WONDERS TO HEALTH SCIENCES BENEFITING A BROAD SPECTRUM OF PATIENTS. 2011 8 2858 20 FROM RILUZOLE TO DEXPRAMIPEXOLE VIA SUBSTITUTED-BENZOTHIAZOLE DERIVATIVES FOR AMYOTROPHIC LATERAL SCLEROSIS DISEASE TREATMENT: CASE STUDIES. THE 1,3-BENZOTHIAZOLE (BTZ) RING MAY OFFER A VALID OPTION FOR SCAFFOLD-HOPPING FROM INDOLE DERIVATIVES. SEVERAL BTZS HAVE CLINICALLY RELEVANT ROLES, MAINLY AS CNS MEDICINES AND DIAGNOSTIC AGENTS, WITH RILUZOLE BEING ONE OF THE MOST FAMOUS EXAMPLES. RILUZOLE IS CURRENTLY THE ONLY APPROVED DRUG TO TREAT AMYOTROPHIC LATERAL SCLEROSIS (ALS) BUT ITS EFFICACY IS MARGINAL. SEVERAL CLINICAL STUDIES HAVE DEMONSTRATED ONLY LIMITED IMPROVEMENTS IN SURVIVAL, WITHOUT BENEFITS TO MOTOR FUNCTION IN PATIENTS WITH ALS. DESPITE SIGNIFICANT CLINICAL TRIAL EFFORTS TO UNDERSTAND THE GENETIC, EPIGENETIC, AND MOLECULAR PATHWAYS LINKED TO ALS PATHOPHYSIOLOGY, THERAPEUTIC TRANSLATION HAS REMAINED DISAPPOINTINGLY SLOW, PROBABLY DUE TO THE COMPLEXITY AND THE HETEROGENEITY OF THIS DISEASE. MANY OTHER DRUGS TO TACKLE ALS HAVE BEEN TESTED FOR 20 YEARS WITHOUT ANY SUCCESS. DEXPRAMIPEXOLE IS A BTZ STRUCTURAL ANALOG OF RILUZOLE AND WAS A GREAT HOPE FOR THE TREATMENT OF ALS. IN THIS REVIEW, AS AN INTERESTING CASE STUDY IN THE DEVELOPMENT OF A NEW MEDICINE TO TREAT ALS, WE PRESENT THE STRATEGY OF THE DEVELOPMENT OF DEXPRAMIPEXOLE, WHICH WAS ONE OF THE MOST PROMISING DRUGS AGAINST ALS. 2020 9 3598 11 IMPLICATIONS ON HYPNOTHERAPY: NEUROPLASTICITY, EPIGENETICS AND PAIN. WE PROVIDE A BRIEF REVIEW ABOUT THE SIGNIFICANCE OF HYPNOSIS WITH RESPECT TO APPLICATIONS AND PHYSIOLOGICAL PROCESSES IN HYPNOTHERAPY. OUR REVIEW CONCLUDES THAT HYPNOSIS IS A PROMISING METHOD TO MANAGE ACUTE AND CHRONIC PAIN. IN ADDITION, WE DISCUSS INDICATIONS POINTING TOWARD THE VIEW THAT HYPNOSIS CAN INDUCE CHANGES IN NEUROPLASTICITY POSSIBLY INVOLVING EPIGENETIC MECHANISMS. 2021 10 5501 24 REWRITING THE EPIGENETIC CODE FOR TUMOR RESENSITIZATION: A REVIEW. IN CANCER CHEMOTHERAPY, ONE AXIOM, WHICH HAS PRACTICALLY SOLIDIFIED INTO DOGMA, IS THAT ACQUIRED RESISTANCE TO ANTITUMOR AGENTS OR REGIMENS, NEARLY INEVITABLE IN ALL PATIENTS WITH METASTATIC DISEASE, REMAINS UNALTERABLE AND IRREVERSIBLE, RENDERING THERAPEUTIC RECHALLENGE FUTILE. HOWEVER, THE INTRODUCTION OF EPIGENETIC THERAPIES, INCLUDING HISTONE DEACETYLASE INHIBITORS (HDACIS) AND DNA METHYLTRANSFERASE INHIBITORS (DNMTIS), PROVIDES ONCOLOGISTS, LIKE COMPUTER PROGRAMMERS, WITH NEW TECHNIQUES TO "OVERWRITE" THE MODIFIABLE SOFTWARE PATTERN OF GENE EXPRESSION IN TUMORS AND CHALLENGE THE "ONE AND DONE" TREATMENT PRESCRIPTION. TAKING THE EPIGENETIC CODE-AS-SOFTWARE ANALOGY A STEP FURTHER, IF CHEMORESISTANCE IS THE PRODUCT OF MULTIPLE NONGENETIC ALTERATIONS, WHICH DEVELOP AND ACCUMULATE OVER TIME IN RESPONSE TO TREATMENT, THEN THE POSSIBILITY TO HACK OR TWEAK THE OPERATING SYSTEM AND FALL BACK ON A "SYSTEM RESTORE" OR "UNDO" FEATURE, LIKE THE ARROW ICON IN THE WINDOWS XP TOOLBAR, RECONFIGURING THE TUMOR TO ITS BASELINE NONRESISTANT STATE, HOLDS TREMENDOUS PROMISE FOR TURNING ADVANCED, METASTATIC CANCER FROM A FATAL DISEASE INTO A CHRONIC, LIVABLE CONDITION. THIS REVIEW AIMS 1) TO EXPLORE THE POTENTIAL MECHANISMS BY WHICH A GROUP OF SMALL MOLECULE AGENTS INCLUDING HDACIS (ENTINOSTAT AND VORINOSTAT), DNMTIS (DECITABINE AND 5-AZACYTIDINE), AND REDOX MODULATORS (RRX-001) MAY REPROGRAM THE TUMOR MICROENVIRONMENT FROM A REFRACTORY TO A NONREFRACTORY STATE, 2) HIGHLIGHT SOME RECENT FINDINGS, AND 3) DISCUSS WHETHER THE CURRENT "ONCE BURNED FOREVER SPURNED" PARADIGM IN THE TREATMENT OF METASTATIC DISEASE SHOULD BE REVISED TO PROMOTE ACTIVE RESENSITIZATION ATTEMPTS WITH FORMERLY FAILED CHEMOTHERAPIES. 2014 11 623 15 BIOINFORMATICS FOR CANCER MANAGEMENT IN THE POST-GENOME ERA. HUMAN CANCER IS CAUSED BY MULTIPLE FACTORS, SUCH AS GENETIC PREDISPOSITION, CHRONIC PERSISTENT INFLAMMATION, ENVIRONMENTAL FACTORS, LIFE STYLE, AND AGING. DYSREGULATED PROLIFERATION, DYSREGULATED ADHESION, RESISTANCE TO APOPTOSIS, RESISTANCE TO SENESCENCE, AND RESISTANCE TO ANTI-CANCER DRUGS ARE FEATURES OF CANCER CELLS. ACCUMULATION OF MULTIPLE EPIGENETIC CHANGES AND GENETIC ALTERATIONS OF CANCER-ASSOCIATED GENES DURING MULTI-STAGE CARCINOGENESIS RESULTS IN MORE MALIGNANT PHENOTYPES. POST-GENOME SCIENCE IS CHARACTERIZED BY OMICS DATA RELATED TO GENOME, TRANSCRIPTOME, PROTEOME, METABOLOME, INTERACTOME, AND EPIGENOME AS WELL AS BY HIGH-THROUGHPUT TECHNOLOGY, SUCH AS WHOLE-GENOME TILING OLIGONUCLEOTIDE ARRAY, ARRAY CGH WITH 32,433 OVERLAPPING BAC CLONES, TRANSCRIPTOME MICROARRAY, MASS SPECTROMETRY, TISSUE-BASED EXPRESSION ARRAY, AND CELL-BASED TRANSFECTION ARRAY. BENCHTOP ONCOLOGY SUPPLIES DESKTOP ONCOLOGY WITH LARGE AMOUNTS OF OMICS DATA PRODUCED BY HIGH-THROUGHPUT TECHNOLOGY. DESKTOP ONCOLOGY ESTABLISHES KNOWLEDGE ON CANCER-RELATED BIOMARKERS, SUCH AS PREDISPOSITION MARKERS, DIAGNOSTIC MARKERS, PROGNOSTIC MARKERS, AND THERAPEUTIC MARKERS, BY USING BIOINFORMATICS AND HUMAN INTELLIGENCE OF EXPERTS FOR DATA MINING AND TEXT MINING. BEDSIDE ONCOLOGY APPLIES THE KNOWLEDGE ESTABLISHED BY DESKTOP ONCOLOGY TO DETERMINE THERAPEUTICS FOR CANCER PATIENTS. ANTIBODY DRUGS (TRASTUZUMAB/HERCEPTIN, CETUXIMAB/ERBITUX, BEVACIZUMAB/AVASTIN, ET CETERA), SMALL MOLECULE INHIBITORS FOR TYROSINE KINASES (GEFITINIB/IRESSA, ERLOTINIB/TARCEVA, IMATINIB/GLEEVEC, ET CETERA), CONVENTIONAL CYTOTOXIC DRUGS, AND ANTI-HORMONAL DRUGS ARE USED FOR CANCER CHEMOTHERAPY. BIOMARKER MONITORING CONTRIBUTES TO THERAPEUTIC OPTIONAL CHOICE AND DRUG DOSAGE DETERMINATION FOR CANCER PATIENTS. KNOWLEDGE ON BIOMARKERS IS FEEDFORWARDED FROM DESKTOP TO BEDSIDE IN THE TRANSLATIONAL RESEARCH, AND THEN BIOMARKER MONITORING IS FEEDBACKED FROM BEDSIDE TO DESKTOP IN THE REVERSE TRANSLATIONAL RESEARCH. DESKTOP ONCOLOGY IS INDISPENSABLE FOR CANCER RESEARCH IN THE POST-GENOME ERA. COMBINATION OF GENETIC SCREENING FOR CANCER PREDISPOSITION IN THE GENERAL POPULATION AND PRECISE SELECTION OF THERAPEUTIC OPTIONS DURING CANCER MANAGEMENT COULD CONTRIBUTE TO THE REALIZATION OF PERSONALIZED PREVENTION AND TO DRAMATICALLY IMPROVE THE PROGNOSIS OF CANCER PATIENTS IN THE FUTURE. 2006 12 5797 24 STEM CELL-BASED THERAPY FOR HIRSCHSPRUNG DISEASE, DO WE HAVE THE GUTS TO TREAT? HIRSCHSPRUNG DISEASE (HSCR) IS A CONGENITAL ANOMALY OF THE COLON THAT RESULTS FROM FAILURE OF ENTERIC NERVOUS SYSTEM FORMATION, LEADING TO A CONSTRICTED DYSFUNCTIONAL SEGMENT OF THE COLON WITH VARIABLE LENGTHS, AND NECESSITATING SURGICAL INTERVENTION. THE UNDERLYING PATHOPHYSIOLOGY INCLUDES A DEFECT IN NEURAL CREST CELLS MIGRATION, PROLIFERATION AND DIFFERENTIATION, WHICH ARE PARTIALLY EXPLAINED BY IDENTIFIED GENETIC AND EPIGENETIC ALTERATIONS. DESPITE THE HIGH SUCCESS RATE OF THE CURATIVE SURGERIES, THEY ARE ASSOCIATED WITH SIGNIFICANT ADVERSE OUTCOMES SUCH AS ENTEROCOLITIS, FECAL SOILING, AND CHRONIC CONSTIPATION. IN ADDITION, SOME PATIENTS SUFFER FROM EXTENSIVE LETHAL VARIANTS OF THE DISEASE, ALL OF WHICH JUSTIFY THE NEED FOR AN ALTERNATIVE CURE. DURING THE LAST 5 YEARS, THERE HAS BEEN CONSIDERABLE PROGRESS IN HSCR STEM CELL-BASED THERAPY RESEARCH. HOWEVER, MANY MAJOR ISSUES REMAIN UNSOLVED. THIS REVIEW WILL PROVIDE CONCISE BACKGROUND INFORMATION ON HSCR, OUTLINE THE FUTURE APPROACHES OF STEM CELL-BASED HSCR THERAPY, REVIEW RECENT KEY PUBLICATIONS, DISCUSS TECHNICAL AND ETHICAL CHALLENGES THE FIELD FACES PRIOR TO CLINICAL TRANSLATION, AND TACKLE SUCH CHALLENGES BY PROPOSING SOLUTIONS AND EVALUATING EXISTING APPROACHES TO PROGRESS FURTHER. 2022 13 1256 21 CURRENT STUDIES AND FUTURE DIRECTIONS FOR MEDULLOBLASTOMA: A REVIEW FROM THE PACIFIC PEDIATRIC NEURO-ONCOLOGY CONSORTIUM (PNOC) DISEASE WORKING GROUP. MEDULLOBLASTOMA (MB) IS THE MOST COMMON MALIGNANT CENTRAL NERVOUS SYSTEM TUMOR OF CHILDHOOD, COMPRISING A HETEROGENOUS GROUP OF TUMORS EACH WITH DISTINCT BIOLOGY, CLINICAL BEHAVIOR, AND PROGNOSIS. LONG-TERM SURVIVAL REMAINS UNACCEPTABLE, AND THOSE WHO DO SURVIVE FACE HIGH LATE MORTALITY RISK, NEW CHRONIC TREATMENT-RELATED MEDICAL CONDITIONS, NEUROCOGNITIVE IMPAIRMENTS, AND POOR HEALTH-RELATED QUALITY OF LIFE. UP-FRONT TREATMENT STRATEGIES NOW INTEGRATE MOLECULAR SUBGROUPING WITH STANDARD CLINICO-RADIOLOGICAL FACTORS TO MORE ACTUALLY RISK STRATIFY NEWLY-DIAGNOSED PATIENTS. TO WHAT EXTENT THIS NEW STRATIFICATION WILL LEAD TO IMPROVEMENTS IN TREATMENT OUTCOME WILL BE DETERMINED IN THE COMING YEARS. IN PARALLEL, DISCOVERY AND APPRECIATION FOR MEDULLOBLASTOMA'S INTER- AND INTRA-TUMORAL HETEROGENEITY CONTINUES GROWING. CLINICAL TRIALS TREATING RELAPSED DISEASE NOW ENCOMPASS PRECISION MEDICINE, EPIGENETIC MODIFICATION, AND IMMUNE THERAPY APPROACHES. THE PACIFIC PEDIATRIC NEURO-ONCOLOGY (PNOC) MEDULLOBLASTOMA WORKING GROUP IS COMMITTED TO DEVELOPING CLINICAL TRIALS BASED ON THESE EVOLVING THERAPEUTIC STRATEGIES AND SUPPORTS TRANSLATIONAL EFFORTS BY PNOC RESEARCHERS AND THE MULTI-STAKEHOLDER MEDULLOBLASTOMA COMMUNITY AT LARGE. 2023 14 1861 14 EMERGENCE OF CANCER STEM CELLS IN HEPATOCELLULAR CARCINOMA. LIVER CANCER REPRESENTS THE SECOND MOST DEADLY HUMAN MALIGNANCY. THE MAJOR HISTOLOGICAL SUBTYPE CALLED HEPATOCELLULAR CARCINOMA (HCC) ARISES BY CHRONIC INFLAMMATION-TRIGGERED REGENERATIVE RESPONSES OF NORMALLY QUIESCENT HEPATOCYTES AND PROGENITORS, RESPECTIVELY. SUCH REGENERATIVE STRESS ACCELERATES THE ACCUMULATION OF GENETIC AND EPIGENETIC CHANGES (YAMASHITA & WANG, 2013), WHILE DETAILED MECHANISMS REMAIN UNCERTAIN. IN THIS ISSUE OF THE EMBO JOURNAL, NIKOLAOU ET AL PRESENT A NOVEL HCC MODEL THAT FACILITATES BOTH ISOLATION AND MOLECULAR CHARACTERIZATION OF SELF-RENEWING, HCC-PROPAGATING CANCER STEM CELLS THAT COULD INSTRUCT FUTURE INTERVENTIONS (NIKOLAOU ET AL, 2014). 2015 15 257 23 ADVANCES IN ONCOANAESTHESIA AND CANCER PAIN. INTRODUCTION: THE GROWING INTEREST ON HOW PERI-?OPERATIVE INTERVENTIONS, ESPECIALLY REGIONAL ANESTHESIA, DURING CANCER SURGERY CAN ALTER ONCOLOGICAL OUTCOME INCREASING DISEASE FREE SURVIVAL IS PROBABLY RESPONSIBLE FOR THE BIRTH OF THE NEW SUBSPECIALTY CALLED ONCO-ANESTHESIA. A PARADIGM SHIFT IN THE CONCEPT OF ANESTHETIC MANAGEMENT HAS OCCURRED RECENTLY OWING TO THE INNUMERABLE DIVERSE REVELATIONS FROM THE ONGOING RESEARCH IN THIS FIELD. DISCUSSION: LONG LASTING BUT REVERSIBLE EPIGENETIC CHANGES CAN OCCUR DUE TO SURGICAL STRESS AND PERIOPERATIVE ANESTHETIC MEDICATIONS. THE EXACT RELATIONSHIP BETWEEN THESE FACTORS AND TUMOR BIOLOGY IS BEING STUDIED FURTHER. A POPULAR TOPIC UNDER RESEARCH NOW IS THE INFLUENCE OF REGIONAL ANESTHESIA ON CANCER RECURRENCE. COMBINING NERVE BLOCKS WITH TOTAL INTRAVENOUS ANESTHESIA (TIVA) BRINGS DOWN THE REQUIREMENT OF OPIOIDS AND VOLATILE ANESTHETIC AGENTS IMPLICATED IN CANCER RECURRENCE. THE STUDY OF MECHANISM OF PAIN AT THE MOLECULAR LEVEL HAS LED TO THE DISCOVERY OF NOVEL MODES OF PREVENTION OF CHRONIC POST-SURGICAL PAIN. NEWER COMBINATION AGGRESSIVE TREATMENT THERAPIES -INTRAOPERATIVE CHEMOTHERAPY AND RADIOTHERAPY, ISOLATED LIMB PERFUSION, PHOTODYNAMIC THERAPY AND ROBOTIC SURGERY REQUIRE SPECIALIZED ANESTHETIC MANAGEMENT. THE COVID PANDEMIC INTRODUCED NEW GUIDELINES FOR SAFE MANAGEMENT OF ONCOSURGICAL PATIENTS .USE OF GENOMIC MAPPING TO PERSONALIZE PAIN MANAGEMENT WILL BE THE BREAKTHROUGH OF THE DECADE. CONCLUSION: THE DISCOVERY THAT ANESTHETIC STRATEGY COULD HAVE SIGNIFICANT ONCOLOGICAL SEQUEL IS A QUANTUM LEAP FORWARD. AVOIDING SOME ANESTHETIC MEDICATIONS MAY DECREASE CANCER RECURRENCE. COMPREHENSIVE CANCER CARE AND TRANSLATIONAL RESEARCH WILL PAVE THE WAY TO UNCOVER SAFE ANESTHETIC PRACTICES. 2021 16 5806 23 STRATEGIES TO REINVIGORATE EXHAUSTED CD8(+) T CELLS IN TUMOR MICROENVIRONMENT. CD8(+) T CELL EXHAUSTION IS A STABLE DYSFUNCTIONAL STATE DRIVEN BY CHRONIC ANTIGEN STIMULATION IN THE TUMOR MICROENVIRONMENT (TME). DIFFERENTIATION OF EXHAUSTED CD8(+) T CELLS (CD8(+) TEXS) IS ACCOMPANIED BY EXTENSIVE TRANSCRIPTIONAL, EPIGENETIC AND METABOLIC REPROGRAMMING. CD8(+) TEXS ARE MAINLY CHARACTERIZED BY IMPAIRED PROLIFERATIVE AND CYTOTOXIC CAPACITY AS WELL AS THE INCREASED EXPRESSION OF MULTIPLE CO-INHIBITORY RECEPTORS. PRECLINICAL TUMOR STUDIES AND CLINICAL COHORTS HAVE DEMONSTRATED THAT T CELL EXHAUSTION IS FIRMLY ASSOCIATED WITH POOR CLINICAL OUTCOMES IN A VARIETY OF CANCERS. MORE IMPORTANTLY, CD8(+) TEXS ARE REGARDED AS THE MAIN RESPONDER TO IMMUNE CHECKPOINT BLOCKADE (ICB). HOWEVER, TO DATE, A LARGE NUMBER OF CANCER PATIENTS HAVE FAILED TO ACHIEVE DURABLE RESPONSES AFTER ICB. THEREFORE, IMPROVING CD8(+) TEXS MAY BE A BREAKTHROUGH POINT TO REVERSE THE CURRENT DILEMMA OF CANCER IMMUNOTHERAPY AND ELIMINATE CANCERS. STRATEGIES TO REINVIGORATE CD8(+) TEXS IN TME MAINLY INCLUDE ICB, TRANSCRIPTION FACTOR-BASED THERAPY, EPIGENETIC THERAPY, METABOLISM-BASED THERAPY AND CYTOKINE THERAPY, WHICH TARGET ON DIFFERENT ASPECTS OF EXHAUSTION PROGRESSION. EACH OF THEM HAS ITS ADVANTAGES AND APPLICATION SCOPE. IN THIS REVIEW, WE MAINLY FOCUS ON THE MAJOR ADVANCES OF CURRENT STRATEGIES TO REINVIGORATE CD8(+) TEXS IN TME. WE SUMMARIZE THEIR EFFICACY AND MECHANISMS, IDENTIFY THE PROMISING MONOTHERAPY AND COMBINED THERAPY AND PROPOSE SUGGESTIONS TO ENHANCE THE TREATMENT EFFICACY TO SIGNIFICANTLY BOOST ANTI-TUMOR IMMUNITY AND ACHIEVE BETTER CLINICAL OUTCOMES. 2023 17 96 12 A PRIMER ON METABOLIC MEMORY: WHY EXISTING DIABESITY TREATMENTS FAIL. DESPITE MASSIVE GOVERNMENT AND PRIVATE SECTOR INVESTMENTS INTO PREVENTION OF CARDIOVASCULAR DISEASE, DIABETES MELLITUS AND OBESITY, EFFORTS HAVE LARGELY FAILED, AND THE BURDEN OF COST REMAINS IN THE TREATMENT OF DOWNSTREAM MORBIDITY AND MORTALITY, WITH OVERALL STAGNATING OUTCOMES. A NEW PARADIGM SHIFT IN THE APPROACH TO THESE PATIENTS MAY EXPLAIN WHY EXISTING TREATMENT STRATEGIES FAIL, AND OFFER NEW TREATMENT TARGETS. THIS REVIEW AIMS TO PROVIDE A CLINICIAN-CENTRED PRIMER ON METABOLIC MEMORY, DEFINED AS THE SUM OF IRREVERSIBLE GENETIC, EPIGENETIC, CELLULAR AND TISSUE-LEVEL ALTERATIONS THAT OCCUR WITH LONG-TIME EXPOSURE TO METABOLIC DERANGEMENTS. 2021 18 6815 13 [EVOLUTIONARY ONTOGENETIC ASPECTS OF PATHOGENETICS OF CHRONIC HUMAN DISEASES]. THIS ARTICLE IS A REVIEW OF SCIENTIFIC PUBLICATIONS, IN WHICH ISSUES OF PATHOGENETICS OF MULTIFACTORIAL DISEASES (MFDS) ARE CONSIDERED FROM THE VIEWPOINT OF EVOLUTION AND ONTOGENY. CONCEPTS EXPLAINING SIGNIFICANCE OF EVOLUTIONARY PROCESSES IN THE FORMATION OF GENETIC ARCHITECTURE OF HUMAN CHRONIC DISEASES ("THRIFTY" GENOMES AND PHENOTYPES, "DRIFTING GENES," DECANALIZATION) ARE ANALYZED. THE ROLES OF NATURAL SELECTION AND GENETIC DRIFT IN THE FORMATION OF HEREDITARY DIVERSITY OF GENES FOR SUSCEPTIBILITY TO MFDS ARE CONSIDERED. THE MODERN CONCEPT OF DISEASE ONTOGENY (SOMATIC MOSAICISM, LOSS OFHETEROZYGOSITY, PARADOMINANT INHERITANCE, EPIGENETIC VARIABILITY) IS DISCUSSED. IT IS DEMONSTRATED THAT THE EVOLUTIONARY AND ONTOGENETIC APPROACHES TO ANALYSIS OF GENIMUC AND OTHER "-OMIC" DATA ARE ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF DISEASES. 2011 19 5763 18 SOME COMMENTS ON MASOCHISM AND THE DELUSION OF OMNIPOTENCE FROM A DEVELOPMENTAL PERSPECTIVE. THIS PAPER EXPLORES THE RELATION OF THE DELUSION OF OMNIPOTENCE TO MASOCHISM AND SUGGESTS THAT THIS FANTASY CONSTITUTES A MAJOR COMPONENT OF THE RESISTANCE SO PROMINENT IN WORK WITH MASOCHISTIC PATIENTS. THE CONNECTIONS AMONG MASOCHISM, OMNIPOTENCE, NEGATIVE THERAPEUTIC REACTION, AND CLINGING TO PAIN ARE DISCUSSED. THE CLASSICAL VIEW HAS BEEN THAT THE FAILURE OF INFANTILE OMNIPOTENCE FORCES THE CHILD TO TURN TO REALITY. OUR EXPERIENCE WITH MASOCHISTIC PATIENTS SUGGESTS THAT IT IS THE REAL FAILURE TO ACHIEVE COMPETENT INTERACTIONS WITH OTHERS THAT FORCES THE CHILD TO TURN TO OMNIPOTENT SOLUTIONS. THE DISTINCTION IS MADE BETWEEN FANTASIES THAT ENHANCE THE REAL CAPACITIES OF THE SELF AND THOSE AIMED AT DENYING AND TRANSFORMING THE PAIN AND INADEQUACY OF THE MOTHER-CHILD RELATIONSHIP. THE EPIGENETIC TRANSFORMATIONS OF OMNIPOTENT FANTASIES THROUGH ALL LEVELS OF DEVELOPMENT ARE DESCRIBED. THE PATIENT'S NEED TO PROTECT THE OMNIPOTENT FANTASY IS DISCUSSED IN RELATION TO RESISTANCE AT EACH PHASE OF ANALYSIS. 1991 20 3157 17 GLYCEMIC MEMORY. PURPOSE OF REVIEW: THE MISTAKE OF PREDICTING THE FUTURE IS PERHAPS NOT TENDING TO REPRESSED OR PAST MEMORIES. HAMLET'S 17TH-CENTURY SOLILOQUY 'THE HEARTACHE AND THE THOUSAND NATURAL SHOCKS, THAT FLESH IS HEIR TO', (3.1. 7-8) IS A TALE THAT LOOKS BEYOND THE PRESENT BY LINKING THE PAST WITH THE FUTURE. THE PRESENT ARTICLE EXAMINES THE RESURGENCE IN THE FIELD TO UNDERSTAND GENE-REGULATING EPIGENETIC CHANGES CONFERRING GLYCEMIC MEMORY. RECENT FINDINGS: CHROMATIN MODIFICATIONS ARE CRITICAL IN REGULATING GENOME STRUCTURE AND FUNCTION AND DESPITE THE SIGNIFICANT ADVANCES OF RECENT YEARS IN IDENTIFYING THE ENZYMES-MEDIATING CHEMICAL CHANGES TO HISTONE TAILS AND THE DNA TEMPLATE, THE PRECISE REGULATION OF GENE EXPRESSION REMAINS INCOMPLETE IN MODELS OF HEALTH AND DIABETIC COMPLICATIONS. SUMMARY: DISPELLING THE MYTH THAT ALL GENOMES ARE DRIVEN AND RESPOND EQUALLY, EXPERIMENTAL RESEARCH IS NOW UNCOVERING THE FUNCTION OF ENZYMES CONFERRING CHROMATIN MODIFICATIONS. WHATEVER THE ROLE OF THE EPIGENOME, SHOWING ITS INVOLVEMENT IN GLYCEMIC SIGNALING IS THE FIRST STEP TO NEW STRATEGIES AND TARGETS TO DEVELOP THERAPIES THAT PREVENT, RETARD OR REVERSE THE LONG-TERM DELETERIOUS END-ORGAN EFFECTS OF CHRONIC, INTERMITTENT AND PRIOR HYPERGLYCEMIA. 2012