1 1256 125 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 2 1952 24 EPIGENETIC AGE ACCELERATION AMONG SURVIVORS OF PEDIATRIC MEDULLOBLASTOMA AND PRIMITIVE NEUROECTODERMAL TUMOR. SURVIVORS OF CHILDHOOD CENTRAL NERVOUS SYSTEM (CNS) TUMORS EXPERIENCE EARLY-ONSET AGING-RELATED PHENOTYPES. DNA METHYLATION (DNAM) AGE IS AN EMERGING EPIGENETIC BIOMARKER OF PHYSIOLOGIC AGE AND MAY BE PREDICTIVE OF CHRONIC HEALTH CONDITIONS IN LONG-TERM SURVIVORS. THIS REPORT DESCRIBES THE COURSE OF EPIGENETIC AGE ACCELERATION USING POST-DIAGNOSIS BLOOD SAMPLES (MEDIAN: 3.9 YEARS POST-DIAGNOSIS; RANGE: 0.04-15.96) FROM 83 SURVIVORS OF PEDIATRIC CNS TUMORS. EPIGENETIC AGE ACCELERATION WAS DETECTED IN 72% OF PATIENTS, WITH AN AVERAGE DIFFERENCE BETWEEN CHRONOLOGIC AND DNAM AGE OF 2.58 YEARS (95% CI: 1.75-3.41, P < 0.001). TIME FROM DIAGNOSIS TO SAMPLE COLLECTION CORRELATED WITH THE MAGNITUDE OF EPIGENETIC AGE ACCELERATION. 2023 3 5599 28 ROLES OF THE NEURON-RESTRICTIVE SILENCER FACTOR IN THE PATHOPHYSIOLOGICAL PROCESS OF THE CENTRAL NERVOUS SYSTEM. THE NEURON-RESTRICTIVE SILENCER FACTOR (NRSF), ALSO KNOWN AS REPRESSOR ELEMENT 1 (RE-1) SILENCING TRANSCRIPTION FACTOR (REST) OR X2 BOX REPRESSOR (XBR), IS A ZINC FINGER TRANSCRIPTION FACTOR THAT IS WIDELY EXPRESSED IN NEURONAL AND NON-NEURONAL CELLS. IT IS A MASTER REGULATOR OF THE NERVOUS SYSTEM, AND THE FUNCTION OF NRSF IS THE BASIS OF NEURONAL DIFFERENTIATION, DIVERSITY, PLASTICITY, AND SURVIVAL. NRSF CAN BIND TO THE NEURON-RESTRICTIVE SILENCER ELEMENT (NRSE), RECRUIT SOME CO-REPRESSORS, AND THEN INHIBIT TRANSCRIPTION OF NRSE DOWNSTREAM GENES THROUGH EPIGENETIC MECHANISMS. IN NEUROGENESIS, NRSF FUNCTIONS NOT ONLY AS A TRANSCRIPTIONAL SILENCER THAT CAN MEDIATE THE TRANSCRIPTIONAL INHIBITION OF NEURON-SPECIFIC GENES IN NON-NEURONAL CELLS AND THUS GIVE NEURON CELLS SPECIFICITY, BUT ALSO AS A TRANSCRIPTIONAL ACTIVATOR TO INDUCE NEURONAL DIFFERENTIATION. MANY STUDIES HAVE CONFIRMED THE ASSOCIATION BETWEEN NRSF AND BRAIN DISORDERS, SUCH AS BRAIN INJURY AND NEURODEGENERATIVE DISEASES. OVEREXPRESSION, UNDEREXPRESSION, OR MUTATION MAY LEAD TO NEUROLOGICAL DISORDERS. IN TUMORIGENESIS, NRSF FUNCTIONS AS AN ONCOGENE IN NEURONAL TUMORS, SUCH AS NEUROBLASTOMAS, MEDULLOBLASTOMAS, AND PHEOCHROMOCYTOMAS, STIMULATING THEIR PROLIFERATION, WHICH RESULTS IN POOR PROGNOSIS. ADDITIONALLY, NRSF-MEDIATED SELECTIVE TARGETS GENE REPRESSION PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT AND MAINTENANCE OF NEUROPATHIC PAIN CAUSED BY NERVE INJURY, CANCER, AND DIABETES. AT PRESENT, SEVERAL COMPOUNDS THAT TARGET NRSF OR ITS CO-REPRESSORS, SUCH AS REST-VP16 AND X5050, HAVE BEEN SHOWN TO BE CLINICALLY EFFECTIVE AGAINST MANY BRAIN DISEASES, SUCH AS SEIZURES, IMPLYING THAT NRSF AND ITS CO-REPRESSORS MAY BE POTENTIAL AND PROMISING THERAPEUTIC TARGETS FOR NEURAL DISORDERS. IN THE PRESENT REVIEW, WE INTRODUCED THE BIOLOGICAL CHARACTERISTICS OF NRSF; REVIEWED THE PROGRESS TO DATE IN UNDERSTANDING THE ROLES OF NRSF IN THE PATHOPHYSIOLOGICAL PROCESSES OF THE NERVOUS SYSTEM, SUCH AS NEUROGENESIS, BRAIN DISORDERS, NEURAL TUMORIGENESIS, AND NEUROPATHIC PAIN; AND SUGGESTED NEW THERAPEUTIC APPROACHES TO SUCH BRAIN DISEASES. 2022 4 2858 31 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 5 81 21 A NEW TYPE OF DENTAL ANOMALY: MOLAR-INCISOR MALFORMATION (MIM). A MOLAR-INCISOR MALFORMATION (MIM) IS A NEWLY DISCOVERED TYPE OF DENTAL ANOMALY OF THE PERMANENT FIRST MOLARS, DECIDUOUS SECOND MOLARS, AND PERMANENT MAXILLARY CENTRAL INCISORS. MIM ANOMALIES OF THE PERMANENT FIRST MOLARS AND DECIDUOUS SECOND MOLARS MAY INCLUDE NORMAL CROWNS WITH A CONSTRICTED CERVICAL REGION AND THIN, NARROW, AND SHORT ROOTS, WHEREAS THE AFFECTED MAXILLARY CENTRAL INCISORS MAY EXHIBIT A HYPOPLASTIC ENAMEL NOTCH NEAR THE CERVICAL THIRD OF THE CLINICAL CROWN. ALTHOUGH THE ETIOLOGY OF MIM REMAINS TO BE DETERMINED, IT IS THOUGHT TO BE ATTRIBUTABLE TO AN EPIGENETIC FACTOR LINKED TO BRAIN- AND CENTRAL NERVOUS SYSTEM-RELATED SYSTEMIC DISEASES AT AROUND AGE 1 TO 2 YEARS. MIM TEETH ARE ASSOCIATED WITH CLINICAL PROBLEMS SUCH AS IMPACTION, EARLY EXFOLIATION, SPACE LOSS, SPONTANEOUS PAIN, PERIAPICAL ABSCESS, AND POOR INCISOR ESTHETICS. CHILDREN WITH MIM TEETH SHOULD BE OBSERVED CLOSELY WITH RESPECT TO THEIR MEDICAL HISTORY, AND DENTISTS SHOULD FORMULATE A WIDER-RANGING TREATMENT PLAN. 2014 6 5776 23 SPHN - THE SWISS AGING CITIZEN REFERENCE (SACR). IN SWITZERLAND BY 2045, WE EXPECT 2.7 MIO CITIZENS AGED 65+ OF WHOM 1.0 MIO. AGED 80+. A PRIORITY AND FOCUS OF PERSONALIZED HEALTH RESEARCH IS THEREFORE AGING BIOLOGY TO EXTEND HEALTHY LIFE EXPECTANCY. NOVEL MOLECULAR AND IMAGING FEATURES WILL EMERGE AS CANDIDATE TARGETS FOR RISK PREDICTION AND SCREENING OF CHRONIC DISEASES. IT IS OF UTMOST IMPORTANCE TO TEST THE CLINICAL AND PUBLIC HEALTH UTILITY OF CANDIDATE BIOMARKERS EVOLVING FROM THIS RESEARCH IN CITIZEN REFERENCE COHORTS. WE WILL BUILD A SWISS AGING CITIZEN REFERENCE (SACR), A TESTABLE AND SCALABLE REFERENCE COHORT OFFERING INTEROPERABLE, SEARCHABLE, AND ACCESSIBLE DATA. 1000 PARTICIPANTS FROM EXISTING SWISS CITIZEN COHORTS WILL BE COMBINED AND ANALYZED FOR DNA METHYLATION AND MRI BRAIN IMAGING. SACR WILL SERVE AS A TESTBED FOR CLINICAL AND PUBLIC HEALTH UTILITY OF CANDIDATE BIOMARKERS. AS FOR A PROOF-OF-CONCEPT STUDY, WE WILL CONDUCT AN AGNOSTIC SEARCH FOR STRUCTURAL AND FUNCTIONAL BRAIN FEATURES ASSOCIATED WITH EPIGENETIC AGING ACCELERATION TO EXAMINE THE POTENTIAL OF EPIGENETIC AGE ACCELERATION AS THE INTERMEDIATE AGING BIOMARKER AND TO BETTER UNDERSTAND THE AGING MECHANISM IN BRAIN. 2020 7 4508 18 MS-11, A MIMETIC OF THE MSIN3-BINDING HELIX IN NRSF, AMELIORATES SOCIAL INTERACTION DEFICITS IN A PRENATAL VALPROIC ACID-INDUCED AUTISM MOUSE MODEL. GROWING EVIDENCE SUGGESTS PIVOTAL ROLES FOR EPIGENETIC MECHANISMS IN BOTH ANIMAL MODELS OF AND INDIVIDUALS WITH AUTISM SPECTRUM DISORDERS (ASD). NEURON-RESTRICTIVE SILENCER FACTOR (NRSF) BINDS TO NEURON-RESTRICTIVE SILENCING ELEMENTS IN NEURONAL GENES AND RECRUITS CO-REPRESSORS, SUCH AS MSIN3, TO EPIGENETICALLY INHIBIT NEURONAL GENE EXPRESSION. BECAUSE DYSREGULATION OF NRSF IS RELATED TO ASD, HERE WE EXAMINED THE EFFECTS OF MS-11, A CHEMICALLY OPTIMIZED MIMETIC OF THE MSIN3-BINDING HELIX IN NRSF, ON THE BEHAVIORAL AND MORPHOLOGICAL ABNORMALITIES FOUND IN A MOUSE MODEL OF VALPROIC ACID (VPA)-INDUCED ASD. CHRONIC TREATMENT WITH MS-11 IMPROVED PRENATAL VPA-INDUCED DEFICITS IN SOCIAL INTERACTION. ADDITIONALLY, WE FOUND THAT NRSF MRNA EXPRESSION WAS GREATER IN THE SOMATOSENSORY CORTEX OF VPA-EXPOSED MICE THAN OF CONTROLS. AGREEING WITH THESE BEHAVIORAL FINDINGS, MICE THAT WERE PRENATALLY EXPOSED TO VPA SHOWED LOWER DENDRITIC SPINE DENSITY IN THE SOMATOSENSORY CORTEX, WHICH WAS REVERSED BY CHRONIC TREATMENT WITH MS-11. THESE FINDINGS SUGGEST THAT MS-11 HAS THE POTENTIAL FOR IMPROVING ASD-RELATED SYMPTOMS THROUGH INHIBITION OF MSIN3-NRSF BINDING. 2019 8 3598 12 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 9 5797 29 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 10 5516 23 RISE OF THE MUTANTS: REPORT FROM THE 19TH CONFERENCE OF THE EUROPEAN HAEMATOLOGY ASSOCIATION, MILAN, 12-15 JUNE 2014. AT THE 19TH CONFERENCE OF THE EUROPEAN HAEMATOLOGY ASSOCIATION IN MILAN, WE SAW THE TRUE AND DRAMATIC CHANGES BROUGHT ABOUT BY THE INTEGRATION OF EXTENSIVE GENOMIC INFORMATION IN CLINICAL PRACTICE, AND THE DILEMMAS THAT ACCOMPANY SUCH A RAPID INCREASE IN KNOWLEDGE. EACH DISEASE IS SLICED MORE AND MORE INTO SMALLER PIECES, EACH WITH ITS OWN BETTER-DETERMINED OUTCOME AND TREATMENT. WE ALSO OBSERVED THE RISE OF MUTANT-SPECIFIC EPIGENETIC AGENTS, WHICH BENEFIT FROM KNOWING THE UNDERLYING GENETIC ABNORMALITY TO SPECIFICALLY ASSIGN AN EPIGENETIC DRUG WHERE IT IS NEEDED. IN CONTRAST TO THE 'ONE MUTATION, ONE DRUG' APPROACH, OTHERS ARE PURSUING THE SEARCH FOR DRUGS TARGETING PATHWAYS FUNDAMENTAL FOR THE SURVIVAL OF ALL OR MOST CANCER CELLS, SOMETIMES LOOKING AT MORE 'EXOTIC' PATHWAYS LIKE NEDDYLATION OR NUCLEAR EXPORT. 2014 11 4759 29 NOVEL TREATMENTS FOR MYELOFIBROSIS: BEYOND JAK INHIBITORS. MYELOFIBROSIS IS A CHRONIC HEMATOLOGIC MALIGNANCY CHARACTERIZED BY CONSTITUTIONAL SYMPTOMS, BONE MARROW FIBROSIS, EXTRAMEDULLARY HEMATOPOIESIS RESULTING IN SPLENOMEGALY AND A PROPENSITY TOWARD LEUKEMIC PROGRESSION. GIVEN THE CENTRAL ROLE OF THE JAK-STAT PATHWAY IN THE PATHOBIOLOGY OF MYELOFIBROSIS, JAK INHIBITORS ARE THE MAINSTAY OF CURRENT PHARMACOLOGIC MANAGEMENT. ALTHOUGH THESE THERAPIES HAVE PRODUCED MEANINGFUL IMPROVEMENTS IN SPLENOMEGALY AND SYMPTOM BURDEN, JAK INHIBITORS DO NOT SIGNIFICANTLY IMPACT DISEASE PROGRESSION. IN ADDITION, MANY PATIENTS ARE INELIGIBLE BECAUSE OF DISEASE-RELATED CYTOPENIAS, WHICH ARE EXACERBATED BY JAK INHIBITORS. THEREFORE, THERE IS A CONTINUED EFFORT TO IDENTIFY TARGETS OUTSIDE THE JAK-STAT PATHWAY. IN THIS REVIEW, WE DISCUSS NOVEL THERAPIES IN DEVELOPMENT FOR MYELOFIBROSIS. WE FOCUS ON THE PRECLINICAL RATIONALE, EFFICACY AND SAFETY DATA FOR NON-JAK INHIBITOR THERAPIES THAT HAVE PUBLISHED OR PRESENTED CLINICAL DATA. SPECIFICALLY, WE DISCUSS AGENTS THAT TARGET EPIGENETIC MODIFICATION (PELABRESIB, BOMEDEMSTAT), APOPTOSIS (NAVITOCLAX, NAVTEMDALIN), SIGNALING PATHWAYS (PARSACLISIB), BONE MARROW FIBROSIS (AVID200, PRM-151), IN ADDITION TO OTHER TARGETS INCLUDING TELOMERASE (IMETELSTAT), SELECTIVE INHIBITOR OF NUCLEAR TRANSPORT (SELINEXOR), CD123 (TAGRAXOFUSP) AND ERYTHROID MATURATION (LUSPATERCEPT). WE END BY PROVIDING COMMENTARY ON THE ONGOING AND FUTURE THERAPEUTIC DEVELOPMENT IN MYELOFIBROSIS. 2022 12 4927 30 PARKINSON'S DISEASE: FROM PATHOGENESIS TO PHARMACOGENOMICS. PARKINSON'S DISEASE (PD) IS THE SECOND MOST IMPORTANT AGE-RELATED NEURODEGENERATIVE DISORDER IN DEVELOPED SOCIETIES, AFTER ALZHEIMER'S DISEASE, WITH A PREVALENCE RANGING FROM 41 PER 100,000 IN THE FOURTH DECADE OF LIFE TO OVER 1900 PER 100,000 IN PEOPLE OVER 80 YEARS OF AGE. AS A MOVEMENT DISORDER, THE PD PHENOTYPE IS CHARACTERIZED BY RIGIDITY, RESTING TREMOR, AND BRADYKINESIA. PARKINSON'S DISEASE -RELATED NEURODEGENERATION IS LIKELY TO OCCUR SEVERAL DECADES BEFORE THE ONSET OF THE MOTOR SYMPTOMS. POTENTIAL RISK FACTORS INCLUDE ENVIRONMENTAL TOXINS, DRUGS, PESTICIDES, BRAIN MICROTRAUMA, FOCAL CEREBROVASCULAR DAMAGE, AND GENOMIC DEFECTS. PARKINSON'S DISEASE NEUROPATHOLOGY IS CHARACTERIZED BY A SELECTIVE LOSS OF DOPAMINERGIC NEURONS IN THE SUBSTANTIA NIGRA PARS COMPACTA, WITH WIDESPREAD INVOLVEMENT OF OTHER CENTRAL NERVOUS SYSTEM (CNS) STRUCTURES AND PERIPHERAL TISSUES. PATHOGENIC MECHANISMS ASSOCIATED WITH GENOMIC, EPIGENETIC AND ENVIRONMENTAL FACTORS LEAD TO CONFORMATIONAL CHANGES AND DEPOSITS OF KEY PROTEINS DUE TO ABNORMALITIES IN THE UBIQUITIN-PROTEASOME SYSTEM TOGETHER WITH DYSREGULATION OF MITOCHONDRIAL FUNCTION AND OXIDATIVE STRESS. CONVENTIONAL PHARMACOLOGICAL TREATMENTS FOR PD ARE DOPAMINE PRECURSORS (LEVODOPA, L-DOPA, L-3,4 DIHIDROXIFENILALANINA), AND OTHER SYMPTOMATIC TREATMENTS INCLUDING DOPAMINE AGONISTS (AMANTADINE, APOMORPHINE, BROMOCRIPTINE, CABERGOLINE, LISURIDE, PERGOLIDE, PRAMIPEXOLE, ROPINIROLE, ROTIGOTINE), MONOAMINE OXIDASE (MAO) INHIBITORS (SELEGILINE, RASAGILINE), AND CATECHOL-O-METHYLTRANSFERASE (COMT) INHIBITORS (ENTACAPONE, TOLCAPONE). THE CHRONIC ADMINISTRATION OF ANTIPARKINSONIAN DRUGS CURRENTLY INDUCES THE "WEARING-OFF PHENOMENON", WITH ADDITIONAL PSYCHOMOTOR AND AUTONOMIC COMPLICATIONS. IN ORDER TO MINIMIZE THESE CLINICAL COMPLICATIONS, NOVEL COMPOUNDS HAVE BEEN DEVELOPED. NOVEL DRUGS AND BIOPRODUCTS FOR THE TREATMENT OF PD SHOULD ADDRESS DOPAMINERGIC NEUROPROTECTION TO REDUCE PREMATURE NEURODEGENERATION IN ADDITION TO ENHANCING DOPAMINERGIC NEUROTRANSMISSION. SINCE BIOCHEMICAL CHANGES AND THERAPEUTIC OUTCOMES ARE HIGHLY DEPENDENT UPON THE GENOMIC PROFILES OF PD PATIENTS, PERSONALIZED TREATMENTS SHOULD RELY ON PHARMACOGENETIC PROCEDURES TO OPTIMIZE THERAPEUTICS. 2017 13 5154 24 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 14 4765 28 NRSF AND ITS EPIGENETIC EFFECTORS: NEW TREATMENTS FOR NEUROLOGICAL DISEASE. THE NEURON RESTRICTIVE SILENCER FACTOR (NRSF) IS THE WELL-KNOWN MASTER TRANSCRIPTIONAL REPRESSOR OF THE NEURONAL PHENOTYPE. RESEARCH TO DATE HAS SHOWN THAT IT IS AN IMPORTANT PLAYER IN THE GROWTH AND DEVELOPMENT OF THE NERVOUS SYSTEM. ITS ROLE IN THE MATURATION OF NEURAL PRECURSOR CELLS TO ADULT NEURONS HAS BEEN WELL CHARACTERIZED IN STEM CELL MODELS. WHILE MUCH HAS BEEN CHARACTERIZED FROM A DEVELOPMENTAL PERSPECTIVE, RESEARCH IS REVEALING THAT NRSF PLAYS A ROLE IN VARIOUS NEUROLOGICAL DISEASES, RANGING FROM NEURODEGENERATIVE, NEUROPSYCHIATRIC, TO CANCER. DYSREGULATION OF NRSF ACTIVITY DISRUPTS DOWNSTREAM GENE EXPRESSION THAT IS RESPONSIBLE FOR NEURONAL CELL HOMEOSTASIS IN SEVERAL MODELS THAT CONTRIBUTE TO PATHOLOGIC STATES. INTERESTINGLY, IT IS NOW BECOMING APPARENT THAT THE DYSREGULATION OF NRSF CONTRIBUTES TO NEUROLOGICAL DISEASE THROUGH EPIGENETIC MECHANISMS. ALTHOUGH NRSF ITSELF IS A TRANSCRIPTION FACTOR, ITS MAJOR EFFECTORS ARE CHROMATIN MODIFIERS. AT THE LEVEL OF EPIGENETICS, CHANGES IN NRSF ACTIVITY HAVE BEEN WELL CHARACTERIZED IN MODELS OF NEUROPATHIC PAIN AND EPILEPSY. BETTER UNDERSTANDING OF THE EPIGENETIC BASIS OF BRAIN DISEASES HAS LED TO DESIGN AND USE OF SMALL MOLECULES THAT CAN PREVENT NRSF FROM REPRESSING GENE EXPRESSION BY NEUTRALIZING ITS INTERACTIONS WITH ITS CHROMATIN REMODELERS. THIS REVIEW WILL ADDRESS THE BASIC FUNCTION OF NRSF AND ITS COFACTORS, INVESTIGATE THEIR MECHANISMS, THEN EXPLORE HOW THEIR DYSFUNCTION CAN CAUSE DISEASE STATES. THIS REVIEW WILL ALSO ADDRESS RESEARCH ON NRSF AS A THERAPEUTIC TARGET AND DELVE INTO NEW THERAPEUTIC STRATEGIES THAT FOCUS ON DISRUPTING NRSF'S ABILITY TO RECRUIT CHROMATIN REMODELERS. 2018 15 3024 28 GENETICS AND PATHOGENESIS OF DIFFUSE LARGE B-CELL LYMPHOMA. BACKGROUND: DIFFUSE LARGE B-CELL LYMPHOMAS (DLBCLS) ARE PHENOTYPICALLY AND GENETICALLY HETEROGENEOUS. GENE-EXPRESSION PROFILING HAS IDENTIFIED SUBGROUPS OF DLBCL (ACTIVATED B-CELL-LIKE [ABC], GERMINAL-CENTER B-CELL-LIKE [GCB], AND UNCLASSIFIED) ACCORDING TO CELL OF ORIGIN THAT ARE ASSOCIATED WITH A DIFFERENTIAL RESPONSE TO CHEMOTHERAPY AND TARGETED AGENTS. WE SOUGHT TO EXTEND THESE FINDINGS BY IDENTIFYING GENETIC SUBTYPES OF DLBCL BASED ON SHARED GENOMIC ABNORMALITIES AND TO UNCOVER THERAPEUTIC VULNERABILITIES BASED ON TUMOR GENETICS. METHODS: WE STUDIED 574 DLBCL BIOPSY SAMPLES USING EXOME AND TRANSCRIPTOME SEQUENCING, ARRAY-BASED DNA COPY-NUMBER ANALYSIS, AND TARGETED AMPLICON RESEQUENCING OF 372 GENES TO IDENTIFY GENES WITH RECURRENT ABERRATIONS. WE DEVELOPED AND IMPLEMENTED AN ALGORITHM TO DISCOVER GENETIC SUBTYPES BASED ON THE CO-OCCURRENCE OF GENETIC ALTERATIONS. RESULTS: WE IDENTIFIED FOUR PROMINENT GENETIC SUBTYPES IN DLBCL, TERMED MCD (BASED ON THE CO-OCCURRENCE OF MYD88(L265P) AND CD79B MUTATIONS), BN2 (BASED ON BCL6 FUSIONS AND NOTCH2 MUTATIONS), N1 (BASED ON NOTCH1 MUTATIONS), AND EZB (BASED ON EZH2 MUTATIONS AND BCL2 TRANSLOCATIONS). GENETIC ABERRATIONS IN MULTIPLE GENES DISTINGUISHED EACH GENETIC SUBTYPE FROM OTHER DLBCLS. THESE SUBTYPES DIFFERED PHENOTYPICALLY, AS JUDGED BY DIFFERENCES IN GENE-EXPRESSION SIGNATURES AND RESPONSES TO IMMUNOCHEMOTHERAPY, WITH FAVORABLE SURVIVAL IN THE BN2 AND EZB SUBTYPES AND INFERIOR OUTCOMES IN THE MCD AND N1 SUBTYPES. ANALYSIS OF GENETIC PATHWAYS SUGGESTED THAT MCD AND BN2 DLBCLS RELY ON "CHRONIC ACTIVE" B-CELL RECEPTOR SIGNALING THAT IS AMENABLE TO THERAPEUTIC INHIBITION. CONCLUSIONS: WE UNCOVERED GENETIC SUBTYPES OF DLBCL WITH DISTINCT GENOTYPIC, EPIGENETIC, AND CLINICAL CHARACTERISTICS, PROVIDING A POTENTIAL NOSOLOGY FOR PRECISION-MEDICINE STRATEGIES IN DLBCL. (FUNDED BY THE INTRAMURAL RESEARCH PROGRAM OF THE NATIONAL INSTITUTES OF HEALTH AND OTHERS.). 2018 16 1205 23 COULD THE INHIBITOR OF DNA BINDING 2 AND 4 PLAY A ROLE IN WHITE MATTER INJURY? WHITE MATTER INJURY (WMI) PREVENTS THE NORMAL DEVELOPMENT OF MYELINATION, LEADING TO CENTRAL NERVOUS SYSTEM MYELINATION DISORDERS AND THE PRODUCTION OF CHRONIC SEQUELAE ASSOCIATED WITH WMI, SUCH AS CHRONIC DYSKINESIA, COGNITIVE IMPAIRMENT AND CEREBRAL PALSY. THIS RESULTS IN A LARGE EMOTIONAL AND SOCIOECONOMIC BURDEN. DECREASED MYELINATION IN PRETERM INFANT WMI IS ASSOCIATED WITH THE DELAYED DEVELOPMENT OR DESTRUCTION OF OLIGODENDROCYTE (OL) LINEAGE CELLS, PARTICULARLY OLIGODENDROCYTE PRECURSOR CELLS (OPCS). THE DEVELOPMENT OF CELLS FROM THE OL LINEAGE INVOLVES THE MIGRATION, PROLIFERATION AND DIFFERENT STAGES OF OL DIFFERENTIATION, FINALLY LEADING TO MYELINATION. A SERIES OF COMPLEX INTRINSIC, EXTRINSIC AND EPIGENETIC FACTORS REGULATE THE OPC CELL CYCLE WITHDRAWAL, OL LINEAGE PROGRESSION AND MYELINATION. WE FOCUS ON THE INHIBITOR OF DNA BINDING 2 (ID2), BECAUSE IT IS WIDELY INVOLVED IN THE DIFFERENT STAGES OF OL DIFFERENTIATION AND GENESIS. ID2 IS A KEY TRANSCRIPTION FACTOR FOR THE NORMAL DEVELOPMENT OF OL LINEAGE CELLS, AND THE PATHOGENESIS OF WMI IS CLOSELY LINKED WITH OL DEVELOPMENTAL DISORDERS. ID4, ANOTHER FAMILY MEMBER OF THE IDS PROTEIN, ALSO PLAYS A SIMILAR ROLE IN OL DIFFERENTIATION AND GENESIS. ID2 AND ID4 BELONG TO THE HELIX-LOOP-HELIX FAMILY; THEY LACK THE DNA-BINDING SEQUENCES AND INHIBIT OLIGODENDROGENESIS AND OPC DIFFERENTIATION. IN THIS REVIEW, WE MAINLY DISCUSS THE ROLES OF ID2 IN OL DEVELOPMENT, ESPECIALLY DURING OPC DIFFERENTIATION, AND SUMMARIZE THE ID2-MEDIATED INTRACELLULAR AND EXTRACELLULAR SIGNALING PATHWAYS THAT REGULATE THESE PROCESSES. WE ALSO DISCUSS ID4 IN RELATION TO BONE MORPHOGENETIC PROTEIN SIGNALING AND OLIGODENDROGENESIS. IT IS LIKELY THAT THESE DEVELOPMENTAL MECHANISMS ARE ALSO INVOLVED IN THE MYELIN REPAIR OR REMYELINATION IN HUMAN NEUROLOGICAL DISEASES. 2019 17 257 35 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 18 6490 21 TRACING SLOW PHENOPTOSIS TO THE PRENATAL STAGE IN SOCIAL VERTEBRATES. VLADIMIR SKULACHEV'S COINING OF THE TERM "PHENOPTOSIS" 25 YEARS AGO (SKULACHEV, V. P., BIOCHEMISTRY (MOSCOW), 62, 1997) HIGHLIGHTED THE THEORETICAL POSSIBILITY THAT AGING IS A PROGRAMMED PROCESS TO SPEED THE EXIT OF INDIVIDUALS POSING SOME DANGER TO THEIR SOCIAL GROUP. WHILE RAPID "ACUTE PHENOPTOSIS" MIGHT OCCUR AT ANY AGE (E.G., TO PREVENT SPREAD OF DEADLY INFECTIONS), "SLOW PHENOPTOSIS" IS GENERALLY CONSIDERED TO OCCUR LATER IN LIFE IN THE FORM OF CHRONIC AGE-RELATED DISORDERS. HOWEVER, RECENT RESEARCH INDICATES THAT RISKS FOR SUCH CHRONIC DISORDERS CAN BE GREATLY RAISED BY EARLY LIFE ADVERSITY, ESPECIALLY DURING THE PRENATAL STAGE. MUCH OF THIS RESEARCH USES INDICATORS OF BIOLOGICAL AGING, THE SPEEDING OR SLOWING OF NATURAL PHYSIOLOGICAL DETERIORATION IN RESPONSE TO ENVIRONMENTAL INPUTS, LEADING TO DIVERGENCE FROM CHRONOLOGICAL AGE. STUDIES USING BIOLOGICAL AGING INDICATORS COMMONLY FIND IT IS ACCELERATED NOT ONLY IN OLDER INDIVIDUALS WITH CHRONIC DISORDERS, BUT ALSO IN VERY YOUNG INDIVIDUALS WITH HEALTH PROBLEMS. THIS REVIEW WILL EXPLAIN HOW ACCELERATED BIOLOGICAL AGING EQUATES TO SLOW PHENOPTOSIS. ITS OCCURRENCE EVEN IN THE PRENATAL STAGE IS THEORETICALLY SUPPORTED BY W. D. HAMILTON'S PROPOSAL THAT OFFSPRINGS DETECTING THEY HAVE DANGEROUS MUTATIONS SHOULD THEN AUTOMATICALLY SPEED THEIR DEMISE, IN ORDER TO IMPROVE THEIR INCLUSIVE FITNESS BY GIVING THEIR PARENTS THE CHANCE TO PRODUCE OTHER FITTER SIBLINGS. 2022 19 6507 17 TRAINING VOCATIONAL REHABILITATION COUNSELORS WHO WORK WITH CHRONIC MENTAL PATIENTS. BECAUSE OF THE INEFFICACY OF DISPARATE PSYCHIATRIC AND REHABILITATIVE APPROACHES TO PSYCHOSOCIAL RESTORATION OF CHRONIC MENTAL PATIENTS, THE AUTHORS DESIGNED THE NEW ENGLAND PSYCHIATRIC REHABILITATION TRAINING PROGRAM FOR VOCATIONAL REHABILITATION COUNSELORS WHO WORK WITH THESE PATIENTS. THE PROGRAM EXTENDS ERIKSON'S EPIGENETIC SEQUENCE TO DEVELOPMENT OF WORK CAPACITY AND EMPHASIZES A COMPREHENSIVE, MULTIAXIAL APPROACH TO PSYCHOPATHOLOGY AND VOCATIONAL REHABILITATION. AFTER 6 WEEKS OF SEMINARS, CLINICAL WORK, AND SUPERVISION, COUNSELORS RETURN TO THEIR AGENCIES AND RECEIVE AN ADDITIONAL 8 WEEKS OF PART-TIME SUPPORT FROM FIELD FACULTY INSTRUCTORS. 1981 20 4636 36 NEUROLOGIC COMPLICATIONS OF ACUTE HIV INFECTION. PURPOSE OF REVIEW: THIS REVIEW FOCUSES ON THE PATHOPHYSIOLOGY OF ACUTE HIV INFECTION (AHI) AND RELATED CENTRAL NERVOUS SYSTEM (CNS) PATHOLOGY, THE CLINICAL CHARACTERISTICS OF NEUROLOGIC COMPLICATIONS OF AHI, AND THE IMPLICATIONS OF THE CNS RESERVOIR AND VIRAL ESCAPE FOR HIV TREATMENT AND CURE STRATEGIES. RECENT FINDINGS: RECENT STUDIES IN NEWLY SEROCONVERTED POPULATIONS SHOW A HIGH PREVALENCE OF PERIPHERAL NEUROPATHY AND COGNITIVE DYSFUNCTION IN AHI, EVEN THOUGH THESE FINDINGS HAVE BEEN CLASSICALLY ASSOCIATED WITH CHRONIC HIV INFECTION. HIV CURE STRATEGIES SUCH AS THE "SHOCK AND KILL" STRATEGY ARE CURRENTLY BEING STUDIED IN VITRO AND EVEN IN SMALL CLINICAL TRIALS, THOUGH THE CNS AS A RESERVOIR FOR LATENT HIV POSES UNIQUE BARRIERS TO THESE TREATMENT STRATEGIES. SUMMARY: LIMITED POINT OF CARE DIAGNOSTIC TESTING FOR AHI AND DELAYED RECOGNITION OF INFECTION CONTINUE TO LEAD TO UNDER-RECOGNITION AND UNDER-REPORTING OF NEUROLOGIC MANIFESTATIONS OF AHI. AHI SHOULD BE ON THE DIFFERENTIAL FOR A BROAD RANGE OF NEUROLOGICAL CONDITIONS, FROM BELL'S PALSY, PERIPHERAL NEUROPATHY, AND ASEPTIC MENINGITIS, TO MORE RARE MANIFESTATIONS SUCH AS ADEM, AIDP, MENINGO-RADICULITIS, TRANSVERSE MYELITIS, AND BRACHIAL NEURITIS. TREATMENT FOR THESE CONDITIONS INVOLVES EARLY INITIATION OF ANTIRETROVIRAL THERAPY (ART) AND THEN STANDARD PRESENTATION-SPECIFIC TREATMENTS. CURRENT HIV CURE STRATEGIES UNDER INVESTIGATION INCLUDE BONE MARROW TRANSPLANT, VIRAL RESERVOIR RE-ACTIVATION AND ERADICATION, AND GENOME AND EPIGENETIC VIRAL TARGETING. HOWEVER, CNS PENETRATION BY HIV-1 OCCURS EARLY ON IN THE DISEASE COURSE WITH THE ESTABLISHMENT OF THE CNS VIRAL RESERVOIR AND IS AN IMPORTANT LIMITING FACTOR FOR THESE THERAPIES. 2020