1 4952 125 PATHOGENESIS OF CHRONIC CHIKUNGUNYA ARTHRITIS: RESEMBLANCES AND LINKS WITH RHEUMATOID ARTHRITIS. CHIKUNGUNYA VIRUS (CHIKV) INFECTION RESULTS FROM TRANSMISSION BY THE MOSQUITO VECTOR. FOLLOWING AN INCUBATION PERIOD OF 5-7 DAYS, PATIENTS DEVELOP AN ACUTE FEBRILE ILLNESS, CHIKUNGUNYA FEVER (CHIKF), CHARACTERIZED BY HIGH FEVERS, MACULOPAPULAR RASH, HEADACHES, POLYARTHRITIS/ARTHRALGIAS, MYALGIAS, NAUSEA, VOMITING, AND DIARRHEA. JOINT PAIN IS OFTEN SEVERE, AND MOST OFTEN INVOLVES THE HANDS, THE WRISTS, THE ANKLES, AND THE METATARSAL-PHALANGEAL JOINTS OF THE FEET. MANY PATIENTS RECOVER WITHIN SEVERAL WEEKS, BUT UP TO 50% DEVELOP CHRONIC JOINT PAIN AND SWELLING FOR MORE THAN 12 WEEKS, THEN WE REFER TO THESE SYMPTOMS AS CHRONIC CHIKUNGUNYA ARTHRITIS (CCA). THE PATHOGENESIS OF CCA IS NOT WELL UNDERSTOOD. IN THIS ARTICLE, WE SUGGEST THAT MESENCHYMAL STEM CELLS (MSCS) MAY PLAY AN IMPORTANT ROLE IN THIS PATHOGENESIS. THIS HETEROGENEOUS GROUP OF MULTIPOTENT CELLS, MORPHOLOGICALLY SIMILAR TO FIBROBLASTS, MAY UNDERGO EPIGENETIC CHANGES CAPABLE OF GENERATING ABERRANT PROGENIES. HOWEVER, WE BELIEVE THAT THERE IS NO NEED FOR A LATENT INFECTION. IN OUR PATHOGENIC HYPOTHESIS, CHIKV INFECTION OF MSCS WOULD CAUSE EPIGENETIC CHANGES BOTH IN MSCS THEMSELVES AND IN THEIR PROGENIES, WITHOUT THE NEED FOR REACTIVATION OF DORMANT VIRUSES. 2023 2 3985 23 LONG-TERM MAINTENANCE OF THE MUCOSAL HEALING INDUCED BY AZACITIDINE THERAPY IN A PATIENT WITH INTESTINAL BEHCET'S-LIKE DISEASE ACCOMPANIED WITH MYELODYSPLASTIC SYNDROME INVOLVING TRISOMY 8. MYELODYSPLASTIC SYNDROMES (MDSS) ARE A GROUP OF MYELOID NEOPLASMS CHARACTERIZED BY BLOOD CELL DEFORMATION AND DYSFUNCTION, AND MDS WITH TRISOMY 8 IS CLOSELY LINKED WITH INTESTINAL BEHCET'S-LIKE DISEASES. INTESTINAL BEHCET'S-LIKE DISEASE IS REFRACTORY TO CONVENTIONAL THERAPIES, INCLUDING PREDNISOLONE, IMMUNOMODULATORS, AND ANTI-TUMOR NECROSIS FACTOR ALPHA AGENTS. HERE, WE DESCRIBE A 56-YEAR-OLD WOMAN WITH INTESTINAL BEHCET'S-LIKE DISEASE ASCRIBED TO MDS WITH TRISOMY 8 WHO HAD MULTIPLE INTRACTABLE INTESTINAL ULCERS. SHE PRESENTED WITH PERIODIC FEVER AND ABDOMINAL PAIN. THE GENETIC ANALYSIS SHOWED A HETEROZYGOUS E148Q MUTATION IN THE MEDITERRANEAN FEVER GENE. THE PATIENT DID NOT TOLERATE TREATMENT WITH COLCHICINE BECAUSE OF DIARRHEA; THEREFORE, AZACITIDINE THERAPY WAS INITIATED. ONE CYCLE OF AZACITIDINE THERAPY IMPROVED THE MULTIPLE INTESTINAL ULCERS, AND THE PERIODIC FEVER AND ABDOMINAL PAIN GRADUALLY DISAPPEARED. AFTER EIGHT CYCLES OF AZACITIDINE THERAPY, ILEOCOLONOSCOPY, HISTOLOGICAL ASSESSMENT AND CAPSULE ENDOSCOPY REVEALED MUCOSAL HEALING. AZACITIDINE THERAPY WAS CONTINUED, AND MUCOSAL HEALING WAS MAINTAINED FOR MORE THAN 2 YEARS. THIS CASE SUGGESTS THAT AZACITIDINE THERAPY WHICH HAS IMMUNOREGULATORY EFFECTS AND EPIGENETIC MODULATIONS, MIGHT CONTROL INTESTINAL BEHCET'S-LIKE DISEASE ASSOCIATED WITH MDS INVOLVING TRISOMY 8. 2019 3 2829 18 FLUSHING OUT CARCINOID SYNDROME: BENEFICIAL EFFECT OF THE ANTICANCER EPIGENETIC AGENT RRX-001 IN A PATIENT WITH A TREATMENT-REFRACTORY NEUROENDOCRINE TUMOR. NEUROENDOCRINE TUMORS (NET) ARE A HETEROGENEOUS GROUP OF NEOPLASMS DEFINED BY THE PRESENCE OF CELLS WITH SECRETORY GRANULES AND THE POTENTIAL TO PRODUCE AND RELEASE HIGH LEVELS OF VASOACTIVE PEPTIDES INTO THE CIRCULATION, LEADING TO SEVERE FLUSHING AND DIARRHEA, WHICH MAY ADVERSELY AFFECT QUALITY OF LIFE. THIS REPORT PRESENTS THE CASE OF A 64-YEAR-OLD MAN WITH CHRONIC REFRACTORY DIARRHEA DUE TO PULMONARY NET TREATED WITH THE EXPERIMENTAL ANTICANCER AGENT RRX-001 IN A PHASE II TRIAL CALLED TRIPLE THREAT WITH SUBSEQUENT RESOLUTION OF HIS DIARRHEA. 2015 4 5231 24 PROBIOTICS AND AMELIORATION OF RHEUMATOID ARTHRITIS: SIGNIFICANT ROLES OF LACTOBACILLUS CASEI AND LACTOBACILLUS ACIDOPHILUS. RHEUMATOID ARTHRITIS IS A CHRONIC AUTOIMMUNE DISORDER THAT CAN LEAD TO DISABILITY CONDITIONS WITH SWOLLEN JOINTS, PAIN, STIFFNESS, CARTILAGE DEGRADATION, AND OSTEOPOROSIS. GENETIC, EPIGENETIC, SEX-SPECIFIC FACTORS, SMOKING, AIR POLLUTION, FOOD, ORAL HYGIENE, PERIODONTITIS, PREVOTELLA, AND IMBALANCE IN THE GASTROINTESTINAL MICROBIOTA ARE POSSIBLE SOURCES OF THE INITIATION OR PROGRESSION OF RHEUMATOID ARTHRITIS, ALTHOUGH THE DETAILED MECHANISMS STILL NEED TO BE ELUCIDATED. PROBIOTICS CONTAINING LACTOBACILLUS SPP. ARE COMMONLY USED AS ALLEVIATING AGENTS OR FOOD SUPPLEMENTS TO MANAGE DIARRHEA, DYSENTERY, DEVELOP IMMUNITY, AND MAINTAIN GENERAL HEALTH. THE MECHANISM OF ACTION OF LACTOBACILLUS SPP. AGAINST RHEUMATOID ARTHRITIS IS STILL NOT CLEARLY KNOWN TO DATE. IN THIS NARRATIVE REVIEW, WE RECAPITULATE THE FINDINGS OF RECENT STUDIES TO UNDERSTAND THE OVERALL PATHOGENESIS OF RHEUMATOID ARTHRITIS AND THE ROLES OF PROBIOTICS, PARTICULARLY L. CASEI OR L. ACIDOPHILUS, IN THE MANAGEMENT OF RHEUMATOID ARTHRITIS IN CLINICAL AND PRECLINICAL STUDIES. 2021 5 255 28 ADVANCES IN MYELOFIBROSIS: A CLINICAL CASE APPROACH. PRIMARY MYELOFIBROSIS IS A MEMBER OF THE MYELOPROLIFERATIVE NEOPLASMS, A DIVERSE GROUP OF BONE MARROW MALIGNANCIES. SYMPTOMS OF MYELOFIBROSIS, PARTICULARLY THOSE ASSOCIATED WITH SPLENOMEGALY (ABDOMINAL DISTENTION AND PAIN, EARLY SATIETY, DYSPNEA, AND DIARRHEA) AND CONSTITUTIONAL SYMPTOMS, REPRESENT A SUBSTANTIAL BURDEN TO PATIENTS. MOST PATIENTS EVENTUALLY DIE FROM THE DISEASE, WITH A MEDIAN SURVIVAL RANGING FROM APPROXIMATELY 5-7 YEARS. MUTATIONS IN JANUS KINASE 2 (JAK2), A KINASE THAT IS ESSENTIAL FOR THE NORMAL DEVELOPMENT OF ERYTHROCYTES, GRANULOCYTES, AND PLATELETS, NOTABLY THE V617F MUTATION, HAVE BEEN IDENTIFIED IN APPROXIMATELY 50% OF PATIENTS WITH MYELOFIBROSIS. THE APPROVAL OF A JAK2 INHIBITOR IN 2011 HAS IMPROVED THE OUTLOOK OF MANY PATIENTS WITH MYELOFIBROSIS AND HAS CHANGED THE TREATMENT LANDSCAPE. THIS ARTICLE FOCUSES ON SOME OF THE IMPORTANT ISSUES IN CURRENT MYELOFIBROSIS TREATMENT MANAGEMENT, INCLUDING DIFFERENTIATION OF MYELOFIBROSIS FROM ESSENTIAL THROMBOCYTHEMIA AND POLYCYTHEMIA VERA, UP-DATED DATA ON THE RESULTS OF JAK2 INHIBITOR THERAPY, THE ROLE OF EPIGENETIC MECHANISMS IN MYELOFIBROSIS PATHOGENESIS, INVESTIGATIONAL THERAPIES FOR MYELOFIBROSIS, AND ADVANCES IN HEMATOPOIETIC STEM CELL TRANSPLANT. THREE MYELOFIBROSIS CASES ARE INCLUDED TO UNDERSCORE THE ISSUES IN DIAGNOSING AND TREATING THIS COMPLEX DISEASE. 2013 6 5559 24 ROLE OF HIPPOCAMPAL CIRCKCNK9 IN VISCERAL HYPERSENSITIVITY AND ANXIETY COMORBIDITY OF IRRITABLE BOWEL SYNDROME. IRRITABLE BOWEL SYNDROME (IBS) IS A COMMON GASTROINTESTINAL DISORDER CHARACTERIZED BY RECURRENT VISCERAL PAIN AND ALTERED BOWEL HABITS (DIARRHEA OR CONSTIPATION). HOWEVER, THE MOLECULAR AND PATHOLOGICAL MECHANISMS ARE POORLY UNDERSTOOD. THIS STUDY FOUND NEONATAL COLORECTAL DISTENSION TO INDUCE VISCERAL HYPERSENSITIVITY AND ANXIETY. THE EXPRESSION OF HIPPOCAMPAL CIRCKCNK9, A NOVEL CIRCRNA, WAS SIGNIFICANTLY INCREASED IN IBS-LIKE RATS. INTERESTINGLY, CA1 SHCIRCKCNK9 TREATMENT INHIBITED LONG-TERM POTENTIATION (LTP) AND ALLEVIATED VISCERAL HYPERSENSITIVITY AND ANXIETY IN IBS-LIKE RATS, WHEREAS OVEREXPRESSION OF CA1 CIRCKCNK9 INDUCED LTP, VISCERAL HYPERSENSITIVITY, AND ANXIETY IN CONTROLS. SEVERAL EXPERIMENTS INDICATED THAT INCREASED CA1 CIRCKCNK9 ACTED AS A MIR-124-3P SPONGE, WHICH RESULTED IN THE INHIBITORY EFFECT OF MIR-124-3P ON GENE SILENCING. THERE WAS A NEGATIVE CORRELATION BETWEEN CIRCKCNK9 AND MIR-124-3P EXPRESSION. AS EXPECTED, CA1 ADMINISTRATION OF AGOMIR-124-3P DECREASED CA1 LTP, VISCERAL HYPERSENSITIVITY, AND ANXIETY IN THE IBS-LIKE RATS. IN CONTRAST, CA1 TREATMENT WITH ANTAGOMIR-124-3P INDUCED LTP, VISCERAL HYPERSENSITIVITY, AND ANXIETY IN THE CONTROLS. FURTHERMORE, BIOINFORMATIC ANALYSIS AND EXPERIMENTAL DATA SHOWED THAT EZH2 IS A CIRCKCNK9/MIR-124-3P TARGET GENE, AND INCREASED EZH2 EXPRESSION WAS INVOLVED IN VISCERAL HYPERSENSITIVITY AND ANXIETY IN IBS-LIKE RATS BY ENHANCING HIPPOCAMPAL SYNAPTIC PLASTICITY. IN CONCLUSION, EARLY LIFE STRESS INDUCES INCREASED EXPRESSION OF CIRCKCNK9 IN THE CA1 OF IBS-LIKE RATS. INCREASED CIRCKCNK9 EXPRESSION REGULATES SYNAPTIC TRANSMISSION AND ENHANCES LTP, LEADING TO VISCERAL HYPERSENSITIVITY AND ANXIETY IN IBS-LIKE RATS. THE UNDERLYING CIRCKCNK9 SIGNALING PATHWAY IS MIR124-3P/EZH2. INCREASED CIRCKCNK9 REINFORCES ITS SPONGING OF MIR124-3P AND STRONGLY SUPPRESSES MIR124-3P ACTIVITY, RESULTING IN INCREASED EXPRESSION OF THE TARGET GENE EZH2. THIS STUDY PROVIDES A NEW EPIGENETIC MECHANISM FOR VISCERAL HYPERSENSITIVITY AND ANXIETY IN IBS-LIKE RATS. 2022 7 3601 23 IMPORTANCE OF PROBIOTICS IN THE PREVENTION AND TREATMENT OF COLORECTAL CANCER. COLORECTAL CANCER (CRC) REMAINS ONE OF THE MOST COMMON AND DEADLY CANCERS. INTESTINAL GUT MICROFLORA IS IMPORTANT TO MAINTAIN AND CONTRIBUTES TO SEVERAL INTESTINAL FUNCTIONS, INCLUDING THE DEVELOPMENT OF THE MUCOSAL IMMUNE SYSTEM, ABSORPTION OF COMPLEX MACROMOLECULES, SYNTHESIS OF AMINO ACIDS/VITAMINS AND THE PROTECTION AGAINST PATHOGENIC MICROORGANISMS. IT IS WELL KNOWN THAT THE GUT MICROBIOTA CHANGES OR DYSBIOSIS MAY HAVE AN ESSENTIAL IMPACT IN THE INITIATION AND PROMOTION OF CHRONIC INFLAMMATORY PATHWAYS AND ALSO HAVE A PROFOUND DIFFERENT GENETIC AND EPIGENETIC ALTERATIONS LEADING TO DYSPLASIA, CLONAL EXPANSION, AND MALIGNANT TRANSFORMATION. PROBIOTIC BACTERIA HAS ANTITUMOR ACTIVITY WITH VARIOUS MECHANISMS SUCH AS NONSPECIFIC PHYSIOLOGICAL AND IMMUNOLOGICAL MECHANISMS. THIS REVIEW EVALUATES THE EFFECTS OF MICROBIOTA AND PROBIOTICS IN CLINICAL TRIALS, IN VITRO AND ANIMAL MODEL STUDIES THAT HAVE EXPLORED HOW PROBIOTIC AGAINST CANCER DEVELOPMENT AND ALSO DISCUSSES THE POSSIBLE IMMUNOMODULATORY MECHANISMS. SEVERAL MECHANISMS ALTERATION OF THE INTESTINAL MICROFLORA; INACTIVATION OF CANCEROGENIC COMPOUNDS; COMPETITION WITH PUTREFACTIVE AND PATHOGENIC MICROBIOTA; IMPROVEMENT OF THE HOST'S IMMUNE RESPONSE; ANTIPROLIFERATIVE EFFECTS VIA REGULATION OF APOPTOSIS AND CELL DIFFERENTIATION; FERMENTATION OF UNDIGESTED FOOD; INHIBITION OF TYROSINE KINASE; REDUCES THE ENTEROPATHOGENIC COMPLICATIONS BEFORE AND AFTER COLON CANCER SURGERY AND IMPROVE DIARRHEA AND IT'S HAVE BEEN ABLE TO CREATE THE INTEGRITY OF GUT MUCOSAL AND HAVE STIMULATORY EFFECTS ON THE SYSTEMIC IMMUNE SYSTEM AND PREVENT THE CRC METASTASIS. RESEARCH IN CLINICAL TRIALS ENCOURAGING FINDINGS THAT SUPPORT A ROLE OF PROBIOTICS IN CRC PREVENTION AND IMPROVE THE SAFETY AND EFFECTIVENESS OF CANCER THERAPY EVEN THOUGH ADDITIONAL CLINICAL RESEARCH IS STILL NECESSARY. 2019 8 4519 20 MULTI-OMICS IN CROHN'S DISEASE: NEW INSIGHTS FROM INSIDE. CROHN'S DISEASE (CD) IS AN INFLAMMATORY BOWEL DISEASE (IBD) WITH COMPLEX CLINICAL MANIFESTATIONS SUCH AS CHRONIC DIARRHEA, WEIGHT LOSS AND HEMATOCHEZIA. DESPITE THE INCREASING INCIDENCE WORLDWIDE, CURE OF CD REMAINS EXTREMELY DIFFICULT. THE RAPID DEVELOPMENT OF HIGH-THROUGHPUT SEQUENCING TECHNOLOGY WITH INTEGRATED-OMICS ANALYSES IN RECENT YEARS HAS PROVIDED A NEW MEANS FOR EXPLORING THE PATHOGENESIS, MINING THE BIOMARKERS AND DESIGNING TARGETED PERSONALIZED THERAPEUTICS OF CD. HOST GENOMICS AND EPIGENOMICS UNVEIL HEREDITY-RELATED MECHANISMS OF SUSCEPTIBLE INDIVIDUALS, WHILE MICROBIOME AND METABOLOMICS MAP HOST-MICROBE INTERACTIONS IN CD PATIENTS. PROTEOMICS SHOWS GREAT POTENTIAL IN SEARCHING FOR PROMISING BIOMARKERS. NONETHELESS, SINGLE OMICS TECHNOLOGY CANNOT HOLISTICALLY CONNECT THE MECHANISMS WITH HETEROGENEITY OF PATHOLOGICAL BEHAVIOR IN CD. THE RISE OF MULTI-OMICS ANALYSIS INTEGRATES GENETIC/EPIGENETIC PROFILES WITH PROTEIN/MICROBIAL METABOLITE FUNCTIONALITY, PROVIDING NEW HOPE FOR COMPREHENSIVE AND IN-DEPTH EXPLORATION OF CD. HEREIN, WE EMPHASIZED THE DIFFERENT OMICS FEATURES AND APPLICATIONS OF CD AND DISCUSSED THE CURRENT RESEARCH AND LIMITATIONS OF MULTI-OMICS IN CD. THIS REVIEW WILL UPDATE AND DEEPEN OUR UNDERSTANDING OF CD FROM INTEGRATION OF BROAD OMICS SPECTRA AND WILL PROVIDE NEW EVIDENCE FOR TARGETED INDIVIDUALIZED THERAPEUTICS. 2023 9 6254 19 THE MICROBIOME AND IRRITABLE BOWEL SYNDROME - A REVIEW ON THE PATHOPHYSIOLOGY, CURRENT RESEARCH AND FUTURE THERAPY. IRRITABLE BOWEL SYNDROME (IBS) IS A FUNCTIONAL DISORDER WHICH AFFECTS A LARGE PROPORTION OF THE POPULATION GLOBALLY. THE PRECISE ETIOLOGY OF IBS IS STILL UNKNOWN, ALTHOUGH CONSENSUS UNDERSTANDING PROPOSES IBS TO BE OF MULTIFACTORIAL ORIGIN WITH YET UNDEFINED SUBTYPES. GENETIC AND EPIGENETIC FACTORS, STRESS-RELATED NERVOUS AND ENDOCRINE SYSTEMS, IMMUNE DYSREGULATION AND THE BRAIN-GUT AXIS SEEM TO BE CONTRIBUTING FACTORS THAT PREDISPOSE INDIVIDUALS TO IBS. IN ADDITION TO FOOD HYPERSENSITIVITY, TOXINS AND ADVERSE LIFE EVENTS, CHRONIC INFECTIONS AND DYSBIOTIC GUT MICROBIOTA HAVE BEEN SUGGESTED TO TRIGGER IBS SYMPTOMS IN TANDEM WITH THE PREDISPOSING FACTORS. THIS REVIEW WILL SUMMARIZE THE PATHOPHYSIOLOGY OF IBS AND THE ROLE OF GUT MICROBIOTA IN RELATION TO IBS. CURRENT METHODOLOGIES FOR MICROBIOME STUDIES IN IBS SUCH AS GENOME SEQUENCING, METAGENOMICS, CULTUROMICS AND ANIMAL MODELS WILL BE DISCUSSED. THE MYRIAD OF THERAPY OPTIONS SUCH AS IMMUNOGLOBULINS (IMMUNE-BASED THERAPY), PROBIOTICS AND PREBIOTICS, DIETARY MODIFICATIONS INCLUDING FODMAP RESTRICTION DIET AND GLUTEN-FREE DIET, AS WELL AS FECAL TRANSPLANTATION WILL BE REVIEWED. FINALLY THIS REVIEW WILL HIGHLIGHT FUTURE DIRECTIONS IN IBS THERAPY RESEARCH, INCLUDING IDENTIFICATION OF NEW MOLECULAR TARGETS, APPLICATION OF 3-D GUT MODEL, GUT-ON-A-CHIP AND PERSONALIZED THERAPY. 2019 10 105 27 A REVIEW OF MICROBIOTA AND IRRITABLE BOWEL SYNDROME: FUTURE IN THERAPIES. IRRITABLE BOWEL SYNDROME (IBS), ONE OF THE MOST FREQUENT DIGESTIVE DISORDERS, IS CHARACTERIZED BY CHRONIC AND RECURRENT ABDOMINAL PAIN AND ALTERED BOWEL HABIT. THE ORIGIN SEEMS TO BE MULTIFACTORIAL AND IS STILL NOT WELL DEFINED FOR THE DIFFERENT SUBTYPES. GENETIC, EPIGENETIC AND SEX-RELATED MODIFICATIONS OF THE FUNCTIONING OF THE NERVOUS AND IMMUNE-ENDOCRINE SUPERSYSTEMS AND REGULATION OF BRAIN-GUT PHYSIOLOGY AND BILE ACID PRODUCTION AND ABSORPTION ARE CERTAINLY INVOLVED. ACQUIRED PREDISPOSITION MAY ACT IN CONJUNCTION WITH INFECTIOUS, TOXIC, DIETARY AND LIFE EVENT-RELATED FACTORS TO ENHANCE EPITHELIAL PERMEABILITY AND ELICIT MUCOSAL MICROINFLAMMATION, IMMUNE ACTIVATION AND DYSBIOSIS. NOTABLY, STRONG EVIDENCE SUPPORTS THE ROLE OF BACTERIAL, VIRAL AND PARASITIC INFECTIONS IN TRIGGERING IBS, AND TARGETING MICROBIOTA SEEMS PROMISING IN VIEW OF THE POSITIVE RESPONSE TO MICROBIOTA-RELATED THERAPIES IN SOME PATIENTS. HOWEVER, THE LACK OF HIGHLY PREDICTIVE DIAGNOSTIC BIOMARKERS AND THE COMPLEXITY AND HETEROGENEITY OF IBS PATIENTS MAKE MANAGEMENT DIFFICULT AND UNSATISFACTORY IN MANY CASES, REDUCING PATIENT HEALTH-RELATED QUALITY OF LIFE AND INCREASING THE SANITARY BURDEN. THIS ARTICLE REVIEWS SPECIFIC ALTERATIONS AND INTERVENTIONS TARGETING THE GUT MICROBIOTA IN IBS, INCLUDING PREBIOTICS, PROBIOTICS, SYNBIOTICS, NON-ABSORBABLE ANTIBIOTICS, DIETS, FECAL TRANSPLANTATION AND OTHER POTENTIAL FUTURE APPROACHES USEFUL FOR THE DIAGNOSIS, PREVENTION AND TREATMENT OF IBS. 2018 11 4518 21 MULTI-OMICS FOR BIOMARKER APPROACHES IN THE DIAGNOSTIC EVALUATION AND MANAGEMENT OF ABDOMINAL PAIN AND IRRITABLE BOWEL SYNDROME: WHAT LIES AHEAD. RELIABLE BIOMARKERS FOR COMMON DISORDERS OF GUT-BRAIN INTERACTION CHARACTERIZED BY ABDOMINAL PAIN, INCLUDING IRRITABLE BOWEL SYNDROME (IBS), ARE CRITICALLY NEEDED TO ENHANCE CARE AND DEVELOP INDIVIDUALIZED THERAPIES. THE DYNAMIC AND HETEROGENEOUS NATURE OF THE PATHOPHYSIOLOGICAL MECHANISMS THAT UNDERLIE VISCERAL HYPERSENSITIVITY HAVE CHALLENGED SUCCESSFUL BIOMARKER DEVELOPMENT. CONSEQUENTLY, EFFECTIVE THERAPIES FOR PAIN IN IBS ARE LACKING. HOWEVER, RECENT ADVANCES IN MODERN OMICS TECHNOLOGIES OFFER NEW OPPORTUNITIES TO ACQUIRE DEEP BIOLOGICAL INSIGHTS INTO MECHANISMS OF PAIN AND NOCICEPTION. NEWER METHODS FOR LARGE-SCALE DATA INTEGRATION OF COMPLEMENTARY OMICS APPROACHES HAVE FURTHER EXPANDED OUR ABILITY TO BUILD A HOLISTIC UNDERSTANDING OF COMPLEX BIOLOGICAL NETWORKS AND THEIR CO-CONTRIBUTIONS TO ABDOMINAL PAIN. HERE, WE REVIEW THE MECHANISMS OF VISCERAL HYPERSENSITIVITY, FOCUSING ON IBS. WE DISCUSS CANDIDATE BIOMARKERS FOR PAIN IN IBS IDENTIFIED THROUGH SINGLE OMICS STUDIES AND SUMMARIZE EMERGING MULTI-OMICS APPROACHES FOR DEVELOPING NOVEL BIOMARKERS THAT MAY TRANSFORM CLINICAL CARE FOR PATIENTS WITH IBS AND ABDOMINAL PAIN. 2023 12 1311 23 DEFINITIONS, BIOLOGY, AND CURRENT THERAPEUTIC LANDSCAPE OF MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS. MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) ARE HEMATOLOGICAL DISORDERS CHARACTERIZED BY BOTH PROLIFERATIVE AND DYSPLASTIC FEATURES. ACCORDING TO THE 2022 INTERNATIONAL CONSENSUS CLASSIFICATION (ICC), MDS/MPN CONSISTS OF CLONAL MONOCYTOSIS OF UNDETERMINED SIGNIFICANCE (CMUS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML), MDS/MPN WITH SF3B1 MUTATION (MDS/MPN-T-SF3B1), MDS/MPN WITH RING SIDEROBLASTS AND THROMBOCYTOSIS NOT OTHERWISE SPECIFIED (MDS/MPN-RS-T-NOS), AND MDS/MPN-NOS. THESE DISORDERS EXHIBIT A DIVERSE RANGE OF GENETIC ALTERATIONS INVOLVING VARIOUS TRANSCRIPTION FACTORS (E.G., RUNX1), SIGNALING MOLECULES (E.G., NRAS, JAK2), SPLICING FACTORS (E.G., SF3B, SRSF2), AND EPIGENETIC REGULATORS (E.G., TET2, ASXL1, DNMT3A), AS WELL AS SPECIFIC CYTOGENETIC ABNORMALITIES (E.G., 8 TRISOMIES, 7 DELETIONS/MONOSOMIES). CLINICAL STUDIES EXPLORING THERAPEUTIC OPTIONS FOR HIGHER-RISK MDS/MPN OVERLAP SYNDROMES MOSTLY INVOLVE HYPOMETHYLATING AGENTS, BUT OTHER TREATMENTS SUCH AS LENALIDOMIDE AND TARGETED AGENTS SUCH AS JAK INHIBITORS AND INHIBITORS TARGETING PARP, HISTONE DEACETYLASES, AND THE RAS PATHWAY ARE UNDER INVESTIGATION. WHILE THESE TREATMENT MODALITIES CAN PROVIDE PARTIAL DISEASE CONTROL, ALLOGENEIC BONE MARROW TRANSPLANTATION (ALLO-BMT) IS THE ONLY POTENTIALLY CURATIVE OPTION FOR PATIENTS. IMPORTANT PROGNOSTIC FACTORS CORRELATING WITH OUTCOMES AFTER ALLO-BMT INCLUDE COMORBIDITIES, SPLENOMEGALY, KARYOTYPE ALTERATIONS, AND THE BONE MARROW BLASTS PERCENTAGE AT THE TIME OF TRANSPLANTATION. FUTURE RESEARCH IS IMPERATIVE TO OPTIMIZING THERAPEUTIC STRATEGIES AND ENHANCING PATIENT OUTCOMES IN MDS/MPN NEOPLASMS. IN THIS REVIEW, WE SUMMARIZE MDS/MPN DIAGNOSTIC CRITERIA, BIOLOGY, AND CURRENT AND FUTURE TREATMENT OPTIONS, INCLUDING BONE MARROW TRANSPLANTATION. 2023 13 5799 22 STEPPING OUT OF ANTIQUITY: AN UPDATE ON EMERGING DRUGS FOR THE TREATMENT OF POLYCYTHEMIA VERA. INTRODUCTION: POLYCYTHEMIA VERA IS A CHRONIC HEMATOLOGIC MALIGNANCY FREQUENTLY PRESENTED WITH CONSTITUTIONAL SYMPTOMS AND ASSOCIATED WITH AN INCREASED RISK OF THROMBOSIS, HEMORRHAGE, AND PROGRESSION TO MYELOFIBROSIS OR ACUTE MYELOID LEUKEMIA. CURRENT TREATMENT STRATEGIES REDUCE THROMBOHEMORRHAGIC RISK BY CONTROLLING BLOOD COUNTS AND INHIBITING PLATELETS, BUT OFTEN FAIL TO ADDRESS DISEASE-RELATED SYMPTOMS OR BIOLOGICALLY MODIFY THE DISEASE.AREAS COVERED: WE REVIEW THE CURRENT PARADIGM FOR TREATING POLYCYTHEMIA VERA, HIGHLIGHT AREAS OF UNMET NEED, REVIEW THERAPEUTIC AGENTS IN LATE STAGE CLINICAL DEVELOPMENT, AND PROVIDE AN OVERARCHING VIEW OF HOW THESE EMERGING AGENT MAY FIT INTO THE FUTURE ARMAMENTARIUM OF POLYCYTHEMIA VERA TREATMENTS.EXPERT OPINION: THE SHIFT FROM FOCUSING SOLELY ON SECONDARY PREVENTION OF THROMBOHEMORRHAGIC EVENTS TO A COMPREHENSIVE TREATMENT STRATEGY THAT ADDITIONALLY AIMS TO IMPROVE QUALITY OF LIFE AND PREVENT DISEASE PROGRESSION HAS RESULTED IN A RAPIDLY EVOLVING THERAPEUTIC LANDSCAPE THAT PROMISES TO MOVE THE TREATMENT OF POLYCYTHEMIA VERA OUT OF ANTIQUITY INTO THE MODERN AGE. 2021 14 1390 13 DIAGNOSING NOCIPLASTIC PAIN IN CANCER SURVIVORS: A MAJOR STEP FORWARD. NOCIPLASTIC PAIN SYNDROMES INCLUDE PARTICULAR FIBROMYALGIA, IRRITABLE BOWEL SYNDROME, HEADACHE, COMPLEX REGIONAL PAIN SYNDROME, AND IDIOPATHIC OROFACIAL PAIN. SEVERAL MECHANISMS HAVE BEEN PROPOSED TO ACCOUNT FOR NOCIPLASTIC PAIN INCLUDING CENTRAL SENSITISATION, ALTERATIONS OF PAIN MODULATORY CONTROLS, EPIGENETIC CHANGES, AND PERIPHERAL MECHANISMS. IMPORTANTLY, NOCIPLASTIC PAIN MIGHT ALSO BE PRESENT IN PATIENTS WITH CANCER PAIN, PARTICULARLY THOSE WITH PAIN RELATED TO COMPLICATIONS OF CANCER TREATMENT. INCREASED AWARENESS OF NOCIPLASTIC PAIN ASSOCIATED WITH CANCER SHOULD HAVE IMPORTANT IMPLICATIONS FOR MONITORING AND MANAGING SUCH PATIENTS. 2023 15 6442 22 THERAPEUTIC APPROACHES IN MYELOFIBROSIS AND MYELODYSPLASTIC/MYELOPROLIFERATIVE OVERLAP SYNDROMES. THE DISCOVERY OF JAK2 (V617F) A DECADE AGO LED TO OPTIMISM FOR A RAPIDLY DEVELOPING TREATMENT REVOLUTION IN PH(-) MYELOPROLIFERATIVE NEOPLASMS. UNLIKE BCR-ABL, HOWEVER, JAK2 WAS FOUND TO HAVE A MORE HETEROGENEOUS ROLE IN CARCINOGENESIS. THEREFORE, FOR YEARS, DEVELOPMENT OF NEW THERAPIES WAS SLOW, DESPITE STANDARD TREATMENT OPTIONS THAT DID NOT ADDRESS THE OVERWHELMING SYMPTOM BURDEN IN PATIENTS WITH PRIMARY MYELOFIBROSIS (MF), POST-ESSENTIAL THROMBOCYTHEMIA MF, POST-POLYCYTHEMIA VERA MF, AND MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) SYNDROMES. JAK-STAT INHIBITORS HAVE CHANGED THIS, DRASTICALLY AMELIORATING SYMPTOMS AND ULTIMATELY BEGINNING TO SHOW EVIDENCE OF IMPACT ON SURVIVAL. NOW, THE GENETIC FOUNDATIONS OF MYELOFIBROSIS AND MDS/MPN ARE RAPIDLY BEING ELUCIDATED AND CONTRIBUTING TO TARGETED THERAPY DEVELOPMENT. THIS HAS BEEN EMPOWERED THROUGH UPDATED RESPONSE CRITERIA FOR MDS/MPN AND REFINED PROGNOSTIC SCORING SYSTEMS IN THESE DISEASES. THE AIM OF THIS ARTICLE IS TO SUMMARIZE CONCISELY THE CURRENT AND RATIONALLY DESIGNED INVESTIGATIONAL THERAPEUTICS DIRECTED AT JAK-STAT, HEDGEHOG, PI3K-AKT, BONE MARROW FIBROSIS, TELOMERASE, AND ROGUE EPIGENETIC SIGNALING. THE REVOLUTION IN IMMUNOTHERAPY AND NOVEL TREATMENTS AIMED AT PREVIOUSLY UNTARGETED SIGNALING PATHWAYS PROVIDES HOPE FOR CONSIDERABLE ADVANCEMENT IN THERAPY OPTIONS FOR THOSE WITH CHRONIC MYELOID DISEASE. 2016 16 5777 18 SPINAL CIRCKCNK9 REGULATES CHRONIC VISCERAL HYPERSENSITIVITY OF IRRITABLE BOWEL SYNDROME. DYSREGULATION OF CIRCULAR RNAS (CIRCRNAS) HAS BEEN REPORTED TO BE FUNCTIONALLY ASSOCIATED WITH CHRONIC PAIN, BUT IT IS UNKNOWN WHETHER AND HOW CIRCRNAS PARTICIPATE IN VISCERAL HYPERSENSITIVITY. THE EXPRESSION OF CIRCKCNK9 WAS INCREASED IN SPINAL NEURONS OF IRRITABLE BOWEL SYNDROME (IBS)-LIKE RATS. SHCIRCKCNK9 ATTENUATED VISCERAL HYPERSENSITIVITY AND INHIBITED C-FOS EXPRESSION IN IBS-LIKE RATS, WHEREAS OVEREXPRESSION OF SPINAL CIRCKCNK9 INDUCED VISCERAL HYPERSENSITIVITY AND INCREASED C-FOS EXPRESSION IN CONTROL RATS. FURTHERMORE, CIRCKCNK9 WAS FOUND TO ACT AS A MIR-124-3P SPONGE. MIR-124-3P ANTAGOMIR RESTORED PAIN RESPONSES DOWNREGULATED BY SHCIRCKCNK9 IN IBS-LIKE RATS. FINALLY, THE SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3), VALIDATED AS A TARGET OF MIR-124-3P, COULD PLAY A CRITICAL ROLE IN VISCERAL HYPERSENSITIVITY BY REGULATING NSF/GLUR2. PERSPECTIVE: SPINAL CIRCKCNK9 FUNCTIONS AS A MIR-124-3P SPONGE TO PROMOTE VISCERAL HYPERSENSITIVITY BY REGULATING THE STAT3/NSF/GLUR2 PATHWAY. THIS PATHWAY MIGHT PROVIDE A NOVEL EPIGENETIC MECHANISM OF VISCERAL HYPERSENSITIVITY AND A POTENTIAL CIRCRNA THERAPEUTIC TARGET FOR IBS. 2023 17 4759 22 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 18 631 25 BIOLOGICAL AND SYNTHETIC TARGET DMARDS IN PSORIATIC ARTHRITIS. PSORIATIC ARTHRITIS (PSA) IS A CHRONIC MULTI-FACETED IMMUNE-MEDIATED SYSTEMIC DISORDER, CHARACTERIZED BY ARTICULAR, CUTANEOUS, ENTHESIS, NAIL AND SPINE INVOLVEMENT. ARTICULAR MANIFESTATIONS OF PSA ARE PARTICULARLY COMMON AND HIGHLY DISABLING FOR PATIENTS, WHILE THE HETEROGENEOUS CLINICAL SUBSETS OF THE DISEASE ARE CHALLENGING FOR CLINICIANS. IN RECENT YEARS, RESEARCH HAS MADE MANY ADVANCES IN UNDERSTANDING THE PATHOGENESIS OF THE DISEASE FROM GENETIC, EPIGENETIC AND MOLECULAR POINTS OF VIEW. NEW DRUGS ARE NOW AVAILABLE FOR THE TREATMENT OF THIS CONDITION, AND, IN PARTICULAR, TNF-ALFA INHIBITORS, HISTORICALLY THE FIRST BIOLOGICALS APPROVED IN PSA, ARE NOW JUXTAPOSED BY NEW BIOLOGICAL DISEASE MODIFYING ANTI-RHEUMATIC DRUGS (BDMARDS) WITH DIFFERENT MODES OF ACTION. TARGETING IL-12/IL-23 P40 COMMON SUBUNIT WITH USTEKINUMAB, IL-17A WITH SECUKINUMAB AND IXEKIZUMAB, T CELLS CO-STIMULATION WITH ABATACEPT, IS NOW POSSIBLE, SAFE AND EFFECTIVE. MOREOVER, TARGETED SYNTHETIC MOLECULES WITH ORAL ADMINISTRATION ARE AVAILABLE, WITH THE POSSIBILITY TO INTERFERE WITH PHOSPHODIESTERASE-4 AND JAK/STAT PATHWAYS. INDEED, NEW DRUGS ARE UNDER DEVELOPMENT, WITH THE POSSIBILITY TO TARGET SELECTIVELY IL-17 RECEPTOR, IL-23, AND OTHER KEY MOLECULAR TARGETS IN THE PATHOGENESIS OF THIS CONDITION. IN THIS NARRATIVE REVIEW, WE PROVIDE AN UP-TO-DATE OVERVIEW OF THE CURRENT APPLICATION OF BIOLOGICAL AND TARGETED SYNTHETIC DMARDS IN THE FIELD OF PSA, WITH PARTICULAR REGARD TO THE CLINICAL SIGNIFICANCE OF THIS POSSIBILITY TO TARGET A HIGHER NUMBER OF DISTINCT IMMUNE-PATHWAYS. 2019 19 4442 24 MOLECULAR GENETICS OF MDS/MPN OVERLAP SYNDROMES. THE MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) ARE A HETEROGENOUS GROUP OF MYELOID MALIGNANCIES HALLMARKED BY CLINICOPATHOLOGIC FEATURES THAT OVERLAP WITH MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. FORMALLY RECOGNIZED BY THE WORLD HEALTH ORGANIZATION, THIS GROUP INCLUDES THE ENTITIES CHRONIC MYELOMONOCYTIC LEUKEMIA, JUVENILE MYELOMONOCYTIC LEUKEMIA, ATYPICAL CHRONIC MYELOID LEUKEMIA, MDS/MPN WITH RING SIDEROBLASTS AND THROMBOCYTOSIS AND MDS/MPN, UNCLASSIFIABLE. ADVANCEMENTS IN NEXT GENERATION SEQUENCING HAVE BEGUN TO UNRAVEL THE MOLECULAR UNDERPINNINGS OF THESE DISEASES, IDENTIFYING AN ARRAY OF RECURRENTLY MUTATED GENES INVOLVED IN EPIGENETIC REGULATION, RNA SPLICING, TRANSCRIPTION, AND CELL SIGNALING. DESPITE MOLECULAR OVERLAP WITH OTHER MYELOID MALIGNANCIES, EACH ENTITY DISPLAYS A UNIQUE SPECTRUM OF SOMATIC MUTATIONS SUPPORTING THEIR UNIQUE PATHOBIOLOGY AND CLINICAL FEATURES. IMPORTANTLY, MOLECULAR PROFILING IS BECOMING AN INTEGRAL TOOL UTILIZED IN ROUTINE CLINICAL PRACTICE. THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF OVERLAP SYNDROMES AND DETAILS THE IMPACT OF SOMATIC MUTATIONS IN DIAGNOSTIC, PROGNOSTIC, AND THERAPEUTIC DECISION-MAKING. 2020 20 2858 24 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