1 498 132 ASSOCIATION BETWEEN DIABETES AND CANCER. CURRENT MECHANISTIC INSIGHTS INTO THE ASSOCIATION AND FUTURE CHALLENGES. COMPELLING PIECES OF EPIDEMIOLOGICAL, CLINICAL, AND EXPERIMENTAL RESEARCH HAVE DEMONSTRATED THAT DIABETES MELLITUS (DM) IS A MAJOR RISK FACTOR ASSOCIATED WITH INCREASED CANCER INCIDENCE AND MORTALITY IN MANY HUMAN NEOPLASMS. IN THE PATHOPHYSIOLOGY CONTEXT OF DM, MANY OF THE MAIN CLASSICAL ACTORS ARE RELEVANT ELEMENTS THAT CAN FUEL THE DIFFERENT STEPS OF THE CARCINOGENESIS PROCESS. HYPERGLYCEMIA, HYPERINSULINEMIA, METABOLIC INFLAMMATION, AND DYSLIPIDEMIA ARE AMONG THE CLASSIC CONTRIBUTORS TO THIS ASSOCIATION. FURTHERMORE, NEW EMERGING ACTORS HAVE RECEIVED PARTICULAR ATTENTION IN THE LAST FEW YEARS, AND COMPELLING DATA SUPPORT THAT THE MICROBIOME, THE EPIGENETIC CHANGES, THE RETICULUM ENDOPLASMIC STRESS, AND THE INCREASED GLYCOLYTIC INFLUX ALSO PLAY IMPORTANT ROLES IN PROMOTING THE DEVELOPMENT OF MANY CANCER TYPES. THE ARSENAL OF GLUCOSE-LOWERING THERAPEUTIC AGENTS USED FOR TREATING DIABETES IS WIDE AND DIVERSE, AND A GROWING BODY OF DATA RAISED DURING THE LAST TWO DECADES HAS TRIED TO CLARIFY THE CONTRIBUTION OF THERAPEUTIC AGENTS TO THIS ASSOCIATION. HOWEVER, THIS RESEARCH AREA REMAINS CONTROVERSIAL, BECAUSE SOME ANTI-DIABETIC DRUGS ARE NOW CONSIDERED AS EITHER PROMOTORS OR PROTECTING ELEMENTS. IN THE PRESENT REVIEW, WE INTEND TO HIGHLIGHT THE COMPELLING EPIDEMIOLOGICAL SHREDS OF EVIDENCE THAT SUPPORT THIS ASSOCIATION, AS WELL AS THE MECHANISTIC CONTRIBUTIONS OF MANY OF THESE POTENTIAL PATHOLOGICAL MECHANISMS, SOME CONTROVERSIAL POINTS AS WELL AS FUTURE CHALLENGES. 2023 2 6896 26 [TARGETED EPIGENETIC THERAPY OF CANCER. ACHIEVEMENTS AND PERSPECTIVES]. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL EPIGENETIC CHANGES OF NORMAL CELLS AND CANCER CELLS, AND EMPHASIZE THE ACHIEVEMENTS AND THE PERSPECTIVES OF CANCER EPIGENETIC THERAPY. CANCER EPIGENETIC ALTERATIONS CORRESPOND FOREMOST TO HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES PROMOTORS, GLOBAL DNA HYPOMETHYLATION, AND OVEREXPRESSION AND ACTIVITY OF HISTONE DEACETYLASES. THE PURPOSE OF EPIGENETIC THERAPY IS TO REVERT THE EPIGENETIC ALTERATIONS IN CANCER CELLS AND OBTAIN THE "NORMAL EPIGENOME" RESTORATION. EPIGENETIC TARGETS IN CANCER THERAPY HAVE FOCUSED ON HDACS AND DNMTS INHIBITION. THE AZACITIDINE AND THE DECITABINE, THE VORINOSTAT AND THE ROMIDEPSIN WERE APPROVED BY US-FDA FOR TREATMENT OF MYELODYSPLASTIC SYNDROME, AND CUTANEOUS T-CELL LYMPHOMA, RESPECTIVELY. EPIGENETIC AND EPIGENOMIC CHANGES IN SINGLE OR MULTIPLE GENES HAVE SHOWED POTENTIAL IMPACT IN CANCER AS EARLY DETECTION, PROGNOSIS AND PREDICTIVE MARKS. THE EPIGENETIC REVOLUTION HAS ARRIVED FOR BIOLOGY. THE SIGNIFICANT PROGRESS IN EPIGENETIC STUDIES HAVE ALLOWED US, TO UNDERSTAND NEW LOOKS IN THE PHYSIOLOGY AND PATHOPHYSIOLOGY OF EMBRYONIC DEVELOPMENT, CANCER AND OTHER CHRONIC DISEASES. SPECIFIC MOLECULAR EPIGENETIC ALTERATIONS IN DIFFERENT CANCER TYPES, GIVE US NEW STRATEGIES TO DESIGN IMPROVED CANCER THERAPY. THE CHALLENGE FOR EPIGENETIC INVESTIGATORS IS DESIGN MORE SPECIFIC EPIDRUGS WITH LESSER SIDE EFFECTS. 2012 3 986 28 CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) AND JUVENILE SPONDYLOARTHRITIS (JSPA): TO WHAT EXTENT ARE THEY RELATED? CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) IS AN AUTOINFLAMMATORY DISEASE OCCURRING MAINLY IN THE PEDIATRIC AGE GROUP (BEFORE 16 YEARS) AND GENERALLY PRESENTS AS A SEPARATE ENTITY. SYNOVITIS, ACNE, PUSTULOSIS, HYPEROSTOSIS AND OSTEITIS (SAPHO) SYNDROME COMBINES OSTEOARTICULAR AND CUTANEOUS INVOLVEMENT, SIMILAR TO CRMO, AND FALLS INTO THE SPECTRUM OF SPONDYLOARTHRITIS (SPA). THE FACT THAT A PATIENT CAN PROGRESS FROM ONE DISEASE TO ANOTHER RAISES THE QUESTION OF WHETHER CRMO, LIKE SAPHO, COULD FALL WITHIN THE SPECTRUM OF SPA, RANGING FROM A PREDOMINANTLY OSTEOARTICULAR FORM TO AN ENTHESITIC FORM WITH MORE OR LESS MARKED SKIN INVOLVEMENT. IN THIS REVIEW, WE SET OUT TO DISCUSS THIS HYPOTHESIS BY HIGHLIGHTING THE DIFFERENCES AND SIMILARITIES BETWEEN CRMO AND JUVENILE SPA IN CLINICAL, RADIOLOGICAL AND PATHOPHYSIOLOGICAL ASPECTS. A COMMON HYPOTHESIS COULD POTENTIALLY CONSIDER INTESTINAL DYSBIOSIS AS THE ORIGIN OF THESE DIFFERENT INFLAMMATORY DISEASES. INTERINDIVIDUAL FACTORS SUCH AS GENDER, ENVIRONMENT, GENETICS AND/OR EPIGENETIC BACKGROUND COULD ACT AS COMBINED DISEASE MODIFIERS. THIS IS WHY WE SUGGEST THAT PATHOPHYSIOLOGY, RATHER THAN CLINICAL PHENOTYPE, BE USED TO RECLASSIFY THESE DISEASES. 2023 4 944 28 CHRONIC LYMPHOCYTIC LEUKEMIA: FROM MOLECULAR PATHOGENESIS TO NOVEL THERAPEUTIC STRATEGIES. CHRONIC LYMPHOCYTIC LEUKEMIA IS A WELL-DEFINED LYMPHOID NEOPLASM WITH VERY HETEROGENEOUS BIOLOGICAL AND CLINICAL BEHAVIOR. THE LAST DECADE HAS BEEN REMARKABLY FRUITFUL IN NOVEL FINDINGS ELUCIDATING MULTIPLE ASPECTS OF THE PATHOGENESIS OF THE DISEASE INCLUDING MECHANISMS OF GENETIC SUSCEPTIBILITY, INSIGHTS INTO THE RELEVANCE OF IMMUNOGENETIC FACTORS DRIVING THE DISEASE, PROFILING OF GENOMIC ALTERATIONS, EPIGENETIC SUBTYPES, GLOBAL EPIGENOMIC TUMOR CELL REPROGRAMMING, MODULATION OF TUMOR CELL AND MICROENVIRONMENT INTERACTIONS, AND DYNAMICS OF CLONAL EVOLUTION FROM EARLY STEPS IN MONOCLONAL B CELL LYMPHOCYTOSIS TO PROGRESSION AND TRANSFORMATION INTO DIFFUSE LARGE B-CELL LYMPHOMA. ALL THIS KNOWLEDGE HAS OFFERED NEW PERSPECTIVES THAT ARE BEING EXPLOITED THERAPEUTICALLY WITH NOVEL TARGET AGENTS AND MANAGEMENT STRATEGIES. IN THIS REVIEW WE PROVIDE AN OVERVIEW OF THESE NOVEL ADVANCES AND HIGHLIGHT QUESTIONS AND PERSPECTIVES THAT NEED FURTHER PROGRESS TO TRANSLATE INTO THE CLINICS THE BIOLOGICAL KNOWLEDGE AND IMPROVE THE OUTCOME OF THE PATIENTS. 2020 5 937 18 CHRONIC LYMPHOCYTIC LEUKAEMIA GENOMICS AND THE PRECISION MEDICINE ERA. MASSIVE GENOMIC ANALYSES HAVE UNDERSCORED THE DIVERSITY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) BETWEEN PATIENTS. GENETIC HETEROGENEITY OF TUMOUR CLONES WITHIN A PATIENT MAY FUEL TUMOUR EVOLUTION. SEVERAL RECURRENTLY DEREGULATED INTRA-CELLULAR PATHWAYS ARE CANDIDATES FOR TARGETED THERAPIES THAT ARE VERY PROMISING AND ARE DRAMATICALLY CHANGING CLINICAL PATIENTS' PERSPECTIVES. IN THIS REVIEW WE PRESENT AN OVERVIEW OF THE GENETIC AND EPIGENETIC FEATURES OF CLL AND THEIR CLINICAL AND BIOLOGICAL IMPLICATIONS. 2017 6 2858 29 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 7 3902 33 LEARNING FROM THE FAILURES OF DRUG DISCOVERY IN B-CELL NON-HODGKIN LYMPHOMAS AND PERSPECTIVES FOR THE FUTURE: CHRONIC LYMPHOCYTIC LEUKEMIA AND DIFFUSE LARGE B-CELL LYMPHOMA AS TWO ENDS OF A SPECTRUM IN DRUG DEVELOPMENT. DESPITE SUBSTANTIAL RECENT ADVANCES, THERE IS STILL AN UNMET NEED FOR BETTER THERAPIES IN B-CELL NON HODGKIN LYMPHOMAS (B-NHL), ESPECIALLY IN RELAPSED OR REFRACTORY DISEASE. MANY NOVEL TARGETED DRUGS HAVE BEEN DEVELOPED BASED ON A BETTER MOLECULAR UNDERSTANDING OF B-NHL. AREAS COVERED: THIS ARTICLE FOCUSES ON CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AS A REPRESENTATIVE FOR INDOLENT LYMPHOMAS AND PARADIGMATIC FOR THE TREMENDOUS PROGRESS IN TREATING B-NHL ON THE ONE HAND AND DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) AS A REPRESENTATIVE FOR AGGRESSIVE LYMPHOMAS AND PARADIGMATIC FOR MANY UNSOLVED PROBLEMS IN LYMPHOMA TREATMENT OR THE OTHER HAND. WE HIGHLIGHT SALIENT POINTS IN CURRENT THERAPIES TARGETING GENETIC, EPIGENETIC, IMMUNOLOGICAL AND MICROENVIRONMENTAL ALTERATIONS. POSSIBLE REASONS FOR DRUG FAILURE IN CLINICAL TRIALS LIKE TUMOR HETEROGENEITY, CLONAL EVOLUTION AND DRUG RESISTANCE MECHANISMS ARE DISCUSSED. BASED THEREON, SOME PERSPECTIVES FOR FURTHER DRUG DISCOVERY ARE GIVEN. EXPERT OPINION: IN VIEW OF THE PATHOGENETIC COMPLEXITY OF LYMPHOMAS, THERAPIES TARGETING EXCLUSIVELY A SINGLE ALTERATION MAY FAIL BECAUSE RESISTANCE MECHANISMS ARE PRESENT EITHER INITIALLY OR EVOLVE DURING TREATMENT. THEREFORE, FUTURE THERAPIES IN B-NHL MAY HAVE TO TARGET THE GREATEST POSSIBLE NUMBER OF GENETIC, IMMUNOLOGICAL OR EPIGENETIC ALTERATIONS STILL ALLOWING TOLERABILITY AND TO MONITOR THESE ALTERATIONS DURING THERAPY. 2017 8 3900 36 LATEST INSIGHTS INTO PATHOGENESIS OF MYCOSIS FUNGOIDES AND CUTANEOUS T-CELL LYMPHOMA. CUTANEOUS T-CELL LYMPHOMA (CTCL) IS A RARE BUT INCREASING MALIGNANCY WHOSE PROTEAN MANIFESTATIONS NECESSARILY PRESENT IN THE INTEGUMENT, BUT CAN ALSO SPREAD TO INVOLVE BLOOD, LYMPH NODES AND INTERNAL ORGANS. WE HAVE DEVELOPED EFFICACIOUS AND VARIED THERAPIES TO TREAT EARLY AND ADVANCED STAGE DISEASE, BUT THERE ARE STILL MANY WHO SUFFER TREMENDOUSLY FROM THIS ILLNESS. ALTHOUGH THE PATHOGENESIS OF THIS CANCER REMAINS FRUSTRATINGLY ELUSIVE, OVER THE LAST 200 YEARS WE HAVE GENERATED A ROBUST BODY OF EVIDENCE THAT POINTS TOWARD POSSIBLE SINGULAR AS WELL AS MULTIFACTORIAL ETIOLOGIES. COMBINING THE HISTORICAL HYPOTHESES WHICH HAVE FOCUSED UPON THE CONCEPT OF INFECTIOUS CAUSES, INCLUDING CARCINOGENIC GENOMIC VIRAL INTEGRATION AND BACTERIAL SUPERANTIGENIC CHRONIC STIMULATION AS WELL AS INDUSTRIAL/OCCUPATIONAL EXPOSURE, ALONG WITH THE MORE RECENT REVELATIONS OF BOTH GENETIC AND EPIGENETIC ALTERATION AND IMMUNE DYSREGULATION, WE ARE CLOSER THAN EVER TO UNDERSTANDING THE ETIOLOGY OF CTCL. IT IS THROUGH THIS KNOWLEDGE AND CONTINUED RESEARCH EFFORTS THAT WE WILL BE ABLE TO BETTER DIAGNOSE, TREAT, AND POTENTIALLY PREVENT OR CURE CTCL. 2017 9 2897 29 GASTRIC TUMOR MICROENVIRONMENT. A COMPELLING BODY OF EVIDENCE HAS DEMONSTRATED THAT GASTRIC CANCER HAS A VERY PARTICULAR TUMOR MICROENVIRONMENT, A SIGNATURE VERY SUITABLE TO PROMOTE TUMOR PROGRESSION AND METASTASIS. RECENT INVESTIGATIONS HAVE PROVIDED NEW INSIGHTS INTO THE MULTIPLE MOLECULAR MECHANISMS, DEFINED BY GENETIC AND EPIGENETIC MECHANISMS, SUPPORTING A VERY ACTIVE CROSS TALK BETWEEN THE COMPONENTS OF THE TUMOR MICROENVIRONMENT AND THUS DEFINING THE FATE OF TUMOR PROGRESSION. IN THIS REVIEW, WE INTEND TO HIGHLIGHT THE ROLE OF VERY ACTIVE CONTRIBUTORS AT GASTRIC CANCER TME, PARTICULARLY CANCER-ASSOCIATED FIBROBLASTS, BONE MARROW-DERIVED CELLS, TUMOR-ASSOCIATED MACROPHAGES, AND TUMOR-INFILTRATING NEUTROPHILS, ALL OF THEM SURROUNDED BY AN OVERTIME CHANGING EXTRACELLULAR MATRIX. IN ADDITION, THE VERY ACTIVE CROSS TALK BETWEEN THE COMPONENTS OF THE TUMOR MICROENVIRONMENT, DEFINED BY GENETIC AND EPIGENETIC MECHANISMS, THUS DEFINING THE FATE OF TUMOR PROGRESSION, IS ALSO REVIEWED. 2020 10 5462 22 RESEARCH PROGRESS ON EPIGENETICS OF SMALL B-CELL LYMPHOMA. SMALL B-CELL LYMPHOMA IS THE CLASSIFICATION OF B-CELL CHRONIC LYMPHOPROLIFERATIVE DISORDERS THAT INCLUDE CHRONIC LYMPHOCYTIC LEUKAEMIA/SMALL LYMPHOCYTIC LYMPHOMA, FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA. THE CLINICAL PRESENTATION IS SOMEWHAT HETEROGENEOUS, AND ITS OCCURRENCE AND DEVELOPMENT MECHANISMS ARE NOT YET PRECISE AND MAY INVOLVE EPIGENETIC CHANGES. EPIGENETIC ALTERATIONS MAINLY INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA, WHICH ARE ESSENTIAL FOR GENETIC DETECTION, EARLY DIAGNOSIS, AND ASSESSMENT OF TREATMENT RESISTANCE IN SMALL B-CELL LYMPHOMA. AS CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA HAS ALREADY BEEN REPORTED IN THE LITERATURE, THIS ARTICLE FOCUSES ON SMALL B-CELL LYMPHOMAS SUCH AS FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, AND WALDENSTROM MACROGLOBULINEMIA. IT DISCUSSES RECENT DEVELOPMENTS IN EPIGENETIC RESEARCH TO DIAGNOSE AND TREAT THIS GROUP OF LYMPHOMAS. THIS REVIEW PROVIDES NEW IDEAS FOR THE TREATMENT AND PROGNOSIS ASSESSMENT OF SMALL B-CELL LYMPHOMA BY EXPLORING THE CONNECTION BETWEEN SMALL B-CELL LYMPHOMA AND EPIGENETICS. 2022 11 2257 21 EPIGENETIC PERSPECTIVES IN SYSTEMIC LUPUS ERYTHEMATOSUS: PATHOGENESIS, BIOMARKERS, AND THERAPEUTIC POTENTIALS. SYSTEM LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY THE PRODUCTION OF AUTOANTIBODIES THAT CAUSE WIDESPREAD TISSUE DAMAGE. THE UNDERLYING ETIOLOGY REMAINS LARGELY UNKNOWN. ABERRANT EPIGENETICS PLAYS ESSENTIAL ROLES IN THE PATHOGENESIS OF SLE. THIS REVIEW EXPLORES THE LINKS BETWEEN DNA METHYLATION, HISTONE MODIFICATIONS, AND MIRNAS IN SLE AND HIGHLIGHTS HOW THESE FACTORS MAY INTERACT IN SLE PATHOGENESIS. WE ALSO DISCUSS HOW FURTHERING OUR KNOWLEDGE OF EPIGENETICS IN LUPUS PROVIDES HOPE FOR FINDING NEW DIAGNOSTIC AND PROGNOSTIC BIOMARKERS AND NOVEL THERAPEUTIC TARGETS AND STRATEGIES. 2010 12 6035 24 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 13 4681 26 NEW OPTIONS IN THE TREATMENT OF MYELODYSPLASTIC SYNDROME. MYELODYSPLASTIC SYNDROME (MDS) IS A HETEROGENEOUS GROUP OF PROGRESSIVE CHRONIC HEMATOPOIETIC DISORDERS, USUALLY PRESENTING AS REFRACTORY ANEMIA OR CYTOPENIA, WITH AN APPROXIMATELY 25% RISK OF PROGRESSION TOWARD ACUTE MYELOID LEUKAEIMA (AML), AND NO PROVEN CURATIVE TREATMENT. NOVEL BIOLOGICAL TREATMENT STRATEGIES TARGETING BOTH THE MALIGNANT BLOOD CELL AND ITS MICROENVIRONMENT CAN OVERCOME RESISTANCE TO CURRENT THERAPIES, AND REPRESENT A PROMISING TREATMENT PARADIGM FOR IMPROVING PATIENT OUTCOME. MANY OF THESE AGENTS HAVE MULTIPLE BIOLOGIC ACTIVITIES. THE OBJECTIVE OF THIS ARTICLE IS TO PRESENT A COMPARATIVE REVIEW OF CLASSIFICATION SYSTEMS IN MDS AND TO DISCUSS THE EVOLVING TRENDS IN THE TREATMENT OF MDS (IMMUNOSUPPRESIVE THERAPY, IMMUNOMODULATORY DRUGS, ARSENIC TRIOXIDE, PROTEASOME INHIBITORS, EPIGENETIC THERAPY). 2005 14 1812 31 EFFECTS OF BIOLOGICAL THERAPIES ON MOLECULAR FEATURES OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS AN AUTOIMMUNE AND CHRONIC INFLAMMATORY DISEASE PRIMARILY AFFECTING THE JOINTS, AND CLOSELY RELATED TO SPECIFIC AUTOANTIBODIES THAT MOSTLY TARGET MODIFIED SELF-EPITOPES. RELEVANT FINDINGS IN THE FIELD OF RA PATHOGENESIS HAVE BEEN DESCRIBED. IN PARTICULAR, NEW INSIGHTS COME FROM STUDIES ON SYNOVIAL FIBROBLASTS AND CELLS BELONGING TO THE INNATE AND ADAPTIVE IMMUNE SYSTEM, WHICH DOCUMENTED THE ABERRANT PRODUCTION OF INFLAMMATORY MEDIATORS, OXIDATIVE STRESS AND NETOSIS, ALONG WITH RELEVANT ALTERATIONS OF THE GENOME AND ON THE REGULATORY EPIGENETIC MECHANISMS. IN RECENT YEARS, THE ADVANCES IN THE UNDERSTANDING OF RA PATHOGENESIS BY IDENTIFYING KEY CELLS AND CYTOKINES ALLOWED THE DEVELOPMENT OF NEW TARGETED DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS). THESE DRUGS CONSIDERABLY IMPROVED TREATMENT OUTCOMES FOR THE MAJORITY OF PATIENTS. MOREOVER, NUMEROUS STUDIES DEMONSTRATED THAT THE PHARMACOLOGICAL THERAPY WITH BIOLOGIC DMARDS (BDMARDS) PROMOTES, IN PARALLEL TO THEIR CLINICAL EFFICACY, SIGNIFICANT IMPROVEMENT IN ALL THESE ALTERED MOLECULAR MECHANISMS. THUS, CONTINUOUS UPDATING OF THE KNOWLEDGE OF MOLECULAR PROCESSES ASSOCIATED WITH THE PATHOGENESIS OF RA, AND ON THE SPECIFIC EFFECTS OF BDMARDS IN THE CORRECTION OF THEIR DYSREGULATION, ARE ESSENTIAL IN THE EARLY AND CORRECT APPROACH TO THE TREATMENT OF THIS COMPLEX AUTOIMMUNE DISORDER. THE PRESENT REVIEW DETAILS BASIC MECHANISMS RELATED TO THE PHYSIOPATHOLOGY OF RA, ALONG WITH THE CORE MECHANISMS OF RESPONSE TO BDMARDS. 2020 15 1867 23 EMERGING GENE-EDITING MODALITIES FOR OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A PATHOLOGICAL DEGENERATIVE CONDITION OF THE JOINTS THAT IS WIDELY PREVALENT WORLDWIDE, RESULTING IN SIGNIFICANT PAIN, DISABILITY, AND IMPAIRED QUALITY OF LIFE. THE DIVERSE ETIOLOGY AND PATHOGENESIS OF OA CAN EXPLAIN THE PAUCITY OF VIABLE PREVENTIVE AND DISEASE-MODIFYING STRATEGIES TO COUNTER IT. ADVANCES IN GENOME-EDITING TECHNIQUES MAY IMPROVE DISEASE-MODIFYING SOLUTIONS BY ADDRESSING INHERITED PREDISPOSING RISK FACTORS AND THE ACTIVITY OF INFLAMMATORY MODULATORS. RECENT PROGRESS ON TECHNOLOGIES SUCH AS CRISPR/CAS9 AND CELL-BASED GENOME-EDITING THERAPIES TARGETING THE GENETIC AND EPIGENETIC ALTERNATIONS IN OA OFFER PROMISING AVENUES FOR EARLY DIAGNOSIS AND THE DEVELOPMENT OF PERSONALIZED THERAPIES. THE PURPOSE OF THIS LITERATURE REVIEW WAS TO CONCISELY SUMMARIZE THE GENOME-EDITING OPTIONS AGAINST CHRONIC DEGENERATIVE JOINT CONDITIONS SUCH AS OA WITH A FOCUS ON THE MORE RECENTLY EMERGING MODALITIES, ESPECIALLY CRISPR/CAS9. FUTURE ADVANCEMENTS IN NOVEL GENOME-EDITING THERAPIES MAY IMPROVE THE EFFICACY OF SUCH TARGETED TREATMENTS. 2020 16 4053 31 MANAGING KELOID SCARS: FROM RADIATION THERAPY TO ACTUAL AND POTENTIAL DRUG DELIVERIES. THE AETIOLOGY OF KELOIDS IS BECOMING CLEARER, BUT MANY QUESTIONS REMAIN, INCLUDING ABOUT THE MOST OPTIMAL TREATMENT. CURRENT THERAPIES INCLUDE SURGICAL EXCISION, RADIOTHERAPY, AND VARIOUS PHARMACEUTICAL DRUGS. HOWEVER, NONE OF THESE DRUGS ARE KELOID-SPECIFIC. MOREOVER, ALL CURRENT INTERVENTIONS ARE ASSOCIATED WITH HIGH RECURRENCE RATES. HERE, WE REVIEW THE PHARMACEUTICAL INTERVENTIONS THAT ARE CURRENTLY AVAILABLE. ALL ARE BASED ON THE FACT THAT KELOIDS ARE AN EXPANDING SOLID MASS WITH INTENSE CHRONIC INFLAMMATION AT ITS ADVANCING EDGES. CONSEQUENTLY, CURRENT PHARMACEUTICALS AIM TO REDUCE THE MASS AND/OR SYMPTOMS OF KELOIDS, SIMILAR TO SURGERY AND RADIOTHERAPY. THEY INCLUDE CHEMOTHERAPIES, IMMUNOTHERAPIES, VOLUME-REDUCING THERAPIES, AND ANTI-INFLAMMATORY THERAPIES. WE ALSO DESCRIBE NEW ADVANCES IN KELOID PHARMACEUTICALS. THEY INCLUDE DRUGS THAT WERE DESIGNED TO TREAT SYSTEMIC DISEASES SUCH AS HYPERTENSION OR BREAST CANCER BUT WERE FOUND TO ALSO TREAT KELOIDS. FURTHERMORE, RECENT PROGRESS IN GENETIC, EPIGENETIC, AND STEM CELL THERAPIES SUGGESTS THAT THEY COULD BECOME USEFUL IN THE KELOID FIELD. THIS REVIEW OF PHARMACEUTICAL ADVANCES WILL HOPEFULLY PROMOTE ADDITIONAL RESEARCH AND THE DEVELOPMENT OF EFFECTIVE AND SPECIFIC PHARMACEUTICALS FOR KELOIDS. 2019 17 792 35 CELLULAR MECHANISMS PROMOTING CACHEXIA AND HOW THEY ARE OPPOSED BY SIRTUINS (1). MANY CHRONIC DISEASES ARE ASSOCIATED WITH UNINTENTIONAL LOSS OF BODY WEIGHT, WHICH IS TERMED "CACHEXIA". CACHEXIA IS A COMPLEX MULTIFACTORIAL SYNDROME ASSOCIATED WITH THE UNDERLYING PRIMARY DISEASE, AND CHARACTERIZED BY LOSS OF SKELETAL MUSCLE WITH OR WITHOUT LOSS OF FAT TISSUE. PATIENTS WITH CACHEXIA FACE DIRE SYMPTOMS LIKE DYSPNEA, FATIGUE, EDEMA, EXERCISE INTOLERANCE, AND LOW RESPONSIVENESS TO MEDICAL THERAPY, WHICH WORSEN QUALITY OF LIFE. BECAUSE CACHEXIA IS NOT A STAND-ALONE DISORDER, TREATING PRIMARY DISEASE - SUCH AS CANCER - TAKES PRECEDENCE FOR THE PHYSICIAN, AND IT REMAINS MOSTLY A NEGLECTED ILLNESS. EXISTING CLINICAL TRIALS HAVE DEMONSTRATED LIMITED SUCCESS MOSTLY BECAUSE OF THEIR MONOTHERAPEUTIC APPROACH AND LATE DETECTION OF THE SYNDROME. TO CONQUER CACHEXIA, IT IS ESSENTIAL TO IDENTIFY AS MANY MOLECULAR TARGETS AS POSSIBLE USING THE LATEST TECHNOLOGIES WE HAVE AT OUR DISPOSAL. IN THIS REVIEW, WE HAVE DISCUSSED DIFFERENT ASPECTS OF CACHEXIA, WHICH INCLUDE VARIOUS DISEASE SETTINGS, ACTIVE MOLECULAR PATHWAYS, AND RECENT NOVEL ADVANCES MADE IN THIS FIELD TO UNDERSTAND CONSEQUENCES OF THIS ILLNESS. WE ALSO DISCUSS ROLES OF THE SIRTUINS, THE NAD(+)-DEPENDENT LYSINE DEACETYLASES, MICRORNAS, CERTAIN DIETARY OPTIONS, AND EPIGENETIC DRUGS AS POTENTIAL APPROACHES, WHICH CAN BE USED TO TACKLE CACHEXIA AS EARLY AS POSSIBLE IN ITS COURSE. 2019 18 4666 31 NEW INSIGHTS AND OPTIONS INTO THE MECHANISMS AND EFFECTS OF COMBINED TARGETED THERAPY AND IMMUNOTHERAPY IN PROSTATE CANCER. CHRONIC INFLAMMATION IS BELIEVED TO DRIVE PROSTATE CARCINOGENESIS BY PRODUCING REACTIVE OXYGEN SPECIES OR REACTIVE NITROGEN SPECIES TO INDUCE DNA DAMAGE. THIS EFFECT MIGHT SUBSEQUENTLY CAUSE EPIGENETIC AND GENOMIC ALTERATIONS, LEADING TO MALIGNANT TRANSFORMATION. ALTHOUGH ESTABLISHED THERAPEUTIC ADVANCES HAVE EXTENDED OVERALL SURVIVAL, TUMORS IN PATIENTS WITH ADVANCED PROSTATE CANCER ARE PRONE TO METASTASIS, TRANSFORMATION INTO METASTATIC CASTRATION-RESISTANT PROSTATE CANCER, AND THERAPEUTIC RESISTANCE. THE TUMOR MICROENVIRONMENT (TME) OF PROSTATE CANCER IS INVOLVED IN CARCINOGENESIS, INVASION AND DRUG RESISTANCE. A PLETHORA OF PRECLINICAL STUDIES HAVE FOCUSED ON IMMUNE-BASED THERAPIES. UNDERSTANDING THE INTRICATE TME SYSTEM IN PROSTATE CANCER MAY HOLD MUCH PROMISE FOR DEVELOPING NOVEL THERAPIES, DESIGNING COMBINATIONAL THERAPEUTIC STRATEGIES, AND FURTHER OVERCOMING RESISTANCE TO ESTABLISHED TREATMENTS TO IMPROVE THE LIVES OF PROSTATE CANCER PATIENTS. IN THIS REVIEW, WE DISCUSS NONIMMUNE COMPONENTS AND VARIOUS IMMUNE CELLS WITHIN THE TME AND THEIR PUTATIVE ROLES DURING PROSTATE CANCER INITIATION, PROGRESSION, AND METASTASIS. WE ALSO OUTLINE THE UPDATED FUNDAMENTAL RESEARCH FOCUSING ON THERAPEUTIC ADVANCES OF TARGETED THERAPY AS WELL AS COMBINATIONAL OPTIONS FOR PROSTATE CANCER. 2023 19 3682 29 INFLAMMATION, FIBROSIS AND CANCER: MECHANISMS, THERAPEUTIC OPTIONS AND CHALLENGES. UNCONTROLLED INFLAMMATION IS A SALIENT FACTOR IN MULTIPLE CHRONIC INFLAMMATORY DISEASES AND CANCERS. IN THIS REVIEW, WE PROVIDED AN IN-DEPTH ANALYSIS OF THE RELATIONSHIPS AND DISTINCTIONS BETWEEN UNCONTROLLED INFLAMMATION, FIBROSIS AND CANCERS, WHILE EMPHASIZING THE CHALLENGES AND OPPORTUNITIES OF DEVELOPING NOVEL THERAPIES FOR THE TREATMENT AND/OR MANAGEMENT OF THESE DISEASES. WE DESCRIBED HOW DRUG DELIVERY SYSTEMS, COMBINATION THERAPY AND THE INTEGRATION OF TISSUE-TARGETED AND/OR PATHWAYS SELECTIVE STRATEGIES COULD OVERCOME THE CHALLENGES OF CURRENT AGENTS FOR MANAGING AND/OR TREATING CHRONIC INFLAMMATORY DISEASES AND CANCERS. WE ALSO RECOGNIZED THE VALUE OF THE RE-EVALUATION OF THE DISEASE-SPECIFIC ROLES OF MULTIPLE PATHWAYS IMPLICATED IN THE PATHOPHYSIOLOGY OF CHRONIC INFLAMMATORY DISEASES AND CANCERS-AS WELL AS THE APPLICATION OF DATA FROM SINGLE-CELL RNA SEQUENCING IN THE SUCCESS OF FUTURE DRUG DISCOVERY ENDEAVORS. 2022 20 5512 26 RICHTER SYNDROME IN CHRONIC LYMPHOCYTIC LEUKEMIA: UPDATES ON BIOLOGY, CLINICAL FEATURES AND THERAPY. RICHTER SYNDROME (RS) OR RICHTER TRANSFORMATION IS THE DEVELOPMENT OF SECONDARY AGGRESSIVE LYMPHOMA IN THE SETTING OF UNDERLYING CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA (CLL/SLL). MOST FREQUENTLY CLL TRANSFORMS INTO DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) (90%) AND RARELY (10%) INTO HODGKIN LYMPHOMA, TERMED HODGKIN VARIANT OF RICHTER SYNDROME (HVRS). RS IS GENERALLY CHARACTERIZED BY AN AGGRESSIVE CLINICAL COURSE AND POOR PROGNOSIS. IN RECENT YEARS, MAJOR ADVANCES HAVE BEEN MADE IN UNDERSTANDING GENETIC EVENTS WHICH RELATE TO THE PROGRESSION OF CLL OR TRANSFORMATION INTO RS. BETTER UNDERSTANDING OF THE MOLECULAR PATHWAYS HAS REVEALED THAT RS IS NOT A SINGLE HOMOGENEOUS ENTITY. THE MAJORITY OF CASES ARE CLONALLY RELATED TO THE ORIGINAL CLL CLONE, WHILE A MINORITY DEVELOP FROM AN UNRELATED CLONE. THIS REVIEW SUMMARIZES NEW DATA RELATING TO THE MOLECULAR BIOLOGY AND THE GENETIC/EPIGENETIC CHANGES OCCURRING DURING RICHTER TRANSFORMATION, AND ALSO CONSIDERS THE CLINICAL FEATURES AND THERAPY FOR BOTH DLBCL-RS AND HODGKIN VARIANT-RS. 2015