1 1284 117 DECIPHERING THE MOLECULAR LANDSCAPE OF CUTANEOUS SQUAMOUS CELL CARCINOMA FOR BETTER DIAGNOSIS AND TREATMENT. CUTANEOUS SQUAMOUS CELL CARCINOMA (CSCC) IS A COMMON TYPE OF NEOPLASIA, REPRESENTING A TERRIBLE BURDEN ON PATIENTS' LIFE AND CLINICAL MANAGEMENT. ALTHOUGH IT SELDOM METASTASIZES, AND MOST CASES CAN BE EFFECTIVELY TREATED WITH SURGICAL INTERVENTION, ONCE METASTATIC CSCC DISPLAYS CONSIDERABLE AGGRESSIVENESS LEADING TO THE DEATH OF AFFECTED INDIVIDUALS. NO CONSENSUS HAS BEEN REACHED AS TO WHICH FEATURES BETTER CHARACTERIZE THE AGGRESSIVE BEHAVIOR OF CSCC, AN ACHIEVEMENT HINDERED BY THE HIGH MUTATIONAL BURDEN CAUSED BY CHRONIC ULTRAVIOLET LIGHT EXPOSURE. EVEN THOUGH SOME SUBTYPES HAVE BEEN RECOGNIZED AS HIGH RISK VARIANTS, DEPENDING ON CERTAIN TUMOR FEATURES, CSCC THAT ARE NORMALLY THOUGHT OF AS LOW RISK COULD POSE AN INCREASED DANGER TO THE PATIENTS. IN LIGHT OF THIS, SPECIFIC GENETIC AND EPIGENETIC MARKERS FOR CUTANEOUS SCC, WHICH COULD SERVE AS RELIABLE DIAGNOSTIC MARKERS AND POSSIBLE TARGETS FOR NOVEL TREATMENT DEVELOPMENT, HAVE BEEN SEARCHED FOR. THIS REVIEW AIMS TO GIVE AN OVERVIEW OF THE MUTATIONAL LANDSCAPE OF CSCC, POINTING OUT ESTABLISHED BIOMARKERS, AS WELL AS NOVEL CANDIDATES, AND FUTURE POSSIBLE MOLECULAR THERAPIES FOR CSCC. 2020 2 1397 28 DIET PHYTOCHEMICALS AND CUTANEOUS CARCINOMA CHEMOPREVENTION: A REVIEW. CUTANEOUS CARCINOMA, WHICH HAS OCCUPIED A PECULIAR PLACE AMONG WORLDWIDE POPULATIONS, IS COMMONLY RESPONSIBLE FOR THE CONSIDERABLY INCREASING MORBIDITY AND MORTALITY RATES. CURRENTLY AVAILABLE MEDICAL PROCEDURES FAIL TO COMPLETELY AVOID CUTANEOUS CARCINOMA DEVELOPMENT OR TO PREVENT MORTALITY. CANCER CHEMOPREVENTION, AS AN ALTERNATIVE STRATEGY, IS BEING CONSIDERED TO REDUCE THE INCIDENCE AND BURDEN OF CANCERS THROUGH CHEMICAL AGENTS. DERIVED FROM DIETARY FOODS, PHYTOCHEMICALS HAVE BECOME SAFE AND RELIABLE COMPOUNDS FOR THE CHEMOPREVENTION OF CUTANEOUS CARCINOMA BY RELIEVING MULTIPLE PATHOLOGICAL PROCESSES, INCLUDING OXIDATIVE DAMAGE, EPIGENETIC ALTERATION, CHRONIC INFLAMMATION, ANGIOGENESIS, ETC. IN THIS REVIEW, WE PRESENTED COMPREHENSIVE KNOWLEDGES, MAIN MOLECULAR MECHANISMS FOR THE INITIATION AND DEVELOPMENT OF CUTANEOUS CARCINOMA AS WELL AS EFFECTS OF VARIOUS DIET PHYTOCHEMICALS ON CHEMOPREVENTION. 2017 3 429 29 ANTI-INFLAMMATORY TOPICAL MEDICATION - NEW DEVELOPMENTS IN THE TREATMENT OF ATOPIC DERMATITIS. ATOPIC DERMATITIS IS A CHRONIC INFLAMMATORY DISEASE THAT ARISES FROM POLYGENIC DISPOSITION, A DYSFUNCTION OF THE PHYSICOCHEMICAL EPITHELIAL BARRIER, A CUTANEOUS DYSBIOSIS, AND A FAULTY NEUROSENSORY ACTIVITY AND SHOWS A HIGHLY INDIVIDUAL ACUITY DUE TO EPIGENETIC FACTORS. AN ESSENTIAL COMPONENT OF THERAPEUTIC MANAGEMENT IS THE APPLICATION OF ANTI-INFLAMMATORY TOPICAL MEDICATION. CURRENTLY, TOPICAL GLUCOCORTICOIDS AND TOPICAL CALCINEURIN INHIBITORS ARE ROUTINELY USED IN REACTIVE AND PROACTIVE THERAPY. IN RECENT YEARS, THE DEVELOPMENT OF MOLECULAR MEDICINE HAS IDENTIFIED SEVERAL NEW THERAPEUTIC TARGETS THAT HAVE ENABLED THE DEVELOPMENT OF INNOVATIVE THERAPEUTIC APPROACHES. IN ADDITION TO PHOSPHODIESTERASE-4 INHIBITORS AND ARYL HYDROCARBON RECEPTOR MODULATORS, IT IS MAINLY JANUS KINASE INHIBITORS WITH DIFFERENT SELECTIVITY THAT ARE EMERGING AS NEW EFFECTIVE AND SAFE OPTIONS FOR TOPICAL THERAPY. THE CURRENT DATA SUGGESTS THAT IN THE COMING MONTHS AND YEARS REPRESENTATIVES OF THE ABOVE-MENTIONED SUBSTANCE CLASSES WILL BE APPROVED FOR TOPICAL USE. 2021 4 631 30 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 5 2726 25 EXPERIMENTAL PHARMACOLOGICAL MANAGEMENT OF PSORIASIS. PSORIASIS IS A CHRONIC, RELAPSING, IMMUNE-MEDIATED SYSTEMIC DISEASE. ITS PATHOGENESIS IS COMPLEX AND NOT FULLY UNDERSTOOD YET. GENETIC AND EPIGENETIC FACTORS INTERACT WITH MOLECULAR PATHWAYS INVOLVING TNF-ALPHA, IL-23/IL-17 AXIS, AND PECULIAR CYTOKINES, AS IL-36 OR PHOSPHODIESTERASE 4. THIS REVIEW DISCUSSES THE MECHANISMS INVOLVED IN THE DEVELOPMENT OF THE DISEASE, AS WELL AS THE THERAPEUTIC OPTIONS PROPOSED FOLLOWING THE INVESTIGATION OF THE INFLAMMATORY PSORIATIC PATHWAYS. WE PERFORMED A COMPREHENSIVE SEARCH USING THE WORDS "PSORIASIS" AND THE NEWEST MOLECULES CURRENTLY UNDER INVESTIGATION AND APPROVAL. FROM THESE DATA, A NEW SCENARIO IN PSORIASIS IS OCCURRING TO PERSONALIZE THE THERAPIES - ESPECIALLY SYSTEMIC ONES AND THOSE USING SMALL MOLECULES - AND AVOID TOPICAL AND INJECTABLE DRUGS. WE REPORTED THE NEWEST THERAPEUTIC OPPORTUNITIES, INCLUDING THE INHIBITORS OF JANUS KINASE/TYROSINE KINASE 2, PHOSPHODIESTERASE-4 AND IL-36 RECEPTOR. TODAY, MORE THAN 20 MOLECULES ARE UNDER INVESTIGATION FOR THE TREATMENT OF CUTANEOUS PSORIASIS. MOST OF THEM ARE CONSTITUTED BY SMALL MOLECULES OR BIOLOGIC THERAPIES. THIS UNDERLINES HOW PSORIASIS NEEDS SYSTEMIC THERAPIES, DUE TO ITS COMPLEX PATHOGENESIS AND MULTISYSTEMIC INVOLVEMENT. 2021 6 6655 35 UPDATE ON THE MOLECULAR PATHOLOGY OF CUTANEOUS SQUAMOUS CELL CARCINOMA. CUTANEOUS SQUAMOUS CELL CARCINOMA (CSCC) IS THE SECOND MOST COMMON SKIN CANCER, ORIGINATING FROM KERATINOCYTES OF THE SPINOUS LAYER. NUMEROUS RISK FACTORS HAVE BEEN DISCOVERED FOR THE INITIATION AND GROWTH OF THIS TYPE OF CANCER, SUCH AS EXPOSURE TO UV AND IONIZING RADIATION, CHEMICAL CARCINOGENS, THE PRESENCE OF IMMUNOSUPPRESSION STATES, CHRONIC INFLAMMATION, INFECTIONS WITH HIGH-RISK VIRAL STRAINS, AND, LAST BUT NOT LEAST, THE PRESENCE OF DISEASES ASSOCIATED WITH GENETIC ALTERATIONS. THE IMPORTANT SOCIO-ECONOMIC IMPACT, AS WELL AS THE DIFFICULTY ASSOCIATED WITH THERAPY FOR ADVANCED FORMS, HAS MADE THE MOLECULAR MECHANISMS UNDERLYING THIS NEOPLASIA MORE AND MORE INTENSIVELY STUDIED, WITH THE INTENTION OF ACHIEVING A BETTER UNDERSTANDING AND ADVANCING THE TREATMENT OF THIS PATHOLOGY. THIS REVIEW AIMS TO PROVIDE A BRIEF FORAY INTO THE MOLECULAR, GENETIC, AND EPIGENETIC ASPECTS OF THIS CANCER, AS WELL AS THE TREATMENT METHODS, RANGING FROM THE FIRST USED TO THE LATEST TARGETED THERAPIES. 2023 7 4452 28 MOLECULAR MECHANISMS AND MANAGEMENT OF A CUTANEOUS INFLAMMATORY DISORDER: PSORIASIS. PSORIASIS IS A COMPLEX CHRONIC INFLAMMATORY CUTANEOUS DISORDER. TO DATE, ROBUST MOLECULAR MECHANISMS OF PSORIASIS HAVE BEEN REPORTED. AMONG DIVERSE ABERRANT IMMUNOPATHOGENETIC MECHANISMS, THE CURRENT MODEL EMPHASIZES THE ROLE OF TH1 AND THE IL-23/TH17 AXIS, SKIN-RESIDENT IMMUNE CELLS AND MAJOR SIGNAL TRANSDUCTION PATHWAYS INVOLVED IN PSORIASIS. THE MULTIPLE GENETIC RISK LOCI FOR PSORIASIS HAVE BEEN RAPIDLY REVEALED WITH THE ADVENT OF A NOVEL TECHNOLOGY. MOREOVER, IDENTIFYING EPIGENETIC MODIFICATIONS COULD BRIDGE THE GAP BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS IN PSORIASIS. THIS REVIEW WILL PROVIDE A BETTER UNDERSTANDING OF THE PATHOGENESIS OF PSORIASIS BY UNRAVELING THE COMPLICATED INTERPLAY AMONG IMMUNOLOGICAL ABNORMALITIES, GENETIC RISK FOCI, EPIGENETIC MODIFICATION AND ENVIRONMENTAL FACTORS OF PSORIASIS. WITH ADVANCES IN MOLECULAR BIOLOGY, DIVERSE NEW TARGETS ARE UNDER INVESTIGATION TO MANAGE PSORIASIS. THE RECENT ADVANCES IN TREATMENT MODALITIES FOR PSORIASIS BASED ON TARGETED MOLECULES ARE ALSO DISCUSSED. 2017 8 6566 30 TRANSLATIONAL PERSPECTIVES TO TREAT EPIDERMOLYSIS BULLOSA-WHERE DO WE STAND? EPIDERMOLYSIS BULLOSA (EB) IS THE PROTOTYPICAL EXAMPLE OF GENETIC SKIN FRAGILITY DISORDERS. GENOTYPIC HETEROGENEITY, MODIFIER GENES, EPIGENETIC, BIOCHEMICAL AND ENVIRONMENTAL FACTORS ALTER AND DETERMINE PATHOGENIC TRAITS AND, ULTIMATELY, THE WIDE AND STRIKING PHENOTYPIC VARIABILITY IN EB. BESIDES THE PRIMARY STRUCTURAL-FUNCTIONAL DEFECT, CHRONIC TISSUE DAMAGE WITH INDUCTION AND DYSREGULATION OF INFLAMMATORY PATHWAYS IS A COMMON PATHOGENIC MECHANISM IN EB. IN LOCALIZED VARIANTS, THE INFLAMMATORY ABERRATIONS MAY MAINLY AFFECT THE MICROMILIEU OF LESIONAL SKIN, WHILE A SYSTEMIC INFLAMMATORY RESPONSE WAS SHOWN TO CONTRIBUTE TO THE SYSTEMIC MORBIDITY IN SEVERE EB SUBTYPES WITH EXTENSIVE CUTANEOUS INVOLVEMENT. OUR CONTINUED UNDERSTANDING OF THE PATHOPHYSIOLOGY OF EB, AS WELL AS ADVANCES IN MOLECULAR TECHNOLOGIES, HAS PAVED THE WAY FOR TRANSLATIONAL THERAPEUTIC APPROACHES. THE SPECTRUM COMPRISES OF CORRECTIVE AND SYMPTOM-RELIEVING THERAPIES THAT INCLUDE INNOVATIVE THERAPEUTIC OPTIONS GARNERED FROM THE BENCH, REPURPOSED DRUGS APPROVED FOR OTHER DISEASES, AS WELL AS STRATEGIES FOR GENE-, PROTEIN- AND CELL-BASED THERAPIES. IMMUNOLOGICAL TRAITS FURTHER DEFINE NEW TARGETS OF THERAPY, AIMED AT IMPROVING SKIN BARRIER RESTORATION, MICROBIAL SURVEILLANCE AND INFECTION CONTROL, WOUND HEALING AND ANTI-NEOPLASTIC EFFECTS. CLINICAL AVAILABILITY AND FEASIBILITY OF THESE APPROACHES FOR ALL EB PATIENTS AND SUBTYPES ARE CURRENTLY LIMITED, REFLECTING ISSUES OF EFFICACY, SPECIFICITY, TOLERABILITY AND SAFETY. A MULTISTEP TARGETING APPROACH AND HIGHLY INDIVIDUALIZED, RISK-STRATIFIED COMBINATORY TREATMENT PLANS WILL THUS BE ESSENTIAL FOR SUSTAINED EFFICACY AND IMPROVED OVERALL QUALITY OF LIFE IN EB. 2020 9 3900 30 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 10 6615 28 ULTRAVIOLET-A1 IRRADIATION THERAPY FOR SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (LUPUS, SLE) IS A CHRONIC AUTOIMMUNE DISEASE CHARACTERIZED BY THE PRODUCTION OF AUTOANTIBODIES, WHICH BIND TO ANTIGENS AND ARE DEPOSITED WITHIN TISSUES TO FIX COMPLEMENT, RESULTING IN WIDESPREAD SYSTEMIC INFLAMMATION. THE STUDIES PRESENTED HEREIN ARE CONSISTENT WITH HYPERPOLARIZED, ADENOSINE TRIPHOSPHATE (ATP)-DEFICIENT MITOCHONDRIA BEING CENTRAL TO THE DISEASE PROCESS. THESE HYPERPOLARIZED MITOCHONDRIA RESIST THE DEPOLARIZATION REQUIRED FOR ACTIVATION-INDUCED APOPTOSIS. THE MITOCHONDRIAL ATP DEFICITS ADD TO THIS RESISTANCE TO APOPTOSIS AND ALSO REDUCE THE MACROPHAGE ENERGY THAT IS NEEDED TO CLEAR APOPTOTIC BODIES. IN BOTH CASES, NECROSIS, THE ALTERNATIVE PATHWAY OF CELL DEATH, RESULTS. INTRACELLULAR CONSTITUENTS SPILL INTO THE BLOOD AND TISSUES, ELICITING INFLAMMATORY RESPONSES DIRECTED AT THEIR REMOVAL. WHAT RESULTS IS "AUTOIMMUNITY." ULTRAVIOLET (UV)-A1 PHOTONS HAVE THE CAPACITY TO REMEDIATE THIS ABERRANCY. EXOGENOUS EXPOSURE TO LOW-DOSE, FULL-BODY, UV-A1 RADIATION GENERATES SINGLET OXYGEN. SINGLET OXYGEN HAS TWO MAJOR PALLIATIVE ACTIONS IN PATIENTS WITH LUPUS AND THE UV-A1 PHOTONS THEMSELVES HAVE SEVERAL MORE. SINGLET OXYGEN DEPOLARIZES THE HYPERPOLARIZED MITOCHONDRION, TRIGGERING NON-ATP-DEPENDENT APOPTOSIS THAT DETERS NECROSIS. NEXT, SINGLET OXYGEN ACTIVATES THE GENE ENCODING HEME OXYGENASE (HO-1), A MAJOR GOVERNOR OF SYSTEMIC HOMEOSTASIS. HO-1 CATALYZES THE DEGRADATION OF THE OXIDANT HEME INTO BILIVERDIN (CONVERTED TO BILIRUBIN), FE, AND CARBON MONOXIDE (CO), THE FIRST THREE OF THESE EXERTING POWERFUL ANTIOXIDANT EFFECTS, AND IN CONJUNCTION WITH A FOURTH, CO, PROTECTING AGAINST INJURY TO THE CORONARY ARTERIES, THE CENTRAL NERVOUS SYSTEM, AND THE LUNGS. THE UV-A1 PHOTONS THEMSELVES DIRECTLY ATTENUATE DISEASE IN LUPUS BY REDUCING B CELL ACTIVITY, PREVENTING THE SUPPRESSION OF CELL-MEDIATED IMMUNITY, SLOWING AN EPIGENETIC PROGRESSION TOWARD SLE, AND AMELIORATING DISCOID AND SUBACUTE CUTANEOUS LUPUS. FINALLY, A COMBINATION OF THESE MECHANISMS REDUCES LEVELS OF ANTICARDIOLIPIN ANTIBODIES AND PROTECTS DURING LUPUS PREGNANCY. CAPPING ALL OF THIS IS THAT UV-A1 IRRADIATION IS AN ESSENTIALLY INNOCUOUS, HIGHLY MANAGEABLE, AND COMFORTABLE THERAPEUTIC AGENCY. 2017 11 6614 22 ULTRAVIOLET IRRADIATION INDUCES KERATINOCYTE PROLIFERATION AND EPIDERMAL HYPERPLASIA THROUGH THE ACTIVATION OF THE EPIDERMAL GROWTH FACTOR RECEPTOR. CHRONIC EXPOSURE TO ULTRAVIOLET (UV) IRRADIATION INDUCES SKIN CANCER, IN PART, THROUGH EPIGENETIC MECHANISMS THAT RESULT IN THE DEREGULATION OF CELL PROLIFERATION. UV IRRADIATION ALSO RAPIDLY ACTIVATES THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR). SINCE EGFR ACTIVATION IS STRONGLY MITOGENIC IN MANY CELL TYPES INCLUDING KERATINOCYTES OF THE SKIN, WE HYPOTHESIZED THAT UV-INDUCED CUTANEOUS PROLIFERATION RESULTS FROM EGFR ACTIVATION. THE ROLE OF EGFR ACTIVATION IN THE RESPONSE OF THE SKIN TO UV WAS DETERMINED USING EGFR-NULL AND EGFR-WILD-TYPE SKIN GRAFTED ONTO ATHYMIC NUDE MOUSE HOSTS, BECAUSE EGFR-NULL MICE SURVIVE ONLY A FEW DAYS AFTER BIRTH. EGFR WAS RAPIDLY ACTIVATED IN MOUSE EPIDERMIS FOLLOWING EXPOSURE TO UV, AS DETECTED BY THE PHOSPHORYLATION OF EGFR ON TYROSINE RESIDUES 992, 1045, 1068 AND 1173. UV INDUCED EPIDERMAL HYPERPLASIA IN EGFR-WILD-TYPE SKIN BETWEEN 48 AND 72 H POST-UV. HOWEVER, NO EPIDERMAL HYPERPLASIA OCCURRED IN EGFR-NULL SKIN. BASELINE CELL PROLIFERATION WAS SIMILAR IN SKIN GRAFTS OF BOTH GENOTYPES. HOWEVER, UV EXPOSURE INCREASED CELL PROLIFERATION, AS MEASURED BY KI67 IMMUNOHISTOCHEMISTRY AND PROLIFERATING CELL NUCLEAR ANTIGEN IMMUNOBLOTTING, MAXIMALLY AT 48 H TO A LEVEL MORE THAN THREE TIMES HIGHER IN WILD-TYPE COMPARED WITH EGFR-NULL SKIN. APOPTOTIC CELL DEATH, AS MEASURED BY TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE BIOTIN-DUTP NICK END LABELING (TUNEL) ANALYSIS, WAS ALSO INCREASED IN UV-EXPOSED EGFR-NULL SKIN WHEN COMPARED WITH WILD-TYPE 1-2 DAYS POST-UV. THESE CHANGES IN CELLULAR HOMEOSTASIS AFTER UV WERE ACCOMPANIED BY INCREASED CYCLIN D EXPRESSION IN WILD-TYPE BUT NOT EGFR-NULL SKIN AND INCREASED EXPRESSION OF P53 AND THE CYCLIN-DEPENDENT KINASE (CDK) INHIBITOR P21WAF1 IN EGFR-NULL SKIN WHEN COMPARED WITH WILD-TYPE. COLLECTIVELY, THESE RESULTS DEMONSTRATE THAT THE UV-INDUCED ACTIVATION OF EGFR AUGMENTS KERATINOCYTE PROLIFERATION AND SUPPRESSES APOPTOSIS, LEADING TO EPIDERMAL HYPERPLASIA, ASSOCIATED WITH INCREASED G1 CYCLIN EXPRESSION AND SUPPRESSION OF CDK INHIBITOR EXPRESSION. 2006 12 6057 22 THE DARK SIDE OF REGULATORY T CELLS IN PSORIASIS. PSORIASIS IS A HEREDITARY DISEASE ELICITED BY CHRONIC ACTIVATION OF CUTANEOUS T CELLS. DELINEATING THE MECHANISTIC INTERPLAY OF THE CELL SUBSETS INVOLVED IS KEY TO DEVELOPING THE NEXT GENERATION OF EFFECTIVE TREATMENTS. IN THIS ISSUE, BOVENSCHEN ET AL. REPORT THAT REGULATORY T CELLS MAINTAIN A FINE BALANCE BETWEEN THE TRANSCRIPTION FACTORS FOXP3 AND RORGAMMAT. IN PATIENTS WITH PSORIASIS, TREGS READILY TURN INTO IL-17-EXPRESSING CELLS, THUS POTENTIALLY PERPETUATING THE INFLAMMATORY PROCESS THAT CHARACTERIZES THE DISEASE. RESULTS DEMONSTRATING THAT THE HISTONE/PROTEIN DEACETYLATION INHIBITOR TRICHOSTATIN A CAN BLOCK THIS CONVERSION SUGGEST THAT AN EPIGENETIC MODIFICATION MAY UNDERLIE REGULATORY T-CELL PLASTICITY. 2011 13 2461 30 EPIGENETIC THERAPY AS A PUTATIVE MOLECULAR TARGET TO MODULATE B CELL BIOLOGY AND BEHAVIOR IN THE CONTEXT OF IMMUNOLOGICAL DISORDERS. HISTONE DEACETYLASE- (HDAC-) DEPENDENT EPIGENETIC MECHANISMS HAVE BEEN WIDELY EXPLORED IN THE LAST DECADE IN DIFFERENT TYPES OF MALIGNANCIES IN PRECLINICAL STUDIES. THIS EFFORT LED TO THE DISCOVERY AND DEVELOPMENT OF A RANGE OF NEW HDAC INHIBITORS (IHDAC) WITH DIFFERENT CHEMICAL PROPERTIES AND SELECTIVE ABILITIES. IN FACT, HEMATOLOGICAL MALIGNANCIES WERE THE FIRST ONES TO HAVE NEW IHDACS APPROVED FOR CLINICAL USE, SUCH AS VORINOSTAT AND ROMIDEPSIN FOR CUTANEOUS T CELL LYMPHOMA AND PANOBINOSTAT FOR MULTIPLE MYELOMA. BESIDES THESE PROMISING ALREADY APPROVED IHDACS, WE HIGHLIGHT A RANGE OF STUDIES FOCUSING ON THE HDAC-DEPENDENT EPIGENETIC CONTROL OF B CELL DEVELOPMENT, BEHAVIOR, AND/OR FUNCTION. HERE, WE HIGHLIGHT 21 IHDACS WHICH HAVE BEEN STUDIED IN THE LITERATURE IN THE CONTEXT OF B CELL DEVELOPMENT AND/OR DYSFUNCTION MOSTLY FOCUSED ON B CELL LYMPHOMAGENESIS. REGARDLESS, WE HAVE IDENTIFIED 55 CLINICAL TRIALS USING 6 OUT OF 21 IHDACS TO APPROACH THEIR PUTATIVE ROLES ON B CELL MALIGNANCIES; NONE OF THEM FOCUSES ON PERITONEAL B CELL POPULATIONS. SINCE CELLS BELONGING TO THIS PECULIAR BODY COMPARTMENT, NAMED B1 CELLS, MAY CONTRIBUTE TO THE DEVELOPMENT OF AUTOIMMUNE PATHOLOGIES, SUCH AS LUPUS, A BETTER UNDERSTANDING OF THE HDAC-DEPENDENT EPIGENETIC MECHANISMS THAT CONTROL ITS BIOLOGY AND BEHAVIOR MIGHT SHED LIGHT ON IHDAC USE TO MANAGE THESE IMMUNOLOGICAL DYSFUNCTIONS. IN THIS SENSE, IHDACS MIGHT EMERGE AS A PROMISING NEW APPROACH FOR TRANSLATIONAL STUDIES IN THIS FIELD. IN THIS REVIEW, WE DISCUSS A PUTATIVE ROLE OF IHDACS IN THE MODULATION OF PERITONEAL B CELL SUBPOPULATION'S BALANCE AS WELL AS THEIR ROLE AS THERAPEUTIC AGENTS IN THE CONTEXT OF CHRONIC DISEASES MEDIATED BY PERITONEAL B CELLS. 2020 14 3104 34 GENOMIC, EPIGENOMIC, TRANSCRIPTOMIC, PROTEOMIC AND METABOLOMIC APPROACHES IN ATOPIC DERMATITIS. ATOPIC DERMATITIS (AD) IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH A HIGH PREVALENCE IN THE DEVELOPED COUNTRIES. IT IS ASSOCIATED WITH ATOPIC AND NON-ATOPIC DISEASES, AND ITS CLOSE CORRELATION WITH ATOPIC COMORBIDITIES HAS BEEN GENETICALLY DEMONSTRATED. ONE OF THE MAIN ROLES OF GENETIC STUDIES IS TO COMPREHEND THE DEFECTS OF THE CUTANEOUS BARRIER DUE TO FILAGGRIN DEFICIT AND EPIDERMAL SPONGIOSIS. RECENTLY, EPIGENETIC STUDIES STARTED TO ANALYZE THE INFLUENCE OF THE ENVIRONMENTAL FACTORS ON GENE EXPRESSION. THE EPIGENOME IS CONSIDERED TO BE A SUPERIOR SECOND CODE THAT CONTROLS THE GENOME, WHICH INCLUDES ALTERATIONS OF THE CHROMATIN. THE EPIGENETIC CHANGES DO NOT ALTER THE GENETIC CODE, HOWEVER, CHANGES IN THE CHROMATIN STRUCTURE COULD ACTIVATE OR INHIBIT THE TRANSCRIPTION PROCESS OF CERTAIN GENES AND CONSEQUENTLY, THE TRANSLATION PROCESS OF THE NEW MRNA INTO A POLYPEPTIDE CHAIN. IN-DEPTH ANALYSIS OF THE TRANSCRIPTOMIC, METABOLOMIC AND PROTEOMIC STUDIES ALLOW TO UNRAVEL DETAILED MECHANISMS THAT CAUSE AD. THE EXTRACELLULAR SPACE AND LIPID METABOLISM ARE ASSOCIATED WITH AD THAT IS INDEPENDENT OF THE FILAGGRIN EXPRESSION. ON THE OTHER HAND, AROUND 45 PROTEINS ARE CONSIDERED AS THE PRINCIPAL COMPONENTS IN THE ATOPIC SKIN. MOREOVER, GENETIC STUDIES BASED ON THE DISRUPTED CUTANEOUS BARRIER CAN LEAD TO THE DEVELOPMENT OF NEW TREATMENTS TARGETING THE CUTANEOUS BARRIER OR CUTANEOUS INFLAMMATION. UNFORTUNATELY, AT PRESENT, THERE ARE NO TARGET THERAPIES THAT FOCUS ON THE EPIGENETIC PROCESS OF AD. HOWEVER, IN THE FUTURE, MIR-143 COULD BE AN IMPORTANT OBJECTIVE FOR NEW THERAPIES, AS IT TARGETS THE MIR-335:SOX AXIS, THEREBY RESTORING THE MIR-335 EXPRESSION, AND REPAIRING THE CUTANEOUS BARRIER DEFECTS. 2023 15 6210 19 THE INTERPLAY BETWEEN KERATINOCYTES AND IMMUNE CELLS IN THE PATHOGENESIS OF PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE RESULTING FROM GENETIC, EPIGENETIC, ENVIRONMENTAL, AND LIFESTYLE FACTORS. TO DATE, SEVERAL IMMUNOPATHOGENIC MECHANISMS OF PSORIASIS HAVE BEEN ELUCIDATED, AND, IN THE CURRENT MODEL, THE CROSS TALK BETWEEN AUTOREACTIVE T CELLS AND RESIDENT KERATINOCYTES GENERATES INFLAMMATORY AND IMMUNE CIRCUITS RESPONSIBLE FOR THE INITIATION, PROGRESSION, AND PERSISTENCE OF THE DISEASE. SEVERAL AUTOANTIGENS DERIVED FROM KERATINOCYTES (I.E., LL37 CATHELECIDIN/NUCLEIC ACID COMPLEXES, NEWLY GENERATED LIPID ANTIGENS) HAVE BEEN IDENTIFIED, WHICH MAY TRIGGER INITIAL ACTIVATION OF T CELLS, PARTICULARLY IL-17-PRODUCING T CELLS, T HELPER (TH)1 AND TH22 CELLS. HENCE, LYMPHOKINES RELEASED IN SKIN LESIONS ARE PIVOTAL FOR KERATINOCYTE ACTIVATION AND PRODUCTION OF INFLAMMATORY MOLECULES, WHICH IN TURN LEAD TO AMPLIFICATION OF THE LOCAL IMMUNE RESPONSES. INTRINSIC GENETIC ALTERATIONS OF KERATINOCYTES IN THE ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS DEPENDENT ON T-CELL-DERIVED CYTOKINES ARE ALSO FUNDAMENTAL. THE CURRENT REVIEW EMPHASIZES THE ABERRANT INTERPLAY OF IMMUNE CELLS AND SKIN-RESIDENT KERATINOCYTES IN ESTABLISHING AND SUSTAINING INFLAMMATORY AND IMMUNE RESPONSES IN PSORIASIS. 2018 16 5663 24 SEZARY SYNDROME COEXISTING WITH B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA: CASE REPORT AND REVIEW OF THE LITERATURE. INTRODUCTION: THE SIMULTANEOUS PRESENTATION OF CHRONIC B-CELL LYMPHOCYTIC LEUKEMIA (B-CLL) AND CUTANEOUS T-CELL LYMPHOMA (CTCL) IS EXTREMELY RARE. CASE REPORT: WE DESCRIBE A PATIENT WITH B-CLL AND SEZARY SYNDROME (SS), AN ERYTHRODERMIC AND LEUKEMIC VARIANT OF CTCL. DESPITE TREATMENT, THE SS PROGRESSED TO INVOLVE INTERNAL ORGANS AND EVENTUAL DEATH OF THE PATIENT FROM SEPSIS. THIS IS THE FIRST REPORTED CASE OF SS COEXISTING WITH CHRONIC LYMPHOCYTIC LEUKEMIA IN WHICH AN ANTI-V BETA 13.6 ANTIBODY WAS USED TO SERIALLY TRACK CHANGES IN CIRCULATING NEOPLASTIC T CELLS VIS-A-VIS NEOPLASTIC B CELLS AND TO DETECT NEOPLASTIC T CELLS IN ASCITIC FLUID NEAR THE END OF THE PATIENT'S LIFE. DISCUSSION: WE SPECULATE THAT THE COEXISTENCE OF B-CLL AND CTCL IS THE RESULT OF AN INITIATING GENETIC OR EPIGENETIC DEFECT AT THE LEVEL OF THE COMMON LYMPHOID STEM CELL THAT PREDISPOSES BOTH B-CELL AND T-CELL LINEAGES TO ADDITIONAL ONCOGENIC CHANGES AT A MORE ADVANCED STAGE OF DIFFERENTIATION. 2008 17 258 27 ADVANCES IN PATHOGENESIS AND NANOPARTICLES (NPS)-MEDIATED TREATMENT OF PSORIASIS. PSORIASIS IS A CHRONIC PAPULOSQUAMOUS SKIN DISEASE WITH AN AUTOIMMUNE PATHOGENIC TRAITS AND STRONG GENETIC PREDISPOSITION. IN THE PAST FEW DECADES, WITH THE RAPID DEVELOPMENT OF MOLECULAR BIOLOGY AND CELL BIOLOGY, THE INHERENT PATHOGENESIS OF PSORIASIS HAS BEEN GRADUALLY ELUCIDATED, IN WHICH CYTOKINE INFLAMMATORY LOOPS, CELL SIGNALING PATHWAYS, AND EPIGENETIC FACTORS SUCH AS MIRNAS HAVE BEEN DEMONSTRATED TO PLAY IMPORTANT ROLES IN REGULATING THE DEVELOPMENT AND PROGRESSION OF PSORIASIS. MORE IMPORTANTLY, UNDERSTANDING THE PATHOGENESIS OF PSORIASIS HAS PROMOTED THE DEVELOPMENT OF EFFECTIVE TREATMENT FOR PSORIASIS. IN THIS REVIEW, WE SYSTEMICALLY SUMMARIZED THE MOLECULAR MECHANISMS REGULATING THE DEVELOPMENT AND PROGRESSION PSORIASIS, INTRODUCED VARIOUS THERAPEUTICS USED FOR CLINICAL PSORIASIS THERAPY, AND HIGHLIGHTED THE RECENT ADVANCES IN NANOPARTICLES (NPS)-MEDIATED DRUG DELIVERY FOR PSORIASIS TREATMENT. 2022 18 6896 28 [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 19 759 37 CASE REPORT OF CUTANEOUS SQUAMOUS CELL CARCINOMA AT THE WRIST JOINT AND THE PUBLIC HEALTH CRISIS OF ARSENICOSIS. CONTEXT: ARSENICOSIS IS CAUSED BY LONG TERM (6 MONTHS PLUS) INGESTION OF ARSENIC ABOVE A SAFE DOSE, CHARACTERIZED BY SKIN LESIONS AND POSSIBLE INVOLVEMENT OF INTERNAL ORGANS. ARSENICOSIS IS COMMON IN INDIA AND BANGLADESH WHERE NATURALLY OCCURRING HIGH CONCENTRATIONS OF ARSENIC IN THE EARTH'S CRUST CONTAMINATE GROUND WATER, CAUSING ADVERSE HEALTH EFFECTS. CASE PRESENTATION: WE REPORT A CASE OF A 55-YEAR-OLD INDIAN MALE, RESIDENT OF A KNOWN ARSENIC ENDEMIC REGION OF UTTAR PRADESH WHO SUFFERED FROM CHARACTERISTIC PULMONARY AND CUTANEOUS FEATURES OF CHRONIC ARSENIC TOXICITY WHICH INCLUDED RADIOLOGICAL FINDINGS OF INTERSTITIAL LUNG DISEASE, HYPERKERATOTIC LESIONS OVER THE PALMS AND SOLES, RAIN DROP LIKE PIGMENTATION OVER THE TRUNK, AND CARCINOMATOUS CHANGES AT THE WRIST JOINT. THE PATIENT WAS STARTED ON CHELATING AGENTS (D-PENICILLAMINE) AND ORAL RETINOIDS (ISOTRETINOIN) FOLLOWED BY THE SURGICAL EXCISION OF THE CARCINOMA. DISCUSSION: ENVIRONMENTAL CONTAMINATION WITH ARSENIC IS A WELL-KNOWN HEALTH HAZARD IN SOUTH ASIAN COUNTRIES. THE MAIN SOURCE IS CONSUMPTION OF CONTAMINATED GROUND WATER FOR DOMESTIC PURPOSES. CUTANEOUS LESIONS, INTERNAL ORGAN INVOLVEMENT INCLUDING INTERSTITIAL LUNG DISEASE AND CARCINOMAS AS OBSERVED IN OUR PATIENT HAVE BEEN REPORTED IN THE LITERATURE. VARIOUS MECHANISMS LIKE EPIGENETIC CHANGES AND ARSENIC-INDUCED IMMUNE SUPPRESSION HAVE BEEN PROPOSED FOR THE DEVELOPMENT OF CUTANEOUS CARCINOMAS WITH PROLONGED EXPOSURE TO ARSENIC. RELEVANCE TO CLINICAL PRACTICE: AMONG THE VARIOUS CAUSES OF PALMO-PLANTAR HYPERKERATOSIS, ARSENICOSIS SHOULD BE KEPT IN MIND WHEN PRESENTING IN COMBINATION WITH PIGMENTARY CHANGES AND CARCINOMATOUS GROWTH FROM AN ARSENIC-ENDEMIC REGION. CONCLUSIONS: PEOPLE RESIDING IN ARSENIC-ENDEMIC REGIONS SHOULD BE MADE AWARE OF ARSENIC-RELATED HEALTH HAZARDS. RAINWATER HARVESTING AND GOOD NUTRITION ARE THE SIMPLEST MEASURES WHICH COULD BE ADOPTED BY THE EXPOSED POPULATION IN AFFECTED AREAS. SEVERAL METHODS HAVE ALSO BEEN EMPLOYED BY GOVERNMENTAL AND NON-GOVERNMENT ORGANIZATIONS TO SEPARATE ARSENIC FROM CONTAMINATED WATER TO COMBAT ARSENIC-RELATED DISEASES AND CARCINOMAS. COMPETING INTERESTS: THE AUTHORS DECLARE NO COMPETING FINANCIAL INTERESTS. 2021 20 986 24 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