1 6623 109 UNDERSTANDING KELOID PATHOBIOLOGY FROM A QUASI-NEOPLASTIC PERSPECTIVE: LESS OF A SCAR AND MORE OF A CHRONIC INFLAMMATORY DISEASE WITH CANCER-LIKE TENDENCIES. KELOIDS ARE CONSIDERED AS BENIGN FIBROPROLIFERATIVE SKIN TUMORS GROWING BEYOND THE SITE OF THE ORIGINAL DERMAL INJURY. ALTHOUGH TRADITIONALLY VIEWED AS A FORM OF SKIN SCARRING, KELOIDS DISPLAY MANY CANCER-LIKE CHARACTERISTICS SUCH AS PROGRESSIVE UNCONTROLLED GROWTH, LACK OF SPONTANEOUS REGRESSION AND EXTREMELY HIGH RATES OF RECURRENCE. PHENOTYPICALLY, KELOIDS ARE CONSISTENT WITH NON-MALIGNANT DERMAL TUMORS THAT ARE DUE TO THE EXCESSIVE OVERPRODUCTION OF COLLAGEN WHICH NEVER METASTASIZE. WITHIN THE REMIT OF KELOID PATHOBIOLOGY, THERE IS INCREASING EVIDENCE FOR THE VARIOUS INTERPLAY OF NEOPLASTIC-PROMOTING AND SUPPRESSING FACTORS, WHICH MAY EXPLAIN ITS AGGRESSIVE CLINICAL BEHAVIOR. AMONGST THE MOST COMPELLING PARALLELS BETWEEN KELOIDS AND CANCER ARE THEIR SHARED CELLULAR BIOENERGETICS, EPIGENETIC METHYLATION PROFILES AND EPITHELIAL-TO-MESENCHYMAL TRANSITION AMONGST OTHER DISEASE BIOLOGICAL (GENOTYPIC AND PHENOTYPIC) BEHAVIORS. THIS REVIEW EXPLORES THE QUASI-NEOPLASTIC OR CANCER-LIKE PROPERTIES OF KELOIDS AND HIGHLIGHTS AREAS FOR FUTURE STUDY. 2019 2 4053 29 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 3 5797 26 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 4 986 31 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 5 1108 13 COMMENTARY ON SOME RECENT THESES RELEVANT TO COMBATING AGING: JUNE 2021. THESES REVIEWED IN THIS ISSUE INCLUDE "ENGINEERING PROTEIN DISAGGREGASES TO COUNTER ALPHA-SYNUCLEIN AND AMYLOID-BETA NEUROTOXICITY," "HYPERGLYCAEMIA INDUCED IMMUNOMODULATION OF MACROPHAGES IN DIABETIC VASCULAR DISEASE," "MICROVASCULATURE-ON-A-CHIP SYSTEMS FOR HUMAN DISEASE MODELING," "SENESCENCE SURVEILLANCE: THE INTERPLAY BETWEEN THE IMMUNE SYSTEM AND SENESCENT CELLS," "THE HMG TRANSCRIPTION FACTOR TOX INDUCES A TRANSCRIPTIONAL AND EPIGENETIC PROGRAM OF CD8(+) T CELL EXHAUSTION IN CHRONIC INFECTION AND CANCER," AND "ZERO TO ONE-TRANSLATIONAL ADVANCEMENTS IN THE FIELD OF XENOTRANSPLANTATION." 2021 6 769 24 CD8 T CELL EXHAUSTION DURING CHRONIC VIRAL INFECTION AND CANCER. EXHAUSTED CD8 T (TEX) CELLS ARE A DISTINCT CELL LINEAGE THAT ARISE DURING CHRONIC INFECTIONS AND CANCERS IN ANIMAL MODELS AND HUMANS. TEX CELLS ARE CHARACTERIZED BY PROGRESSIVE LOSS OF EFFECTOR FUNCTIONS, HIGH AND SUSTAINED INHIBITORY RECEPTOR EXPRESSION, METABOLIC DYSREGULATION, POOR MEMORY RECALL AND HOMEOSTATIC SELF-RENEWAL, AND DISTINCT TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS. THE ABILITY TO REINVIGORATE TEX CELLS THROUGH INHIBITORY RECEPTOR BLOCKADE, SUCH AS ALPHAPD-1, HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF TARGETING THIS POPULATION. EMERGING INSIGHTS INTO THE MECHANISMS OF EXHAUSTION ARE INFORMING IMMUNOTHERAPIES FOR CANCER AND CHRONIC INFECTIONS. HOWEVER, LIKE OTHER IMMUNE CELLS, TEX CELLS ARE HETEROGENEOUS AND INCLUDE PROGENITOR AND TERMINAL SUBSETS WITH UNIQUE CHARACTERISTICS AND RESPONSES TO CHECKPOINT BLOCKADE. HERE, WE REVIEW OUR CURRENT UNDERSTANDING OF TEX CELL BIOLOGY, INCLUDING THE DEVELOPMENTAL PATHS, TRANSCRIPTIONAL AND EPIGENETIC FEATURES, AND CELL INTRINSIC AND EXTRINSIC FACTORS CONTRIBUTING TO EXHAUSTION AND HOW THIS KNOWLEDGE MAY INFORM THERAPEUTIC TARGETING OF TEX CELLS IN CHRONIC INFECTIONS, AUTOIMMUNITY, AND CANCER. 2019 7 1379 17 DEVELOPMENTAL RELATIONSHIPS OF FOUR EXHAUSTED CD8(+) T CELL SUBSETS REVEALS UNDERLYING TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPE CONTROL MECHANISMS. CD8(+) T CELL EXHAUSTION IS A MAJOR BARRIER TO CURRENT ANTI-CANCER IMMUNOTHERAPIES. DESPITE THIS, THE DEVELOPMENTAL BIOLOGY OF EXHAUSTED CD8(+) T CELLS (TEX) REMAINS POORLY DEFINED, RESTRAINING IMPROVEMENT OF STRATEGIES AIMED AT "RE-INVIGORATING" TEX CELLS. HERE, WE DEFINED A FOUR-CELL-STAGE DEVELOPMENTAL FRAMEWORK FOR TEX CELLS. TWO TCF1(+) PROGENITOR SUBSETS WERE IDENTIFIED, ONE TISSUE RESTRICTED AND QUIESCENT AND ONE MORE BLOOD ACCESSIBLE, THAT GRADUALLY LOST TCF1 AS IT DIVIDED AND CONVERTED TO A THIRD INTERMEDIATE TEX SUBSET. THIS INTERMEDIATE SUBSET RE-ENGAGED SOME EFFECTOR BIOLOGY AND INCREASED UPON PD-L1 BLOCKADE BUT ULTIMATELY CONVERTED INTO A FOURTH, TERMINALLY EXHAUSTED SUBSET. BY USING TRANSCRIPTIONAL AND EPIGENETIC ANALYSES, WE IDENTIFIED THE CONTROL MECHANISMS UNDERLYING SUBSET TRANSITIONS AND DEFINED A KEY INTERPLAY BETWEEN TCF1, T-BET, AND TOX IN THE PROCESS. THESE DATA REVEAL A FOUR-STAGE DEVELOPMENTAL HIERARCHY FOR TEX CELLS AND DEFINE THE MOLECULAR, TRANSCRIPTIONAL, AND EPIGENETIC MECHANISMS THAT COULD PROVIDE OPPORTUNITIES TO IMPROVE CANCER IMMUNOTHERAPY. 2020 8 6319 24 THE ROAD LESS TAKEN: LESS APPRECIATED PATHWAYS FOR MANIPULATING CD8(+) T CELL EXHAUSTION. EXHAUSTED CD8(+) T (TEX) CELLS ARE A DISTINCT CELL POPULATION THAT ARISE DURING PERSISTENT ANTIGEN EXPOSURE IN THE CONTEXT OF CHRONIC INFECTIONS AND CANCERS. ALTHOUGH CHARACTERIZED BY PROGRESSIVE LOSS OF EFFECTOR FUNCTIONS, HIGH AND SUSTAINED INHIBITORY RECEPTOR EXPRESSION AND DISTINCT TRANSCRIPTIONAL AND EPIGENETIC PROGRAMS, TEX CELLS ARE HETEROGENEOUS. AMONG THESE, A SELF-RENEWING TCF-1(+) TEX POPULATION, HAVING UNIQUE CHARACTERISTICS AND THE ABILITY TO RESPOND TO IMMUNE-CHECKPOINT BLOCKADE, GIVES RISE TO TCF-1(-) TERMINALLY TEX CELLS. THESE TCF-1(+) CELLS HAVE STEM CELL-LIKE PROPERTIES SIMILAR TO MEMORY T CELL POPULATIONS, BUT THE SIGNALS THAT REGULATE THE DEVELOPMENTAL PATHWAYS AND RELATIONSHIPS AMONG EXHAUSTED CELL POPULATIONS ARE STILL UNCLEAR. HERE, WE REVIEW OUR CURRENT UNDERSTANDING OF TEX CELL BIOLOGY, AND DISCUSS SOME LESS APPRECIATED MOLECULES AND PATHWAYS AFFECTING T CELL EXHAUSTION. WE HIGHLIGHT TWO CO-STIMULATORY RECEPTORS, CD226 AND CD137, AND THEIR ROLE IN INDUCING OR RESTRAINING T CELL EXHAUSTION, AS WELL AS SIGNALING PATHWAYS THAT MAY BE AMENABLE TO PHARMACOLOGICAL INHIBITION WITH A FOCUS ON PHOSPHOINOSITIDE-3 KINASE AND IL-2 PARTIAL AGONISTS. FINALLY, WE DISCUSS NOVEL METHODS THAT MAY INCREASE TCF-1(+) POPULATIONS AND THEREFORE IMPROVE IMMUNOTHERAPY RESPONSIVENESS. UNDERSTANDING FEATURES OF AND PATHWAYS TO EXHAUSTION HAS IMPORTANT IMPLICATIONS FOR THE SUCCESS OF IMMUNOTHERAPY, INCLUDING CHECKPOINT BLOCKADE AND ADOPTIVE T-CELL TRANSFER THERAPIES. 2022 9 4178 15 MEMORY T-CELL HETEROGENEITY AND TERMINOLOGY. IMMUNOLOGICAL MEMORY AND EXHAUSTION ARE FUNDAMENTAL FEATURES OF ADAPTIVE IMMUNITY. RECENT ADVANCES REVEAL INCREASING HETEROGENEITY AND DIVERSITY AMONG CD8 T-CELL SUBSETS, RESULTING IN NEW SUBSETS TO ANNOTATE AND UNDERSTAND. HERE, WE REVIEW OUR CURRENT KNOWLEDGE OF DIFFERENTIATION AND MAINTENANCE OF MEMORY AND EXHAUSTED CD8 T CELLS, INCLUDING PHENOTYPIC CLASSIFICATION, DEVELOPMENTAL PATHS, TRANSCRIPTIONAL AND EPIGENETIC FEATURES, AND CELL INTRINSIC AND EXTRINSIC FACTORS. ADDITIONALLY, WE USE THIS OUTLINE TO DISCUSS THE NOMENCLATURE OF EFFECTOR, MEMORY, AND EXHAUSTED CD8 T CELLS. FINALLY, WE DISCUSS HOW NEW FINDINGS ABOUT THESE CELL TYPES MAY IMPACT THE THERAPEUTIC EFFICACY AND DEVELOPMENT OF IMMUNOTHERAPIES TARGETING EFFECTOR, MEMORY, AND/OR EXHAUSTED CD8 T CELLS IN CHRONIC INFECTIONS AND CANCER. 2021 10 1886 36 ENDOGENOUS BIOLOGICAL DRIVERS IN DIABETIC LOWER LIMB WOUNDS RECURRENCE: HYPOTHETICAL REFLECTIONS. AN IMPAIRED HEALING RESPONSE UNDERLIES DIABETIC FOOT WOUND CHRONICITY, FREQUENTLY TRANSLATING TO AMPUTATION, DISABILITY, AND MORTALITY. DIABETICS SUFFER FROM UNDERAPPRECIATED EPISODES OF POST-EPITHELIZATION ULCER RECURRENCE. RECURRENCE EPIDEMIOLOGICAL DATA ARE ALARMINGLY HIGH, SO THE ULCER IS CONSIDERED IN "REMISSION" AND NOT HEALED FROM THE TIME IT REMAINS EPITHELIALIZED. RECURRENCE MAY RESULT FROM THE COMBINED EFFECTS OF BEHAVIORAL AND ENDOGENOUS BIOLOGICAL FACTORS. ALTHOUGH THE DAMAGING ROLE OF BEHAVIORAL, CLINICAL PREDISPOSING FACTORS IS UNDEBATABLE, IT STILL REMAINS ELUSIVE IN THE IDENTIFICATION OF ENDOGENOUS BIOLOGICAL CULPRITS THAT MAY PRIME THE RESIDUAL SCAR TISSUE FOR RECURRENCE. FURTHERMORE, THE EVENT OF ULCER RECURRENCE STILL WAITS FOR THE IDENTIFICATION OF A MOLECULAR PREDICTOR. WE PROPOSE THAT ULCER RECURRENCE IS DEEPLY IMPINGED BY CHRONIC HYPERGLYCEMIA AND ITS DOWNSTREAM BIOLOGICAL EFFECTORS, WHICH ORIGINATE EPIGENETIC DRIVERS THAT ENFORCE ABNORMAL PATHOLOGIC PHENOTYPES TO DERMAL FIBROBLASTS AND KERATINOCYTES AS MEMORY CELLS. HYPERGLYCEMIA-DERIVED CYTOTOXIC REACTANTS ACCUMULATE AND MODIFY DERMAL PROTEINS, REDUCE SCAR TISSUE MECHANICAL TOLERANCE, AND DISRUPT FIBROBLAST-SECRETORY ACTIVITY. ACCORDINGLY, THE COMBINATION OF EPIGENETIC AND LOCAL AND SYSTEMIC CYTOTOXIC SIGNALERS INDUCE THE ONSET OF "AT-RISK PHENOTYPES" SUCH AS PREMATURE SKIN CELL AGING, DYSMETABOLISM, INFLAMMATORY, PRO-DEGRADATIVE, AND OXIDATIVE PROGRAMS THAT MAY ULTIMATELY CONVERGE TO SCAR CELL DEMISE. POST-EPITHELIALIZATION RECURRENCE RATE DATA ARE MISSING IN CLINICAL STUDIES OF REPUTED ULCER HEALING THERAPIES DURING FOLLOW-UP PERIODS. INTRA-ULCER INFILTRATION OF EPIDERMAL GROWTH FACTOR EXHIBITS THE MOST CONSISTENT REMISSION DATA WITH THE LOWEST RECURRENCES DURING 12-MONTH FOLLOW-UP. RECURRENCE DATA SHOULD BE REGARDED AS A VALUABLE CLINICAL ENDPOINT DURING THE INVESTIGATIONAL PERIOD FOR EACH EMERGENT HEALING CANDIDATE. 2023 11 5806 24 STRATEGIES TO REINVIGORATE EXHAUSTED CD8(+) T CELLS IN TUMOR MICROENVIRONMENT. CD8(+) T CELL EXHAUSTION IS A STABLE DYSFUNCTIONAL STATE DRIVEN BY CHRONIC ANTIGEN STIMULATION IN THE TUMOR MICROENVIRONMENT (TME). DIFFERENTIATION OF EXHAUSTED CD8(+) T CELLS (CD8(+) TEXS) IS ACCOMPANIED BY EXTENSIVE TRANSCRIPTIONAL, EPIGENETIC AND METABOLIC REPROGRAMMING. CD8(+) TEXS ARE MAINLY CHARACTERIZED BY IMPAIRED PROLIFERATIVE AND CYTOTOXIC CAPACITY AS WELL AS THE INCREASED EXPRESSION OF MULTIPLE CO-INHIBITORY RECEPTORS. PRECLINICAL TUMOR STUDIES AND CLINICAL COHORTS HAVE DEMONSTRATED THAT T CELL EXHAUSTION IS FIRMLY ASSOCIATED WITH POOR CLINICAL OUTCOMES IN A VARIETY OF CANCERS. MORE IMPORTANTLY, CD8(+) TEXS ARE REGARDED AS THE MAIN RESPONDER TO IMMUNE CHECKPOINT BLOCKADE (ICB). HOWEVER, TO DATE, A LARGE NUMBER OF CANCER PATIENTS HAVE FAILED TO ACHIEVE DURABLE RESPONSES AFTER ICB. THEREFORE, IMPROVING CD8(+) TEXS MAY BE A BREAKTHROUGH POINT TO REVERSE THE CURRENT DILEMMA OF CANCER IMMUNOTHERAPY AND ELIMINATE CANCERS. STRATEGIES TO REINVIGORATE CD8(+) TEXS IN TME MAINLY INCLUDE ICB, TRANSCRIPTION FACTOR-BASED THERAPY, EPIGENETIC THERAPY, METABOLISM-BASED THERAPY AND CYTOKINE THERAPY, WHICH TARGET ON DIFFERENT ASPECTS OF EXHAUSTION PROGRESSION. EACH OF THEM HAS ITS ADVANTAGES AND APPLICATION SCOPE. IN THIS REVIEW, WE MAINLY FOCUS ON THE MAJOR ADVANCES OF CURRENT STRATEGIES TO REINVIGORATE CD8(+) TEXS IN TME. WE SUMMARIZE THEIR EFFICACY AND MECHANISMS, IDENTIFY THE PROMISING MONOTHERAPY AND COMBINED THERAPY AND PROPOSE SUGGESTIONS TO ENHANCE THE TREATMENT EFFICACY TO SIGNIFICANTLY BOOST ANTI-TUMOR IMMUNITY AND ACHIEVE BETTER CLINICAL OUTCOMES. 2023 12 4101 19 MDCT AND MR UROGRAM SPECTRUM OF CONGENITAL ANOMALIES OF THE KIDNEY AND URINARY TRACT DIAGNOSED IN ADULTHOOD. OBJECTIVE: CONGENITAL ANOMALIES OF THE KIDNEYS AND URINARY TRACT (CAKUT) ENCOMPASS A SPECTRUM OF ANOMALIES THAT RESULT FROM GENETIC, EPIGENETIC, ENVIRONMENTAL, AND MOLECULAR SIGNAL ABERRATIONS AT KEY STAGES OF URINARY TRACT DEVELOPMENT. CAKUT CAN BE SEEN INCIDENTALLY ON CROSS-SECTIONAL IMAGING OF THE ABDOMEN OR CAN BE A CAUSE FOR ADULT-ONSET CHRONIC KIDNEY DISEASE, POSING NEW CHALLENGES FOR NEPHROLOGISTS, UROLOGISTS, AND RADIOLOGISTS. CONCLUSION: AWARENESS OF CAKUT AND FAMILIARITY WITH THEIR IMAGING FINDINGS PERMIT OPTIMAL PATIENT MANAGEMENT AND THOROUGH WORKUP TO PREVENT HYPERTENSION AND PROGRESSION FROM CAKUT TO RENAL FAILURE. THE PURPOSE OF THIS ARTICLE IS TO REVIEW THE CROSS-SECTIONAL IMAGING FINDINGS OF CAKUT THAT MAY PRESENT IN ADULTHOOD. 2015 13 770 22 CD8(+) T CELL DYSFUNCTION BY TOX INTOXICATION: A PROTUMORIGENIC EVENT IN THE TUMOR MICROENVIRONMENT. ACCUMULATING EVIDENCE SUGGESTS THE ROLE OF CELLULAR COMPONENTS IN ACHIEVING ANTITUMOR TO PROTUMOR MICROENVIRONMENTS. AMONG THE VARIOUS TYPES OF CELLS WITHIN THE TUMOR NICHE, THE STATE OF CD8(+) T CELLS APPARENTLY CHANGES FROM CYTOTOXIC T EFFECTOR CELLS AND MEMORY T CELLS TO EXHAUSTED CD8(+) T CELLS. THESE CHANGES IN THE PHENOTYPE OF CD8(+) T CELLS PROMOTE THE PROTUMOR MICROENVIRONMENT. RECENTLY, COMPREHENSIVE EXPERIMENTAL DATA DELINEATED THE ROLE OF THYMOCYTE SELECTION-ASSOCIATED HIGH-MOBILITY GROUP-BOX PROTEIN (TOX), WHICH REGULATES THE TRANSCRIPTIONAL PROCESS AND EPIGENETIC REMODELING, WITH IMPLICATIONS IN TUMOR AND CHRONIC VIRAL INFECTIONS. THIS PERSPECTIVE SUMMARIZES THE MOLECULAR MECHANISMS THAT LINK CD8(+) T CELLS, TOX, AND TRANSCRIPTIONAL AND EPIGENETIC REPROGRAMMING AS WELL AS FUTURE DIRECTIONS FOR DETERMINING NEW AVENUES OF CANCER THERAPEUTICS. 2021 14 4513 18 MULTI-OMIC APPROACHES TO ACUTE KIDNEY INJURY AND REPAIR. THE KIDNEY HAS A REMARKABLE REGENERATIVE CAPACITY. IN RESPONSE TO ISCHEMIC OR TOXIC INJURY, PROXIMAL TUBULE CELLS CAN PROLIFERATE TO REBUILD DAMAGED TUBULES AND RESTORE KIDNEY FUNCTION. HOWEVER, SEVERE ACUTE KIDNEY INJURY (AKI) OR RECURRENT AKI EVENTS CAN LEAD TO MALADAPTIVE REPAIR AND DISEASE PROGRESSION FROM AKI TO CHRONIC KIDNEY DISEASE (CKD). THE APPLICATION OF SINGLE CELL TECHNOLOGIES HAS IDENTIFIED INJURED PROXIMAL TUBULE CELL STATES WEEKS AFTER AKI, DISTINGUISHED BY A PRO-INFLAMMATORY SENESCENT MOLECULAR SIGNATURE. EPIGENETIC STUDIES HIGHLIGHTED DYNAMIC CHANGES IN THE CHROMATIN LANDSCAPE OF THE KIDNEY FOLLOWING AKI AND DESCRIBED KEY TRANSCRIPTION FACTORS LINKED TO THE AKI RESPONSE. THE INTEGRATION OF MULTI-OMIC TECHNOLOGIES OPENS NEW POSSIBILITIES TO IMPROVE OUR UNDERSTANDING OF AKI AND THE DRIVING FORCES BEHIND THE AKI-TO-CKD TRANSITION, WITH THE ULTIMATE GOAL OF DESIGNING TAILORED DIAGNOSTIC AND THERAPEUTIC STRATEGIES TO IMPROVE AKI OUTCOMES AND PREVENT KIDNEY DISEASE PROGRESSION. 2021 15 2409 21 EPIGENETIC SCARRING OF EXHAUSTED T CELLS HINDERS MEMORY DIFFERENTIATION UPON ELIMINATING CHRONIC ANTIGENIC STIMULATION. EXHAUSTED CD8 T CELLS (T(EX)) ARE A DISTINCT STATE OF T CELL DIFFERENTIATION ASSOCIATED WITH FAILURE TO CLEAR CHRONIC VIRUSES AND CANCER. IMMUNOTHERAPIES SUCH AS PD-1 BLOCKADE CAN REINVIGORATE T(EX) CELLS, BUT REINVIGORATION IS NOT DURABLE. A MAJOR UNANSWERED QUESTION IS WHETHER T(EX) CELLS DIFFERENTIATE INTO FUNCTIONAL DURABLE MEMORY T CELLS (T(MEM)) UPON ANTIGEN CLEARANCE. HERE, USING A MOUSE MODEL, WE FOUND THAT UPON ELIMINATING CHRONIC ANTIGENIC STIMULATION, T(EX) CELLS PARTIALLY (RE)ACQUIRE PHENOTYPIC AND TRANSCRIPTIONAL FEATURES OF T(MEM) CELLS. THESE 'RECOVERING' T(EX) CELLS ORIGINATED FROM THE T CELL FACTOR (TCF-1(+)) T(EX) PROGENITOR SUBSET. NEVERTHELESS, THE RECALL CAPACITY OF THESE RECOVERING T(EX) CELLS REMAINED COMPROMISED AS COMPARED TO T(MEM) CELLS. CHROMATIN-ACCESSIBILITY PROFILING REVEALED A FAILURE TO RECOVER CORE MEMORY EPIGENETIC CIRCUITS AND MAINTENANCE OF A LARGELY EXHAUSTED OPEN CHROMATIN LANDSCAPE. THUS, DESPITE SOME PHENOTYPIC AND TRANSCRIPTIONAL RECOVERY UPON ANTIGEN CLEARANCE, EXHAUSTION LEAVES DURABLE EPIGENETIC SCARS CONSTRAINING FUTURE IMMUNE RESPONSES. THESE RESULTS SUPPORT EPIGENETIC REMODELING INTERVENTIONS FOR T(EX) CELL-TARGETED IMMUNOTHERAPIES. 2021 16 4734 32 NOVEL CONCEPTS IN RADIATION-INDUCED CARDIOVASCULAR DISEASE. RADIATION-INDUCED CARDIOVASCULAR DISEASE (RICVD) IS THE MOST COMMON NONMALIGNANT CAUSE OF MORBIDITY AND MORTALITY AMONG CANCER SURVIVORS WHO HAVE UNDERGONE MEDIASTINAL RADIATION THERAPY (RT). CARDIOVASCULAR COMPLICATIONS INCLUDE EFFUSIVE OR CONSTRICTIVE PERICARDITIS, CARDIOMYOPATHY, VALVULAR HEART DISEASE, AND CORONARY/VASCULAR DISEASE. THESE ARE PATHOPHYSIOLOGICALLY DISTINCT DISEASE ENTITIES WHOSE PREVALENCE VARIES DEPENDING ON THE TIMING AND EXTENT OF RADIATION EXPOSURE TO THE HEART AND GREAT VESSELS. ALTHOUGH REFINEMENTS IN RT DOSIMETRY AND SHIELDING WILL INEVITABLY LIMIT FUTURE CASES OF RICVD, THE INCREASING NUMBER OF LONG-TERM CANCER SURVIVORS, INCLUDING THOSE TREATED WITH OLDER HIGHER-DOSE RT REGIMENS, WILL ENSURE A STEADY FLOW OF AFFLICTED PATIENTS FOR THE FORESEEABLE FUTURE. THUS, THERE IS A PRESSING NEED FOR ENHANCED UNDERSTANDING OF THE DISEASE MECHANISMS, AND IMPROVED DETECTION METHODS AND TREATMENT STRATEGIES. NEWLY CHARACTERIZED MECHANISMS RESPONSIBLE FOR THE ESTABLISHMENT OF CHRONIC FIBROSIS, SUCH AS OXIDATIVE STRESS, INFLAMMATION AND EPIGENETIC MODIFICATIONS, ARE DISCUSSED AND LINKED TO POTENTIAL TREATMENTS CURRENTLY UNDER STUDY. NOVEL IMAGING MODALITIES MAY SERVE AS POWERFUL SCREENING TOOLS IN RICVD, AND RECENT RESEARCH AND EXPERT OPINION ADVOCATING THEIR USE IS INTRODUCED. DATA ARGUING FOR THE AGGRESSIVE USE OF PERCUTANEOUS INTERVENTIONS, SUCH AS TRANSCUTANEOUS VALVE REPLACEMENT AND DRUG-ELUTING STENTS, ARE EXAMINED AND CONSIDERED IN THE CONTEXT OF PRIOR THERAPEUTIC APPROACHES. RICVD AND ITS TREATMENT OPTIONS ARE THE SUBJECT OF A RICH AND DYNAMIC BODY OF RESEARCH, AND PATIENTS WHO ARE AT RISK OR SUFFERING FROM THIS DISEASE WILL BENEFIT FROM THE CARE OF PHYSICIANS WITH SPECIALTY EXPERTISE IN THE EMERGING FIELD OF CARDIO-ONCOLOGY. 2016 17 461 33 ARCHITECTS OF PITUITARY TUMOUR GROWTH. THE PITUITARY IS A MASTER GLAND RESPONSIBLE FOR THE MODULATION OF CRITICAL ENDOCRINE FUNCTIONS. PITUITARY NEUROENDOCRINE TUMOURS (PITNETS) DISPLAY A CONSIDERABLE PREVALENCE OF 1/1106, FREQUENTLY OBSERVED AS BENIGN SOLID TUMOURS. PITNETS STILL REPRESENT A CAUSE OF IMPORTANT MORBIDITY, DUE TO HORMONAL SYSTEMIC DEREGULATION, WITH SURGICAL, RADIOLOGICAL OR CHRONIC TREATMENT REQUIRED FOR ILLNESS MANAGEMENT. THE APPARENT SCARCENESS, UNCOMMON BEHAVIOUR AND MOLECULAR FEATURES OF PITNETS HAVE RESULTED IN A RELATIVELY SLOW PROGRESS IN DEPICTING THEIR PATHOGENESIS. AN APPROPRIATE INTERPRETATION OF DIFFERENT PHENOTYPES OR CELLULAR OUTCOMES DURING TUMOUR GROWTH IS DESIRABLE, SINCE HISTOPATHOLOGICAL CHARACTERIZATION STILL REMAINS THE MAIN OPTION FOR PROGNOSIS ELUCIDATION. IMPROVED KNOWLEDGE OBTAINED IN RECENT DECADES ABOUT PITUITARY TUMORIGENESIS HAS REVEALED THAT THIS PROCESS INVOLVES SEVERAL CELLULAR ROUTES IN ADDITION TO PROLIFERATION AND DEATH, WITH ITS MODULATION DEPENDING ON MANY SIGNALLING PATHWAYS RATHER THAN BEING THE RESULT OF ABNORMALITIES OF A UNIQUE PROLIFERATION PATHWAY, AS SOMETIMES PRESENTED. PITNETS CAN DISPLAY INTRINSIC HETEROGENEITY AND CELL SUBPOPULATIONS WITH DIVERSE BIOLOGICAL, GENETIC AND EPIGENETIC PARTICULARITIES, INCLUDING TUMORIGENIC POTENTIAL. HENCE, TO OBTAIN A BETTER UNDERSTANDING OF PITNET GROWTH NEW APPROACHES ARE REQUIRED AND THE SYSTEMATIZATION OF THE AVAILABLE DATA, WITH THE ROLE OF CELL DEATH PROGRAMS, AUTOPHAGY, STEM CELLS, CELLULAR SENESCENCE, MITOCHONDRIAL FUNCTION, METABOLIC REPROGRAMMING STILL BEING EMERGING FIELDS IN PITUITARY RESEARCH. WE ENVISAGE THAT THROUGH THE COMBINATION OF MOLECULAR, GENETIC AND EPIGENETIC DATA, TOGETHER WITH THE IMPROVED MORPHOLOGICAL, BIOCHEMICAL, PHYSIOLOGICAL AND METABOLICALLY KNOWLEDGE ON PITUITARY NEOPLASTIC POTENTIAL ACCUMULATED IN RECENT DECADES, TUMOUR CLASSIFICATION SCHEMES WILL BECOME MORE ACCURATE REGARDING TUMOUR ORIGIN, BEHAVIOUR AND PLAUSIBLE CLINICAL RESULTS. 2022 18 3900 25 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 19 4749 22 NOVEL PROSPECTS FOR SCARLESS WOUND HEALING: THE ROLES OF MYOFIBROBLASTS AND ADIPOCYTES. DISTURBANCES OR DEFECTS IN THE PROCESS OF WOUND REPAIR CAN DISRUPT THE DELICATE BALANCE OF CELLS AND MOLECULES NECESSARY FOR COMPLETE WOUND HEALING, THUS LEADING TO CHRONIC WOUNDS OR FIBROTIC SCARS. MYOFIBROBLASTS ARE ONE OF THE MOST IMPORTANT CELLS INVOLVED IN FIBROTIC SCARS, AND REPROGRAMMING PROVIDES A POTENTIAL AVENUE TO INCREASE MYOFIBROBLAST CLEARANCE. ALTHOUGH MYOFIBROBLASTS HAVE LONG BEEN RECOGNIZED AS TERMINALLY DIFFERENTIATED CELLS, RECENT STUDIES HAVE SHOWN THAT MYOFIBROBLASTS HAVE THE CAPACITY TO BE REPROGRAMMED INTO ADIPOCYTES. THIS REVIEW INTENDS TO SUMMARIZE THE POTENTIAL OF REPROGRAMMING MYOFIBROBLASTS INTO ADIPOCYTES. WE WILL DISCUSS MYOFIBROBLAST LINEAGE TRACING, AS WELL AS THE KNOWN MECHANISMS UNDERLYING ADIPOCYTE REGENERATION FROM MYOFIBROBLASTS. IN ADDITION, WE INVESTIGATED DIFFERENT CHANGES IN MYOFIBROBLAST GENE EXPRESSION, TRANSCRIPTIONAL REGULATORS, SIGNALLING PATHWAYS AND EPIGENETIC REGULATORS DURING SKIN WOUND HEALING. IN THE FUTURE, MYOFIBROBLAST REPROGRAMMING IN WOUND HEALING WILL BE BETTER UNDERSTOOD AND APPRECIATED, WHICH MAY PROVIDE NEW IDEAS FOR THE TREATMENT OF SCARLESS WOUND HEALING. 2022 20 4757 24 NOVEL TREATMENT OPPORTUNITIES FOR SULFUR MUSTARD-RELATED CANCERS: GENETIC AND EPIGENETIC PERSPECTIVES. SULFUR MUSTARD (SM), ALSO KNOWN AS MUSTARD GAS, IS A CHEMICAL WEAPON WHICH BY NOW HAS BEEN USED IN MANY WARS. THE MOST CONCERNING SM TOXIC EFFECT IS PROBABLE CARCINOGENICITY. IN THIS STUDY, THE GENETIC AND EPIGENETIC MECHANISMS OF SM CARCINOGENICITY, BY FOCUSING ON TREATMENT OF SM-ASSOCIATED MALIGNANCIES, PARTICULARLY GENE THERAPEUTICS, CANCER VACCINES, AND EPIGENETIC MEDICATIONS, HAVE BEEN CRITICIZED. THE REQUIRED DATA WERE COLLECTED THROUGH AN ORGANIZED SEARCH ON VALID SCIENTIFIC DATABASES. FOR SM CARCINOGENICITY DUE TO ACUTE OR CHRONIC EXPOSURE, THE ENTIRE ORIGINAL AND REVIEW ARTICLES WERE EVALUATED. IN ADDITION, STUDIES ON THE THERAPEUTIC EFFECTS OF AVAILABLE GENETIC AND EPIGENETIC MEDICATIONS WERE INCLUDED. CURRENTLY, FOUR GENE THERAPEUTICS, TWO CANCER VACCINES WITH GENETIC BASES, AND SEVEN EPIGENETIC MEDICATIONS ARE AVAILABLE FOR CANCER TREATMENT. GENETIC AND EPIGENETIC CANCER TREATMENTS INCLUDING GENDICINE, IMLYGIC, PROVENGE, CIMAVAX-EGF, AZACITIDINE, VORINOSTAT, ROMIDEPSIN, AND BELINOSTAT WILL YIELD OUTSTANDING BENEFITS FOR SM-EXPOSED PATIENTS WHO SUFFER FROM CANCER. 2017