1  2998 115 GENETIC VARIANTS IN TELOMERASE REVERSE TRANSCRIPTASE CONTRIBUTE TO SOLAR LENTIGINES. SOLAR LENTIGINES (SLS) ARE A HALLMARK OF HUMAN SKIN AGING. THEY RESULT FROM CHRONIC EXPOSURE TO SUNLIGHT AND OTHER ENVIRONMENTAL STRESSORS. RECENT STUDIES ALSO IMPLY GENETIC FACTORS, BUT FINDINGS ARE PARTIALLY CONFLICTING AND LACK OF REPLICATION. THROUGH A MULTI-TRAIT BASED ANALYSIS STRATEGY, WE DISCOVERED THAT GENETIC VARIANTS IN TELOMERASE REVERSE TRANSCRIPTASE WERE SIGNIFICANTLY ASSOCIATED WITH NON-FACIAL SL IN TWO EAST ASIAN (TAIZHOU LONGITUDINAL COHORT, N = 2,964 AND NATIONAL SURVEY OF PHYSICAL TRAITS, N = 2,954) AND ONE CAUCASIAN POPULATION (SALIA, N = 462), TOP SNP RS2853672 (P-VALUE FOR TAIZHOU LONGITUDINAL COHORT = 1.32 X 10(?28) AND P-VALUE FOR NATIONAL SURVEY OF PHYSICAL TRAITS = 3.66 X 10(?17) AND P-VALUE FOR SALIA = 0.0007 AND P(META) = 4.93 X 10(?44)). THE SAME VARIANTS WERE NOMINALLY ASSOCIATED WITH FACIAL SL BUT NOT WITH OTHER SKIN AGING OR SKIN PIGMENTATION TRAITS. THE SL-ENHANCED ALLELE/HAPLOTYPE UPREGULATED THE TRANSCRIPTION OF THE TELOMERASE REVERSE TRANSCRIPTASE GENE. OF NOTE, WELL-KNOWN TELOMERASE REVERSE TRANSCRIPTASE?RELATED AGING MARKERS SUCH AS LEUKOCYTE TELOMERE LENGTH AND INTRINSIC EPIGENETIC AGE ACCELERATION WERE NOT ASSOCIATED WITH SL. OUR RESULTS INDICATE A PREVIOUSLY UNRECOGNIZED ROLE OF TELOMERASE REVERSE TRANSCRIPTASE IN SKIN AGING?RELATED LENTIGINES FORMATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  1323  23 DENDRITIC CELLS IN SYSTEMIC LUPUS ERYTHEMATOSUS: FROM PATHOGENESIS TO THERAPEUTIC APPLICATIONS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A SEVERE CHRONIC SYSTEMIC AUTOIMMUNE DISEASE CAUSED BY COMPLICATED INTERACTIONS AMONG GENETIC, EPIGENETIC, AND IMMUNOLOGICAL FACTORS. DENDRITIC CELLS (DCS), AS THE MOST IMPORTANT ANTIGEN-PRESENTING CELLS, PLAY PIVOTAL ROLES IN BOTH TRIGGERING PATHOGENIC AUTOIMMUNE RESPONSES, AND ALSO MAINTAINING IMMUNE TOLERANCE. DISTINCT DC SUBSETS ARE ENDOWED WITH DIVERSIFIED PHENOTYPIC AND FUNCTIONAL CHARACTERISTICS, AND PLAY VARIABLE ROLES IN SHAPING IMMUNITY AND TOLERANCE DURING THE DEVELOPMENT OF SLE. ABNORMAL ACTIVATION OR DISABLED TOLERANCE OF DCS NOT ONLY TRIGGERS ABERRANT PRODUCTION OF INFLAMMATORY MEDIATORS AND TYPE I INTERFERONS LEADING TO PATHOGENIC INNATE IMMUNITY AND AUTOINFLAMMATION, BUT ALSO CAUSES AN IMBALANCE OF EFFECTOR VERSUS REGULATORY T CELL RESPONSES AND SUSTAINED PRODUCTION OF AUTO-ANTIBODIES FROM B CELLS, LEADING TO CONTINUOUSLY AMPLIFIED AUTOIMMUNE PATHOGENESIS IN SLE. OVER THE PAST DECADE, SIGNIFICANT PROGRESS HAS BEEN MADE IN REVEALING THE CHANGES OF DC ACCUMULATION OR FUNCTION IN SLE, AND HOW THE FUNCTIONAL DYSREGULATIONS OF DCS CONTRIBUTE TO THE PATHOLOGICAL INFLAMMATION OF SLE, LEADING TO BREAKTHROUGHS IN DC-BASED THERAPEUTICS IN THE TREATMENT OF SLE. IN THIS REVIEW, WE REVIEW THE RECENT ADVANCES IN THE ACTIVATION AND FUNCTION OF THE MAJOR DC SUBSETS IN THE PATHOGENESIS OF SLE AS WELL AS THE THERAPEUTIC POTENTIAL OF TARGETING DC SUBSET OR STATUS AGAINST SLE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
3  3596  27 IMPLICATIONS OF SPHINGOLIPIDS ON AGING AND AGE-RELATED DISEASES. AGING IS A PROCESS LEADING TO A PROGRESSIVE LOSS OF PHYSIOLOGICAL INTEGRITY AND HOMEOSTASIS, AND A PRIMARY RISK FACTOR FOR MANY LATE-ONSET CHRONIC DISEASES. THE MECHANISMS UNDERLYING AGING HAVE LONG PIQUED THE CURIOSITY OF SCIENTISTS. HOWEVER, THE IDEA THAT AGING IS A BIOLOGICAL PROCESS SUSCEPTIBLE TO GENETIC MANIPULATION WAS NOT WELL ESTABLISHED UNTIL THE DISCOVERY THAT THE INHIBITION OF INSULIN/IGF-1 SIGNALING EXTENDED THE LIFESPAN OF C. ELEGANS. ALTHOUGH AGING IS A COMPLEX MULTISYSTEM PROCESS, LOPEZ-OTIN ET AL. DESCRIBED AGING IN REFERENCE TO NINE HALLMARKS OF AGING. THESE NINE HALLMARKS INCLUDE: GENOMIC INSTABILITY, TELOMERE ATTRITION, EPIGENETIC ALTERATIONS, LOSS OF PROTEOSTASIS, DEREGULATED NUTRIENT SENSING, MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, STEM CELL EXHAUSTION, AND ALTERED INTERCELLULAR COMMUNICATION. DUE TO RECENT ADVANCES IN LIPIDOMIC, INVESTIGATION INTO THE ROLE OF LIPIDS IN BIOLOGICAL AGING HAS INTENSIFIED, PARTICULARLY THE ROLE OF SPHINGOLIPIDS (SL). SLS ARE A DIVERSE GROUP OF LIPIDS ORIGINATING FROM THE ENDOPLASMIC RETICULUM (ER) AND CAN BE MODIFIED TO CREATE A VASTLY DIVERSE GROUP OF BIOACTIVE METABOLITES THAT REGULATE ALMOST EVERY MAJOR CELLULAR PROCESS, INCLUDING CELL CYCLE REGULATION, SENESCENCE, PROLIFERATION, AND APOPTOSIS. ALTHOUGH SL BIOLOGY REACHES ALL NINE HALLMARKS OF AGING, ITS CONTRIBUTION TO EACH HALLMARK IS DISPROPORTIONATE. IN THIS REVIEW, WE WILL DISCUSS IN DETAIL THE MAJOR CONTRIBUTIONS OF SLS TO THE HALLMARKS OF AGING AND AGE-RELATED DISEASES WHILE ALSO SUMMARIZING THE IMPORTANCE OF THEIR OTHER MINOR BUT INTEGRAL CONTRIBUTIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4  6509  18 TRANSCRIPTION FACTOR RFX1 IS UBIQUITINATED BY E3 LIGASE STUB1 IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE DISEASE CAUSED BY COMPLEX INTERACTIONS BETWEEN GENES AND THE ENVIRONMENT. THE EXPRESSION LEVEL OF TRANSCRIPTION FACTOR REGULATORY FACTOR X 1 (RFX1) IS REDUCED IN T CELLS FROM SLE PATIENTS. RFX1 CAN REGULATE EPIGENETIC MODIFICATIONS OF CD70 AND CD11A AND PLAYS AN IMPORTANT ROLE IN THE DEVELOPMENT OF SLE. HOWEVER, THE MECHANISMS THAT MEDIATE REDUCTION OF RFX1 IN SLE ARE UNCLEAR. HERE, WE DEMONSTRATE THAT RFX1 PROTEIN EXPRESSION CAN BE TIGHTLY REGULATED BY POLYUBIQUITINATION-MEDIATED PROTEOSOMAL DEGRADATION VIA STIP1 HOMOLOGY AND U-BOX CONTAINING PROTEIN 1 (STUB1). THE E3 LIGASE STUB1 IS UPREGULATED IN CD4(+)T CELLS OF SLE PATIENTS COMPARED TO HEALTHY SUBJECTS. OVEREXPRESSION OF STUB1 IN CD4(+)T CELLS LEADS TO UPREGULATION OF LEVELS OF CD70 AND CD11A IN T CELLS. THE MODULATION OF STUB1 ACTIVITY MAY PROVIDE A NOVEL THERAPEUTIC APPROACH FOR SLE.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
5  4012  24 LOW-DENSITY GRANULOCYTES IN SYSTEMIC AUTOIMMUNITY AND AUTOINFLAMMATION. A BODY OF EVIDENCE HAS RE-ENERGIZED THE INTEREST ON THE ROLE NEUTROPHILS IN INFLAMMATORY AND AUTOIMMUNE CONDITIONS. FOR DECADES, NEUTROPHILS HAVE BEEN CONSIDERED A HOMOGENOUS POPULATION. NEVERTHELESS, ACCUMULATING EVIDENCE SUGGESTS THAT NEUTROPHILS ARE MORE VERSATILE AND HETEROGENEOUS THAN INITIALLY CONSIDERED. THE NOTION OF NEUTROPHIL HETEROGENEITY HAS BEEN SUPPORTED BY THE IDENTIFICATION OF LOW-DENSITY GRANULOCYTES (LDGS) IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND OTHER SYSTEMIC AUTOIMMUNE AND AUTOINFLAMMATORY CONDITIONS. TRANSCRIPTOMIC, EPIGENETIC, PROTEOMIC, AND FUNCTIONAL ANALYSES SUPPORT THAT LDGS ARE A DISTINCT SUBSET OF PROINFLAMMATORY NEUTROPHILS IMPLICATED IN THE PATHOGENESIS OF SLE AND OTHER AUTOIMMUNE DISEASES. IMPORTANTLY, IT REMAINS INCOMPLETELY CHARACTERIZED WHETHER LDGS DETECTED IN OTHER INFLAMMATORY/AUTOIMMUNE CONDITIONS DISPLAY THE SAME PHENOTYPE THAT THOSE PRESENT IN SLE. A SHARED FEATURE OF LDGS ACROSS DISEASES IS THEIR ASSOCIATION WITH VASCULAR DAMAGE, AN IMPORTANT CONTRIBUTOR TO MORBIDITY AND MORTALITY IN CHRONIC INFLAMMATORY CONDITIONS. ADDITIONALLY, THE LACK OF SPECIFIC MARKERS TO IDENTIFY LDGS IN CIRCULATION OR IN TISSUE, MAKES IT A CHALLENGE TO ELUCIDATE THEIR ROLE IN THE PATHOGENESIS OF INFLAMMATORY AND AUTOIMMUNE CONDITIONS. IN THIS REVIEW, WE AIM TO EXAMINE THE EVIDENCE ON THE BIOLOGY AND THE PUTATIVE PATHOGENIC ROLE OF LDGS IN SYSTEMIC AUTOIMMUNE DISEASES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6  1555  28 DNA METHYLATION MAPPING IDENTIFIES GENE REGULATORY EFFECTS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS. OBJECTIVES: SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC AUTOIMMUNE CONDITION WITH HETEROGENEOUS PRESENTATION AND COMPLEX AETIOLOGY WHERE DNA METHYLATION CHANGES ARE EMERGING AS A CONTRIBUTING FACTOR. IN ORDER TO DISCOVER NOVEL EPIGENETIC ASSOCIATIONS AND INVESTIGATE THEIR RELATIONSHIP TO GENETIC RISK FOR SLE, WE ANALYSED DNA METHYLATION PROFILES IN A LARGE COLLECTION OF PATIENTS WITH SLE AND HEALTHY INDIVIDUALS. METHODS: DNA EXTRACTED FROM BLOOD FROM 548 PATIENTS WITH SLE AND 587 HEALTHY CONTROLS WERE ANALYSED ON THE ILLUMINA HUMANMETHYLATION 450 K BEADCHIP, WHICH TARGETS 485 000 CPG SITES ACROSS THE GENOME. SINGLE NUCLEOTIDE POLYMORPHISM (SNP) GENOTYPE DATA FOR 196 524 SNPS ON THE ILLUMINA IMMUNOCHIP FROM THE SAME INDIVIDUALS WERE UTILISED FOR METHYLATION QUANTITATIVE TRAIT LOCI (CIS-MEQTLS) ANALYSES. RESULTS: WE IDENTIFIED AND REPLICATED DIFFERENTIALLY METHYLATED CPGS (DMCS) IN SLE AT 7245 CPG SITES IN THE GENOME. THE LARGEST METHYLATION DIFFERENCES WERE OBSERVED AT TYPE I INTERFERON-REGULATED GENES WHICH EXHIBITED DECREASED METHYLATION IN SLE. WE MAPPED CIS-MEQTLS AND IDENTIFIED GENETIC REGULATION OF METHYLATION LEVELS AT 466 OF THE DMCS IN SLE. THE MEQTLS FOR DMCS IN SLE WERE ENRICHED FOR GENETIC ASSOCIATION TO SLE, AND INCLUDED SEVEN SLE GENOME-WIDE ASSOCIATION STUDY (GWAS) LOCI: PTPRC (CD45), MHC-CLASS III, UHRF1BP1, IRF5, IRF7, IKZF3 AND UBE2L3. IN ADDITION, WE OBSERVED ASSOCIATION BETWEEN GENOTYPE AND VARIANCE OF METHYLATION AT 20 DMCS IN SLE, INCLUDING AT THE HLA-DQB2 LOCUS. CONCLUSIONS: OUR RESULTS SUGGEST THAT SEVERAL OF THE GENETIC RISK VARIANTS FOR SLE MAY EXERT THEIR INFLUENCE ON THE PHENOTYPE THROUGH ALTERATION OF DNA METHYLATION LEVELS AT REGULATORY REGIONS OF TARGET GENES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
7  1735  25 EARLY AND SUSTAINED EXPANSION OF ADAPTIVE NATURAL KILLER CELLS FOLLOWING HAPLOIDENTICAL TRANSPLANTATION AND CTLA4IG-PRIMED DONOR LYMPHOCYTE INFUSIONS DISSOCIATE GRAFT-VERSUS-LEUKEMIA AND GRAFT-VERSUS-HOST EFFECTS. BACKGROUND: ADAPTIVE OR MEMORY NATURAL KILLER (NK) CELLS WITH EPIGENETIC IMPRINTS SIMILAR TO MEMORY T CELLS HAVE BEEN SHOWN TO DEVELOP IN RESPONSE TO CYTOMEGALOVIRUS (CMV) INFECTION WITH UPREGULATION OF ACTIVATING RECEPTOR NKG2C. THESE CELLS HAVE BEEN SHOWN TO POSSESS STRONG ANTI-TUMOUR EFFICACY BOTH IN-VITRO AS WELL AS IN-VIVO. OBJECTIVES: TO DETERMINE IF RECONSTITUTION OF ADAPTIVE NK CELLS (CD56(DIM)NKG2C(+)NKG2A(-)) IN PATIENTS WITH ADVANCED LEUKEMIA UNDERGOING HAPLOIDENTICAL HCT HAD ANY IMPACT ON DISEASE PROGRESSION (DP). STUDY DESIGN: THE STUDY COHORT COMPRISED OF 60 PATIENTS WITH ADVANCED ACUTE LEUKEMIA, AGED 2-65 YEARS, RECEIVING MYELOABLATIVE PTCY BASED HAPLOIDENTICAL TRANSPLANTATION FROM CMV SEROPOSITIVE DONORS, FOLLOWED BY CTLA4IG-PRIMED DONOR LYMPHOCYTE INFUSIONS (DLI). THEY WERE EVALUATED FOR THE KINETICS OF RECONSTITUTION OF ADAPTIVE NK CELLS, BOTH PHENOTYPIC AND FUNCTIONAL, AT DAYS +30,+60, +90 AND AT REGULAR INTERVALS, TO 3 YEARS OF FOLLOW-UP, IN RELATION TO DP. RECONSTITUTION OF ADAPTIVE NK CELLS WAS COMPARED WITH A RETROSPECTIVE COHORT OF PATIENTS IN THE SAME PROTOCOL RECEIVING DLI WITHOUT CTLA4IG. RESULTS: NON-RELAPSE MORTALITY, ACUTE AND CHRONIC GVHD WERE 5.1%, 10.3% AND 14.5%. DP WAS 17.5% AT A MEDIAN FOLLOW-UP OF 28 MONTHS. ADAPTIVE NK CELLS WERE SIGNIFICANTLY HIGHER IN PATIENTS WITHOUT DP AT DAYS+30, +60 AND +90 (P = 0.0001), IRRESPECTIVE OF CMV REACTIVATION AND REMAINED ELEVATED UNTIL 36 MONTHS POST-HCT. THESE CELLS MAINTAINED THEIR FUNCTIONAL COMPETENCE AS MEASURED BY ROBUST INTERFERON-GAMMA PRODUCTION WITH HIGHER EXPRESSIONS OF KIR, NKG2D AND CD57, WITHOUT ANY INCREASE IN PD1 EXPRESSION. GRAFTS FROM DONORS WITH HIGHER ADAPTIVE NK CELLS WERE ASSOCIATED WITH A LOWER RISK OF DP (P = 0.0001). IN MULTIVARIATE ANALYSIS, ADAPTIVE NK CELL RECOVERY AT DAY +90 HAD THE MOST FAVORABLE IMPACT ON DP (HR-0.7). TREGS RECONSTITUTED BRISKLY ALONG WITH THE ADAPTIVE NK CELLS AND WERE SUSTAINED AS WELL, WITHOUT COMPROMISING THE GVL EFFECT. COMPARISON WITH A RETROSPECTIVE COHORT RECEIVING THE SAME PROTOCOL WITH DLI WITHOUT CTLA4IG, SHOWED A SUPERIOR RECONSTITUTION OF ADAPTIVE NK CELLS IN THOSE RECEIVING CTLA4IG-DLI (P < 0.0001). CONCLUSION: OUR STUDY SUGGESTS THAT MYELOABLATIVE TRANSPLANTATION FROM CMV SEROPOSITIVE HAPLOIDENTICAL DONORS AUGMENTED WITH CTLA4IG-PRIMED DLI MIGHT FAVOR EARLY AND SUSTAINED EXPANSION OF FUNCTIONALLY COMPETENT ADAPTIVE NK CELLS IRRESPECTIVE OF CMV REACTIVATION, WITH A FAVORABLE OUTCOME.	2021	

8  6782  16 [CHRONIC DISEASES, PRECANCER, AND CANCER OF THE LUNG, WHICH ARE ASSOCIATED WITH PATHOLOGY OF THE CLUB CELLS OF RESPIRATORY AND TERMINAL BRONCHIOLES]. THE REVIEW OF THE LITERATURE DEALS WITH THE PARTICIPATION OF CLARA CELLS NOW CALLED CLUB CELLS (CCS) OF THE EPITHELIUM IN THE RESPIRATORY AND TERMINAL BRONCHIOLES IN THE PATHOGENESIS AND MORPHOGENESIS OF CHRONIC INFLAMMATORY DISEASES, PRECANCER, AND CANCER OF THE LUNG, WHICH DEVELOP IN THE RESPIRATORY SEGMENTS. THE REVIEW SUMMARIZES DATA ON THE HISTOPHYSIOLOGY OF CCS AND THEIR PARTICIPATION IN THE PATHOGENESIS AND MORPHOGENESIS OF CHRONIC INTERSTITIAL LUNG DISEASES, PNEUMOCONIOSIS, CHRONIC OBSTRUCTIVE DISEASES, ADENOMATOSIS, AND ADENOCARCINOMA OF THE LUNG. IN THIS AREA, THERE IS A BRONCHIOLOALVEOLAR JUNCTION AREA (BAJA), ONE OF THE MOST IMPORTANT STEM CELL NICHES. CCS ARE LOCATED IN THE BAJA; THEY ARE PROGENITOR TISSUE STEM CELLS AND PLAY AN IMPORTANT ROLE IN THE REGENERATION OF THE EPITHELIUM OF THE RESPIRATORY BRONCHIOLES AND ALVEOLI. PATHOLOGY OF CCS IN THE BAJA LEADS TO THE MAINTENANCE OF CHRONIC INFLAMMATION, TO THE DESTRUCTION OF THE LUNG ELASTIC FRAME, AND TO IMPAIRED EPITHELIAL REGENERATION, INTERSTITIAL FIBROSIS, AND ADENOMATOSIS. IN THIS CASE, DECOMPENSATED INFLAMMATION, PATHOLOGICAL REGENERATION, AND FIBROSIS DEVELOP, WHICH, ALONG WITH THE ACTION OF CARCINOGENIC AGENTS, CAN CONTRIBUTE TO THE ACCUMULATION OF MUTATIONS AND EPIGENETIC REARRANGEMENTS IN THE CCS, WHICH SUBSEQUENTLY RESULTS IN ATYPICAL ADENOMATOUS HYPERPLASIA AND ADENOCARCINOMA OF THE LUNG.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  6705  22 VHL INACTIVATION IN PRECANCEROUS KIDNEY CELLS INDUCES AN INFLAMMATORY RESPONSE VIA ER STRESS-ACTIVATED IRE1ALPHA SIGNALING. MUTATIONS AND EPIGENETIC INACTIVATION OF THE TUMOR SUPPRESSOR GENE VON HIPPEL-LINDAU (VHL) ARE MAJOR CAUSES OF CLEAR-CELL RENAL CELL CARCINOMA (CCRCC) THAT MAY ORIGINATE FROM CHRONIC INFLAMMATION. HOWEVER, THE ROLE OF VHL LOSS OF FUNCTION IN THE DEVELOPMENT OF CCRCC VIA INFLAMMATION REMAINS POORLY UNDERSTOOD. VHL-MUTANT CELLS EXHIBIT METABOLIC ABNORMALITIES THAT CAN CAUSE CHRONIC ENDOPLASMIC RETICULUM (ER) STRESS AND UNFOLDED PROTEIN RESPONSE. WE HYPOTHESIZE THAT UNRESOLVED ER STRESS INDUCES THE INFLAMMATORY RESPONSES OBSERVED IN CCRCC. ER STRESS MARKERS INCLUDING BIP AND XBP1S WERE SIGNIFICANTLY INCREASED IN CULTURED AND PRIMARY VHL LOSS-OF-FUNCTION KIDNEY CELLS. IN EPITHELIAL CELLS, THE KINASE ACTIVITY OF IRE1ALPHA WAS REQUIRED FOR THE INDUCTION OF NF-KAPPAB AND JNK AND FOR THE RECRUITMENT OF MACROPHAGES. IRE1ALPHA KINASE ACTIVITY WAS ALSO IMPORTANT FOR THE DEVELOPMENT OF FIBROTIC PHENOTYPE IN CONDITIONAL VHLH KNOCKOUT MICE. OUR RESULTS OFFER INSIGHTS INTO THE THERAPEUTIC POTENTIAL AGAINST CCRCC DEVELOPMENT BY RELIEVING METABOLIC STRESS. SUCH CANCER PREVENTION STRATEGY MAY BE CRITICAL FOR HIGH-RISK COHORTS SUCH AS THE FAMILIAL VHL DISEASE PATIENTS. CANCER RES; 77(13); 3406-16. (C)2017 AACR.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10   170  31 ABNORMALITIES OF THE TYPE I INTERFERON SIGNALING PATHWAY IN LUPUS AUTOIMMUNITY. TYPE I INTERFERONS (IFNS), MOSTLY IFNALPHA AND IFNBETA, AND THE TYPE I IFN SIGNATURE ARE IMPORTANT IN THE PATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), AN AUTOIMMUNE CHRONIC CONDITION LINKED TO INFLAMMATION. BOTH IFNALPHA AND IFNBETA TRIGGER A SIGNALING CASCADE THAT, THROUGH THE ACTIVATION OF JAK1, TYK2, STAT1 AND STAT2, INITIATES GENE TRANSCRIPTION OF IFN STIMULATED GENES (ISGS). NOTEWORTHY, OTHER STAT FAMILY MEMBERS AND IFN RESPONSIVE FACTORS (IRFS) CAN ALSO CONTRIBUTE TO THE ACTIVATION OF THE IFN RESPONSE. ABERRANT TYPE I IFN SIGNALING, THEREFORE, CAN EXACERBATE SLE BY DEREGULATED HOMEOSTASIS LEADING TO UNNECESSARY PERSISTENCE OF THE BIOLOGICAL EFFECTS OF TYPE I IFNS. THE ETIOPATHOGENESIS OF SLE IS PARTIALLY KNOWN AND CONSIDERED MULTIFACTORIAL. FAMILY-BASED AND GENOME WIDE ASSOCIATION STUDIES (GWAS) HAVE IDENTIFIED GENETIC AND TRANSCRIPTIONAL ABNORMALITIES IN KEY MOLECULES DIRECTLY INVOLVED IN THE TYPE I IFN SIGNALING PATHWAY, NAMELY TYK2, STAT1 AND STAT4, AND IRF5. GAIN-OF-FUNCTION MUTATIONS THAT HEIGHTEN IFNALPHA/BETA PRODUCTION, WHICH IN TURN MAINTAINS TYPE I IFN SIGNALING, ARE FOUND IN OTHER PATHOLOGIES LIKE THE INTERFERONOPATHIES. HOWEVER, THE DISTINCTIVE CHARACTERISTICS HAVE YET TO BE DETERMINED. SIGNALING MOLECULES ACTIVATED IN RESPONSE TO TYPE I IFNS ARE UPREGULATED IN IMMUNE CELL SUBSETS AND AFFECTED TISSUES OF SLE PATIENTS. MOREOVER, TYPE I IFNS INDUCE CHROMATIN REMODELING LEADING TO A STATE PERMISSIVE TO TRANSCRIPTION, AND SLE PATIENTS HAVE INCREASED GLOBAL AND GENE-SPECIFIC EPIGENETIC MODIFICATIONS, SUCH AS HYPOMETHYLATION OF DNA AND HISTONE ACETYLATION. EPIGENOME WIDE ASSOCIATION STUDIES (EWAS) HIGHLIGHT IMPORTANT DIFFERENCES BETWEEN SLE PATIENTS AND HEALTHY CONTROLS IN INTERFERON STIMULATED GENES (ISGS). THE COMBINATION OF ENVIRONMENTAL AND GENETIC FACTORS MAY STIMULATE TYPE I IFN SIGNALING TRANSIENTLY AND PRODUCE LONG-LASTING DETRIMENTAL EFFECTS THROUGH EPIGENETIC ALTERATIONS. SUBSTANTIAL EVIDENCE FOR THE PATHOGENIC ROLE OF TYPE I IFNS IN SLE ADVOCATES THE CLINICAL USE OF NEUTRALIZING ANTI-TYPE I IFN RECEPTOR ANTIBODIES AS A THERAPEUTIC STRATEGY, WITH CLINICAL STUDIES ALREADY SHOWING PROMISING RESULTS. CURRENT AND FUTURE CLINICAL TRIALS WILL DETERMINE WHETHER DRUGS TARGETING MOLECULES OF THE TYPE I IFN SIGNALING PATHWAY, LIKE NON-SELECTIVE JAK INHIBITORS OR SPECIFIC TYK2 INHIBITORS, MAY BENEFIT PEOPLE LIVING WITH LUPUS.	2021	
                                                                                                                                                                                                               
11  3381  23 HLA AND AUTOIMMUNE DISEASES: TYPE 1 DIABETES (T1D) AS AN EXAMPLE. AUTOIMMUNE DISEASES NEED TO BE CONSIDERED AT A GENETIC AND MECHANISTIC LEVEL. T1D IS AN AUTOIMMUNE, CHRONIC, MULTIFACTORIAL AND POLYGENIC DISEASE CHARACTERIZED BY THE DESTRUCTION OF THE PANCREATIC BETA-CELLS ASSOCIATED WITH LONG TERM DYSFUNCTION OF SEVERAL ORGANS AND TISSUES. MECHANISMS OF SUSCEPTIBILITY INCLUDE EPI-GENETIC AND POST-TRANSCRIPTIONAL EFFECTS THAT REGULATE TRANSMISSION AND EXPRESSION OF THE INHERITED GENES. THE HLA COMPLEX, CONSTITUTES THE MOST RELEVANT REGION CONTRIBUTING 50% OF THE INHERITED RISK FOR T1D. AN ADDITIONAL 17 GENES WITH VARIABLE BUT SMALL EFFECTS HAVE BEEN DESCRIBED. IN NON-CAUCASIANS, THE PRESENCE OF E-DRBETA1-74 AND/OR D-DRBETA1-57 ARE RELEVANT IN PREDISPOSITION. THE "DIABETOGENIC HAPLOTYPES" IN MEXICANS WERE DRB1*0301-DQA1*0501-DQB1*0201 (OR = 21.4); DRB1*0405-DQA1-*0301-DQB1*0302 (OR = 44.5) AND THE SAME DQA1/DQB1 WITH DRB1*0404/*0401 CONFERRING LOWER RISK, INCREASING (OR = 61.3) WITH AN EARLY AGE AT ONSET AND A HETEROZYGOTE DR3/DR4 GENOTYPE. IN MOST POPULATIONS, THE ABSENCE OF D-57 AND THE PRESENCE OF R-52 ARE IMPORTANT TO THE SUSCEPTIBILITY, BUT IN HISPANICS, ALL DR4S (INCLUDING THE PROTECTIVE DRB1*0403/*0407/*0411) ARE IN LINKAGE DISEQUILIBRIUM WITH DQA1/DQB1 SUSCEPTIBILITY ALLELES. THUS, SUSCEPTIBILITY ALLELES IN LATIN AMERICAN MESTIZOS ARE OF MEDITERRANEAN ANCESTRY WHEREAS PROTECTIVE ALLELES ARE OF AMERINDIAN ORIGIN. IN THIS REVIEW, WE DISCUSS THE COMPLEXITY OF T1D AND SOME ASPECTS OF PREVENTION/INTERVENTION BASED ON IMMUNOGENETICS.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12  1303  23 DEFECTIVE TRAINED IMMUNITY IN PATIENTS WITH STAT-1-DEPENDENT CHRONIC MUCOCUTANEAOUS CANDIDIASIS. PATIENTS WITH SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION-1 (STAT1)-DEPENDENT CHRONIC MUCOCUTANEOUS CANDIDIASIS (CMC) AND PATIENTS WITH STAT3-DEPENDENT HYPER-IMMUNOGLOBULIN (IG)E SYNDROME (HIES) DISPLAY DEFECTS IN T HELPER TYPE 17 (TH17) CYTOKINE PRODUCTION CAPACITY. DESPITE THIS SIMILAR IMMUNE DEFECT IN TH17 FUNCTION, THEY SHOW IMPORTANT DIFFERENCES IN THE TYPE OF INFECTIONS TO WHICH THEY ARE SUSCEPTIBLE. RECENTLY, OUR GROUP REPORTED DIFFERENTIAL REGULATION OF STAT-1 AND STAT-3 TRANSCRIPTION FACTORS DURING EPIGENETIC REPROGRAMMING OF TRAINED IMMUNITY, AN IMPORTANT HOST DEFENCE MECHANISM BASED ON INNATE IMMUNE MEMORY. WE THEREFORE HYPOTHESIZED THAT STAT1 AND STAT3 DEFECTS HAVE DIFFERENT EFFECTS ON TRAINED IMMUNITY, AND THIS MAY PARTLY EXPLAIN THE DIFFERENCES BETWEEN CMC AND HIES REGARDING THE SUSCEPTIBILITY TO INFECTIONS. INDEED, WHILE TRAINED IMMUNITY WAS NORMALLY INDUCED IN CELLS ISOLATED FROM PATIENTS WITH HIES, THE INDUCTION OF INNATE TRAINING WAS DEFECTIVE IN CMC PATIENTS. THIS DEFECT WAS SPECIFIC FOR TRAINING WITH CANDIDA ALBICANS, THE MAIN PATHOGEN ENCOUNTERED IN CMC, AND IT INVOLVED A TYPE II INTERFERON-DEPENDENT MECHANISM. THESE FINDINGS DESCRIBE THE ROLE OF STAT-1 FOR THE INDUCTION OF TRAINED IMMUNITY, AND MAY CONTRIBUTE TO THE UNDERSTANDING OF THE DIFFERENCES IN SUSCEPTIBILITY TO INFECTION BETWEEN CMC AND HIES PATIENTS. THIS STUDY COULD ALSO PROVIDE DIRECTIONS FOR PERSONALIZED IMMUNOTHERAPY IN PATIENTS SUFFERING FROM THESE IMMUNODEFICIENCIES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  4005  18 LOSS OF THE TUMOR SUPPRESSOR BAP1 CAUSES MYELOID TRANSFORMATION. DE-UBIQUITINATING ENZYME BAP1 IS MUTATED IN A HEREDITARY CANCER SYNDROME WITH INCREASED RISK OF MESOTHELIOMA AND UVEAL MELANOMA. SOMATIC BAP1 MUTATIONS OCCUR IN VARIOUS MALIGNANCIES. WE SHOW THAT MOUSE BAP1 GENE DELETION IS LETHAL DURING EMBRYOGENESIS, BUT SYSTEMIC OR HEMATOPOIETIC-RESTRICTED DELETION IN ADULTS RECAPITULATES FEATURES OF HUMAN MYELODYSPLASTIC SYNDROME (MDS). KNOCKIN MICE EXPRESSING BAP1 WITH A 3XFLAG TAG REVEALED THAT BAP1 INTERACTS WITH HOST CELL FACTOR-1 (HCF-1), O-LINKED N-ACETYLGLUCOSAMINE TRANSFERASE (OGT), AND THE POLYCOMB GROUP PROTEINS ASXL1 AND ASXL2 IN VIVO. OGT AND HCF-1 LEVELS WERE DECREASED BY BAP1 DELETION, INDICATING A CRITICAL ROLE FOR BAP1 IN STABILIZING THESE EPIGENETIC REGULATORS. HUMAN ASXL1 IS MUTATED FREQUENTLY IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) SO AN ASXL/BAP1 COMPLEX MAY SUPPRESS CMML. A BAP1 CATALYTIC MUTATION FOUND IN A MDS PATIENT IMPLIES THAT BAP1 LOSS OF FUNCTION HAS SIMILAR CONSEQUENCES IN MICE AND HUMANS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
14  5371  22 RECENT ADVANCES IN UNDERSTANDING THE GENETIC BASIS OF SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A POLYGENIC CHRONIC AUTOIMMUNE DISEASE LEADING TO MULTIPLE ORGAN DAMAGE. A LARGE HERITABILITY OF UP TO 66% IS ESTIMATED IN SLE, WITH ROUGHLY 180 REPORTED SUSCEPTIBILITY LOCI THAT HAVE BEEN IDENTIFIED MOSTLY BY GENOME-WIDE ASSOCIATION STUDIES (GWASS) AND ACCOUNT FOR APPROXIMATELY 30% OF GENETIC HERITABILITY. A VAST MAJORITY OF RISK VARIANTS RESIDE IN NON-CODING REGIONS, WHICH MAKES IT QUITE CHALLENGING TO INTERPRET THEIR FUNCTIONAL IMPLICATIONS IN THE SLE-AFFECTED IMMUNE SYSTEM, SUGGESTING THE IMPORTANCE OF UNDERSTANDING CELL TYPE-SPECIFIC EPIGENETIC REGULATION AROUND SLE GWAS VARIANTS. THE LATEST GENETIC STUDIES HAVE BEEN HIGHLY FRUITFUL AS SEVERAL DOZENS OF SLE LOCI WERE NEWLY DISCOVERED IN THE LAST FEW YEARS AND MANY LOCI HAVE COME TO BE UNDERSTOOD IN SYSTEMIC APPROACHES INTEGRATING GWAS SIGNALS WITH OTHER BIOLOGICAL RESOURCES. IN THIS REVIEW, WE SUMMARIZE SLE-ASSOCIATED GENETIC VARIANTS IN BOTH THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) AND NON-MHC LOCI, EXAMINING POLYGENETIC RISK SCORES FOR SLE AND THEIR ASSOCIATIONS WITH CLINICAL FEATURES. FINALLY, VARIANT-DRIVEN PATHOGENETIC FUNCTIONS UNDERLYING GENETIC ASSOCIATIONS ARE DESCRIBED, COUPLED WITH DISCUSSION ABOUT CHALLENGES AND FUTURE DIRECTIONS IN GENETIC STUDIES ON SLE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15  1477  23 DIVERSE PHENOTYPIC EXPRESSION OF NPHP4 MUTATIONS IN FOUR SIBLINGS. NEPHRONOPHTHISIS (NPHP) IS AN AUTOSOMAL RECESSIVE DISEASE CHARACTERIZED BY RENAL TUBULAR BASEMENT MEMBRANE DISRUPTION, INTERSTITIAL FIBROSIS AND TUBULAR CYSTS THAT PROGRESSES TO END-STAGE KIDNEY DISEASE (ESKD). THERE ARE ALSO CHARACTERISTIC EXTRARENAL MANIFESTATIONS. MUTATIONS OF MORE THAN THIRTEEN GENES THAT CAN CAUSE NPHP HAVE BEEN IDENTIFIED. WE HEREIN REPORT FOUR SIBLINGS FROM A CONSANGUINEOUS FAMILY, WHO CARRIED THE SAME NPHP4 MUTATIONS BUT PRESENTED WITH DIFFERENT DISEASE PHENOTYPES RANGING FROM ENURESIS NOCTURNA TO ESKD. DILUTED URINE AND ECHOGENIC KIDNEYS IN ULTRASOUND EXAMINATION WERE CONSISTENT, WHICH IS TYPICAL FOR 100% OF THE NPHP CASES THAT HAVE BEEN DESCRIBED. CHRONIC KIDNEY DISEASE DEVELOPED IN THE OLDER TWO BROTHERS. THE OBSERVED PHENOTYPIC DIFFERENCES ARE LIKELY TO BE RELATED TO ENVIRONMENTAL AND EPIGENETIC FACTORS, OLIGOGENIC INHERITANCE AND MODIFIER GENES AFFECTING THE AGE OF PRESENTATION OF SIGNS AND SYMPTOMS. NPHP SHOULD BE CONSIDERED AS AN IMPORTANT CAUSE OF CKD IN CHILDREN, WHICH INSIDIOUSLY PROGRESSES TO ESKD, WITH NO SPECIFIC THERAPY AVAILABLE.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
16  4570  20 MYELOMONOCYTIC CELLS IN GIANT CELL ARTERITIS ACTIVATE TRAINED IMMUNITY PROGRAMS SUSTAINING INFLAMMATION AND CYTOKINE PRODUCTION. OBJECTIVE: TRAINED IMMUNITY (TI) IS A DE FACTO MEMORY PROGRAM OF INNATE IMMUNE CELLS, CHARACTERIZED BY IMMUNOMETABOLIC AND EPIGENETIC CHANGES SUSTAINING ENHANCED PRODUCTION OF CYTOKINES. TI EVOLVED AS A PROTECTIVE MECHANISM AGAINST INFECTIONS; HOWEVER, INAPPROPRIATE ACTIVATION CAN CAUSE DETRIMENTAL INFLAMMATION AND MIGHT BE IMPLICATED IN THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES. IN THIS STUDY, WE INVESTIGATED THE ROLE OF TI IN THE PATHOGENESIS OF GIANT CELL ARTERITIS (GCA), A LARGE-VESSEL VASCULITIS CHARACTERIZED BY ABERRANT MACROPHAGE ACTIVATION AND EXCESS CYTOKINE PRODUCTION. METHODS: MONOCYTES FROM GCA PATIENTS AND FROM AGE- AND SEX-MATCHED HEALTHY DONORS WERE SUBJECTED TO POLYFUNCTIONAL STUDIES, INCLUDING CYTOKINE PRODUCTION ASSAYS AT BASELINE AND FOLLOWING STIMULATION, INTRACELLULAR METABOLOMICS, CHROMATIN IMMUNOPRECIPITATION-QPCR, AND COMBINED ATAC/RNA SEQUENCING. IMMUNOMETABOLIC ACTIVATION (I.E. GLYCOLYSIS) WAS ASSESSED IN INFLAMED VESSELS OF GCA PATIENTS WITH FDG-PET AND IMMUNOHISTOCHEMISTRY (IHC), AND THE ROLE OF THIS PATHWAY IN SUSTAINING CYTOKINE PRODUCTION WAS CONFIRMED WITH SELECTIVE PHARMACOLOGIC INHIBITION IN GCA MONOCYTES. RESULTS: GCA MONOCYTES EXHIBITED HALLMARK MOLECULAR FEATURES OF TI. SPECIFICALLY, THESE INCLUDED ENHANCED IL-6 PRODUCTION UPON STIMULATION, TYPICAL IMMUNOMETABOLIC CHANGES (E.G. INCREASED GLYCOLYSIS AND GLUTAMINOLYSIS) AND EPIGENETIC CHANGES PROMOTING ENHANCED TRANSCRIPTION OF GENES GOVERNING PRO-INFLAMMATORY ACTIVATION. IMMUNOMETABOLIC CHANGES OF TI (I.E. GLYCOLYSIS) WERE A FEATURE OF MYELOMONOCYTIC CELLS IN GCA LESIONS AND WERE REQUIRED FOR ENHANCED CYTOKINE PRODUCTION. CONCLUSIONS: MYELOMONOCYTIC CELLS IN GCA ACTIVATE TI PROGRAMS SUSTAINING ENHANCED INFLAMMATORY ACTIVATION WITH EXCESS CYTOKINE PRODUCTION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17   565  11 BASAL INSTINCT: PERSISTENCE OF BARRIER DYSFUNCTION. IN A RECENT ISSUE OF NATURE, ORDOVAS-MONTANES ET AL. (2018) USED CUTTING-EDGE GENOMIC, EPIGENETIC, AND INTERVENTIONAL TECHNIQUES TO CHARACTERIZE THE CELLULAR ECOSYSTEM IN ALLERGIC CHRONIC RHINOSINUSITIS. THEY SHOWED THAT BASAL EPITHELIAL CELLS "REMEMBER" TYPE 2 INFLAMMATORY STIMULI TO MAINTAIN A CHRONIC ALLERGIC DISEASE PHENOTYPE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
18   117  29 A STUDY ON NUTRITIONAL STATUS AND TOOTH CROWN SIZE AMONG 6-9-YEAR-OLD CHILDREN: AN OBSERVATIONAL CROSS-SECTIONAL STUDY. BACKGROUND: NUMEROUS FACTORS CONTRIBUTE TO VARIATION IN TOOTH SIZE. THIS IS BROADLY DESCRIBED AS GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. A STRONG GENETIC CONTRIBUTION HAS BEEN SHOWN, BUT ENVIRONMENTAL FACTORS MAY ALSO PLAY A ROLE. AIM: THE AIM OF THIS STUDY WAS TO DETERMINE THE RELATIONSHIP BETWEEN NUTRITIONAL STATUS AND TOOTH CROWN SIZE. DESIGN: AN OBSERVATIONAL CROSS-SECTIONAL SURVEY WAS CONDUCTED AMONG 100 SCHOOL-GOING CHILDREN OF 6-9 YEARS. THE VALUE OBTAINED WAS PLOTTED ON AGE- AND GENDER-SPECIFIC PERCENTILE CURVES CHART GIVEN BY THE CENTERS FOR DISEASE CONTROL AND PREVENTION; INDIVIDUALS WERE CATEGORIZED BASED ON BODY MASS INDEX CRITERIA. THE PARTICIPANTS WERE EXAMINED FOR THE MESIODISTAL WIDTH OF PRIMARY SECOND MOLAR AND PERMANENT FIRST MOLAR BY THREE DIFFERENT OBSERVERS USING A VERNIER CALIPER. DATA OBTAINED WERE STATISTICALLY ANALYZED. RESULTS: TOTAL OF 45, 40, AND 15 BELONGED TO UNDERWEIGHT, NORMAL, AND OVERWEIGHT CATEGORY, RESPECTIVELY. THE TOOTH SIZE OF PRIMARY MOLAR BETWEEN HEALTHY, OVERWEIGHT, AND UNDERWEIGHT CHILDREN WAS 9.87 +/- 0.23, 9.47 +/- 0.48, AND 9.61 +/- 0.7, RESPECTIVELY, AND FOR PERMANENT MOLAR BETWEEN HEALTHY, OVERWEIGHT, AND UNDERWEIGHT CHILDREN WAS 10.63 +/- 0.2, 10.56 +/- 0.5, AND 10.57 +/- 0.6, RESPECTIVELY. CONCLUSION: THE CORRELATION BETWEEN TOOTH CROWN SIZE WITH AN EXOGENOUS CHRONIC STRESSOR, I.E., MALNUTRITION, WAS FOUND TO BE NONSIGNIFICANT WHEN COMPARED WITH THE HEALTHY INDIVIDUALS. THE FINDINGS INDICATE THAT NUTRITIONAL STATUS DOES NOT SIGNIFICANTLY INFLUENCE THE DETERMINATION OF TOOTH SIZE IN HUMANS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
19  6196  20 THE IMPACT OF THE TH17:TREG AXIS ON THE IGA-BIOME ACROSS THE GLYCEMIC SPECTRUM. SECRETORY IGA (SIGA) IS RELEASED INTO MUCOSAL SURFACES WHERE ITS FUNCTION EXTENDS BEYOND THAT OF HOST DEFENSE TO INCLUDE THE SHAPING OF RESIDENT MICROBIAL COMMUNITIES BY MEDIATING EXCLUSION/INCLUSION OF RESPECTIVE MICROBES AND REGULATING BACTERIAL GENE EXPRESSION. IN THIS CAPACITY, SIGA ACTS AS THE FULCRUM ON WHICH HOST IMMUNITY AND THE HEALTH OF THE MICROBIOTA ARE BALANCED. WE RECENTLY COMPLETED AN ANALYSIS OF THE GUT AND SALIVARY IGA-BIOMES (16S RDNA SEQUENCING OF SIGA-COATED/UNCOATED BACTERIA) IN MEXICAN-AMERICAN ADULTS THAT IDENTIFIED IGA-BIOME DIFFERENCES ACROSS THE GLYCEMIC SPECTRUM. AS TH17:TREG RATIO IMBALANCES ARE ASSOCIATED WITH GUT MICROBIOME DYSBIOSIS AND CHRONIC INFLAMMATORY CONDITIONS SUCH AS TYPE 2 DIABETES, THE PRESENT STUDY EXTENDS OUR PRIOR WORK BY EXAMINING THE IMPACT OF TH17:TREG RATIOS (PRO-INFLAMMATORY:ANTI-INFLAMMATORY T-CELL RATIOS) AND THE SIGA RESPONSE (TH17:TREG-SIGA AXIS) IN SHAPING MICROBIAL COMMUNITIES. EXAMINING THE IMPACT OF TH17:TREG RATIOS (DETERMINED BY EPIGENETIC QPCR LYMPHOCYTE SUBSET QUANTIFICATION) ON THE IGA-BIOME ACROSS DIABETES PHENOTYPES IDENTIFIED A PROPORTIONAL RELATIONSHIP BETWEEN TH17:TREG RATIOS AND ALPHA DIVERSITY IN THE STOOL IGA-BIOME OF THOSE WITH DYSGLYCEMIA, SIGNIFICANT CHANGES IN COMMUNITY COMPOSITION OF THE STOOL AND SALIVARY MICROBIOMES ACROSS GLYCEMIC PROFILES, AND GENERA PREFERENTIALLY ABUNDANT BY T-CELL INFLAMMATORY PHENOTYPE. THIS IS THE FIRST STUDY TO ASSOCIATE EPIGENETICALLY QUANTIFIED TH17:TREG RATIOS WITH BOTH THE LARGER AND SIGA-FRACTIONATED MICROBIOME, ASSESS THESE ASSOCIATIONS IN THE CONTEXT OF A CHRONIC INFLAMMATORY DISEASE, AND OFFERS A NOVEL FRAME THROUGH WHICH TO EVALUATE MUCOSAL MICROBIOMES IN THE CONTEXT OF HOST RESPONSES AND INFLAMMATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20   991  19 CHRONIC STIMULATION DRIVES HUMAN NK CELL DYSFUNCTION AND EPIGENETIC REPROGRAMING. A POPULATION OF NATURAL KILLER (NK) CELLS EXPRESSING THE ACTIVATING RECEPTOR NKG2C AND THE MATURATION MARKER CD57 EXPANDS IN RESPONSE TO HUMAN CYTOMEGALOVIRUS (HCMV) INFECTION. CD3-CD56DIMCD57+NKG2C+ NK CELLS ARE SIMILAR TO CD8+ MEMORY T CELLS WITH RAPID AND ROBUST EFFECTOR FUNCTION UPON RE-STIMULATION, PERSISTENCE, AND EPIGENETIC REMODELING OF THE IFNG LOCUS. CHRONIC ANTIGEN STIMULATION DRIVES CD8+ MEMORY T CELL PROLIFERATION WHILE ALSO INDUCING GENOME-WIDE EPIGENETIC REPROGRAMING AND DYSFUNCTION. WE HYPOTHESIZED THAT CHRONIC STIMULATION COULD SIMILARLY INDUCE EPIGENETIC REPROGRAMING AND DYSFUNCTION IN NK CELLS. HERE WE SHOW THAT CHRONIC STIMULATION OF ADAPTIVE NK CELLS THROUGH NKG2C USING PLATE-BOUND AGONISTIC ANTIBODIES IN COMBINATION WITH IL-15 DROVE ROBUST PROLIFERATION AND ACTIVATION OF CD3-CD56DIMCD57+NKG2C+ NK CELLS WHILE SIMULTANEOUSLY INDUCING HIGH EXPRESSION OF THE CHECKPOINT INHIBITORY RECEPTORS LAG-3 AND PD-1. MARKED INDUCTION OF CHECKPOINT INHIBITORY RECEPTORS WAS ALSO OBSERVED ON THE SURFACE OF ADAPTIVE NK CELLS CO-CULTURED WITH HCMV-INFECTED ENDOTHELIAL CELLS. CHRONICALLY STIMULATED ADAPTIVE NK CELLS WERE DYSFUNCTIONAL WHEN CHALLENGED WITH TUMOR TARGETS. THESE CELLS EXHIBITED A PATTERN OF EPIGENETIC REPROGRAMING, WITH GENOME-WIDE ALTERATIONS IN DNA METHYLATION. OUR STUDY HAS IMPORTANT IMPLICATIONS FOR CANCER IMMUNOTHERAPY AND SUGGEST THAT EXHAUSTED NK CELLS COULD BE TARGETED WITH INHIBITORY CHECKPOINT RECEPTOR BLOCKADE.	2019