1  5663 95 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2  3900 29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3  5512 26 RICHTER SYNDROME IN CHRONIC LYMPHOCYTIC LEUKEMIA: UPDATES ON BIOLOGY, CLINICAL FEATURES AND THERAPY. RICHTER SYNDROME (RS) OR RICHTER TRANSFORMATION IS THE DEVELOPMENT OF SECONDARY AGGRESSIVE LYMPHOMA IN THE SETTING OF UNDERLYING CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA (CLL/SLL). MOST FREQUENTLY CLL TRANSFORMS INTO DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) (90%) AND RARELY (10%) INTO HODGKIN LYMPHOMA, TERMED HODGKIN VARIANT OF RICHTER SYNDROME (HVRS). RS IS GENERALLY CHARACTERIZED BY AN AGGRESSIVE CLINICAL COURSE AND POOR PROGNOSIS. IN RECENT YEARS, MAJOR ADVANCES HAVE BEEN MADE IN UNDERSTANDING GENETIC EVENTS WHICH RELATE TO THE PROGRESSION OF CLL OR TRANSFORMATION INTO RS. BETTER UNDERSTANDING OF THE MOLECULAR PATHWAYS HAS REVEALED THAT RS IS NOT A SINGLE HOMOGENEOUS ENTITY. THE MAJORITY OF CASES ARE CLONALLY RELATED TO THE ORIGINAL CLL CLONE, WHILE A MINORITY DEVELOP FROM AN UNRELATED CLONE. THIS REVIEW SUMMARIZES NEW DATA RELATING TO THE MOLECULAR BIOLOGY AND THE GENETIC/EPIGENETIC CHANGES OCCURRING DURING RICHTER TRANSFORMATION, AND ALSO CONSIDERS THE CLINICAL FEATURES AND THERAPY FOR BOTH DLBCL-RS AND HODGKIN VARIANT-RS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
4    31 22 A CASE OF INFECTION-ASSOCIATED ANTIPROTEINASE-3-NEGATIVE CYTOPLASMIC ANTINEUTROPHIL CYTOPLASMIC ANTIBODY PAUCI-IMMUNE FOCAL NECROTIZING GLOMERULONEPHRITIS. WE PRESENT THE CASE OF A MAN WITH GRAM-NEGATIVE SEPSIS AND EXPOSURE TO ORAL SILICA WHO DEVELOPED PAUCI-IMMUNE FOCAL NECROTIZING GLOMERULONEPHRITIS (PI-FNGN) IN THE SETTING OF A SUBACUTE POLYMICROBIAL CENTRAL VENOUS LINE (CVL) INFECTION. HE DEVELOPED A CYTOPLASMIC ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODY (C-ANCA) THAT WAS ANTIPROTEINASE-3 (PR-3) AND ANTIMYELOPEROXIDASE (MPO) ANTIBODY NEGATIVE. WE BELIEVE THIS IS THE FIRST REPORTED CASE OF GRAM-NEGATIVE SEPSIS-ASSOCIATED PI-FNGN. CHRONIC SILICA EXPOSURE IS A LEADING ENVIRONMENTAL RISK FACTOR IN THE DEVELOPMENT OF ANCA VASCULITIS. ORAL SILICA IS A COMMON PHARMACEUTICAL ADDITIVE AND ITS BIOAVAILABILITY IS BEING RECOGNIZED. ORAL SILICA, THEREFORE, MAY ALSO BE A RISK FOR DEVELOPMENT OF AUTOREACTIVITY. THE PI-FNGN RESOLVED WITH ANTIBIOTIC THERAPY ALONE. THE C-ANCA TITER DECLINED AS THE PI-FNGN RESOLVED. THE CASE SUPPORTS EXPERIMENTAL AND OBSERVATIONAL RESEARCH THAT ENVIRONMENTAL EXPOSURES ACT AS ADJUVANTS FOR AN IMMUNE RESPONSE AND ALSO PROVIDE EPIGENETIC TRIGGERS FOR AUTOREACTIVITY. THE C-ANCA WAS NEGATIVE FOR PR-3, ITS MAJOR ANTIGEN. C-ANCA ANTIGEN SPECIFICITY MAY DEPEND ON THE PATHOGENESIS OF THE UNDERLYING DISEASE, POTENTIALLY ELICITED BY A CROSS-REACTION OF AN ANTIBODY TO FOREIGN AND SELF TARGET ANTIGEN SEQUENCE HOMOLOGY OR ALTERNATIVELY ELICITED BY ANTIGENIC EPITOPE SPREAD.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
5  6769 17 ["EDUCATION" IN AN AGE OF INCREASING EQUALITY--A PATH TOWARDS 'OCHLOCRACY"?]. A PHILOSOPHICAL AND SCIENTIFIC ANALYSIS OF HOW THE CONCEPT OF EQUALITY HAS DEVELOPED FROM BIOLOGICAL, POLITICAL, SOCIOLOGICAL, SOCIAL, ECONOMIC AND--NOT LEAST--CULTURAL POINTS OF VIEW. THE FOCUS HERE IS ON THE GERMAN CHRONIC SHORTAGE OF EDUCATIONAL FACILITIES CONTINUING FOR DECADES, A CULTURAL REVOLUTION WITHOUT ANY FORESEEABLE END. THESE REFLECTIONS ENCOMPASS A PERIOD OF AROUND TWO AND A HALF MILLENNIA, BEGINNING WITH THE ANCIENT GREEK STATE PHILOSOPHY, REACHING INTO OUR EPOCH OF ADVANCED GLOBALISATION WITH MOMENTOUS CHANGES IN WESTERN SOCIAL WELFARE STATES. IN CONSIDERATION OF A BIOCHEMICAL AND INTRINSIC INDIVIDUALITY BASED ON GENETIC AND EPI-GENETIC FACTORS, EQUAL OPPORTUNITIES ARE AN UNLIKELY PREREQUISITE IN EVOLUTION. WITH REGARD TO FREE EDUCATION, EQUALITY CAN ONLY BE A STARTING POINT SINCE, DUE TO INDIVIDUAL DIFFERENCES, EGALITARIAN AIMS OF EDUCATION WITHIN A "GROUP UNIVERSITY" CAN NEVER OPEN UP EQUALLY GOOD CHANCES TO EVERYBODY. BECAUSE OF A MISUNDERSTANDING OF EQUALITY, THE STUDENT REVOLT IN 1968 BROUGHT FORTH AN EGALITARIAN REMODELING OF SCHOOL AND UNIVERSITY CAREERS ACCOMPANIED BY A LEVELING, AMONG OTHER THINGS A "UNIVERSITY OF EDUCATION FOR THE MASSES". INSTEAD OF "EDUCATIONAL KNOWLEDGE" BASED ON SCIENTIFIC NATURE, AN EDUCATION TOWARDS VOCATIONAL KNOWLEDGE AND REGULATION OF STUDIES TOOK PLACE. AT PRESENT, A SOCIALISTIC REVERSAL OF THE SCHOOL SYSTEM AIMED AT LEARNING TOGETHER IN ,COMMUNITY SCHOOLS" UNTIL THE 10TH GRADE IS IN PROGRESS. THE UNITY OF (PURE) RESEARCH AND TEACHING NO LONGER EXISTS. THE CHANGE IN THE SYSTEM SUPPORTED BY A WELFARE STATE WILL HAVE CONSEQUENCES IN WORLDWIDE COMPETITION. THE FINAL POINT OF THE CULTURAL REVOLUTION, FOLLOWING HISTORICAL EXAMPLES, COULD BE THE EMERGENCE OF A DEGENERATE FORM OF DEMOCRACY: OCHLOCRACY.	2012	
                                                                                                                                                                                                                                      
6  5763 16 SOME COMMENTS ON MASOCHISM AND THE DELUSION OF OMNIPOTENCE FROM A DEVELOPMENTAL PERSPECTIVE. THIS PAPER EXPLORES THE RELATION OF THE DELUSION OF OMNIPOTENCE TO MASOCHISM AND SUGGESTS THAT THIS FANTASY CONSTITUTES A MAJOR COMPONENT OF THE RESISTANCE SO PROMINENT IN WORK WITH MASOCHISTIC PATIENTS. THE CONNECTIONS AMONG MASOCHISM, OMNIPOTENCE, NEGATIVE THERAPEUTIC REACTION, AND CLINGING TO PAIN ARE DISCUSSED. THE CLASSICAL VIEW HAS BEEN THAT THE FAILURE OF INFANTILE OMNIPOTENCE FORCES THE CHILD TO TURN TO REALITY. OUR EXPERIENCE WITH MASOCHISTIC PATIENTS SUGGESTS THAT IT IS THE REAL FAILURE TO ACHIEVE COMPETENT INTERACTIONS WITH OTHERS THAT FORCES THE CHILD TO TURN TO OMNIPOTENT SOLUTIONS. THE DISTINCTION IS MADE BETWEEN FANTASIES THAT ENHANCE THE REAL CAPACITIES OF THE SELF AND THOSE AIMED AT DENYING AND TRANSFORMING THE PAIN AND INADEQUACY OF THE MOTHER-CHILD RELATIONSHIP. THE EPIGENETIC TRANSFORMATIONS OF OMNIPOTENT FANTASIES THROUGH ALL LEVELS OF DEVELOPMENT ARE DESCRIBED. THE PATIENT'S NEED TO PROTECT THE OMNIPOTENT FANTASY IS DISCUSSED IN RELATION TO RESISTANCE AT EACH PHASE OF ANALYSIS.	1991	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
7  3009 21 GENETICS AND EPIGENETICS IN NEOPLASMS WITH PLASMACYTOID DENDRITIC CELLS. PLASMACYTOID DENDRITIC CELLS (PDC) ARE TYPE I INTERFERON (IFN)-PRODUCING CELLS THAT PLAY A KEY ROLE IN IMMUNE RESPONSES. TWO MAJOR TYPES OF NEOPLASTIC COUNTERPARTS FOR PDC ARE NOW DISCRIMINATED: BLASTIC PDC NEOPLASM (BPDCN) AND MATURE PDC PROLIFERATION (MPDCP), ASSOCIATED WITH MYELOID NEOPLASM. TWO TYPES OF MPDCP ARE NOW BETTER DESCRIBED: CHRONIC MYELOMONOCYTIC LEUKEMIA WITH PDC EXPANSION (PDC-CMML) AND ACUTE MYELOID LEUKEMIA WITH PDC EXPANSION (PDC-AML). DIFFERENTIAL DIAGNOSIS BETWEEN PDC-AML AND BPDCN IS PARTICULARLY CHALLENGING, AND GENOMIC FEATURES CAN HELP FOR DIAGNOSIS. HERE, WE SYSTEMATICALLY REVIEW THE CYTOGENETIC, MOLECULAR, AND TRANSCRIPTIONAL CHARACTERISTICS OF BPDCN AND PDC-AML. BPDCN ARE CHARACTERIZED BY FREQUENT COMPLEX KARYOTYPES WITH RECURRENT MYB/MYC REARRANGEMENTS AS WELL AS RECURRENT DELETIONS INVOLVING ETV6, IKZF1, RB1, AND TP53 LOCI. EPIGENETIC AND SPLICING PATHWAYS ARE ALSO PARTICULARLY MUTATED, WHILE ORIGINAL PROCESSES ARE DYSREGULATED, SUCH AS NF-KB, TCF4, BCL2, AND IFN PATHWAYS; NEUTROPHIL-SPECIFIC RECEPTORS; AND CHOLINERGIC SIGNALING. IN CONTRAST, CYTOGENETIC ABNORMALITIES ARE LIMITED IN PDC-AML AND ARE QUITE SIMILAR TO OTHER AML. INTERESTINGLY, RUNX1 IS THE MOST FREQUENTLY MUTATED GENE (70% OF CASES). THESE TYPICAL GENOMIC FEATURES ARE OF POTENTIAL INTEREST FOR DIAGNOSIS, AND ALSO FROM A PROGNOSTIC OR THERAPEUTIC PERSPECTIVE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8  3500 30 IDENTIFICATION OF NOVEL, CLONALLY STABLE, SOMATIC MUTATIONS TARGETING TRANSCRIPTION FACTORS PAX5 AND NKX2-3, THE EPIGENETIC REGULATOR LRIF1, AND BRAF IN A CASE OF ATYPICAL B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA HARBORING A T(14;18)(Q32;Q21). DIAGNOSIS OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) IS USUALLY STRAIGHTFORWARD, INVOLVING CLINICAL, IMMUNOPHENOTYPIC (MATUTES SCORE), AND (IMMUNO)GENETIC ANALYSES (TO REFINE PATIENT PROGNOSIS FOR TREATMENT). CLL CASES WITH ATYPICAL PRESENTATION (E.G., MATUTES </= 3) ARE ALSO ENCOUNTERED, AND FOR THESE DISEASES, BIOLOGY AND PROGNOSTIC IMPACT ARE LESS CLEAR. HERE WE REPORT THE GENOMIC CHARACTERIZATION OF A CASE OF ATYPICAL B-CLL IN A 70-YR-OLD MALE PATIENT; B-CLL CELLS SHOWED A MATUTES SCORE OF 3, CHROMOSOMAL TRANSLOCATION T(14;18)(Q32;Q21) (BCL2/IGH), MUTATED IGHV, DELETION 17P, AND MUTATIONS IN BCL2, NOTCH1 (SUBCLONAL), AND TP53 (SUBCLONAL). QUITE STRIKINGLY, A NOVEL PAX5 MUTATION THAT WAS PREDICTED TO BE LOSS OF FUNCTION WAS ALSO SEEN. EXOME SEQUENCING IDENTIFIED, IN ADDITION, A POTENTIALLY ACTIONABLE BRAF MUTATION, TOGETHER WITH NOVEL SOMATIC MUTATIONS AFFECTING THE HOMEOBOX TRANSCRIPTION FACTOR NKX2-3, KNOWN TO CONTROL B-LYMPHOCYTE DEVELOPMENT AND HOMING, AND THE EPIGENETIC REGULATOR LRIF1, WHICH IS IMPLICATED IN CHROMATIN COMPACTION AND GENE SILENCING. NEITHER NKX2-3 NOR LRIF1 MUTATIONS, PREDICTED TO BE LOSS OF FUNCTION, HAVE PREVIOUSLY BEEN REPORTED IN B-CLL. SEQUENCING CONFIRMED THE PRESENCE OF THESE MUTATIONS TOGETHER WITH BCL2, NOTCH1, AND BRAF MUTATIONS, WITH THE T(14;18)(Q32;Q21) TRANSLOCATION, IN THE INITIAL DIAGNOSTIC SAMPLE OBTAINED 12 YR PRIOR. THIS IS SUGGESTIVE OF A ROLE FOR THESE NOVEL MUTATIONS IN B-CLL INITIATION AND STABLE CLONAL EVOLUTION, INCLUDING UPON TREATMENT WITHDRAWAL. THIS CASE EXTENDS THE SPECTRUM OF ATYPICAL B-CLL WITH T(14;18)(Q32;Q21) AND HIGHLIGHTS THE VALUE OF MORE GLOBAL PRECISION GENOMICS FOR PATIENT FOLLOW-UP AND TREATMENT IN THESE PATIENTS.	2021	
                                                                                                                                      
9  2819 16 FILARIAL AND WOLBACHIA GENOMICS. FILARIAL NEMATODE PARASITES, THE CAUSATIVE AGENTS FOR A SPECTRUM OF ACUTE AND CHRONIC DISEASES INCLUDING LYMPHATIC FILARIASIS AND RIVER BLINDNESS, THREATEN THE WELL-BEING AND LIVELIHOOD OF HUNDREDS OF MILLIONS OF PEOPLE IN THE DEVELOPING REGIONS OF THE WORLD. THE 2007 PUBLICATION ON A DRAFT ASSEMBLY OF THE 95-MB GENOME OF THE HUMAN FILARIAL PARASITE BRUGIA MALAYI- REPRESENTING THE FIRST HELMINTH PARASITE GENOME TO BE SEQUENCED - HAS BEEN FOLLOWED IN RAPID SUCCESSION BY PROJECTS THAT HAVE RESULTED IN THE GENOME SEQUENCING OF SIX ADDITIONAL FILARIAL SPECIES, SEVEN NONFILARIAL NEMATODE PARASITES OF ANIMALS AND NEARLY 30 PLANT PARASITIC AND FREE-LIVING SPECIES. PARALLEL TO THE GENOMIC SEQUENCING, TRANSCRIPTOMIC AND PROTEOMIC PROJECTS HAVE FACILITATED GENOME ANNOTATION, EXPANDED OUR UNDERSTANDING OF STAGE-ASSOCIATED GENE EXPRESSION AND PROVIDED A FIRST LOOK AT THE ROLE OF EPIGENETIC REGULATION OF FILARIAL GENOMES THROUGH MICRORNAS. THE EXPANSION IN FILARIAL GENOMICS WILL ALSO PROVIDE A SIGNIFICANT ENRICHMENT IN OUR KNOWLEDGE OF THE DIVERSITY AND VARIABILITY IN THE GENOMES OF THE ENDOSYMBIOTIC BACTERIUM WOLBACHIA LEADING TO A BETTER UNDERSTANDING OF THE GENETIC PRINCIPLES THAT GOVERN FILARIAL-WOLBACHIA MUTUALISM. THE GOAL HERE IS TO PROVIDE AN OVERVIEW OF THE TRENDS AND ADVANCES IN FILARIAL AND WOLBACHIA GENOMICS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10  5853 21 SUBSETS OF EXHAUSTED CD8(+) T CELLS DIFFERENTIALLY MEDIATE TUMOR CONTROL AND RESPOND TO CHECKPOINT BLOCKADE. T CELL DYSFUNCTION IS A HALLMARK OF MANY CANCERS, BUT THE BASIS FOR T CELL DYSFUNCTION AND THE MECHANISMS BY WHICH ANTIBODY BLOCKADE OF THE INHIBITORY RECEPTOR PD-1 (ANTI-PD-1) REINVIGORATES T CELLS ARE NOT FULLY UNDERSTOOD. HERE WE SHOW THAT SUCH THERAPY ACTS ON A SPECIFIC SUBPOPULATION OF EXHAUSTED CD8(+) TUMOR-INFILTRATING LYMPHOCYTES (TILS). DYSFUNCTIONAL CD8(+) TILS POSSESS CANONICAL EPIGENETIC AND TRANSCRIPTIONAL FEATURES OF EXHAUSTION THAT MIRROR THOSE SEEN IN CHRONIC VIRAL INFECTION. EXHAUSTED CD8(+) TILS INCLUDE A SUBPOPULATION OF 'PROGENITOR EXHAUSTED' CELLS THAT RETAIN POLYFUNCTIONALITY, PERSIST LONG TERM AND DIFFERENTIATE INTO 'TERMINALLY EXHAUSTED' TILS. CONSEQUENTLY, PROGENITOR EXHAUSTED CD8(+) TILS ARE BETTER ABLE TO CONTROL TUMOR GROWTH THAN ARE TERMINALLY EXHAUSTED T CELLS. PROGENITOR EXHAUSTED TILS CAN RESPOND TO ANTI-PD-1 THERAPY, BUT TERMINALLY EXHAUSTED TILS CANNOT. PATIENTS WITH MELANOMA WHO HAVE A HIGHER PERCENTAGE OF PROGENITOR EXHAUSTED CELLS EXPERIENCE A LONGER DURATION OF RESPONSE TO CHECKPOINT-BLOCKADE THERAPY. THUS, APPROACHES TO EXPAND THE POPULATION OF PROGENITOR EXHAUSTED CD8(+) T CELLS MIGHT BE AN IMPORTANT COMPONENT OF IMPROVING THE RESPONSE TO CHECKPOINT BLOCKADE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11  2649 19 EPIGENOMIC, GENOMIC, AND TRANSCRIPTOMIC LANDSCAPE OF SCHWANNOMATOSIS. SCHWANNOMATOSIS (SWNTS) IS A GENETIC CANCER PREDISPOSITION SYNDROME THAT MANIFESTS AS MULTIPLE AND OFTEN PAINFUL NEURONAL TUMORS CALLED SCHWANNOMAS (SWNS). WHILE GERMLINE MUTATIONS IN SMARCB1 OR LZTR1, PLUS SOMATIC MUTATIONS IN NF2 AND LOSS OF HETEROZYGOSITY IN CHROMOSOME 22Q HAVE BEEN IDENTIFIED IN A SUBSET OF PATIENTS, LITTLE IS KNOWN ABOUT THE EPIGENOMIC AND GENOMIC ALTERATIONS THAT DRIVE SWNTS-RELATED SWNS (SWNTS-SWNS) IN A MAJORITY OF THE CASES. WE PERFORMED MULTIPLATFORM GENOMIC ANALYSIS AND ESTABLISHED THE MOLECULAR SIGNATURE OF SWNTS-SWNS. WE SHOW THAT SWNTS-SWNS HARBOR DISTINCT GENOMIC FEATURES RELATIVE TO THE HISTOLOGICALLY IDENTICAL NON-SYNDROMIC SPORADIC SWNS (NS-SWNS). WE DEMONSTRATE THE EXISTENCE OF FOUR DISTINCT DNA METHYLATION SUBGROUPS OF SWNTS-SWNS THAT ARE ASSOCIATED WITH SPECIFIC TRANSCRIPTIONAL PROGRAMS AND TUMOR LOCATION. WE SHOW SEVERAL NOVEL RECURRENT NON-22Q DELETIONS AND STRUCTURAL REARRANGEMENTS. WE DETECTED THE SH3PXD2A-HTRA1 GENE FUSION IN SWNTS-SWNS, WITH PREDOMINANCE IN LZTR1-MUTANT TUMORS. IN ADDITION, WE IDENTIFIED SPECIFIC GENETIC, EPIGENETIC, AND ACTIONABLE TRANSCRIPTIONAL PROGRAMS ASSOCIATED WITH PAINFUL SWNTS-SWNS INCLUDING PIGF, VEGF, MEK, AND MTOR PATHWAYS, WHICH MAY BE HARNESSED FOR MANAGEMENT OF THIS SYNDROME.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12  2469 16 EPIGENETIC TRAJECTORIES OF THE PREMALIGNANT-TO-MALIGNANT TRANSITION OF CHRONIC LYMPHOCYTIC LEUKEMIA. KRETZMER AND COLLEAGUES SHOW THAT THE TRANSITION TO ALTERED METHYLOME OCCURS VERY EARLY IN CHRONIC LYMPHOCYTIC LEUKEMIA, AND ONCE ACQUIRED, IT IS A CLONAL AND EXTREMELY STABLE CHANGE. HOWEVER, THE PRECISE TIME POINT WHEN THE LEUKEMIC CLONE STARTS DEVIATING SIGNIFICANTLY FROM THE NORMAL B-CELL DIFFERENTIATION TRAJECTORY IS STILL ELUSIVE. SEE RELATED ARTICLE BY KRETZMER ET AL., P. 54.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13  6526 18 TRANSCRIPTIONAL CHANGES IN THE OVARIES OF PERCH FROM CHERNOBYL. FISH HAVE BEEN HIGHLY EXPOSED TO RADIATION IN FRESHWATER SYSTEMS AFTER THE CHERNOBYL NUCLEAR POWER PLANT (NPP) ACCIDENT IN 1986 AND IN FRESHWATER AND MARINE SYSTEMS AFTER THE MORE RECENT FUKUSHIMA NPP ACCIDENT IN 2011. IN THE YEARS AFTER THE ACCIDENT, THE RADIOACTIVITY LEVELS RAPIDLY DECLINED DUE TO RADIOACTIVE DECAY AND ENVIRONMENTAL PROCESSES, BUT CHRONIC LOWER DOSE EXPOSURES PERSISTED. TO GAIN INSIGHTS INTO THE LONG-TERM EFFECTS OF ENVIRONMENTAL LOW DOSE RADIATION ON FISH OVARIES DEVELOPMENT, A HIGH-THROUGHPUT TRANSCRIPTOMIC APPROACH INCLUDING A DE NOVO ASSEMBLY WAS APPLIED TO DIFFERENT GONAD PHENOTYPES OF FEMALE PERCH: DEVELOPED GONADS FROM REFERENCE LAKES, DEVELOPED/IRRADIATED FROM MEDIUM CONTAMINATED LAKE, AND BOTH DEVELOPED/IRRADIATED AND UNDEVELOPED FROM MORE HIGHLY CONTAMINATED LAKES. THIS IS THE MOST COMPREHENSIVE ANALYSIS TO DATE OF THE GENE RESPONSES IN WILDLIFE REPRODUCTIVE SYSTEM TO RADIATION. SOME GENE RESPONSES THAT WERE MODULATED IN IRRADIATED GONADS WERE FOUND TO BE INVOLVED IN BIOLOGICAL PROCESSES INCLUDING CELL DIFFERENTIATION AND PROLIFERATION (GGNB2, MOD5, RERGL), CYTOSKELETON ORGANIZATION (K1C18, MTPN), GONAD DEVELOPMENT (NELL2, TCP4), LIPID METABOLISM (LDAH, AT11B, NLTP), REPRODUCTION (CYB5, CYP17A, OVOS), DNA DAMAGE REPAIR (WDHD1, RAD51, HUS1), AND EPIGENETIC MECHANISMS (DMAP1). IDENTIFICATION OF THESE GENES PROVIDES A BETTER UNDERSTANDING OF THE UNDERLYING MOLECULAR MECHANISMS UNDERPINNING THE DEVELOPMENT OF THE GONAD PHENOTYPES OF WILD PERCH AND HOW FISH MAY RESPOND TO CHRONIC EXPOSURE TO RADIATION IN THEIR NATURAL ENVIRONMENT, THOUGH CAUSAL ATTRIBUTION OF GENE RESPONSES REMAINS UNCLEAR IN THE UNDEVELOPED GONADS.	2020	
                                                                                                                                                                                                                                                                                                                                                                 
14   553 15 AUTOINFLAMMATORY RETINOPATHY IN CHRONIC INFANTILE NEUROLOGICAL CUTANEOUS AND ARTICULAR (CINCA) SYNDROME. CHRONIC INFANTILE NEUROLOGICAL CUTANEOUS AND ARTICULAR (CINCA) SYNDROME IS A RARE AUTOSOMAL DOMINANT AUTOINFLAMMATORY DISEASE. WE REPORT THE CASES OF MONOZYGOTIC TWINS WITH CINCA SYNDROME WHOSE PREDOMINANT OCULAR MANIFESTATION WAS INFLAMMATORY ROD-CONE RETINAL DYSTROPHY. ATYPICALLY, THERE WERE SIGNIFICANT DIFFERENCES BETWEEN TWINS IN PHENOTYPE SEVERITY, SUGGESTIVE OF EPIGENETIC DIFFERENCES AND/OR INVOLVEMENT OF ENVIRONMENTAL FACTORS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15  5004 21 PERIPHERAL B CELLS FROM PATIENTS WITH HEPATITIS C VIRUS-ASSOCIATED LYMPHOMA EXHIBIT CLONAL EXPANSION AND AN ANERGIC-LIKE TRANSCRIPTIONAL PROFILE. CHRONIC HCV INFECTION REMAINS A GLOBAL HEALTH CONCERN DUE TO ITS INVOLVEMENT IN HEPATIC AND EXTRAHEPATIC DISEASES, INCLUDING B CELL NON-HODGKIN LYMPHOMA (BNHL). CLINICAL AND EPIDEMIOLOGICAL EVIDENCE SUPPORT A CAUSAL ROLE FOR HCV IN BNHL DEVELOPMENT, ALTHOUGH MECHANISTIC INSIGHT IS LACKING. WE PERFORMED RNA-SEQUENCING ON PERIPHERAL B CELLS FROM PATIENTS WITH HCV ALONE, BNHL ALONE, AND HCV-ASSOCIATED BNHL TO IDENTIFY UNIQUE AND SHARED TRANSCRIPTIONAL PROFILES ASSOCIATED WITH TRANSFORMATION. IN PATIENTS WITH HCV-ASSOCIATED BNHL, WE OBSERVED THE ENRICHMENT OF AN ANERGIC-LIKE GENE SIGNATURE AND EVIDENCE OF CLONAL EXPANSION THAT WAS CORRELATED WITH THE EXPRESSION OF EPIGENETIC REGULATORY GENES. OUR DATA SUPPORT A ROLE FOR VIRAL-MEDIATED CLONAL EXPANSION OF ANERGIC-LIKE B CELLS IN HCV-ASSOCIATED BNHL DEVELOPMENT AND SUGGEST EPIGENETIC DYSREGULATION AS A POTENTIAL MECHANISM DRIVING EXPANSION. WE PROPOSE EPIGENETIC MECHANISMS MAY BE INVOLVED IN BOTH HCV-ASSOCIATED LYMPHOMA AND REGULATION OF B CELL ANERGY, REPRESENTING AN ATTRACTIVE TARGET FOR CLINICAL INTERVENTIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16   628 26 BIOLOGICAL AND CLINICAL INSIGHT FROM ANALYSIS OF THE TUMOR B-CELL RECEPTOR STRUCTURE AND FUNCTION IN CHRONIC LYMPHOCYTIC LEUKEMIA. THE B-CELL RECEPTOR (BCR) IS ESSENTIAL TO THE BEHAVIOR OF THE MAJORITY OF NORMAL AND NEOPLASTIC MATURE B CELLS. THE IDENTIFICATION IN 1999 OF THE TWO MAJOR CLL SUBSETS EXPRESSING UNMUTATED IMMUNOGLOBULIN (IG) VARIABLE REGION GENES (U-IGHV, U-CLL) OF PRE-GERMINAL CENTER ORIGIN AND POOR PROGNOSIS, AND MUTATED IGHV (M-CLL) OF POST-GERMINAL CENTER ORIGIN AND GOOD PROGNOSIS, IGNITED INTENSIVE INVESTIGATIONS ON STRUCTURE AND FUNCTION OF THE TUMOR BCR. THESE INVESTIGATIONS HAVE PROVIDED FUNDAMENTAL INSIGHT INTO CLL BIOLOGY AND EVENTUALLY THE MECHANISTIC RATIONALE FOR THE DEVELOPMENT OF SUCCESSFUL THERAPIES TARGETING BCR SIGNALING. U-CLL AND M-CLL ARE CHARACTERIZED BY VARIABLE LOW SURFACE IGM (SIGM) EXPRESSION AND SIGNALING CAPACITY. VARIABILITY OF SIGM CAN IN PART BE EXPLAINED BY CHRONIC ENGAGEMENT WITH (AUTO)ANTIGEN AT TISSUE SITES. HOWEVER, OTHER ENVIRONMENTAL ELEMENTS, GENETIC CHANGES, AND EPIGENETIC SIGNATURES ALSO CONTRIBUTE TO THE SIGM VARIABILITY. THE VARIABLE LEVELS HAVE CONSEQUENCES ON THE BEHAVIOR OF CLL, WHICH IS IN A STATE OF ANERGY WITH AN INDOLENT CLINICAL COURSE WHEN SIGM EXPRESSION IS LOW, OR PUSHED TOWARDS PROLIFERATION AND A MORE AGGRESSIVE CLINICAL COURSE WHEN SIGM EXPRESSION IS HIGH. EFFICACY OF THERAPIES THAT TARGET BTK MAY ALSO BE AFFECTED BY THE VARIABLE SIGM LEVELS AND SIGNALING AND, IN PART, EXPLAIN THE DEVELOPMENT OF RESISTANCE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  4556 17 MUTATIONAL SPECTRUM OF MYELOID MALIGNANCIES WITH INV(3)/T(3;3) REVEALS A PREDOMINANT INVOLVEMENT OF RAS/RTK SIGNALING PATHWAYS. MYELOID MALIGNANCIES BEARING CHROMOSOMAL INV(3)/T(3;3) ABNORMALITIES ARE AMONG THE MOST THERAPY-RESISTANT LEUKEMIAS. DEREGULATED EXPRESSION OF EVI1 IS THE MOLECULAR HALLMARK OF THIS DISEASE; HOWEVER, THE GENOME-WIDE SPECTRUM OF COOPERATING MUTATIONS IN THIS DISEASE SUBSET HAS NOT BEEN SYSTEMATICALLY ELUCIDATED. HERE, WE SHOW THAT 98% OF INV(3)/T(3;3) MYELOID MALIGNANCIES HARBOR MUTATIONS IN GENES ACTIVATING RAS/RECEPTOR TYROSINE KINASE (RTK) SIGNALING PATHWAYS. IN ADDITION, HEMIZYGOUS MUTATIONS IN GATA2, AS WELL AS HETEROZYGOUS ALTERATIONS IN RUNX1, SF3B1, AND GENES ENCODING EPIGENETIC MODIFIERS, FREQUENTLY CO-OCCUR WITH THE INV(3)/T(3;3) ABERRATION. NOTABLY, NEITHER MUTATIONAL PATTERNS NOR GENE EXPRESSION PROFILES DIFFER ACROSS INV(3)/T(3;3) ACUTE MYELOID LEUKEMIA, CHRONIC MYELOID LEUKEMIA, AND MYELODYSPLASTIC SYNDROME CASES, SUGGESTING RECOGNITION OF INV(3)/T(3;3) MYELOID MALIGNANCIES AS A SINGLE DISEASE ENTITY IRRESPECTIVE OF BLAST COUNT. THE HIGH INCIDENCE OF ACTIVATING RAS/RTK SIGNALING MUTATIONS MAY PROVIDE A TARGET FOR A RATIONAL TREATMENT STRATEGY IN THIS HIGH-RISK PATIENT GROUP.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18  3381 22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19   867 30 CHRONIC ACTIVE EPSTEIN-BARR VIRUS INFECTION OF T/NK-CELL TYPE MIMICKING CLASSIC HODGKIN LYMPHOMA: CLINICOPATHOLOGIC AND GENETIC FEATURES OF 8 CASES SUPPORTING A VARIANT WITH "HODGKIN/REED-STERNBERG-LIKE" CELLS OF NK PHENOTYPE. CHRONIC ACTIVE EPSTEIN-BARR VIRUS (EBV) INFECTION OF T-CELL AND NK-CELL TYPE, SYSTEMIC FORM (CAEBV-T/NK-S) IS CHARACTERIZED BY EBV T-CELL AND/OR NK-CELL PROLIFERATION WITH NO CHANGES SUGGESTING MALIGNANCY. THEREFORE, WHEN HODGKIN/REED-STERNBERG (HRS)-LIKE CELLS ARE SCATTERED IN CAEBV-T/NK-S, IT IS MORE LIKELY TO BE MISDIAGNOSED AS CLASSIC HODGKIN LYMPHOMA. WE ENCOUNTERED A CASE WHEREIN THE PATIENT SHOWED HRS-LIKE CELLS WITH TYPICAL NK PHENOTYPE. THEREFORE, WE FURTHER INVESTIGATED 8 SIMILAR CASES TO PROVIDE CLINICOPATHOLOGIC AND GENETIC FEATURES AND DISCUSS THEIR DISTINCTION FROM OTHER RELATED DISEASES. CLINICALLY, ALL CASES MET THE DIAGNOSTIC CRITERIA OF CAEBV. MOREOVER, 4/8 PATIENTS HAD HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS. THE MEDIAN SURVIVAL WAS 16 MONTHS (RANGE, 5 TO 35 MO). PATHOLOGICALLY, ALL LYMPH NODE SAMPLES HAD A REMARKABLY SIMILAR MORPHOLOGY WITH SCATTERED HRS-LIKE CELLS SURROUNDED BY A MIXTURE OF SMALL-SIZED LYMPHOCYTES, PLASMA CELLS, AND MACROPHAGES THAT MASQUERADED CLASSIC HODGKIN LYMPHOMA. BESIDES, ERYTHROPHAGOCYTOSIS WAS DETECTED IN 4/11 SAMPLES. THE HRS-LIKE CELLS WERE POSITIVE FOR CD2, CD3P, CD30, CD56, GRB, AND EBER-ISH, BUT NEGATIVE FOR CD20, CD5, PAX-5, AND LMP-1. THE SURROUNDING LYMPHOCYTES WERE MAINLY CD8 CYTOTOXIC T CELLS, WITHOUT OBVIOUS ABERRANT EXPRESSION. IN ADDITION, ALL PATIENTS WERE POLYCLONAL IN THE T-CELL RECEPTOR GAMMA REARRANGEMENT TEST. THE HARBORED MUTATIONS WERE MAINLY IN EPIGENETIC MODIFIERS, JAK-STAT SIGNALING PATHWAY, AND APOPTOSIS/CELL CYCLE PATHWAY, INCLUDING SOCS1, DDX3X, AND KMT2D, SIMILAR TO OTHER EBV-ASSOCIATED T/NK-CELL LYMPHOPROLIFERATIVE DISORDERS. THEREFORE, THE EVIDENCE INDICATES THAT "HRS-LIKE CELLS OF NK PHENOTYPE" IS A VARIANT OF CAEBV-T/NK-S. THIS STUDY MAY RAISE AWARENESS OF SUCH CONFOUNDING CAEBV-T/N-S CASES IN CLINICAL PRACTICE TO AVOID MISDIAGNOSIS AND TREATMENT DELAY.	2019	

20  6815 16 [EVOLUTIONARY ONTOGENETIC ASPECTS OF PATHOGENETICS OF CHRONIC HUMAN DISEASES]. THIS ARTICLE IS A REVIEW OF SCIENTIFIC PUBLICATIONS, IN WHICH ISSUES OF PATHOGENETICS OF MULTIFACTORIAL DISEASES (MFDS) ARE CONSIDERED FROM THE VIEWPOINT OF EVOLUTION AND ONTOGENY. CONCEPTS EXPLAINING SIGNIFICANCE OF EVOLUTIONARY PROCESSES IN THE FORMATION OF GENETIC ARCHITECTURE OF HUMAN CHRONIC DISEASES ("THRIFTY" GENOMES AND PHENOTYPES, "DRIFTING GENES," DECANALIZATION) ARE ANALYZED. THE ROLES OF NATURAL SELECTION AND GENETIC DRIFT IN THE FORMATION OF HEREDITARY DIVERSITY OF GENES FOR SUSCEPTIBILITY TO MFDS ARE CONSIDERED. THE MODERN CONCEPT OF DISEASE ONTOGENY (SOMATIC MOSAICISM, LOSS OFHETEROZYGOSITY, PARADOMINANT INHERITANCE, EPIGENETIC VARIABILITY) IS DISCUSSED. IT IS DEMONSTRATED THAT THE EVOLUTIONARY AND ONTOGENETIC APPROACHES TO ANALYSIS OF GENIMUC AND OTHER "-OMIC" DATA ARE ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF DISEASES.	2011