1 1684 149 DRUG-TOLERANT CANCER CELLS SHOW REDUCED TUMOR-INITIATING CAPACITY: DEPLETION OF CD44 CELLS AND EVIDENCE FOR EPIGENETIC MECHANISMS. CANCER STEM CELLS (CSCS) POSSESS HIGH TUMOR-INITIATING CAPACITY AND HAVE BEEN REPORTED TO BE RESISTANT TO THERAPEUTICS. VICE VERSA, THERAPY-RESISTANT CANCER CELLS SEEM TO MANIFEST CSC PHENOTYPES AND PROPERTIES. IT HAS BEEN GENERALLY ASSUMED THAT DRUG-RESISTANT CANCER CELLS MAY ALL BE CSCS ALTHOUGH THE GENERALITY OF THIS ASSUMPTION IS UNKNOWN. HERE, WE CHRONICALLY TREATED DU145 PROSTATE CANCER CELLS WITH ETOPOSIDE, PACLITAXEL AND SOME EXPERIMENTAL DRUGS (I.E., STAUROSPORINE AND 2 PACLITAXEL ANALOGS), WHICH LED TO POPULATIONS OF DRUG-TOLERANT CELLS (DTCS). SURPRISINGLY, THESE DTCS, WHEN IMPLANTED EITHER SUBCUTANEOUSLY OR ORTHOTOPICALLY INTO NOD/SCID MICE, EXHIBITED MUCH REDUCED TUMORIGENICITY OR WERE EVEN NON-TUMORIGENIC. DRUG-TOLERANT DLD1 COLON CANCER CELLS SELECTED BY A SIMILAR CHRONIC SELECTION PROTOCOL ALSO DISPLAYED REDUCED TUMORIGENICITY WHEREAS DRUG-TOLERANT UC14 BLADDER CANCER CELLS DEMONSTRATED EITHER INCREASED OR DECREASED TUMOR-REGENERATING CAPACITY. DRUG-TOLERANT DU145 CELLS DEMONSTRATED LOW PROLIFERATIVE AND CLONOGENIC POTENTIAL AND WERE VIRTUALLY DEVOID OF CD44(+) CELLS. PROSPECTIVE KNOCKDOWN OF CD44 IN DU145 CELLS INHIBITED CELL PROLIFERATION AND TUMOR REGENERATION, WHEREAS RESTORATION OF CD44 EXPRESSION IN DRUG-TOLERANT DU145 CELLS INCREASED CELL PROLIFERATION AND PARTIALLY INCREASED TUMORIGENICITY. INTERESTINGLY, DRUG-TOLERANT DU145 CELLS SHOWED BOTH INCREASES AND DECREASES IN MANY "STEMNESS" GENES. FINALLY, EVIDENCE WAS PROVIDED THAT CHRONIC DRUG EXPOSURE GENERATED DTCS VIA EPIGENETIC MECHANISMS INVOLVING MOLECULES SUCH AS CD44 AND KDM5A. OUR RESULTS THUS REVEAL THAT 1) NOT ALL DTCS ARE NECESSARILY CSCS; 2) CONVENTIONAL CHEMOTHERAPEUTIC DRUGS SUCH AS TAXOL AND ETOPOSIDE MAY DIRECTLY TARGET CD44(+) TUMOR-INITIATING CELLS; AND 3) DTCS GENERATED VIA CHRONIC DRUG SELECTION INVOLVE EPIGENETIC MECHANISMS. 2011 2 1704 41 DYNAMICS OF MINIMAL RESIDUAL DISEASE IN NEUROBLASTOMA PATIENTS. NEUROBLASTOMA IS A COMMON EXTRACRANIAL SOLID TUMOR OF NEURAL CREST (NC) ORIGIN THAT ACCOUNTS FOR UP TO 15% OF ALL PEDIATRIC CANCER DEATHS. THE DISEASE ARISES FROM A TRANSIENT POPULATION OF NC CELLS THAT UNDERGO AN EPITHELIAL-MESENCHYMAL TRANSITION (EMT) AND GENERATE DIVERSE CELL-TYPES AND TISSUES. PATIENTS WITH NEUROBLASTOMA ARE CHARACTERIZED BY THEIR EXTREME HETEROGENEITY RANGING FROM SPONTANEOUS REGRESSION TO MALIGNANT PROGRESSION. MORE THAN HALF OF NEWLY DIAGNOSED PATIENTS PRESENT HIGHLY METASTATIC TUMORS AND ARE STRATIFIED INTO A HIGH-RISK GROUP WITH DISMAL OUTCOME. AS MANY AS 20% OF HIGH-RISK PATIENTS HAVE RESIDUAL DISEASE THAT IS REFRACTORY OR PROGRESSIVE DURING INDUCTION CHEMOTHERAPY. ALTHOUGH A MAJORITY OF HIGH-RISK PATIENTS ACHIEVE REMISSION, LARGER PART OF THOSE PATIENTS HAS MINIMAL RESIDUAL DISEASE (MRD) THAT CAUSES RELAPSE EVEN AFTER ADDITIONAL CONSOLIDATION THERAPY. MRD IS COMPOSED OF DRUG-RESISTANT TUMOR CELLS AND DYNAMICALLY PRESENTED AS CANCER STEM CELLS (CSCS) IN RESIDUAL TUMORS, CIRCULATING TUMOR CELLS (CTCS) IN PERIPHERAL BLOOD (PB), AND DISSEMINATED TUMOR CELLS (DTCS) IN BONE MARROW (BM) AND OTHER METASTATIC SITES. EMT APPEARS TO BE A KEY MECHANISM FOR CANCER CELLS TO ACQUIRE MRD PHENOTYPES AND MALIGNANT AGGRESSIVENESS. DUE TO THE RESTRICTED AVAILABILITY OF RESIDUAL TUMORS, PB AND BM HAVE BEEN USED TO ISOLATE AND ANALYZE CTCS AND DTCS TO EVALUATE MRD IN CANCER PATIENTS. IN ADDITION, RECENT TECHNICAL ADVANCES MAKE IT POSSIBLE TO USE CIRCULATING TUMOR DNA (CTDNA) SHED FROM TUMOR CELLS INTO PB FOR MRD EVALUATION. BECAUSE MRD CAN BE DETECTED BY TUMOR-SPECIFIC ANTIGENS, GENETIC OR EPIGENETIC CHANGES, AND MRNAS, NUMEROUS ASSAYS USING DIFFERENT METHODS AND SAMPLES HAVE BEEN REPORTED TO DETECT MRD IN CANCER PATIENTS. IN CONTRAST TO THE TUMOR-SPECIFIC GENE-REARRANGEMENT-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) AND THE ONCOGENIC FUSION-GENE-POSITIVE CHRONIC MYELOGENOUS LEUKEMIA (CML) AND SEVERAL SOLID TUMORS, THE CLINICAL SIGNIFICANCE OF MRD REMAINS TO BE ESTABLISHED IN NEUROBLASTOMA. GIVEN THE EXTREME HETEROGENEITY OF NEUROBLASTOMA, DYNAMICS OF MRD IN NEUROBLASTOMA PATIENTS WILL HOLD A KEY TO THE CLINICAL VALIDATION. IN THIS REVIEW, WE SUMMARIZE THE BIOLOGY AND DETECTION METHODS OF CANCER MRD IN GENERAL AND EVALUATE THE AVAILABLE ASSAYS AND CLINICAL SIGNIFICANCE OF NEUROBLASTOMA MRD TO CLARIFY ITS DYNAMICS IN NEUROBLASTOMA PATIENTS. 2019 3 1031 30 CIRCULATING TUMOR DNA DETECTION AND ITS APPLICATION STATUS IN GASTRIC CANCER: A NARRATIVE REVIEW. CIRCULATING TUMOR DNA (CTDNA) IS THE SMALL GENOMIC FRAGMENT RELEASED BY TUMOR CELLS INTO THE CIRCULATING SYSTEM, WHICH CARRIES THE GENE VARIATION FEATURES, SUCH AS MUTATION, INSERTION, DELETION, REARRANGEMENT, COPY NUMBER VARIATION (CNV) AND METHYLATION, RENDERING IT AN IMPORTANT BIOMARKER. IT CAN BE USED NOT ONLY TO DIAGNOSE CERTAIN TYPES OF SOLID TUMORS, BUT ALSO TO MONITOR THE THERAPEUTIC RESPONSE AND EXPLORE THE MINIMAL RESIDUAL DISEASE (MRD) AND RESISTANT MUTATION OF TARGETED THERAPY. THEREFORE, CTDNA DETECTION MAY BECOME THE PREFERRED NON-INVASIVE TUMOR SCREENING METHOD. FOR PATIENTS WHO CANNOT RECEIVE FURTHER GENE DETECTION DUE TO INSUFFICIENT OR RESTRICTED SAMPLE COLLECTION WITH THE DEFINED PATHOLOGICAL DIAGNOSIS, CTDNA DETECTION CAN BE CARRIED OUT TO DETERMINE THE GENE MUTATION TYPE, WITH NO NEED FOR REPEATED SAMPLING. GASTRIC CANCER (GC) IS A MALIGNANCY WITH EXTREMELY HIGH MORBIDITY AND MORTALITY, AND ITS GENESIS AND DEVELOPMENT ARE THE CONSEQUENCE OF INTERACTIONS OF MULTIPLE FACTORS, INCLUDING ENVIRONMENT, DIET, HEREDITY, HELICOBACTER PYLORI INFECTION, CHRONIC INFLAMMATORY INFILTRATION, AND PRECANCEROUS LESION. AS THE RESEARCH ON GC MOVES FORWARD, THE EXISTING RESEARCH MAINLY FOCUSES ON GENETIC AND EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, NON-CODING RNA CHANGES, GENE MUTATION, GENE HETEROZYGOSITY LOSS AND MICROSATELLITE INSTABILITY. THIS PAPER AIMED TO SUMMARIZE THE CONTENTS OF CTDNA DETECTION, ITS APPLICATION STATUS IN GC AND CLINICAL SIGNIFICANCE. 2021 4 4533 42 MULTIPLE GENE KNOCKDOWN STRATEGIES FOR INVESTIGATING THE PROPERTIES OF HUMAN LEUKEMIA STEM CELLS AND EXPLORING NEW THERAPIES. THE PAST TWO DECADES HAVE WITNESSED SIGNIFICANT STRIDES IN LEUKEMIA THERAPIES THROUGH APPROVAL OF THERAPEUTIC INHIBITORS TARGETING ONCOGENE-DRIVING DYSREGULATED TYROSINE KINASE ACTIVITIES AND KEY EPIGENETIC AND APOPTOSIS REGULATORS. ALTHOUGH THESE DRUGS HAVE BROUGHT ABOUT COMPLETE REMISSION IN THE MAJORITY OF PATIENTS, MANY PATIENTS FACE RELAPSE OR HAVE REFRACTORY DISEASE. THE MAIN FACTOR CONTRIBUTING TO RELAPSE IS THE PRESENCE OF A SMALL SUBPOPULATION OF DORMANT DRUG-RESISTANT LEUKEMIA CELLS THAT POSSESS STEM CELL FEATURES (TERMED AS LEUKEMIA STEM CELLS OR LSCS). THUS, OVERCOMING DRUG RESISTANCE AND TARGETING LSCS REMAIN MAJOR CHALLENGES FOR CURATIVE TREATMENT OF HUMAN LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A GOOD EXAMPLE, WITH RARE, PROPAGATING LSCS AND DRUG-RESISTANT CELLS THAT CANNOT BE ERADICATED BY BCR-ABL-DIRECTED TYROSINE KINASE INHIBITOR (TKI) MONOTHERAPY AND THAT ARE RESPONSIBLE FOR DISEASE RELAPSE/PROGRESSION. THEREFORE, IT IS IMPERATIVE TO IDENTIFY KEY PLAYERS IN REGULATING BCR-ABL1-DEPENDENT AND INDEPENDENT DRUG-RESISTANCE MECHANISMS, AND THEIR KEY PATHWAYS, SO THAT CML LSCS CAN BE SELECTIVELY TARGETED OR SENSITIZED TO TKIS. HERE, WE DESCRIBE SEVERAL EASILY ADAPTABLE GENE KNOCKDOWN APPROACHES IN CD34(+) CML STEM/PROGENITOR CELLS THAT CAN BE USED TO INVESTIGATE THE BIOLOGICAL PROPERTIES OF LSCS AND MOLECULAR EFFECTS OF GENES OF INTEREST (GOI), WHICH CAN BE FURTHER EXPLORED AS THERAPEUTIC MODALITIES AGAINST LSCS IN THE CONTEXT OF HUMAN LEUKEMIA. 2022 5 2665 37 ESTABLISHMENT OF A NOVEL MYELODYSPLASTIC SYNDROME (MDS) XENOTRANSPLANTATION MODEL. BACKGROUND: MYELODYSPLASTIC SYNDROME (MDS) IS A CLONAL DISEASE OF THE ELDERLY CHARACTERIZED BY CHRONIC CYTOPENIA, DYSPLASIA, AND A HIGH RISK OF PROGRESSION TO ACUTE MYELOID LEUKEMIA (AML). UP UNTIL NOW, FEW ANIMAL MODELS THAT FULLY RECAPITULATE CLINICAL FEATURES OF THIS DISEASE HAVE BEEN AVAILABLE. METHODS: THIS STUDY AIMED TO ESTABLISH A NEW MDS XENOGRAFT MODEL UTILIZING A HUMAN MDS-DERIVED CELL LINE WITH HETEROZYGOUS Y641C MUTATION OF EZH2 (SKM-1). 1 X 107 SKM-1 CELLS WERE INOCULATED INTO ANTI-MOUSE CD122 MONOANTIBODY CONDITIONED NONOBESE DIABETIC SEVERE COMBINED IMMUNODEFICIENCY (NOD/SCID) MICE BY INTRAVENOUS INJECTION. DECITABINE WAS INJECTED INTRAPERITONEALLY FOR EVALUATION OF EPIGENETIC DRUGS IN VIVO. RESULTS: IT IS SHOWN THAT THE HETEROZYGOUS Y641C MUTATION IN THE EZH2 GENE MUTATION, WHICH MAY DESTABILIZE THE PROTEIN (??G = 1.46 KCAL/MOL), CAN BE FOUND IN SKM-1 CELLS. MOST MICE PRESENTED ANEMIA AND LEUKOPENIA AT THREE TO FOUR WEEKS AFTER INOCULATION. THE PERIPHERAL BLOOD AND BONE MARROW SMEAR SHOWED PROMINENT DYSPLASIA ON ERYTHROCYTES AND GRANULOCYTES AS WELL AS MONOCYTES. CONCLUSIONS: THESE FINDINGS SUGGEST THAT INTRAVENOUS INOCULATION OF CELLS FROM THE HUMAN MDS-DERIVED CELL LINE PRIOR TO TARGETED DEPLETION OF CD122+ CELLS COULD PROVIDE A NOVEL MDS-LIKE XENOTRANSPLANT MOUSE MODEL. IT IS A USEFUL TOOL FOR EVALUATING POTENTIAL EXISTING AND NOVEL THERAPEUTICS FOR MDS. 2016 6 5283 28 PROPHYLACTIC OR PREEMPTIVE LOW-DOSE AZACITIDINE AND DONOR LYMPHOCYTE INFUSION TO PREVENT DISEASE RELAPSE FOLLOWING ALLOGENEIC TRANSPLANTATION IN PATIENTS WITH HIGH-RISK ACUTE MYELOGENOUS LEUKEMIA OR MYELODYSPLASTIC SYNDROME. BECAUSE OF THE PERSISTENTLY HIGH RATES OF RELAPSE OF PATIENTS WITH HIGH-RISK ACUTE MYELOGENOUS LEUKEMIA (AML) AND MYELODYSPLASTIC SYNDROME (MDS) FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT), POST-TRANSPLANTATION MAINTENANCE THERAPY HAS BEEN PROPOSED. WE PREVIOUSLY INITIATED A PHASE II TRIAL IN WHICH EPIGENETIC THERAPY WAS COMBINED WITH IMMUNOTHERAPY IN AN ATTEMPT TO REDUCE DISEASE RELAPSE. IN THAT STUDY, LOW-DOSE AZACITIDINE (AZA) AND ESCALATING DOSES OF DONOR LYMPHOCYTE INFUSION (DLI) WERE GIVEN AS POST-ALLO-HSCT MAINTENANCE TREATMENT. IN THE PRESENT STUDY, WE RETROSPECTIVELY ANALYZE A LARGER COHORT OF PATIENTS RECEIVING POST-TRANSPLANTATION MAINTENANCE THERAPY AND PROVIDE UPDATES ON SOME PATIENTS OF THE EARLIER STUDY. THE OBJECTIVES OF THE PRESENT STUDY WERE TO ANALYZE THE CUMULATIVE INCIDENCE OF RELAPSE (CIR), OVERALL SURVIVAL (OS), AND PROGRESSION-FREE SURVIVAL (PFS) AND THE INCIDENCE OF ACUTE AND CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD) OF PATIENTS WITH HIGH-RISK AML OR MDS RECEIVING POST-TRANSPLANTATION MAINTENANCE TREATMENT WITH AZA WITH OR WITHOUT DLI. WE RETROSPECTIVELY ANALYZED 77 PATIENTS (54 WITH AML, 23 WITH MDS) CONSIDERED AT HIGH RISK BASED ON EITHER THEIR GENOMIC OR CLINICAL STATUS AT TRANSPLANTATION. FOLLOWING ALLOGENEIC TRANSPLANTATION, THEY RECEIVED AT LEAST 1 CYCLE OF PROPHYLACTIC OR PREEMPTIVE LOW-DOSE AZA WITH OR WITHOUT ESCALATING DOSES OF DLI TO PREVENT DISEASE RELAPSE. ALMOST ONE-HALF OF THE PATIENTS (47%) WERE ABLE TO RECEIVE THE FULL 12 CYCLES OF SCHEDULED AZA, AND A MAJORITY (79%) RECEIVED AT LEAST 1 DLI. WITH A MEDIAN FOLLOW-UP OF 24 MONTHS, 19 PATIENTS (25%; 16 WITH AML, 3 WITH MDS) RELAPSED, AT A MEDIAN OF 9.8 MONTHS (RANGE, 4 TO 58.6 MONTHS), GIVING A 22% CIR AT 24 MONTHS. OS AND PFS AT 24 MONTHS WERE 70.8% AND 68.3%, RESPECTIVELY. THE CUMULATIVE INCIDENCES OF GRADE II-IV ACUTE GVHD AND CHRONIC GVHD WERE 27.4% AND 45%, RESPECTIVELY. ONLY A MINORITY OF PATIENTS (11%) REQUIRED DELAYED ADMINISTRATION OF AZA. THESE FINDINGS CONFIRM THAT AZA-DLI MAINTENANCE IS BOTH TOLERABLE AND EFFECTIVE IN REDUCING THE RISK OF POST-TRANSPLANTATION RELAPSE. 2021 7 1469 36 DISTINCT EVOLUTIONARY PATHS IN CHRONIC LYMPHOCYTIC LEUKEMIA DURING RESISTANCE TO THE GRAFT-VERSUS-LEUKEMIA EFFECT. LEUKEMIC RELAPSE REMAINS A MAJOR BARRIER TO SUCCESSFUL ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLO-HSCT) FOR AGGRESSIVE HEMATOLOGIC MALIGNANCIES. THE BASIS FOR RELAPSE OF ADVANCED LYMPHOID MALIGNANCIES REMAINS INCOMPLETELY UNDERSTOOD AND MAY INVOLVE ESCAPE FROM THE GRAFT-VERSUS-LEUKEMIA (GVL) EFFECT. WE HYPOTHESIZED THAT FOR PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREATED WITH ALLO-HSCT, LEUKEMIC CELL-INTRINSIC FEATURES INFLUENCE TRANSPLANT OUTCOMES BY DIRECTING THE EVOLUTIONARY TRAJECTORIES OF CLL CELLS. INTEGRATED GENETIC, TRANSCRIPTOMIC, AND EPIGENETIC ANALYSES OF CLL CELLS FROM 10 PATIENTS REVEALED THAT THE CLINICAL KINETICS OF POST-HSCT RELAPSE ARE SHAPED BY DISTINCT MOLECULAR DYNAMICS. EARLY RELAPSES AFTER ALLO-HSCT EXHIBITED NOTABLE GENETIC STABILITY; SINGLE CLL CELL TRANSCRIPTIONAL ANALYSIS DEMONSTRATED A CELLULAR HETEROGENEITY THAT WAS STATIC OVER TIME. IN CONTRAST, CLL CELLS RELAPSING LATE AFTER ALLO-HSCT DISPLAYED NOTABLE GENETIC EVOLUTION AND EVIDENCE OF NEOANTIGEN DEPLETION, CONSISTENT WITH MARKED SINGLE-CELL TRANSCRIPTIONAL SHIFTS THAT WERE UNIQUE TO EACH PATIENT. WE OBSERVED A GREATER RATE OF EPIGENETIC CHANGE FOR LATE RELAPSES NOT SEEN IN EARLY RELAPSES OR RELAPSES AFTER CHEMOTHERAPY ALONE, SUGGESTING THAT THE SELECTION PRESSURES OF THE GVL BOTTLENECK ARE UNLIKE THOSE IMPOSED BY CHEMOTHERAPY. NO SELECTIVE ADVANTAGE FOR HUMAN LEUKOCYTE ANTIGEN (HLA) LOSS WAS OBSERVED, EVEN WHEN PRESENT IN PRETRANSPLANT SUBPOPULATIONS. GAIN OF STEM CELL MODULES WAS A COMMON SIGNATURE ASSOCIATED WITH LEUKEMIA RELAPSE REGARDLESS OF POSTTRANSPLANT RELAPSE KINETICS. THESE DATA ELUCIDATE THE BIOLOGICAL PATHWAYS THAT UNDERLIE GVL RESISTANCE AND POSTTRANSPLANT RELAPSE. 2020 8 3839 31 IPSC-DERIVED NEURAL PRECURSOR CELLS: POTENTIAL FOR CELL TRANSPLANTATION THERAPY IN SPINAL CORD INJURY. A NUMBER OF STUDIES HAVE DEMONSTRATED THAT TRANSPLANTATION OF NEURAL PRECURSOR CELLS (NPCS) PROMOTES FUNCTIONAL RECOVERY AFTER SPINAL CORD INJURY (SCI). HOWEVER, THE NPCS HAD BEEN MOSTLY HARVESTED FROM EMBRYONIC STEM CELLS OR FETAL TISSUE, RAISING THE ETHICAL CONCERN. YAMANAKA AND HIS COLLEAGUES ESTABLISHED INDUCED PLURIPOTENT STEM CELLS (IPSCS) WHICH COULD BE GENERATED FROM SOMATIC CELLS, AND THIS INNOVATIVE DEVELOPMENT HAS MADE RAPID PROGRESSION IN THE FIELD OF SCI REGENERATION. WE AND OTHER GROUPS SUCCEEDED IN PRODUCING NPCS FROM IPSCS, AND DEMONSTRATED BENEFICIAL EFFECTS AFTER TRANSPLANTATION FOR ANIMAL MODELS OF SCI. IN PARTICULAR, EFFICACY OF HUMAN IPSC-NPCS IN NON-HUMAN PRIMATE SCI MODELS FOSTERED MOMENTUM OF CLINICAL APPLICATION FOR SCI PATIENTS. AT THE SAME TIME, HOWEVER, ARTIFICIAL INDUCTION METHODS IN IPSC TECHNOLOGY CREATED ALTERNATIVE ISSUES INCLUDING GENETIC AND EPIGENETIC ABNORMALITIES, AND TUMORIGENICITY AFTER TRANSPLANTATION. TO OVERCOME THESE PROBLEMS, IT IS CRITICALLY IMPORTANT TO SELECT ORIGINS OF SOMATIC CELLS, USE INTEGRATION-FREE SYSTEM DURING TRANSFECTION OF REPROGRAMMING FACTORS, AND THOROUGHLY INVESTIGATE THE CHARACTERISTICS OF IPSC-NPCS WITH RESPECT TO QUALITY MANAGEMENT. MOREOVER, SINCE MOST OF THE PREVIOUS STUDIES HAVE FOCUSED ON SUBACUTE PHASE OF SCI, ESTABLISHMENT OF EFFECTIVE NPC TRANSPLANTATION SHOULD BE EVALUATED FOR CHRONIC PHASE HEREAFTER. OUR GROUP IS CURRENTLY PREPARING CLINICAL-GRADE HUMAN IPSC-NPCS, AND WILL MOVE FORWARD TOWARD CLINICAL STUDY FOR SUBACUTE SCI PATIENTS SOON IN THE NEAR FUTURE. 2018 9 6574 24 TREATMENT OF CHRONIC MYELOMONOCYTIC LEUKEMIA WITH 5-AZACYTIDINE: CASE REPORTS. EPIGENETIC THERAPY WITH HYPOMETHYLATING AGENT (5-AZACYTIDINE; AZA) IS COMMON IN THE MANAGEMENT OF SPECIFIC SUBTYPES OF MYELODYSPLASTIC SYNDROME (MDS), BUT THERE ARE ONLY FEW STUDIES IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) PATIENTS. IN THIS PAPER OUR EXPERIENCE WITH 3 CMML PATIENTS TREATED WITH AZA IS DESCRIBED. IN ONE PATIENT TRANSFUSION INDEPENDENCY WAS OBSERVED AFTER 4 TREATMENT CYCLES; IN ONE CASE A PARTIAL RESPONSE WAS RECORDED, BUT A PROGRESSION TO ACUTE MYELOID LEUKEMIA (AML) AFTER 13 AZA CYCLES HAS APPEARED. IN ONE PATIENT, AZA IN REDUCED DOSAGE WAS ADMINISTERED AS A BRIDGING TREATMENT BEFORE ALLOGENEIC STEM CELL TRANSPLANTATION (ASCT), BUT IN THE CONTROL BONE MARROW ASPIRATE (BEFORE ASCT) A PROGRESSION TO AML WAS RECORDED. FUTURE STUDIES ARE MANDATORY FOR EVALUATION OF NEW MOLECULAR AND CLINICAL FEATURES WHICH COULD PREDICT THE EFFICIENCY OF HYPOMETHYLATING AGENTS IN CMML THERAPY WITH RESPECT TO OVERALL SURVIVAL, EVENT-FREE SURVIVAL, QUALITY-ADJUSTED LIFE YEAR, AND PHARMACOECONOMY. 2012 10 6143 34 THE EVOLVING LANDSCAPE OF CANCER STEM CELLS AND WAYS TO OVERCOME CANCER HETEROGENEITY. CANCER STEM CELLS (CSCS) WITH THERAPEUTIC RESISTANCE AND PLASTICITY CAN BE FOUND IN VARIOUS TYPES OF TUMORS AND ARE RECOGNIZED AS ATTRACTIVE TARGETS FOR TREATMENTS. AS CSCS ARE DERIVED FROM TISSUE STEM OR PROGENITOR CELLS, AND/OR DEDIFFERENTIATED MATURE CELLS, THEIR SIGNAL TRANSDUCTION PATHWAYS ARE CRITICAL IN THE REGULATION OF CSCS; CHRONIC INFLAMMATION CAUSES THE ACCUMULATION OF GENETIC MUTATIONS AND ABERRANT EPIGENETIC CHANGES IN THESE CELLS, POTENTIALLY LEADING TO THE PRODUCTION OF CSCS. HOWEVER, THE NATURE OF CSCS APPEARS TO BE STRONGER THAN THE TREATMENTS OF THE PAST. TO IMPROVE THE TREATMENTS TARGETING CSCS, IT IS IMPORTANT TO INHIBIT SEVERAL MOLECULES ON THE SIGNALING CASCADES IN CSCS SIMULTANEOUSLY, AND TO OVERCOME CANCER HETEROGENEITY CAUSED BY THE PLASTICITY. TO SELECT SUITABLE TARGET MOLECULES FOR CSCS, WE HAVE TO EXPLORE THE LANDSCAPE OF CSCS FROM THE PERSPECTIVE OF CANCER STEMNESS AND SIGNALING SYSTEMS, BASED ON THE CURATED DATABASES OF CANCER-RELATED GENES. WE HAVE BEEN STUDYING THE INTEGRATION OF A BROAD RANGE OF KNOWLEDGE AND EXPERIENCES FROM CANCER BIOLOGY, AND ALSO FROM OTHER INTERDISCIPLINARY BASIC SCIENCES. IN THIS REVIEW, WE HAVE INTRODUCED THE CONCEPT OF DEVELOPING NOVEL STRATEGIES TARGETING CSCS. 2019 11 3811 35 INTRATUMORAL HETEROGENEITY: CLONAL COOPERATION IN EPITHELIAL-TO-MESENCHYMAL TRANSITION AND METASTASIS. ALTHOUGH PHENOTYPIC INTRATUMORAL HETEROGENEITY WAS FIRST DESCRIBED MANY DECADES AGO, THE ADVENT OF NEXT-GENERATION SEQUENCING HAS PROVIDED CONCLUSIVE EVIDENCE THAT IN ADDITION TO PHENOTYPIC DIVERSITY, SIGNIFICANT GENOTYPIC DIVERSITY EXISTS WITHIN TUMORS. TUMOR HETEROGENEITY LIKELY ARISES BOTH FROM CLONAL EXPANSIONS, AS WELL AS FROM DIFFERENTIATION HIERARCHIES EXISTENT IN THE TUMOR, SUCH AS THAT ESTABLISHED BY CANCER STEM CELLS (CSCS) AND NON-CSCS. THESE DIFFERENTIATION HIERARCHIES MAY ARISE DUE TO GENETIC MUTATIONS, EPIGENETIC ALTERATIONS, OR MICROENVIRONMENTAL INFLUENCES. AN ADDITIONAL DIFFERENTIATION HIERARCHY WITHIN EPITHELIAL TUMORS MAY ARISE WHEN ONLY A FEW TUMOR CELLS TRANS-DIFFERENTIATE INTO MESENCHYMAL-LIKE CELLS, A PROCESS KNOWN AS EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT). AGAIN, THIS PROCESS CAN BE INFLUENCED BY BOTH GENETIC AND NON-GENETIC FACTORS. IN THIS REVIEW WE DISCUSS THE EVIDENCE FOR CLONAL INTERACTION AND COOPERATION FOR TUMOR MAINTENANCE AND PROGRESSION, PARTICULARLY WITH RESPECT TO EMT, AND FURTHER ADDRESS THE FAR-REACHING EFFECTS THAT TUMOR HETEROGENEITY MAY HAVE ON CANCER THERAPY. 2015 12 1685 38 DRUGGABLE BIOCHEMICAL PATHWAYS AND POTENTIAL THERAPEUTIC ALTERNATIVES TO TARGET LEUKEMIC STEM CELLS AND ELIMINATE THE RESIDUAL DISEASE IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A DISEASE ARISING IN STEM CELLS EXPRESSING THE BCR-ABL ONCOGENIC TYROSINE KINASE THAT TRANSFORMS ONE HEMATOPOIETIC STEM/PROGENITOR CELL INTO A LEUKEMIC STEM CELL (LSC) AT THE ORIGIN OF DIFFERENTIATED AND PROLIFERATING LEUKEMIC CELLS IN THE BONE MARROW (BM). CML-LSCS ARE RECOGNIZED AS BEING RESPONSIBLE FOR RESISTANCES AND RELAPSES THAT OCCUR DESPITE THE ADVENT OF BCR-ABL-TARGETING THERAPIES WITH TYROSINE KINASE INHIBITORS (TKIS). LSCS SHARE A LOT OF FUNCTIONAL PROPERTIES WITH HEMATOPOIETIC STEM CELLS (HSCS) ALTHOUGH SOME PHENOTYPICAL AND FUNCTIONAL DIFFERENCES HAVE BEEN DESCRIBED DURING THE LAST TWO DECADES. SUBVERTED MECHANISMS AFFECTING EPIGENETIC PROCESSES, APOPTOSIS, AUTOPHAGY AND MORE RECENTLY METABOLISM AND IMMUNOLOGY IN THE BONE MARROW MICROENVIRONMENT (BMM) HAVE BEEN REPORTED. THE AIM OF THIS REVIEW IS TO BRING TOGETHER THE MODIFICATIONS AND MOLECULAR MECHANISMS THAT ARE KNOWN TO ACCOUNT FOR TKI RESISTANCE IN PRIMARY CML-LSCS AND TO FOCUS ON THE POTENTIAL SOLUTIONS THAT CAN CIRCUMVENT THESE RESISTANCES, IN PARTICULAR THOSE THAT HAVE BEEN, OR WILL BE TESTED IN CLINICAL TRIALS. 2019 13 6857 36 [NOVEL CONVENTIONAL THERAPIES IN ONCO-HEMATHOLOGY]. CYTOGENETIC, MOLECULAR AND PHENOTYPING FEATURES OF MALIGNANT HEMATOLOGIC DISEASES SUCCEEDED IN IMPROVING THEIR MANAGEMENT BY A MORE ACCURATE STRATIFICATION OF PATIENTS ACCORDING TO SEVERAL GROUPS OF RISK AND BY PROVIDING A RATIONAL FOR TARGETED THERAPY. THREE MAJOR TYPES OF TREATMENT (EXCLUDING CELLULAR THERAPY) ARE CURRENTLY AVAILABLE IN ONCO-HEMATOLOGY: CONVENTIONAL CHEMOTHERAPY, SMALL MOLECULES FOR TARGETED THERAPY AND MONOCLONAL ANTIBODIES. CONVENTIONAL CHEMOTHERAPY WITH OPTIMIZATION OF DOSES AND MULTIDRUG-BASED REGIMENS ALLOWED TO SUBSTANTIALLY IMPROVE SURVIVAL OF PATIENTS AND KEEPS A PLACE OF CHOICE IN TREATMENT OF THESE DISEASES. TARGETED TREATMENTS CAME FROM THE CYTOGENETIC AND MOLECULAR CHARACTERIZATION OF HEMOPATHIES. THUS, THE KINASE BCR-ABL, AS A RESULT OF THE TRANSLOCATION T(9;22)(Q34;Q11), HAS BEEN SUCCESSFULLY TARGETED BY TYROSINE KINASE INHIBITORS (TKI) IN CHRONIC MYELOID LEUKEMIA AND PH+ ACUTE LYMPHOBLASTIC LEUKEMIA. MOLECULAR ABNORMALITIES LIKE INTERNAL-TANDEM DUPLICATION/POINT ACTIVATING MUTATIONS IN FLT3 IN SOME ACUTE MYELOBLASTIC LEUKEMIA OR EPIGENETIC DYSREGULATIONS IN SOME BLOOD MALIGNANCIES CAN ALSO BE TARGETED BY SMALL MOLECULES. HEMATOPOIETIC MALIGNANT CELLS ARE PHENOTYPICALLY CHARACTERIZED BY EXPRESSION OF CLUSTER OF DIFFERENTIATION (CD) ON THEIR SURFACE. THESE CD ARE DETECTED BY FLOW CYTOMETRY USING SPECIFIC ANTIBODIES. MONOCLONAL ANTIBODIES TARGETING DIFFERENT CD HAVE BEEN DEVELOPED FOR TREATMENT. RITUXIMAB, AN ANTI-CD20 ANTIBODY, WAS THE FIRST MONOCLONAL ANTIBODY SUCCESSFULLY DEVELOPED FOR TREATMENT OF MALIGNANT HEMATOLOGIC DISEASES. SINCE RITUXIMAB, MANY OTHER MONOCLONAL ANTIBODIES ARE BEING DEVELOPED. TRENDS IN MALIGNANT HEMATOLOGIC DISEASES PRESENTED HERE WILL INCLUDE TREATMENTS, WHICH HAVE AT LEAST ENTERED PHASE I/II CLINICAL TRIALS IN ADULT OR CHILDHOOD LEUKEMIA. THEY INCLUDE SOME NOVEL DRUGS OF CONVENTIONAL CHEMOTHERAPY LIKE SECOND-GENERATION NUCLEOSIDE ANALOGUES. WE WILL GIVE AN OVERVIEW OF THE SMALL MOLECULES TARGETING THE DIFFERENT CELLULAR PATHWAYS AND WE WILL HIGHLIGHT THOSE APPEARING AS THE MOST PROMISING LIKE NOVEL TKIS. THE LARGE FIELD OF MONOCLONAL ANTIBODIES WILL BE ALSO APPROACHED FOCUSING ON ANTIBODIES DEVELOPED IN LEUKEMIAS. 2011 14 3934 46 LIVER TUMOR INDUCTION. THE SIGNIFICANCE OF THE DEVELOPMENT OF NODULAR LIVER LESIONS IN RODENTS FOLLOWING THE ADMINISTRATION OF TEST AGENTS RAISES SEVERAL QUESTIONS WHICH COULD BE PLACED IN ONE OF TWO GENERAL CATEGORIES: DIAGNOSTIC AND INTERPRETATIONAL. FROM A DIAGNOSTIC POINT OF VIEW, THE PROPER CLASSIFICATION OF LIVER TUMORS INTO A BENIGN AND MALIGNANT CATEGORY HAS TO BE BASED ON THE DIRECT CORRELATION BETWEEN THE MORPHOLOGY AND THE BIOLOGIC BEHAVIOR OF THE LESIONS. THEREFORE, EXTREME CARE SHOULD BE TAKEN TO SEPARATE THE MALIGNANT TUMORS FROM THE BENIGN AND THE BENIGN NEOPLASIA FROM THE HYPERPLASIA. THE SUBSTITUTION OF THE TERM "NEOPLASTIC NODULE" FOR HYPERPLASTIC NODULE IN RATS IS MISLEADING. MOST OF THESE NODULES, WHEN INDUCED UNDER SPECIAL EXPERIMENTAL CONDITIONS, MAY REGRESS OR REMODEL AND THUS THEY ARE NOT NEOPLASTIC IN NATURE. CHRONIC CARCINOGENICITY BIOASSAYS SHOULD INCLUDE "STOP" TYPE OF TREATMENT LEAVING ENOUGH OF THE OBSERVATIONAL TIME TO ESTABLISH THE FATE OF INDUCED NODULAR LESIONS. THE INDUCTION OF HISTOCHEMICALLY CHANGED FOCI CAN SERVE ONLY AS AN INDICATION OF POTENTIAL HEPATOCARCINOGENICITY AND SHOULD NOT BE EQUATED WITH THE INDUCTION OF BONA FIDE CANCER. THE BIOLOGIC INTERPRETATION OF NODULAR LIVER LESIONS, ESPECIALLY IN MICE, NEEDS FURTHER SCRUTINY BECAUSE THESE LESIONS HAVE A TENDENCY TO DEVELOP SPONTANEOUSLY WITH HIGH INCIDENCE IN SOME STRAINS. THIS CHARACTERISTIC THEN RAISES THE QUESTION AS TO THE MECHANISM BY WHICH VARIOUS AGENTS AUGMENT AND/OR ACCELERATE THE DEVELOPMENT OF SUCH TUMORS. IS THIS ACTION PRIMARILY PROMOTING OR INITIATING IN NATURE OR DOES IT REPRESENT THE INDUCTION OF TUMORS DE NOVO? THE ANSWER TO THIS DILEMMA MAY HAVE A DECISIVE BEARING ON CARCINOGENIC RISK ASSESSMENT AND THE TYPE OF REGULATORY ACTION, SINCE THE PROMOTING AGENTS POSSESS A THRESHOLD EFFECT AND THE PROMOTED CHANGES MAY REGRESS FOLLOWING WITHDRAWAL OF TREATMENT. THE INTERPRETATION OF HEPATOCARCINOGENESIS IS FURTHER COMPLICATED BY THE FACT THAT SEVERAL FACTORS, SUCH AS SEX HORMONAL ENVIRONMENT, INCREASED MITOTIC ACTIVITY FOLLOWING AN EXCESSIVE LOSS OF PARENCHYMAL CELLS, DEGREE OF CALORIC INTAKE, ENZYMATIC COMPLEMENT, AND ANIMALS' AGE AT THE TIME OF THE EXPOSURE TO A TEST AGENT, MAY INFLUENCE THE OUTCOME OF LIVER TUMOR DEVELOPMENT BY MODULATING "INITIATION" AND/OR "PROMOTION" OF CARCINOGENESIS. BROAD FLUCTUATION IN THE HISTORIC INCIDENCE OF LIVER TUMORS FURTHER COMPOUNDS THE COMPLEXITY OF THE PROPER BIOASSAY INTERPRETATION. THE SPECIFICALLY DESIGNED EXPERIMENTS MAY HAVE THE OBJECTIVE TO EXPLORE PREDOMINANTLY THE INITIATING OR PROMOTING EFFECTS OF THE AGENT. SUCH PROTOCOLS SHOULD BE USED WHENEVER NECESSARY TO DIFFERENTIATE BETWEEN THESE TWO MECHANISMS OF ACTION. IN THE CAUCASIANS, THE "SPONTANEOUS" DEVELOPMENT OF THE PRIMARY HEPATOCELLULAR TUMORS IS RARE. THE MAJORITY OF THESE TUMORS ARE MALIGNANT AND RAPIDLY FATAL. ACCORDING TO SOME HUMAN PATHOLOGISTS, THE BENIGN VARIETY OF LIVER TUMORS IS RARE AND IT DOES NOT REPRESENT NECESSARILY A PREMALIGNANT STAGE IN TUMOR DEVELOPMENT. CARCINOMA OF THE LIVER MAY OCCUR IN INFANCY, ESPECIALLY IN MALES BEFORE THE AGE OF 2 YEARS. THIS SUGGESTS A GENETIC CAUSATION OR CARCINOGENIC EXPOSURE IN UTERO. ONE OF THE GEOGRAPHIC FACTORS WHICH SIGNIFICANTLY ENHANCES THE INCIDENCE OF HEPATOCELLULAR CARCINOMA IN HUMANS IS EXPOSURE TO AFLATOXIN B(1) WHICH IS APPARENTLY POTENTIATED BY CONCURRENT LIVER CIRRHOSIS. BECAUSE MANY MORE AGENTS HAVE BEEN FOUND TO BE HEPATOCARCINOGENIC IN MICE AND RATS THAN IN MEN, A QUESTION ARISES AS TO THE DIRECT RELEVANCE OF RODENT STUDIES TO HUMANS. A BALANCED ASSESSMENT OF THE CARCINOGENICITY OF THE AGENT COULD ONLY BE REACHED IN CONSIDERING BOTH THE PHARMACOKINETICS AND THE DEVELOPMENT OF MALIGNANT NEOPLASIA IN OTHER ORGANS. IN THE CASE OF POSITIVE CARCINOGENICITY ASSESSMENT, THE OUTCOME OF THE MUTAGENICITY BIOASSAYS CAN SUGGEST GENIC (GENOTOXIC) OR PARAGENIC (EPIGENETIC) MODE OF ACTION IN MAMMALIAN SYSTEMS. 1982 15 5440 33 RENAL DIFFERENTIATION OF AMNIOTIC FLUID STEM CELLS: PERSPECTIVES FOR CLINICAL APPLICATION AND FOR STUDIES ON SPECIFIC HUMAN GENETIC DISEASES. BACKGROUND: OWING TO GROWING RATES OF DIABETES, HYPERTENSION AND THE AGEING POPULATION, THE PREVALENCE OF END-STAGE RENAL DISEASE, DEVELOPED FROM EARLIER STAGES OF CHRONIC KIDNEY DISEASE, AND OF ACUTE RENAL FAILURE IS DRAMATICALLY INCREASING. DIALYSIS AND PREFERABLE RENAL TRANSPLANTATION ARE WIDELY APPLIED THERAPIES FOR THIS INCURABLE CONDITION. HOWEVER THESE OPTIONS ARE LIMITED BECAUSE OF MORBIDITY, SHORTAGE OF COMPATIBLE ORGANS AND COSTS. THEREFORE, STEM CELL-BASED APPROACHES ARE BECOMING INCREASINGLY ACCEPTED AS AN ALTERNATIVE THERAPEUTIC STRATEGY. DESIGN: THIS REVIEW SUMMARIZES THE CURRENT FINDINGS ON THE NEPHROGENIC POTENTIAL OF AMNIOTIC FLUID STEM (AFS) CELLS AND THEIR PUTATIVE IMPLICATIONS FOR CLINICAL APPLICATIONS AND FOR STUDIES ON SPECIFIC HUMAN GENETIC DISEASES. RESULTS: SINCE THEIR DISCOVERY IN 2003, AFS CELLS HAVE BEEN SHOWN TO BE PLURIPOTENT WITH THE POTENTIAL TO FORM EMBRYOID BODIES. COMPARED TO ADULT STEM CELLS, INDUCED PLURIPOTENT STEM CELLS OR EMBRYONIC STEM CELLS, AFS CELLS HARBOUR A VARIETY OF ADVANTAGES, SUCH AS THEIR HIGH DIFFERENTIATION AND PROLIFERATIVE POTENTIAL, NO NEED FOR ECTOPIC INDUCTION OF PLURIPOTENCY AND NO SOMATIC MUTATIONS AND EPIGENETIC MEMORY OF SOURCE CELLS, AND NO TUMOURIGENIC POTENTIAL AND ASSOCIATED ETHICAL CONTROVERSIES, RESPECTIVELY. CONCLUSIONS: RECENTLY, THE RESULTS OF DIFFERENT INDEPENDENT STUDIES PROVIDED EVIDENCE THAT AFS CELLS COULD INDEED BE A POWERFUL TOOL FOR RENAL REGENERATIVE MEDICINE. 2012 16 740 44 CANCER/TESTIS ANTIGENS: EXPRESSION, REGULATION, TUMOR INVASION, AND USE IN IMMUNOTHERAPY OF CANCERS. CANCER/TESTIS ANTIGENS (CTAS) ARE NAMED BASED ON THEIR EXPRESSION PATTERN THAT IS RESTRICTED IN A NUMBER OF NORMAL AND ABNORMAL TISSUES. TUMOR CELLS FREQUENTLY EXPRESS ANTIGENS WHOSE EXPRESSION IS TYPICALLY RESTRICTED TO GERM CELLS. THEIR UNIQUE EXPRESSION PATTERN IS GUARANTEED BY PRECISE EPIGENETIC REGULATORY MECHANISMS. BECAUSE OF THEIR TUMOR-LIMITED, HIGH IMMUNOGENICITY, AND BIASED EXPRESSION, DISCOVERY OF THESE MOLECULES PROVIDES UNPRECEDENTED OPPORTUNITIES FOR FURTHER RESEARCH AND CLINICAL DEVELOPMENT IN THE FIELD OF CANCER DIAGNOSIS AND IMMUNOTHERAPY. EVOLVING EVIDENCE REVEALS THAT A NUMBER OF CTAS STIMULATE EPITHELIAL MESENCHYMAL TRANSITION (EMT) AND GENERATION OF CANCER STEM-LIKE CELLS, INTENSIFYING METASTASIS, INVASION, AND TUMORIGENESIS. BASED ON THESE FEATURES, CTAS ATTRACT ATTENTION TO BE CONSIDERED AS IDEAL TARGETS FOR DEVELOPING SEVERAL CLINICAL TRIALS, MANY OF THEM CONCENTRATING ON CTA VACCINE THERAPY. ACCORDING TO RECENT PRACTICAL CLINICAL INTEREST, MORE CHARACTERIZATIONS OF CTA REGULATION ARE IDENTIFIED. CTA EXPRESSION HAS BEEN DEMONSTRATED IN A VARIETY OF HUMAN CANCER TISSUES, AND SOME OF THEM HAVE BEEN FOUND TO ELICIT HUMORAL AND/OR CELLULAR IMMUNE RESPONSES IN CANCER PATIENTS. CTAS ARE BRILLIANT TARGETS FOR ANTICANCER DRUG DISCOVERY, TARGETED TUMOR THERAPY, AND DIAGNOSTIC BIOMARKERS, FURTHERMORE, VALUED GENES IN THE STUDY OF IMMUNOTHERAPY, PROMOTING TUMORIGENESIS, AND MALIGNANT PROGRESSION. THIS REVIEW OUTLINES AND CATEGORIZES OUR CURRENT UNDERSTANDING OF THE COMPLEX AND BIASED PROCESS OF CTAS MRNA AND PROTEIN EXPRESSION IN CANCER, AND SUPPLIES THE MOST RECENT INFORMATION ON THEIR REGULATION AND FUNCTION. BESIDES, A CONCISE SYNOPSIS OF THE MAJOR CLINICAL TRIALS INVOLVING CTAS, AS THERAPEUTIC AVENUES, IS DISCUSSED. ABBREVIATIONS: AIRE: AUTOIMMUNE REGULATOR; CAMP: CYCLIC ADENOSINE 3',5'-CYCLIC MONOPHOSPHATE; CEA: CARCINOEMBRYONIC ANTIGEN; CML: CHRONIC MYELOID LEUKEMIA; CREB: CYCLICAMP RESPONSE ELEMENT BINDING; CSCS: CANCER STEM CELLS; CTAS: CANCER/TESTIS ANTIGENS; CTL: CYTOTOXIC T LYMPHOCYTE; DCS: DENDRITIC CELLS; EMT: EPITHELIAL-MESENCHYMAL TRANSITION; ERK: EXTRACELLULAR SIGNAL-REGULATED KINASE; ESCC: ESOPHAGEAL SQUAMOUS CELL CARCINOMA; ETS: E26 TRANSFORMATION-SPECIFIC; HIS: HISTIDINE; HLA: HUMAN LEUKOCYTE ANTIGEN; HNSCC: HEAD AND NECK SQUAMOUS CELL CARCINOMA; IFN-GAMMA: INTERFERON-GAMMA; IHC: IMMUNOHISTOCHEMISTRY; IL-7: INTERLEUKIN7; MHC: MAJOR HISTOCOMPATIBILITY COMPLEX; MMP2: MATRIX METALLOPROTEINASE 2; MTECS: MEDULLARY THYMUS EPITHELIAL CELLS; MUC1: MUCIN 1; NSCLC: NON-SMALL CELL LUNG CANCER; PRAME: PREFERENTIALLY EXPRESSED ANTIGEN IN MELANOMA; RDA: REPRESENTATIONAL DIFFERENCE ANALYSIS; SEREX: SEROLOGICAL ANALYSIS OF CDNA EXPRESSION; SSX: SYNOVIAL SARCOMA X CHROMOSOME; TAAS: TUMOR-ASSOCIATED ANTIGENS; TCR: T-CELL RECEPTOR; TCGA: THE CANCER GENOME ATLAS; TGF-BETA: TRANSFORMING GROWTH FACTOR-BETA. 2016 17 2765 29 EXPRESSION, EPIGENETIC REGULATION, AND HUMORAL IMMUNOGENICITY OF CANCER-TESTIS ANTIGENS IN CHRONIC MYELOID LEUKEMIA. OBJECTIVE: CANCER-TESTIS (CT) ANTIGENS REPRESENT ATTRACTIVE TARGETS FOR TUMOR IMMUNOTHERAPY BASED ON THEIR TUMOR-RESTRICTED EXPRESSION AND IMMUNOGENICITY. HOWEVER, A BROAD PICTURE OF THE EXPRESSION OF CT ANTIGENS AND ASSOCIATED HUMORAL IMMUNE RESPONSES IN CHRONIC MYELOID LEUKEMIA (CML) IS STILL MISSING. METHODS: WE SCREENED CML CELL LINES AND BONE MARROW (BM) SAMPLES FROM HEALTHY DONORS BY RT-PCR FOR THE EXPRESSION OF 31 CT ANTIGENS BEFORE AND AFTER TREATMENT WITH EPIGENETIC AGENTS. EXPRESSION OF TUMOR-RESTRICTED ANTIGENS WAS FURTHER EXAMINED IN 60 CML PATIENTS AND HUMORAL IMMUNE RESPONSES AGAINST 15 CT ANTIGENS WERE SCREENED BY ELISA. RESULTS: IN UNTREATED CELL LINES WE DETECTED THE EXPRESSION OF 17 CT ANTIGENS THAT WERE ABSENT FROM NORMAL BM. EXPRESSION OF MOST ANTIGENS INCREASED FOLLOWING DEMETHYLATING TREATMENT WITH 5'-AZA-2'-DEOXYCYTIDINE. IN THESE SAMPLES, ONLY PRAME WAS REPEATEDLY DETECTED AND EXPRESSION CORRELATED WITH SEVERAL CLINICOPATHOLOGICAL PARAMETERS AND DECREASED OVERALL SURVIVAL. WE FURTHER SHOW THAT A LOWER FREQUENCY OF PRAME-POSITIVE SAMPLES DURING IMATINIB TREATMENT WAS NOT CAUSED BY GENE-SPECIFIC DOWNREGULATION. ANALYZING THE PATIENTS' ANTIBODY RESPONSES WE FOUND THAT THE VAST MAJORITY OF PATIENTS LACKED SPONTANEOUS IMMUNITY AGAINST CT ANTIGENS INCLUDING PRAME. CONCLUSIONS: CT ANTIGEN EXPRESSION CAN BE INCREASED BY THE APPLICATION OF EPIGENETIC AGENTS AND THE EXPRESSION OF PRAME CORRELATES WITH CLINICOPATHOLOGICAL PARAMETERS AND OVERALL SURVIVAL IN PATIENTS WITH CML, BUT DOES NOT LEAD TO HUMORAL IMMUNE RESPONSES. PRAME-SPECIFIC IMMUNOTHERAPY MIGHT REPRESENT A PROMISING APPROACH FOR THE ERADICATION OF RESIDUAL THERAPY-RESISTANT LEUKEMIC CELLS DUE TO ITS FREQUENT EXPRESSION AND STABILITY UNDER IMATINIB TREATMENT. 2010 18 1122 42 COMPARISON OF GENE EXPRESSION PROFILES IN CHROMATE TRANSFORMED BEAS-2B CELLS. BACKGROUND: HEXAVALENT CHROMIUM [CR(VI)] IS A POTENT HUMAN CARCINOGEN. OCCUPATIONAL EXPOSURE HAS BEEN ASSOCIATED WITH INCREASED RISK OF RESPIRATORY CANCER. MULTIPLE MECHANISMS HAVE BEEN SHOWN TO CONTRIBUTE TO CR(VI) INDUCED CARCINOGENESIS, INCLUDING DNA DAMAGE, GENOMIC INSTABILITY, AND EPIGENETIC MODULATION, HOWEVER, THE MOLECULAR MECHANISM AND DOWNSTREAM GENES MEDIATING CHROMIUM'S CARCINOGENICITY REMAIN TO BE ELUCIDATED. METHODS/RESULTS: WE ESTABLISHED CHROMATE TRANSFORMED CELL LINES BY CHRONIC EXPOSURE OF NORMAL HUMAN BRONCHIAL EPITHELIAL BEAS-2B CELLS TO LOW DOSES OF CR(VI) FOLLOWED BY ANCHORAGE-INDEPENDENT GROWTH. THESE TRANSFORMED CELL LINES NOT ONLY EXHIBITED CONSISTENT MORPHOLOGICAL CHANGES BUT ALSO ACQUIRED ALTERED AND DISTINCT GENE EXPRESSION PATTERNS COMPARED WITH NORMAL BEAS-2B CELLS AND CONTROL CELL LINES (UNTREATED) THAT AROSE SPONTANEOUSLY IN SOFT AGAR. INTERESTINGLY, THE GENE EXPRESSION PROFILES OF SIX CR(VI) TRANSFORMED CELL LINES WERE REMARKABLY SIMILAR TO EACH OTHER YET DIFFERED SIGNIFICANTLY FROM THAT OF EITHER CONTROL CELL LINES OR NORMAL BEAS-2B CELLS. A TOTAL OF 409 DIFFERENTIALLY EXPRESSED GENES WERE IDENTIFIED IN CR(VI) TRANSFORMED CELLS COMPARED TO CONTROL CELLS. GENES RELATED TO CELL-TO-CELL JUNCTION WERE UPREGULATED IN ALL CR(VI) TRANSFORMED CELLS, WHILE GENES ASSOCIATED WITH THE INTERACTION BETWEEN CELLS AND THEIR EXTRACELLULAR MATRICES WERE DOWN-REGULATED. ADDITIONALLY, EXPRESSION OF GENES INVOLVED IN CELL PROLIFERATION AND APOPTOSIS WERE ALSO CHANGED. CONCLUSION: THIS STUDY IS THE FIRST TO REPORT GENE EXPRESSION PROFILING OF CR(VI) TRANSFORMED CELLS. THE GENE EXPRESSION CHANGES ACROSS INDIVIDUAL CHROMATE EXPOSED CLONES WERE REMARKABLY SIMILAR TO EACH OTHER BUT DIFFERED SIGNIFICANTLY FROM THE GENE EXPRESSION FOUND IN ANCHORAGE-INDEPENDENT CLONES THAT AROSE SPONTANEOUSLY. OUR ANALYSIS IDENTIFIED MANY NOVEL GENE EXPRESSION CHANGES THAT MAY CONTRIBUTE TO CHROMATE INDUCED CELL TRANSFORMATION, AND COLLECTIVELY THIS TYPE OF INFORMATION WILL PROVIDE A BETTER UNDERSTANDING OF THE MECHANISM UNDERLYING CHROMATE CARCINOGENICITY. 2011 19 4148 34 MECHANISTIC BASIS OF EX VIVO UMBILICAL CORD BLOOD STEM PROGENITOR CELL EXPANSION. UMBILICAL CORD BLOOD (CB) TRANSPLANTATION HAS BEEN USED SUCCESSFULLY IN HUMANS FOR THREE DECADES DUE TO ITS RAPID AVAILABILITY FOR PATIENTS LACKING A SUITABLE ALLOGENEIC DONOR, LESS STRINGENT HLA MATCHING REQUIREMENTS, AND LOW RATES OF RELAPSE AND CHRONIC GRAFT-VERSUS-HOST DISEASE (GVHD). HOWEVER, CB TRANSPLANTATION IS ASSOCIATED WITH COMPLICATIONS, SUCH AS DELAYED HEMATOPOIETIC ENGRAFTMENT, GRAFT FAILURE, WHICH INCREASES INFECTION AND BLEEDING AND CAUSES LONGER HOSPITAL STAYS, AND TRANSPLANT-RELATED MORTALITY. THE MAJORITY OF THESE BIOLOGICAL LIMITATIONS ARE DUE TO THE UNFORESEEABLE FUNCTIONAL POTENCY OF MULTIPOTENT HEMATOPOIETIC STEM CELLS (HSCS), WHICH REDUCE THE PREDICTABILITY OF SUCCESSFUL TRANSPLANTATION; HOWEVER, SEVERAL STRATEGIES HAVE BEEN DEVELOPED TO INCREASE THE NUMBER OF HEMATOPOIETIC STEM PROGENITOR CELLS (HSPCS) INFUSED DURING CB TRANSPLANTATION. THIS REVIEW PRIMARILY ADDRESSES THE METHODS THAT PROMOTE EX VIVO CB EXPANSION WITHIN THE CONTEXT OF SYMMETRICAL AND ASYMMETRICAL HSC DIVISION AND THOSE THAT RELY ON EPIGENETIC MECHANISMS, ALONG WITH THE REPORTEDLY MOST SUCCESSFUL CYTOKINE COMBINATIONS. WE ALSO REVIEW RECENT CLINICAL RESEARCH ON SMALL MOLECULES (STEMREGENIN-1, UM171, AND NICOTINAMIDE) IN EX VIVO EXPANDED CB AND DISCUSS YET UNVALIDATED PRECLINICAL STRATEGIES. EXPANDING AND TRANSPLANTING CB GRAFT ENRICHED IN HSPCS IN A SINGLE CB UNIT IS A PARTICULARLY EXCITING PROSPECT WITH THE POTENTIAL TO IMPROVE THE USE AND AVAILABILITY OF CB GRAFTS. GREATER KNOWLEDGE OF OPTIMAL EX VIVO EXPANSION STRATEGIES, CELL LONGEVITY, AND GRAFT POTENCY WILL EXPAND THE SCOPE OF CELLULAR THERAPIES. ALSO THE DEVELOPMENT OF ADEQUATE EX VIVO HSPC EXPANSION STRATEGIES COULD BRING EXPANDED CORD BLOOD GRAFTS TO THE FOREFRONT OF TRANSPLANT THERAPY AND REGENERATIVE MEDICINE. 2020 20 791 28 CELLULAR AND MOLECULAR NETWORKS IN CHRONIC MYELOID LEUKEMIA: THE LEUKEMIC STEM, PROGENITOR AND STROMAL CELL INTERPLAY. THE USE OF IMATINIB, SECOND AND THIRD GENERATION ABL TYROSINE KINASE INHIBITORS (TKI) (I.E. DASATINIB, NILOTINIB, BOSUTINIB AND PONATINIB) MADE CML A CLINICALLY MANAGEABLE AND, IN A SMALL PERCENTAGE OF CASES, A CURED DISEASE. TKI THERAPY ALSO TURNED CML BLASTIC TRANSFORMATION INTO A RARE EVENT; HOWEVER, DISEASE PROGRESSION STILL OCCURS IN THOSE PATIENTS WHO ARE REFRACTORY, NOT COMPLIANT WITH TKI THERAPY OR DEVELOP RESISTANCE TO MULTIPLE TKIS. IN THE PAST FEW YEARS, IT BECAME CLEAR THAT THE BCRABL1 ONCOGENE DOES NOT OPERATE ALONE TO DRIVE DISEASE EMERGENCE, MAINTENANCE AND PROGRESSION. INDEED, IT SEEMS THAT BONE MARROW (BM) MICROENVIRONMENT-GENERATED SIGNALS AND CELL AUTONOMOUS BCRABL1 KINASE-INDEPENDENT GENETIC AND EPIGENETIC ALTERATIONS ALL CONTRIBUTE TO: I. PERSISTENCE OF A QUIESCENT LEUKEMIC STEM CELL (LSC) RESERVOIR, II. INNATE OR ACQUIRED RESISTANCE TO TKIS, AND III. PROGRESSION INTO THE FATAL BLAST CRISIS STAGE. HEREIN, WE REVIEW THE INTRICATE LEUKEMIC NETWORK IN WHICH ABERRANT, BUT FINELY TUNED, SURVIVAL, MITOGENIC AND SELF-RENEWAL SIGNALS ARE GENERATED BY LEUKEMIC PROGENITORS, STROMAL CELLS, IMMUNE CELLS AND METABOLIC MICROENVIRONMENTAL CONDITIONS (E.G. HYPOXIA) TO PROMOTE LSC MAINTENANCE AND BLASTIC TRANSFORMATION. 2017