1 6813 123 [EPILEPSY-ASSOCIATED TUMORS OF THE CENTRAL NERVOUS SYSTEM: EPILEPSY SURGERY AND ONCOLOGICAL ASPECTS]. BACKGROUND: AMONG THE TUMORS ASSOCIATED WITH CHRONIC EPILEPSY, DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR AND GANGLIOGLIOMA ARE THE MOST COMMON BESIDES ANGIOCENTRIC GLIOMA, PLEOMORPHIC XANTHOASTROCYTOMA AND PILOCYTIC ASTROCYTOMA. THESE TUMORS ARE USUALLY CONSIDERED AS BEING BENIGN. OBJECTIVE: TO DETERMINE THE BEST CONSERVATIVE AND SURGICAL TREATMENT OF TUMORS ASSOCIATED WITH EPILEPSY. MATERIAL AND METHODS: THIS ARTICLE PRESENTS CASE REPORTS OF MALIGNANT TRANSFORMATION OF A DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR AND OF A TUMOR INITIALLY DIAGNOSED AS A GANGLIOGLIOMA BASED ON MAGNETIC RESONANCE IMAGING (MRI) CRITERIA. DESCRIPTION OF REFERENCES IN THE LITERATURE ON EPILEPSY SURGERY AND THE NEURO-ONCOLOGY OF EPILEPSY-ASSOCIATED TUMORS. RESULTS: IN THE CASE OF THE INITIALLY HISTOPATHOLOGICALLY DIAGNOSED DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR, A MALIGNANT TRANSFORMATION OCCURRED 5 YEARS AFTER INCOMPLETE RESECTION. THE DIFFERENTIATION FROM A GLIOBLASTOMA WAS POSSIBLE THROUGH THE ANALYSIS OF THE METHYLATION PROFILE. IN ANOTHER CASE A TUMOR ASSUMED TO BE A GANGLIOGLIOMA SHOWED AN INCREASE IN SIZE AFTER 6 YEARS. INITIAL HISTOPATHOLOGICAL RESULTS REVEALED A GLIOBLASTOMA. THE ANALYSIS OF THE METHYLATION PROFILE SUGGESTED THE DIAGNOSIS OF AN ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA AND AS A DIFFERENTIAL DIAGNOSIS AN ANAPLASTIC GANGLIOGLIOMA. TUMOR PROGRESS CORRELATED WITH THE WORSENING OF SEIZURES. CONCLUSION: RECENT STUDIES HAVE SHOWN THAT IN THE TREATMENT OF PREDOMINANTLY BENIGN EPILEPSY-ASSOCIATED TUMORS NEURO-ONCOLOGICAL ASPECTS SHOULD ALSO BE TAKEN INTO ACCOUNT IN ADDITION TO THE EPILEPTOLOGICAL CONSIDERATIONS. IN THE CASE OF MALIGNANT TRANSFORMATION EPIGENETIC SCREENING (METHYLATION PROFILES) CAN HELP TO CLASSIFY THE TUMOR ENTITY MORE PRECISELY. 2016 2 3694 33 INFLAMMATORY COMPONENTS OF THE THYROID CANCER MICROENVIRONMENT: AN AVENUE FOR IDENTIFICATION OF NOVEL BIOMARKERS. THE INCIDENCE OF THYROID CANCER IN THE UNITED STATES IS ON THE RISE WITH AN APPRECIABLY HIGH DISEASE RECURRENCE RATE OF 20-30%. ANAPLASTIC THYROID CANCER (ATC), ALTHOUGH RARE IN OCCURRENCE, IS AN AGGRESSIVE FORM OF CANCER WITH LIMITED TREATMENT OPTIONS AND BLEAK CURE RATES. THIS CHAPTER USES DISCUSSIONS OF IN VITRO MODELS THAT ARE REPRESENTATIVE OF PAPILLARY, ANAPLASTIC, AND FOLLICULAR THYROID CANCER TO EVALUATE THE CROSSTALK BETWEEN SPECIFIC CELLS OF THE TUMOR MICROENVIRONMENT (TME), WHICH SERVES AS A HIGHLY HETEROGENEOUS REALM OF SIGNALING CASCADES AND METABOLISM THAT ARE ASSOCIATED WITH TUMORIGENESIS. THE CELLULAR CONSTITUENTS OF THE TME CARRY OUT VARYING CHARACTERISTIC IMMUNOMODULATORY FUNCTIONS THAT ARE DISCUSSED THROUGHOUT THIS CHAPTER. THE AFOREMENTIONED CELL TYPES INCLUDE CANCER-ASSOCIATED FIBROBLASTS (CAFS), ENDOTHELIAL CELLS (ECS), AND CANCER STEM CELLS (CSCS), AS WELL AS SPECIFIC IMMUNE CELLS, INCLUDING NATURAL KILLER (NK) CELLS, DENDRITIC CELLS (DCS), MAST CELLS, T REGULATORY (TREG) CELLS, CD8+ T CELLS, AND TUMOR-ASSOCIATED MACROPHAGES (TAMS). TAM-MEDIATED INFLAMMATION IS ASSOCIATED WITH A POOR PROGNOSIS OF THYROID CANCER, AND THE MOLECULAR BASIS OF THE CELLULAR CROSSTALK BETWEEN MACROPHAGES AND THYROID CANCER CELLS WITH RESPECT TO INDUCING A METASTATIC PHENOTYPE IS NOT YET KNOWN. THE DYNAMIC NATURE OF THE PHYSIOLOGICAL TRANSITION TO PATHOLOGICAL METASTATIC PHENOTYPES WHEN ESTABLISHING THE TME ENCOMPASSES A WIDE RANGE OF CHARACTERISTICS THAT ARE FURTHER EXPLORED WITHIN THIS CHAPTER, INCLUDING THE ROLES OF SOMATIC MUTATIONS AND EPIGENETIC ALTERATIONS THAT DRIVE THE GENETIC HETEROGENEITY OF CANCER CELLS, ALLOWING FOR SELECTIVE ADVANTAGES THAT AID IN THEIR PROLIFERATION. INDUCTION OF THESE PROLIFERATING CELLS IS TYPICALLY ACCOMPLISHED THROUGH INFLAMMATORY INDUCTION, WHEREBY CHRONIC INFLAMMATION SETS UP A CONSTANT PHYSIOLOGICAL STATE OF INFLAMMATORY CELL RECRUITMENT. THE SECRETIONS OF THESE INFLAMMATORY CELLS CAN ALTER THE GENETIC MAKEUP OF PROLIFERATING CELLS, WHICH CAN IN TURN, PROMOTE TUMOR GROWTH.THIS CHAPTER ALSO PRESENTS AN IN-DEPTH ANALYSIS OF MOLECULAR INTERACTIONS WITHIN THE TME, INCLUDING SECRETORY CYTOKINES AND EXOSOMES. SINCE THE EXOSOMAL CARGO OF A CELL IS A REFLECTION AND FINGERPRINT OF THE ORIGINATING PARENTAL CELLS, THE PROFILING OF EXOSOMAL MIRNA DERIVED FROM THYROID CANCER CELLS AND MACROPHAGES IN THE TME MAY SERVE AS AN IMPORTANT STEP IN BIOMARKER DISCOVERY. IDENTIFICATION OF A DISTINCT SET OF TUMOR SUPPRESSIVE MIRNAS DOWNREGULATED IN ATC-SECRETED EXOSOMES INDICATES THEIR ROLE IN THE REGULATION OF TUMOR SUPPRESSIVE GENES THAT MAY INCREASE THE METASTATIC PROPENSITY OF ATC. ADDITIONALLY, THE HIGH EXPRESSION OF PRO-INFLAMMATORY CYTOKINES IN STUDIES LOOKING AT THYROID CANCER AND ACTIVATED MACROPHAGE CONDITIONED MEDIA SUGGESTS THE EXISTENCE OF AN INFLAMMATORY TME IN THYROID CANCER. NEW FINDINGS ARE SUGGESTIVE OF THE PRESENCE OF A METASTATIC NICHE IN ATC TISSUES THAT IS INFLUENCED BY THYROID TUMOR MICROENVIRONMENT SECRETOME-INDUCED EPITHELIAL TO MESENCHYMAL TRANSITION (EMT), MEDIATED BY A RECIPROCAL INTERACTION BETWEEN THE PRO-INFLAMMATORY M1 MACROPHAGES AND THE THYROID CANCER CELLS. THUS, TARGETING THE METASTATIC THYROID CARCINOMA MICROENVIRONMENT COULD OFFER POTENTIAL THERAPEUTIC BENEFITS AND SHOULD BE EXPLORED FURTHER IN PRECLINICAL AND TRANSLATIONAL MODELS OF HUMAN METASTATIC THYROID CANCER. 2021 3 3934 42 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 4 5944 25 TARGETING SMALL MOLECULE TYROSINE KINASES BY POLYPHENOLS: NEW MOVE TOWARDS ANTI-TUMOR DRUG DISCOVERY. BACKGROUND: CANCER IS A COMPLEX DISEASE INVOLVING GENETIC AND EPIGENETIC ALTERATION THAT ALLOWS CELLS TO ESCAPE NORMAL HOMEOSTASIS. KINASES PLAY A CRUCIAL ROLE IN SIGNALING PATHWAYS THAT REGULATE CELL FUNCTIONS. DEREGULATION OF KINASES LEADS TO A VARIETY OF PATHOLOGICAL CHANGES, ACTIVATING CANCER CELL PROLIFERATION AND METASTASES. THE MOLECULAR MECHANISM OF CANCER IS COMPLEX AND THE DYSREGULATION OF TYROSINE KINASES LIKE ANAPLASTIC LYMPHOMA KINASE (ALK), BCR-ABL (FUSION GENE FOUND IN PATIENT WITH CHRONIC MYELOGENOUS LEUKEMIA (CML), JAK (JANUS ACTIVATED KINASE), SRC FAMILY KINASES (SFKS), ALK (ANAPLASTIC LYMPHOMA KINASE), C-MET (MESENCHYMAL- EPITHELIAL TRANSITION), EGFR (EPIDERMAL GROWTH FACTOR RECEPTOR), PDGFR (PLATELET-DERIVED GROWTH FACTOR RECEPTOR), RET (REARRANGED DURING TRANSFECTION) AND VEGFR (VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR) PLAYS MAJOR ROLE IN THE PROCESS OF CARCINOGENESIS. RECENTLY, KINASE INHIBITORS HAVE OVERCOME MANY PROBLEMS OF TRADITIONAL CANCER CHEMOTHERAPY AS THEY EFFECTIVELY SEPARATE OUT NORMAL, NON-CANCER CELLS AS WELL AS RAPIDLY MULTIPLYING CANCER CELLS. METHODS: ELECTRONIC DATABASES WERE SEARCHED TO EXPLORE THE SMALL MOLECULE TYROSINE KINASES BY POLYPHENOLS WITH THE HELP OF DOCKING STUDY (GLIDE-7.6 PROGRAM INTERFACED WITH MAESTRO-V11.3 OF SCHRODINGER 2017) TO SHOW THE BINDING ENERGIES OF POLYPHENOLS INHIBITOR WITH DIFFERENT TYROSINE KINASES IN ORDER TO DIFFERENTIATE BETWEEN THE TARGETS. RESULTS: FROM THE LITERATURE SURVEY, IT WAS OBSERVED THAT THE NUMBER OF POLYPHENOLS DERIVED FROM NATURAL SOURCES ALTERS THE EXPRESSION AND SIGNALING CASCADE OF TYROSINE KINASE IN VARIOUS TUMOR MODELS. THEREFORE, THE DEVELOPMENT OF POLYPHENOLS AS A TYROSINE KINASE INHIBITOR AGAINST TARGETED PROTEINS IS REGARDED AS AN UPCOMING TREND FOR CHEMOPREVENTION. CONCLUSION: IN THIS REVIEW, WE HAVE DISCUSSED THE ROLE OF POLYPHENOLS AS CHEMORECEPTIVE WHICH WILL HELP IN FUTURE FOR THE DEVELOPMENT AND DISCOVERY OF NOVEL SEMISYNTHETIC ANTICANCER AGENTS COUPLED WITH POLYPHENOLS. 2020 5 4963 39 PATHOGENESIS OF THYROID NODULES: HISTOLOGICAL CLASSIFICATION? THYROID NODULE GENESIS MAY BE CONSIDERED AS AN AMPLIFICATION OF THYROID HETEROGENEITY DUE TO GENETIC AND/OR EPIGENETIC MECHANISMS. WE CLASSIFIED THE THYROID NODULES IN FIVE TYPES WITH DISTINCT HISTOLOGICAL FEATURES: HYPERPLASTIC, NEOPLASTIC, COLLOID, CYSTIC AND THYROIDITIC NODULES. HYPERPLASTIC: THYROCYTE PROLIFERATION IS UNDER THE CONTROL OF TSH BUT SEVERAL OTHER PARACRINE AND AUTOCRINE FACTORS ARE SECRETED BY FOLLICULAR CELLS, THE STROMAL APPARATUS AND THE LYMPHOCYTES, WHICH ARE IMPLICATED IN INITIATION AND PERPETUATION OF THYROID HYPERPLASIA. GROWTH OCCURS MAINLY THROUGH TSHR, CAMP AND PKA. CONSTITUTIVE CAMP OVERPRODUCTION HAS BEEN SHOWN TO BE DUE TO POINT MUTATION OF THE TSHR OR GS PROTEIN, PRODUCING OVERGROWTH AND HYPERFUNCTION. NEOPLASTIC: SEVERAL ACTIVATED ONCOGENES HAVE BEEN IDENTIFIED IN THYROID MALIGNANCIES. ONCOGENES RELEVANT TO THE THYROID CARCINOGENESIS ARE: MUTATED TSHR AND GSP (CONSTITUTIVE ACTIVATION OF CAMP); TRK (RECEPTOR FOR NGF); RET/PTC (PHOSPHORYLATION OF TYROSINE KINASE RECEPTOR)--AN ISOFORM OF THIS ONCOGENE IS INDUCED BY RADIATION: RAS (IT ENCODES GS PROTEINS TRANSDUCING MITOGENIC SIGNALS); AND C-MET (RECEPTOR FOR HEPATOCYTE GROWTH FACTOR). THE EVOLUTION OF A DIFFERENTIATED THYROID CANCER TOWARDS AN UNDIFFERENTIATED CANCER IS DUE TO A MUTATION OF A FAMILY OF PROTEINS (I.E., P53), WHICH ACTS AS A BRAKE, PREVENTING THE GENOMIC INSTABILITY OF CANCER. IT IS SUGGESTED THAT A TUMOR INITIATES BY RET OR RAS AND POSSIBLY PROGRESSES--AS A RESULT OF ADDITIONAL MUTATIONS AND BY P53 MUTATION--TO ANAPLASTIC CARCINOMA. COLLOID: FLATTENING OF THE EPITHELIUM AND DILATATION OF FOLLICLES CONTAINING VISCOUS MATERIAL--MADE UP BY A CONCENTRATED SOLUTION OF THYROGLOBULIN (HTG)--IS THE CHARACTERISTIC OF THE COLLOID NODULE. A DEFECT OF INTRALUMINAL REABSORPTION OF HTG HAS BEEN SUGGESTED BUT NOT PROVEN. EXPERIMENTALLY, A LOAD OF IODINE IS ABLE TO CHANGE THYROID HYPERPLASIA TO A COLLOID FEATURE; HOWEVER, A LOAD OF IODINE IS RARELY FOUND IN THE CLINICAL HISTORY OF PATIENTS. A NEW CLUE TO THE PATHOGENESIS COMES FROM THE FINDING THAT A RELEVANT PART OF THE COLLOID (10-20%) IS MADE UP OF INSOLUBLE GLOBULES, WHERE HTG IS COMPACTED IN A POLYMERIC FORM. IT IS SUGGESTED THAT STOCKING HTG INTO GLOBULES IS DEFECTIVE IN COLLOID NODULES, LEADING TO ENORMOUS ENLARGEMENT OF THE FOLLICLE. CYSTIC: IT IS ESTIMATED THAT BETWEEN 15 AND 40% OF THYROID NODULES ARE PARTLY OR ENTIRELY CYSTIC. THE 'TRUE CYST' IS RARE; MOST OF THE SO-CALLED CYSTIC NODULES ARE 'PSEUDOCYSTS', WHICH FOLLOW NECROSIS AND COLLIQUATION. NECROSIS ISSUES AS AN IMBALANCE BETWEEN GROWTH AND THE PRECISELY REGULATED PROCESS OF ANGIOGENESIS. MORE RECENTLY, THE VEGF/VPF HAS BEEN FOUND TO BE AT THE ORIGIN OF RECENT AND RECURRENT CYSTS. IMMUNOTOXIC AND APOPTOTIC MECHANISMS HAVE ALSO BEEN SUGGESTED. CHEMICAL ANALYSIS OF CYSTIC FLUID SHOWED A 'DENATURED' AND 'SERUM-LIKE' PATTERN SUGGESTING DIFFERENT MECHANISMS IN THE PATHOGENESIS OF THE PSEUDOCYSTIC THYROID NODULES. THYROIDITIC: NODULAR LYMPHOCYTIC THYROIDITIS (NLT) INCLUDES TWO DIFFERENT ENTITIES: 1) LYMPHOCYTE THYROIDITIS GROWING AS A NODULE IN A HYPERPLASTIC OR NORMAL GLAND, AND 2) LYMPHOCYTE THYROIDITIS ASSOCIATED IN THE SAME NODULE WITH OTHER NODULAR DISEASES OF THE THYROID: PAPILLARY THYROID CARCINOMA AND LYMPHOMA HAVE BEEN FOUND TO BE ASSOCIATED TO CHRONIC LYMPHOCYTIC THYROIDITIS. 2001 6 2326 23 EPIGENETIC REGULATION OF HOTAIR IN ADVANCED CHRONIC MYELOID LEUKEMIA. PURPOSE: CHRONIC MYELOID LEUKEMIA (CML) ACCOUNTS FOR ~10% OF LEUKEMIA CASES, AND ITS PROGRESSION INVOLVES EPIGENETIC GENE REGULATION. THIS STUDY INVESTIGATED EPIGENETIC REGULATION OF HOTAIR AND ITS TARGET MICRORNA, MIR-143, IN ADVANCED CML. PATIENTS AND METHODS: WE FIRST ISOLATED BONE MARROW MONONUCLEAR CELLS FROM 70 PATIENTS WITH DIFFERENT PHASES OF CML AND FROM HEALTHY DONORS AS NORMAL CONTROL; WE ALSO CULTURED K562 AND KCL22 CELLS, TREATED WITH DEMETHYLATION DRUG; MTT ASSAY, FLOW CYTOMETRY, QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION (QPCR), METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), WESTERN BLOT, LUCIFERASE ASSAY, RNA PULL-DOWN ASSAY AND RNA-BINDING PROTEIN IMMUNOPRECIPITATION (RIP) ASSAY WERE PERFORMED. RESULT: AS MEASURED BY QPCR, HOTAIR EXPRESSION IN K562 CELLS, KCL22 CELLS, AND SAMPLES FROM CASES OF ADVANCED-STAGE CML INCREASED WITH LEVELS OF SEVERAL DNA METHYLTRANSFERASES AND HISTONE DEACETYLATES, INCLUDING DNMT1, DNMT3A, HDAC1, EZH2, AND LSD1, AND MIR-143 LEVELS WERE DECREASED AND HOTAIR LEVELS WERE INCREASED. TREATMENT WITH 5-AZACYTIDINE, A DNA METHYLATION INHIBITOR, DECREASED DNMT1, DNMT3A, HDAC1, EZH2, LSD1 MRNA, PROTEIN LEVELS, AND HOTAIR MRNA LEVELS BUT INCREASED MIR-143 LEVELS. HOTAIR KNOCKDOWN AND MIR-143 OVEREXPRESSION BOTH INHIBITED PROLIFERATION AND PROMOTED APOPTOSIS IN KCL22 AND K562 CELLS THROUGH THE PI3K/AKT PATHWAY. RNA PULL-DOWN, MASS SPECTROMETRY, AND RIP ASSAYS SHOWED THAT HOTAIR INTERACTED WITH EZH2 AND LSD1. A DUAL-LUCIFERASE ASSAY DEMONSTRATED THAT HOTAIR INTERACTED WITH MIR-143. CONCLUSION: OUR FINDINGS DEMONSTRATE THE KEY EPIGENETIC INTERACTIONS OF HOTAIR RELATED TO CML PROGRESSION AND SUGGEST HOTAIR AS A POTENTIAL THERAPEUTIC TARGET FOR ADVANCED CML. FURTHERMORE, OUR RESULTS SUPPORT THE USE OF DEMETHYLATION DRUGS AS A CML TREATMENT STRATEGY. 2018 7 1481 22 DIVERSITY OF GENOME PROFILES IN MALIGNANT LYMPHOMA. CHARACTERISTIC CHROMOSOME TRANSLOCATIONS ARE ASSOCIATED WITH SPECIFIC DISEASE ENTITIES, AND ARE KNOWN TO PLAY A PIVOTAL ROLE IN LYMPHOMA DEVELOPMENT. CHROMOSOME TRANSLOCATION ALONE, HOWEVER, IS NOT SUFFICIENT TO PRODUCE TUMORS. FACTORS INCLUDING THE MICROENVIRONMENT AND EPIGENETIC AND GENETIC ALTERATIONS OTHER THAN CHROMOSOME TRANSLOCATIONS HAVE BEEN SHOWN TO PLAY A ROLE IN LYMPHOMA DEVELOPMENT. FOLLICULAR LYMPHOMA CELLS PROLIFERATE IN CLOSE CONTACT WITH FOLLICULAR DENDRITIC CELLS. MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA CELLS PROLIFERATE AT THE MARGINAL ZONE AREA OF REACTIVE FOLLICLES WHICH ARE FORMED BY PRECEDING CHRONIC INFLAMMATION. THE IMPORTANCE OF GENETIC ALTERATIONS OTHER THAN CHROMOSOME TRANSLOCATION HAS BEEN RECOGNIZED SINCE THE INTRODUCTION OF ARRAY COMPARATIVE GENOMIC HYBRIDIZATION (ARRAY CGH). VARIATIONS IN THE GENOMIC PROFILE AMONG PATIENTS WITH THE SAME DISEASE ENTITY HAVE BEEN FOUND BY ARRAY CGH ANALYSES. THESE VARIATIONS INDICATE THAT MULTIPLE GENETIC PATHWAYS LEADING TO THE DEVELOPMENT OF LYMPHOMAS MAY EXIST AND HENCE RESULT IN THE VARIABLE CLINICOPATHOLOGICAL FEATURES OBSERVED. 2010 8 6539 21 TRANSCRIPTIONAL VARIATIONS IN THE WIDER PERITUMORAL TISSUE ENVIRONMENT OF PANCREATIC CANCER. TRANSCRIPTIONAL PROFILING WAS PERFORMED ON 452 RNA PREPARATIONS ISOLATED FROM VARIOUS TYPES OF PANCREATIC TISSUE FROM TUMOUR PATIENTS AND HEALTHY DONORS, WITH A PARTICULAR FOCUS ON PERITUMORAL SAMPLES. PANCREATIC DUCTAL ADENOCARCINOMAS (PDAC) AND CYSTIC TUMOURS WERE MOST DIFFERENT IN THESE NON-TUMOROUS TISSUES SURROUNDING THEM, WHEREAS THE ACTUAL TUMOURS EXHIBITED RATHER SIMILAR TRANSCRIPT PATTERNS. THE ENVIRONMENT OF CYSTIC TUMOURS WAS TRANSCRIPTIONALLY NEARLY IDENTICAL TO NORMAL PANCREAS TISSUE. IN CONTRAST, THE TISSUE AROUND PDAC BEHAVED A LOT LIKE THE TUMOUR, INDICATING SOME KIND OF FIELD DEFECT, WHILE SHOWING FAR LESS MOLECULAR RESEMBLANCE TO BOTH CHRONIC PANCREATITIS AND HEALTHY TISSUE. THIS SUGGESTS THAT THE MAJOR PATHOGENIC DIFFERENCE BETWEEN CYSTIC AND DUCTAL TUMOURS MAY BE DUE TO THEIR CELLULAR ENVIRONMENT RATHER THAN THE FEW VARIATIONS BETWEEN THE TUMOURS. LACK OF CORRELATION BETWEEN DNA METHYLATION AND TRANSCRIPT LEVELS MAKES IT UNLIKELY THAT THE OBSERVED FIELD DEFECT IN THE PERITUMORAL TISSUE OF PDAC IS CONTROLLED TO A LARGE EXTENT BY SUCH EPIGENETIC REGULATION. FUNCTIONALLY, A STRIKINGLY LARGE NUMBER OF AUTOPHAGY-RELATED TRANSCRIPTS WAS CHANGED IN BOTH PDAC AND ITS PERITUMORAL TISSUE, BUT NOT IN OTHER PANCREATIC TUMOURS. A TRANSCRIPTION SIGNATURE OF 15 AUTOPHAGY-RELATED GENES WAS ESTABLISHED THAT PERMITS A PROGNOSIS OF SURVIVAL WITH HIGH ACCURACY AND INDICATES THE ROLE OF AUTOPHAGY IN TUMOUR BIOLOGY. 2018 9 4303 27 MICRORNA-223 INHIBITS TISSUE FACTOR EXPRESSION IN VASCULAR ENDOTHELIAL CELLS. OBJECTIVE: ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY PROCESS, IN WHICH VASCULAR ENDOTHELIAL CELLS (ECS) BECOME DYSFUNCTIONAL OWING TO THE EFFECTS OF CHEMICAL SUBSTANCES, SUCH AS INFLAMMATORY FACTOR AND GROWTH FACTORS. TISSUE FACTOR (TF) EXPRESSION IS INDUCED BY THE ABOVE CHEMICAL SUBSTANCES IN ACTIVATED ECS. TF INITIATES THROMBOSIS ON DISRUPTED ATHEROSCLEROTIC PLAQUES WHICH PLAYS AN ESSENTIAL ROLE DURING THE ONSET OF ACUTE CORONARY SYNDROMES (ACS). INCREASING EVIDENCES SUGGEST THE IMPORTANT ROLE OF MICRORNAS AS EPIGENETIC REGULATORS OF ATHEROSCLEROTIC DISEASE. THE AIM OF OUR STUDY IS TO IDENTIFY IF MICRORNA-223 (MIR-223) TARGETS TF IN ECS. METHODS AND RESULTS: BIOINFORMATIC ANALYSIS SHOWED THAT TF IS A TARGET CANDIDATE OF MIR-223. WESTERN BLOTTING ANALYSIS REVEALED THAT TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA) INCREASED TF EXPRESSION IN AORTA OF C57BL/6J MICE AND CULTURED ECS (EA.HY926 CELLS AND HUVEC) AFTER 4 H TREATMENT. IN TNF-ALPHA TREATED ECS, TF MRNA WAS ALSO INCREASED MEASURED BY REAL-TIME PCR. REAL-TIME PCR RESULTS SHOWED THAT MIR-223 LEVELS WERE DOWNREGULATED IN TNF-ALPHA-TREATED AORTA OF C57BL/6J MICE AND CULTURED ECS. TRANSFECTION OF ECS WITH MIR-223 MIMIC OR MIR-223 INHIBITOR MODIFIED TF EXPRESSION BOTH IN MRNA AND PROTEIN LEVELS. LUCIFERASE ASSAYS CONFIRMED THAT MIR-223 SUPPRESSED TF EXPRESSION BY BINDING TO THE SEQUENCE OF TF 3'-UNTRANSLATED REGIONS (3'UTR). TF PROCOAGULANT ACTIVITY WAS INHIBITED BY OVEREXPRESSING MIR-223 WITH OR WITHOUT TNF-ALPHA STIMULATION. CONCLUSIONS: MIR-223-MEDIATED SUPPRESSION OF TF EXPRESSION PROVIDES A NOVEL MOLECULAR MECHANISM FOR THE REGULATION OF COAGULATION CASCADE, AND SUGGESTS A CLUE AGAINST THROMBOGENESIS DURING THE PROCESS OF ATHEROSCLEROTIC PLAQUE RUPTURE. 2014 10 4491 29 MONOSOMY 7 MYELOPROLIFERATIVE DISEASE IN CHILDREN WITH NEUROFIBROMATOSIS, TYPE 1: EPIDEMIOLOGY AND MOLECULAR ANALYSIS. LOSS OF CONSTITUTIONAL HETEROZYGOSITY IS A COMMON MOLECULAR FEATURE OF CANCERS IN WHICH INACTIVATION OF ONE OR MORE TUMOR SUPPRESSOR GENES IS THOUGHT TO CONTRIBUTE TO TUMORIGENESIS. RECENT EVIDENCE SUGGESTS THAT THE GENE RESPONSIBLE FOR NEUROFIBROMATOSIS, TYPE 1 (NF-1), BELONGS TO THIS CLASS OF HERITABLE CANCER GENES. CHILDREN WITH NF-1 SHOW AN INCREASED INCIDENCE OF MYELOID LEUKEMIA, INCLUDING JUVENILE CHRONIC MYELOGENOUS LEUKEMIA (JCML) AND, PERHAPS, THE MYELOPROLIFERATIVE SYNDROME (MPS) ASSOCIATED WITH BONE MARROW MONOSOMY 7 (MO 7). WE HAVE INVESTIGATED FIVE CHILDREN WITH MO 7: THREE WITH NF-1 AND TWO OTHERS WITH SUGGESTIVE EVIDENCE OF NF-1. SOUTHERN BLOTTING EXPERIMENTS PERFORMED IN FOUR PATIENTS SHOWED NO LOSS OF HETEROZYGOSITY IN BONE MARROW SPECIMENS USING PROBES LINKED TO THE NF-1 LOCUS ON THE LONG ARM OF CHROMOSOME 17. BOTH OF OUR PATIENTS WITH FAMILIAL NF-1 INHERITED THE DISEASE FROM THEIR MOTHERS, AS DID 14 OF 19 OTHER CASES OF MYELOID LEUKEMIA IN CHILDREN WITH FAMILIAL NF-1. SEVENTEEN OF THESE 21 CHILDREN WERE BOYS. MYELOID LEUKEMIA DEVELOPED IN 12 BOYS AND FOUR GIRLS WHO INHERITED NF-1 FROM THEIR MOTHERS, AND IN FIVE BOYS WHO INHERITED THE DISEASE FROM THEIR FATHERS. FATHER-TO-DAUGHTER TRANSMISSION WAS NOT OBSERVED. TAKEN TOGETHER, THE PRESENCE OF CHROMOSOME 7 DELETIONS IN THE LEUKEMIAS OF CHILDREN WITH NF-1, A PATTERN OF INHERITANCE FAVORING MATERNAL TRANSMISSION OF NF-1, AND THE MARKED PREDILECTION FOR BOYS TO DEVELOP JCML AND MO 7 SUGGEST A MULTISTEP MECHANISM OF ONCOGENESIS IN WHICH EPIGENETIC FACTORS MIGHT PLAY A ROLE. FURTHER INVESTIGATION IS REQUIRED TO DETERMINE IF THE NF-1 GENES IN THE LEUKEMIC BONE MARROWS OF THESE PATIENTS HAVE ACQUIRED POINT MUTATIONS OR SMALL DELETIONS. 1992 11 4562 23 MYELODYSPLASTIC SYNDROME/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROMES: A FOCUSED REVIEW. MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) OVERLAP SYNDROMES ARE UNIQUE MYELOID NEOPLASMS, WITH OVERLAPPING FEATURES OF MDS AND MPN. THEY CONSIST OF FOUR ADULT ONSET ENTITIES INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), MDS/MPN-RING SIDEROBLASTS-THROMBOCYTOSIS (MDS/MPN-RS-T), BCR-ABL1 NEGATIVE ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) AND MDS/MPN-UNCLASSIFIABLE (MDS/MPN-U); WITH JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) BEING THE ONLY PEDIATRIC ONSET ENTITY. AMONG THESE OVERLAP NEOPLASMS, CMML IS THE MOST FREQUENT AND IS HALLMARKED BY THE PRESENCE OF SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS WITH RECURRENT MUTATIONS INVOLVING TET2 (60%), SRSF2 (50%) AND ASXL1 (40%); WITH RAS PATHWAY MUTATIONS AND JAK2V617F BEING RELATIVELY ENRICHED IN PROLIFERATIVE CMML SUBTYPES (WBC >/=13 X 109/L). CMML USUALLY PRESENTS IN THE 7TH DECADE OF LIFE, WITH A MALE PREPONDERANCE AND IS ASSOCIATED WITH A MEDIAN OVERALL SURVIVAL OF <36 MONTHS. ADVERSE PROGNOSTICATORS IN CMML INCLUDE INCREASING AGE, HIGH WBC, PRESENCE OF CIRCULATING IMMATURE MYELOID CELLS, ANEMIA, THROMBOCYTOPENIA AND TRUNCATING ASXL1 MUTATIONS. WHILE ALLOGENEIC STEM CELL TRANSPLANTATION REMAINS THE ONLY CURATIVE OPTION, GIVEN THE LATE ONSET OF THIS NEOPLASM AND HIGH FREQUENCY OF COMORBIDITIES, MOST PATIENTS REMAIN INELIGIBLE. HYPOMETHYLATING AGENTS SUCH AS AZACITIDINE, DECITABINE AND ORAL DECITABINE/CEDAZURIDINE HAVE BEEN US FDA APPROVED FOR THE MANAGEMENT OF CMML, WITH OVERALL RESPONSE RATES OF 40-50% AND COMPLETE REMISSION RATES OF <20%. WHILE THESE AGENTS EPIGENETICALLY RESTORE HEMATOPOIESIS IN A SUBSET OF RESPONDING PATIENTS, THEY DO NOT IMPACT MUTATIONAL ALLELE BURDENS AND EVENTUAL DISEASE PROGRESSION TO AML REMAINS INEVITABLE. NEWER TREATMENT MODALITIES EXPLOITING EPIGENETIC, SIGNALING AND SPLICING ABNORMALITIES COMMONLY SEEN IN CMML ARE MUCH NEEDED. 2020 12 2437 29 EPIGENETIC SILENCING OF SONIC HEDGEHOG ELICITS ANTITUMOR IMMUNE RESPONSE AND SUPPRESSES TUMOR GROWTH BY INHIBITING THE HEDGEHOG SIGNALING PATHWAY IN METASTATIC SPINE TUMORS IN SPRAGUE-DAWLEY RATS. BACKGROUND: PATIENTS WITH METASTATIC SPINE TUMORS MAY SUFFER FROM PAIN OR NEUROLOGIC DEFICIT, AND THE DISEASE MAY BE DETECTED IN PATIENTS WITH A KNOWN MALIGNANCY. SONIC HEDGEHOG (SHH) HAS RECEIVED SPECIAL ATTENTION DUE TO ITS ROLE IN CANCERS. THEREFORE, THIS STUDY INVESTIGATED THE EFFECTS OF EPIGENETIC SILENCING OF SHH ON ANTITUMOR IMMUNE RESPONSE AND TUMOR GROWTH BY REGULATING THE HEDGEHOG (HH) SIGNALING PATHWAY IN METASTATIC SPINE TUMORS. METHODS: RAT MODELS OF METASTATIC SPINE TUMORS WERE SUCCESSFULLY ESTABLISHED. WE FIRST CALCULATED THE TUMOR VOLUME AND THE INHIBITION RATE OF TUMOR GROWTH TO INVESTIGATE THE EFFECT OF SHH ON TUMOR GROWTH. AFTERWARDS, IMMUNOHISTOCHEMISTRY WAS USED TO DETERMINE WHETHER PROLIFERATION WAS DELAYED BY SHH DEPLETION, AND THE 3-(4,5-DIMETHYLTHIAZOL-2-YL)-2,5-DIPHENYLTETRAZOLIUM BROMIDE ASSAY WAS CONDUCTED TO TEST THE CHANGES IN THE LYMPHOCYTE TRANSFORMATION RATE IN THE SPLEEN TRIGGERED BY SHH SILENCING. THEN, THE INFLUENCE OF SHH DEPLETION ON IMMUNE FUNCTION WAS INVESTIGATED. LATER, QUANTITATIVE REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION AND WESTERN BLOT ASSAY WERE PERFORMED TO EXPLORE THE HH SIGNALING PATHWAY-RELATED FACTORS. FINALLY, WE ADDED THE HH SIGNALING PATHWAY INHIBITOR, GDC-0449, TO CONFIRM THE ROLE OF THE PATHWAY IN TUMOR PROGRESSION. RESULTS: INITIALLY, WE OBSERVED THAT SHH DEPLETION WAS A NEGATIVE FACTOR FOR TUMOR GROWTH. AFTERWARDS, IT WAS REVEALED THAT EPIGENETIC SILENCING OF SHH SERVED AS AN INHIBITOR FACTOR FOR THE FUNCTION OF SPLEEN LYMPHOCYTE TRANSFORMATION AND INFLAMMATION WHILE PROMOTING ANTITUMOR IMMUNE FUNCTION. CONCLUSION: OUR PRELIMINARY RESULTS INDICATE THAT EPIGENETIC SILENCING OF SHH ELICITS AN ANTITUMOR IMMUNE RESPONSE AND SUPPRESSES TUMOR GROWTH BY INHIBITING THE HH SIGNALING PATHWAY IN METASTATIC SPINE TUMORS. 2018 13 1107 30 COMBINING CYTOGENETIC AND EPIGENETIC APPROACHES IN CHRONIC LYMPHOCYTIC LEUKEMIA IMPROVES PROGNOSIS PREDICTION FOR PATIENTS WITH ISOLATED 13Q DELETION. BACKGROUND: BOTH DEFECTIVE DNA METHYLATION AND ACTIVE DNA DEMETHYLATION PROCESSES ARE EMERGING AS IMPORTANT RISK FACTORS IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). HOWEVER, ASSOCIATIONS BETWEEN 5-CYTOSINE EPIGENETIC MARKERS AND THE MOST FREQUENT CHROMOSOMAL ABNORMALITIES DETECTED IN CLL REMAIN TO BE ESTABLISHED. METHODS: CLL PATIENTS WERE RETROSPECTIVELY CLASSIFIED INTO A CYTOGENETIC LOW-RISK GROUP (ISOLATED 13Q DELETION), AN INTERMEDIATE-RISK GROUP (NORMAL KARYOTYPE OR TRISOMY 12), AND A HIGH-RISK GROUP (11Q DELETION, 17P DELETION, OR COMPLEX KARYOTYPE [>/= 3 BREAKPOINTS]). THE TWO 5-CYTOSINE DERIVATIVES, 5-METHYLCYTOSINE (5-MCYT) AND 5-HYDROXYMETHYLCYTOSINE (5-HMCYT), WERE TESTED BY ELISA (N = 60), WHILE REAL-TIME QUANTITATIVE PCR WAS USED FOR DETERMINING TRANSCRIPTIONAL EXPRESSION LEVELS OF DNMT AND TET (N = 24). RESULTS: BY USING GLOBAL DNA METHYLATION/DEMETHYLATION LEVELS, IN THE LOW-RISK DISEASE GROUP, TWO SUBGROUPS WITH SIGNIFICANTLY DIFFERENT CLINICAL OUTCOMES HAVE BEEN IDENTIFIED (MEDIAN TREATMENT-FREE SURVIVAL [TFS] 45 VERSUS > 120 MONTHS FOR 5-MCYT, P = 0.0008, AND 63 VERSUS > 120 MONTHS FOR 5-HMCYT, P = 0.04). A DEFECTIVE 5-MCYT STATUS WAS FURTHER ASSOCIATED WITH A HIGHER PERCENTAGE OF 13Q DELETED NUCLEI (> 80%), THUS SUGGESTING AN ACQUIRED PROCESS. WHEN CONSIDERING THE CYTOGENETIC INTERMEDIATE/HIGH-RISK DISEASE GROUPS, AN ASSOCIATION OF 5-MCYT STATUS WITH LYMPHOCYTOSIS (P = 0.0008) AND THE LYMPHOCYTE DOUBLING TIME (P = 0.04) BUT NOT WITH TFS WAS OBSERVED, AS WELL AS A REDUCTION OF DNMT3A, TET1, AND TET2 TRANSCRIPTS. CONCLUSIONS: COMBINING CYTOGENETIC STUDIES WITH 5-MCYT ASSESSMENT ADDS ACCURACY TO CLL PATIENTS' PROGNOSES AND PARTICULARLY FOR THOSE WITH 13Q DELETION AS A SOLE CYTOGENETIC ABNORMALITY. 2017 14 4052 47 MALIGNANT TRANSFORMATION OF A DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR (DNET) CHARACTERIZED BY GENOME-WIDE METHYLATION ANALYSIS. DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS (DNET) ARE CONSIDERED TO BE RARE, BENIGN, AND ASSOCIATED WITH CHRONIC EPILEPSY. WE PRESENT THE CASE OF A 28-YEAR-OLD MAN WITH A HISTORY OF EPILEPSY SINCE AGE 12. SURGERY OF AN OCCIPITAL CORTICAL LESION IN 2009 REVEALED A DNET. FIVE YEARS LATER, A RECURRENT TUMOR AT THE EDGE OF THE RESECTION CAVITY WAS REMOVED, AND THE TISSUE UNDERWENT AN INTENSIVE DIAGNOSTIC WORKUP. THE FIRST TUMOR WAS UNEQUIVOCALLY CHARACTERIZED AS A DNET, BUT NEUROPATHOLOGICAL DIAGNOSTICS OF THE RECURRENT TUMOR REVEALED A GLIOBLASTOMA. AFTER 6 MONTHS, ANOTHER RECURRENT TUMOR WAS DETECTED NEXT TO THE LOCATION OF THE ORIGINAL TUMOR, AND THIS WAS ALSO RESECTED. AN ILLUMINA 450 K BEADCHIP METHYLATION ARRAY WAS PERFORMED TO CHARACTERIZE ALL OF THE TUMORS. THE METHYLATION PROFILE OF THESE TUMORS SIGNIFICANTLY DIFFERED FROM OTHER GLIOBLASTOMA AND EPILEPSY-ASSOCIATED TUMOR PROFILES AND REVEALED A DNET-LIKE METHYLATION PROFILE. THUS, MOLECULAR CHARACTERIZATION OF THESE RECURRENT TUMORS SUGGESTS MALIGNANT TRANSFORMATION OF A PREVIOUSLY BENIGN DNET. WE FOUND INCREASED COPY NUMBER CHANGES IN THE RECURRENT DNET TUMORS AFTER MALIGNANT TRANSFORMATION. MODERN HIGH-THROUGHPUT ANALYSIS ADDS ESSENTIAL MOLECULAR INFORMATION IN ADDITION TO STANDARD HISTOPATHOLOGY FOR PROPER IDENTIFICATION OF RARE BRAIN TUMORS THAT PRESENT WITH AN UNUSUAL CLINICAL COURSE. 2016 15 3872 34 JUVENILE MYELOMONOCYTIC LEUKEMIA-A COMPREHENSIVE REVIEW AND RECENT ADVANCES IN MANAGEMENT. JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) IS A RARE PEDIATRIC MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM OVERLAP DISEASE. JMML IS ASSOCIATED WITH MUTATIONS IN THE RAS PATHWAY GENES RESULTING IN THE MYELOID PROGENITORS BEING SENSITIVE TO GRANULOCYTE MONOCYTE COLONY-STIMULATING FACTOR (GM-CSF). KARYOTYPE ABNORMALITIES AND ADDITIONAL EPIGENETIC ALTERATIONS CAN ALSO BE FOUND IN JMML. NEUROFIBROMATOSIS AND NOONAN'S SYNDROME HAVE A PREDISPOSITION FOR JMML. IN A FEW PATIENTS, THE RAS GENES (NRAS, KRAS, AND PTPN11) ARE MUTATED AT THE GERMLINE AND THIS USUALLY RESULTS IN A TRANSIENT MYELOPROLIFERATIVE DISORDER WITH A GOOD PROGNOSIS. JMML WITH SOMATIC RAS MUTATION BEHAVES AGGRESSIVELY. JMML PRESENTS WITH CYTOPENIAS AND LEUKEMIC INFILTRATION INTO ORGANS. THE LABORATORY FINDINGS INCLUDE HYPERLEUKOCYTOSIS, MONOCYTOSIS, INCREASED HEMOGLOBIN-F LEVELS, AND CIRCULATING MYELOID PRECURSORS. THE BLAST CELLS IN THE PERIPHERAL BLOOD/BONE-MARROW ASPIRATE ARE LESS THAN 20% AND THE ABSENCE OF THE BCR-ABL TRANSLOCATION HELPS TO DIFFERENTIATE FROM CHRONIC MYELOID LEUKEMIA. JMML SHOULD BE DIFFERENTIATED FROM IMMUNODEFICIENCIES, VIRAL INFECTIONS, INTRAUTERINE INFECTIONS, HEMOPHAGOLYMPHOHISTIOCYTOSIS, OTHER MYELOPROLIFERATIVE DISORDERS, AND LEUKEMIAS. CHEMOTHERAPY IS EMPLOYED AS A BRIDGE TO HSCT, EXCEPT IN FEW WITH LESS AGGRESSIVE DISEASE, IN WHICH CHEMOTHERAPY ALONE CAN RESULT IN LONG TERM REMISSION. AZACITIDINE HAS SHOWN PROMISE AS A SINGLE AGENT TO STABILIZE THE DISEASE. THE PROGNOSIS OF JMML IS POOR WITH ABOUT 50% OF PATIENTS SURVIVING AFTER AN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). ALLOGENEIC HSCT IS THE ONLY KNOWN CURE FOR JMML TO DATE. MYELOABLATIVE CONDITIONING IS MOST COMMONLY USED WITH GRAFT VERSUS HOST DISEASE (GVHD) PROPHYLAXIS TAILORED TO THE AGGRESSIVENESS OF THE DISEASE. RELAPSES ARE COMMON EVEN AFTER HSCT AND A SECOND HSCT CAN SALVAGE A THIRD OF THESE PATIENTS. NOVEL OPTIONS IN THE TREATMENT OF JMML E.G., HYPOMETHYLATING AGENTS, MEK INHIBITORS, JAK INHIBITORS, TYROSINE KINASE INHIBITORS, ETC. ARE BEING EXPLORED. 2021 16 6386 32 THE ROLE OF QUANTITATIVE NPTX2 HYPERMETHYLATION AS A NOVEL SERUM DIAGNOSTIC MARKER IN PANCREATIC CANCER. OBJECTIVES: THE MAJORITY OF PANCREATIC CANCERS ARE FOUND TO BE UNRESECTABLE, AND THE ONLY CHANCE FOR CURE LIES ON EARLY DETECTION AND COMPLETE RESECTION. SEVERAL GENES HAVE BEEN DISCOVERED TO BE ABERRANTLY METHYLATED IN PRIMARY PANCREATIC CANCER TISSUE, AND THIS CANCER DNA CAN BE DETECTED IN THE PLASMA. THE AIMS OF THIS STUDY WERE TO DEVELOP A NOVEL DIAGNOSTIC MARKER BASED ON EPIGENETIC CHARACTERISTICS OF PANCREATIC CANCER. METHODS: WE ENROLLED 104 PATIENTS WITH PANCREATIC CANCER, 60 WITH CHRONIC PANCREATITIS, AND 5 WITH BENIGN BILIARY STONE DISEASES. THE BLOOD SAMPLES WERE COLLECTED BEFORE SURGERY OR ANY KINDS OF TREATMENT MODALITIES. DNA WAS EXTRACTED FROM THE PLASMA OF EACH PATIENT, AND NPTX2 (NEURONAL PENTRAXIN II) CPG ISLAND HYPERMETHYLATION WAS EXAMINED QUANTITATIVELY BY REAL-TIME POLYMERASE CHAIN REACTION. RESULTS: NPTX2 HYPERMETHYLATION LEVELS WERE SIGNIFICANTLY HIGHER COMPARED WITH CHRONIC PANCREATITIS (P = 0.016). THE SENSITIVITY AND SPECIFICITY WERE 80% AND 76%, RESPECTIVELY (CUTOFF = 0.015). NPTX2 GENE HYPERMETHYLATION LEVEL WAS SIGNIFICANTLY ELEVATED IN CORRELATION WITH HIGHER AMERICAN JOINT COMMITTEE ON CANCER STAGES. CONCLUSIONS: THE ABERRANTLY METHYLATED NPTX2 GENE MAY HELP TO DISTINGUISH BETWEEN CHRONIC PANCREATITIS AND PANCREATIC CANCER WITH CONVENTIONAL DIAGNOSTIC TOOLS AND COULD BECOME A VALUABLE DIAGNOSTIC MARKER. 2012 17 5613 25 SAFETY AND EFFICACY OF ABEXINOSTAT, A PAN-HISTONE DEACETYLASE INHIBITOR, IN NON-HODGKIN LYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA: RESULTS OF A PHASE II STUDY. HISTONE DEACETYLASE INHIBITORS ARE MEMBERS OF A CLASS OF EPIGENETIC DRUGS THAT HAVE PROVEN ACTIVITY IN T-CELL MALIGNANCIES, BUT LITTLE IS KNOWN ABOUT THEIR EFFICACY IN B-CELL LYMPHOMAS. ABEXINOSTAT IS AN ORALLY AVAILABLE HYDROXAMATE-CONTAINING HISTONE DEACETYLASE INHIBITOR THAT DIFFERS FROM APPROVED INHIBITORS; ITS UNIQUE PHARMACOKINETIC PROFILE AND ORAL DOSING SCHEDULE, TWICE DAILY FOUR HOURS APART, ALLOWS FOR CONTINUOUS EXPOSURE AT CONCENTRATIONS REQUIRED TO EFFICIENTLY KILL TUMOR CELLS. IN THIS PHASE II STUDY, PATIENTS WITH RELAPSED/REFRACTORY NON-HODGKIN LYMPHOMA OR CHRONIC LYMPHOCYTIC LEUKEMIA RECEIVED ORAL ABEXINOSTAT AT 80 MG BID FOR 14 DAYS OF A 21-DAY CYCLE AND CONTINUED UNTIL PROGRESSIVE DISEASE OR UNACCEPTABLE TOXICITY. A TOTAL OF 100 PATIENTS WITH B-CELL MALIGNANCIES AND T-CELL LYMPHOMAS WERE ENROLLED BETWEEN OCTOBER 2011 AND JULY 2014. ALL PATIENTS RECEIVED AT LEAST ONE DOSE OF STUDY DRUG. PRIMARY REASONS FOR DISCONTINUATION INCLUDED PROGRESSIVE DISEASE (56%) AND ADVERSE EVENTS (25%). GRADE 3 OR OVER ADVERSE EVENTS AND ANY SERIOUS ADVERSE EVENTS WERE REPORTED IN 88% AND 73% OF PATIENTS, RESPECTIVELY. THE MOST FREQUENTLY REPORTED GRADE 3 OR OVER TREATMENT-EMERGENT RELATED ADVERSE EVENTS WERE THROMBOCYTOPENIA (80%), NEUTROPENIA (27%), AND ANEMIA (12%). AMONG THE 87 PATIENTS EVALUABLE FOR EFFICACY, OVERALL RESPONSE RATE WAS 28% (COMPLETE RESPONSE 5%), WITH HIGHEST RESPONSES OBSERVED IN PATIENTS WITH FOLLICULAR LYMPHOMA (OVERALL RESPONSE RATE 56%), T-CELL LYMPHOMA (OVERALL RESPONSE RATE 40%), AND DIFFUSE LARGE B-CELL LYMPHOMA (OVERALL RESPONSE RATE 31%). FURTHER INVESTIGATION OF THE SAFETY AND EFFICACY OF ABEXINOSTAT IN FOLLICULAR LYMPHOMA, T-CELL LYMPHOMA, AND DIFFUSE LARGE B-CELL LYMPHOMA IMPLEMENTING A LESS DOSE-INTENSE WEEK-ON-WEEK-OFF SCHEDULE IS WARRANTED. (TRIAL REGISTERED AT: EUDRACT-2009-013691-47). 2017 18 740 28 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 19 22 23 5-HYDROXYMETHYLCYTOSINE AS A CLINICAL BIOMARKER: FLUORESCENCE-BASED ASSAY FOR HIGH-THROUGHPUT EPIGENETIC QUANTIFICATION IN HUMAN TISSUES. EPIGENETIC TRANSFORMATIONS MAY PROVIDE EARLY INDICATORS FOR CANCER AND OTHER DISEASE. SPECIFICALLY, THE AMOUNT OF GENOMIC 5-HYDROXYMETHYLCYTOSINE (5-HMC) WAS SHOWN TO BE GLOBALLY REDUCED IN A WIDE RANGE OF CANCERS. THE INTEGRATION OF THIS GLOBAL BIOMARKER INTO DIAGNOSTIC WORKFLOWS IS HAMPERED BY THE LIMITATIONS OF CURRENT 5-HMC QUANTIFICATION METHODS. HERE WE PRESENT AND VALIDATE A FLUORESCENCE-BASED PLATFORM FOR HIGH-THROUGHPUT AND COST-EFFECTIVE QUANTIFICATION OF GLOBAL GENOMIC 5-HMC LEVELS. WE UTILIZED THE ASSAY TO CHARACTERIZE CANCEROUS TISSUES BASED ON THEIR 5-HMC CONTENT, AND OBSERVED A PRONOUNCED REDUCTION IN 5-HMC LEVEL IN VARIOUS CANCER TYPES. WE PRESENT DATA FOR GLIOBLASTOMA, COLORECTAL CANCER, MULTIPLE MYELOMA, CHRONIC LYMPHOCYTIC LEUKEMIA AND PANCREATIC CANCER, COMPARED TO CORRESPONDING CONTROLS. POTENTIALLY, THE TECHNIQUE COULD ALSO BE USED TO FOLLOW RESPONSE TO TREATMENT FOR PERSONALIZED TREATMENT SELECTION. WE PRESENT INITIAL PROOF-OF-CONCEPT DATA FOR TREATMENT OF FAMILIAL ADENOMATOUS POLYPOSIS. 2020 20 3636 23 INCREASED DNA METHYLTRANSFERASE ACTIVITY AND DNA METHYLATION FOLLOWING EPIDERMAL GROWTH FACTOR STIMULATION IN OVARIAN CANCER CELLS. OVARIAN CANCER PROGRESSION IS CORRELATED WITH ACCUMULATION OF ABERRANT CPG ISLAND METHYLATION. IN OVARIAN CANCER, ASCITES FLUID CONTAINS NUMEROUS EPIDERMAL-GROWTH-FACTOR-RECEPTOR (EGFR) ACTIVATORS, WHICH COULD RESULT IN A TUMOR MICROENVIRONMENT OF CONSTANT EGFR ACTIVATION. SIGNALING PATHWAYS DOWNSTREAM OF EGFR, SUCH AS RAS, REGULATE DNA METHYLATION. WE HYPOTHESIZED THAT CHRONIC EGFR ACTIVATION COULD ALTER DNA METHYLATION. WE FOUND THAT EGFR ACTIVATION INCREASED DNA METHYLTRANSFERASE (DNMT) ACTIVITY ACUTELY, AS WELL AS AFTER LONG-TERM EGF TREATMENT OR EXPRESSION OF A MUTATIONALLY ACTIVATED EGFR. FURTHERMORE, THIS INCREASE IN DNMT ACTIVITY WAS DEPENDENT ON EGFR CATALYTIC ACTIVITY AND RESULTED IN INCREASED GLOBAL DNA METHYLATION. ADDITIONALLY, TREATMENT WITH THE DNMT INHIBITOR/HYPOMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE (AZA) INHIBITED THE EGF INDUCED INCREASE OF BOTH DNMT ACTIVITY AND GLOBAL METHYLATION. THESE DATA SUPPORT A ROLE FOR EGFR IN THE PROCESS OF ACCUMULATED DNA METHYLATION DURING OVARIAN CANCER PROGRESSION AND SUGGEST THAT EPIGENETIC THERAPY MAY BE BENEFICIAL FOR THE TREATMENT OF OVARIAN CANCER. 2012