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1
Erdemir, Halil. "Mısır'ın Fransızlar Tarafından İşgali Örneğinde Uluslararası İlişkilerde Realizm". History Studies International Journal Of History 1, n.º 1 (2009): 197–211. http://dx.doi.org/10.9737/hist_14.
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Balcı, Tamer. "İslam'ın Millileştirilmesinden Milliyetçiliğin Özelleştirilmesine: İslamiyet ve Türk Milli Kimliği". History Studies International Journal Of History 1, n.º 1 (2009): 82–107. http://dx.doi.org/10.9737/hist_10.
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Altın, Hamza. "The İmportance of Ziya Gokalp for our Educational History". History Studies International Journal Of History Volume 2 Issue 2 (2024): 493–509. http://dx.doi.org/10.9737/hist_104.
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L. Menchinger, Ethan. ""'Gems for Royal Pofit': Prefaces and The Practice of Eighteenth-Century Ottoman Court History". History Studies International Journal Of History Volume 2 Issue 2 (2024): 127–51. http://dx.doi.org/10.9737/hist_114.
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Selçuk, Hava. "Cizye Vergisinin Kayseri Sancağında Uygulanması ve 1699 Terihli Cizye Beratı". History Studies International Journal Of History Volume 2 Issue 2 (2024): 85–99. http://dx.doi.org/10.9737/hist_124.
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Nazır, Bayram. "Dersaadet Chamber of Commerce and International Exhibitions". History Studies International Journal Of History 1, n.º 1 (2009): 179–96. http://dx.doi.org/10.9737/hist_13.
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Güldüoğlu, Emine. "An Assessment on Property Sales in Kayseri According to The Şer'iye Sicilleri (1678-1679)". History Studies International Journal Of History Volume 2 Issue 2 (2024): 71–84. http://dx.doi.org/10.9737/hist_134.
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Ayar, Mesut. "The Ongoing İmpact Of The Most Dreadful Disease Of World History Plague In The Ottoman Empire In The Early 20th Century Within The Contexts Of 1900 Izmir And 1901 Istanbul Epidemics". History Studies International Journal Of History Volume 2 Issue 2 (2024): 173–88. http://dx.doi.org/10.9737/hist_141.
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Çolak, Songül. "The Statement of Ottoman Army in the 17.th Century According to the Aziz Efendi's Report". History Studies International Journal Of History Volume 2 Issue 2 (2024): 101–12. http://dx.doi.org/10.9737/hist_143.
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Köse, Osman. "The Official Document “Receipt”Given to Russia By Otoman State Pertaining to Crimea (1784)". History Studies International Journal Of History Volume 2 Issue 2 (2024): 353–62. http://dx.doi.org/10.9737/hist_144.
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İlgazi, Abdullah. "Mizanci Murad and The Young Turks". History Studies International Journal Of History 1, n.º 1 (2009): 108–33. http://dx.doi.org/10.9737/hist_16.
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Sakal, Fahri. "One Party's Citziens and the People who Became to Otherize". History Studies International Journal Of History 1, n.º 1 (2009): 134–60. http://dx.doi.org/10.9737/hist_17.
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Ayan, Ergin. "The Atabeg of Marâghah Aksungur Al-Ahmadili". History Studies International Journal Of History 1, n.º 1 (2009): 161–78. http://dx.doi.org/10.9737/hist_18.
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Kıvrım, İsmail. "Cash-waqfs Establıshed in Gumushane and its Vicinity in The Ottaman Period". History Studies International Journal Of History Volume 2 Issue 3 (2010): 231–43. http://dx.doi.org/10.9737/hist_214.
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yuca, sami. "Tarihselcilik Sorunu, Tin Bilimlerinde Dogmatik Düşünme Formu ve Tarihselcilik Sorunu". History Studies International Journal Of History Volume 3 Issue 2, n.º 3 (2011): 419–23. http://dx.doi.org/10.9737/hist_314.
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Polatel, Oğuz. "Nikomediadan İzmite Bir Kent Adının Dö". History Studies International Journal of History, Prof. Dr. Enver Konukçu (1 de janeiro de 2012): 279. http://dx.doi.org/10.9737/hist_514.
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ÖKSÜZ, Melek. "In Pursuit of Legal Statü in Ottoman Terrotories and American Instutions in the Fight for Existence". History Studies International Journal Of History Volume 2 Issue 1, n.º 2 (2010): 147–87. http://dx.doi.org/10.9737/hist_74.
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Dingeç, Emine. "The Contrubutions of Women to Production in Ottoman Society". History Studies International Journal Of History Volume 2 Issue 1, n.º 2 (2010): 9–31. http://dx.doi.org/10.9737/hist_84.
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Turan, Ömer. "2th Ergenekon". History Studies International Journal Of History Volume 2 Issue 1, n.º 2 (2010): 378–83. http://dx.doi.org/10.9737/hist_94.
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Agromayor, Monica, Jez G. Carlton, John P. Phelan, Daniel R. Matthews, Leo M. Carlin, Simon Ameer-Beg, Katherine Bowers e Juan Martin-Serrano. "Essential Role of hIST1 in Cytokinesis". Molecular Biology of the Cell 20, n.º 5 (março de 2009): 1374–87. http://dx.doi.org/10.1091/mbc.e08-05-0474.
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The last steps of multivesicular body (MVB) formation, human immunodeficiency virus (HIV)-1 budding and cytokinesis require a functional endosomal sorting complex required for transport (ESCRT) machinery to facilitate topologically equivalent membrane fission events. Increased sodium tolerance (IST) 1, a new positive modulator of the ESCRT pathway, has been described recently, but an essential function of this highly conserved protein has not been identified. Here, we describe the previously uncharacterized KIAA0174 as the human homologue of IST1 (hIST1), and we report its conserved interaction with VPS4, CHMP1A/B, and LIP5. We also identify a microtubule interacting and transport (MIT) domain interacting motif (MIM) in hIST1 that is necessary for its interaction with VPS4, LIP5 and other MIT domain-containing proteins, namely, MITD1, AMSH, UBPY, and Spastin. Importantly, hIST1 is essential for cytokinesis in mammalian cells but not for HIV-1 budding, thus providing a novel mechanism of functional diversification of the ESCRT machinery. Last, we show that the hIST1 MIM activity is essential for cytokinesis, suggesting possible mechanisms to explain the role of hIST1 in the last step of mammalian cell division.
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Silva, Ana Margarida Dias da, e Fernando B. Figueiredo. "“Preces a Nosso Senhor para dar bom tempo”. Preces e Procissões de Penitência da Ordem Franciscana Secular de Coimbra (séculos XVIII-XIX)". História: Revista da Faculdade de Letras da Universidade do Porto 8, n.º 1 (2018): 54–77. http://dx.doi.org/10.21747/0871164x/hist8a4.
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Tiberi, Guillaume, Aleksandra Pekowska, Claire Oudin, Adam Ivey, Thomas Prebet, Myriam Koubi, Frederique Lembo et al. "H3K27me3 Level of the HIST1 Cluster Defines an Epigenetic Marker of Acute Myeloid Leukemia with Prognostic Value". Blood 124, n.º 21 (6 de dezembro de 2014): 2326. http://dx.doi.org/10.1182/blood.v124.21.2326.2326.
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Abstract Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adults, characterized by significant heterogeneity in terms of biology and clinical outcome. Improvements in sequencing technologies have led to the discovery of frequent somatic mutations in epigenetic modifiers, placing epigenetic deregulation in the center of AML. Yet, the global view and the impact of this deregulation on disease characteristics are under investigation. To gain a more comprehensive understanding of epigenetic deregulation in AML, particularly the heterogeneous subset with normal karyotype (CN-AML), associated with intermediate clinical prognosis, we performed H3K27me3 profiling on CN-AML patient samples. Primary bone marrow or peripheral blood samples containing more than 80% of blasts were selected from the Institut Paoli-Calmettes Biological Resources Center inventory for the purpose of genetic and epigenetic studies. We initially analyzed 35 CN-AML samples by ChIP coupled with hybridization on oligonucleotide promoter arrays (Chip-chip) for genomic H3K27me3 distribution. Clustering analysis revealed 586 highly H3K27me3-variable genomic regions across patients corresponding to 461 genes mostly involved in chromatin organization. The heterogeneity in the H3K27me3 profile was characterized by a remarkable H3K27me3 enrichment at the chromosome 6 p22.2-22 region that encompasses 70 kbp within the major HIST1 cluster. This striking H3K27me3 enrichment was covering 11 histone genes and was partially overlapping with the focal deletion at 6p22 found in acute lymphoblastic leukemia. The HIST1 H3K27me3 enrichment profile clearly distinguished 2 groups of CN-AML patients based on their HIST1 H3K27me3 level. In order to independently extend this observation, we analyzed the H3K27me3 status by using ChIP followed by qPCR (ChIP-qPCR) at the same HIST1 genomic locations, in an independent cohort of 51 CN-AML patients. This revealed the presence of this abnormal epigenetic profile in about 50% of the patients. CN-AML samples were split in two groups, according to the median H3K27me3 enrichment levels at the HIST1 cluster genes. These two groups were analyzed for clinical and molecular characteristics. Patients with high HIST1 H3K27me3 level had a markedly higher incidence of NPM1 mutation (89% vs. 40%; p= 1.75x10-5) and a lower incidence of WT1 mutation (0% vs. 20%; p=0.028). No significant association was observed with FLT3 (ITD and TKD), IDH1/2, DNMT3A nor ASXL1 mutations. Patients with high HIST1 H3K27me3 level had a significant longer leukemia free survival at 5 years (allo-grafted patients censored, LFS-allo; 13.33 vs. 8.92 months p=0.0053). Moreover, multivariate analysis showed that HIST1 H3K27me3 status provided a more powerful prognostic indicator than the NPM1mut/FLT3-ITDneg and NPM1/FLT3-ITD genotypes. In conclusion,using epigenetic profiling, our analysis has enabled the discovery of a new epigenetic alteration that affects CN-AML and impacts prognosis. We demonstrate that the HIST1 cluster is targeted by epigenetic events that lead to high H3K27me3 level and predicts a good prognosis. This may help refine risk stratification in AML, identifying a further group of patients unlikely to benefit from allogeneic transplantation in first remission. Overall, our data provide a proof of concept that epigenetic profiling could be used to discover new biomarkers with prognostic value. Disclosures No relevant conflicts of interest to declare.
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Kleene, Ralf, Gabriele Loers e Melitta Schachner. "The KDET Motif in the Intracellular Domain of the Cell Adhesion Molecule L1 Interacts with Several Nuclear, Cytoplasmic, and Mitochondrial Proteins Essential for Neuronal Functions". International Journal of Molecular Sciences 24, n.º 2 (4 de janeiro de 2023): 932. http://dx.doi.org/10.3390/ijms24020932.
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Abnormal functions of the cell adhesion molecule L1 are linked to several neural diseases. Proteolytic L1 fragments were reported to interact with nuclear and mitochondrial proteins to regulate events in the developing and the adult nervous system. Recently, we identified a 55 kDa L1 fragment (L1-55) that interacts with methyl CpG binding protein 2 (MeCP2) and heterochromatin protein 1 (HP1) via the KDET motif. We now show that L1-55 also interacts with histone H1.4 (HistH1e) via this motif. Moreover, we show that this motif binds to NADH dehydrogenase ubiquinone flavoprotein 2 (NDUFV2), splicing factor proline/glutamine-rich (SFPQ), the non-POU domain containing octamer-binding protein (NonO), paraspeckle component 1 (PSPC1), WD-repeat protein 5 (WDR5), heat shock cognate protein 71 kDa (Hsc70), and synaptotagmin 1 (SYT1). Furthermore, applications of HistH1e, NDUFV2, SFPQ, NonO, PSPC1, WDR5, Hsc70, or SYT1 siRNAs or a cell-penetrating KDET-carrying peptide decrease L1-dependent neurite outgrowth and the survival of cultured neurons. These findings indicate that L1’s KDET motif binds to an unexpectedly large number of molecules that are essential for nervous system-related functions, such as neurite outgrowth and neuronal survival. In summary, L1 interacts with cytoplasmic, nuclear and mitochondrial proteins to regulate development and, in adults, the formation, maintenance, and flexibility of neural functions.
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Viloria, Alexis. "Reflexiones en torno al texto "Lógica, hermenéutica y filosofía de la historia en República Dominicana"". Revista ECOS UASD 19, n.º 11 (11 de novembro de 2011): 87–108. http://dx.doi.org/10.51274/ecos.v19i11.pp87-108.
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Los autores del libro "Lógica, Hermenéutica y Filosofía de la Hist01ia en República Dominicana" abordan tres pensadores y sus respectivos textos de lógica en sus contenidos, métodos, enfoques y contextos históricos, que son, sin duda alguna, clásicos del pensamiento filosófico dominicano. Joseph Mendoza y Juan de la Cruz, en treinta (30) ensayos, hacen un recorrido analítico-reflexivo por las lógicas que representan concepciones filosóficas y contextos distintos en el pensamiento dominicano: la lógica sensualista de Andrés López de Medrano.
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He, Rong-Quan, Zhi-Guang Huang, Tian-Yu Li, Yan-Ping Wei, Gang Chen, Xing-Gu Lin e Qiu-Yan Wang. "RNA-Sequencing Data Reveal a Prognostic Four-lncRNA-Based Risk Score for Bladder Urothelial Carcinoma: An in Silico Update". Cellular Physiology and Biochemistry 50, n.º 4 (2018): 1474–95. http://dx.doi.org/10.1159/000494647.
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Background/Aims: Current practical advances in high-throughput data technologies including RNA-sequencing have led to the identification of long non-coding RNAs (lncRNAs) for potential clinical application against bladder urothelial cancer (BLCA). However, most previous studies focused on the clinical value of individual lncRNAs, which has limited the potential for future clinical application. Methods: In this study, RNA-sequencing data of lncRNAs was downloaded from The Cancer Genome Atlas database. Risk score was constructed based on survival-associated lncRNAs identified using differential expression analysis as well as univariate and multivariate Cox proportional hazards regression analysis. Receiver operating characteristic and Kaplan-Meier curve analyses were employed to evaluate the clinical and prognostic value of risk scores. Bioinformatics analyses were used to investigate the potential mechanisms of newly identified lncRNAs. Results: Among 2,127 differentially expressed lncRNAs (DELs), four new lncRNAs (AC145124.1, AC010168.2, MIR200CHG, and AC098613.1) showed valuable prognostic effects in BLCA patients. More importantly, the four-DEL-based risk score had the potential to become an independent marker for the survival status prediction of BLCA patients. Distinct co-expressed genes and signaling pathways were identified when BLCA was categorized into low- and high-risk groups. Furthermore, a protein-coding gene, HIST4H4 was found only 68 bp from the AC010168.2 DEL. HIST4H4 expression level was evidently up-regulated and positively correlated with AC010168.2 in BLCA patients. Conclusion: This in silico investigation pioneers the future investigation of the utility of prognostic lncRNAs for BLCA.
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Scourzic, Laurianne, Franco Izzo, Lucretia Cucereavii, Matthew Teater, Alexander Polyzos, Christopher Chin, Coraline Mlynarczyk et al. "T-Cell Signaling Mediates the Epigenetic Priming of Germinal Center B-Cell Plasticity and Stem Functionality". Blood 142, Supplement 1 (28 de novembro de 2023): 2767. http://dx.doi.org/10.1182/blood-2023-190437.
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Chemo-immunotherapy can prolong life expectancy of patients with Diffuse Large B-cell Lymphomas (DLBCL). However, the emergence of donor-derived lymphoma cases after stem cell transplantation and the relapse of a third of DLBCL patients, strongly suggests the existence of persisting lymphoma repopulating cells (LRC) with stem-like functionality. This apparently controversial concept arises from the fact that DLBCLs originate from mature rather than progenitor cells. Identifying the biological and epigenetic features of these elusive LRC, and how they arise from normal germinal center (GC) B cells, is therefore critical and remains underexplored. Although fully mature, GC B cells naturally manifest remarkable phenotypic plasticity as compared to other cell types. We hypothesized that this plasticity reflects stem-like programming and functionality. Along these lines, we found that GC B cells are uniquely enriched for pluripotent stem cell transcriptional signatures, and increased chromatin accessibility at stem cell enhancers. We reasoned that the capacity to undergo induced Pluripotent Stem Cells (iPSC) reprogramming could serve as a surrogate assay for stem-like plasticity. Therefore, we investigated the potential of GC B cells to form iPSCs using a doxycycline-dependent mouse strain that enables the inducible expression of Yamanaka transcription factors (TF) in any given cell. Strikingly, GC B cells isolated from our mice manifested a 10-fold (p<0.0001) increase in iPSC reprogramming as compared to other mature B cells. GC B cells are a heterogenous mix of functionally distinct subpopulations. Using single cell RNA-seq and iPSC assays in sorted cells, we noted that the rare population (~3%) of GC B cells selected by T-cell help manifested the stem-like transcriptional profile and iPSC reprogramming phenotype. Moreover, blocking T-cell help during the GC reaction in vivo using CD40 blockade abrogated iPSC forming capacity. Lymphoma-associated EZH2 Y641F mutations impair GC B-cell interactions with T FH cells due to aberrant repression of immune synapse genes. Accordingly, EZH2 Y641F GC B cells manifested loss of the iPSC phenotype. T-cell help induces MYC in GC B cells. However, induction of MYC in mature naïve B cells did not confer them with iPSC potential indicating that other mechanisms must be at play. Lymphoma-associated Btg1 Q36Hmutations confer fitness in GC B cells by enhancing their response to T-cell help. Reciprocal to EZH2 Y641F, Btg1 Q36Hmutant GC B cells manifested further significant increase in iPSC formation. Performing multi-ome (simultaneous single-cell RNAseq and ATACseq) studies in GC B cells revealed massive gain in chromatin accessibility of bona fide stem cell super-enhancers in GC B cells that received T-cell help. There was also a reduced accessibility at genes that maintain B-cell lineage (e.g. Pax5) and GC phenotypes (e.g. Foxo1). Finally, lymphoma-associated Histone 1 mutations induce upregulation of stem cell programs in GCs and could enhance iPSC reprogramming in fibroblasts. We therefore hypothesized that H1 deficiency would overcome the GC dependency on T-cells for their plasticity phenotype. Indeed, increased iPSC formation occurred across all GC subpopulations in H1 C/E-/- (HIST1C/HIST1E knockout) mice. We speculate that restricting plasticity to B cells under selection by T cells, limits the potential for GC B cells to acquire high levels of plasticity, hence reducing the potential for these cells to initiate lymphomas. Consistent with this notion, we found that DLBCL patients enriched for these stem cell signatures manifested inferior clinical outcomes.
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Tiberi, G., A. Pekowska, C. Oudin, A. Ivey, A. Autret, T. Prebet, M. Koubi et al. "PcG methylation of the HIST1 cluster defines an epigenetic marker of acute myeloid leukemia". Leukemia 29, n.º 5 (8 de dezembro de 2014): 1202–6. http://dx.doi.org/10.1038/leu.2014.339.
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Fortino, Vittorio, Lukas Wisgrill, Paulina Werner, Sari Suomela, Nina Linder, Erja Jalonen, Alina Suomalainen et al. "Machine-learning–driven biomarker discovery for the discrimination between allergic and irritant contact dermatitis". Proceedings of the National Academy of Sciences 117, n.º 52 (14 de dezembro de 2020): 33474–85. http://dx.doi.org/10.1073/pnas.2009192117.
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Contact dermatitis tremendously impacts the quality of life of suffering patients. Currently, diagnostic regimes rely on allergy testing, exposure specification, and follow-up visits; however, distinguishing the clinical phenotype of irritant and allergic contact dermatitis remains challenging. Employing integrative transcriptomic analysis and machine-learning approaches, we aimed to decipher disease-related signature genes to find suitable sets of biomarkers. A total of 89 positive patch-test reaction biopsies against four contact allergens and two irritants were analyzed via microarray. Coexpression network analysis and Random Forest classification were used to discover potential biomarkers and selected biomarker models were validated in an independent patient group. Differential gene-expression analysis identified major gene-expression changes depending on the stimulus. Random Forest classification identified CD47, BATF, FASLG, RGS16, SYNPO, SELE, PTPN7, WARS, PRC1, EXO1, RRM2, PBK, RAD54L, KIFC1, SPC25, PKMYT, HISTH1A, TPX2, DLGAP5, TPX2, CH25H, and IL37 as potential biomarkers to distinguish allergic and irritant contact dermatitis in human skin. Validation experiments and prediction performances on external testing datasets demonstrated potential applicability of the identified biomarker models in the clinic. Capitalizing on this knowledge, novel diagnostic tools can be developed to guide clinical diagnosis of contact allergies.
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Zhang, You-You, Xi Li, Shu-Wen Qian, Liang Guo, Hai-Yan Huang, Qun He, Yuan Liu, Chun-Gu Ma e Qi-Qun Tang. "Transcriptional activation of histone H4 by C/EBPβ during the mitotic clonal expansion of 3T3-L1 adipocyte differentiation". Molecular Biology of the Cell 22, n.º 13 (julho de 2011): 2165–74. http://dx.doi.org/10.1091/mbc.e10-11-0912.
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CCAAT enhancer binding protein β (C/EBPβ) is required for both mitotic clonal expansion (MCE) and terminal differentiation during the 3T3-L1 adipocyte differentiation program. Whereas the mechanism of C/EBPβ during terminal differentiation is well understood, the mechanism of C/EBPβ in MCE is not. We provide evidence that histone H4, the most conserved cell cycle–related histone, the change of which is strictly correlated with DNA content change during the cell cycle, is transcriptionally activated by C/EBPβ during MCE. Expression of histone H4 is increased at 16 h after induction when 3T3-L1 preadipocytes synchronously reenter S phase, which is correlated with the sequential phosphorylation and activation of C/EBPβ, and expression was partially suppressed when A-C/EBP (dominant negative for C/EBP protein) was overexpressed. One C/EBP-binding site was identified in one of the histone H4 gene promoters (hist4h4), confirmed by both electrophoretic mobility shift assay and chromatin immunoprecipitation assay. C/EBP-binding sites were also found in 9 of 11 other histone H4 promoters, which can also be transactivated by C/EBPβ. Knockdown of C/EBPβ by stealth small interfering RNA partially decreased H4 gene expression and arrested cells in G1 phase as indicated by bromodeoxyuridine incorporation and fluorescence-activated cell sorting analysis of DNA content. This study provides new insights into why C/EBPβ is required for MCE during 3T3-L1 adipocyte differentiation and why C/EBPβ plays important roles in the proliferation of other cell types.
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Ling, Zhi-an, Dan-dan Xiong, Rong-mei Meng, Jie-Mei Cen, Na Zhao, Gang Chen, Ruo-lin Li e Yi-wu Dang. "LncRNA NEAT1 Promotes Deterioration of Hepatocellular Carcinoma Based on In Vitro Experiments, Data Mining, and RT-qPCR Analysis". Cellular Physiology and Biochemistry 48, n.º 2 (2018): 540–55. http://dx.doi.org/10.1159/000491811.
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Background/Aims: Accumulated evidence indicates that lncRNA NEAT1 has important roles in various malignant tumors. In this study, we conducted a comprehensive analysis to explore the exact role of NEAT1 in hepatocellular carcinoma (HCC). Methods: The effects of NEAT1 on cell proliferation, apoptosis, migration, and invasion were measured by in vitro experiments. The expression level and clinical value of NEAT1 in HCC was evaluated based on data from The Cancer Genome Atlas (TCGA), Oncomine, and in-house real-time quantitative (RT-qPCR). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) network analyses were conducted to investigate the potential molecular mechanisms of NEAT1. Results: NEAT1 siRNA not only inhibited proliferation, migration, and invasion of HCC cells but also induced HCC cell apoptosis. A total of four records from TCGA, Oncomine, and RT-qPCR analysis were combined to assess the expression level of NEAT1 in HCC. The pooled standard mean deviation (SMD) indicated that NEAT1 was up-regulated in HCC (SMD = 0.54; 95% CI, 0.36–0.73; P < 0.0001). The area under the curve value of the summary receiver operating characteristic curve was 0.71. NEAT1 expression was also related to race (P = 0.025) and distant metastasis (P = 0.002). Additionally, the results of GO, KEGG pathway, and PPI network analyses suggest that NEAT1 may promote the progression of HCC by interacting with several tumor-related genes (SP1, MDM4, CREBBP, TRAF5, CASP8, TRAF1, KAT2A, and HIST4H4). Conclusions: NEAT1 contributes to the deterioration of HCC and provides a potential biomarker for the diagnosis and therapy of HCC.
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Roeder, G. S., C. Beard, M. Smith e S. Keranen. "Isolation and characterization of the SPT2 gene, a negative regulator of Ty-controlled yeast gene expression". Molecular and Cellular Biology 5, n.º 7 (julho de 1985): 1543–53. http://dx.doi.org/10.1128/mcb.5.7.1543-1553.1985.
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The his4-917 mutation of Saccharomyces cerevisiae results from the insertion of the Ty element Ty917 into the regulatory region of the HIS4 gene and renders the cell His-. The hist4-912 delta mutant, which carries a solo delta in the 5'-noncoding region of HIS4, is His+ at 37 degrees C but His- at 23 degrees C. Both these mutations interfere with HIS4 expression at the transcriptional level. The His- phenotype of both insertion mutations is suppressed by mutations at the SPT2 locus. The product of the wild-type SPT2 gene apparently represses HIS4 transcription in these mutant strains; this repression is relieved when the SPT2 gene is destroyed by mutation. The repression of transcription by SPT2 presumably results from an interaction between the SPT2+ gene product and Ty or delta sequences. In this paper, we report the cloning and DNA sequence analysis of the wild-type SPT2 gene and show that the gene is capable of encoding a protein of 333 amino acids in length. In addition, we show that a dominant mutation of the SPT2 gene results from the generation of an ochre codon which is presumed to lead to a shortened SPT2 gene product.
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Roeder, G. S., C. Beard, M. Smith e S. Keranen. "Isolation and characterization of the SPT2 gene, a negative regulator of Ty-controlled yeast gene expression." Molecular and Cellular Biology 5, n.º 7 (julho de 1985): 1543–53. http://dx.doi.org/10.1128/mcb.5.7.1543.
Texto completo da fonteResumo:
The his4-917 mutation of Saccharomyces cerevisiae results from the insertion of the Ty element Ty917 into the regulatory region of the HIS4 gene and renders the cell His-. The hist4-912 delta mutant, which carries a solo delta in the 5'-noncoding region of HIS4, is His+ at 37 degrees C but His- at 23 degrees C. Both these mutations interfere with HIS4 expression at the transcriptional level. The His- phenotype of both insertion mutations is suppressed by mutations at the SPT2 locus. The product of the wild-type SPT2 gene apparently represses HIS4 transcription in these mutant strains; this repression is relieved when the SPT2 gene is destroyed by mutation. The repression of transcription by SPT2 presumably results from an interaction between the SPT2+ gene product and Ty or delta sequences. In this paper, we report the cloning and DNA sequence analysis of the wild-type SPT2 gene and show that the gene is capable of encoding a protein of 333 amino acids in length. In addition, we show that a dominant mutation of the SPT2 gene results from the generation of an ochre codon which is presumed to lead to a shortened SPT2 gene product.
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Sangatsuda, Yuhei, Fumihito Miura, Hiromitsu Araki, Masahiro Mizuguchi, Nobuhiro Hata, Daisuke Kuga, Ryusuke Hatae et al. "TBIO-08. BASE-RESOLUTION METHYLOMES OF GLIOMAS BEARING HISTONE H3.3 MUTATIONS REVEAL A G34 MUTANT-SPECIFIC SIGNATURE SHARED WITH BONE TUMORS". Neuro-Oncology 22, Supplement_3 (1 de dezembro de 2020): iii468. http://dx.doi.org/10.1093/neuonc/noaa222.836.
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Abstract BACKGROUND Two recurrent mutations, K27M and G34R/V, in H3F3A, encoding non-canonical histone H3.3, are reported in pediatric and young adult gliomas, whereas G34W mutation was prevalent in bone tumors. In contrast to K27 mutation, it remains elusive how G34 mutations affect the epigenome. Here we performed whole-genome bisulfite sequencing of four G34R-mutated gliomas and the G34V-mutated glioma cell line KNS-42. Similarly, we analyzed seven and three gliomas harboring K27M and no mutations in H3F3A, respectively. These data were compared with those on bone tumors. RESULTS G34R-mutated gliomas exhibited lower global methylation levels, similar CpG island (CGI) methylation levels, and compromised hypermethylation of telomere-proximal CGIs compared with those bearing K27M and no mutations. Hypermethylated regions specific to G34R-mutated gliomas were enriched for CGIs, including those of OLIG1, OLIG2, and canonical histone genes in the HIST1 cluster. These CGIs were hypermethylated in osteosarcomas with, but not without, the G34W mutation. In KNS-42 cells, CGIs with G34V-mutated histone H3.3 exhibited higher methylation levels than those with wild-type histone H3.3. This effect was also observed in the G34R-mutated glioma samples. CONCLUSIONS Gliomas bearing G34R/V mutations display characteristic methylomic alterations, some of which are shared by osteosarcomas with the G34W mutation. Deposition of G34 variants may lead to elevated methylation of otherwise hypomethylated, histone H3.3-bearing CGIs.
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Sandahl, Julie Damgaard, Eva A. Coenen, Erik Forestier, Jochen Harbott, Bertil Johansson, Gitte Kerndrup, Souichi Adachi et al. "Translocation t(6;9)(p22;q34)/DEK-NUP214 rearranged Pediatric AML: A Retrospective International Study". Blood 120, n.º 21 (16 de novembro de 2012): 538. http://dx.doi.org/10.1182/blood.v120.21.538.538.
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Abstract Abstract 538 The cytogenetic subgroup t(6;9)(p22;q34), previously often reported as a breakpoint in 6p23, is defined as a distinct entity in the 2008 WHO classification of acute myeloid leukemia (AML). The translocation results in a chimeric fusion between DEK at 6p22.3 and NUP214 at 9q34.13 generating the DEK-NUP214 fusion gene. In adults, t(6;9) is associated with young age, very poor outcome, and a higher prevalence of FLT3-ITD than in any other type of AML. To date, the clinical impact of t(6;9) has not been independently described in a pediatric cohort. In this retrospective study, we aimed to characterize the clinical, genetic and morphological features of t(6;9) in childhood AML and to evaluate outcome. Children aged 0–18 years and diagnosed with t(6;9)-positive AML or MDS within the period January 1, 1993 to December 31, 2011 were included. The presence of the translocation was determined by conventional karyotyping, FISH, or RT-PCR. Patients with Down syndrome and therapy-related AML were excluded. All major pediatric AML study groups were invited to submit clinical data. In addition, diagnostic smears and biopsies were requested for central reviewing and viable cells or RNA for gene expression profiling (GEP). All karyotypes were centrally reviewed and described according to the International System for Human Cytogenetic Nomenclature. GEP was performed on available frozen diagnostic samples from 297 pediatric AML patients including 6 patients with t(6;9). Based on p-value, log-fold change and biological relevance, the following 4 genes were selected for validation by quantitative real-time PCR (RT-qPCR); eyes absent homolog 3 at 1p35.3 (EYA3), sestrin 1 at 6q21(SESN1), PR domain containing 2, with ZNF domain at 1p36.21 (PRDM2, also known as RIZ1), and histone cluster 2, H4a at 1q21.2 (HIST2H4). Validation was performed on 48 patient samples: t(6;9) (n=17), other pediatric AML (n=31) and 14 cell lines including one with t(6;9)(p22;q34). A total of 58 pediatric patients with a DEK-NUP214 t(6;9) myeloid malignancy from 24 study groups were included in the study: 50 were diagnosed as de novo AML (0.5% of all AML during the study period) and 8 as MDS. Patients with t(6;9) were characterized by a late onset as well as male preponderance; median age was 11 years (range 3–18 years) and the male:female ratio 39:19 (p<0.01). The median white blood cell count (WBC) was 15.6×109/L (range 0.2–191). Bilinear dysplasia with pseudo-Pelger-Huët cells was commonly seen (92% of reviewed evaluable material), and Auer rods were reported in 10 patients, whereas basophilia, in contrast to adults, was absent in this pediatric cohort. FAB-M2 dominated (45%), followed by M4 in 24%. The t(6;9) was the sole cytogenetic abnormality in 81%. Trisomies 8 and 13 constituted 40% of the additional aberrations, either alone or together. FLT3-ITD was present in 44% (n=11) of the cohort with known FLT3 status. The 5-year OS for AML and MDS was 55% and 86%, 5-year EFS was 33% and 56%, respectively. Presence of FLT3-ITD had a non-significant negative effect on OS: 32% for FLT3-ITD-positive cases vs. 67% for FLT3-ITD-negative cases, (p=0.15). The 5-year OS for patients treated with stem cell transplant (SCT) in 1st complete remission (CR) or with refractory disease (RD) was 82% (n=20) vs. 56% with chemotherapy (n=30), (p=0.10). Children who died within 3 months from diagnosis were excluded from the analysis of SCT vs. chemotherapy. The GEP performed on 6 pediatric t(6;9) positive patients showed a unique signature with 180 significantly differentially expressed genes. High expression of EYA3, SESN1, PRDM2/RIZ1 and HIST2H4, was confirmed by RT q-PCR. The levels of expression were significantly elevated for all 4 genes in the t(6;9)-positive cases compared with other AML subtypes. In conclusion, we present a large international series of 58 children with DEK-NUP214/ t(6;9)(p22;q34)-positive myeloid leukemia, representing 0.5% of all childhood AML. The cases were characterized by late onset, male predominance, myelodysplasia, and a unique gene expression signature. The 5-year OS was intermediate and substantially better than reported in adults. SCT in 1st CR or in RD did non-significantly improve the OS compared with conventional chemotherapy alone. Disclosures: No relevant conflicts of interest to declare.
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Nagel, Stefan, Corinna Meyer, Maren Kaufmann, Roderick AF MacLeod e Hans G. Drexler. "Aberrant Chromatin Modifications Mediate Ectopic Expression of Homeobox Gene NKX2-1 in B-Cell Lymphoma". Blood 120, n.º 21 (16 de novembro de 2012): 3494. http://dx.doi.org/10.1182/blood.v120.21.3494.3494.
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Abstract Abstract 3494 Homeobox genes encode transcription factors ubiquitously involved in basic developmental processes, and when deregulated promote cell transformation in multiple cancers including hematopoietic malignancies. In this context several members of the NKL family of homeobox genes are aberrantly expressed in acute T-cell leukemia by chromosomal aberrations. Here, analysis of 20 cell lines of T- and B-cell leukemia/lymphoma by expression arrays (Affymetrix, HGU133plus2) revealed exclusive activity of NKL homeobox gene NKX2-1 in a diffuse large B-cell lymphoma (DLBCL) cell line. NKX2-1 is physiologically expressed in embryonic lung and thyroid tissues where it regulates differentiation. RQ-PCR analysis of gene expression in primary hematopoietic samples, including bone marrow, lymph node, thymus, peripheral mononuclear blood cells, T-cells and B-cells, confirmed silencing therein highlighting ectopic expression of NKX2-1 in the cell line. Copy number analysis by genomic array data (Broad Institute), spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) excluded chromosomal rearrangements at the NKX2-1 locus in expressing cells. Comparative expression analysis of NKX2-1 negative DLBCL cell lines implicated several candidate genes involved in NKX2-1 regulation, variously encoding transcription factors (TFs), chromatin modifiers and signaling components. Accordingly, siRNA-mediated knockdown and overexpression studies confirmed TF HEY1 in ectopic NKX2-1 expression and NKX2-1 in HEY1 expression in DLBCL cells, indicating reciprocal activation of these TFs. Moreover, chromatin immunoprecipitation (ChIP) analysis demonstrated direct binding of NKX2-1 to the HEY1 promoter. HEY1 belongs to the basic helix-loop-helix family disturbing lymphoid differentiation if deregulated. Enhanced expression levels of histone H3K4 methyltransferase MLL correlated with downstream rearrangement and amplification of the MLL-locus at 11q23. SiRNA-mediated knockdown of MLL was accompanied by reduced expression of NKX2-1 but not of HEY1, showing that MLL supports expression of NKX2-1. Furthermore, ChIP analyses demonstrated presence of both activatory H3K4me3 and inhibitory H3K27me3 at the promoter region of NKX2-1, while at the HEY1 promoter only H3K27me3 was detected. Such bivalent histone marks have been described for developmental genes in progenitor cells, indicating a permissive role for aberrant chromatin structures at the NKX2-1 locus in this cell line. Chromosomal alteration del(6p22) as detected by SKY and subsequently mapped by FISH was shown to target the histone gene locus HIST1. Expression analysis at the RNA and protein levels showed elevated expression of core-histones including H2B. Additionally, mono-ubiquitinated H2B was strongly enhanced in this DLBCL cell line when analyzed by Western blot. This histone mark supports the MLL-mediated formation of active chromatin structures, suggesting cooperative action of the chromosomal aberrations targeting MLL and HIST1. Array data also indicated aberrant expression of polycomb repressor complex 2 (PRC2) members which counteract the activity of MLL. Accordingly, siRNA-mediated knockdown analyses demonstrated regulatory impacts of HOPX, E2F6 and JMJD3 in NKX2-1 expression. The potential impact of signaling pathways in NKX2-1 expression, comprising NFkB, SMADs and phosphodiesterases was confirmed by treatments with TNFa, TGFb and cAMP/cGMP, respectively. Taken together, we have identified ectopic expression of NKX2-1 in DLBCL cells, involved in an oncogenic regulative network which may compromise B-cell differentiation via activation of HEY1. Combined analyses of chromosomal alterations and comparative gene expressions identified aberrant chromatin structures underlying expression of NKX2-1, representing the central player in that network. Therefore, our data extend the paradigm of NKL homeobox gene deregulation in lymphoid malignancy. Disclosures: No relevant conflicts of interest to declare.
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Amin, Samirkumar, Kevin Anderson, Beth Bourdreau, Emmanuel Martínez, Emre Kocakavuk, Kevin C. Johnson, Floris Barthel et al. "GENE-57. COMPARATIVE MOLECULAR LIFE HISTORY OF SPONTANEOUS CANINE AND HUMAN GLIOMA". Neuro-Oncology 21, Supplement_6 (novembro de 2019): vi110. http://dx.doi.org/10.1093/neuonc/noz175.459.
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Abstract Diffuse gliomas are the commonest of malignant brain tumors with high-grade tumors carrying dismal prognosis. Preclinical models have proven themselves as poor predictors of clinical efficacy, attributed to the lack of a comparable tumor microenvironment. Comparative genomics of canine and human gliomas provide an attractive alternative modality to identify conserved drivers and underlying mutational processes of glioma as well as evaluate life history tradeoffs related to tissue context and aging that can shape type and relative timing of drivers in gliomagenesis. We performed a comparative genomics analysis between whole genome-, exome-, transcriptome- and methylation-sequencing of 77 canine gliomas, and human pediatric (n=217) and adult gliomas (n=822). We found alterations in common with those in human pediatric and adult gliomas in the Tp53 and cell cycle pathways, receptor tyrosine kinase and Idh1 R132 mutations. Canine gliomas showed similarity to human pediatric gliomas in terms of lower mutational rates (0.2–0.29 per megabase), hotspot mutations and amplifications of Pdgfrα, and robust aneuploidy constrained within the syntenic regions of Pdgfrα and Myc, but also in the known pediatric drivers, Hist1 and Acvr1 genes. A mutational signature reflecting homologous repair defect was detected in canine and pediatric but not adult gliomas, potentially resulting in the observed higher rates of genomic instability. Canine gliomas in majority classified as pediatric tumors using a commonly used human brain methylation classifier (Capper et al. 2018) and cell-of-origin analysis by deconvoluting canine transcriptome using lineage-specific gene signatures. By providing a large canine glioma genomic-sequencing dataset and comparing it with human glioma, our study provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations. Further, our results effectively position preclinical models of spontaneous canine glioma for use in understanding glioma drivers, and evaluate novel therapies targeting aneuploidy, especially for pediatric brain tumors.
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Choi, I., J. H. Lee e K. Campbell. "28 EFFECT OF TREATMENT OF OVINE OOCYTES WITH CAFFEINE ON GENE EXPRESSION IN NUCLEAR TRANSFER EMBRYOS". Reproduction, Fertility and Development 18, n.º 2 (2006): 122. http://dx.doi.org/10.1071/rdv18n2ab28.
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The efficiency of animal production by somatic cell nuclear transfer (SCNT) remains low and this has been linked to incomplete epigenetic reprogramming of the donor somatic cell nucleus. Previous studies have reported that embryos produced by SCNT exhibit abnormal expression patterns for a number of genes, including IL6, FGF4, FGFr2, Hsp, IF-tau, DNMT, and Mash2 (Daniels et al. 2000 Biol. Reprod. 63, 1034-1040; Wrenzycki et al. 2001 Biol. Reprod. 65, 309-317). Recently, we demonstrated that treatment of telophase I or metaphase II ovine oocytes with 10 mM caffeine for 6 h increased the activities of both MPF and MAPK kinases. In NT embryos produced using caffeine treated oocytes as recipient cytoplasts, no increase in the frequency of development to the blastocyst stage was observed; however, blastocyst stage embryos had an increased cell number (Lee and Campbell 2005 Reprod. Fertil. Dev. 16, 125). The objective of the present study was to examine the effects of caffeine treatment on the expression levels of a number of genes involved in early development. Target genes were categorized into seven groups based on their function: (1) transcription factors (Oct-4, Sox-2), (2) growth factors (IGF-1, IGF-1r, IGF-2r, FGF-2, and FGF-4), (3) stress adaptation (Hsp70.1 and Hsp27), (4) metabolism (Glut-1, Glut-3, and Glut-4), (5) compaction/cavitation (DcII), (6) trophoblastic function (IF-tau), and (7) nuclear reprogramming factors (Hist4h4, H2A.Z, and Lmna). To determine the transcript levels semiquantitatively, different PCR cycle parameters were used (35 and 40 cycles). Expression levels were compared in blastocyst-stage embryos obtained from five groups produced as previously described (Lee and Campbell 2005; Maalouf et al. 2005 Reproduction 32, 49): (I) IVF embryos, (II) caffeine-treated IVF embryos, (III) parthenotes, (IV) SCNT embryos, and (V) caffeine treated SCNT embryos. No differences in overall expression patterns were observed among groups I, II, and III. In group IV non-treated SCNT-derived embryos, an aberrant gene expression pattern was found with respect to Oct-4 and genes regulated by Oct-4: H2A.Z, IF-tau, and FGF-4, Oct-4, H2A.Z, and FGF-4 were down-regulated and IF-tau was up-regulated. In contrast, the expression patterns of group V caffeine-treated SCNT embryos resembled those of control groups I, II, and III. In comparison to gene expression in group IV embryos, Oct-4, FGF-4, and H2A.Z were up-regulated but IF-tau was down-regulated. Previous studies have demonstrated that FGF-4 and H2A.Z play an important role in early development and implantation, whereas expression of IF-tau is related to embryo quality (Feldman et al. 1995 Science 267, 246-249; Fasst et al. 2001 Curr. Biol. 11, 1183-1187; Wrenzycki et al. 2001). Our results demonstrate that treatment of oocytes with caffeine prior to embryo reconstruction can alter the expression patterns of developmentally regulated genes in SCNT embryos to more closely resemble those of IVF controls.
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Kosheleva, Natalia G., Marina A. Gusareva, Gennady V. Balitsky, Natalia A. Lyman, Peter N. Gabrichidze, Umar Muhmadovich Gaziev, Anna A. Solntseva et al. "The genes CNV and expression as a factors of HT-29 cells radioresistance." Journal of Clinical Oncology 38, n.º 15_suppl (20 de maio de 2020): e15590-e15590. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15590.
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e15590 Background: The initial radioresistance of tumor cells associated with certain molecular genetic features has a great influence on the effectiveness of radiation therapy (RD). These features include the transcriptional activity of genes that regulate DNA repair, cell cycle and apoptosis, and their copy number variation (CNV). The aim of the study was to analyze the expression and CNV of genes that regulate DNA repair, cell cycle and apoptosis in HT-29 cells subjected to RD. Methods: HT-29 cell culture was used in the study. For the model experiment, doses of 5 and 7 Gy were used (irradiation was performed 5 times every 24 hours on a Novalis TX linear accelerator). Cell counting was carried out in Goryaev chamber (0.4% trypan blue solution). On the 5th day of irradiation, HT-29 was removed from the substrate with Trypsin / Versen solution. RNA was isolated according to the method of Chomczynski&Sacchi. For cDNA synthesis was used a "REVERTA-L". reagent. The phenol-chloroform method was used to DNA isolate. The RT-qPCR method was used to determine the CNV and expression of 32 genes: AKT, ATM, BRIP, BRCA1, BRCA2, CDK1, CDKN1B, CCND1, CCND3, EXO1, FGFR2, HIST1, H2AX, KU70, PTEN, RAD50, RAP80, RIF1, RNF8 TOPB1, TP53, XRCC4, BAX, CASP8, CASP3, CASP9, MDM2, BCL2, RBBP8, EP300, LIG4, C-FLIP. Statistical analysis was performed using ANOVA and Spearman's rank correlation coefficient (r). Results: After irradiation, only a specific pool of HT-29 cells remained viable: 32% for 5 Gy and 20% for 7 Gy of the initial number of cells. In HT-29 cells irradiated with 7 Gy, the CNV of the BRCA2, H2AX, CASP9 and RBBP8 genes was increased (p < 0.05) and the CNV of BCL2 gene was reduced (p < 0.05) relative to intact cells. In cells irradiated with 5 Gy only CASP9 and RBBP8 CNV was statistically significantly (p < 0.05) increased. In cells irradiated with 5 and 7 Gy, expression of BRCA2, H2AX, CASP9 and RBBP8 genes was statistically significantly (p < 0.05) increased and the expression of the BCL2 gene was reduced relative to intact cells. A strong positive correlation was observed between CNV and expression of the studied genes: r = 0.998 for control, r = 0.989 for cells irradiated at 5 Gy, and r = 0.993 for cells irradiated at 7 Gy. Conclusions: The study showed that 5 day RD at 5 and 7 Gy leads to selective survival of 32% and 20% of cells, respectively, with increased CNV and expression of BRCA2, H2AX, RBBP8 CASP9 genes and reduced CNV and expression of BCL2 gene.
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Pellagatti, Andrea, Mario Cazzola, Aristoteles Giagounidis, Luca Malcovati, Matteo G. Della Porta, Martin Jädersten, Sally Killick et al. "Expression Profiling of CD34+ Cells in Patients with Myelodysplastic Syndromes: Involvement of Interferon-Stimulated Genes and Correlation to FAB Subtype and Karyotype." Blood 108, n.º 11 (16 de novembro de 2006): 2626. http://dx.doi.org/10.1182/blood.v108.11.2626.2626.
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Abstract The myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic malignancies. We have used Affymetrix microarray technology to determine the gene expression profiles in CD34+ cells of 84 MDS patients (25 RA, 28 RARS and 31 RAEB) and 16 healthy controls. Twenty-five of 84 patients had a del(5q). CD34+ cells were isolated from bone marrow samples using MACS magnetic columns. Extracted total RNA was amplified using the Two-Cycle Target Labelling kit (Affymetrix) and samples were hybridized to Affymetrix U133 Plus2.0 chips (representing 39,000 human genes). Cell intensity calculation and scaling was performed using GeneChip Operating Software and data analysis using GeneSpring 7.3. The expression profiles of MDS CD34+ cells showed many similarities to reported interferon-γ induced gene expression in normal CD34+ cells. Indeed the two most up-regulated genes, IFIT1 and IFITM1, are interferon-stimulated genes. IFIT1 and IFITM1 were up-regulated by >2-fold in 58/84 and 53/84 MDS patients respectively. Genes down-regulated by >2-fold in the majority of MDS patients include the putative tumor suppressor gene Gravin/AKAP12, ARPP-21, CD24 and MME. The association of distinct gene expression profiles with specific FAB and cytogenetic groups was determined using data from 55 MDS patients as a training set. Hierarchical clustering performed using 457 significantly different genes between different FAB subtypes showed that MDS patients with RARS constitute a homogeneous group, while MDS patients with RA and RAEB show more overlap. CD34+ cells from patients with RARS showed up-regulation of mitochondrial-related genes, and in particular of those of heme synthesis (e.g. ALAS2). Statistical analysis showed that 889 probe-sets could discriminate MDS patients with a del(5q) from those without a del(5q). MDS patients with the del(5q) showed distinctive down-regulation of genes mapping to chromosome 5q, and up-regulation of the histone HIST1 gene cluster at chromosome 6p21 and of genes related to the actin cytoskeleton. In order to identify genes differentially expressed between early and advanced MDS, a comparison was made between the 18 patients with RA and the nine MDS patients with RAEBII. 762 significantly different probe sets were identified that could group together MDS patients with RAEBII. The most significant genes identified include CASP3 and FLT3, and represent potential prognostic markers or markers of disease progression. The remaining 29 MDS patients were used as a test set for class prediction using support vector machines. The FAB subtype was correctly predicted for 83% of the test samples. The presence or absence of a del(5q) was predicted correctly for 93% of the test samples. Finally, 94% of the test samples were predicted correctly as RA or RAEBII. This study provides important and new insights into the pathophysiology of MDS.
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Dreyfuss, Alexandra, Beatrice Fregonese, Jennifer Ma, Reith R. Sarkar, Gustav Cederquist, Saad Z. Usmani, Carla Hajj, Brandon S. Imber e Joachim Yahalom. "Recent Patterns of Radiotherapy Use in Multiple Myeloma: Clinical Outcomes and Possible Radiologic, Biochemical, and Genomic Correlates of Response". Blood 142, Supplement 1 (28 de novembro de 2023): 6648. http://dx.doi.org/10.1182/blood-2023-188172.
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Background/Objectives: Systemic therapies for multiple myeloma (MM) have advanced considerably, changing the landscape of MM treatment paradigms. Yet, the use of radiotherapy (RT) has remained heterogeneous, and even controversial, due to minimal data on outcomes. With the ultimate goal of guiding the design of prospective trials incorporating RT, we initiated a study of our institutional experience treating MM with RT since 1/1/2000. Here we report a preliminary feasibility analysis of an initial sample cohort, identifying patterns of RT use, outcomes, and the impact of RT on radiographic and biochemical markers, with genomic characterization for more recently treated patients. Materials/Methods: 506 pathologically confirmed MM patients who received RT to 1190 sites between 1/1/2000 and 6/1/2022 were identified. Patient, disease, and treatment characteristics were analyzed for 50 consecutive patients treated in 2019 (recent sampling but with reasonable follow for analysis) and tested for association with cumulative incidence of local and distant failure (LF, DF) using univariable and multivariable analysis. Genomic data was obtained via next generation sequencing using an institutional targeted sequencing panel (Memorial Sloan Kettering IMPACT). Results: Among the 50 patients analyzed (median 63 years), 90 lesions were treated with RT, 33% with concurrent systemic therapy, to a median dose of 20 Gy (8-46 Gy) over a median of 5 fractions (1-25). RT Indications were pain (56%), critical structure involvement (25%), peri-operative (9%), salvage/consolidation (8%), and bridging therapy (2%). Median size of RT-treated lesions was 4.2 cm (1.4-7.9) and included non-vertebral bones (62%), spine (24%), and extramedullary sites (14%). The median number of lines of pre-RT therapy was 7 (1-14) and 51% had >9 lesions on imaging, 47% involving both medullary and extramedullary sites. Pre-RT PET imaging was performed in a majority of patients (62%). With a median follow-up of 12.4 months (0.5-46), LF occurred in 5% of treated sites and 89% had DF, most commonly in both medullary + extramedullary (51.4%) sites. Of the patients with DF, 93% had sustained local control of the irradiated site. Absolute decreases 1-week to 1-month post-RT were observed in marrow plasma cell percentage, (median 4.0%), M spike (0.30 g/dL), total protein (0.3 g/dL), K:L ratio (0.01), lesion size (1.5cm), and lesion SUV (3.1) but in this limited sample, none were significantly associated with disease control. A cohort of 62 RT-treated MM patients from 2016-2022 had genomic data available; most common tumor mutations were in TP53 (35%), HIST1 (34%), NRAS (34%), and KRAS (23%). Conclusion: In this pilot analysis of a sampling cohort of RT-treated MM, we report on patterns of utilization, outcomes, and biochemical and radiographic correlates. Ultimately, we aim to characterize the role of RT in the modern era of systemic therapy to guide the design of future prospective trials and to inform novel approaches for incorporating RT into the treatment paradigm. At the meeting, we will present data from a larger cohort of MM patients, with further sub-analyses on the relevance of baseline imaging to subsequent irradiated lesions, as well as toxicity and outcomes data with the use of radiotherapy in conjunction with newer systemic agents (bi-specific antibodies and chimeric antigen receptor T-cell therapy).
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Agrusa, Jennifer, Elmoataz A. Abdel Fattah, Howard Lin, Rikhia Chakraborty, Brooks Scull, Harshal Abhyankar, Nmazuo Wudo Ozuah et al. "Comprehensive Cell Specific Transcriptome Profiling of a Pediatric Hodgkin Lymphoma Cohort". Blood 134, Supplement_1 (13 de novembro de 2019): 2773. http://dx.doi.org/10.1182/blood-2019-125982.
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Introduction: Pathogenic Hodgkin Reed-Sternberg (HRS) cells constitute approximately 1% of Hodgkin lymphoma (HL) tumor cells. Studies characterizing genomic lesions and gene expression of HRS gene cells have been limited due to technical challenges of studying these rare cells, and the majority of existing data has focused on adult HL. We therefore developed a multi-parameter flow sorting strategy to isolate viable cells from pediatric HL tumors and to define the transcriptomes of HRS cells and infiltrating lymphocytes in order to inform underlying mechanisms of HL pathogenesis and also create an opportunity to identify cell-specific biomarkers to predict disease risk and response to therapy. Methods : Flow cytometry was used to sort HRS cells, CD4+ T cells, CD8+ T cells, and CD20+/30+B cells from pediatric subjects' HL lesions and control tonsils. Purity was confirmed by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). Affymetrix GeneChip HTA 2.0 was used to assess the gene expression profiles (GEPs) for 16 HRS primary tumor cell samples, 14 HL CD4+ and CD8+ T cell samples, 6 control tonsillar CD20+, CD30+, CD4+, and CD8+ cell samples, and 6 HL cell lines. Unsupervised hierarchical clustering and principal component analysis (PCA) were used to determine relatedness, and Cibersort was performed to confirm the phenotype of the sorted cell types. GEPs of HRS, HL CD4+, and HL CD8+ cells were compared to respective controls using a univariate t-test. Significance was determined using a multivariate permutation test with the confidence level of FDR assessment at 80 percent and the maximum allowed proportion of false-positive proteins at 0.1. Gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) were performed to analyze DEGs. Results: Effectiveness of the sorting strategy of HRS cells was confirmed by quantitative RT-PCR and IHC that demonstrated significant enrichment of CD30expression and CD30+ cells in the sorted HRS cell fraction. GEP comparisons were performed for 13 HL samples with matched HRS/CD4+/CD8+ cells: HRS vs. control tonsil CD20+/CD30+ (1934 and 3846 DEGs, respectively), HL CD4+ vs. control CD4+ (635 DEGs), HL CD8+ vs. control CD8+ (2 DEGs). We carried out a transcriptomic analysis of HRS cells, and a set of multifunctional genes were more than 2-fold downregulated (P < .001), involved in telomere maintenance and packaging (TERF2, RFC3, DNA2 and a group of HIST1) when compared to healthy lymph node CD30+ cells. A set of genes related to cytokine/chemokine dysregulation was also upregulated in HRS cells, including IL6, CCL18, and CXCL9. IPA and GSEA of specific HRS genes were also performed and demonstrated pathways associated with HL pathogenesis, including NFĸB activation and T cell exhaustion. Over-expression of genes associated with T cell pathways was demonstrated in HRS cells. While this may be a result of T cell rosetting and contamination, it may also reflect innate T cell signature within HRS cells, as HRS cells clustered separately from T cells in both unsupervised hierarchical clustering and PCA. Cibersort analysis of HRS cells revealed a heterogeneous phenotype that may reflect aberrant differentiation. In comparing clinical characteristics within HRS cells, TCEAL1 was elevated in slow vs. rapid early responders and 3 DEGs were identified when comparing EBV+/- samples. Within HL CD8 cells, KLF2 was elevated in EBV- samples. Conclusions: This study was the first to successfully isolate highly purified HRS cell populations from whole HL lesions in a pediatric HL cohort. Transcriptomic analysis of pediatric HRS cells identified mechanisms previously associated with HL pathogenesis, and also identified potential novel mechanisms, including telomere maintenance. Additional analyses demonstrated significant heterogeneity of HRS trasncriptomes across specimens that may reflect distinct differentiation pathways and differences in HRS-immune cell interactions. Finally, this study identified increased expression of some genes associated with EBV status and response to therapy. Future studies in an expanded cohort will validate these findings, compare pediatric and adult GEPs, and test these cell-specific biomarkers into the current risk stratification strategies of prospective clinical trials. Disclosures No relevant conflicts of interest to declare.
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Cuenca, Isabel, Beatriz Sanchez-Vega, Bruno Paiva, David Gomez-Sanchez, Santiago Barrio, Diego Alignani, Marta Lasa et al. "Genetic Profiling and Novel Recurrent Chromosomal Alterations in Patients with Light Chain Amyloidosis". Blood 132, Supplement 1 (29 de novembro de 2018): 4488. http://dx.doi.org/10.1182/blood-2018-99-114543.
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Abstract Introduction High-throughput sequencing studies have rendered seminal knowledge in monoclonal gammopathies such as multiple myeloma (MM) and Waldenström's macroglobulinemia (WM). Unfortunately, the low incidence of AL amyloidosis and its typically low tumor burden, often masked by a polyclonal plasma cell (PC) background, account for the limited information on its tumor cell biology. Thus, it remains unknown if AL amyloidosis harbors a unifying mutation as occurs in WM or if, in its absence, there are recurrent mutations and if these overlap with those observed in MM. With this background , the aim of this study is to perform a whole exome sequencing (WES) in a series of patients with AL amyloidosis and to compare mutational profiles in AL amyloidosis vs MM and analyze the copy number variation in this series of patients. Methods A total of 27 patients with confirmed diagnosis of AL were included. WES was performed in 56 paired samples of FACSorted bone marrow tumor plasma cells and peripheral blood mononucleated cells. Each tumor sample was captured in triplicate using Agilent's SureSelect Human All Exon V6 + UTR kit and sequenced on the Illumina NextSeq 500 platform. Data was analyzed with Strelka software to discard germinal mutations, ANNOVAR for functional annotation, and a data reduction strategy to identify candidate variants. The mutational signature was analyzed with Mutational Signatures in Cancer (MuSiCa) software. We used the MMRF CoMMpass dataset (895 patients) to compare the mutational landscape of MM vs AL. We also determined immunoglobulin gene rearrangements in AL by next generation sequencing. Besides, we analyzed the copy number variation (CNV) with CNVkit program. Results The mean depth coverage for control and tumor samples was 64x and 186x, respectively. A total of 1983 somatic SNV and 133 INDEL were identified, with an average of 71 (20-281) SNV and 5 (0-25) INDEL per patient. Overall, the most frequently mutated genes in this series were IGLL5 and MUC16 (recurrence of 17% each). When compared to MM (average of 66 SNV and 2,5 INDEL), we observed a similar mutational load. However, none of the most frequently mutated genes in MM (i.e. KRAS, NRAS, FAM46C, BRAF, TP53, DIS3, PRDM1, SP140, RGR1, TRAF3, ATM,CCND1, HISTH1E, LTB, IRF4, FGFR3,RB1, ACTG1, CYLD, MAX, ATR) were recurrently mutated in patients with AL. The only genes commonly mutated in AL amyloidosis and MM were MUC16 (recurrence of 17% and 8%, respectively) and IGLL5 (recurrence of 17% each).Most patients with AL harbored between 1 and 8 mutational signatures, implying that multiple mutational processes are operative. The most frequent mutational signature were (signatures 6, 15 and 20) associated with mismatch repair protein deficiency (MMR) and high microsatellite instability (93%), mutational signature 2 (89%), related with the aberrant activity of APOBECs, a family of proteins that enzymatically modify single-stranded DNA and mutational signature 1 (81%), profile that appear in all types of cancers and has been correlated with the age of cancer diagnosis. The signature 2 is also representative of MM. Regarding the immunoglobulin gene repertoire, we noted that 26% of patients with AL harbored more than one clone; this extent in clonal heterogeneity being similar to that found in MM (23%).The most frequent IGH gene involved was IGHV3-30 in both AL (recurrence of 10%) and MM (recurrence of 12%).Regarding CNV, recurrent gains included chromosomes 1q (29%), 5 (38%), 6p (14%), 7 (43%), 9 (43%), 15 (24%), 18 (14%) and 19 (43%). Recurrent losses affected chromosome 13 (33%), 6q (14%) and 16q (19%). Conclusions This is the first WES study performed in a series of patients with AL. We demonstrated the lack of a common driver mutation in this disease and unveiled that recurrently mutated genes in AL amyloidosis do not overlap with those observed in MM. We also confirm the existence of numerous chromosomal alterations in patients with AL. The frequencies of aberrations and alterations detected by NGS are comparable with those describe in previous studies by copy number array analysis, but here we show some novel recurrent chromosomal aberrations as gain of chromosome 7 (43%) and losses of chromosome 18 (14%). Overall, these results may have significant impact in our understanding of the pathogenesis of AL amyloidosis and its differential diagnosis vs other monoclonal gammopathies. Disclosures Ocio: BMS: Consultancy; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Honoraria; Pharmamar: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Oriol:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Puig:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Lahuerta:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Mateos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria. Martinez Lopez:Novartis: Research Funding, Speakers Bureau; Jansen: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau.
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Balasubramanian, Sriram, Brendan Hodkinson, Stephen J. Schuster, Nathan H. Fowler, Judith Trotman, Georg Hess, Bruce Cheson et al. "Identification of a Genetic Signature Enriching for Response to Ibrutinib in Relapsed/Refractory Follicular Lymphoma in the Dawn Phase 2 Trial". Blood 132, Supplement 1 (29 de novembro de 2018): 4147. http://dx.doi.org/10.1182/blood-2018-99-116472.
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Abstract Introduction The DAWN study (NCT01779791) evaluated efficacy and safety of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib as monotherapy in relapsed/refractory (R/R) follicular lymphoma (FL) patients (Gopal AK, et al. J Clin Oncol. doi: 10.1200/JCO.2017.76.8853). The overall response rate (ORR) for ibrutinib was 20.9% (95% confidence interval, 13.7-29.7), not meeting the primary end point; however, responders experienced a long duration of response with a median of 19.4 months. We present the results of a biomarker investigation performed on samples from the DAWN study to determine whether somatic mutations could be used to identify FL patients who responded to ibrutinib. Methods DAWN was a multicenter, single-arm, phase 2 study of ibrutinib (560 mg QD) in FL pts with ≥ 2 prior lines of therapy and progressive disease (PD) ≤ 12 months after chemoimmunotherapy (CIT). The primary end point was ORR (complete response [CR] + partial response [PR]). Whole exome sequencing was performed on formalin-fixed, paraffin-embedded tumor samples from 83 patients with available response data - either "responder" (CR + PR; n = 17) or "nonresponder" (stable disease [SD] + PD; n = 66) following ibrutinib treatment. Multiple filters were applied to rule out potential germline variants, and a custom panel of 1216 genes known to be involved in cancer was used for further analysis. Variants enriched in responders or nonresponders were identified using Fisher's exact test. Classifiers were built with variable numbers of genes ranked with a greedy algorithm that selected genes that would, at each iteration, allow the removal of the greatest number of nonresponders from the patient pool, while severely penalizing the removal of responders; classifier performance was assessed using 10-fold cross-validation. Results The overall pattern of variant frequencies identified from the whole exome sequencing in this study was comparable to previously published studies in FL (Krysiak K, et al. Blood. 2017;129:473-483). As there were many more nonresponders than responders in this study, univariate analysis yielded mostly variants significantly enriched in ibrutinib responders but in very low numbers, eg, FANCA, HISTH1B, ANXA6, and PARP10; interestingly, 2 patients with variants in BTG1, which is considered a tumor suppressor, also responded to ibrutinib. Few nonresponder genes were identified in univariate analysis, including NBPF1, ATP6AP1, EP400, and CNOT1; mutations in these genes may activate pathways that bypass BTK, including the mTOR and JAK/STAT pathways. From the selected panel, a 17-gene classifier was developed (Figure) that included variants in ATP6AP1, EP400, ARID1A, SOCS1, TBL1XR1, CNOT1, and KDM2B. Many of these mutated genes have previously been associated with a poor prognosis in cancers, including FL; the biological functions of these genes involve transcription, cell cycle, DNA repair, cell adhesion, protein processing, and transport. Notably, few significant variants emerged that are directly involved in the BTK pathway, unlike previous reports in diffuse large B-cell lymphoma, although, as mentioned above, a few may represent bypass mechanisms to this pathway. Conclusions Mutational analysis of genes in patients from the phase 2 DAWN trial yielded insights into the mechanism of ibrutinib response and resistance in R/R FL. The genes involved in this mechanism demonstrate a large variety of biological functions and show that ibrutinib activity in FL may extend beyond the BTK-NF-kB pathway to gene and protein regulation, DNA repair, adhesion, and other cellular and microenvironmental processes. We have shown previously that its immune activity is also an important mechanism of action in FL (Gopal 2018). A gene-based classifier has been developed that we hypothesize may prove useful in enriching for ibrutinib response in FL; however, this will need to be validated in other data sets. Funding source Sponsored by Janssen Research & Development, LLC. Writing assistance was provided by Jill See of PAREXEL and funded by Janssen Global Services, LLC. Disclosures Balasubramanian: Janssen Research & Development: Employment, Equity Ownership. Hodkinson:Janssen Research & Development: Employment. Schuster:Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding; Dava Oncology: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Trotman:Takeda: Other: unremunerated advisory role; Celgene: Other: unremunerated advisory role; Roche: Other: unremunerated advisory role; Janssen: Consultancy, Research Funding. Hess:CTI: Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Schaffer:Janssen Research & Development: Employment, Equity Ownership. Wang:Janssen Research & Development: Employment. Deshpande:Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment, Equity Ownership. Salles:Gilead: Honoraria, Other: Advisory Board; Amgen: Honoraria; Servier: Honoraria, Other: Advisory Board; Merck: Honoraria; BMS: Honoraria, Other: Advisory Board; Servier: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Epizyme: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; Janssen: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria; Takeda: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Acerta: Honoraria. Gopal:Teva: Research Funding; Brim: Consultancy; Asana: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Research Funding; Aptevo: Consultancy; BMS: Research Funding; Incyte: Consultancy; Spectrum: Research Funding.
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"Histone cluster 4, H4 (HIST4H4)". Science-Business eXchange 2, n.º 45 (novembro de 2009): 1669. http://dx.doi.org/10.1038/scibx.2009.1669.
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Kaçar, Turhan. History Studies International Journal Of History 1, n.º 1 (2009): 342–45. http://dx.doi.org/10.9737/hist_24.
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"Histone cluster 1 H1A (HIST1A1; HIST1)". Science-Business eXchange 3, n.º 38 (setembro de 2010): 1155. http://dx.doi.org/10.1038/scibx.2010.1155.
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Garciaz, Sylvain, Lia N’guyen Dasi, Pascal Finetti, Christine Chevalier, Julien Vernerey, Mathilde Poplineau, Nadine Platet et al. "Epigenetic down-regulation of the HIST1 locus predicts better prognosis in acute myeloid leukemia with NPM1 mutation". Clinical Epigenetics 11, n.º 1 (12 de outubro de 2019). http://dx.doi.org/10.1186/s13148-019-0738-6.
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Abstract Background The epigenetic machinery is frequently altered in acute myeloid leukemia. Focusing on cytogenetically normal (CN) AML, we previously described an abnormal H3K27me3 enrichment covering 70 kb on the HIST1 cluster (6.p22) in CN-AML patient blasts. Here, we further investigate the molecular, functional, and prognosis significance of this epigenetic alteration named H3K27me3 HIST1 in NPM1-mutated (NPM1mut) CN-AML. Results We found that three quarter of the NPM1mut CN-AML patients were H3K27me3 HIST1high. H3K27me3 HIST1high group of patients was associated with a favorable outcome independently of known molecular risk factors. In gene expression profiling, the H3K27me3 HIST1high mark was associated with lower expression of the histone genes HIST1H1D, HIST1H2BG, HIST1H2AE, and HIST1H3F and an upregulation of genes involved in myelomonocytic differentiation. Mass spectrometry analyses confirmed that the linker histone protein H1d, but not the other histone H1 subtypes, was downregulated in the H3K27me3 HIST1high group of patients. H1d knockdown primed ATRA-mediated differentiation of OCI-AML3 and U937 AML cell lines, as assessed on CD11b/CD11c markers, morphological and gene expression analyses. Conclusions Our data suggest that NPM1mut AML prognosis depends on the epigenetic silencing of the HIST1 cluster and that, among the H3K27me3 silenced histone genes, HIST1H1D plays a role in AML blast differentiation. Graphical abstract
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Loveday, Tristan, Gerben Duns, Lisa M. Rimsza, Karen L. Rech, James R. Cook, Ryan S. Robetorye, Allison C. Rosenthal et al. "Transformation of FL into DLBCL with a PMBL gene expression signature". Blood Advances, 14 de outubro de 2022. http://dx.doi.org/10.1182/bloodadvances.2022007360.
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We investigated the clinicopathologic features of 5 follicular lymphomas (FL) that transformed to morphologic diffuse large B-cell lymphomas (DLBCL) and had a primary mediastinal large B-cell lymphoma (PMBL)-like gene expression profile (tFL-PMBLsig-pos). None of the tFL-PMBLsig-pos arose in the mediastinum, all cases tested had a germinal center B-cell phenotype, 20% were CD30+, 60% CD23+, 80% MAL+, 20% CD200+, and 0% CD273/PDL2+. Whole exome sequencing detected alterations in genes associated with both FL/DLBCL (CREBBP, KMT2C, KMT2D, ARID1A, HIST1 members, and TNFRSF14) and PMBL (JAK-STAT pathway genes, B2M, and CD58). Copy number (CN) analysis detected gains/amplification of REL and STAT6 in 60%, gains of SOCS1 in 40%, and gains of chromosome 16, including IL4R, in 40%. CN gains/amplification of BCL6 and MYC and loss of TNFRSF14 and TNFAIP3 were identified in 20%. 3/5 cases lacked a BCL2 rearrangement. Despite having some features that are less common in DLBCL (MAL and CD23 expression, JAK-STAT activation), these tFL-PMBLsig-pos cases lack the most characteristic CN alteration seen in PMBL (9p24.1 gain/amplification). This cohort expands the biologic heterogeneity of tFL, illustrating a subset with gene expression and some genetic features reminiscent of PMBL, with potential treatment implications that include the use of novel targeted therapies.
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Sangatsuda, Yuhei, Fumihito Miura, Hiromitsu Araki, Masahiro Mizoguchi, Nobuhiro Hata, Daisuke Kuga, Ryusuke Hatae et al. "Base-resolution methylomes of gliomas bearing histone H3.3 mutations reveal a G34 mutant-specific signature shared with bone tumors". Scientific Reports 10, n.º 1 (30 de setembro de 2020). http://dx.doi.org/10.1038/s41598-020-73116-x.
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Abstract Two recurrent mutations, K27M and G34R/V, in H3F3A, encoding non-canonical histone H3.3, are reported in pediatric and young adult gliomas, whereas G34W mutation is prevalent in bone tumors. In contrast to K27M mutation, it remains elusive how G34 mutations affect the epigenome. Here we performed whole-genome bisulfite sequencing of four G34R-mutated gliomas and the G34V-mutated glioma cell line KNS-42 for comparison with gliomas harboring K27M and no mutations in H3F3A and with G34W-mutated bone tumors. G34R-mutated gliomas exhibited lower global methylation levels, similar CpG island (CGI) methylation levels, and compromised hypermethylation of telomere-proximal CGIs, compared to the other two glioma subgroups. Hypermethylated regions specific to G34R-mutated gliomas were enriched for CGIs, including those of OLIG1, OLIG2, and canonical histone genes in the HIST1 cluster. They were notably hypermethylated in osteosarcomas with, but not without, G34W mutation. Independent component analysis revealed that G34 mutation-specific components shared a significant similarity between glioma and osteosarcoma, suggesting that G34 mutations exert characteristic methylomic effects regardless of the tumor tissue-of-origin. CRISPR/Cas9-mediated disruption of G34V-allele in KNS-42 cells led to demethylation of a subset of CGIs hypermethylated in G34R-mutated gliomas. These findings will provide a basis for elucidating epigenomic roles of G34 oncohistone in tumorigenesis.
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Laan, Loora, Joakim Klar, Maria Sobol, Jan Hoeber, Mansoureh Shahsavani, Malin Kele, Ambrin Fatima et al. "DNA methylation changes in Down syndrome derived neural iPSCs uncover co-dysregulation of ZNF and HOX3 families of transcription factors". Clinical Epigenetics 12, n.º 1 (8 de janeiro de 2020). http://dx.doi.org/10.1186/s13148-019-0803-1.
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Abstract Background Down syndrome (DS) is characterized by neurodevelopmental abnormalities caused by partial or complete trisomy of human chromosome 21 (T21). Analysis of Down syndrome brain specimens has shown global epigenetic and transcriptional changes but their interplay during early neurogenesis remains largely unknown. We differentiated induced pluripotent stem cells (iPSCs) established from two DS patients with complete T21 and matched euploid donors into two distinct neural stages corresponding to early- and mid-gestational ages. Results Using the Illumina Infinium 450K array, we assessed the DNA methylation pattern of known CpG regions and promoters across the genome in trisomic neural iPSC derivatives, and we identified a total of 500 stably and differentially methylated CpGs that were annotated to CpG islands of 151 genes. The genes were enriched within the DNA binding category, uncovering 37 factors of importance for transcriptional regulation and chromatin structure. In particular, we observed regional epigenetic changes of the transcription factor genes ZNF69, ZNF700 and ZNF763 as well as the HOXA3, HOXB3 and HOXD3 genes. A similar clustering of differential methylation was found in the CpG islands of the HIST1 genes suggesting effects on chromatin remodeling. Conclusions The study shows that early established differential methylation in neural iPSC derivatives with T21 are associated with a set of genes relevant for DS brain development, providing a novel framework for further studies on epigenetic changes and transcriptional dysregulation during T21 neurogenesis.