Articoli di riviste: "BAF47"

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Arafah, Maria A., e Muna I. Aljuboury. "Primary Vulval Rhabdoid Tumor in an Adult: A Case Report, Immunohistochemical Profile and Literature Review". Case Reports in Medicine 2011 (2011): 1–4. http://dx.doi.org/10.1155/2011/162709.

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We report a rare case of primary vulval rhabdoid tumor in an adult. The diagnosis was confirmed using the recently emerging INI1/BAF47 immunostain. We also demonstrate the expression of ER and PR hormonal receptors by the tumor cells.

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Yan, Li, Si Xie, Yongming Du e Chengmin Qian. "Structural Insights into BAF47 and BAF155 Complex Formation". Journal of Molecular Biology 429, n. 11 (giugno 2017): 1650–60. http://dx.doi.org/10.1016/j.jmb.2017.04.008.

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Harada, Akihito, Masayasu Hayashi, Yuuki Kuniyoshi, Yuichiro Semba, Satoko Sugahara, Taro Tachibana, Yasuyuki Ohkawa e Masatoshi Fujita. "Generation of a Monoclonal Antibody for INI1/hSNF5/BAF47". Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 33, n. 1 (febbraio 2014): 49–51. http://dx.doi.org/10.1089/mab.2013.0065.

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Cui, Kairong, Prafullakumar Tailor, Hong Liu, Xin Chen, Keiko Ozato e Keji Zhao. "The Chromatin-Remodeling BAF Complex Mediates Cellular Antiviral Activities by Promoter Priming". Molecular and Cellular Biology 24, n. 10 (15 maggio 2004): 4476–86. http://dx.doi.org/10.1128/mcb.24.10.4476-4486.2004.

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ABSTRACT The elicitation of cellular antiviral activities is dependent on the rapid transcriptional activation of interferon (IFN) target genes. It is not clear how the interferon target promoters, which are organized into chromatin structures in cells, rapidly respond to interferon or viral stimulation. In this report, we show that alpha IFN (IFN-α) treatment of HeLa cells induced hundreds of genes. The induction of the majority of these genes was inhibited when one critical subunit of the chromatin-remodeling SWI/SNF-like BAF complexes, BAF47, was knocked down via RNA interference. Inhibition of BAF47 blocked the cellular response to viral infection and impaired cellular antiviral activity by inhibiting many IFN- and virus-inducible genes. We show that the BAF complex was required to mediate both the basal-level expression and the rapid induction of the antiviral genes. Further analyses indicated that the BAF complex primed some IFN target promoters by utilizing ATP-derived energy to maintain the chromatin in a constitutively open conformation, allowing faster and more potent induction after IFN-α treatment. We propose that constitutive binding of the BAF complex is an important mechanism for the IFN-inducible promoters to respond rapidly to IFN and virus stimulation.

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Kimura, Noriko, Masaru Hasegawa e Kenzo Hiroshima. "SMARCB1/INI1/BAF47- deficient pleural malignant mesothelioma with rhabdoid features". Pathology International 68, n. 2 (5 gennaio 2018): 128–32. http://dx.doi.org/10.1111/pin.12623.

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Numata, Masakatsu, Soichiro Morinaga, Takuo Watanabe, Hiroshi Tamagawa, Naoto Yamamoto, Manabu Shiozawa, Kameda Yoichi et al. "The clinical significance of SWI/SNF complex in pancreatic cancer." Journal of Clinical Oncology 31, n. 4_suppl (1 febbraio 2013): 149. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.149.

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149 Background: Chromatin remodeling factors have been the subject of great interest in oncology. However, little is known about their role in pancreatic cancer. The objective of this study is to clarify the clinical significance of SWI/SNF complex, one of the major chromatin remodeling machineries, in patients with pancreatic cancer. Methods: 68 cases with pancreatic cancer who underwent R0, 1 resection were enrolled. Cancer tissues were processed to tissue microarray, then stained immunohistochemically by using antibody of SWI/SNF components; BRM, BRG1, BAF250a, BAF180, and BAF47. The correlation of expression level and clinicopathological outcome including overall survival were analyzed. Results: Expression level of the SWI/SNF components was categorized as low or high according to the median value of Histo score. Statistical analysis revealed that related factors were tumor size, T factor, M factor, lymphatic invasion, and Stage in BRM, histology and Stage in BRG1, tumor size in BAF180, lymphatic invasion in BAF47, respectively. Multivariate Cox propotional hazard analysis showed high-BRM and low-BAF180 expression level were independent predictors of worse survival in patients with pancreatic cancer. The hazard analysis was also examined in the patients treated with adjuvant gemcitabine, indicating that high-BRM, and low-BAF180 were independent prognostic factors for poor survival. Conclusions: These results suggest that the specific cofactors of SWI/SNF chromatin remodeling complex certainly have roles in pancreatic cancer. High-BRM, and low-BAF180 are useful markers for prognosis of pancreatic cancer.

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Hoffman, Lindsey M., Elizabeth Anne Richardson, Ben Ho, Ashley Margol, Alyssa Reddy, Lucie Lafay-Cousin, Susan Chi et al. "Advancing biology-based therapeutic approaches for atypical teratoid rhabdoid tumors". Neuro-Oncology 22, n. 7 (4 marzo 2020): 944–54. http://dx.doi.org/10.1093/neuonc/noaa046.

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Abstract Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable. Recent use of intensified therapies has modestly improved survival for ATRT; however, a majority of patients will still succumb to their disease. While ATRTs almost universally exhibit loss of SMARCB1 (BAF47/INI1/SNF5), recent whole genome, transcriptome, and epigenomic analyses of large cohorts reveal previously underappreciated molecular heterogeneity. These discoveries provide novel insights into how SMARCB1 loss drives oncogenesis and confer specific therapeutic vulnerabilities, raising exciting prospects for molecularly stratified treatment for patients with ATRT.

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Pan, Xuefang, Lei Zhai, Ru Sun, Xiaoyun Li e Xianlu Zeng. "INI1/hSNF5/BAF47 represses c-fos transcription via a histone deacetylase-dependent manner". Biochemical and Biophysical Research Communications 337, n. 4 (dicembre 2005): 1052–58. http://dx.doi.org/10.1016/j.bbrc.2005.09.155.

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McLendon, Roger E., Adesina Adekunle, Veena Rajaram, Mehmet Koçak e Susan M. Blaney. "Embryonal Central Nervous System Neoplasms Arising in Infants and Young Children: A Pediatric Brain Tumor Consortium Study". Archives of Pathology & Laboratory Medicine 135, n. 8 (1 agosto 2011): 984–93. http://dx.doi.org/10.5858/2010-0515-oar1.

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Context.—Medulloblastomas (MBs) and atypical teratoid/rhabdoid tumors (AT/RTs) arising in infants and children can be difficult to distinguish; however, histologic characterization is prognostically important. Objective.—To determine histologic and phenotypic markers associated with utility with progression-free survival (PFS) and overall survival (OS) in children younger than 3 years with MBs and AT/RTs. Design.—We undertook a histologic and immunophenotypic study of MBs and AT/RTs arising in infants and children younger than 3 years treated in a Pediatric Brain Tumor Consortium study. The 41 girls and 55 boys ranged in age from 2 to 36 months at enrollment. These infants and children exhibited 51 MBs, 26 AT/RTs, and 24 other tumors (not further studied). Median follow-up of the patients was 17.2 months from diagnosis (range: 1.4–93 months). Results.—Infants and children with AT/RT exhibited a statistically significant shorter PFS and OS when compared to infants and children with MBs (both P < .001). A lack of nuclear BAF47 immunohistochemical reactivity proved reliable in identifying AT/RTs. Among MBs, our data suggest an association of nodularity and prolonged PFS and OS, which must be independently confirmed. Anaplasia correlated with OTX2 reactivity and both OTX2 and moderate to severe anaplasia correlated with PFS but not with OS. Conclusion.—Distinguishing AT/RT from MBs is clinically important. For expert neuropathologists, the diagnoses of AT/RT and MB can be reliably made from hematoxylin-eosin stains in the vast majority of cases. However certain rare small cell variants of AT/RT can be confused with MB. We also found that immunohistochemical reactivity for BAF47 is clinically useful in distinguishing MBs from AT/RTs and for identifying certain small cell AT/RTs. Among MBs, nodularity may be an important prognostic factor for improved PFS and OS in infants and children.

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Rekhi, Bharat, e Ulrich Vogel. "Utility of characteristic ‘Weak to Absent’ INI1/SMARCB1/BAF47 expression in diagnosis of synovial sarcomas". APMIS 123, n. 7 (24 aprile 2015): 618–28. http://dx.doi.org/10.1111/apm.12395.

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Rekhi, Bharat, e Ulrich Vogel. "Value of characteristic ‘weak to absent’ INI1/SMARCB1/BAF47 expression in diagnosis of synovial sarcomas". Pathology 48 (febbraio 2016): S152. http://dx.doi.org/10.1016/j.pathol.2015.12.415.

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Ye, Youpi, Hao Wu, Kangjing Chen, Cedric R. Clapier, Naveen Verma, Wenhao Zhang, Haiteng Deng, Bradley R. Cairns, Ning Gao e Zhucheng Chen. "Structure of the RSC complex bound to the nucleosome". Science 366, n. 6467 (31 ottobre 2019): 838–43. http://dx.doi.org/10.1126/science.aay0033.

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The RSC complex remodels chromatin structure and regulates gene transcription. We used cryo–electron microscopy to determine the structure of yeast RSC bound to the nucleosome. RSC is delineated into the adenosine triphosphatase motor, the actin-related protein module, and the substrate recruitment module (SRM). RSC binds the nucleosome mainly through the motor, with the auxiliary subunit Sfh1 engaging the H2A-H2B acidic patch to enable nucleosome ejection. SRM is organized into three substrate-binding lobes poised to bind their respective nucleosomal epitopes. The relative orientations of the SRM and the motor on the nucleosome explain the directionality of DNA translocation and promoter nucleosome repositioning by RSC. Our findings shed light on RSC assembly and functionality, and they provide a framework to understand the mammalian homologs BAF/PBAF and the Sfh1 ortholog INI1/BAF47, which are frequently mutated in cancers.

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Stevens, E. Andrew, Constance A. Stanton, Kyle Nichols e Thomas L. Ellis. "Rare intraparenchymal choroid plexus carcinoma resembling atypical teratoid/rhabdoid tumor diagnosed by immunostaining for INI1 protein". Journal of Neurosurgery: Pediatrics 4, n. 4 (ottobre 2009): 368–71. http://dx.doi.org/10.3171/2009.5.peds0955.

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The authors present the case of a rare extraventricular, intraparenchymal choroid plexus carcinoma (CPC). This 6-year-old girl presented to the emergency department with a 1-week history of headaches, nausea, and vomiting. Imaging studies revealed an intraaxial cystic and solid mass located in the right frontal lobe with central nodular enhancement and minimally enhancing cyst walls. Gross-total resection was accomplished via craniotomy without complications. The initial pathological diagnosis was atypical teratoid/rhabdoid tumor (AT/RT); however, immunostaining for INI1 protein (using the BAF47/SNF5 antibody) showed retention of nuclear staining in the tumor cells, resulting in a change in the diagnosis to CPC. There was no evidence of recurrence at the last follow-up 2.5 years after treatment, which supports the diagnosis of CPC over AT/RT. This case emphasizes the importance of immunostaining for INI1 protein for distinguishing CPC from AT/RT in cases with atypical or indeterminate features.

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DeCristofaro, Marc F., Bryan L. Betz, Weidong Wang e Bernard E. Weissman. "Alteration of hSNF5/INI1/BAF47 detected in rhabdoid cell lines and primary rhabdomyosarcomas but not Wilms' tumors". Oncogene 18, n. 52 (dicembre 1999): 7559–65. http://dx.doi.org/10.1038/sj.onc.1203168.

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Pan, Xuefang, Zhaoxia Song, Lei Zhai, Xiaoyun Li e Xianlu Zeng. "Chromatin-remodeling Factor INI1/hSNF5/BAF47 Is Involved in Activation of the Colony Stimulating Factor 1 Promoter". Molecules and Cells 20, n. 2 (ottobre 2005): 183–88. http://dx.doi.org/10.1016/s1016-8478(23)25244-9.

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Edgar, Mark A., e Marc K. Rosenblum. "The Differential Diagnosis of Central Nervous System Tumors: A Critical Examination of Some Recent Immunohistochemical Applications". Archives of Pathology & Laboratory Medicine 132, n. 3 (1 marzo 2008): 500–509. http://dx.doi.org/10.5858/2008-132-500-tddocn.

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Abstract Context.—As we write, novel antibodies that may well alter the routine practice of surgical neuropathology are in development, characterization, and the early stages of clinical use. These will be used for purposes of tumor subclassification, as prognostic markers, as identifiers of potential therapeutic targets, and as predictors of treatment response. Objective.—To provide for nonspecialists a critical assessment of the peer-reviewed literature (necessarily colored by our own experience) as it pertains to several immunohistochemical reagents that have been recently forwarded as adjuncts to the histologic typing of central nervous system tumors. Data Sources.—We address in these pages only antibodies that are commercially available, that have been the subjects of multiple published series, and that we have had occasion to use in the course of everyday problem solving. Conclusions.—Discussion concentrates on the use of 4 antibodies: BAF47 in the diagnosis of atypical teratoid/ rhabdoid tumor, OCT4 in intracranial germinoma, β-catenin in craniopharyngioma, and NeuN as a marker of neuronal differentiation in neuroepithelial neoplasms.

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Ohba, Shigeo, Kazunari Yoshida, Yuichi Hirose, Eiji Ikeda, Yoichi Nakazato e Takeshi Kawase. "Cerebral tumor with extensive rhabdoid features and a favorable prognosis". Journal of Neurosurgery 111, n. 3 (settembre 2009): 492–96. http://dx.doi.org/10.3171/2008.11.jns08776.

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This 32-year-old woman, 27 weeks pregnant, harbored a cystic mass with a solid component in the left frontal lobe. Histologically, the lesion was hypercellular and contained a diffuse sheet of eosinophilic cells of various sizes. The cells were almost round and had a few prominent, eccentrically placed, hyperchromatic nuclei of various sizes. Immunohistochemically, the tumor was reactive for vimentin, epithelial membrane antigen, cytokeratin AE1/AE3, smooth muscle actin, and BAF47/INI-1, and negative for glial fibrillary acidic protein, neurofilament protein, S100 protein, CK7, CK20, HMB-45, MIC2, and Bcl-2. The Ki 67 labeling index was 4.2%. Comparative genomic hybridization analysis revealed aberrations of the chromosomal copy number of +7 and −10. This tumor could not be categorized according to the present World Health Organization classification. Results of staining with glial fibrillary acidic protein were not consistent with a glioma, and staining with INI-1 was inconsistent with atypical teratoid/rhabdoid tumor. The tumor was therefore designated as a “cerebral tumor with extensive rhabdoid features.”

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Joliot, Véronique, Ouardia Ait-Mohamed, Valentine Battisti, Julien Pontis, Ophélie Philipot, Philippe Robin, Hidenori Ito e Slimane Ait-Si-Ali. "The SWI/SNF Subunit/Tumor Suppressor BAF47/INI1 Is Essential in Cell Cycle Arrest upon Skeletal Muscle Terminal Differentiation". PLoS ONE 9, n. 10 (1 ottobre 2014): e108858. http://dx.doi.org/10.1371/journal.pone.0108858.

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Bourgo, Ryan J., Hasan Siddiqui, Sejal Fox, David Solomon, Courtney G. Sansam, Moshe Yaniv, Christian Muchardt et al. "SWI/SNF Deficiency Results in Aberrant Chromatin Organization, Mitotic Failure, and Diminished Proliferative Capacity". Molecular Biology of the Cell 20, n. 14 (15 luglio 2009): 3192–99. http://dx.doi.org/10.1091/mbc.e08-12-1224.

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Switch (SWI)/sucrose nonfermentable (SNF) is an evolutionarily conserved complex with ATPase function, capable of regulating nucleosome position to alter transcriptional programs within the cell. It is known that the SWI/SNF complex is responsible for regulation of many genes involved in cell cycle control and proliferation, and it has recently been implicated in cancer development. The ATPase action of SWI/SNF is conferred through either the brahma-related gene 1 (Brg1) or brahma (Brm) subunit of the complex, and it is of central importance to the modification of nucleosome position. In this study, the role of the Brg1 and Brm subunits were examined as they relate to chromatin structure and organization. Deletion of the Brg1 ATPase results in dissolution of pericentromeric heterochromatin domains and a redistribution of histone modifications associated with these structures. This effect was highly specific to Brg1 and is not reproduced by the loss of Brm or SNF5/BAF47/INI1. Brg1 deficiency is associated with the appearance of micronuclei and aberrant mitoses that are a by-product of dissociated chromatin structure. Thus, Brg1 plays a critical role in maintaining chromatin structural integrity.

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Sarkar, Koustav, Sanjoy Sadhukhan, Seong-Su Han e Yatin Vyas. "Nucleosomal remodeling defects at gene promoters underlie cross-phenotype effects in X-linked thrombocytopenia/Wiskott-Aldrich syndrome (IRM6P.655)". Journal of Immunology 194, n. 1_Supplement (1 maggio 2015): 60.5. http://dx.doi.org/10.4049/jimmunol.194.supp.60.5.

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Abstract Loss-of-function mutations in Wiskott-Aldrich-Syndrome (WAS) gene associate with either X-linked thrombocytopenia (XLT) or XLT that progresses to immunodeficiency, yet the biological basis for gene-pleiotropy remains unknown. WASp, the protein deficient in WAS, generates F-actin in the cytosol via VCA-domain and supports transcription in the nucleus, the latter by an unknown mechanism. We report that nuclear-WASp, independently of its VCA-domain, is required for the recruitment of BAF47, BAF170, and EP400 to IFNG and TBX21 promoters during TH1-differentiation, but not to IL4 or GATA3 during TH2-differentiation. XLT-causing Thr45Met mutation that progresses to immunodeficiency, impairs recruitment of the above chromatin-remodelers, NF-κB(p65), and STAT1 to TH1-gene promoters, which show paucity of H2A.Z containing nucleosomes, and are therefore sub-optimally transcribed. Dissimilarly, Ala236Gly and Arg477Lys mutations that manifest in XLT without progressing to immunodeficiency do not impair TH1-transcriptional reprogramming. We identify a functional link between nuclear-WASp and SWI/SNF-complexes in T lymphocytes, perturbation of which provides a mechanism for the development of clinical crossphenotypes in human XLT/WAS.

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Andreeva, N. A., E. I. Lyudovskikh, D. M. Konovalov, M. V. Teleshova, A. M. Mitrofanova, M. A. Kurnikova, L. A. Yasko et al. "SMARCA4-associated malignant rhabdoid tumors: case report and literature review". Russian Journal of Pediatric Hematology and Oncology 9, n. 2 (15 agosto 2022): 75–84. http://dx.doi.org/10.21682/2311-1267-2022-9-2-75-84.

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Malignant rhabdoid tumor (MRT) is a rare malignant neoplasm of childhood, characterized by an aggressive course and an extremely unfavorable prognosis. The frequency of MRT outside the central nervous system (extracranial MRT) is 0.02–0.03 per 100,000 children. In most cases, MRT is based on an inactivating mutations of the tumor suppressor gene SMARCB1, which leads to the absence of expression of the SMARCB1 ((INI1/hSNF5/BAF47) protein in tumor cells. Aberrations of the SMARCA4 gene, which is an extremely rare molecular event, have been described among the MRTs expressing SMARCB1 (INI1). Few case reports have been described in the international literature.This article contains a description of a clinical case of a patient diagnosed with soft tissue MRT with SMARCA4 gene alteration. The distinctive features of the presented case are the congenital nature of the tumor, atypical localization, and extremely aggressive clinical course of the disease. On the example of the described clinical case, diagnostics of SMARCA4-associated MRT are presented, as well as the place of molecular methods in diagnosis verification. In addition, it is highlighted that the detection of somatic changes in the SMARCB1 and SMARCA4 genes requires additional investigation of their germinal status to exclude or confirm the rhabdoid tumor predisposition syndrome.

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McKenna, Elizabeth S., Courtney G. Sansam, Yoon-Jae Cho, Heidi Greulich, Julia A. Evans, Christopher S. Thom, Lisa A. Moreau, Jaclyn A. Biegel, Scott L. Pomeroy e Charles W. M. Roberts. "Loss of the Epigenetic Tumor Suppressor SNF5 Leads to Cancer without Genomic Instability". Molecular and Cellular Biology 28, n. 20 (18 agosto 2008): 6223–33. http://dx.doi.org/10.1128/mcb.00658-08.

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ABSTRACT There is a growing appreciation of the role that epigenetic alterations can play in oncogenesis. However, given the large number of genetic anomalies present in most cancers, it has been difficult to evaluate the extent to which epigenetic changes contribute to cancer. SNF5 (INI1/SMARCB1/BAF47) is a tumor suppressor that regulates the epigenome as a core member of the SWI/SNF chromatin remodeling complex. While the SWI/SNF complex displays potent tumor suppressor activity, it is unknown whether this activity is exerted genetically via maintenance of genome integrity or epigenetically via transcriptional regulation. Here we show that Snf5-deficient primary cells do not show altered sensitivity to DNA damaging agents, defects in γ-H2AX induction, or an abrogated DNA damage checkpoint. Further, the aggressive malignancies that arise following SNF5 loss are diploid and genomically stable. Remarkably, we demonstrate that most human SNF5-deficient cancers lack genomic amplifications/deletions and, aside from SNF5 loss, are indistinguishable from normal cells on single-nucleotide polymorphism arrays. Finally, we show that epigenetically based changes in transcription that occur following SNF5 loss correlate with the tumor phenotype. Collectively, our results provide novel insight into the mechanisms of oncogenesis by demonstrating that disruption of a chromatin remodeling complex can largely, if not completely, substitute for genomic instability in the genesis of aggressive cancer.

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Betz, Bryan L., Matthew W. Strobeck, David N. Reisman, Erik S. Knudsen e Bernard E. Weissman. "Re-expression of hSNF5/INI1/BAF47 in pediatric tumor cells leads to G1arrest associated with induction of p16ink4a and activation of RB". Oncogene 21, n. 34 (agosto 2002): 5193–203. http://dx.doi.org/10.1038/sj.onc.1205706.

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Boese, Annette, Peter Sommer, Daniela Holzer, Reinhard Maier e Ulf Nehrbass. "Integrase interactor 1 (Ini1/hSNF5) is a repressor of basal human immunodeficiency virus type 1 promoter activity". Journal of General Virology 90, n. 10 (1 ottobre 2009): 2503–12. http://dx.doi.org/10.1099/vir.0.013656-0.

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Integrase interactor 1 (Ini1/hSNF5/BAF47/SMARCB1), the core subunit of the ATP-dependent chromatin-remodelling complex SWI/SNF, is a cellular interaction partner of the human immunodeficiency virus type 1 (HIV-1) integrase. Ini1/hSNF5 is recruited to HIV-1 pre-integration complexes before nuclear migration, suggesting a function in the integration process itself or a contribution to the preferential selection of transcriptionally active genes as integration sites of HIV-1. More recent evidence indicates, however, that, whilst Ini1/hSNF5 is dispensable for HIV-1 transduction per se, it may have an inhibitory effect on the early steps of HIV-1 replication but facilitates proviral transcription by enhancing Tat function. These partially contradictory observations prompted an investigation of the immediate and long-term effects of Ini1/hSNF5 depletion on the basal transcriptional potential of the virus promoter. Using small interfering RNAs, it was shown that Ini1/hSNF5-containing SWI/SNF complexes mediate transcriptional repression of the basal activity of the integrated HIV-1 long terminal repeat. Transient depletion of Ini1/hSNF5 during integration was accompanied by an early boost of HIV-1 replication. After the reappearance of Ini1/hSNF5, expression levels decreased and this was associated with increased levels of histone methylation at the virus promoter in the long term, indicative of epigenetic gene silencing. These results demonstrate the opposing effects of Ini1/hSNF5-containing SWI/SNF complexes on basal and Tat-dependent transcriptional activity of the HIV-1 promoter. It is proposed that Ini1/hSNF5 may be recruited to the HIV-1 pre-integration complex to initiate, immediately after integration, one of two mutually exclusive transcription programmes, namely post-integration latency or high-level, Tat-dependent gene expression.

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Roberts, Charles W. M. "Abstract IA006: Synthetic lethalities for SWI/SNF mutant cancers". Molecular Cancer Therapeutics 23, n. 6_Supplement (10 giugno 2024): IA006. http://dx.doi.org/10.1158/1538-8514.synthleth24-ia006.

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Abstract Genes that encode subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in over 20% of cancers. These include recurrent mutations of ARID1A (BAF250a) in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers and neuroblastoma; of the SMARCA4 (BRG1) subunit in medulloblastomas and non-small cell lung cancers; of the PBRM1 subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription. My laboratory began studying the SWI/SNF complex when SMARCB1 (INI1/SNF5/BAF47) became the first SWI/SNF subunit linked to tumor suppression when it was found to be biallelically inactivated in nearly all cases of a highly aggressive type of pediatric cancer called malignant rhabdoid tumor (MRT). Despite the extremely aggressive and lethal nature of MRT we have shown that these cancers are diploid and have remarkably simple genomes. We leverage this model tumor to identify how SWI/SNF complexes function, to determine how mutation of SWI/SNF subunits drive cancer and other diseases, and to identify therapeutic vulnerabilities that result from SWI/SNF mutations. We have leverage the Cancer Dependency Map, and the Pediatric Cancer Dependencies Accelerator, to systematically identify robust and impactful synthethic lethalities resulting from SWI/SNF mutations. These mechanisms and insights will be presented. Citation Format: Charles W.M. Roberts. Synthetic lethalities for SWI/SNF mutant cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA006.

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Pawel, Bruce R. "SMARCB1-deficient Tumors of Childhood: A Practical Guide". Pediatric and Developmental Pathology 21, n. 1 (27 dicembre 2017): 6–28. http://dx.doi.org/10.1177/1093526617749671.

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The SMARCB1 gene ( INI1, BAF47) is a member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, involved in the epigenetic regulation of gene transcription. SMARCB1 acts as a tumor suppressor gene, and loss of function of both alleles gives rise to SMARCB1-deficient tumors. The prototypical SMARCB1-deficient tumor is the malignant rhabdoid tumor (MRT) which was first described in the kidney but also occurs in soft tissue, viscera, and the brain (where it is referred to as atypical teratoid rhabdoid tumor or AT/RT). These are overwhelmingly tumors of the very young, and most follow an aggressive and ultimately lethal course. Morphologically, most but not all contain a population of “rhabdoid” cells, which are large cells with abundant cytoplasm, perinuclear spherical inclusions, and eccentric vesicular nuclei with large inclusion-like nucleoli. MRT immunohistochemistry reveals complete loss of SMARCB1 nuclear expression, and molecular analysis confirms biallelic SMARCB1 inactivation in the vast majority. Rare AT/RTs have loss of SMARCA4, another SWI/SNF member, rather than SMARCB1. With the widespread adoption of SMARCB1 immunohistochemistry, an increasing number of SMARCB1-deficient tumors outside of the MRT-AT/RT spectrum have been described. In addition to MRT and AT/RT, pediatric tumors with complete loss of SMARCB1 expression include cribriform neuroepithelial tumor, renal medullary carcinoma, and epithelioid sarcoma. Tumors with variable loss of SMARCB1 expression include subsets of epithelioid malignant peripheral nerve sheath tumor, schwannomas arising in schwannomatosis, subsets of chordomas, myoepithelial carcinomas, and sinonasal carcinomas. Variable and reduced expression of SMARCB1 is characteristic of synovial sarcoma. In this review, the historical background, clinical characteristics, morphology, immunohistochemical features, and molecular genetics most germane to these tumors are summarized. In addition, familial occurrence of these tumors (the rhabdoid tumor predisposition syndrome) is discussed. It is hoped that this review may provide practical guidance to pathologists encountering tumors that have altered expression of SMARCB1.

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Kadoch, Cigall, e Gerald R. Crabtree. "Reversing the oncogenic roles of misdirected chromatin remodeling: Mechanistic insights into the SS18-SSX fusion protein in synovial sarcoma." Journal of Clinical Oncology 31, n. 15_suppl (20 maggio 2013): 10515. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10515.

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10515 Background: Synovial sarcoma (SS) accounts for ~10% of soft-tissue malignancies and is generally resistant to chemotherapy-based approaches, underscoring the need for a mechanistic understanding of its pathogenesis and the development of disease-specific biologic agents. The hallmark molecular feature is a precise and uniform translocation, t(X;18), which results in the fusion of exactly 78 amino acids of SSX to the SS18 C-terminus. Because the SS18-SSX genetic lesion is observed in 100% of cases, it is likely the driving oncogenic event in these tumors; however, the molecular basis for its role in oncogenesis is undefined. Methods: We performed an affinity purification-/mass spectrometry-based analysis of endogenous mSWI/SNF (BAF) chromatin remodeling complexes in several primary cell types. Using these data in combination with protein biochemical methods, we discovered that SS18 is a dedicated, non-exchangeable subunit of these complexes with a binding affinity comparable to that of ribosomal subunits. Subsequent biochemical and functional investigations were performed to assess the oncogenic consequences of addition of 78aa of SSX to the SS18 subunit in SS. Results: We demonstrate that the SS18-SSX fusion incorporates into BAF complexes, evicting both wild-type (WT) SS18 and the tumor suppressor subunit, hSNF5 (BAF47), known to be biallelically inactivated in pediatric malignant rhabdoid tumors (MRTs). The altered complex binds the Sox2 locus, reversing polycomb-mediated repression and activating Sox2. Sox2, a pro-pluripotency transcription factor, is uniformly expressed in SS tumors and is essential for proliferation. Remarkably, increasing the concentration of WT SS18 leads to reassembly of WT complexes, retargeting of BAF complexes, returned polycomb-mediated repression at the Sox2 locus and cessation of SS cell proliferation. This mechanism of transformation depends on a region of only two amino acids of SSX, and hence provides a strong foundation for therapeutic intervention. Conclusions: These studies provide a novel oncogenic mechanism for SS tumors and inform strategies for therapeutic development in this intractable cancer.

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Patel, Krutika, Sara Avalos Hernandez, S. Shawn Liu, J. Elliot Carter e Elizabeth Manci. "Tubular Entrapment May Be Inconspicuous in Clear Cell Sarcoma of the Kidney in Early Infancy, Compared to Childhood: An In-Depth Case Comparison". American Journal of Clinical Pathology 152, Supplement_1 (11 settembre 2019): S59—S60. http://dx.doi.org/10.1093/ajcp/aqz113.056.

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Abstract Introduction Clear cell sarcoma of kidney (CCSK) is a rare malignancy accounting for <0.5% of all primary renal tumors, commonly diagnosed between 2 and 4 years of age and rarely occurring in early infancy. The challenging differentiation between CCSK and blastemal Wilms tumor is important because of the distinct clinical pattern of CCSK to recur and metastasize to bone and brain. The aim of this study is to discern subtle features that could assist pathologists in diagnosing CCSK in infancy. Method In-depth comparison of clinical, histological, and immunohistochemical findings in a case of CCSK diagnosed at 5 months of age with two cases of CCSK diagnosed at 2 and 3 years of age. Results Both groups were male, and each presented with an abdominal mass. Grossly, a single, firm, well-demarcated tumor, morphologically comprising monotonous small primitive round-to-polygonal/spindle cells, was seen in both groups. The major differences between the study groups were growth patterns and stromal reactions. In infancy, the growth pattern was diffusely uniform sheets of malignant cells with no entrapment of tubules and inconspicuous stromal changes. However, in childhood cases, the growth pattern included well-defined tubular entrapment, as well as focal microcyst formation, myxomatous stroma, palisading bodies, and anaplastic and/or rhabdoid histology. In both study groups, the immunohistochemistry showed strong immunoreactivity with cyclin D1 and nonspecific positivity for vimentin, CD99, and BAF47. Conclusion CCSK has notoriously diverse histological heterogeneity and mimics other pediatric renal tumors, making diagnosis treacherous, and commonly erroneous as Wilms tumor with unfavorable histology. Despite the advent of immunohistochemical and molecular techniques, a thorough morphologic analysis remains key in accurately diagnosing CCSK at any age, especially in early infancy. This small in-depth comparison of CCSK by age groups suggests that tubular entrapment and stromal changes may be less conspicuous in CCSK in early infancy than at older ages.

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Link, Kevin A., Craig J. Burd, Erin Williams, Thomas Marshall, Gary Rosson, Erin Henry, Bernard Weissman e Karen E. Knudsen. "BAF57 Governs Androgen Receptor Action and Androgen-Dependent Proliferation through SWI/SNF". Molecular and Cellular Biology 25, n. 6 (15 marzo 2005): 2200–2215. http://dx.doi.org/10.1128/mcb.25.6.2200-2215.2005.

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ABSTRACT Androgen receptor (AR) activity is required for prostate cancer development and progression. Thus, there is a major impetus to understand the regulation of AR action. We and others have previously shown that AR transactivation potential is dependent on the presence of an active SWI/SNF chromatin remodeling complex. However, the mechanisms underlying SWI/SNF regulation of the AR remained unsolved. We show here that the BAF57 subunit, an accessory component of the remodeling complex, is a critical regulator of AR function. We show that BAF57 is expressed in the luminal epithelia of the prostate and is required for AR-dependent transactivation in prostatic adenocarcinoma cells. Our data reveal that BAF57 can directly bind to the AR and is recruited to endogenous AR targets upon ligand activation. Loss of BAF57 or inhibition of BAF57 function severely compromised AR activity, as observed with both exogenous and endogenous AR targets. Rescue of BAF57 function restored AR activity, thus demonstrating a specific requirement of BAF57 for AR activity. This action of BAF57 proved to be dependent on SWI/SNF ATPase function. BAF57 has previously been implicated in nuclear receptor coactivator function, and we show that, although BAF57 facilitated coactivator activity, only a selected subset required BAF57 for coactivator function. Lastly, we demonstrate that both BAF57 and BRM are required for the proliferation of AR-dependent prostatic adenocarcinoma cells. In summary, these findings identify BAF57 as a critical modulator of the AR that is capable of altering AR activity, coactivator function, and AR-dependent proliferation.

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Wang, Li, Robert A. Baiocchi, Sharmistha Pal, George Mosialos, Michael Caligiuri e Saïd Sif. "The BRG1- and hBRM-Associated Factor BAF57 Induces Apoptosis by Stimulating Expression of the Cylindromatosis Tumor Suppressor Gene". Molecular and Cellular Biology 25, n. 18 (15 settembre 2005): 7953–65. http://dx.doi.org/10.1128/mcb.25.18.7953-7965.2005.

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ABSTRACT Mutation of BRG1, hBRM, and their associated factors, INI1 and BAF57, in primary human tumors has suggested that inactivation of human SWI/SNF (hSWI/SNF) complexes may be involved in neoplastic transformation. BT549 is an invasive human breast carcinoma cell line that lacks expression of BAF57, a key hSWI/SNF subunit that mediates interaction with transcriptional activators and corepressors. In this study we investigated the role of BAF57 in suppressing tumorigenesis by establishing BT549 stable cell lines that expresses full-length BAF57 protein. BT549 clones expressing BAF57 demonstrated marked phenotypic changes, slow growth kinetics, and restoration of contact inhibition. Altered growth was found to be due in part to cell cycle arrest and induction of apoptosis. Furthermore, microarray analysis revealed that BAF57-mediated cell death was associated with up-regulation of proapoptotic genes including the tumor suppressor familial cylindromatosis (CYLD), which was found to be a direct target of BAF57 as determined by chromatin immunoprecipitation analysis. Increased expression of CYLD in BT549 cells induced apoptosis, while its suppression by small interfering RNA inhibited cell death in BAF57 expressing BT549 cells. These findings demonstrate the importance of BAF57 in cell growth regulation and provide a novel link between hSWI/SNF chromatin remodelers and apoptosis.

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Msaouel, Pavlos, Rebecca Slack-Tidwell e Nizar M. Tannir. "Phase II trial of nivolumab (nivo) plus ipilimumab (ipi) in patients with SMARCB1-deficient kidney malignancies." Journal of Clinical Oncology 37, n. 7_suppl (1 marzo 2019): TPS677. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.tps677.

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TPS677 Background: The potent tumor suppressor SMARCB1 (also known as INI-1, hSNF5, or BAF47) is inactivated in all cases of renal medullary carcinoma (RMC) and renal cell carcinoma unclassified with medullary phenotype (RCCU-MP), as well as most malignant rhabdoid tumors (MRT) of the kidney. Although rare, these kidney malignancies are highly lethal and often occur in young patients. The role of immune checkpoint inhibitor therapy remains to be prospectively defined in tumors harboring SMARCB1 defects. Although a case report noted efficacy of single-agent Nivo in a patient with RMC (Beckermann et al J Immunother Cancer, 2017), there were no durable responses in subsequent cases (Sodji et al. J Immunother Cancer, 2017). We hypothesize that the combination of anti-PD1 (Nivo) with anti-CTLA4 (Ipi) immune checkpoint inhibitor therapy will lead to more potent antitumor responses compared to those reported with single-agent Nivo. Methods: This single-arm phase II trial will test the efficacy of Nivo + Ipi in up to 30 patients with SMARCB1-negative RMC, RCCU-MP, and adult-onset kidney MRTs. Any number of prior therapies is allowed. Patients will be treated with Ipi 1 mg/kg + Nivo 3 mg/kg every 3 weeks x4 doses followed by maintenance Nivo 480 mg every 4 weeks for up to 2 years. Ongoing monitoring for safety and futility will be implemented per the method of Thall et al. (Stat Med, 1995; 14:357-79) using cohorts of 10 patients each. The primary endpoint is objective response rate (ORR) and the trial objective is to achieve a similar or greater ORR compared with the historical ORR of 29% achieved in our institution using conventional cytotoxic chemotherapies. Secondary endpoints include progression-free survival, overall survival, and disease control rate. To evaluate potential biomarkers for treatment response, correlative analyses will be performed in tumor tissue and peripheral blood samples obtained i) pre- treatment (baseline) up to 6 weeks (42 days) prior to initiation of treatment on Day 1, ii) after completion of the combination therapy (Nivo + Ipi) phase, and iii) upon disease progression. At the time of the abstract submission, 2 patients have been enrolled on this study. Clinical trial information: NCT03274258.

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Msaouel, Pavlos, Rebecca Slack-Tidwell, Giannicola Genovese, Najat C. Daw, Arlene O. Siefker-Radtke e Nizar M. Tannir. "Phase II trial of ixazomib combined with gemcitabine and doxorubicin in patients with SMARCB1-deficient kidney malignancies." Journal of Clinical Oncology 37, n. 7_suppl (1 marzo 2019): TPS678. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.tps678.

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TPS678 Background: SMARCB1 (also known as INI-1, hSNF5, or BAF47) is a potent tumor suppressor inactivated in all cases of renal medullary carcinoma (RMC) and renal cell carcinoma unclassified with medullary phenotype (RCCU-MP), as well as the majority of malignant rhabdoid tumors (MRT). These highly aggressive malignancies often occur in young patients (pts) and are associated with poor prognosis. There are currently no approved therapies targeting SMARCB1 defects. We previously showed that SMARCB1 loss induces a synthetically lethal vulnerability to perturbations of the cellular proteostasis machinery by proteasome inhibitors (Genovese et al. Nature, 542:362-366, 2017). The present study was designed to determine whether the addition of the second-generation proteasome inhibitor ixazomib to cytotoxic chemotherapy with gemcitabine and doxorubicin (IGD regimen) can improve outcomes of pts with aggressive SMARCB1-deficient kidney malignancies. Methods: This single-arm trial uses the Bayesian optimal phase II (BOP2) design (Heng et al. Stat Med 2017) to determine if the IGD regimen will improve the two co-primary endpoints of objective response rate (ORR) to 50% and 28-week disease control rate (DCR) to 30% compared with the historical ORR and 28-week DCR of 29% and 14%, respectively, achieved using gemcitabine plus doxorubicin alone as first-line or salvage therapy in pts with SMARCB1-negative RMC, RCCU-MP, and adult-onset kidney MRTs treated at our institution. Up to 30 pts aged ≥ 12 years old will be enrolled and any number of prior therapies is allowed. Ongoing monitoring for safety and futility will be implemented in 10-patient cohorts. If both the ORR and DCR improve to 50% and 30%, respectively, then there is only a 3.5% chance of stopping early and a 93.1% chance of claiming that IGD is efficacious. Secondary endpoints include progression-free survival, and overall survival. Tissue correlative analyses will be performed to determine whether tumors from pts responding to IGD have increased levels of endoplasmic reticulum stress markers involved in protein turnover. At the time of the abstract submission, 5 pts have been enrolled on this study. Clinical trial information: NCT03587662.

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Chen, Jianguang, e Trevor K. Archer. "Regulating SWI/SNF Subunit Levels via Protein-Protein Interactions and Proteasomal Degradation: BAF155 and BAF170 Limit Expression of BAF57". Molecular and Cellular Biology 25, n. 20 (15 ottobre 2005): 9016–27. http://dx.doi.org/10.1128/mcb.25.20.9016-9027.2005.

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ABSTRACT The mammalian SWI/SNF chromatin remodeling complex, whose function is of critical importance in transcriptional regulation, contains approximately 10 protein components. The expression levels of the core SWI/SNF subunits, including BRG1/Brm, BAF155, BAF170, BAF60, hSNF/Ini1, and BAF57, are stoichiometric, with few to no unbound molecules in the cell. Here we report that exogenous expression of the wild type or certain deletion mutants of BAF57, a key subunit that mediates the interaction between the remodeling complex and transcription factors, results in diminished expression of endogenous BAF57. This down-regulation process is mediated by an increase in proteasome-dependent degradation of the BAF57 protein. Furthermore, the protein levels of BAF155/170 dictate the maximum cellular amount of BAF57. We mapped the domains responsible for the interaction between BAF57 and BAF155 and demonstrated that protein-protein interactions between them play an important role in this regulatory process. These findings provide insights into the physiological mechanisms responsible for maintaining the proper stoichiometric levels of the protein components comprising multimeric enzyme complexes.

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Liu, J., S. Yeon, T. Valyi-Nagy e S. Garzon. "Uncommon Presentation of Pulmonary Adenoid Cystic Carcinoma: A Case of Brain Metastasis in a Young Smoker". American Journal of Clinical Pathology 162, Supplement_1 (ottobre 2024): S140. http://dx.doi.org/10.1093/ajcp/aqae129.310.

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Abstract Introduction/Objective Pulmonary adenoid cystic carcinoma (PACC) is a rare entity, accounting for only 0.04-0.2% lung cancers, and mainly originating from the small salivary glands in the tracheobronchial tree. Due to slow-growing pattern and unspecific symptoms, the diagnosis is often delayed. While metastasis in PACC is uncommon, reports of brain metastasis are exceedingly rare. We present a case of PACC with metastasis to the brain in a young smoker. Methods/Case Report A 29-year-old female with history of smoking presented with headache, hypersomnia, episodes of vomiting and falling. Physical examination revealed multiple palpable nodes on the mid head, left temporal and right parietal area, left shoulder area were found. CT scan demonstrated complex cystic mass with a mural nodule within the left cerebellar hemisphere, with displacement of the cerebellar tonsils, as well as a 7.4 cm left infrahilar mass with heterogenous enhancement. Patient underwent craniotomy with tumor resection and left lower lobe endobronchial biopsy. Touch smear of the brain lesion showed clusters of hyperchromatic cells with myxoid like and hyalinized stroma. H&E stain showed cords of neoplastic cells embedded in a basophilic/myxoid stroma. Lung biopsy showed similar histological patterns. IHC stain showed the tumor cells were positive for epithelial and myoepithelial cells markers(CAM5.2, CK7, p63, Sox 10), retained INI1/BAF47 and BRG1 expression, negative for NUT and BCOR. Salivary Gland NGS Fusion Panel was performed and detected a MYBL1::NFIB [t(8;9)(8q13.1;9p23)] fusion alteration, which confirmed the diagnosis of adenoid cystic carcinoma. Considering no lesion was found in the patient’s head and neck, diagnosis of PACC was made. Results (if a Case Study enter NA) NA Conclusion PACC manifests three histologic subtypes: cribriform (most common), trabecular, and solid. In this case, brain and lung lesions exhibited similar patterns - nests of small, monomorphic cells within a myxoid-like and basophilic stroma background, consistent with trabecular pattern. Cytologically, densely packed cellular clusters were embedded in a myxoid like matrix. Distinguishing PACC from other salivary gland tumors is challenging. Immunostains for epithelial and myoepithelial cells, along with morphology, aid in diagnosis. The MYB::NFIB fusion helps differentiate from other lung salivary gland malignancies, but is found in a lower percentage of PACC cases (~40%) compared to other primary adnoid cystic carcinoma (~85%).

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La Porte, Annalena, Jennifer Cano, Xuhong Wu, Doyel Mitra e Ganjam V. Kalpana. "An Essential Role of INI1/hSNF5 Chromatin Remodeling Protein in HIV-1 Posttranscriptional Events and Gag/Gag-Pol Stability". Journal of Virology 90, n. 21 (24 agosto 2016): 9889–904. http://dx.doi.org/10.1128/jvi.00323-16.

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ABSTRACTINI1/hSNF5/SMARCB1/BAF47 is an HIV-specific integrase (IN)-binding protein that influences HIV-1 transcription and particle production. INI1 binds to SAP18 (Sin3a-associated protein, 18 kDa), and both INI1 and SAP18 are incorporated into HIV-1 virions. To determine the significance of INI1 and the INI1-SAP18 interaction during HIV-1 replication, we isolated a panel ofSAP18-interaction-defective (SID)-INI1 mutants using a yeast reverse two-hybrid screen. The SID-INI1 mutants, which retained the ability to bind to IN, cMYC, and INI1 but were impaired for binding to SAP18, were tested for their effects on HIV-1 particle production. SID-INI1 dramatically reduced the intracellular Gag/Gag-Pol protein levels and, in addition, decreased viral particle production. The SID-INI1-mediated effects were less dramatic intranscomplementation assays using IN deletion mutant viruses with Vpr-reverse transcriptase (RT)-IN. SID-INI1 did not inhibit long-terminal-repeat (LTR)-mediated transcription, but it marginally decreased the steady-stategagRNA levels, suggesting a posttranscriptional effect. Pulse-chase analysis indicated that in SID-INI1-expressing cells, the pr55Gag levels decreased rapidly. RNA interference analysis indicated that small hairpin RNA (shRNA)-mediated knockdown ofINI1reduced the intracellular Gag/Gag-Pol levels and further inhibited HIV-1 particle production. These results suggest that SID-INI1 mutants inhibit multiple stages of posttranscriptional events of HIV-1 replication, including intracellular Gag/Gag-Pol RNA and protein levels, which in turn inhibits assembly and particle production. Interfering INI1 leads to a decrease in particle production and Gag/Gag-Pol protein levels. Understanding the role of INI1 and SAP18 in HIV-1 replication is likely to provide novel insight into the stability of Gag/Gag-Pol, which may lead to the development of novel therapeutic strategies to inhibit HIV-1 late events.IMPORTANCESignificant gaps exist in our current understanding of the mechanisms and host factors that influence HIV-1 posttranscriptional events, includinggagRNA levels, Gag/Gag-Pol protein levels, assembly, and particle production. Our previous studies suggested that the IN-binding host factor INI1 plays a role in HIV-1 assembly. An ectopically expressed minimal IN-binding domain of INI1, S6, potently and selectively inhibited HIV-1 Gag/Gag-Pol trafficking and particle production. However, whether or not endogenous INI1 and its interacting partners, such as SAP18, are required for late events was unknown. Here, we report that endogenous INI1 and its interaction with SAP18 are necessary to maintain intracellular levels of Gag/Gag-Pol and for particle production. Interfering INI1 or the INI1-SAP18 interaction leads to the impairment of these processes, suggesting a novel strategy for inhibiting posttranscriptional events of HIV-1 replication.

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Feng, Jianguo, Xichao Xu, Xin Fan, Qian Yi e Liling Tang. "BAF57/SMARCE1 Interacting with Splicing Factor SRSF1 Regulates Mechanical Stress-Induced Alternative Splicing of Cyclin D1". Genes 12, n. 2 (21 febbraio 2021): 306. http://dx.doi.org/10.3390/genes12020306.

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Background: Cyclin D1 regulates cyclin-dependent protein kinase activity of the cell cycle, and cyclin D1 alternative splicing generates a cyclin D1b isoform, acting as a mediator of aberrant cellular proliferation. As alternative splicing processes are sensitive to mechanical stimuli, whether the alternative splicing of cyclin D1 is regulated by mechanical stress and what kinds of factors may act as the regulator of mechano-induced alternative splicing remain unknown. Methods: The alternative splicing of Cyclin D1 was examined using reverse transcription polymerase chain reaction (RT-PCR) in osteoblast cell lines and keratinocyte cells loaded by a cyclic stretch. The expression of splicing factors and switching defective/sucrose non-fermenting (SWI/SNF) complex subunits were detected in stretched cells using real-time quantitative PCR (RT-qPCR). The protein interaction was tested by co-immunoprecipitation assay (Co-IP). Results:Cyclin D1 expression decreased with its splice variant upregulated in stretched cells. Serine/arginine-rich splicing factor 1 (SRSF1) and SWI/SNF complex subunit Brahma-related gene-1-associated factor 57 (BAF57), also named SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 (SMARCE1), could respond to mechanical stimuli. Overexpression and knockdown experiments indicated the BAF57/SMARCE1 is probably a critical factor regulating the alternative splicing of cyclin D1. Co-IP showed an interaction between BAF57/SMARCE1 and SRSF1, implying a possible underlying mechanism of the regulator role of BAF57/SMARCE1 in the splicing process of cyclin D1. Conclusions: The splicing factor SRSF1 and BAF57/SMARCE1 are possibly responsible for the mechanical stress-induced alternative splicing of cyclin D1.

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Balasubramaniam, Sucharitha, Clay E. S. Comstock, Adam Ertel, Kwang Won Jeong, Michael R. Stallcup, Sankar Addya, Peter A. McCue, William F. Ostrander, Michael A. Augello e Karen E. Knudsen. "Aberrant BAF57 Signaling Facilitates Prometastatic Phenotypes". Clinical Cancer Research 19, n. 10 (14 marzo 2013): 2657–67. http://dx.doi.org/10.1158/1078-0432.ccr-12-3049.

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Moon, Jae-Seung, Hong-Jai Lee, Chun-Chang Ho, Jin-Su Shin, Sankar Ghosh, Jung-Ho Kim e Sang-Kyou Lee. "Immuno-suppressive function of nucleus-transducible BAF57-ΔPH in T cell activation via degradation of endogenous BAF57". International Journal of Hematology 108, n. 4 (5 luglio 2018): 375–83. http://dx.doi.org/10.1007/s12185-018-2491-6.

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Wooff, David A. "Bayes Linear Sufficiency in Non-exchangeable Multivariate Multiple Regressions". Bayesian Analysis 9, n. 1 (marzo 2014): 77–96. http://dx.doi.org/10.1214/13-ba847.

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Carbonari, Luan Tiago dos Santos, Rita Carolina de Melo, Paulo Henrique Cerutti, Altamir Frederico Guidolin e Jefferson Luís Meirelles Coimbra. "Análise multivariada aplicada na discriminação de genótipos em caracteres do tempo de cozimento em feijão (Phaseolus vulgaris L.)". Revista de Ciências Agroveterinárias 22, n. 3 (4 agosto 2023): 358–66. http://dx.doi.org/10.5965/223811712232023358.

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Abstract (sommario):

As avaliações rotineiras do caráter tempo de cozimento em feijão (Phaseolus vulgaris L.) podem ser efetuadas de distintas maneiras resultando em diferentes variáveis. Por vez, a análise estatística univariada não considera as interdependêcias entre as variáveis, podendo omitir importantes informações a respeito dos genótipos. Com isso, o objetivo do trabalho foi dispor uma proposta alternativa para análise do tempo de cozimento em feijão, permitindo a discriminação entre genótipos. O experimento utilizado para esta abordagem foi conduzido em condições de campo na safra agrícola do ano 2017/18 em Lages, Santa Catarina, Brasil. Os tratamentos foram compostos por doze genótipos, sendo quatro genitores, estruturados em dois cruzamentos BAF50 x BAF07 e BAF09 x IPR 88 Uirapuru, com suas gerações F2, F3, F8 e F9. O delineamento utilizado foi blocos casualizados, com dois blocos e duas observações em cada unidade experimental. Posteriormente a colheita, a variável resposta tempo de cocção dos grãos de feijão foi mensurada com o cozedor Mattson, sendo considerado o tempo de cocção das 13 hastes iniciais. Na análise multivariada, as variáveis tempo de cocção da segunda (TCH2), décima segunda (TCH12) e décima terceira haste (TCH13) foram utilizadas com base em sua significância pelo método de seleção de variáveis passo a passo (stepwise). A análise de variância multivariada demonstrou diferença entre os genótipos (P<0,05). A partir da matriz de dissimilaridade com as distâncias de Mahalanobis e o dendrograma de agrupamento, foi possível verificar as distâncias dos genótipos derivados dos cruzamentos BAF50 x BAF07 e BAF09 x IPR 88 Uirapuru. Com isso, a análise multivariada possibilitou a discriminação dos genótipos, adicionalmente o cruzamento BAF50 x BAF07 demonstrou maiores estimativas de dissimilaridade nas progênies.

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Witzel, Maximilian, Daniel Petersheim, Yanxin Fan, Ehsan Bahrami, Tomas Racek, Meino Rohlfs, Jacek Puchalka et al. "SWI/SNF Protein SMARCD2 Orchestrates Transcriptional Networks Controlling Hematopoiesis and Neutrophil Granulocytes in Humans, Mice and Zebrafish". Blood 128, n. 22 (2 dicembre 2016): 2. http://dx.doi.org/10.1182/blood.v128.22.2.2.

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Abstract Differentiation of hematopoietic stem cells follows a hierarchical program of transcriptional-regulated events. We here identify SMARCD2 (Swi/Snf-related matrix associated actin dependent regulator of chromatin, subfamily D, member 2) as critical regulator of myelopoiesis in humans, mice, and zebrafish. We studied four patients from three unrelated pedigrees presenting with a novel syndromatic phenotype comprising congenital neutropenia, specific granule deficiency, susceptibility to myelodysplasia with excess of blasts, and various skeletal anomalies. All patients had homozygous loss-of-function mutations in SMARCD2. In contrast to wildtype alleles, the variant alleles did not give rise to proteins with capacity to interact with the SWI/SNF subunits BRG1, BAF170, BAF155, and BAF47, as shown by co-immunoprecipitation experiments. In vitro, knockdown of SMARCD2 in promyelocytic NB4 cells, differentiated in the presence of ATRA, led to decreased expression of genes encoding the primary granule proteins cathelicidin (CAMP) and alpha-1-antitrypsin (AAT) as well as specific granule proteins matrix metalloproteinase-8 (MMP8), transcobalamin (TCN1) and lactoferrin (LTF). This phenotype is reminiscent of patients with specific granule deficiency, characterized by mutations in CEBPE, a known transcription factor controlling terminal neutrophil development. We therefore hypothesized that SMARCD2 may act via CEBPe and performed immunoprecipitation studies in transfected cells. Upon pull-down of SMARCD2, CEPBE could be detected, and vice versa, suggesting that both proteins physically interact to control transcriptional networks. To interrogate effects of SMARCD2 deficiency on global chromatin accessibility we made use of ATAC sequencing of undifferentiated and ATRA-differentiated NB4 cells and compared this data with comprehensive RNA-sequencing results. A specific subset of genes was found deregulated in both assays, affecting vesicular trafficking, migration and signalling pathways. To validate a role for SMARCD2 in hematopoiesis in vivo, we generated murine and zebrafish model systems. We generated Smarcd2-/- mice by injection of Smarcd2+/- murine ES cells into blastocysts, transfer into pseudo-pregnant mice and interbreeding of heterozygous Smarcd2+/- offsprings. The mutant allele was inherited in a Mendelian fashion but no viable mice were born. 14.5dpc embryos were characterized by anemia and reduced size compared to their littermates. Analysis of fetal liver hematopoiesis revealed a complete absence of CD11b+Gr1+ and CD11b+Ly6c+ cells, whereas the number of LSK stem cells was not affected. Futhermore, Smarcd2-/- embryos showed aberrations in erythroid cells such as extensive anisocytosis, multinucleated cells, and perturbed mitosis. In cytokine-driven colony forming unit assays, GM-CSF, M-CSF, and G-CSF induced myeloid cell differentiation was decreased. Transcriptional profiling of LSK stem cells revealed a striking dysbalance affecting genes involved in signaling pathways and host defence, including CEBPE-dependent genes. Among a total of 12362 detected genes, we found 4290 to be differentially expressed (DESeq2, FDR<10%). Interestingly, the majority (79%) of the 605 genes with a relatively large difference (fold-change > 1.4, FDR<1%) were up- and not downregulated. Next, we generated three Smarcd2-deficient zebrafish models using a) morpholino-mediated knockdown in Tg(mpx:EGFP)i114 and Tg(lyz:dsRed)nz50 strains of the orthologous gene or b) Crisp/Cas9-mediated genomic engineering of this locus in Tg(mpx:EGFP)i114. In all models, the numbers of neutrophil granulocytes were significantly reduced. We conclude that SMARCD2 is a critical factor orchestrating transcriptional networks controlling hematopoiesis across species, in particular regulation and maintenance of neutrophil differentation and prevention of leukemogenesis. Disclosures Abboud: Novartis: Honoraria; MAST Therapeutics: Research Funding; Eli Lilly and Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees.

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Joaquim Júnior, Carlos Zacarias, Paulo Henrique Cerutti, Luan Tiago dos Santos Carbonari, Marcio dos Santos, Bernardino Domingos Mango, Jessiane Mary Jastrombek, Jorge Luis Tejada et al. "Seleção de genótipos de feijão com potencial uso no melhoramento de novas cultivares tolerantes ao S-metolachlor". OBSERVATÓRIO DE LA ECONOMÍA LATINOAMERICANA 22, n. 4 (19 aprile 2024): e4263. http://dx.doi.org/10.55905/oelv22n4-153.

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Abstract (sommario):

O feijão é uma das leguminosas mais importantes para o consumo humano e um alimento básico para milhões de pessoas em todo o mundo, devido ao seu alto valor nutricional como proteína, minerais, antioxidantes e compostos bioativos. Entretanto, vários fatores são limitantes na produtividade desta cultura, sendo um deles a interferência que é causada pelas plantas daninhas. Por isso, o uso de herbicidas vem sendo uma alternativa para o controle destas espécies no cultivo. A utilização do S-metolachlor para controle de plantas daninhas, exige que a cultura seja tolerante a este herbicida, o que as vezes não é verificado, uma vez que na cultura pode haver variabilidade na resposta de genótipos aos herbicidas. Com isso, o estudo objetivou-se em selecionar genótipos de feijão com características promissoras para uso no melhoramento de novas cultivares tolerantes ao S-metolachlor. O estudo foi conduzido em delineamento de blocos completos casualizados, em esquema fatorial 8x2 (genótipo vs herbicida), com quatro repetições. O fator genótipo foi constituído por oito níveis correspondentes à uma cultivar (Caviano) e sete acessos (BAF02, BAF159, BAF40, BAF45, BAF05, BAF109 e BAF88). O fator herbicida foi composto por dois níveis (com e sem) do S-metolachlor (1200 g i. a. ha-1) aplicado um dia após a semeadura. Foram realizadas as avaliações de fitointoxicação (FI), estatura da planta (EP), diâmetro do caule (DC), o número de folhas (NF), a massa seca da parte aérea (MSPA) e massa seca da raiz (MSR). Os dados foram submetidos a análise de variância ANOVA e em seguida foi aplicada a análise de componentes principais PCA. As análises foram realizadas por meio do software “Statistical Analysis System - SAS” na versão acadêmica (SAS University Edition). No entanto, por meio das duas primeiras dimensões canônicas foram gerados gráficos biplot, visando observar o agrupamento de genótipos em relação às variáveis contribuintes para sua discriminação, através do software “RSTUDIO”, na versão acadêmica. O agrupamento dos genótipos em dois grupos permitiu observar o efeito das variáveis contribuintes em sua separação, onde observou-se que entre genótipos avaliados, o BAF88 foi o mais tolerante aos herbicidas em relação demais genótipos por ele possuir maior desempenho quanto às variáveis como EP, DC, NF, MSPA e MSR. No entanto, o BAF88 representa um genótipo promissor o melhoramento de novas cultivares tolerantes ao herbicida S-metolachlor, sendo importante sua introdução nos programas de melhoramento.

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43

SUZUMURA, HIROFUMI, MASASHI TSURUTA, KOJI OKABAYASHI, KOHEI SHIGETA, RYO SEISHIMA, TAKASHI ISHIDA, TAKEHIRO SHIMADA et al. "BAF57 Is a Potential Determinant of Colorectal Cancer Malignancy". Anticancer Research 41, n. 11 (novembre 2021): 5445–52. http://dx.doi.org/10.21873/anticanres.15356.

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44

Domingos, Pedro M., Tetyana V. Obukhanych, Curtis R. Altmann e A. Hemmati-Brivanlou. "Cloning and developmental expression of Baf57 in Xenopus laevis". Mechanisms of Development 116, n. 1-2 (agosto 2002): 177–81. http://dx.doi.org/10.1016/s0925-4773(02)00129-6.

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45

Dye, Collin, Sean Keenan, Brandon M. Carius, Paul E. Loos, Michael A. Remley, Brandon Mendes, Jacob L. Arnold et al. "Airway Management in Prolonged Field Care". Journal of Special Operations Medicine 20, n. 3 (2020): 141. http://dx.doi.org/10.55460/baf7-3bm3.

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46

Yamaguchi, Takahiro, Tomoko Kurita, Kazuto Nishio, Junichi Tsukada, Toru Hachisuga, Yasuo Morimoto, Yoshiko Iwai e Hiroto Izumi. "Expression of BAF57 in ovarian cancer cells and drug sensitivity". Cancer Science 106, n. 4 (25 febbraio 2015): 359–66. http://dx.doi.org/10.1111/cas.12612.

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47

Kiskinis, Evangelos, Juana M. García-Pedrero, M. Angeles Villaronga, Malcolm G. Parker e Borja Belandia. "Identification of BAF57 mutations in human breast cancer cell lines". Breast Cancer Research and Treatment 98, n. 2 (15 marzo 2006): 191–98. http://dx.doi.org/10.1007/s10549-005-9149-9.

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48

Yeh, Jeng-Hsien. "Effect of Thymol on Ca^(2+) Homeostasis and Viability in PC3 Human Prostate Cancer Cells". Chinese Journal of Physiology 60, n. 1 (28 febbraio 2017): 32–40. http://dx.doi.org/10.4077/cjp.2017.baf447.

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49

Stjepanovic, Mirko. "Swimming Three Ice Miles within Fifteen Hours". Chinese Journal of Physiology 60, n. 4 (31 agosto 2017): 197–206. http://dx.doi.org/10.4077/cjp.2017.baf467.

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Huang, Wen-Ching. "The Modulative Effects of Microcurrent Electrical Nerve Stimulation on Diabetic Mice". Chinese Journal of Physiology 60, n. 1 (28 febbraio 2017): 62–72. http://dx.doi.org/10.4077/cjp.2017.baf476.

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