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Epigenetic Alterations in Alzheimer’s Disease and Its Therapeutic and Dietary Interventions
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
P. M. Aswathy, C. M. Shafeeque, Moinak Banerjee
DNA methylation profiles of hippocampal tissues from control and AD patients have identified the presence of promoter hypermethylation of the gene Dual‐Specificity Phosphatase 22 (DUSP22), that inhibits protein kinase A (PKA) activity and, thereby determines tau phosphorylation status and cyclic AMP-responsive element-binding protein (CREB) signaling in AD (Sanchez-Mut et al. 2014). The methylation status of DUSP22 correlated positively with the Braak stages of the patient (Sanchez-Mut et al. 2014). Decreased expression of another phosphatase, DUSP6, that regulates tau production, through hypermethylation, was recently shown in AD brains (Watson et al. 2016). The Bridging Integrator1 (BIN1), which mediates AD risk by modulating tau pathology (Chapuis et al. 2013), was shown to be aberrantly hypermethylated in AD, resulting in Aβ load (De Jager et al. 2014; Yu et al. 2015).
Update on the classification of T-cell lymphomas, Hodgkin lymphomas, and histiocytic/dendritic cell neoplasms
Published in Expert Review of Hematology, 2019
Akira Satou, N. Nora Bennani, Andrew L. Feldman
Overall, ALK-negative ALCL has a prognosis inferior to that of ALK-positive ALCL. However, about 30% of ALK-negative ALCLs demonstrate chromosomal rearrangements of the DUSP22/IRF4 locus on chromosome 6p25.3 and are associated with favorable outcomes similar to those seen in ALK-positive ALCL [18,19]. Recently, gene expression profiling and subsequent methylation and protein studies of DUSP22-rearranged ALCL revealed that they lacked expression of activated STAT3 and demonstrated an immunogenic phenotype [20]. Specifically, DUSP22-rearranged ALCLs were markedly hypomethylated and overexpressed immunogenic cancer-testis antigen genes as well as costimulatory genes such as CD58 and HLA class II. In addition, they showed minimal expression of PD-L1, suggesting that their favorable clinical outcomes might be related to their immunogenic phenotype and that DUSP22-rearranged ALCL is a molecularly distinct subgroup of ALCL. Of note, DUSP22 rearrangements are not specific for ALK-negative ALCL, and may be seen in approximately 20% of primary cutaneous ALCLs and occasional cases of lymphomatoid papulosis [21,22]. An additional group of ALK-negative ALCLs discussed in the WHO classification bears rearrangements of the TP63 gene, a finding consistently associated with aggressive clinical behavior [18,19]. TP63 rearrangements encode oncogenic fusion genes, mostly associated with inv(3)(q26q28) generating a TBL1XR1-TP63 fusion, and occur in 5–8% of systemic ALK-negative ALCLs. Immunohistochemistry for p63 is highly sensitive for the resultant p63 fusion proteins and is a useful screening test; however, unlike the use of immunohistochemistry for ALK in ALCL, immunohistochemistry for p63 is not specific and when positive the presence of a TP63 rearrangement must be confirmed by another method such as fluorescence in situ hybridization [23].
Advances in the treatment and prognosis of anaplastic lymphoma kinase negative anaplastic large cell lymphoma
Published in Hematology, 2019
Xiaoli Wang, Jingjing Wu, Mingzhi Zhang
ALCL is a rare and heterogeneous malignant tumor, with high expression of CD30 and includes ALK+ ALCL, ALK- ALCL, pcALCL, and BIA ALCL subtypes. In this review, the molecular biology, clinical manifestation, treatment and prognosis of ALK- ALCL are summarized, which is a definite entity in the WHO 2016 Classification. The etiology and pathogenesis of ALK- ALCL is uncertain. Morphologic patterns include common, lymphohistiocytic, small cell, Hodgkin-like, and composite. The first is the most common. ALK- ALCL tumor cells are positive for CD3 and CD2, and negative for CD15 and PAX5. Some patients exist with DUSP22 rearrangement and TP63 rearrangement. Peak onset age is 40 to 65 years. The ratio of male to female is 0.9:1. Patients often reveal advanced disease, with B symptoms, high IPI score, elevated LDH, extranodal involved and an aggressive clinical course. ALK- ALCL is easily misdiagnosed as PTCL-NOS and HL, nodular-sclerosis. There is no standard treatment yet for ALK- ALCL. Currently, CHOP or CHOP-like regimens are first-line treatment regimens. HSCT is a controversial treatment after first-line remission. Targeted therapy is a hot topic, as represented by CD30 monoclonal antibody. Small molecule inhibitors can benefit patients. Substantial clinical studies are still needed for CART treatment. The prognosis of DUSP22-rearranged ALCLs is similar to that of ALK+ ALCL. The prognosis of TP63-rearranged ALCLs is worse than that of ALK- ALCL patients lacking DUSP22 and TP63 rearrangement. Besides, CR before transplantation is related to better outcomes. Early stage ALCL may indicate a better prognosis. Older age, elevated LDH, elevated β2 microglobulin level, short time of relapse or progression after the first treatment, extranodular involvement, and histological type of lymphohistiocytic or small cell component are associated with poor prognosis. More research is needed to explore more effective treatments to improve patient survival.
A case of childhood glaucoma with a combined partial monosomy 6p25 and partial trisomy 18p11 due to an unbalanced translocation
Published in Ophthalmic Genetics, 2020
Katsuhiro Hosono, Kazuhide Kawase, Kentaro Kurata, Yusuke Niimi, Hirotomo Saitsu, Shinsei Minoshima, Hidenori Ohnishi, Takahiro Yamamoto, Akiko Hikoya, Nobutaka Tachibana, Toshiyuki Fukao, Tetsuya Yamamoto, Yoshihiro Hotta
First, we performed Sanger sequencing of all 13 exons of PAX6, a gene closely associated with Peters anomaly and one of the glaucoma-related genes. The analysis revealed no pathogenic PAX6 variants (16). To identify chromosomal aberrations in the patient with clinically suspected 6p25 deletion syndrome, we performed cytogenetic analysis (G-banding and M-FISH). Cytogenetic analyses revealed a derivative chromosome 6 with its distal short arm replaced by an extra copy of the short arm of chromosome 18, resulting from an unbalanced translocation (Figure 2(a,b)). The karyotype was designated as 46,XX,der(6)t(6;18)(p25;p11). The patient’s parents presented with a normal karyotype, indicating that de novo rearrangement had occurred (data not shown). These regions of 6p25 loss and 18p11 gain were further characterized by array-CGH analysis. Array-CGH analysis revealed a terminal deletion of approximately 4.6-Mb from the 6pter to the 6p25.1 region and duplication of approximately 8.9-Mb from the 18pter to the 18p11.22 region (Figure 3(a,b)). These findings are consistent with the results of cytogenetic analyses. Although the 130-kb region completely encompassed DUSP22 at the most distal terminal end of the 6p25 region showed no loss of the genomic copy number (Figure 3(a)), the terminal region including DUSP22 has been reported to undergo copy number loss and gain in DGV, which may explain why this region maintained its genomic copy number even when other adjacent regions showed variable copy number losses. To determine the breakpoint of the unbalanced rearrangement at the single base-level, we performed long-range PCR to amplify the junctional fragment of the translocation breakpoint. By sequencing the junctional fragment, we defined the unbalanced translocation as g.chr6:pter_4594783delinschr18:pter_8911541(Figure 4). The boundary regions of breakpoints at chromosomes 6 and 18 were within highly repetitive sequences (L1ME3B and AluJb, respectively) (Figure 4), suggesting the involvement of repetitive sequences in the rearrangement.