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Summary: Structural variations involving enhancer hijacking induce aberrant oncogene expression and cause tumorigenesis. A rare translocation, t(3;8)(q26.2;q24), is associated with MECOM and MYC rearrangement, causing myeloid neoplasms with a dismal prognosis. The most recent World Health Organization classification recognises myeloid neoplasms with MECOM rearrangement as acute myeloid leukaemia (AML) with defining genetic abnormalities. Recently, the increasing use of induced pluripotent stem cell (iPSC) technology has helped elucidate the pathogenic processes of haematological malignancies. However, its utility for investigating enhancer hijacking in myeloid neoplasms remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harbouring t(3;8)(q26.2;q24) and differentiated them into haematopoietic progenitor cells to model the pathophysiology of MDS with t(3;8)(q26.2;q24). Our iPSC model reproduced the primary patient's MECOM expression changes and histone H3 lysine 27 acetylation (H3K27ac) patterns in the MECOM promoter and MYC blood enhancer cluster (BENC). Furthermore, we revealed the apoptotic effects of the bromodomain and extra‐terminal motif (BET) inhibitor on iPSC‐derived MDS cells by suppressing activated MECOM. Our study demonstrates the usefulness of iPSC models for uncovering the precise mechanism of enhancer hijacking due to chromosomal structural changes and discovering potential therapeutic drug candidates for cancer treatment. [ABSTRACT FROM AUTHOR]

Photochemical multi-component coupling reactions initiated by the activation of glycosyl bromides in the presence of 1,4-bis(diphenylamino)benzene (BDB) as an organic photocatalyst were developed. C-glycosides accompanied by olefin (di)functionalization were obtained. This method allows us to access various C-glycosides with alkene, carbonyl, alcohol, ether, and amide functionalities. [ABSTRACT FROM AUTHOR]

SF3B1 is the most commonly mutated RNA splicing factor in cancer.sup.1-4, but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here we integrated pan-cancer splicing analyses with a positive-enrichment CRISPR screen to prioritize splicing alterations that promote tumorigenesis. We report that diverse SF3B1 mutations converge on repression of BRD9, which is a core component of the recently described non-canonical BAF chromatin-remodelling complex that also contains GLTSCR1 and GLTSCR1L.sup.5-7. Mutant SF3B1 recognizes an aberrant, deep intronic branchpoint within BRD9 and thereby induces the inclusion of a poison exon that is derived from an endogenous retroviral element and subsequent degradation of BRD9 mRNA. Depletion of BRD9 causes the loss of non-canonical BAF at CTCF-associated loci and promotes melanomagenesis. BRD9 is a potent tumour suppressor in uveal melanoma, such that correcting mis-splicing of BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppresses tumour growth. Our results implicate the disruption of non-canonical BAF in the diverse cancer types that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies. A range of SF3B1 mutations promote tumorigenesis through the repression of BRD9, a core component of the non-canonical BAF complex, and correcting BRD9 mis-splicing in these SF3B1-mutant cells suppresses tumour growth., Author(s): Daichi Inoue [sup.1] [sup.2] , Guo-Liang Chew [sup.3] [sup.4] , Bo Liu [sup.1] , Brittany C. Michel [sup.5] [sup.6] [sup.7] , Joseph Pangallo [sup.3] [sup.4] , Andrew R. D'Avino [...]

Rotaxane‐type fluorescence dyes promise applications of optical and biological interest because their inner fluorescence cores are protected in inseparable host–guest systems. However, there are few relevant reports of such rotaxane‐type fluorescence dyes due to the difficulty of their syntheses. Here, a versatile synthetic method is established for [5]rotaxane‐type fluorescence dyes by employing a cooperative capture strategy. Using this method, [5]rotaxanes with emission colors ranging from blue to red are synthesized successfully. These [5]rotaxanes show higher emission quantum yields than the corresponding naked fluorescence dyes in water and even in the solid state. Furthermore, these rotaxanes show photostability and chemical stability, demonstrating the high applicability of [5]rotaxane‐type fluorescence dyes for a variety of emitting materials. [ABSTRACT FROM AUTHOR]

Rearrangements involving the neurotrophic receptor kinase genes (NTRK1, NTRK2, and NTRK3; hereafter referred to as TRK) produce oncogenic fusions in a wide variety of cancers in adults and children. Although TRK fusions occur in fewer than 1% of all solid tumors, inhibition of TRK results in profound therapeutic responses, resulting in Breakthrough Therapy FDA approval of the TRK inhibitor larotrectinib for adult and pediatric patients with solid tumors, regardless of histology. In contrast to solid tumors, the frequency of TRK fusions and the clinical effects of targeting TRK in hematologic malignancies are unknown. Here, through an evaluation for TRK fusions across more than 7,000 patients with hematologic malignancies, we identified TRK fusions in acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), histiocytosis, multiple myeloma, and dendritic cell neoplasms. Although TRK fusions occurred in only 0.1% of patients (8 of 7,311 patients), they conferred responsiveness to TRK inhibition in vitro and in vivo in a patient-derived xenograft and a corresponding AML patient with ETV6-NTRK2 fusion. These data identify that despite their individual rarity, collectively, TRK fusions are present in a wide variety of hematologic malignancies and predict clinically significant therapeutic responses to TRK inhibition., Introduction Fusions involving neurotrophic receptor tyrosine kinases (NTRKs) were among the first gene translocations described in cancer (1, 2). NTRK1, NTRK2, and NTRK3 (encoding TrkA, TrkB, and TrkC, respectively; hereafter [...]

Purpose: To analyze whether response to the GnRH test is a predictor of empty follicle syndrome (EFS) and to analyze independent risk factors for EFS. Methods: The GnRH test results of 3765 patients from 2016 to 2018 were used to define the reference range of the GnRH test. Risk factors for EFS were estimated by multivariate logistic analysis of 5282 cycles (5247 oocyte‐retrieved cycles with GnRH agonist trigger and 35 cycles of EFS) conducted from 2016 to 2019. Results: GnRH testing showed basal hormone values as follows: median LH 5.2 (95 percentile; 1.3–12.6) mIU/mL, LH 30 min 22.0 (6.8–57.1), basal FSH 7.3 (3.0–20.5), FSH 30 min 11.5 (5.1–30.4) and FSH/LH ratio 1.5 (0.6–4.1). Independent risk factors for EFS were antral follicle count (adjusted odds ratio; 0.94, 95% CI; 0.89–0.99), basal LH (0.78, 0.66–0.90), and days duration of ovarian stimulation (1.41, 1.21–1. 60). The respective thresholds were 8 for AFC, 5.0 for basal LH, and 16 days for duration. Conclusions: LH 30 min values of the GnRH test did not predict EFS. Independent risk factors for EFS were AFC, basal LH and days duration of ovarian stimulation. [ABSTRACT FROM AUTHOR]

Recurrent mutations in the gene encoding additional sex combs-like 1 (ASXL1) are found in various hematologic malignancies and associated with poor prognosis. In particular, ASXL1 mutations are common in patients with hematologic malignancies associated with myelodysplasia, including myelodysplastic syndromes (MDSs), and chronic myelomonocytic leukemia. Although loss-of-function ASXL1 mutations promote myeloid transformation, a large subset of ASXL1 mutations is thought to result in stable truncation of ASXL1. Here we demonstrate that C-terminal-truncating Asxl1 mutations (ASXL1-MTs) inhibited myeloid differentiation and induced MDS-like disease in mice. ASXL1-MT mice displayed features of human-associated MDS, including multi-lineage myelodysplasia, pancytopenia, and occasional progression to overt leukemia. ASXL1-MT resulted in derepression of homeobox A9 (Hoxa9) and microRNA-125a (miR-125a) expression through inhibition of polycomb repressive complex 2-mediated (PRC2-mediated) methylation of histone H3K27. miR-125a reduced expression of C-type lectin domain family 5, member a (Clec5a), which is involved in myeloid differentiation. In addition, HOXA9 expression was high in MDS patients with ASXL1-MT, while CLEC5A expression was generally low. Thus, ASXL1-MT-induced MDS-like disease in mice is associated with derepression of Hoxa9 and miR-125a and with Clec5a dysregulation. Our data provide evidence for an axis of MDS pathogenesis that implicates both ASXL1 mutations and miR-125a as therapeutic targets in MDS., Introduction Additional sex combs-like 1 (ASXL1) is 1 of 3 mammalian homo-logs of the Drosophila additional sex combs (Asx), and plays critical roles both in activation and suppression of Hox [...]

Pre‐mRNA splicing is now widely recognized as a cotranscriptional and post‐transcriptional mechanism essential for regulating gene expression and modifying gene product function. Mutations in genes encoding core spliceosomal proteins and accessory regulatory splicing factors are now considered among the most recurrent genetic abnormalities in patients with cancer, particularly hematologic malignancies. These include mutations in the major (U2‐type) and minor (U12‐type) spliceosomes, which remove >99% and ~0.35% of introns, respectively. Growing evidence indicates that aberrant splicing of evolutionarily conserved U12‐type minor introns plays a crucial role in cancer as the minor spliceosome component, ZRSR2, is subject to recurrent, leukemia‐associated mutations, and intronic mutations have been shown to disrupt the splicing of minor introns. Here, we review the importance of minor intron regulation, the molecular effects of the minor (U12‐type) spliceosomal mutations and cis‐regulatory regions, and the development of minor intron studies for better understanding of cancer biology. [ABSTRACT FROM AUTHOR]

In the gonadotropin‐releasing hormone (GnRH) antagonist protocol, it is necessary to reinforce contraceptive guidance assuming that luteinizing hormone surge is not detected by measurement of serum level and ovulation is not suppressed by GnRH antagonist. [ABSTRACT FROM AUTHOR]

CHRM-ing away anemia: By studying red blood cell precursors and their self-renewal mechanisms, Trivedi et al. identified a potential approach to helping relieve multiple types of anemia. The authors specifically focused on burst-forming unit erythroid, a type of early erythroid progenitor, showing that a specific acetylcholine receptor called cholinergic receptor, muscarinic 4 (CHRM4) regulates the self-renewal of these progenitor cells. Genetic or pharmacologic inhibition of CHRM4 increased erythrocyte production and alleviated anemia in a variety of mouse models, suggesting the therapeutic potential of this approach. Adult stem and progenitor cells are uniquely capable of self-renewal, and targeting this process represents a potential therapeutic opportunity. The early erythroid progenitor, burst-forming unit erythroid (BFU-E), has substantial self-renewal potential and serves as a key cell type for the treatment of anemias. However, our understanding of mechanisms underlying BFU-E self-renewal is extremely limited. Here, we found that the muscarinic acetylcholine receptor, cholinergic receptor, muscarinic 4 (CHRM4), pathway regulates BFU-E self-renewal and that pharmacological inhibition of CHRM4 corrects anemias of myelodysplastic syndrome (MDS), aging, and hemolysis. Genetic down-regulation of CHRM4 or pharmacologic inhibition of CHRM4 using the selective antagonist PD102807 promoted BFU-E self-renewal, whereas deletion of Chrm4 increased erythroid cell production under stress conditions in vivo. Moreover, muscarinic acetylcholine receptor antagonists corrected anemias in mouse models of MDS, aging, and hemolysis in vivo, extending the survival of mice with MDS relative to that of controls. The effects of muscarinic receptor antagonism on promoting expansion of BFU-Es were mediated by cyclic AMP induction of the transcription factor CREB, whose targets up-regulated key regulators of BFU-E self-renewal. On the basis of these data, we propose a model of hematopoietic progenitor self-renewal through a cholinergic-mediated "hematopoietic reflex" and identify muscarinic acetylcholine receptor antagonists as potential therapies for anemias associated with MDS, aging, and hemolysis. [ABSTRACT FROM AUTHOR]

Purpose: The clinical utility of chlormadinone acetate tablets (Lutoral™), an orally active progestin which has been available since June 2007, was compared to an in‐house vaginal suppository formulation of progesterone used between 2006 and 2007 for assisted reproductive technology (ART). Methods: We retrospectively evaluated the efficacy and safety of chlormadinone acetate by comparing the pregnancy rates and the incidences of birth defects and hypospadias in frozen‐thawed embryo transfer cycles using the in‐house vaginal progesterone and those using chlormadinone acetate for luteal phase support. Results: The pregnancy rates in the frozen‐thawed embryo transfer cycles were 31.2% (259/831) with vaginal progesterone for luteal phase support and 31.6% (4228/13 381) with chlormadinone acetate (no significant difference). In the cycles resulting in live birth following administration of chlormadinone acetate between July 2007 and December 2015, the incidence of birth defects was 2.8% (80/2893), and the incidence of hypospadias was 0.03% (1/2893). Conclusions: These results indicate that the pregnancy rate following frozen‐thawed embryo transfer using chlormadinone acetate for luteal phase support was comparable with that using vaginal progesterone, with no increased risk of birth defects, including hypospadias, which has been a concern following the use of progestins. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the performance of anti‐Müllerian hormone (AMH) measured by the Beckman Coulter fully automated Access assay to predict oocyte yield following controlled ovarian stimulation (COS) for in vitro fertilization (IVF). Methods: The correlation between the Access assay and the pre‐mixing method with Generation II ELISA assay (Gen II pre‐mix assay) was assessed using 230 blood samples. The relationship of AMH level measured by the Access assay and the actual number of oocytes retrieved following COS was assessed using 3296 IVF cycles. The performances of AMH, follicle stimulating hormone (FSH), and estradiol (E2) in predicting the responses to COS were also evaluated by constructing receiver operating characteristic (ROC) curves. Results: The AMH levels measured just before oocyte retrieval by the Access assay and the number of oocytes retrieved following COS showed a good correlation with R = 0.655. The ROC analysis revealed that the sensitivity of AMH was comparable with or lower than that of E2 but higher than that of FSH. Conclusions: With the improved Access AMH assays, AMH was as sensitive as E2 and could become an accurate marker of ovarian response to COS in more than 3000 Japanese IVF patients. [ABSTRACT FROM AUTHOR]