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Macrophages have been recognized as pivotal players in the progression of MASLD/MASH. However, the molecular mechanisms underlying their multifaceted functions in the disease remain to be further clarified. In the current study, we developed a new mouse model with YAP activation in macrophages to delineate the effect and mechanism of YAP signaling in the pathogenesis of MASLD/MASH. Genetically modified mice, featuring specific depletion of both Mst1 and Mst2 in macrophages/monocytes, were generated and exposed to a high‐fat diet for 12 weeks to induce MASLD. Following this period, livers were collected for histopathological examination, and liver non‐parenchymal cells were isolated and subjected to various analyses, including single‐cell RNA‐sequencing, immunofluorescence and immunoblotting and qRT‐PCR to investigate the impact of YAP signaling on the progression of MASLD. Our data revealed that Mst1/2 depletion in liver macrophages enhanced liver inflammation and fibrosis in MASLD. Using single‐cell RNA‐sequencing, we showed that YAP activation via Mst1/2 depletion upregulated the expressions of both pro‐inflammatory genes and genes associated with resolution/tissue repair. We observed that YAP activation increases Kupffer cell populations (i.e., Kupffer‐2 and Kupffer‐3) which are importantly implicated in the pathogenesis of MASLD/MASH. Our data indicate that YAP activation via Mst1/2 deletion enhances both the pro‐inflammatory and tissue repairing functions of Kupffer‐1 and ‐2 cells at least in part through C1q. These YAP‐regulatory mechanisms control the plasticity of liver macrophages in the context of MASLD/MASH. Our findings provide important evidence supporting the critical regulatory role of YAP signaling in liver macrophage plasticity and the progression of MASLD. Therefore, targeting the Hippo‐YAP pathway may present a promising therapeutic strategy for the treatment of MASH. [ABSTRACT FROM AUTHOR]

Human trophoblast cells are crucial for healthy pregnancy. However, whether the defective homologous recombination (HR) repair of dsDNA break (DSB) in trophoblast cells may induce miscarriage is completely unknown. Moreover, the abundance of BRCA1 (a crucial protein for HR repair), its recruitment to DSB foci, and its epigenetic regulatory mechanisms, are also fully unexplored. In this work, it is identified that a novel lnc‐HZ10, which is highly experssed in villous tissues of recurrent miscarriage (RM) vs their healthy control group, suppresses HR repair of DSB in trophoblast cell. Lnc‐HZ10 and AhR (aryl hydrocarbon receptor) form a positive feedback loop. AhR acts as a transcription factor to promote lnc‐HZ10 transcription. Meanwhile, lnc‐HZ10 also increases AhR levels by suppressing its CUL4B‐mediated ubiquitination degradation. Subsequently, AhR suppresses BRCA1 transcription; and lnc‐HZ10 (mainly 1‐447 nt) interacts with γ‐H2AX; and thus, impairs its interactions with BRCA1. BPDE exposure may trigger this loop to suppress HR repair in trophoblast cells, possibly inducing miscarriage. Knockdown of murine Ahr efficiently recovers HR repair in placental tissues and alleviates miscarriage in a mouse miscarriage model. Therefore, it is suggested that AhR/lnc‐HZ10/BRCA1 axis may be a promising target for alleviation of unexplained miscarriage. [ABSTRACT FROM AUTHOR]

Background: Fluorescence labeled DNA probes and in situ hybridization methods had shorter turn round time for results revolutionized their clinical application. Signals obtained from these probes are highly specific, yet they can produce fusion signals not necessarily representing fusion of actual genes due to other genes included in the probe design. In this study we evaluated discordance between cytogenetic, FISH and RNAseq results in 3 different patients with hematologic malignancies and illustrated the need to perform next generation sequencing (NGS) or RNASeq to accurately interpret FISH results. Methods: Bone marrow or peripheral blood karyotypes and FISH were performed to detect recurring translocations associated with hematologic malignancies in clinical samples routinely referred to our clinical cytogenetics laboratory. When required, NGS was performed on DNA and RNA libraries to detect somatic alterations and gene fusions in some of these specimens. Discordance in results between these methods is further evaluated. Results: For a patient with plasma cell leukemia standard FGFR3 / IGH dual fusion FISH assay detected fusion that was interpreted as FGFR3 -positive leukemia, whereas NGS/RNASeq detected NSD2::IGH. For a pediatric acute lymphoblastic leukemia patient, a genetic diagnosis of PDGFRB -positive ALL was rendered because the PDGFRB break-apart probe detected clonal rearrangement, whereas NGS detected MEF2D::CSF1R. A MYC -positive B-prolymphocytic leukemia was rendered for another patient with a cytogenetically identified t(8;14) and MYC::IGH by FISH, whereas NGS detected a novel PVT1::RCOR1 not previously reported. Conclusions: These are 3 cases in a series of several other concordant results, nevertheless, elucidate limitations when interpreting FISH results in clinical applications, particularly when other genes are included in probe design. In addition, when the observed FISH signals are atypical, this study illustrates the necessity to perform complementary laboratory assays, such as NGS and/or RNASeq, to accurately identify fusion genes in tumorigenic translocations. [ABSTRACT FROM AUTHOR]

International students, particularly international English as a Second Language (ESL) students who come to the United States with relatively lower levels of English oral language proficiency, are often reluctant to participate in academic discussions. In a graduate-level TESOL program with a majority of international ESL students, a video recording, sharing, and discussion platform, Flip, was utilized in the program's teaching innovation. Flip is widely adopted by educators of all grade levels worldwide, as it enables educators to create a less formal online space to meet the holistic needs of international ESL students, including both academic and social needs. The article explains the teaching context of the practice, four stages of course integration with Flip, reasons for the integration, reflections, and future pedagogical directions. Incorporating Flip in this program promotes linguistic benefits, teacher identity and skill development, a community of belonging, and increased equity in assessment. Practical pedagogical considerations are also provided at the end of the article. [ABSTRACT FROM AUTHOR]

Malignant tumours area leading cause of death globally, accounting for approximately 13% of all deaths. A detailed understanding of the mechanism(s) of the occurrence and development of malignant tumours and identification of relevant therapeutic targets are therefore key to tumour treatment. tsRNAs(tRNA-derived small RNAs)—also known as TRFs (tRNA-derived fragments), tiRNAs (tRNA-derived stress-induced RNAs), tRNA halves, etc.—are a recently identified class of small noncoding RNAs that are generated from mature tRNA or tRNA precursors through cleavage by enzymes such as angiogenin, Dicer, RNase Z, and RNase P. Several studies have confirmed that dysregulation of tsRNAs is closely related to the tumorigenesis of breast cancer, nasopharyngeal cancer, lung cancer, and so on. Furthermore, research indicates that tsRNAs can be used as clinical diagnostic markers and therapeutic targets for cancer. In our review, we summarized the recent research progress on the role and clinical application of tsRNAs in tumorigenesis and progression. 7eoLqMrdYDzDu_VESawvVo Video Abstract [ABSTRACT FROM AUTHOR]

Benzo(a)pyrene (BaP) or benzo (a) pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE) exposure causes trophoblast cell dysfunctions and induces miscarriage, which is generally epigenetically regulated. Homologous recombination (HR) repair of DNA double strand break (DSB) plays a crucial role in maintenance of genetic stability and cell normal functions. However, whether BaP/BPDE might suppress HR repair in human trophoblast cells to induce miscarriage, as well as its epigenetic regulatory mechanism, is largely unclear. In this study, we find that BaP/BPDE suppresses HR repair of DSB in trophoblast cells and eventually induces miscarriage by up-regulating lnc-HZ08. In mechanism, lnc-HZ08 (1) down-regulates the expression levels of FOXA1 (forkhead box A1) and thus suppresses FOXA1-mediated mRNA transcription of BRCA1 (Breast cancer susceptibility gene 1) and CtIP (CtBP-interacting protein), (2) impairs BRCA1 and CtIP protein interactions by competitive binding with CtIP through lnc-HZ08-1 fragment, and also (3) suppresses BRCA1-mediated CtIP ubiquitination without affecting CtIP stability, three of which eventually suppress HR repair in human trophoblast cells. Supplement with murine Ctip could efficiently restore (i.e. increase) HR repair and alleviate miscarriage in BaP-exposed mouse model. Collectively, this study not only reveals the association and causality among BaP/BPDE exposure, the defective HR repair, and miscarriage, but also discovers novel mechanism in lnc-HZ08-regulated BRCA1/CtIP-mediated HR repair, bridging epigenetic regulation and genetic instability and also providing an efficient approach for treatment against BaP/BPDE-induced unexplained miscarriage. [ABSTRACT FROM AUTHOR]

Sno‐lncRNAs are intron‐derived long noncoding RNAs (lncRNAs) with snoRNA ends. Sno‐lncRNAs were first discovered in the human Prader–Willi (PWS)/Angelman (AS) imprinted domain. Here, we report the identification and characterization of four sno‐lncRNA types (sno‐lncRNA1, sno‐lncRNA2, sno‐lncRNA3, and sno‐lncRNA4) in the bovine PWS/AS imprinted domain. Reverse transcription–PCR first determined the cDNA sequences of the four bovine sno‐lncRNAs. A gene structure analysis showed that sno‐lncRNA1 lacks introns, but sno‐lncRNA2 and sno‐lncRNA3 have one and two introns respectively. The three sno‐lncRNAs have similar snoRNA ends. Moreover, the three have similar snoRNAs at their 5′ and 3′ ends. The head‐to‐tail orientation has six sno‐lncRNA copies arranged between bovine SNORD116‐6 and SNORD116‐12. Moreover, only a copy of sno‐lncRNA4 was located between SNORD116‐3 and SNORD116‐4. The expression of the four sno‐lncRNAs was analyzed in the bovine heart, liver, spleen, lung, kidney, muscle, fat, brain, and placenta tissues. The monoallelic expression of sno‐lncRNA4 was determined in bovine tissues. The results showed that the four sno‐lncRNAs are widely expressed in the nine tissues, although sno‐lncRNA3 and sno‐lncRNA4 were undetected in the placenta. Moreover, an informative single nucleotide polymorphism (rs448706424) revealed the allelic expression of sno‐lncRNA4 in exon 2 of sno‐lncRNA4. The bovine genome had six copies of sno‐lncRNA1, sno‐lncRNA2, and sno‐lncRNA3, but their allelic expression was not identified. [ABSTRACT FROM AUTHOR]

BPDE up-regulates lnc-HZ11, which down-regulates EGR1/NF-κB/CXCL12 pathway and suppresses trophoblast cell migration/invasion at intracellular levels. BPDE promotes donor trophoblast cells to secrete more EV-HZ11, which suppresses migration/invasion of the recipient trophoblast cells at intercellular levels, and is associated with unexplained miscarriage. Knockdown of murine lnc-Hz11 by EV-AS-Hz11 could efficiently alleviate miscarriage in BaP-exposed mice. The levels of EV-HZ11 in serum could predict the risk of miscarriage. [Display omitted] • BPDE up-regulates lnc-HZ11, which suppresses EGR1/NF-κB/CXCL12 and migration/invasion of trophoblast cells. • BPDE or lnc-HZ11 promotes trophoblast cells to secrete more EV-HZ11. • EV-HZ11 is transferred from donor cells to recipient cells and suppresses their migration/invasion. • Lnc-HZ11 and EV-HZ11 are closely associated with miscarriage. • Knockdown of murine lnc-Hz11 recovers migration/invasion and alleviates mouse miscarriage. • EV-HZ11 in serum predicts miscarriage risk. Extracellular vesicles (EVs) mediate the intercellular crosstalk by transferring functional cargoes. Recently, we have discovered that BaP/BPDE exposure suppresses trophoblast cell migration/invasion and induces miscarriage, which are also regulate by lncRNAs at intracelluar levels. However, the EVs-mediated intercellular regulatory mechanisms are completely unexplored. Specifically, whether EVs might transfer BPDE-induced toxic lncRNA to fresh recipient trophoblast cells and suppress their migration/invasion to further induce miscarriage is completely unknown. In this study, we find that BPDE exposure up-regulates a novel lnc-HZ11, which suppresses EGR1/NF-κB/CXCL12 pathway and migration/invasion of trophoblast cells. Intercellular studies show that EV-HZ11 (lnc-HZ11 in EVs), which is highly expressed in BPDE-exposed donor cells, suppresses EGR1/NF-κB/CXCL12 pathway and migration/invasion in recipient cells by transferring lnc-HZ11 through EVs. Analysis of villous tissues collected from UM (unexplained miscarriage) patients and HC (healthy control) group shows that the levels of BPDE-DNA adducts, lnc-HZ11 or EV-lnc-HZ11, and EGR1/NF-κB/CXCL12 pathway are all associated with miscarriage. Mouse assays show that BaP exposure up-regulates the levels of lnc-Hz11 or EV-Hz11, suppresses Egr1/Nf-κb/Cxcl12 pathway, and eventually induces miscarriage. Knockdown of lnc-Hz11 by injecting EV-AS-Hz11 could effectively alleviate miscarriage in BaP-exposed mice. Furthermore, EV-HZ11 in serum samples could well predict the risk of miscarriage. Collectively, this study not only discovers EVs-HZ11-mediated intercellular mechanisms that BaP/BPDE suppresses trophoblast cell migration/invasion and induces miscarriage but also provides new approach for treatment against unexplained miscarriage through EV-HZ11. [ABSTRACT FROM AUTHOR]

For the airborne pod strapdown inertial navigation system, it is necessary to use the host aircraft's inertial navigation system for the transfer alignment as quickly and accurately as possible in the flight process of the aircraft. The purpose of this paper is to propose an adaptive transfer alignment method based on the observability analysis for the strapdown inertial navigation system, which is able to meet the practical need of maintaining the navigation accuracy of the airborne pod. The observability of each state variable is obtained by observability analysis of system state variables. According to the weight of the observability, a transfer alignment filter algorithm based on adaptive adjustment factor is constructed to reduce the influence of weak observability state variables on the whole filter, which can improve the estimation accuracy of transfer alignment. Simulations and experiment tests of the airborne pod and the master strapdown inertial navigation systems show that the adaptive transfer alignment method based on the observability analysis can overcome the shortage of the weak observability state variables, so as to improve the alignment and the navigation performance in practical applications, thus improving the adaptability of the airborne pod. [ABSTRACT FROM AUTHOR]

Dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) are two typical non-volatile disinfection by-products (DBPs) found in drinking water. Increasing evidence has demonstrated that they show reproductive toxicity. However, whether they might have endocrine disrupting properties remains largely unknown. To discover this, we treated male mice or pregnant mice with 0, 1-, 102-, 103-, 104-, or 5 × 104-fold maximal concentration level (MCL) of DCAA or TCAA in drinking water. In male mice, the levels of testosterone in serum and androgen receptor (AR) in testis were declined with ≥ 103-fold MCL of DCAA (26.4 mg/kg/d) or TCAA (52.7 mg/kg/d). In pregnant mice, miscarriage rates were increased with ≥ 104-fold MCL of DCAA (264 mg/kg/d) or ≥ 103-fold MCL of TCAA. The levels of FSH in serum were increased and those of estradiol and progesterone were reduced with ≥ 103-fold MCL of DCAA or TCAA. The protein levels of estrogen receptors (ERα and ERβ) in ovary were reduced with ≥ 102-fold MCL of DCAA (2.64 mg/kg/d) or TCAA (5.27 mg/kg/d). Exposure to some certain fold MCL of DCAA or TCAA also altered the protein levels of ERα and ERβ in uterus and placenta. Exposure to 5 × 104-fold MCL of both DCAA and TCAA showed the combined effects. Therefore, both DCAA and TCAA could be considered as novel reproductive endocrine disrupting chemicals, which might be helpful for further assessment of the toxicological effects of DCAA and TCAA and the awareness of reproductive endocrine disrupting properties caused by DCAA and TCAA in drinking water. [Display omitted] • DCAA and TCAA function as endocrine-disrupting chemicals. • DCAA and TCAA reduce the levels of testosterone in serum and androgen receptor (AR) in testis of male mice. • DCAA and TCAA induce pregnant mouse miscarriage. • DCAA and TCAA increase follicle stimulating hormone levels and reduce estradiol and progesterone levels in serum of pregnant mice. • DCAA and TCAA reduce the levels of estrogen receptors (ERα and ERβ) in ovaries, uterus, and placenta of pregnant mice. [ABSTRACT FROM AUTHOR]

Genomic imprinting is an epigenetic regulation in mammals in which a small subset of genes is monoallelically expressed dependent on their parental origin. A large imprinted domain, SGCE/PEG10 locus, is located on human chromosome 7q21s and mouse proximal chromosome 6. However, genomic imprinting of bovine SGCE/PEG10 cluster has not been systematically studied. In this study, we investigated allele expression of 14 genes of the SGCE/PEG10 locus in bovine somatic tissues and term placenta using a single nucleotide polymorphism (SNP)‐based sequencing method. In addition to SGCE and PEG10, two conserved paternally expressed genes in human and mice, five other genes (TFPI2, GNG11, ASB4, PON1, and PON3) were paternally expressed. Three genes, BET1, COL1A2, and CASD1, exhibited tissue‐specific monoallelic expression. CALCR showed monoallelic expression in tissues but biallelic expression in the placenta. Three genes, GNGT1, PPP1R9A, and PON2, showed biallelic expression in cattle. Five differentially methylated regions (DMRs) were found to be associated with the allelic expression of TFPI2, COL1A2, SGCE/PEG10, PON3, and ASB4 genes, respectively. The SGCE/PEG10 DMR is a maternally hypermethylated germline DMR, but TFPI2, COL1A2, PON3, and ASB4 DMRs are secondary DMRs. In summary, we identified five novel bovine imprinted genes (GNG11, BET1, COL1A2, CASD1, and PON1) and four secondary DMRs at the SGCE/PEG10 locus. [ABSTRACT FROM AUTHOR]

Food fraud – intentional deception for economic gain using food – is an emerging research field due to increased awareness of the health hazard, increased regulatory scrutiny, increased awareness of the costs, a seemingly endless stream of identified incidents, and new compliance requirements. Beyond the laws and regulations that are being more routinely applied, commercial standards have expanded to address food fraud. Specifically, since January 2018 the Global Food Safety Initiative (GFSI) has required that Food Safety Management Systems include a Food Fraud Vulnerability Assessment (FFVA) and a Food Fraud Prevention Strategy (FFPS). When an entity begins to address the topic, the first consideration is what is food fraud and includes is food fraud really a problem , the focus then shifts to how to detect food fraud including the development of test methods. At that point, there are more fundamental and practical implementation questions such as how to start, what to do, and how much is enough, and how to measure success. The review of these questions has resulted in one unmet need for a method to manage the information and activities in the FFPS. Consideration of these concepts provided the realization that there was a need to connect the steps into an interconnected and dynamic system. The objective was to connect everything to everything. The Food Fraud Prevention Cycle (FFPC) was developed to meet this unmet need. This research paper includes four illustrative examples including a response to: new public policy priorities, a new food fraud incident, and a review of a new countermeasure or control system. The adoption of a holistic and all-encompassing information management cycle will enable a harmonized approach and the sharing of best practices. • The complex food fraud vulnerability requires an interdisciplinary approach. • The new assessments must compare findings to all other enterprise-wide risks. • Current food fraud countermeasures are often tactical testing not strategic management. • A management system should connect all activities with a focus on prevention not detection. • The Food Fraud Prevention Cycle is an efficient method to address these needs. [ABSTRACT FROM AUTHOR]

• We identified genetic heterogeneity, not reported previously, in the origin of double minute chromosomes in tumor cells. • Double minutes in tumor cells indicate amplified genes; previous studies have shown that they are derived from one cellular gene involved in oncogenesis. • Contrary to this, we found concurrent amplification of different oncogenes in different double minutes. • In addition we demonstrated that two different chromosomal mechanisms underlie the genesis of amplification. • These findings necessitate evaluation of the genetic origin of double minutes in tumors because of its implications in the management of disease. Breast cancer patients treated with adjuvant chemotherapy regimens containing alkylating agents and anthracyclines are at an increased risk for secondary myeloid malignancies, either acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Complex genomic changes (karyotypes and/or gene amplification) accompany the development of the secondary neoplasms. Here we present a unique case of a breast cancer patient who developed secondary AML within 18 months of treatment with trastuzumab, pertuzumab, docetaxel, carboplatin (TCHP) and radiation. Leukemia cells had catastrophic alterations in chromosomes 8, 11, and 17. Genetic abnormalities in the leukemia cells included amplification of MYC and KMT2A as double minutes, and deletion and mutational inactivation of TP53 Concurrent amplification of different genes at different levels and on different double minutes, we have named "double minute heterogeneity." Clinically, this case highlights the need to identify genes amplified in secondary myeloid malignancies by cytogenomic microarray (CMA) analysis since these may have therapeutic implications. [ABSTRACT FROM AUTHOR]

Highlights • Cytogenetic and clinical data of our institutional patients diagnosed with plasma cell myeloma was evaluated for recurring cytogenetic abnormalities, types and impact of MYC related abnormalities on clinical outcome. • Using Capri algorithm of TRONCO package we constructed evolutionary pathways for the identified recurring abnormalities to identify abnormalities at the entry and those developed during clonal evolution. • Using Rtreemix library we estimated the genetic progression score for these tumors. Finally we evaluated the clinical impact of the GPS score and MYC related abnormalities on the clinical outcome. • Our results indicate unfavorable outcome for patients with any type of MYC related abnormality, and this appeared to holding true even in tumors with low genetic progression score. Abstract Clinically and genomically, plasma cell myeloma (PCM) is a complex disease affecting the elderly population and has often had a poor prognosis. Karyotypic analysis of tumor cells is somewhat limited due to a low proliferative index coupled with a low frequency of tumor cells in clinical samples. Nevertheless, complex karyotypes with a multitude of numerical, balanced and unbalanced structural aberrations have been reported in these tumors. In this study we evaluated the karyotypes obtained in a single institution to identify recurring cytogenetic abnormalities. We constructed evolutionary pathways to differentiate abnormalities present at the beginning of evolution from those that developed later in evolution. We then estimated genetic progression scores and the clinical impact of the cytogenetic abnormalities on survival. In addition, we also evaluated the clinical significance of MYC related abnormalities (translocations and numerical changes) in disease evolution and on survival. Our results indicate that PCM with MYC related abnormalities in general have advanced tumors and adverse outcomes even with low proliferation. Trisomy 8 also contributes to unfavorable outcomes in PCM, this has not been reported previously. [ABSTRACT FROM AUTHOR]

BACKGROUND: Classification of fresh and processing strawberry cultivars is important to make the best utilization of different cultivars in processing. The aim of the study was to investigate whether support vector machine (SVM) and extreme learning machine (ELM) could assist the classification of 15 strawberry cultivars. Twenty-two characteristic indexes were analyzed, including not only appearance indexes but also nutritional indexes. RESULTS: The results showed that classification accuracies of 100% and 88.52% were obtained by using SVM and ELM with 3-fold cross validation, respectively. Moreover, seven characteristic variables extracted from 22 quality indexes by SVM could make it possible to determine the adaptability of a particular cultivar by measuring relatively small number of indexes. CONCLUSION: Both ELM and SVM models are feasible to identify fresh and processing cultivars. However, SVM showed better performance for its accuracy and simplicity, indicating that SVM would be a good choice for classification of strawberry cultivars. [ABSTRACT FROM AUTHOR]

Mixed phenotype acute leukemia (MPAL) is a heterogenous group of acute leukemias characterized by leukemic blasts that express markers of multiple lineages. The revised 4th edition WHO classification of MPAL excludes AML with myelodysplasia related changes (AML-MRC), including those with complex karyotype (CK), from a diagnosis of MPAL. Abnormal karyotype is frequent in MPAL with the reported rate of CK in MPAL ranging from 19% to 32%. Due its rarity, the clinical and genetic features of MPAL with CK remain poorly characterized. This study aims to further characterize the genetic features of MPAL with CK in comparison to cases of AML and ALL with CK. Cases of de novo MPAL, AML, and B- and T-ALL patients with CK were collected from 8 member institutions of the Bone Marrow Pathology Group. We found no significant difference in overall survival between MPAL with CK compared to AML and ALL with CK. AML with CK was more strongly associated with TP53 mutations, however the presence of TP53 mutations conferred a worse prognosis regardless of lineage. ALL with CK seems to show increased IKZF1 mutation rates which is known to confer a worse prognosis in ALL. Additionally, MPAL with CK showed similarly poor outcomes regardless of whether a lymphoid or myeloid chemotherapy regimen is chosen. Our results suggest that acute leukemias with complex karyotype show a similarly poor outcome regardless of lineage differentiation and that mutation in TP53 confers a poor prognosis in all lineages. Our results support the exclusion of immunophenotypic MPAL with CK from MPAL and appear to confirm the approach proposed in the revised 4th edition WHO to include them as AML with myelodysplasia-related changes and similar myelodysplasia-related AML categories of newer classifications. • Acute leukemias with CK show poor outcome regardless of lineage differentiation. • TP53 mutation confers poor prognosis in acute leukemias with CK regardless of lineage. • Lymphoid and myeloid-directed chemotherapy regimens show poor outcome in MPAL with CK. • Results support including MPAL with CK within myelodysplasia-related AML categories. [ABSTRACT FROM AUTHOR]

The NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of the 15(S)-hydroxyl group of prostaglandin E2 (PGE2), converting the pro-inflammatory PGE2 to the anti-inflammatory 15-keto-PGE2 (an endogenous ligand for peroxisome proliferator-activated receptor-gamma [PPAR-γ]). To evaluate the significance of 15-PGDH/15-keto-PGE2 cascade in liver inflammation and tissue injury, we generated transgenic mice with targeted expression of 15-PGDH in the liver (15-PGDH Tg) and the animals were subjected to lipopolysaccharide (LPS)/Galactosamine (GalN)-induced acute liver inflammation and injury. Compared to the wild type mice, the 15-PGDH Tg mice showed lower levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), less liver tissue damage, less hepatic apoptosis/necrosis, less macrophage activation, and lower inflammatory cytokine production. In cultured Kupffer cells, treatment with 15-keto-PGE2 or the conditioned medium (CM) from 15-PGDH Tg hepatocyes inhibited LPS-induced cytokine production, in vitro. Both 15-keto-PGE2 and the CM from15-PGDH Tg hepatocyes also up-regulated the expression of PPAR-γ downstream genes in Kupffer cells. In cultured hepatocytes, 15-keto-PGE2 treatment or 15-PGDH overexpression did not influence TNF-α-induced hepatocyte apoptosis. These findings suggest that 15-PGDH protects against LPS/GalN-induced liver injury and the effect is mediated via 15-keto-PGE2, which activates PPAR-γ in Kupffer cells and thus inhibits their ability to produce inflammatory cytokines. Accordingly, we observed that the PPAR-γ antagonist, GW9662, reversed the effect of 15-keto-PGE2 in Kupffer cell in vitro and restored the susceptibility of 15-PGDH Tg mice to LPS/GalN-induced acute liver injury in vivo. Collectively, our findings suggest that 15-PGDH-derived 15-keto-PGE2 from hepatocytes is able to activate PPAR-γ and inhibit inflammatory cytokine production in Kupffer cells and that this paracrine mechanism negatively regulates LPS-induced necro-inflammatory response in the liver. Therefore, induction of 15-PGDH expression or utilization of 15-keto-PGE2 analogue may have therapeutic benefits for the treatment of endotoxin-associated liver inflammation/injury. [ABSTRACT FROM AUTHOR]

The process of the transfer alignment for the shipborne inertial navigation system is greatly affected by its external environment. Under the entire influence of its external environment, the structure of the ship will be deformated. First of all, the flexural deformation is analyzed in the environment of the engine vibration and the impact of waves, taking the lever arm effect into consideration. Secondly, the specific force integration matching scheme which is suitable to the moving of carriers in the environment of the low speed is adopted in order to accomplish transfer alignment between master and slave inertial navigation system. Thirdly, a method has been well designed to improve the Kalman filter techniques based on the extended state observer. The usage of the method makes it possible to estimate the disturbance of the uncertain model and realizes dynamic feedback linearization in the inertial navigation system for ship during the process of transfer alignment. Finally, the above theoretical analyses are verified through simulation. [ABSTRACT FROM AUTHOR]

The article explores A 40-year-old man presented with a newly diagnosed diffuse large Bcell lymphoma with involvement of the cervical lymph nodes. Serum chemistry analysis showed an elevated uric acid level (100 mg/L), and the patient was started on rasburicase for treatment of presumptive tumor lysis syndrome (TLS). One day after initiation of rasburicase.

Background: RNA N6-Methyladenosine (m6A) modification is implicated in the progression of human cancers including cholangiocarcinoma (CCA). METTL16 is recently identified as a new RNA methyltransferase responsible for m6A modification, although the role of METTL16 in CCA has not yet been examined. The current study aims to investigate the effect and mechanism of the RNA methyltransferase METTL16 in CCA. Methods: The expression of METTL16 in CCA was examined by analyzing publicly available datasets or by IHC staining on tumor samples. siRNA or CRISPR/Cas9-mediated loss of function studies were performed in vitro and in vivo to investigate the oncogenic role of METTL16 in CCA. MeRIP-Seq was carried out to identify the downstream target of METTL16. ChIP-qPCR, immunoprecipitation, and immunoblots were used to explore the regulation mechanisms for METTL16 expression in CCA. Results: We observed that the expression of METTL16 was noticeably increased in human CCA tissues. Depletion of METTL16 significantly inhibited CCA cell proliferation and decreased tumor progression. PRDM15 was identified as a key target of METTL16 in CCA cells. Mechanistically, our data showed that METTL16 regulated PRDM15 protein expression via YTHDF1-dependent translation. Accordingly, we observed that restoration of PRDM15 expression could rescue the deficiency of CCA cell proliferation/colony formation induced by METTL16 depletion. Our subsequent analyses revealed that METTL16-PRDM15 signaling regulated the expression of FGFR4 in CCA cells. Specifically, we observed that PRDM15 protein was associated with the FGFR4 promoter to regulate its expression. Furthermore, we showed that the histone acetyltransferase p300 cooperated with the transcription factor YY1 to regulate METTL16 gene expression via histone H3 lysine 27 (H3K27) acetylation in CCA cells. Conclusions: This study describes a novel METTL16-PRDM15-FGFR4 signaling axis which is crucial for CCA growth and may have important therapeutic implications. We showed that depletion of METTL16 significantly inhibited CCA cell proliferation and decreased tumor progression. [ABSTRACT FROM AUTHOR]

Although miR-150 is implicated in the regulation of immune cell differentiation and activation, it remains unknown whether miR-150 is involved in liver biology and disease. This study was performed to explore the potential role of miR-150 in LPS/D-GalN and Fas-induced liver injuries by using wild type and miR-150 knockout (KO) mice. Whereas knockout of miR-150 did not significantly alter LPS/D-GalN-induced animal death and liver injury, it protected against Fas-induced liver injury and mortality. The Jo2-induced increase in serum transaminases, apoptotic hepatocytes, PARP cleavage, as well as caspase-3/7, caspase-8, and caspase-9 activities were significantly attenuated in miR-150 KO mice. The liver tissues from Jo2-treated miR-150 KO mice expressed higher levels of Akt1, Akt2, total Akt, as well as p-Akt(Ser473) compared to the wild type livers. Pretreatment with the Akt inhibitor V reversed Jo2-induced liver injury in miR-150 KO mice. The primary hepatocytes isolated from miR-150 KO mice also showed protection against Fas-induced apoptosis in vitro (characterized by less prominent PARP cleavage, less nuclear fragmentation and less caspase activation) in comparison to hepatocytes from wild type mice. Luciferase reporter assays in hepatocytes transfected with the Akt1 or Akt2 3’-UTR reporter constructs (with or without mutation of miR-150 binding site) established Akt1 and Akt2 as direct targets of miR-150. Tail vein injection of lentiviral particles containing pre-miR-150 enhanced Jo2-induced liver injury in miR-150 KO mice. These findings demonstrate that miR-150 deficiency prevents Fas-induced hepatocyte apoptosis and liver injury through regulation of the Akt pathway. [ABSTRACT FROM AUTHOR]

Chromosome translocations involving an immunoglobulin ( IG ) locus and another gene, either BCL or MYC , are common events in B-cell lymphoma. Occasionally, two IG loci, one with BCL and the other with MYC , are simultaneously involved; such cases are classified as double-hit (DH) lymphomas. These tumors often show intermediate histologic features between those of diffuse large B-cell lymphoma and those of Burkitt lymphoma. Patients with DH lymphoma have a poor prognosis. Rarely, lymphomas in which three IG loci are simultaneously involved with two different BCL genes and MYC have been reported. These cases are classified as triple-hit lymphomas; virtually all these are aggressive tumors with an even worse prognosis. We present here a unique case of follicular lymphoma (FL) with rearranged BCL2 , BCL6 , and BCL1 (also known as CCND1 ) genes. Lymphoma cells at first clinical relapse had a complex karyotype that included a t(3;22)(q27;q11) and t(14;18)(q32;q21). About 15 years after initial diagnosis, the lymphoma cells showed clonal cytogenetic evolution and acquired a t(11;14)(q13;q32). This article is the first case report of a low grade B-cell lymphoma that had three lymphoma-associated reciprocal translocations not involving MYC and that had a long indolent clinical course. [ABSTRACT FROM AUTHOR]

Advances in genome-wide molecular cytogenetics allow identification of novel submicroscopic DNA copy number alterations (aCNAs) and copy-neutral loss of heterozygosity (cnLOH) resulting in homozygosity for known gene mutations in myeloid neoplasms. We describe the use of an oligo-SNP array for genomic profiling of aCNA and cnLOH, together with sequence analysis of recurrently mutated genes, in a patient with myelodysplastic syndrome (MDS) presenting with normal karyotype and FISH results. Oligo-SNP array analysis revealed a hemizygous deletion of 896 kb at chromosome 5q31.2, representing the smallest 5q deletion reported to date. The deletion involved multiple genes, including two tumor suppressor candidate genes (CTNNA1 and HSPA9) that are associated with MDS/AML. The SNP-array study also detected 3 segments of somatic cnLOH: one involved the entire long arm of chromosome 4; the second involved the distal half of the long arm of chromosome 7, and the third encompassed the entire chromosome 22 (UPD 22). Sequence analysis revealed mutations in TET2 (4q), EZH2 (7q), ASXL1 (20q11.21), and RUNX1 (21q22.3). Coincidently, TET2 and EZH2 were located at segments of cnLOH resulting in their homozygosity. Loss of heterozygosity affecting these two chromosomes and mutations in TET2 and EZH2 are indicative of a myelodysplastic syndrome with a poor prognosis. Deletion of the tumor suppressor genes CTNNA1 and HSPA9 is also likely to contribute to a poor prognosis. Furthermore, the original cnLOHs in multiple chromosomes and additional cnLOH 14q in the follow-up study suggest genetic evolution of the disease and poor prognosis. This study attests to the fact that some patients with a myelodysplastic syndrome who exhibit a normal karyotype may have underlying genetic abnormalities detectable by chromosomal microarray and/or targeted mutation analyses. [ABSTRACT FROM AUTHOR]

R3452 --> 376.6 --> N6‐methyladenosine (m6A) modification is the most abundant mRNA modification which plays important roles in the regulation of mRNA stability, splicing, translocation, and translation. Methyltransferase‐like 3 (METTL3), a primary RNA methyltransferase that catalyzes RNA m6A modification, is implicated in several human cancers including hepatocellular carcinoma (HCC), although its mechanisms of actions remain to be further defined. In the current study, we aimed to further determine the effect and mechanism of METTL3‐derived m6A in HCC. We have analyzed the TCGA database and observed that METTL3 expression is significantly upregulated in HCC patients which is associated with lower survival rate (P < 0.001). In a mouse model of HCC induced by hydrodynamic tail vein injection of hyperactive form of YAP and β‐catenin in conjunction with the sleeping beauty (SB) transposon system, we observed that the expression of METTL3 was notably high in YAP/β‐catenin‐induced HCC. In cultured human HCC cell lines (Huh7 and PLC/PRF/5), we observed that stable knockdown of METTL3 by shRNA significantly decreased tumor cell proliferation, colony formation and migration, in vitro. When Huh and PLC/PRF/5 cells with shRNA knockdown of METTL3 were inoculated into the livers of SCID mice, we found that METTL3 knockdown significantly inhibited xenograft tumor growth, in vivo. We next delivered METTL3 and YAP expression plasmids to the livers of wild type mice via hydrodynamic tail vein injection and observed that co‐expression of METTL3 plus YAP induced the development of HCC which involves almost the entire livers (20 weeks after tail vein injection). These findings provide important evidence for a tumor‐promoting role of METTL3 in HCC development. Through N6‐methyladenosine‐sequencing (m6A‐Seq) and RNA sequencing (RNA‐Seq), we identified BMI1 and RNF2, two key components of the polycomb repressive complex 1 (PRC1), as direct downstream targets of METTL3 in HCC. Our further analyses revealed that both BMI1 and RNF2 were significantly elevated in HCC patients and were associated with lower survival rate and that the expression of BMI1 and RNF2 were positively correlated with METTL3 in human HCC tissues. Consistent with the above results, our further data showed that knockdown of METTL3 in Huh7 and PLC/PRF/5 significantly decreased the expression of BMI1 and RNF2. Accordingly, treatment of Huh7 and PLC/PRF/5 cells with the METTL3 inhibitor, STM2457, significantly reduced the expression of BMI1 and RNF2 and decreased tumor cell proliferation and colony formation. Moreover, our data showed that inhibition of the m6A reader YTHDF1 by siRNA significantly decreased the expression of BMI1 and RNF2 in human HCC cells. Collectively, our study provides important evidence that METTL3 promotes HCC development and progression through m6A modification of BMI1 and RNF2 mRNAs which involve a YTHDF1 dependent mechanism. It is conceivable that the METTL3‐m6A‐BMI1/RNF2 axis may represent a promising target for HCC treatment. [ABSTRACT FROM AUTHOR]

The original article can be found online at https://doi.org/10.1038/s41598-021-04732-4. Correction to: I Scientific Reports i https://doi.org/10.1038/s41598-021-04732-4, published online 18 January 2022 In the original version of this Article, Zhong Yang was omitted as a corresponding author. [Extracted from the article]

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin Lymphoma comprising of greater than 30% of adult non-Hodgkin Lymphomas. DLBCL represents a diverse set of lymphomas, defined as diffuse proliferation of large B lymphoid cells. Numerous cytogenetic studies including karyotypes and fluorescent in situ hybridization (FISH), as well as morphological, biological, clinical, microarray and sequencing technologies have attempted to categorize DLBCL into morphological variants, molecular and immunophenotypic subgroups, as well as distinct disease entities. Despite such efforts, most lymphoma remains undistinguishable and falls into DLBCL, not otherwise specified (DLBCL-NOS). The advent of microarray-based studies (chromosome, RNA, gene expression, etc) has provided a plethora of high-resolution data that could potentially facilitate the finer classification of DLBCL. This review covers the microarray data currently published for DLBCL. We will focus on these types of data; 1) array based CGH; 2) classical CGH; and 3) gene expression profiling studies. The aims of this review were three-fold: (1) to catalog chromosome loci that are present in at least 20% or more of distinct DLBCL subtypes; a detailed list of gains and losses for different subtypes was generated in a table form to illustrate specific chromosome loci affected in selected subtypes; (2) to determine common and distinct copy number alterations among the different subtypes and based on this information, characteristic and similar chromosome loci for the different subtypes were depicted in two separate chromosome ideograms; and, (3) to list re-classified subtypes and those that remained indistinguishable after review of the microarray data. To the best of our knowledge, this is the first effort to compile and review available literatures on microarray analysis data and their practical utility in classifying DLBCL subtypes. Although conventional cytogenetic methods such as Karyotypes and FISH have played a major role in classification schemes of lymphomas, better classification models are clearly needed to further understanding the biology, disease outcome and therapeutic management of DLBCL. In summary, microarray data reviewed here can provide better subtype specific classifications models for DLBCL. [ABSTRACT FROM AUTHOR]

Background & Aims: Cytosolic phospholipase A2α (cPLA2α) is a rate-limiting key enzyme controlling the release of arachidonic acid (AA) substrate for the synthesis of prostaglandins and leukotrienes. This study was designed to explore the role of hepatocyte cPLA2α in Fas-mediated liver injury, in vivo. Methods: Transgenic mice with targeted expression of cPLA2α under control of the albumin-promoter enhancer and wild-type mice were injected intraperitoneally with anti-Fas antibody Jo2 or lipopolysaccharide plus d-galactosamine and monitored for liver injury and survival at various time points. Results: The cPLA2α Tg mice resist Fas-induced liver failure, as reflected by the lower serum transaminase levels, fewer apoptotic hepatocytes, reduced caspase activation, and reduced PARP cleavage when compared to the matched wild type mice. Inhibition of cPLA2α by its pharmacological inhibitor, pyrrolidine, enhanced Jo2-induced liver injury in both cPLA2α Tg and wild type mice. Hepatic overexpression of cPLA2α increases the expression of EGFR in the liver and the EGFR inhibitor, AG1478, exacerbated Jo2-mediated liver injury. The cPLA2α transgenic mice develop more prominent liver tissue damage than wild-type mice after LPS/d-galactosamine injection. Conclusions: Hepatocyte cPLA2α protects against Fas-induced liver injury and this effect is mediated at least in part through the upregulation of EGFR. [ABSTRACT FROM AUTHOR]

Abstract: Myeloid sarcoma is an extramedullary tumor mass composed of immature myeloid cells. Myeloid sarcoma may develop de novo, concurrently with acute myeloid leukemia (AML), or at relapse. Although myeloid sarcoma can occur at any site, myeloid sarcoma involving the heart is extremely rare. Reported here is the case of a 30-year-old man, initially diagnosed with acute promyelocytic leukemia (APL) in bone marrow, who presented later with myeloid sarcoma at multiple anatomical sites (left scapula, thoracic vertebra, right atrium, and supraclavicular mass) in multiple relapses. Conventional cytogenetic studies performed on the atrial sample revealed a karyotype with additional material on the short arm of chromosome 7, at 7p22. Fluorescence in situ hybridization studies confirmed a cryptic PML–RARA fusion on the short arm of chromosome 7, as well as a second fusion on one copy of chromosome 15. With the fourth and latest relapse, molecular cytogenetic studies performed on interphase nuclei of the myeloid sarcoma specimen (a supraclavicular mass) showed evidence of six related abnormal clones with a PML–RARA fusion, suggesting clonal evolution. This represents a rare case of APL with a cryptic PML–RARA rearrangement presenting as myeloid sarcoma at multiple relapses and involving multiple anatomical sites, including cardiac atrium. [Copyright &y& Elsevier]

Context.—Heterozygous mutation of the nucleophosmin gene (NPM1) has recently been described as one of the most frequent genetic lesions in acute myeloid leukemia (AML). Objective.—(1) To discuss the clinical, morphologic, immunophenotypic, and genetic features of AML with NPM1 gene mutations, along with various detection methods, (2) To explore the mechanisms by which NPM1 gene mutations contribute to leukemogenesis. Data sources/extraction.-Data were analyzed from 7 recently published papers. Results.—NPM1 gene mutations tend to occur more frequently in women, and also tend to be associated with a higher white blood cell count. There is no significant age difference. NPM1-mutated AML is preferentially associated with AML with monocytic differentiation (in particular FAB M5b), lack of CD34, normal cytogenetics, FLT3 gene mutations, and a trend toward favorable clinical outcome, especially in patients without FLT3 gene mutation. NPM1 gene mutations cause a frame shift in the C-terminus of exon 12, disrupting the NPM nucleolar-localization signal or generating a leucine-rich nuclear export motif, resulting in abnormal cytoplasmic accumulation of NPM. Several methods are suitable for detecting NPM1 gene mutation, including molecular and immunohistochemical studies. These mutations may contribute to leukemogenesis, at least in part, through disruption of the p14ARF (alternative reading frame) MDM2-p53 pathway and centrosomal duplication. Conclusions.—Detection of NPM1 gene mutations may allow dissection of the heterogeneous group of AML with normal karyotype into prognostically different subgroups. Exploring the mechanisms may lead to a better understanding of how mutant NPM protein becomes leukemogenic, thereby providing insights for the development of new chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Deals with a study which examined the effect of inhibition of p38 mitogen-activated protein kinase alpha/beta during ischemia and preconditioning by using the inhibitor SB-202190. Methods; Results; Discussion.

Discusses that the inhibition of p38 mitogen-activated protein kinase alpha/beta reduces ischemic injury and does not block protective effects of preconditioning. Absence of significant differences in heart rate or left ventricular developed pressure; Intracellular pH during ischemia and reperfusion; Energetic effects of inhibitor SB-202190.

Simple Summary: In mammals, imprinted genes play key roles in embryonic growth and postnatal behavior and their misregulation has been associated with several developmental syndrome and cancers. At present, more than 150 imprinted genes have been identified in humans and mice. Cattle is an economically important farm animal, but compared to humans and mice, few genes have been reported as imprinted in this species. MKRN3, MAGEL2 and NDN are three maternally imprinted genes in the human Prader-Willi and Angelman syndromes imprinted locus at 15q11-q13. In this study, we determined that the bovine MKRN3, MAGEL2 and NDN genes are three paternally expressed gene, and their expression is regulated by the DNA methylation. This work could advance the genomic imprinting by increasing the knowledge of imprinted genes in bovine and also facilitate future studies to detect the physiological roles of MKRN3, MAGEL2 and NDN genes. Genomic imprinting is the epigenetic mechanism of transcriptional regulation that involves differential DNA methylation modification. Comparative analysis of imprinted genes between species can help us to investigate the biological significance and regulatory mechanisms of genomic imprinting. MKRN3, MAGEL2 and NDN are three maternally imprinted genes identified in the human PWS/AS imprinted locus. This study aimed to assess the allelic expression of MKRN3, MAGEL2 and NDN and to examine the differentially methylated regions (DMRs) of bovine PWS/AS imprinted domains. An expressed single-nucleotide polymorphism (SNP)-based approach was used to investigate the allelic expression of MKRN3, MAGEL2 and NDN genes in bovine adult tissues and placenta. Consistent with the expression in humans and mice, we found that the MKRN3, MAGEL2 and NDN genes exhibit monoallelic expression in bovine somatic tissues and the paternal allele expressed in the bovine placenta. Three DMRs, PWS-IC, MKRN3 and NDN DMR, were identified in the bovine PWS/AS imprinted region by analysis of the DNA methylation status in bovine tissues using the bisulfite sequencing method and were located in the promoter and exon 1 of the SNRPN gene, NDN promoter and 5' untranslated region (5'UTR) of MKRN3 gene, respectively. The PWS-IC DMR is a primary DMR inherited from the male or female gamete, but NDN and MKRN3 DMR are secondary DMRs that occurred after fertilization by examining the methylation status in gametes. [ABSTRACT FROM AUTHOR]

Provides information on a study which tested the hypothesis that activation of the 12-lipoxygenase pathway of arachidonic acid metabolism contributes to the protective effect of protein kinase (PK) C activation and ischemic preconditioning. Account of related publications; Materials and methods; Results and discussion.

A 27-year-old female with a history of acute myeloid leukaemia (AML) with t(8;21)(q22;q22.1); I RUNX1-RUNX1T1 i , in remission, presented for routine bone marrow (BM) follow-up. Interestingly, some mature dysplastic neutrophils with pseudo-Pelger-Huët nuclei also had multiple large salmon-coloured cytoplasmic granules (right, orange arrow, ×100). The BM aspirate film, however, showed a few scattered myeloblasts (2% of total cells) with either large salmon-coloured granules/pseudo-Chédiak-Higashi granules (top left, orange arrow; Wright-Giemsa stain, ×100 objective) or Auer rods intermingled with salmon-coloured granules (bottom left, green arrow). [Extracted from the article]

R2196 --> EZH2 regulates gene expression through epigenetic machinery. Increased expression of EZH2 is present in cholangiocarcinoma (CCA). Importantly, EZH2 level in CCA is closely correlated with patient prognosis. The objective of this study is to further delineate the effect of EZH2 in CCA. Alb‐CRE/EZH2flox/flox mice were subjected to hydrodynamic tail vein injection of transposase‐based plasmids expressing AKT and Notch intracellular domain (NICD). This model was employed, along with xenograft and CCA cells, to assess the effect and mechanism of EZH2. ChIP‐seq, small RNA‐seq and bioinformatics analyses were performed to identify the targets of EZH2. In CCA induction by HDTV injection of NICD/AKT, we observed that the Alb‐CRE/EZH2flox/flox mice exhibited significantly decreased tumor burden and prolonged overall survival. These findings reveal an important role of EZH2 in CCA development. In a CCA xenograft model with intrahepatic inoculation of human CCA cell line (CCLP1), we observed that EZH2 knockdown by shRNA significantly decreased CCA progression. Further in vitro studies showed that EZH2 depletion by shRNA significantly reduced the growth and colony formation capability of human CCA cells (CCLP1) and mouse CCA cells. RNA‐seq and RT‐PCR analysis revealed that depletion of EZH2 by shRNA in CCA cells restored the expression of 12 putative tumor suppressor genes (including Osgin1, Pax3, Itga7, Il1rn, Gas1, Cdkn1a, Bbc3, Wnt11, Wt1, Sulf, Sfrp1, and Ptprv). By analyzing the human CCA database GSE76297 (containing 91 CCA and 92 paired non‐tumor tissues), we found that the expression levels of 12 tumor suppressor genes in CCA tissues were decreased by an average of 1.7 ‐folds in comparison to paired non‐tumorous liver tissues. The tumor inhibitory effects of the identified genes were verified in CCA cells with altered EZH2 expression. Furthermore, we observed that intraperitoneal injection of the EZH2 inhibitor, GSK126, decreased CCA tumor burden in mice receiving HDTV injection of NICD/AKT. Treatment of human and mouse CCA cells with GSK126 restored the expression of the 12 tumor suppressor genes. These results indicate that EZH2 downregulates multiple tumor suppressor genes in CCA cells. We next carried out ChIP‐seq (using anti‐H3K9me2 or anit‐EZH2) and small RNA‐seq to determine the mechanisms underlying EZH2‐mediated downregulation of tumor suppressor genes. The ChIP‐seq results showed that both anti‐H3K9me2 and anti‐EZH2 IP led to significant enrichments of the DNA fragments of 5 out of 12 genes. The small RNA‐seq analyses identified a group of EZH2‐regulated microRNAs which target the 12 tumor suppressor genes. Our findings suggest that EZH2 downregulates the expression of tumor suppressor genes either directly through histone methylation or indirectly through specific microRNAs. Taken together, our findings disclose a novel mechanism by which EZH2 drives cholangiocarcinogenesis through downregulation of tumor suppressors genes via histone methylation and microRNAs. Our results provided further evidence supporting EZH2 inhibition for CCA treatment. [ABSTRACT FROM AUTHOR]

Abstract: Rearrangements of JAK2 are rare and have been described in various hematological neoplasms. We report a novel JAK2 rearrangement resulting from a t(9;22)(p24;q11.2) in a 14-year-old male with a diagnosis of B lymphoblastic leukemia. He was treated with Children''s Oncology Group''s protocol (AALL0232) but failed to achieve remission by day 29. He underwent a second induction and entered remission. His clinical course suggested that this JAK2 rearrangement might portend an unfavorable prognosis. This case brings the total number of JAK2 rearranged lymphoblastic leukemia cases in the literature to seven. The molecular genetic and clinicopathologic features of these cases were reviewed. [Copyright &y& Elsevier]

The purpose of this paper is to propose a new transfer alignment approach based on the inertial network. The inertial network is described, and the measurement models are built firstly. The inertial device fusion and fault detection algorithm are analyzed with the redundancy technology of devices in the inertial network to enhance the reliability and security of the system. Then the improved model of the system is built and the transfer alignment algorithm method for the inertial network is proposed. Several experiments have been performed to validate the performance of the proposed transfer alignment scheme. Different simulation experiments and real ground vehicle test results showed that the transfer alignment with the inertial network can obtain the better precision result and shorter convergence time, which can also improve the fault detection and recognition ability of the system. A transfer alignment method based on the inertial network is proposed to improve the fault tolerance ability and enhance the accuracy of the system. The primary advantage is that each node is able to communicate with other nodes, which allows for sharing information in the inertial network. [ABSTRACT FROM AUTHOR]

The prevalence of central nervous system (CNS) involvement in patients with acute myeloid leukemia (AML) is variable with a reported range of 0.6% to 46%. Unfortunately, the clinical consequences of untreated CNS involvement in AML which include complete paraplegia and bilateral total blindness, can be devastating. In addition, both the diagnostic evaluation and treatment of CNS involvement are associated with potential significant morbidity. Thus, there is a need to predict CNS involvement in a noninvasive manner in patients with AML. The leukocyte immunoglobulin-like receptors are a family of receptors that regulate the activity of cancer stem cells, cancer development and relapse. These receptors are expressed on many cell types and the leukocyte immunoglobulin-like receptor B4 (LILRB-4) is expressed on monocytic myeloid cells. To investigate whether measurement of LILRB-4 is predictive of CNS involvement in patients with AML. Fifty-six patients with AML and followed at the University of Texas Southwestern medical system had measurement of the LILRB-4 by flow cytometry. Demographic, laboratory, risk stratification, cytogenetics and clinical variables were acquired from electronic medical chart review. The study cohort of 56 patients with AML had a median age of 60 years (range: 0.83 - 92); 52% male; and racial/ethnic composition of African American 20%, Asians 4%, White Hispanic 13% and White Non-Hispanic 64%. Eleven (20%) patients were diagnosed with CNS involvement (CNS+). LILRB-4 was positive in 91% of patients with CNS+ compared to 38% without CNS (CNS-) (p<0.002). In univariate logistic analysis: age, White Non-Hispanic and positive LILRB-4 (LILRB-4+) were statistically predictive for CNS+ [OR, 95% CI, p value]: 0.95, 0.92-0.99, p<0.01; 4.31, 1.08-17.25, p<0.04; 16.46, 1.93-140.2, p<0.02, respectively. Traditional risk factors such as white blood cell count, FLT-internal tandem duplication mutation, National Comprehensive Cancer Network (NCCN) risk stratification scheme and serum lactate dehydrogenase levels were not predictive for CNS+. A positive LILRB-4 has a sensitivity of 91% and specificity of 62% for CNS+. A positive LILRB-4 by flow cytometry on leukemia cells is strongly associated with CNS involvement in patients with AML. These novel findings suggest that LILRB-4+ may be useful in risk stratification for CNS+. Moreover, combined with preclinical studies, LILRB-4 may provide insight into the pathogenesis of AML seeding the CNS. Further prospective studies are needed to confirm these intriguing results. [ABSTRACT FROM AUTHOR]

FLT3 gene mutations, either internal tandem duplication or point mutation type, are common in acute myeloid leukaemia (AML). We describe 21 AML cases with both types of gene mutations, so-called dual mutations, representing approximately 1% of all cases. Most newly diagnosed AML with FLT3 dual mutations had monocytic differentiation and a normal karyotype. Over the disease course, changes in FLT3 mutation status were seen in 89% of cases, and were associated with cytogenetic changes. We conclude that FLT3 dual mutations occur rarely in AML, and appear to be related to clonal evolution. [ABSTRACT FROM AUTHOR]

Summary: T/myeloid mixed phenotype acute leukaemia (MPAL) is a rare aggressive acute leukaemia with poorly understood pathogenesis. Herein, we report two cases of T/myeloid MPAL harbouring BCL11B‐associated structural variants that activate TLX3 (TLX3::BCL11B‐TLX3‐activation) by genome sequencing and transcriptomic analyses. Both patients were young males with extramedullary involvement. Cooperative gene alterations characteristic of T/myeloid MPAL and T‐lymphoblastic leukaemia (T‐ALL) were detected. Both patients achieved initial remission following lineage‐matched ALL‐based therapy with one patient requiring a lineage‐switched myeloid‐based therapy. Our study is the first to demonstrate the clinicopathological and genomic features of TLX3::BCL11B‐TLX3‐activated T/myeloid MPAL and provide insights into leukaemogenesis. [ABSTRACT FROM AUTHOR]

Introduction: The mechanism of relapsed CD19(−) B‐ALL after anti‐CD19 immunotherapy (Kymriah [CART‐19] and blinatumomab) is under active investigation. Our study aims to assess LILRB1 as a novel B‐cell marker for detecting CD19(−) B‐lymphoblasts and to analyze the clinicopathologic/genetic features of such disease to provide biological insight into relapse. Methods: Six patients (3 males/3 females, median age of 14 years) with relapsed CD19(−) B‐ALL were analyzed for cytogenetic/genetic profile and immunophenotype. Results: CD19(−) B‐ALL emerged after an interval of 5.8 months following anti‐CD19 therapy. Five of six patients had B‐cell aplasia, indicative of a persistent effect of CART or blinatumomab at relapse. Importantly, LILRB1 was variably expressed on CD19(−) and CD19(+) B lymphoblasts, strong on CD34(+) lymphoblasts and dim/partial on CD34(−) lymphoblasts. Three of six patients with paired B‐ALL samples (pre‐ and post‐anti‐CD19 therapy) carried complex and different cytogenetic abnormalities, either as completely different or sharing a subset of cytogenetic abnormalities. Conclusion: LILRB1 can be used as a novel B‐cell marker to identify CD19(−) B lymphoblasts. The emergence of CD19(−) B‐ALL appears to be associated with complex cytogenetic evolutions. The mechanism of CD19(−) B‐ALL relapse under anti‐CD19 immune pressure remains to be explored by comprehensive molecular studies. [ABSTRACT FROM AUTHOR]

Isolated central nervous system lymphomatoid granulomatosis (CNS‐LYG) can mimic aggressive glioblastomas. We describe a complex presentation of CNS‐LYG coexisting with immune thrombocytopenia successfully managed with rituximab and ultra‐low‐dose radiation therapy. [ABSTRACT FROM AUTHOR]

The article explores a specific type of paroxysmal nocturnal haemoglobinuria (PNH) known as ahemolytic PNH or white cell PNH. Unlike typical PNH, this subtype does not exhibit signs of hemolysis but is characterized by bone marrow failure and thrombophilia. The document suggests that this subtype may be caused by a PIGA mutation in a committed progenitor cell rather than a stem cell. The authors recommend considering screening for ahemolytic PNH in cases of thromboembolic events and bone marrow failure without hemolysis. [Extracted from the article]

Objective: To describe cases of Kaposi's sarcoma‐associated herpesvirus (KSHV)‐associated multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL) in patients with HIV from a large, safety‐net hospital system in Dallas, Texas, USA. Methods: We conducted a retrospective review of patients with HIV‐associated PEL and/or MCD. Results: Twelve patients with PEL and 10 patients with MCD were identified. All patients were male and 17 of 20 were men who have sex with men; 66.7% of PEL patients and 50% of MCD patients had concurrent KS at the time of diagnosis; 42% of patients with PEL and 20% of patients with MCD died during the follow‐up period. We noted improved survival in our cohort compared to previous studies, particularly in our PEL patients with a median survival of 11.4 months compared to 3–6‐month median survival historically. Median follow‐up time for MCD patients was 17.5 months. This improved survival is despite suboptimal antiretroviral therapy (ART) adherence at diagnosis, with only 50% of patients on ART at the time of MCD/PEL diagnosis. Conclusion: These data highlight the importance of early recognition of PEL and MCD, and the larger‐scale efforts needed to better understand the pathogenetic drivers of clinical outcomes in patients affected by KSHV‐related diseases. [ABSTRACT FROM AUTHOR]

Fibrin-associated large B-cell lymphoma (FA-LBCL) is a rare subtype of Epstein-Barr virus (EBV)-associated lymphoma, recognized as an independent entity per the 5th edition of the WHO classification of hematolymphoid neoplasms. It is usually associated with longstanding chronic inflammation and arises within fibrinous material in confined anatomic spaces. We report the clinicopathologic manifestations of two patients of FA-LBCL involving the adrenal gland and kidney. Both tumors were diagnosed after presenting as cystic masses on imaging studies. These lymphomas were non-invasive, with microscopic aggregates of large B-lymphoma cells along/within cystic wall and admixed with fibrinous material and without prominent inflammation. By immunohistochemistry and in-situ hybridization, lymphoma cells were positive for CD45, PAX5, CD79a, MUM1, BCL2, PD-L1, and EBV/EBER (Epstein-Barr virus encoded small RNA) with a high proliferation index. Both patients remain in remission after management with complete surgical resection and additional chemo-immunotherapy in one patient. Considering its rarity, scant tumor cells, and varied clinical presentations, FA-LBCL may pose diagnostic challenges, especially when presenting as extensively necrotic cystic lesions, needing multidisciplinary collaboration in formulating management. [ABSTRACT FROM AUTHOR]

Objectives Our study aimed to develop a machine learning (ML) model to accurately classify acute promyelocytic leukemia (APL) from other types of acute myeloid leukemia (other AML) using multicolor flow cytometry (MFC) data. Multicolor flow cytometry is used to determine immunophenotypes that serve as disease signatures for diagnosis. Methods We used a data set of MFC files from 27 patients with APL and 41 patients with other AML, including those with uncommon immunophenotypes. Our ML pipeline involved training a graph neural network (GNN) to output graph-level labels and identifying the most crucial MFC parameters and cells for predictions using an input perturbation method. Results The top-performing GNN achieved 100% accuracy on the training/validation and test sets on classifying APL from other AML and used MFC parameters similarly to expert pathologists. Pipeline performance is amenable to use in a clinical decision support system, and our deep learning architecture readily enables prediction explanations. Conclusions Our ML pipeline shows robust performance on predicting APL and could be used to screen for APL using MFC data. It also allowed for intuitive interrogation of the model's predictions by clinicians. [ABSTRACT FROM AUTHOR]

The article describes the case of an 88-year-old human immunodeficiency virus-negative man. The patient had a history of chronic obstructive pulmonary disease and pulmonary tuberculosis and he presented with dyspnea. He was diagnosed with primary effusion lymphoma but with an unusual cytokeratin expression, adding to the growing list of lymphomas that can show cytokeratin positivity.