Acquired hemophilia A (AHA) is a rare disease in which an autoantibody causes bleeding by interacting with and inhibiting the coagulation activity of endogenous factor VIII (FVIII). Most cases of AHA ...are idiopathic; known causes include autoimmune diseases, malignant tumors, pregnancy, drugs, and viral infections. An 86-year-old man was diagnosed with AHA based on the following results: an activated partial thromboplastin time (aPTT) extension of 130.7 seconds, presence of an inhibitor pattern in a mixing study, an endogenous factor VIII (FVIII) level of <1%, and an FVIII inhibitor titer of >5.1 Bethesda units (BU). The activity of von Willebrand factor (vWF) was diminished (<10%), which was considered a complication of acquired von Willebrand syndrome (AVWS). The patient was started on prednisolone, and the inhibitor level eventually became negative. vWF values also became normal. However, 1 year later, he was hospitalized for treatment of coronavirus disease 2019 (COVID-19). Blood testing showed an aPTT extension of 110.5 seconds, FVIII level of 4%, and FVIII inhibitor titer of 0.8 BU; thus, a relapse of AHA was diagnosed. After administration of corticosteroid and remdesivir, he recovered from COVID-19 and AHA. The inhibitor level became negative on the 9th day of admission. Several studies have implicated COVID-19 infection and vaccination in AHA. We recommend that aPTT be measured when patients with AHA are infected with SARS-CoV2, to confirm AHA relapse.
Germ layer formation is driven by embryonic cell sorting during the early developmental stages. Starfish (Patiria pectinifera) embryos have a connected endoderm and ectoderm, albeit with few contact ...surfaces between the epithelia. To better understand the association between cell sorting and germ layer formation, we reconstructed P. pectinifera embryos and examined their germ layer formation. Initial observations showed that the presumptive endodermal (pEN) and presumptive ectodermal (pEC) portions of the embryonic body at the late‐blastula stage were preserved throughout development. Based on this, cells that were dissociated from each dermal fragment were mixed in a reconstruction experiment. Our results showed that the pEN and pEC cells were located inside and outside the reaggregates, respectively, to form an embryonic body containing two epithelial layers, separated by a blastocoel. During this process, the pEN cells were motile and shifted from smaller clumps to form a large clump. In contrast, in reaggregates formed in separate cultures, the pEN cells showed strong adhesion abilities, whereas the pEC cells underwent epithelialization. Unlike that in pEN cells, the reaggregation of pEC cells preceded cadherin expression. Filamentous actin was similarly observed in both reaggregates. These results suggest that during the reconstruction of starfish embryos, germ layer formation occurs via the sorting of pEN and pEC cells, depending on their adhesiveness, motility, and epithelialization. In vivo, these properties might embody the physiological significance of cell adhesion in the germ layers constituting the epithelial monolayer.
Our results showed that presumptive endodermal (pEN) and presumptive ectodermal (pEC) portions of the embryonic body at the late‐blastula stage were preserved throughout development. In the main part of this article, we described identifications that the pEN and pEC cells had different adhesion, motility, and epithelialization properties, which enabled them to aggregate to their own kinds. Additionally, the differences in the adhesion, motility and epithelialization characteristics defined the shape and size of the pEN and pEC aggregates.
Anaplastic lymphoma kinase (ALK)
and the related leukocyte tyrosine kinase (LTK)
are recently deorphanized receptor tyrosine kinases
. Together with their activating cytokines, ALKAL1 and ALKAL2
...(also called FAM150A and FAM150B or AUGβ and AUGα, respectively), they are involved in neural development
, cancer
and autoimmune diseases
. Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain
, consistent with a metabolic role for Drosophila ALK
. Despite such functional pleiotropy and growing therapeutic relevance
, structural insights into ALK and LTK and their complexes with cognate cytokines have remained scarce. Here we show that the cytokine-binding segments of human ALK and LTK comprise a novel architectural chimera of a permuted TNF-like module that braces a glycine-rich subdomain featuring a hexagonal lattice of long polyglycine type II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles, yet their binding to ALK and LTK elicits similar dimeric assemblies with two-fold symmetry, that tent a single cytokine molecule proximal to the cell membrane. We show that the membrane-proximal EGF-like domain dictates the apparent cytokine preference of ALK. Assisted by these diverse structure-function findings, we propose a structural and mechanistic blueprint for complexes of ALK family receptors, and thereby extend the repertoire of ligand-mediated dimerization mechanisms adopted by receptor tyrosine kinases.
Acquired hemophilia A (AHA) is a rare disease in which an autoantibody causes bleeding by interacting with and inhibiting the coagulation activity of endogenous factor VIII (FⅧ). Most cases of AHA ...are idiopathic, and other causes include autoimmune diseases, malignant tumors, pregnancy, drugs, and viral infections. An 86-year-old man was diagnosed with AHA based on the following results: activated partial thromboplastin time (aPTT) extension of 130.7 seconds, inhibitor pattern by mixing study, endogenous factor VIII (FⅧ) level at <1%, and FⅧ inhibitor titer at >5.1 Bethesda units (BU). The activity of von Willebrand factor (vWF) decreased (<10%), which was considered to be a complication of acquired von Willebrand syndrome (AVWS). The patient was started on prednisolone, and the inhibitor level eventually became negative. vWF values also became normal. However, 1 year later, he was hospitalized due to Coronavirus disease 2019 (COVID-19). His blood test showed an aPTT extension of 110.5 seconds, FⅧ level at 4%, and FⅧ inhibitor titer at 0.8 BU; thus, he was diagnosed with a relapse of AHA. After the administration of corticosteroid and remdesivir, he recovered from COVID-19 and AHA. The inhibitor level became negative on the 9th day of admission. Several articles have reported that COVID-19 infection and vaccination are implicated with AHA. We suggest that the aPTT should be measured when patients with AHA are infected with SARS-CoV2 to confirm AHA relapse.
Abstract
Many disease-associated genomic variants disrupt gene function through abnormal splicing. With the advancement of genomic medicine, identifying disease-associated splicing associated ...variants has become more important than ever. Most bioinformatics approaches to detect splicing associated variants require both genome and transcriptomic data. However, there are not many datasets where both of them are available. In this study, we develop a methodology to detect genomic variants that cause splicing changes (more specifically, intron retention), using transcriptome sequencing data alone. After evaluating its sensitivity and precision, we apply it to 230,988 transcriptome sequencing data from the publicly available repository and identified 27,049 intron retention associated variants (IRAVs). In addition, by exploring positional relationships with variants registered in existing disease databases, we extract 3,000 putative disease-associated IRAVs, which range from cancer drivers to variants linked with autosomal recessive disorders. The in-silico screening framework demonstrates the possibility of near-automatically acquiring medical knowledge, making the most of massively accumulated publicly available sequencing data. Collections of IRAVs identified in this study are available through IRAVDB (
https://iravdb.io/
).
In core-binding factor acute myeloid leukemia (CBF-AML), there have been conflicting reports regarding the status as an unfavorable prognostic factor of mutation in the KIT gene, the significance of ...which remains unclear. We previously reported that prognoses differ between the KIT D816V and N822K mutations. In the present study, we compared in vitro the cell-proliferative and anti-apoptotic ability of D816V and N822K. We transduced these KIT mutations into the interleukin-3–dependent cell line TF-1 (TF-1 KITD816V , TF-1 KITN822K ). When these KIT mutations were transduced into TF-1 cells, the cells acquired a proliferative ability independent of growth factor, which was significantly higher in TF-1 KITD816V than in TF-1 KITN822K ( p = 0.022). When Ara-C was added in the absence of growth factor, Annexin V assay revealed that TF-1 KITD816V was associated with a significantly lower proportion of apoptotic cells than TF-1 KITN822K ( p < 0.001). Regarding signal transduction pathways, both KIT D816V and KIT N822K underwent autophosphorylation in the absence of growth factor. This was followed in KIT D816V by downstream activation of the SRC family kinase pathway in addition to the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, and in KIT N822K by downstream activation of the mitogen-activated protein kinase (MAPK) pathway in addition to the JAK/STAT pathway. These findings establish that D816V and N822K mutations are situated closely on the KIT receptor activation loop, but D816V has greater cell-proliferative and anti-apoptotic ability than N822K.
Background: Because peripheral blood stem cell (PBSC) collection places a burden on the patient and should ideally be completed in a single procedure, a convenient clinical predictive factor is ...needed. Methods: This retrospective study included 72 patients who underwent autologous PBSC collection. A median volume of 3.9 × 106 CD34-positive cells/kg (range: 0.3-47.4 × 106 cells/kg) was collected on the first day. We defined failure as inability to collect 2.0 × 106 cells/kg on the first day. PBSC collection was classified as failed (n = 25, 34.7%) and successful (n = 47, 65.3%), and patient clinical characteristics were analyzed. Results: The success group had significantly more cases in which a differential white blood cell count in peripheral blood on the day of PBSC collection detected promyelocytes (n = 34 72.3% vs. n = 11 44.0% in the failure group; P = 0.008). Sixty-two patients underwent autologous PBSC transplantation (median number of transplanted cells, 5.6 × 106/μL; range: 1.60-47.4 × 106 cells/μL). Among transplanted patients, the success and failure groups did not significantly differ in relation to the interval until neutrophil, platelet, or red blood cell engraftment. Conclusion: The presence of promyelocytes in peripheral blood may be a useful indicator of the optimal timing for single-step PBSC collection.
In the opinion of the European LeukemiaNet (ELN), nucleophosmin member 1 gene mutation (NPM1 mut)–positive acute myeloid leukemia (AML) with an fms-like kinase 3-internal tandem duplication ...(FLT3-ITD) allele ratio (AR) <0.5 (low AR) has a favorable prognosis, and allogeneic hematopoietic stem cell transplant (allo-HSCT) in the first complete remission (CR1) period is not actively recommended. We studied 147 patients with FLT3-ITD gene mutation–positive AML, dividing them into those with low AR and those with AR of ≥0.5 (high AR), and examined the prognostic impact according to allo-HSCT in CR1. Although FLT3-ITD AR and NPM1 mut are used in the prognostic stratification, we found that NPM1 mut–positive AML with FLT3-ITD low AR was not associated with favorable outcome (overall survival OS, 41.3%). Moreover, patients in this group who underwent allo-HSCT in CR1 had a significantly more favorable outcome than those who did not (relapse-free survival RFS P = .013; OS P = .003). Multivariate analysis identified allo-HSCT in CR1 as the sole favorable prognostic factor (RFS P < .001; OS P < .001). The present study found that prognosis was unfavorable in NPM1 mut–positive AML with FLT3-ITD low AR when allo-HSCT was not carried out in CR1.
•The ELN guideline classifying FLT3-ITD low allele ratio with NPM1 mutation as having a favorable prognosis is questionable.•Performing allo-HSCT during CR1 irrespective of the FLT3-ITD allele ratio and NPM1 mut status significantly improves outcome.
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Background: Because the cause of liver dysfunction after allogeneic hematopoietic stem cell transplantation (HSCT) is difficult to identify in the early stages, treatment may be delayed. Therefore, ...early factors associated with unfavorable outcomes of liver dysfunction must be identified. The objective of this study was to identify unfavorable prognostic factors for liver dysfunction during the early period after transplantation. Methods: We defined liver dysfunction as elevated liver or biliary enzyme levels (corresponding to Grade 2 in the Common Terminology Criteria for Adverse Events version 4.0) within 30 days of transplantation and retrospectively investigated data from 82 patients who had undergone allogeneic HSCT at our center. Results: Elevated liver or biliary enzyme levels were observed in almost half of the patients studied (n=40, 48.7%). Elevated total bilirubin (T-Bil) level was the most frequently observed unfavorable prognostic factor and had the greatest effect on overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) (probability of unfavorable outcome in patients without and with elevated T-Bil level: OS, 58.9% vs. 15.4%, p < 0.001; PFS, 46.4% vs. 15.4%, p < 0.001; NRM, 10.7% vs. 53.8%, p < 0.001). Moreover, the probability of an unfavorable outcome increased in relation to the degree of T-Bil elevation and absence of improvement over time in T-Bil level. Conclusion: Elevated T-Bil level was an important marker of outcomes for liver dysfunction after allogeneic HSCT.
Aim
The MEAM regimen consisting of ranimustine (MCNU), etoposide (ETP), cytarabine (Ara‐C), and melphalan (MEL) is widely used before auto‐peripheral blood stem cell transplantation (auto‐PBSCT) for ...malignant lymphoma in Japan. The MEAM regimen generally consists of 200–400 mg/m2 for 4 days, but we decided to increase the dosage of Ara‐C from the standard to 2 g/m2 for 2 days with the aim of increasing drug transferability to the central nervous system. We evaluate the safety and therapeutic efficacy of high‐dose Ara‐C MEAM therapy.
Methods
The high‐dose Ara‐C MEAM protocol consisted of MCNU 300 mg/m2 on day –7, ETP 200 mg/m2 on days –6, –5, –4, –3 and Ara‐C 2 g/m2 on day –4 –3, and MEL 140 mg/m2 on day –2. We retrospectively analyzed 37 cases of malignant lymphoma at our institution between May 2014 and July 2020.
Results
All patients got engraftment and there were no cases of treatment‐related mortality. In all cases, the 3‐year overall survival (OS) and progression‐free survival (PFS) after transplantation were 80.6% and 65.7%, respectively. Twenty‐one cases of diffuse large B‐cell lymphoma recurrence, for which there is proven usefulness of auto‐PBSCT, showed good results after transplantation, with the 3‐year OS and PFS after transplantation being 100% and 74.3%, respectively.
Conclusion
The safety and efficacy of high‐dose Ara‐C MEAM therapy were demonstrated, but the expected therapeutic effect on central nervous system lesions could not be fully evaluated owing to the small number of cases.
We retrospectively analyzed malignant lymphoma in patients who underwent auto‐peripheral blood stem cell transplantation, with high‐dose cytarabine MEAM therapy as the conditioning regimen. In all cases, the 3‐year overall survival after transplantation was 80.6% and the 3‐year progression‐free survival after transplantation was 65.7%. There were no cases of treatment‐related mortality with this therapy, and this one tended to be more effective than ICE and BU/CY/VP‐16 therapies.
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