Acute erythroleukemia (FAB M6), a rare form of acute myeloid leukemia, consists of two subtypes: M6a-erythroid/myeloid leukemia and M6b-pure erythroid leukemia (PEL). The diagnosis of PEL is often difficult due to the negativity of classical erythroid cell markers. Recently, an epithelial calcium-dependent cell adhesion protein (E-cadherin) has been identified as a marker of immature erythroid precursors. Here, we report an elderly case of PEL in which E-cadherin positivity and strong P53 positivity were the key clues for diagnosis. The patient was treated with a daunomycin/Ara-C regimen followed by a venetoclax/azacitidine regimen but responded to neither treatment.
Summary SARS-CoV-2 Lambda, a new variant of interest, is now spreading in some South American countries; however, its virological features and evolutionary trait remain unknown. Here we reveal that the spike protein of the Lambda variant is more infectious and it is attributed to the T76I and L452Q mutations. The RSYLTPGD246-253N mutation, a unique 7-amino-acid deletion mutation in the N-terminal domain of the Lambda spike protein, is responsible for evasion from neutralizing antibodies. Since the Lambda variant has dominantly spread according to the increasing frequency of the isolates harboring the RSYLTPGD246-253N mutation, our data suggest that the insertion of the RSYLTPGD246-253N mutation is closely associated with the massive infection spread of the Lambda variant in South America. Highlights Lambda S is highly infectious and T76I and L452Q are responsible for this property Lambda S is more susceptible to an infection-enhancing antibody RSYLTPGD246-253N, L452Q and F490S confer resistance to antiviral immunity Graphical Abstract
The utility of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from sources other than matched related donors (alternative donors) in the management of elderly acute myeloid leukemia (AML) patients in first complete remission (CR1) has not been clarified. To investigate the benefit of allo-HCST in the management of elderly AML patients in CR1, we retrospectively collected data from consecutive AML patients aged 60-66 years, who had been diagnosed between 2000 and 2014 and achieved CR. A total of 43 patients were included in this study, and 12 patients received allo-HSCT in CR1 only from alternative donors. Compared to chemotherapy alone, allo-HSCT improved overall survival (OS) (P=0.050) and cumulative incidence of relapse (CIR) (P=0.0059) in univariate analysis. OS and CIR at 3 years from CR1 were 82.5% vs 34.2%, and 17.5% vs 74.6%, respectively. In multivariate analysis, allo-HSCT also improved OS (hazard ratio (HR), 0.18; 95% confidence interval (CI), 0.039-0.80) and CIR (HR, 0.090; 95% CI, 0.029-0.28). Allo-HSCT from an alternative donor is a credible option in the treatment of elderly AML patients in CR1.
Abstract APOBEC3B cytidine deaminase (A3B) catalyzes cytosine into uracil in single-strand DNA and induces C-to-T mutations in genomic DNA of various types of tumors. Accumulation of APOBEC signature mutations is correlated with a worse prognosis for patients with breast cancer or multiple myeloma, suggesting that A3B activity might be a cause of the unfavorable DNA mutations and clonal evolution in these tumors. Phosphorylation of conserved threonine residues of other cytidine deaminases, activation induced deaminase (AID) and APOBEC3G, inhibits their activity. Here we show that protein kinase A (PKA) physically binds to A3B and phosphorylates Thr214. In vitro deaminase assays and foreign DNA editing assays in cells confirm that phosphomimetic A3B mutants, T214D and T214E, completely lose deaminase activity. Molecular dynamics simulation of A3B phosphorylation reveals that Thr214 phosphorylation disrupts binding between the phospho-A3B catalytic core and ssDNA. These mutants still inhibit retroviral infectivity at least partially, and also retain full anti-retrotransposition activity. These results imply that PKA-mediated phosphorylation inhibits A3B mutagenic activity without destructing its innate immune functions. Therefore, PKA activation could reduce further accumulation of mutations in A3B overexpressing tumors.
Neurolymphomatosis is a rare entity defined as nerve infiltration by neurotropic abnormal lymphocytes which can lead to the development of neuropathy, with typical presentations including pain, hypoesthesia, paresthesis and palsy. We herein report two cases where critical bilateral vocal cord paralysis due to neurolymphomatosis in recurrent nerves occurred in refractory Burkitt lymphoma and adult T-cell lymphoma patients. High-dose methotrexate and intrathecal chemotherapy injection for the nervous lesions were ineffective, and the patients died. Neurolymphomatosis of the recurrent nerve is an emergent and difficult complication and should be suspected when sudden onset of aphasia, hoarseness or shortness of breath is found in refractory lymphoma patients.
Erdheim-Chester Disease (ECD) is a type of systemic histiocytosis mostly observed in adults, characterized by the infiltration of foamy CD68+ and CD1a- histiocytes into multiple organ systems, often associated with MAPK pathway mutations. Conventional treatment of ECD has been challenging. Currently, targeted drugs (BRAF and MEK inhibitors) are recommended. This report aimed to describe the necessity of targeted therapy for ECD. A 39-year-old Japanese man presented with complaints of weight loss, polyuria/polydipsia, bilateral leg pain, and facial xanthoma/xanthelasma palpebrarum (XP) lesions. A biopsy of the bone lesions confirmed BRAF-positive ECD. The ECD lesions initially showed a good response to the cladribine/dexamethasone regimen; however, XP lesions were exacerbated during infliximab therapy, and did not respond to other conventional regimens. Eventually, XP lesions improved with trametinib (a MEK inhibitor) and dabrafenib (a BRAF inhibitor). Targeted therapy is indispensable in the management of ECD.
In late 2022, various Omicron subvariants emerged and cocirculated worldwide. These variants convergently acquired amino acid substitutions at critical residues in the spike protein, including residues R346, K444, L452, N460, and F486. Here, we characterize the convergent evolution of Omicron subvariants and the properties of one recent lineage of concern, BQ.1.1. Our phylogenetic analysis suggests that these five substitutions are recurrently acquired, particularly in younger Omicron lineages. Epidemic dynamics modelling suggests that the five substitutions increase viral fitness, and a large proportion of the fitness variation within Omicron lineages can be explained by these substitutions. Compared to BA.5, BQ.1.1 evades breakthrough BA.2 and BA.5 infection sera more efficiently, as demonstrated by neutralization assays. The pathogenicity of BQ.1.1 in hamsters is lower than that of BA.5. Our multiscale investigations illuminate the evolutionary rules governing the convergent evolution for known Omicron lineages as of 2022.
Abstract SARS-CoV-2 Omicron variants are highly resistant to vaccine-induced immunity and human monoclonal antibodies. Here, we demonstrate that a novel nanobody TP86 potently neutralized both BA.1 and BA.2 Omicron variants, and that the TP17 and TP86 nanobody cocktail broadly neutralized in vitro all VOCs as well as D614G. Furthermore, this cocktail showed therapeutic efficacy in vivo on VOCs using human ACE2 transgenic mice.
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