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Luminescent radicals have been intensively studied as a new class of materials exhibiting novel photofunctions unique to open-shell systems. When luminescent radicals are assembled, intriguing spin-correlated luminescence phenomena emerge, including excimer-like emission and magnetic-field effects on luminescence (i.e., magnetoluminescence, MagLum). However, the underlying mechanisms of these phenomena arising from spin multiplicity and spin-dependent excited-state dynamics are poorly understood due to the limited number of luminescent polyradical systems available for study. In particular, the correlation between stronger intramolecular exchange interactions (|2J/kB| > â¼10 K, where J and kB are the intramolecular exchange coupling constant and the Boltzmann constant, respectively) and luminescence properties has not been fully explained. In this study, a novel carbazole-containing diradical emitter (1) and the corresponding monoradical (2) were prepared for the in-depth study of spin-correlated luminescence properties, with luminescence measurements under magnetic fields of up to 18 T. Diradical 1 has a negative 2J/kB value of several tens of kelvin and exhibits a single-molecule MagLum and thermally activated luminescence, whereas 2 does not. Detailed quantitative analyses revealed that both the spin-correlated luminescence properties of 1 are strongly dominated by ground-state spin statistics based on the Boltzmann distribution (i.e., 2J/kB values). Furthermore, diradical 1 exhibits external heavy-atom effects in heavy-atom-containing solvents such as iodobenzene, whereas monoradical 2 does not. This is the first experimental verification of external heavy-atom effects in polyradical emitters. This work demonstrates that polyradical emitters can be designed based on spin degrees of freedom in both ground and excited states.
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Various autoimmune diseases have been reported to develop as a result of a coronavirus disease 19 (COVID-19) infection. There have been some reports of COVID-19-triggered autoimmune hepatitis and autoimmune hemolytic anemia infection, but none have reported simultaneous onset of these diseases. A 15-year-old girl was admitted to our hospital with severe liver injury and anemia. Three weeks before admission, her father was diagnosed with COVID-19, after which she became aware of a sore throat. Two weeks later, she visited her doctor for malaise. She was referred to our hospital due to severe anemia, elevated hepatobiliary enzymes, and jaundice. A COVID-19 polymerase chain reaction test was positive at the time of referral. She was diagnosed with autoimmune hemolytic anemia based on decreased hemoglobin and haptoglobin, positive direct Coombs test, and increased urinary urobilinogen. Blood tests were positive for antinuclear antibodies, and a liver biopsy revealed interface hepatitis and plasma cell infiltration, consistent with autoimmune hepatitis. Based on these findings, a diagnosis of autoimmune hepatitis and autoimmune hemolytic anemia triggered by COVID-19 infection was made. Steroid therapy was initiated, which resulted in rapid improvement of blood markers and symptoms.
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Anemia Hemolítica Autoimune , COVID-19 , Hepatite Autoimune , Humanos , Anemia Hemolítica Autoimune/etiologia , Anemia Hemolítica Autoimune/complicações , COVID-19/complicações , Hepatite Autoimune/complicações , Feminino , Adolescente , SARS-CoV-2 , Glucocorticoides/uso terapêuticoRESUMO
A 64-year-old woman presented with fine motor impairment in both hands. MRI revealed a contrast-enhanced lesion in the medulla oblongata. Lymphoid cells with abnormal blebs were observed and a CD4+/CD8+ double positive (DP) T cell population was detected by flow cytometry (FCM) in the bone marrow (BM) and the peripheral blood (PB). CLEC16A::IL2 fusion gene was identified by whole exome sequencing with DNA prepared from DP T cells. Clonal rearrangement of the T-cell receptor gene and expression of TCL1A protein were detected. This led to a diagnosis of T-cell prolymphocytic leukemia (T-PLL) with central nervous system (CNS) infiltration. Abnormal cells in BM and PB became undetectable on microscopy and FCM, and the CNS lesion disappeared on MRI after second-line therapy with alemtuzumab. Meanwhile, the CLEC16A::IL2 fusion mRNA remained detectable in PB. Allogeneic hematopoietic stem-cell transplantation was performed, and the fusion mRNA has now been undetectable for more than 5 years since transplantation. This is the first report of a T-PLL case with a CLEC16A::IL2 fusion gene.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Prolinfocítica de Células T , Feminino , Humanos , Pessoa de Meia-Idade , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/metabolismo , Leucemia Prolinfocítica de Células T/terapia , Interleucina-2/metabolismo , Alemtuzumab , RNA Mensageiro , Proteínas de Transporte de Monossacarídeos , Lectinas Tipo C/genéticaRESUMO
Organic radicals are attracting increasing interest as a new class of molecular emitters. They demonstrate electronic excitation and relaxation dynamics based on their doublet or higher multiplet spin states, which are different from those based on singlet-triplet manifolds of conventional closed-shell molecules. Recent studies have disclosed luminescence properties and excited state dynamics unique to radicals, such as highly efficient electron-photon conversion in OLEDs, NIR emission, magnetoluminescence, an absence of heavy atom effect, and spin-dependent and spin-selective dynamics. These are difficult or sometimes impossible to achieve with closed-shell luminophores. This review focuses on luminescent organic radicals as an emerging photofunctional molecular system, and introduces the material developments, fundamental properties including luminescence, and photofunctions. Materials covered in this review range from monoradicals, radical oligomers, and radical polymers to metal complexes with radical ligands demonstrating radical-involved emission. In addition to stable radicals, transiently formed radicals generated in situ by external stimuli are introduced. This review shows that luminescent organic radicals have great potential to expand the chemical and spin spaces of luminescent molecular materials and thus broaden their applicability to photofunctional systems.
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BACKGROUND: Hypomethylating agents, including azacytidine (AZA), are standard therapeutics for patients with high-risk myelodysplastic syndromes (MDS), a group of myeloid neoplasms. However, treatment schedules are not unified in real-world practice; in addition to the standard 7-day (standard-dose) schedule, shortened (reduced-dose) schedules are also used. AIMS: The aim of this study was to discover the patient group(s) which show differential efficacy between standard-and reduced-dose AZA to MDS. METHODS AND RESULTS: The outcome of different AZA doses in a cohort of 151 MDS patients were retrospectively analyzed. Overall survival (OS) was not significantly different between standard- and reduced-dose AZA groups by multivariate analysis. However, an interaction was found between either the sex (female vs. male), the platelet counts (< 40 × 103 /µl vs. ≥ 40 × 103 /µl), or the karyotype risk (< poor vs. ≥ poor) and standard-dose AZA for longer OS. Subgroup analyses revealed better OS with standard- over reduced-dose AZA in female patients (HR, 0.27 [95% CI, 0.090-0.79]; p = 0.011), and those with platelet counts ≥ 40 × 103 /µl (HR, 0.51 [95% CI, 0.26-0.99]; p = 0.041). The union of female and preserved platelet count subgroups also benefited from standard-dose AZA. With this as a test cohort, we next analyzed patients registered in the JALSG MDS212 study, for whom 7-day and 5-day AZA treatment strategies were prospectively compared, as a validation cohort (N = 172). That cohort showed the same tendency as the retrospective results. CONCLUSION: We identified the union of female and preserved platelet count subgroups which benefited from standard-dose AZA, imparting crucial information to physicians planning treatment regimens in MDS patients.
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Azacitidina , Síndromes Mielodisplásicas , Humanos , Masculino , Feminino , Azacitidina/efeitos adversos , Contagem de Plaquetas , Estudos Retrospectivos , Antimetabólitos Antineoplásicos/efeitos adversos , Resultado do Tratamento , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológicoRESUMO
Graft failure and delayed hematopoietic recovery are the major limitations of cord-blood transplantation (CBT). Romiplostim, a thrombopoietin-receptor agonist, promotes megakaryopoiesis and multilineage hematopoiesis in aplastic anemia. The decreased number of hematopoietic stem cells in the early phase after CBT and aplastic anemia share certain characteristics. Therefore, we hypothesized that romiplostim administration immediately after CBT may promote multilineage hematopoietic recovery. We investigated the safety and preliminary efficacy of administering romiplostim a day after CBT. This phase 1 dose-escalation study included six adults with hematologic malignancies in remission. Romiplostim was administered subcutaneously within 7 days after single-unit CBT, initially at doses of 5 µg/kg or 10 µg/kg in three patients, then once a week for 14 weeks or until platelet recovery. The maximum dose was 20 µg/kg. The median number of romiplostim administrations was 6 (range, 3-15). Romiplostim-related adverse events included bone pain (3/6) and injection site reaction (1/6). Non-hematological grade ≥ 3 toxicities were observed in four patients; febrile neutropenia was the most common (4/6). All patients achieved neutrophil engraftment and the median time was 14 days (range, 12-32). Platelet counts ≥ 50 × 109 /L were recorded in all patients except for one who died on day 48; the median time was 34 days (range, 29-98). No relapse, thrombosis, or bone marrow fibrosis was observed during a median follow-up of 34 months. Romiplostim may be safely administered in the early phase of CBT. Further phase 2 trial is warranted for its efficacy evaluation. Trial registration number: UMIN000033799, August 18, 2018.
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Anemia Aplástica , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Trombopoetina/efeitos adversos , Recidiva Local de NeoplasiaRESUMO
Luminescent radicals are an emerging class of materials that exhibit unique photofunctions not found in closed-shell molecules due to their open-shell electronic structure. Particularly promising are photofunctions in which radical's spin and luminescence are correlated; for example, when a magnetic field can affect luminescence (i.e., magnetoluminescence, ML). These photofunctions could be useful in the new science of spin photonics. However, previous observations of ML in radicals have been limited to systems in which radicals are randomly doped in host crystals or polymerized through metal complexation. This study shows that a covalently linked luminescent radical dimer (diradical) can exhibit ML as a single-molecular property. This facilitates detailed elucidation of the requirements for and mechanisms of ML in radicals and can aid the rational design of ML-active radicals based on synthetic chemistry.
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Fenestrated and blood-brain barrier (BBB)-forming endothelial cells constitute major brain capillaries, and this vascular heterogeneity is crucial for region-specific neural function and brain homeostasis. How these capillary types emerge in a brain region-specific manner and subsequently establish intra-brain vascular heterogeneity remains unclear. Here, we performed a comparative analysis of vascularization across the zebrafish choroid plexuses (CPs), circumventricular organs (CVOs), and retinal choroid, and show common angiogenic mechanisms critical for fenestrated brain capillary formation. We found that zebrafish deficient for Gpr124, Reck, or Wnt7aa exhibit severely impaired BBB angiogenesis without any apparent defect in fenestrated capillary formation in the CPs, CVOs, and retinal choroid. Conversely, genetic loss of various Vegf combinations caused significant disruptions in Wnt7/Gpr124/Reck signaling-independent vascularization of these organs. The phenotypic variation and specificity revealed heterogeneous endothelial requirements for Vegfs-dependent angiogenesis during CP and CVO vascularization, identifying unexpected interplay of Vegfc/d and Vegfa in this process. Mechanistically, expression analysis and paracrine activity-deficient vegfc mutant characterization suggest that endothelial cells and non-neuronal specialized cell types present in the CPs and CVOs are major sources of Vegfs responsible for regionally restricted angiogenic interplay. Thus, brain region-specific presentations and interplay of Vegfc/d and Vegfa control emergence of fenestrated capillaries, providing insight into the mechanisms driving intra-brain vascular heterogeneity and fenestrated vessel formation in other organs.
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Células Endoteliais , Peixe-Zebra , Animais , Barreira Hematoencefálica/fisiologia , Encéfalo/irrigação sanguínea , Capilares , Células Endoteliais/fisiologia , Neovascularização Fisiológica/genética , Peixe-Zebra/genéticaRESUMO
An 80-year-old man with an approximately 3-cm mass in the right submandibular region presented to our institution. Magnetic resonance imaging revealed enlarged lymph nodes (LNs) in the right neck, and fluorine-18-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) indicated positive FDG accumulation in the right neck LNs only. Excisional biopsy was performed for suspected malignant lymphoma, and the biopsy revealed melanoma. Close examination of the skin, nasal cavity, oral pharyngeal and laryngeal cavities, and gastrointestinal tract were performed. No primary tumor was detected by these examinations, and the patient was diagnosed with cervical LN metastasis from melanoma of unknown primary of clinical stage T0N3bM0 stage IIIC. The patient refused cervical neck dissection because of his age and comorbidity of Alzheimer's disease and instead opted for proton beam therapy (PBT) at a total dose of 69 Gy (relative biological effectiveness) in 23 fractions. He did not receive any systemic therapy. The enlarged LNs shrunk slowly, and FDG PET/CT at 1 year after PBT showed that the right submandibular LN had shrunk from 27 to 7 mm in length, and there was no significant FDG accumulation. At 6 years and 4 months after PBT, the patient is alive without any recurrence.
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A 51-year-old man with the chief complaint of glove- and stocking-type dysesthesia for >3 years was diagnosed with Waldenström's macroglobulinemia (WM) based on IgM-type M-proteinemia, bone marrow infiltration of plasmacytoid B cells, multiple lymphadenopathies, and splenomegaly. A nerve conduction examination suggested demyelinating neuropathy. Serum anti-myelin-associated glycoprotein antibody was negative. Sural nerve biopsy showed myelin thinning, suggesting demyelination. Axonal damage and tumor cell infiltration in the intrafascicular epineurium were also observed. After chemotherapies with rituximab and bendamustine, M-proteinemia and lymphadenopathies disappeared. However, abnormalities in the nerve conduction examination and dysesthesia were only slightly alleviated. As articles describing patients with WM with peripheral nerve infiltration are limited, we report this case with a literature review.
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Linfadenopatia , Doenças do Sistema Nervoso Periférico , Macroglobulinemia de Waldenstrom , Masculino , Humanos , Pessoa de Meia-Idade , Macroglobulinemia de Waldenstrom/complicações , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Parestesia/complicações , Doenças do Sistema Nervoso Periférico/complicações , Doenças do Sistema Nervoso Periférico/patologia , Rituximab/uso terapêutico , Linfadenopatia/complicações , Imunoglobulina MRESUMO
Sequencing technology has identified aplastic anemia (AA) not only as an autoimmune bone marrow failure syndrome, but also as a clonal hematopoietic disease. Here, we present a case in which an ASXL1-mutated clone was predominantly expanded during the treatment of AA. A 58-year-old man with chronic glomerulonephritis on maintenance hemodialysis presented with pancytopenia. The findings of bone marrow biopsy indicated a hypoplastic bone marrow. Magnetic resonant imaging showed fatty changes in the bone marrow. The patient was eventually diagnosed with severe AA. He was treated with anti-human thymocyte globulin, cyclosporine, granulocyte colony-stimulating factor, and the thrombopoietin receptor agonist (TPO-RA) eltrombopag. After switching to another TPO-RA, romiplostim, the neutrophil, reticulocyte, and platelet counts gradually improved, and blood transfusion was not needed 1 year after treatment. Mutational analyses revealed that reconstituted hematopoietic cells originated from the ASXL1-mutated clone. Nevertheless, the patient's blood cell counts remained normal 2 years after treatment.
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Anemia Aplástica , Masculino , Humanos , Pessoa de Meia-Idade , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/genética , Medula Óssea , Terapia de Imunossupressão , Células-Tronco Hematopoéticas , Soro Antilinfocitário , Transtornos da Insuficiência da Medula Óssea , Células Clonais , Proteínas RepressorasRESUMO
A 61-year-old female was referred to our hospital because of pancytopenia and febrile neutropenia. On admission, computed tomography showed mild hepatosplenomegaly and intra-abdominal abscess formation in the right pelvic region; however, no lymphadenopathy was found. Bone marrow (BM) examination showed severe fibrosis by silver staining. Several small- to medium-sized lymphocytes with a constriction in the nuclei were observed, exhibiting CD3 (-), CD10 (-), CD20 (+), BCL-2 (+-), and CD138 (+-). Genetic testing revealed that BM cells were positive for MYD88 mutation and positive for IgH rearrangement, whereas neither JAK2 nor CALR mutation was positive. A diagnosis of BM infiltration of lymphoplasmacytic lymphoma (LPL) was made. Rituximab monotherapy was administered once a week for four times. BM examination 4 weeks after the end of treatment showed that lymphoma cells had disappeared and that myelofibrosis had been almost gone. The MYD88 mutation of BM turned out to be negative at that moment.
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Linfoma de Células B , Mielofibrose Primária , Macroglobulinemia de Waldenstrom , Feminino , Humanos , Pessoa de Meia-Idade , Mielofibrose Primária/complicações , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , Fator 88 de Diferenciação Mieloide/genética , Medula Óssea/patologia , Linfoma de Células B/diagnóstico , Rituximab , Macroglobulinemia de Waldenstrom/complicações , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genéticaRESUMO
Angioimmunoblastic T-cell lymphoma (AITL) is an intractable type of T-cell lymphoma. We and others have identified that the p.Gly17Val RHOA mutation is specifically identified in AITL. We herein report a patient whose condition deteriorated, resulting from massive pericardial effusion one month after undergoing autologous transplantation for AITL. He was diagnosed with cardiac tamponade caused by AITL recurrence in the presence of the p.Gly17Val RHOA mutation as well as T-lineage cells with an aberrant immune-phenotype in the pericardial effusion. This case suggests that a precision medicine approach by detecting the presence of a p.Gly17Val RHOA mutation is useful for the management of AITL.
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Tamponamento Cardíaco , Linfadenopatia Imunoblástica , Linfoma de Células T , Derrame Pericárdico , Masculino , Humanos , Linfadenopatia Imunoblástica/complicações , Linfadenopatia Imunoblástica/genética , Linfadenopatia Imunoblástica/diagnóstico , Mutação/genética , Linfoma de Células T/complicações , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Proteína rhoA de Ligação ao GTP/genéticaRESUMO
Triple-negative essential thrombocythemia (ET) is a condition in which mutations in JAK2, CALR and MPL are all negative. Transformation to acute myeloid leukemia may occur during the course of ET, while B-acute lymphoblastic leukemia B-(ALL) is rare. We experienced a case diagnosed as B-ALL during the course of triple-negative ET. Notably, cytoreduction was required for the excessive increase in blood cells during the bone marrow recovery period after chemotherapies. Whole exome sequencing identified 17 somatic mutations: 9 were identified in both ET and B-ALL samples, while 8 were specific to B-ALL, suggesting that these 8 might have caused the transformation.
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Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Trombocitemia Essencial , Humanos , Trombocitemia Essencial/complicações , Trombocitemia Essencial/genética , Trombocitemia Essencial/diagnóstico , Leucemia Mieloide Aguda/genética , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Calreticulina/genéticaRESUMO
Donor-radical acceptor systems have recently attracted much attention as efficient doublet emitters that offer significant advantages for applications such as OLEDs. We employed an alkylbenzene (mesityl group) as the simplest donor to date and added it to a diphenylpyridylmethyl radical acceptor. The (3,5-difluoro-4-pyridyl)bis[2,6-dichloro-4-(2,4,6-trimethylphenyl)phenyl]methyl radical (Mes2F2PyBTM) was prepared in only three steps from commercially available reagents. A stable radical composed of only one pyridine ring, four benzene rings, methyl groups, halogens, and hydrogens showed fluorescence of over 60% photoluminescence quantum yield (PLQY) in chloroform, dichloromethane, and PMMA. The key to high fluorescence efficiency was benzene rings perpendicular to the diphenylpyridylmethyl radical in the doublet ground (D0) state. The relatively low energy of the ß-HOMO and the electron-accepting character of the radical enabled the use of benzenes as electron donors. Furthermore, the structural relaxation of the doublet lowest excited (D1) state was minimized by steric hindrance of the methyl groups. The reasons for this high efficiency include the relatively fast fluorescence transition and the slow internal conversion, both of which were explained by the overlap density between the D1 and D0 states.
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CASE: A 47-year-old Japanese woman with a medical history of xanthoma disseminatum (XD) presented with posterior neck pain and abnormal gait without a history of trauma. Imaging studies revealed odontoid process thinning resulting in its fracture due to XD involvement in the atlantoaxial joint and subsequent cervical myelopathy. Posterior C1-C2 fusion surgery improved the patient's symptoms. An XD lesion around the odontoid process was confirmed intraoperatively. CONCLUSION: We report cervical myelopathy caused by XD involvement in the C1-C2 joint, showing that early fusion surgery is critical for treating pathological fractures in patients with XD.
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Histiocitose de Células não Langerhans , Processo Odontoide , Doenças da Medula Espinal , Fraturas da Coluna Vertebral , Fusão Vertebral , Feminino , Histiocitose de Células não Langerhans/complicações , Humanos , Pessoa de Meia-Idade , Processo Odontoide/lesões , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/etiologia , Doenças da Medula Espinal/cirurgia , Fraturas da Coluna Vertebral/complicações , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fusão Vertebral/efeitos adversosRESUMO
Vanishing bile duct syndrome (VBDS) is a rare hepatic disorder which leads to liver failure as a result of progressive destruction of the intrahepatic bile ducts. There are no treatment modalities for VBDS itself and severe hepatic dysfunction restricts the treatment of underlying diseases. We safely treated a case of classic Hodgkin lymphoma (HL) with VBDS using brentuximab vedotin (BV). The patient was treated with 5 cycles of reduced BV and a partial metabolic response was obtained. Moreover, a standard dose of BV for another 5 cycles was accomplished with minimal adverse events. Our experience indicates that BV could be a treatment option for classic HL with VBDS.
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Doença de Hodgkin , Falência Hepática , Ductos Biliares Intra-Hepáticos/patologia , Brentuximab Vedotin , Doença de Hodgkin/complicações , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , HumanosRESUMO
Although vaccines have been effective against the worldwide pandemic of Coronavirus Disease 19 (COVID-19), some case reports have described autoimmune hepatitis triggered by COVID-19 vaccination. Meanwhile, hepatitis C virus (HCV) is known to be related to autoimmune diseases. Here, we report a case of autoimmune hepatitis with history of HCV treatment triggered by COVID-19 vaccination. An 82-year-old woman was referred to our hospital for severe liver injury. She had received a COVID-19 vaccination 7 days prior. She had a history of HCV treatment with direct-acting antivirals 7 years previously. In her blood data, despite HCV antibody positivity, she was negative for HCV RNA by real-time RT-PCR. Anti-nuclear antibody was positive and IgG was elevated. Interface hepatitis and plasma cell infiltration were confirmed pathologically. She was diagnosed as autoimmune hepatitis and her liver injury quickly improved after initiation of steroid administration. This is a first case report of autoimmune hepatitis with history of HCV treatment triggered by COVID-19 vaccination.