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A characteristic clinical feature of COVID-19 is the frequent incidence of microvascular thrombosis. In fact, COVID-19 autopsy reports have shown widespread thrombotic microangiopathy characterized by extensive diffuse microthrombi within peripheral capillaries and arterioles in lungs, hearts, and other organs, resulting in multiorgan failure. However, the underlying process of COVID-19-associated microvascular thrombosis remains elusive due to the lack of tools to statistically examine platelet aggregation (i.e., the initiation of microthrombus formation) in detail. Here we present a method for massive image-based profiling, temporal monitoring, and big data analysis of circulating platelets and platelet aggregates in the blood of COVID-19 patients at single-cell resolution, to provide previously unattainable insights into the disease. In fact, our analysis of the image data from 110 hospitalized patients shows the anomalous presence of excessive platelet aggregates in nearly 90% of all COVID-19 patients. Furthermore, results indicate strong links between the concentration of platelet aggregates and the severity, mortality, and respiratory condition of patients with COVID-19. Finally, high-dimensional analysis based on deep learning shows that the disease behaves as systemic thrombosis.

A characteristic clinical feature of COVID-19 is the frequent occurrence of thrombotic events. Furthermore, many cases of multiorgan failure are thrombotic in nature. Since the outbreak of COVID-19, D-dimer testing has been used extensively to evaluate COVID-19-associated thrombosis, but does not provide a complete view of the disease because it probes blood coagulation, but not platelet activity. Due to this limitation, D-dimer testing fails to account for thrombotic events which occur despite low D-dimer levels, such as sudden stroke in young patients and autopsy-identified widespread microthrombi in multiple organs. Here we report the landscape of circulating platelet aggregates in COVID-19 obtained by large-scale single-cell image-based profiling and temporal monitoring of the blood of COVID-19 patients (n = 110). Surprisingly, our analysis shows the anomalous presence of excessive platelet aggregates in nearly 90% of all COVID-19 patients, including those who were not clinically diagnosed with thrombosis and those with low D-dimer levels (≤1 µg/mL). Additionally, results indicate a strong link between the concentration of platelet aggregates and the severity and mortality of COVID-19. Finally, high-dimensional analysis and comparison with other diseases reveal that COVID-19 behaves as a product of thrombosis (localized) and infectious diseases (systemic), as a cause of systemic thrombosis.

Mediastinal gray zone lymphoma (MGZL) is a provisional entity with intermediate features between classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma. Outcomes for patients with MGZL are reportedly poorer than those for patients with cHL or primary mediastinal large B-cell lymphoma. Additionally, no standard management guidelines for patients with MGZL are available, primarily due to its recent identification, rarity, and challenges in diagnosis. Although recent several studies have suggested dose-adjusted EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide, prednisolone, and rituximab) may improve outcomes in patients with MGZL, numerous patients still suffer from relapsed/refractory MGZL, and the optimal management for such patients remains uncertain. Here, we report the first case of successful treatment of refractory MGZL by tandem high-dose chemotherapy supported by autologous stem cell transplantations (auto-SCTs) and consolidative radiotherapy (RT). To date, the patient remains in CR 33 months after the completion of RT, with no significant complications. This case suggests that tandem auto-SCTs may be a promising therapeutic option for relapsed/refractory MGZL.

We have previously reported that the tetrahydrotetramethylnaphthalene (TMN) derivative TMNAA is a selective inhibitor of Adult T-cell Leukemia (ATL) and HTLV-1-infected cell lines but not non-ATL cell lines and peripheral blood mononuclear cells (PBMCs). In this study, several derivatives of TMNAA were synthesized and examined for their inhibitory effect on the proliferation of various T cell lines and PBMCs by a tetrazolium dye method. The modes of cell death and cell cycle arrest were also examined by flow cytometry. Among the compounds, MN417 having a tetrahydrotetramethylbenzophenanthridinone structure was found to be a more potent inhibitor of ATL and HTLV-1-infected cell lines than TMNAA. The 50% inhibitory concentrations (IC50s) of MN417 and TMNAA for ATL and HTLV-1-infected cell lines, including S1T and MT-2 cells, were 0.59-6.6 and 2.2-34.2 μM, respectively, depending on the test cell lines. In contrast, the IC50s of MN417 and TMNAA for non-ATL cell lines, such as MOLT-4 and CEM cells, were > 20 and > 100 µM, respectively. The elimination of the TMN moiety from MN417 failed to inhibit the proliferation of ATL and HTLV-1-infected cell lines, suggesting that the TMN moiety was required for the selective inhibition of these cell lines. Furthermore, both MN417 and TMNAA hardly induced apoptosis and cell cycle arrest. Thus, although the target molecule for inhibition of ATL cells remains to be elucidated, the compounds may have potential as novel and selective chemotherapeutic agents ATL.