No abstract

Excessive monocyte/macrophage activation with the development of a cytokine storm and subsequent acute lung injury, leading to acute respiratory distress syndrome (ARDS), is a feared consequence of infection with COVID-19. The ability to recognize and potentially intervene early in those patients at greatest risk of developing this complication could be of great clinical utility. In this study, we performed flow cytometric analysis of peripheral blood samples from 34 COVID-19 patients in early 2020 in an attempt to identify factors that could help predict the severity of disease and patient outcome. Although we did not detect significant differences in the number of monocytes between patients with COVID-19 and normal healthy individuals, we did identify significant morphologic and functional differences, which are more pronounced in patients requiring prolonged hospitalization and intensive care unit (ICU) admission. Patients with COVID-19 have larger than normal monocytes, easily identified on forward scatter (FSC), side scatter analysis by routine flow cytometry, with the presence of a distinct population of monocytes with high FSC (FSC-high). On more detailed analysis, these CD14 + CD16 + , FSC-high monocytes show features of mixed M1/M2 macrophage polarization with higher expression of CD80 +

Background:Excessive monocyte/macrophage activation with the development of a cytokine storm and

Hypoxia is associated with increased metastatic potential and poor prognosis in solid tumors. In this study, we demonstrated in the murine 5T33MM model that multiple myeloma (MM) cells localize in an extensively hypoxic niche compared with the naive bone marrow. Next, we investigated whether hypoxia could be used as a treatment target for MM by evaluating the effects of a new hypoxiaactivated prodrug TH-302 in vitro and in vivo. In severely hypoxic conditions, TH-302 induces G 0 /G 1 cell-cycle arrest by down-regulating cyclinD1/2/3, CDK4/6, p21 cip-1 , p27 kip-1 , and pRb expression, and triggers apoptosis in MM cells by upregulating the cleaved proapoptotic caspase-3, -8, and -9 and poly ADP-ribose polymerase while having no significant effects under normoxic conditions. In vivo treatment of 5T33MM mice induces apoptosis of the MM cells within the bone marrow microenvironment and decreases paraprotein secretion. Our data support that hypoxia-activated treatment with TH-302 provides a potential new treatment option for MM. (Blood. 2010;116(9):1524-1527) IntroductionMultiple myeloma (MM) is an incurable clonal B-cell malignancy characterized by the accumulation of neoplastic plasma cells in the bone marrow (BM). 1 Studies have shown that the intimate reciprocal relationship between tumor cells and the cellular and noncellular microenvironment plays a pivotal role in MM growth and survival. 2,3 Hypoxia, one of the important microenvironmental factors, is well known to be highly associated with increased angiogenesis and metastatic potential as well as poor prognosis in solid tumors. More recently, hypoxia has been demonstrated to be crucial for normal marrow hematopoiesis. [4][5][6] However, the role of hypoxia in the etiology, pathogenesis, and possible treatment of hematologic malignancies, such as MM, is still unknown.Given very low oxygen levels, as found in tumors, are rarely observed in normal tissues, the presence of hypoxic tumor cells is therefore regarded not only as an adverse prognostic factor but also as a potential target for tumor-specific treatment. Currently, several hypoxia-targeted therapeutics are under development. 7-12 TH-302 is a new hypoxia-activated prodrug that is being evaluated in phase 1/2 clinical trials for the treatment of solid tumors as a monotherapy and in combination with 4 chemotherapeutic agents (gemcitabine, pemetrexed, doxorubicin, and docetaxel). TH-302 is a 2-nitroimidazole prodrug of the cytotoxin bromo-isophosphoramide mustard, with a favorable physicochemical, metabolic, and pharmacokinetic profile and exhibits hypoxiaselective cytotoxicity across a broad spectrum of human cancer cell lines in vitro and in vivo efficacy in a large panel of human tumor xenografts. 13,14 The doses used in the clinical studies are in the same range as the doses demonstrating efficacy in both in vitro and in vivo preclinical models.In this study, we investigated the hypoxic nature of MM by staining the BM of naive and 5T33MM mice with the exogenous hypoxia marker pimonidazole and endogenou...