Despite the magnitude of the Ebola virus disease (EVD) outbreak in West Africa, there is still a fundamental lack of knowledge about the pathophysiology of EVD1. In particular, very little is known about human immune responses to Ebola virus (EBOV)2,3. Here, we have for the first time evaluated the physiology of the human T cell immune response in EVD patients at the time of admission at the Ebola Treatment Center (ETC) in Guinea, and longitudinally until discharge or death. Through the use of multiparametric flow cytometry established by the European Mobile Laboratory in the field, we have identified an immune signature that is unique in EVD fatalities. Fatal EVD was characterized by high percentage of CD4 and CD8 T cells expressing the inhibitory molecules cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1), which was correlated with elevated inflammatory markers and high virus load. Conversely, surviving individuals showed significantly lower expression of CTLA-4 and PD-1 as well as lower inflammation despite comparable overall T cell activation. Concommittant with virus clearance, survivors mounted a robust EBOV-specific T cell response. Our findings suggest that dysregulation of the T cell response is a key component of EVD pathophysiology.
The myelodysplastic syndromes (MDS) comprise a heterogenous group of myeloid disorders with a highly variable disease course. Diagnostic criteria to better stratify patients with MDS continue to evolve, based on morphology, cytogenetics, and the presence of cytopenias. More accurate classification of patients will allow for better treatment guidance. Treatment encompasses supportive care, treatment of anemia, low-intensity therapy, and high-intensity therapy. This portion of the guidelines focuses on diagnostic classification, molecular abnormalities, therapeutic options, and recommended treatment approaches.
IntroductionThe SET protein is a potent physiologic inhibitor of protein phosphatase 2A (PP2A) 1 that was isolated from a chromosomal rearrangement at 9q34 in a patient with acute undifferentiated leukemia. 2 The SET protein is overexpressed in chronic myelogenous leukemia (CML) cells, and SET protein levels are further elevated during blast crisis. 3 SET overexpression in CML cells correlates with decreased PP2A activity. 3 This indicates that many of the SET oncogenic activities may be manifest through inhibition of PP2A. PP2A plays a role in many cellular processes, including cell cycle regulation, cell proliferation, apoptosis, development, cytoskeleton dynamics, cell motility, and stem cell self-renewal. 4 In addition, PP2A is a critical tumor suppressor gene that regulates multiple important oncogenic signal transduction pathways. [5][6][7] PP2A inhibition is essential for cell transformation and tumor formation, 8,9 but overexpression of PP2A inhibitory proteins in chronic lymphocytic leukemia (CLL) has not been reported.Of the nearly 84 000 annual cases of leukemia in the Western world, B-cell CLL is the most common, accounting for ϳ 30% of adult leukemia cases. 10 Characterized by accumulation of monoclonal mature B cells, 11 the CLL clinical course is heterogeneous, with some patients experiencing an aggressive course that demands early treatment and others experiencing long survival without disease-related symptoms or ever requiring treatment. 11 Aberrant apoptosis in CLL cells correlates with arrest either in the G 0 or early G 1 phases of the cell cycle. 12,13 This defective apoptosis in CLL cells is partly the result of aberrant signaling through the Akt kinase and the ERK MAPK pathways, in which phosphorylated-Akt is necessary for survival of the leukemia cells. 14,15 The observation of aberrantly activated Akt and downstream pathways in CLL cells also suggests that the normal regulator of these pathways, PP2A, is unable to perform its normal role.We thus sought to determine whether SET is overexpressed in CLL cells relative to normal B cells. We found that SET is significantly overexpressed in CLL cells and related non-Hodgkin lymphoma (NHL) cell line cells. In freshly isolated CLL patient samples, higher cellular levels of the SET correlated with more aggressive disease requiring earlier treatment. Antagonism of SET using shRNA-mediated knockdown or pharmacologic antagonism with novel cell-permeable SET antagonist peptides induced apoptosis, reduced cellular levels of Mcl-1, and caused death of CLL and NHL cells, but normal B cells were scarcely affected by SET antagonism. We also found that pharmacologic SET antagonism in vivo inhibited growth of B-cell NHL tumor xenografts in SCID mice. Methods GeneralAll reagents were from Sigma-Aldrich unless noted otherwise. Anti-SET antibody was from Santa Cruz Biotechnology. Anti--actin, total c-Myc, pS62 c-Myc, and Mcl-1 were from Abcam. All primary antibodies were used at a 1:1000 dilution, except for -actin, which was used at 1:10 000. All secondary ...
BACKGROUND:In patients with multiple myeloma, renal impairment (RI) at the time of diagnosis is associated with poor survival. To the authors' knowledge, the current retrospective analysis presented is the first to assess the impact of various degrees of renal dysfunction on safety and efficacy outcomes in a large cohort of patients with relapsed and/or refractory multiple myeloma who received treatment with lenalidomide plus dexamethasone. METHODS: Three hundred fifty-three patients from 2 large phase 3 trials were randomized to receive lenalidomide (25 mg) plus dexamethasone (40 mg). For the purpose of this analysis, RI was defined according to the calculated creatinine clearance (CL Cr ) level as follows: mild or no RI (CL Cr 60 mL/minute), moderate RI (CL Cr from 30 mL/minute to <60 mL/minute), and severe RI (CL Cr <30 mL/minute). RESULTS: The RI subgroups did not differ significantly in terms of the overall response rate (range, 50%-64%) or response quality (very good partial response or better, 27%-37%). In all RI subgroups, the time to progression and progression-free survival did not differ significantly compared with the mild or no RI group. Patients with RI experienced an increased incidence of thrombocytopenia, required more frequent lenalidomide dose reduction or interruption, and had shorter overall survival than patients with mild or no RI (P ¼ .006). Lenalidomide plus dexamethasone led to improvement in renal function in the majority of patients. CONCLUSIONS: The results from this study indicated that, with careful monitoring of the CL Cr level and adverse events as well as appropriate dose adjustments, lenalidomide plus dexamethasone is an effective and well tolerated treatment option for patients with multiple myeloma who have RI.
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