Search

Abstract Background Platelets and erythrocytes constitute over 95% of all hematopoietic stem cell output. However, the clonal dynamics of HSC contribution to these lineages remains largely unexplored. Results We use lentiviral genetic labeling of mouse hematopoietic stem cells to quantify output from all lineages, nucleate, and anucleate, simultaneously linking these with stem and progenitor cell transcriptomic phenotypes using single-cell RNA-sequencing. We observe dynamic shifts of clonal behaviors through time in same-animal peripheral blood and demonstrate that acute platelet depletion shifts the output of multipotent hematopoietic stem cells to the exclusive production of platelets. Additionally, we observe the emergence of new myeloid-biased clones, which support short- and long-term production of blood cells. Conclusions Our approach enables kinetic studies of multi-lineage output in the peripheral blood and transcriptional heterogeneity of individual hematopoietic stem cells. Our results give a unique insight into hematopoietic stem cell reactivation upon platelet depletion and of clonal dynamics in both steady state and under stress.

Platelets are key mediators of thrombus formation and inflammation during the acute phase of ischaemic stroke. Particularly, the platelet glycoprotein (GP) receptors GPIbα and GPVI have been shown to mediate platelet adhesion and activation in the ischaemic brain. GPIbα and GPVI blockade could reduce infarct volumes and improve functional outcome in mouse models of acute ischaemic stroke, without concomitantly increasing intracerebral haemorrhage. However, the functional role of platelets during long-term stroke recovery has not been elucidated so far.Thus, we here examined the impact of platelet depletion on post-stroke recovery after transient middle cerebral artery occlusion (tMCAO) in adult male mice. Platelet depleting antibodies or isotype control were applied from day 3–28 after tMCAO in mice matched for infarct size. Long-term functional recovery was assessed over the course of 28 days by behavioural testing encompassing motor and sensorimotorical functions, as well as anxiety-like or spontaneous behaviour. Whole brain flow cytometry and light sheet fluorescent microscopy were used to identify resident and infiltrated immune cell types, and to determine the effects of platelet depletion on the cerebral vascular architecture, respectively.We found that delayed platelet depletion does not improve long-term functional outcome in the tMCAO stroke model. Immune cell abundance, the extent of thrombosis and the organisation of the cerebral vasculature were also comparable between platelet-depleted and control mice. Our study demonstrates that, despite their critical role in the acute stroke setting, platelets appear to contribute only marginally to tissue reorganisation and functional recovery at later stroke stages.

ObjectiveTo explore the risk factors and predictive indexes of severe thrombocytopenia during concurrent radio-chemotherapy of nasopharyngeal carcinomas.MethodsRetrospective analysis was performed from the hospitalized patients with nasopharyngeal carcinoma from August 2014 to July 2017, and induction chemotherapy and concurrent radio-chemotherapy were completed. According to the lowest platelet count during concurrent chemotherapy, patients were divided into observation and control groups. General information and laboratory examinations were recorded and analyzed by univariate analysis, multivariate regression analysis, and ROC curve analysis.ResultsFactors, including age, PLT, IBIL, APTT at first visit, WBC, RBC, HGB, PLT, NEUT, APTT, IBIL, FFA, Crea, and urea before radio-chemotherapy, which are significant in univariate analysis into multivariate regression analysis, were taken. It turned out that RBC (OR = 10.060, 95% CI 2.679–37.777, p = 0.001), PLT (OR = 1.020, 95% CI 1.006–1.034, p = 0.005), and IBIL (OR = 0.710, 95% CI 0.561–0.898, p = 0.004) are independent predictors of severe TP in NPC. ROC analysis showed that the AUC of RBC, IBIL, PLT, and AGE is 0.746 (p < 0.001), 0.735 (p < 0.001), 0.702 (p = 0.001), and 0.734 (p < 0.001). New variables called joint predictors were calculated by a regression equation (Y = 2.309 * RBC - 0.343 * IBIL + 0.02 * PLT - 10.007), the AUC of which is 0.8700 (p < 0.001); best truncation value is >5.87 mmol/l.ConclusionsLower RBC, PLT, and higher IBIL before concurrent radio-chemotherapy are independent risk factors causing severe TP during concurrent radio-chemotherapy of NPC. The RBC, PLT, and IBIL before concurrent radio-chemotherapy and joint predictor have a good predictive value to evaluate the risk of severe TP during concurrent radio-chemotherapy of NPC.

Objective: To explore the risk factors and predictive indexes of severe thrombocytopenia during concurrent radio-chemotherapy of nasopharyngeal carcinomas. Methods: Retrospective analysis was performed from the hospitalized patients with nasopharyngeal carcinoma from August 2014 to July 2017, and induction chemotherapy and concurrent radio-chemotherapy were completed. According to the lowest platelet count during concurrent chemotherapy, patients were divided into observation and control groups. General information and laboratory examinations were recorded and analyzed by univariate analysis, multivariate regression analysis, and ROC curve analysis. Results: Factors, including age, PLT, IBIL, APTT at first visit, WBC, RBC, HGB, PLT, NEUT, APTT, IBIL, FFA, Crea, and urea before radio-chemotherapy, which are significant in univariate analysis into multivariate regression analysis, were taken. It turned out that RBC (OR = 10.060, 95% CI 2.679–37.777, p = 0.001), PLT (OR = 1.020, 95% CI 1.006–1.034, p = 0.005), and IBIL (OR = 0.710, 95% CI 0.561–0.898, p = 0.004) are independent predictors of severe TP in NPC. ROC analysis showed that the AUC of RBC, IBIL, PLT, and AGE is 0.746 (p < 0.001), 0.735 (p < 0.001), 0.702 (p = 0.001), and 0.734 (p < 0.001). New variables called joint predictors were calculated by a regression equation (Y = 2.309 * RBC - 0.343 * IBIL + 0.02 * PLT - 10.007), the AUC of which is 0.8700 (p < 0.001); best truncation value is >5.87 mmol/l. Conclusions: Lower RBC, PLT, and higher IBIL before concurrent radio-chemotherapy are independent risk factors causing severe TP during concurrent radio-chemotherapy of NPC. The RBC, PLT, and IBIL before concurrent radio-chemotherapy and joint predictor have a good predictive value to evaluate the risk of severe TP during concurrent radio-chemotherapy of NPC. [ABSTRACT FROM AUTHOR]

Dengue hemorrhagic fever is shown to correlate with secondary infection with a virus serotype different from the previous infection. However, only a small fraction of secondary infections leads to hemorrhagic fever. A recent Science paper suggests that the fucosylation state and isotype of IgGs elicited in patients may enhance disease severity. [ABSTRACT FROM AUTHOR]

The stable effector functionLess (SEFL) antibody was designed as an IgG1 antibody with a constant region that lacks the ability to interact with Fcγ receptors. The engineering and stability and pharmacokinetic assessments of the SEFL scaffold is described in the accompanying article (Jacobsen, F. W., Stevenson, R., Li, C., Salimi-Moosavi, H., Liu, L., Wen, J., Luo, Q., Daris, K., Buck, L., Miller, S., Ho, S-Y., Wang, W., Chen, Q., Walker, K., Wypych, J., Narhi, L., and Gunasekaran, K. (2017) J. Biol. Chem 292). The biological properties of these SEFL antibodies were assessed in a variety of human and cynomolgus monkey in vitro assays. Binding of parent molecules and their SEFL variants to human and cynomolgus monkey FcγRs were evaluated using flow cytometry-based binding assays. The SEFL variants tested showed decreased binding affinity to human and cynomolgus FcγRs compared with the wild-type IgG1 antibody. In addition, SEFL variants demonstrated no antibody-dependent cell-mediated cytotoxicity in vitro against Daudi cells with cynomolgus monkey peripheral blood mononuclear cells, and had minimal complement-dependent cytotoxicity activity similar to that of the negative control IgG2 in a CD20 + human Raji lymphoma cell line. SEFL mutations eliminated off-target antibody-dependent monocyte phagocytosis of cynomolgus monkey platelets, and cynomolgus platelet activation in vitro These experiments demonstrate that the SEFL modifications successfully eliminated Fc-associated effector binding and functions., (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)