Fireflies-on-a-chip

15th International Conference on Miniaturized Systems for Chemistry and Life Sciences 2011, MicroTAS 20112951-95

On-drop separation and sensing with compound droplet microfluidics

14th International Conference on Miniaturized Systems for Chemistry and Life Sciences 2010, MicroTAS 201031823-182

Right ventricular function and vasoactive peptides for early prediction of bronchopulmonary dysplasia

Background To assess the prognostic value of early echocardiographic indices of right ventricular function and vasoactive peptides for prediction of bronchopulmonary dysplasia (BPD) or death in very preterm infants. Methods Prospective study involving 294 very preterm infants (median [IQR] gestational age 28.4 [26.4-30.4] weeks, birth weight 1065 [800-1380] g), of whom 57 developed BPD (oxygen supplementation at 36 weeks postmenstrual age) and 10 died. Tricuspid annular plane systolic excursion (TAPSE), right ventricular index of myocardial performance (RIMP), plasma concentrations of mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET1) were measured on day 7 of life. Results RIMP was significantly increased (median [IQR] 0.3 [0.23-0.38] vs 0.22 [0.15-0.29]), TAPSE decreased (median [IQR] 5.0 [5.0-6.0] vs 6.0 [5.4-7.0] mm), MR-proANP increased (median [IQR] 784 [540-936] vs 353 [247-625] pmol/L), and CT-proET1 increased (median [IQR] 249 [190-345] vs 199 [158-284] pmol/L) in infants who developed BPD or died, as compared to controls. All variables showed significant but weak correlations with each other (r(S) -0.182 to 0.359) and predicted BPD/death with similar accuracy (areas under receiver operator characteristic curves 0.62 to 0.77). Multiple regression revealed only RIMP and birth weight as independent predictors of BPD or death. Conclusions Vasoactive peptide concentrations and echocardiographic assessment employing standardized measures, notably RIMP, on day 7 of life are useful to identify preterm infants at increased risk for BPD or death

Progesterone and HMOX-1 promote fetal growth by CD8(+) T cell modulation

Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved in the pathogenesis of placental insufficiency and IUGR are largely unknown. Here, we developed a mouse model of fetal-growth restriction and placental insufficiency that is induced by a midgestational stress challenge. Compared with control animals, pregnant dams subjected to gestational stress exhibited reduced progesterone levels and placental heme oxygenase 1 (Hmox1) expression and increased methylation at distinct regions of the placental Hmox1 promoter. These stress-triggered changes were accompanied by an altered CD8(+) T cell response, as evidenced by a reduction of tolerogenic CD8(+)CD122(+) T cells and an increase of cytotoxic CD8(+) T cells. Using progesterone receptor- or Hmox1-deficient mice, we identified progesterone as an upstream modulator of placental Hmox1 expression. Supplementation of progesterone or depletion of CD8(+) T cells revealed that progesterone suppresses CD8(+) T cell cytotoxicity, whereas the generation of CD8(+)CD122(+) T cells is supported by Hmox1 and ameliorates fetal-growth restriction in Hmox1 deficiency. These observations in mice could promote the identification of pregnancies at risk for IUGR and the generation of clinical interventional strategies

Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis

Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through the endothelial layer of blood vessels to escape the hostile circulation and establish metastases at distant organ sites. Here, we identified the membrane-bound metalloprotease ADAM17 on endothelial cells as a key driver of metastasis. We show that TNFR1-dependent tumor cell-induced endothelial cell death, tumor cell extravasation, and subsequent metastatic seeding is dependent on the activity of endothelial ADAM17. Moreover, we reveal that ADAM17-mediated TNFR1 ectodomain shedding and subsequent processing by the gamma-secretase complex is required for the induction of TNF-induced necroptosis. Consequently, genetic ablation of ADAM17 in endothelial cells as well as short-term pharmacological inhibition of ADAM17 prevents long-term metastases formation in the lung. Thus, our data identified ADAM17 as a novel essential regulator of necroptosis and as a new promising target for antimetastatic and advanced-stage cancer therapies. Metastasis is the leading cause of death in cancer patients. We discovered that proteolytic processing of endothelial TNFR1 by the metalloprotease ADAM17 is essential for metastases formation. Based on our findings, we present a novel therapeutic approach to target metastasis