Elimination of 15N-thymidine after oral administration in human infants.

Background: We have developed a new clinical research approach for the quantification of cellular proliferation in human infants to address unanswered questions about tissue renewal and regeneration. The approach consists of oral 15N-thymidine administration to label cells in S-phase, followed by Multi-isotope Imaging Mass Spectrometry for detection of the incorporated label in cell nuclei. To establish the approach, we performed an observational study to examine uptake and elimination of 15N-thymidine.

Cangrelor PK/PD analysis in post-operative neonatal cardiac patients at risk for thrombosis.

Essentials An optimal therapeutic strategy has yet to be established to prevent early shunt thrombosis. A phase 1 study of cangrelor was performed in neonates after palliation of congenital heart disease. PD endpoint of >90% platelet inhibition in 60% of patients was achieved at 0.

P2Y Receptor Function and Response to Cangrelor in Neonates With Cyanotic Congenital Heart Disease.

Shunt thrombosis remains a major cause of morbidity and mortality, especially during the initial palliation for single-ventricle physiology. The authors present evidence that the P2Y inhibitor cangrelor may fill a therapeutic void in thromboprophylaxis. They base this theory on results showing that platelets from neonatal patients with cyanotic congenital heart disease have a robust response to adenosine diphosphate and are amenable to P2Y inhibition with cangrelor.

Exploiting the kinetic interplay between GPIbα-VWF binding interfaces to regulate hemostasis and thrombosis.

Platelet-von Willebrand factor (VWF) interactions must be tightly regulated in order to promote effective hemostasis and prevent occlusive thrombus formation. However, it is unclear what role the inherent properties of the bond formed between the platelet receptor glycoprotein Ibα and the A1 domain of VWF play in these processes. Using VWF-A1 knock-in mice with mutations that enhance (I1309V) or disrupt (R1326H) platelet receptor glycoprotein Ibα binding, we now demonstrate that the kinetic interplay between two distinct contact surfaces influences the site and extent to which platelets bind VWF.

Role of PI3Kdelta and PI3Kgamma in inflammatory arthritis and tissue localization of neutrophils.

The p110delta isoform of class I phosphoinositide 3-kinase (PI3K) plays a major role in B cell receptor signaling, while its p110gamma counterpart is thought to predominate in leukocyte chemotaxis. Consequently, emphasis has been placed on developing PI3Kgamma selective inhibitors to treat disease states that result from inappropriate tissue accumulation of leukocytes. We now demonstrate that PI3Kdelta blockade is effective in treating an autoimmune disorder in which neutrophil infiltration is required for tissue injury.

Modifying murine von Willebrand factor A1 domain for in vivo assessment of human platelet therapies.

The A1 domain of von Willebrand factor (VWF-A1) plays a crucial role in hemostasis and thrombosis by initiating platelet adhesion at sites of arterial injury through interactions with the platelet receptor glycoprotein Ib alpha (GPIbalpha). Here we report that murine VWF-A1 supports limited binding of human platelets. However, atomic models of GPIbalpha-VWF-A1 complexes identified an electrostatic 'hot-spot' that, when mutated in murine VWF-A1, switches its binding specificity from mouse to human GPIbalpha.