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Background Optimal antiplatelet inhibition is vital during cerebrovascular stenting procedures, yet no standardized recommendation exists for antithrombotic therapy in these scenarios. Cangrelor is an intravenous P2Y12 inhibitor with a favorable pharmacokinetic profile for use during neuroendovascular stenting. Methods A retrospective review of all neuroendovascular patients who underwent stenting between 1 January 2019 and 22 March 2020 and were treated with cangrelor was conducted. Thirty-seven patients met inclusion criteria. Results All patients were administered a bolus of 5 mcg/kg of cangrelor followed by a maintenance infusion. Antiplatelet effects of cangrelor were monitored using platelet reactivity units (PRU). Based on the initial PRU, seven patients’ doses were adjusted with subsequent PRUs in or near the goal range of 50–150. One patient experienced an acute intraprocedural occlusion likely related to a subtherapeutic PRU which subsequently resolved with cangrelor dose adjustment and intra-arterial tirofiban administration, and one patient experienced a post-procedure stent occlusion which required a thrombectomy and intra-arterial tirofiban administration. No hemorrhagic complications occurred. Discussion Cangrelor utilization during neuroendovascular stenting with maintenance doses of <2 mcg/kg/min with dose adjustments based on platelet function testing has not been previously described. Cangrelor presents many advantages compared to standard therapy in patients undergoing stent placement related to its pharmacokinetic profile, rapid onset of action, ease of transition to oral P2Y12 antiplatelet agents, and measurability. Conclusion Cangrelor is a promising alternative to currently available therapies, especially in patients with a high hemorrhagic risk.

We recently reported a novel form of BMP2, designated nBMP2, which is translated from an alternative downstream start codon and is localized to the nucleus rather than secreted from the cell. To examine the function of nBMP2 in the nucleus, we engineered a gene-targeted mutant mouse model (nBmp2NLStm) in which nBMP2 cannot be translocated to the nucleus. Immunohistochemistry demonstrated the presence of nBMP2 staining in the myonuclei of wild type but not mutant skeletal muscle. The nBmp2NLStm mouse exhibits altered function of skeletal muscle as demonstrated by a significant increase in the time required for relaxation following a stimulated twitch contraction. Force frequency analysis showed elevated force production in mutant muscles compared to controls from 10 to 60 Hz stimulation frequency, consistent with the mutant muscle's reduced ability to relax between rapidly stimulated contractions. Muscle relaxation after contraction is mediated by the active transport of Ca2+ from the cytoplasm to the sarcoplasmic reticulum by sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), and enzyme activity assays revealed that SERCA activity in skeletal muscle from nBmp2NLStm mice was reduced to approximately 80% of wild type. These results suggest that nBMP2 plays a role in the establishment or maintenance of intracellular Ca2+ transport pathways in skeletal muscle.

The transcription factor Lc-Maf, which is a splice variant of c-Maf, is expressed in cartilage undergoing endochondral ossification and participates in the regulation of type II collagen through a cartilage-specific Col2a1 enhancer element. Type XXVII and type XI collagens are also expressed in cartilage during endochondral ossification, and so enhancer/reporter assays were used to determine whether Lc-Maf could regulate cartilage-specific enhancers from the Col27a1 and Col11a2 genes. The Col27a1 enhancer was upregulated over 4-fold by Lc-Maf, while the Col11a2 enhancer was downregulated slightly. To confirm the results of these reporter assays, rat chondrosarcoma (RCS) cells were transiently transfected with an Lc-Maf expression plasmid, and quantitative RT-PCR was performed to measure the expression of endogenous Col27a1 and Col11a2 genes. Endogenous Col27a1 was upregulated 6-fold by Lc-Maf overexpression, while endogenous Col11a2 was unchanged. Finally, in situ hybridization and immunohistochemistry were performed in the radius and ulna of embryonic day 17 mouse forelimbs undergoing endochondral ossification. Results demonstrated that Lc-Maf and Col27a1 mRNAs are coexpressed in proliferating and prehypertrophic regions, as would be predicted if Lc-Maf regulates Col27a1 expression. Type XXVII collagen protein was also most abundant in prehypertrophic and proliferating chondrocytes. Others have shown that mice that are null for Lc-Maf and c-Maf have expanded hypertrophic regions with reduced ossification and delayed vascularization. Separate studies have indicated that Col27a1 may serve as a scaffold for ossification and vascularization. The work presented here suggests that Lc-Maf may affect the process of endochondral ossification by participating in the regulation of Col27a1 expression.