Background: Intrinsic resistance to androgen receptor signalling inhibitors (ARSI) occurs in 20À30% of men with metastatic castration-resistant prostate cancer (mCRPC). Ceramide metabolism may have a role in ARSI resistance. Our study's aim is to investigate the association of the ceramide-sphingosine-1-phosphate (ceramide-S1P) signalling axis with ARSI resistance in mCRPC. Methods: Lipidomic analysis (»700 lipids) was performed on plasma collected from 132 men with mCRPC, before commencing enzalutamide or abiraterone. AR gene aberrations in 77 of these men were identified by deep sequencing of circulating tumour DNA. Associations between circulating lipids, radiological progression-free survival (rPFS) and overall survival (OS) were examined by Cox regression. Inhibition of ceramide-S1P signalling with sphingosine kinase (SPHK) inhibitors (PF-543 and ABC294640) on enzalutamide efficacy was investigated with in vitro assays, and transcriptomic and lipidomic analyses of prostate cancer (PC) cell lines (LNCaP, C42B, 22Rv1). Findings: Men with elevated circulating ceramide levels had shorter rPFS (HR=2¢3, 95% CI=1¢5À3¢6, p = 0¢0004) and shorter OS (HR=2¢3, 95% CI=1¢4À36, p = 0¢0005). The combined presence of an AR aberration with elevated ceramide levels conferred a worse prognosis than the presence of only one or none of these characteristics (median rPFS time = 3¢9 vs 8¢3 vs 17¢7 months; median OS time = 8¢9 vs 19¢8 vs 34¢4 months). SPHK inhibitors enhanced enzalutamide efficacy in PC cell lines. Transcriptomic and lipidomic analyses

Background: Hemorrhage causes significant morbidity and mortality in persons under 65. A lyophilized platelet-derived hemostatic agent (Thrombosomes) demonstrated hemostatic efficacy in animal models. We report the results of the first safety trial of autologous Thrombosomes given to normal subjects. Study Design And Methods: Ten subjects received autologous Thrombosomes prepared from their apheresis platelets and 5 control subjects received a buffer solution. There were 5 Cohorts, 3 subjects/Cohort (2 Thrombosomes, 1 Control). Doses escalated from 1/1,000 to 1/10 of a proposed efficacious dose. Cohorts 4 and 5 received the highest dose, but, in Cohort 5, ½ the dose was infused two hours apart. Cohorts 1–3 were monitored for 42 days, Cohorts 4–5 for 60 days using hematology, coagulation and chemistry assays, and antibody testing. Results: There were no serious adverse events (SAEs) and no subject withdrawals. There were 8 treatment related adverse events (TRAEs) in 5/15 subjects (33%) [4 Thrombosomes (40%), 1 control]. Three of 4 subjects receiving the highest doses had TRAEs. One had elevated D-dimer, Prothrombin Fragment 1+2, and WBC (subject had concurrent upper respiratory infection), one had T-wave inversions in pre-cordial leads V2 and V3 without elevated Troponin or symptoms, and one had a platelet autoantibody without change in platelet count. All subjects TRAEs resolved by day 21. Conclusion: As there were no SAEs in this small study. Thrombosomes were considered safe at the doses assessed. Future, larger trials will be needed to further assess safety and efficacy.

In this swine model of liver injury, human lyophilized platelets increased intraoperative blood loss. With the use of species-specific lyophilized platelets, however, this effect was abolished, with a decrease in blood loss at 48 h after injury.

BACKGROUND Current limitations of platelet shelf life to 5 days have led to an increasingly greater demand for hemostatic agents with greater longevity. The objective of this study was to evaluate the function of a lyophilized platelet‐derived hemostatic product (thrombosome [TS]) as a potential alternative to fresh platelets. METHODS Platelets were collected from whole blood from healthy donors. TSs were reconstituted with water and added to various configurations of reassembled whole blood (platelets, plasma, and RBCs); measures included rotational thromboelastometry (ROTEM), optical aggregometry, mitochondrial function, calibrated automated thrombogram, collagen adhesion under flow (shear flow assay), and flow cytometry. RESULTS In ROTEM, no differences were observed between maximum clot formation values for contact pathway activation thromboelastometry tests with TSs or platelet samples. Significantly decreased aggregation was observed in the TSs versus platelets (p < 0.001 for all agonists). Flow cytometry measures demonstrated significant decreases in glycoprotein Ib expression and increases in phosphatidylserine expression in the TS group (p < 0.01). The calibrated automated thrombogram assay was suggestive (lag time and peak thrombin) that the TSs might have some thrombogenic properties. Measurements of mitochondrial function revealed that TSs had no functional mitochondria. CONCLUSION In this study, TSs were shown to have nonfunctional mitochondria. ROTEM measures revealed that the TSs had no impact on clot strength. Likewise, compared to platelets, the TSs displayed minimal aggregation, had significantly more phosphatidylserine (measure of activation status), but had the ability to adhere to a collagen surface under flow conditions and contribute to clot formation and induced greater thrombin generation.

Background: Periodontal disease is the leading cause of tooth loss worldwide. Current periodontal treatment is limited by its dependency on patients learning and maintaining good dental habits, and repeated visits to oral health physicians. Vitamin C’s role in collagen synthesis and immune function makes it important in wound healing and possibly periodontal healing. Therefore, if some patients are deficient, this may worsen patient outcomes. Methods: Patients were invited to participate following assessment and treatment at the Westmead Centre of Oral Health Periodontic Clinic, regardless of current disease stage or treatment. Adults were eligible if they gave informed consent and had current periodontal disease. Study involvement consisted of periodontal assessment and care followed by an interview and measurement of serum vitamin C and C-reactive protein (CRP). Results: A total of 6 out of 20 patients had vitamin C levels less than the institutional normal range, of whom 2 had levels <11.4 μmol/L and one <28 μmol/L. Low vitamin C was associated with higher periodontal disease stage (p = 0.03). Elevated CRP was found in 2/3 of people with low vitamin C and CRP was negatively correlated with vitamin C (p < 0.01). Vitamin C did not correlate with patient-reported fruit or vegetable consumption, but high processed meat intake was associated with lower vitamin C. Conclusion: Although a small study, this rate of vitamin C deficiency in the periodontal clinic is clinically important and correlations with disease severity and CRP suggests biological importance. This warrants further studies to assess vitamin C and whether supplementation improves periodontal outcomes, particularly in deficient subjects.