ABSTRACT
Essentials The rs773902 SNP results in differences in platelet protease-activated receptor (PAR4) function. The functional consequences of rs773902 were analyzed in human platelets and stroke patients. rs773902 affects thrombin-induced platelet function, PAR4 desensitization, stroke association. Enhanced PAR4 Thr120 effects on platelet function are blocked by ticagrelor. SUMMARY: Background F2RL3 encodes protease-activated receptor (PAR) 4 and harbors an A/G single-nucleotide polymorphism (SNP) (rs773902) with racially dimorphic allelic frequencies. This SNP mediates an alanine to threonine substitution at residue 120 that alters platelet PAR4 activation by the artificial PAR4-activation peptide (PAR4-AP) AYPGKF. Objectives To determine the functional effects of rs773902 on stimulation by a physiological agonist, thrombin, and on antiplatelet antagonist activity. Methods Healthy human donors were screened and genotyped for rs773902. Platelet function in response to thrombin was assessed without and with antiplatelet antagonists. The association of rs773902 alleles with stroke was assessed in the Stroke Genetics Network study. Results As compared with rs773902 GG donors, platelets from rs773902 AA donors had increased aggregation in response to subnanomolar concentrations of thrombin, increased granule secretion, and decreased sensitivity to PAR4 desensitization. In the presence of PAR1 blockade, this genotype effect was abolished by higher concentrations of or longer exposure to thrombin. We were unable to detect a genotype effect on thrombin-induced PAR4 cleavage, dimerization, and lipid raft localization; however, rs773902 AA platelets required a three-fold higher level of PAR4-AP for receptor desensitization. Ticagrelor, but not vorapaxar, abolished the PAR4 variant effect on thrombin-induced platelet aggregation. A significant association of modest effect was detected between the rs773902 A allele and stroke. Conclusion The F2RL3 rs773902 SNP alters platelet reactivity to thrombin; the allelic effect requires P2Y12 , and is not affected by gender. Ticagrelor blocks the enhanced reactivity of rs773902 A platelets. PAR4 encoded by the rs773902 A allele is relatively resistant to desensitization and may contribute to stroke risk.
Subject(s)
Blood Platelets/drug effects , Pharmacogenomic Variants , Platelet Aggregation Inhibitors/pharmacology , Polymorphism, Single Nucleotide , Purinergic P2Y Receptor Antagonists/pharmacology , Receptors, Purinergic P2Y12/drug effects , Receptors, Thrombin/agonists , Receptors, Thrombin/genetics , Thrombin/pharmacology , Ticagrelor/pharmacology , Adult , Animals , Blood Platelets/metabolism , COS Cells , Chlorocebus aethiops , Drug Interactions , Female , HEK293 Cells , Humans , Male , Middle Aged , Platelet Aggregation/drug effects , Receptors, Purinergic P2Y12/metabolism , Receptors, Thrombin/metabolism , Risk Factors , Stroke/blood , Stroke/genetics , Young AdultABSTRACT
In 2000, we monitored the course and persistence of human papillomavirus (HPV) infection in 54 women who were HPV positive and free of any cytological disease using HPV-DNA genotyping with a linear array assay (baseline). The impact of HPV infection on development of cervical cytological abnormality (dyskaryosis) was monitored by repeat HPV genotyping and cytological assessment 2 years later. Detection of mRNA transcripts of known HPV oncogenes E6 and E7 using NASBA methodology and specific molecular beacons for five common HPV types was also performed at both time points. A total of 11/54 (20%) women developed dyskaryosis after 2 years with 31/54 and 23/54 women exhibiting transient and persistent infections respectively, as monitored by DNA genotyping. Women who maintained type-specific persistent HPV infection were significantly more likely to develop dyskaryosis compared to those who exhibited a transient infection (P = 0.001). The presence of HPV mRNA E6/E7 transcripts was less sensitive but more specific for the detection of disease at follow up. Moreover, women who were DNA positive and also positive for mRNA transcripts at baseline were significantly more likely to harbour persistent infection compared to those in whom DNA only was detected at baseline (P = 0.013). This study highlights the importance of detecting persistent type specific HPV infection to identify those women more at risk of developing cervical abnormalities, either by repeated DNA genotyping, or potentially by RNA based techniques that may be more predictive of persistent infection if performed at a single time point.
Subject(s)
Papillomaviridae/classification , Papillomaviridae/pathogenicity , Papillomavirus Infections/virology , Uterine Cervicitis/virology , Adult , DNA, Viral/genetics , DNA, Viral/isolation & purification , Female , Follow-Up Studies , Genotype , Humans , Papillomaviridae/genetics , Papillomaviridae/isolation & purification , Papillomavirus Infections/etiology , RNA, Messenger/genetics , RNA, Messenger/isolation & purification , RNA, Viral/genetics , RNA, Viral/isolation & purification , Uterine Cervical Dysplasia/etiology , Uterine Cervical Dysplasia/virology , Uterine Cervical Neoplasms/etiology , Uterine Cervical Neoplasms/virology , Uterine Cervicitis/etiologyABSTRACT
Oncology nursing is a specialty that continuously incorporates new technologic advances into everyday practice. These advances, coupled with an increasing acuity level of the patient with cancer, generate a demand for excellence. The successful development of the expert oncology nurse will be imperative in meeting these challenges. This paper provides a practical framework for examining expertise and describes characteristics of the expert oncology nurse.