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Tyrosine kinase inhibitors (TKIs) have emerged as a promising class of target-directed, small molecule inhibitors used to treat hematologic malignancies, inflammatory diseases, and autoimmune disorders. Recently, TKIs have also gained interest as potential antiplatelet-directed therapeutics that could be leveraged to reduce pathologic thrombus formation and atherothrombotic complications, while minimally affecting platelet hemostatic function. This review provides a mechanistic overview and summarizes the known effects of tyrosine kinase inhibitors on platelet signaling and function, detailing prominent platelet signaling pathways downstream of the glycoprotein VI (GPVI) receptor, integrin αIIbβ3, and G protein-coupled receptors (GPCRs). This review focuses on mechanistic as well as clinically relevant and emerging TKIs targeting major families of tyrosine kinases including but not limited to Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (Syk), Src family kinases (SFKs), Janus kinases (JAK), and signal transducers and activators of transcription (STAT) and evaluates their effects on platelet aggregation and adhesion, granule secretion, receptor expression and activation, and protein phosphorylation events. In summation, this review highlights current advances and knowledge on the effects of select TKIs on platelet biology and furthers insight on signaling pathways that may represent novel druggable targets coupled to specific platelet functional responses. [ABSTRACT FROM AUTHOR]

Introduction: Inflammatory activation of the vascular endothelium leads to overexpression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), contributing to the pro-thrombotic state underpinning atherogenesis. While the role of TEC family kinases (TFKs) in mediating inflammatory cell and platelet activation is well defined, the role of TFKs in vascular endothelial activation remains unclear. We investigated the role of TFKs in endothelial cell activation in vitro and in a nonhuman primate model of diet-induced atherosclerosis in vivo. Methods and Results: In vitro, we found that ibrutinib blocked activation of the TFK member, BMX, by vascular endothelial growth factors (VEGF)-A in human aortic endothelial cells (HAECs). Blockade of BMX activation with ibrutinib or pharmacologically distinct BMX inhibitors eliminated the ability of VEGF-A to stimulate VCAM-1 expression in HAECs. We validated that treatment with ibrutinib inhibited TFK-mediated platelet activation and aggregation in both human and primate samples as measured using flow cytometry and light transmission aggregometry. We utilized contrast-enhanced ultrasound molecular imaging to measure platelet GPIbα and endothelial VCAM-1 expression in atherosclerosis-prone carotid arteries of obese nonhuman primates. We observed that the TFK inhibitor, ibrutinib, inhibited platelet deposition and endothelial cell activation in vivo. Conclusion: Herein we found that VEGF-A signals through BMX to induce VCAM-1 expression in endothelial cells, and that VCAM-1 expression is sensitive to ibrutinib in vitro and in atherosclerosis-prone carotid arteries in vivo. These findings suggest that TFKs may contribute to the pathogenesis of atherosclerosis and could represent a novel therapeutic target. [ABSTRACT FROM AUTHOR]

This study examines the unique effects of hospitality employees' perceptions of two types of motivation factors (intrinsic and extrinsic-hygiene) on their turnover intention and service-oriented organizational citizenship behavior (SOCB). Further, the study investigates the moderating role of power distance on the impacts of these two types of employee motivation factors. A series of hierarchical multiple regression analyses were performed to test the research hypotheses using the responses to a structured survey of 203 hospitality employees in New Zealand. The findings demonstrate that hospitality employees' perception of extrinsic-hygiene motivation factors has a stronger influence on their turnover intention while their perception of intrinsic motivation factors has a more salient impact on the exhibition of SOCB. The moderating role of power distance was found in the effect of hygiene factors on turnover intention (stronger in low power distance), that of intrinsic factors on turnover intention (stronger in low power distance), and that of intrinsic factors on SOCB (stronger in high power distance). The implications of the findings for researchers and practitioners and recommendations for future research are elucidated. [ABSTRACT FROM AUTHOR]

Circulating platelets establish a variety of immunological programs and orchestrate inflammatory responses at the endothelium. Platelets express the innate immunity family of Toll-like receptors (TLRs). While TLR2/TLR1 ligands are known to activate platelets, the effects of TLR2/TLR6 ligands on platelet function remain unclear. Here, we aim to determine whether the TLR2/TLR6 agonists Pam2CSK4 and FSL-1 activate human platelets. In addition, human umbilical vein endothelial cells (HUVECs) and platelets were co-cultured to analyze the role of platelet TLR2/TLR6 on inflammation and adhesion to endothelial cells. Pam2CSK4, but not FSL-1, induced platelet granule secretion and integrin αIIbβ3 activation in a concentration-dependent manner. Moreover, Pam2CSK4 promoted platelet aggregation and increased platelet adhesion to collagen-coated surfaces. Mechanistic studies with blocking antibodies and pharmacologic inhibitors demonstrated that the TLR2/Nuclear factor-κB axis, Bruton's-tyrosine kinase, and a secondary ADP feedback loop are involved in Pam2CSK4-induced platelet functional responses. Interestingly, Pam2CSK4 showed cooperation with immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling to enhance platelet activation. Finally, the presence of platelets increased inflammatory responses in HUVECs treated with Pam2CSK4, and platelets challenged with Pam2CSK4 showed increased adhesion to HUVECs under static and physiologically relevant flow conditions. Herein, we define a functional role for platelet TLR2-mediated signaling, which may represent a druggable target to dampen excessive platelet activation in thrombo-inflammatory diseases. [ABSTRACT FROM AUTHOR]

Spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (BTK) play critical roles in platelet physiology, facilitating intracellular immunoreceptor tyrosine-based activation motif (ITAM)-mediated signaling downstream of platelet glycoprotein VI (GPVI) and GPIIb/IIIa receptors. Small molecule tyrosine kinase inhibitors (TKIs) targeting Syk and BTK have been developed as antineoplastic and anti-inflammatory therapeutics and have also gained interest as antiplatelet agents. Here, we investigate the effects of 12 different Syk and BTK inhibitors on GPVI-mediated platelet signaling and function. These inhibitors include four Syk inhibitors, Bay 61-3606, R406 (fostamatinib), entospletinib, TAK-659; four irreversible BTK inhibitors, ibrutinib, acalabrutinib, ONO-4059 (tirabrutinib), AVL-292 (spebrutinib); and four reversible BTK inhibitors, CG-806, BMS-935177, BMS-986195, and fenebrutinib. In vitro, TKIs targeting Syk or BTK reduced platelet adhesion to collagen, dense granule secretion, and alpha granule secretion in response to the GPVI agonist cross-linked collagen-related peptide (CRP-XL). Similarly, these TKIs reduced the percentage of activated integrin αIIbβ3 on the platelet surface in response to CRP-XL, as determined by PAC-1 binding. Although all TKIs tested inhibited phospholipase C γ2 (PLCγ2) phosphorylation following GPVI-mediated activation, other downstream signaling events proximal to phosphoinositide 3-kinase (PI3K) and PKC were differentially affected. In addition, reversible BTK inhibitors had less pronounced effects on GPIIb/IIIa-mediated platelet spreading on fibrinogen and differentially altered the organization of PI3K around microtubules during platelets spreading on fibrinogen. Select TKIs also inhibited platelet aggregate formation on collagen under physiological flow conditions. Together, our results suggest that TKIs targeting Syk or BTK inhibit central platelet functional responses but may differentially affect protein activities and organization in critical systems downstream of Syk and BTK in platelets. [ABSTRACT FROM AUTHOR]

HIV and syphilis are pronounced among men who have sex with men (MSM) in China and often occur as co-infections, while testing remains low. Few studies examine common predictors across these outcomes. This observational venue-based sample of 546 MSM in Shanghai, China used a common set of psychosocial predictors to construct logistic models for the outcomes (HIV non-testing, syphilis non-testing, HIV sero-status, and syphilis sero-status). Fifty-seven (10.7%) participants tested positive for HIV, 126 (23.5%) for syphilis, and 33% of HIV-positive participants had a co-infection. Non-sex working MSM had consistently higher odds of HIV and syphilis non-testing (OR= 2.2, 95% CI 1.4-3.5, p < 0.001; OR = 2.4, 95, 95% CI 1.5-3.8, p < 0.001, respectively) compared to 'money boy' sex workers. Participants with a 0 score on HIV knowledge had 4.1 times (95% CI 1.4-12.5, p = 0.01) the odds of reporting HIV non-testing, 6.0 (95% CI 1.96-18.5, p < 0.01) times the odds of reporting non-testing for syphilis, and 8.44 times (95% CI 1.19-59.7, p = 0.03) the odds of testing positive for HIV, compared to a score of 8. The results highlighted the importance of integrating HIV/syphilis education and promoting testing for both HIV and syphilis among all sub-groups of MSM in China. [ABSTRACT FROM AUTHOR]

Men who have sex with men (MSM) are the group at highest risk for HIV in China. Researchers have used various recruitment methods to reach this population hidden from the hetero-normative culture. To inform future recruitment strategies, we compared estimates of socio-demographic characteristics, HIV risk behaviors, depression, and intimate partner violence (IPV) across three samples of MSM and money boys in Shanghai, China. Data were collected from three community-based samples of MSM and money boys (n = 1352) recruited via respondent-driven sampling (RDS) (n = 404), community popular opinion leaders (CPOL) (n = 385), and Internet and venue-based sampling (VBS) (n = 546). Different recruitment methods generated samples with statistically significant differences among a number of socio-demographic characteristics, sexual behaviors, drug use, depression scores, and exposure to IPV. Specifically, RDS participants had lower education (p = .002), income levels (p < .001), and were more likely to report condomless sex with a woman (p < .001). CPOL participants were younger (p < .001), more likely to report lifetime condomless anal sex (p = .009), more than 10 male partners in the past 30 days (p < .001), and were less likely to experience violence by a male intimate partner (p = .001). VBS participants had lowest depression score (p = .005) and were more likely to report lifetime drug use (p = .003). Our findings reinforce that each recruitment method may reach a sub-group of MSM with a specific risk profile, so multiple methods may be needed to obtain a representative sample of MSM. Interventions may use specific recruitment methods to target certain segments of the MSM population. [ABSTRACT FROM PUBLISHER]

Background: This study explores patterns of drug use and related correlates among a sample of men who have sex with men (MSM) and men who sell sex to other men (aka 'money boys') in China. Objectives: Data were collected from MSM and money boys (MBs) in Shanghai, China using a Community Popular Opinion Leader (CPOL) research design with a self-administered cross-sectional survey to: (1) describe drug use and drug use correlates and (2) examine relationships between drug use and sexual behaviors in general MSM and MBs. Methods: The sample consisted of 402 MSM (203 MBs) who live in Shanghai, China. Descriptive statistics and regression analyses were used to explore associations between drug use and sexual behaviors and make comparisons between MBs and general MSM. Results: MBs reported using more drugs in the last week, 3 months and ever; sex after using drugs, and unprotected sex after using drugs more frequently than general MSM. Additionally, many MBs reported receiving free drugs from their clients and those who did receive free drugs were very likely to report having unprotected sex. Conclusions: It is crucial to increase research and include Chinese MSM and their drug use in the Chinese policy conversation. These data suggest that drug use and sexual behaviors after drug use among Chinese MSM differ widely based upon selling sex and separate intervention strategies may be appropriate. [ABSTRACT FROM AUTHOR]

Although the Chinese government provides free-of-charge voluntary HIV counseling and testing, HIV testing rates among men who have sex with men (MSM) are reported to be extremely low. This study examines the association of structural and psychosocial factors and social network characteristics with HIV testing behaviors among 'money boys' and general MSM in Shanghai. Overall, 28.5% of 'money boys' and 50.5% of general MSM had never tested for HIV despite high rates of reported HIV risk behaviors. Factors associated with not testing for HIV included: not knowing of a testing site, limited HIV knowledge, low perceived HIV risk, concern about HIV testing confidentiality, being a closeted gay, not using the Internet, and having a small social network or network with few members who had tested for HIV. Future efforts to promote HIV testing should focus on outreach to general MSM, confidentiality protection, decreasing the stigma of homosexuality, and encouraging peer education and support through the Internet and social networks. [ABSTRACT FROM AUTHOR]

The use and misuse of alcohol and their relation to risky sex have received modest scholarly attention in China. This type of research in high HIV/STI groups such as men who have sex with men (general MSM) and men who sell sex to other men (“money boys”) (MB) in China is essentially absent. Therefore, the primary purpose of this exploratory study was to describe the types of alcohol consumed and levels of daily alcohol consumption among Chinese general MSM and MB in Shanghai, China. A secondary purpose was to explore demographic, lifetime sexual behavior, and psychosocial correlates of daily consumption levels. The sample consisted of 404 MSM (200 MB) who live in Shanghai, China. Participants were recruited using respondent-driven sampling and filled out a cross-sectional behavioral survey. Where appropriate, comparisons were made between MB and general MSM. Over 73% of participants reported drinking at least moderately every day. MB reported drinking Western red wine and other Western hard liquors (e.g., vodka) more frequently than general MSM. Conversely, general MSM consumed Chinese white wine more frequently than MB. Results from the regression analyses showed that MSM having higher lifetime sexual risks were more likely to drink in excess; though MB with greater social provisions were less likely to drink in excess. These results begin to highlight high levels of drinking and drinking-sexual risk relationships among groups of general MSM and MB and are useful for guiding intervention efforts among high-risk groups in China. [ABSTRACT FROM PUBLISHER]

Introduction: Smokefree street policies are relatively rare, and little has been published on the methods for establishing an evidence base to inform such policy making. We aimed to (a) pilot methods for such data collection in New Zealand, a country where local governments are actively pursuing outdoor smokefree policies and (a) to provide data on smoking behavior, attitudes toward smokefree policies, and levels of smoke exposure on streets in Wellington. Methods: Three methods were piloted: (a) systematic observation of smoking behavior by observers walking a standard route of major streets, the “Golden Mile” (GM) in Wellington (n = 42 observation runs); (b) measurement of fine particulate levels (PM2.5) along this route and with purposeful sampling in selected settings; and (c) an attitudinal survey of pedestrians along sections of this route. Results: Each of the 3 methods proved to be feasible in this urban setting. A total of 932 smokers were observed during 21 hr of observation, an average of 7 smokers every 10 min of walking. Air monitoring indicated fine particulate exposure. Levels of (mean) PM2.5 were 1.5 times higher during periods when smoking was observed than when they were not (9.3 vs. 6.3 μg/m3, p = .002). Dose–response patterns were observed for smoking proximity and for smoker numbers. Surveying pedestrians (n = 220) with a brief questionnaire achieved an 81% response rate and was able to identify variation in support for a smokefree GM by different groups (overall support was 55.9%, 95% CI = 49.3%–62.4%). Reasons for support were also identified, for example, perceived health hazards, at 34.1%, was the main reason. Conclusions: These methods can provide information that may contribute to the smokefree streets policymaking process and may also be relevant to informing other smokefree outdoor policies. [ABSTRACT FROM AUTHOR]

Introduction: Men who have sex with men (MSM) have higher smoking rates than the general population in the United States, but less is known about smoking among MSM in developing countries. Thus, we examined the prevalence and correlates of smoking among MSM in China. Methods: We conducted a cross-sectional study of 404 MSM in Shanghai, China (half of whom were male sex workers), recruited through respondent-driven sampling. Assessments included sociodemographics; tobacco, alcohol, and drug use; the Center for Epidemiological Studies Depression Scale (CES-D); the Social Provisions Scale (SPS); and the Lesbian, Gay, and Bisexual Identity Scale (LGBIS). Results: Smoking prevalence was 65.9% in this sample. Recent smoking (i.e., in the past 3 months) was significantly associated with lower education, greater alcohol use, and higher LGBIS scores, after controlling for important sociodemographics. Among smokers, smoking ≥10 cigarettes per day (CPD), in comparison with <10 CPD, was related to older age and lower LGBIS scores and marginally related to heavy alcohol use. Although bivariate analyses indicated a relationship of CES-D and SPS scores to recent smoking, these factors did not contribute to the regression models. Conclusions: Smoking rates among MSM in China are higher than MSM in the United States and men in China. Less comfort with one’s sexual orientation was related to smoking, particularly light smoking. Heavier alcohol consumption, lower education, and older age were also associated with smoking. Future research should confirm these findings and examine mediators and moderators of these relationships in order to inform cessation interventions and tobacco control policy. [ABSTRACT FROM AUTHOR]

The primary objective was to examine prevalence and correlates of social support and depressive symptoms among male sex workers (known as 'money boys' (MBs)) and general men who have sex with men (MSM) in Shanghai. The Social Provision Scale (SPS), which consists of 24 items, scored out of 4 for social provision, was used to evaluate the functions of social relationships. The score for each item ranges from 1 to 4, with a higher score indicating more social provision. The overall mean SPS score was 68.1 (s.d. = 6.53) for MBs and 69.3 (s.d. = 6.99) for general MSM. Depression was measured with a 12-item version of the Center for Epidemiological Studies Depression Scale (CES-D), where a score of 9 has been recommended as the cutoff score to indicate possible depressive symptoms. The prevalence of depressive symptoms was 57.9%, with MBs having a higher level of depressive symptoms than general MSM (70.0% v. 46.1%) (odds ratio = 1.86, 95% confidence interval = 1.07-3.24). Social support was a protective factor for depressive symptoms (odds ratio = 0.92, 95% confidence interval = 0.89-0.96). MSM in China, particularly MBs, are vulnerable to low social support and high depressive symptoms, highlighting the need for tailored psychological programs targeting this population. [ABSTRACT FROM AUTHOR]