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BackgroundChina has low seasonal influenza vaccination rates among children and older adults. This quasi-experimental pragmatic trial examined the effectiveness of a pay-it-forward intervention on influenza vaccination compared to standard-of-care (user-paid vaccination) among children and older people in China. Pay-it-forward offered a free influenza vaccine from a local group and an opportunity to donate financially to support future individuals.MethodsAt each of the three study sites, participants were recruited into the standard-of-care arm first until expected sample size was reached and then recruited into the pay-it-forward arm. The primary outcome was vaccine uptake. Secondary outcomes included vaccine confidence and costs. Regression methods compared influenza vaccine uptake and vaccine confidence between the two arms.ResultsAmong 300 participants enrolled, 55/150(36.7%) in the standard-of-care arm 111/150(74.0%) in the pay-it-forward arm received an influenza vaccine. People in the pay-it-forward arm were more likely to receive the vaccine compared to people in the standard-of-care arm (adjusted odds ratio (aOR)= 6.7, 95%CI [2.7, 16.6] among children; aOR=5.0, [2.3, 10.8] among older adults). People in the pay-it-forward arm had greater confidence in vaccine safety, importance, and effectiveness. In the pay-it-forward arm, 107/111 (96.4%) of participants donated money for subsequent vaccinations, and 19 of 60 invited (31.7%) created postcard messages. The pay-it-forward arm had a lower economic cost per person vaccinated ($45.60) than the standard-of-care arm ($64.67).ConclusionsPay-it-forward was effective in improving influenza vaccine uptake and public engagement. Our data have implications for pro-social interventions to enhance influenza vaccine uptake in countries where influenza vaccines are available for a fee.Trial registrationChiCTR2000040048Main point summaryPay-it-forward substantially increased influenza vaccine uptake among children and older adults compared to standard of care user-paid vaccination.

Background: The modulations of subcutaneous allergen immunotherapy (SCIT) on lymphocyte subsets and cytokine productions are not fully clarified. Objective: We investigated the changes of T-lymphocyte subsets and serum Dermatophagoides pteronyssinus specific immunoglobulin G4 (Der-p-sIgG4), and cytokine productions in allergic asthmatics during Der-p SCIT. Methods: This study involved 20 allergic asthmatics receiving 156-week Der-p SCIT, 20 patients without SCIT (non-SCIT). Symptom and medication scores (SMS), serum Der-p-sIgG4 levels, CD4+CD25+Foxp3+ T regulatory (Treg), CD4+IL-4-IFN-γ+ T-helper (Th) 1, CD4+IL-4+IFN-γ- Th2 lymphocyte percentage in peripheral blood mononuclear cells (PBMCs) with/without Der-p extract stimulation at weeks 0, 4, 12, 16, 52, 104, and 156 were measured. Serum from SCIT and non-SCIT patients were incubated with Der-p allergen and Der-p sensitized PBMCs. Levels of interleukin (IL) -4, IL-5, IL-10, IL-13, IL-17, interferon (IFN) -γ, tumor necrosis factor (TNF) -α and transfer growth factor (TGF) -β1 in supernatant were detected. Results: SCIT patients had significantly lower SMS after week 52. Der-p-sIgG4 levels in SCIT patients significantly increased at week 16 compared to non-SCIT subjects. CD4+IL-4+IFN-γ- Th2 percentage in SCIT patients showed a significant decrease from week 104 to 156 comparing to week 0, while no change was observed in CD4+CD25+Foxp3+ Treg and CD4+IL-4-IFN-γ+ Th1 percentage. IL-5, IL-13, IL-4, IL-17, and TNF-α levels in supernatant of Der-p-sensitized PBMCs, cultured with serum of SCIT patients after 16 weeks decreased significantly compared with non-SCIT patients, and showed significant reverse associations with Der-p-sIgG4 levels. Conclusion: SCIT down-regulated Th2 cytokine productions associated reversely with Dep-p-sIgG4 levels in Der-p allergic asthma patients.

© The Author(s) 2018. Cardiovascular disease (CVD) is the leading cause of death in the world and our approach to the control and management of CVD mortality is limited. Nattokinase (NK), the most active ingredient of natto, possesses a variety of favourable cardiovascular effects and the consumption of Natto has been linked to a reduction in CVD mortality. Recent research has demonstrated that NK has potent fibrinolytic activity, antihypertensive, anti-atherosclerotic, and lipid-lowering, antiplatelet, and neuroprotective effects. This review covers the major pharmacologic effects of NK with a focus on its clinical relevance to CVD. It outlines the advantages of NK and the outstanding issues pertaining to NK pharmacokinetics. Available evidence suggests that NK is a unique natural compound that possesses several key cardiovascular beneficial effects for patients with CVD and is therefore an ideal drug candidate for the prevention and treatment of CVD. Nattokinase is a promising alternative in the management of CVD.

© Copyright 2018, Mary Ann Liebert, Inc. Lung cancer, caused mainly by smoking, is one of the most prevalent diseases in China, resulting in high mortality rates. The increasing incidence of chronic disease due to lung cancer places a huge burden on the welfare and cost to the Chinese society. Amplification of the fibroblast growth factor receptor 1 (FGFR1) is associated with high incidence and mortality in lung cancer patients. FGFR1 signaling is implicated in oncogenic traits such as proliferation, cell survival, angiogenesis, and migration. Targeting FGFR1 and its ligand basic FGF (bFGF) is a key step forward in developing new therapies for this crippling disease. Lung adenocarcinoma is the most common subtype of non-small-cell lung cancer. In this study, A549, a lung adenocarcinoma cell line widely used in vitro as a model for drug metabolism and as a transfection host, was used to study FGFR1. A stable lentiviral FGFR1 over-expression system in lung cancer cells is described for the study of anti-lung cancer drug candidates targeting FGFR1. Ligand binding to FGFR1 activates the PI3K/Akt/mTOR signaling pathway and increases adhesion, invasion, and migration in this model. Using a unique FGF monoclonal antibody developed in the laboratory, the overactive PI3K pathway was effectively blocked, abrogating the negative metastatic signaling pathways in lung cancer cells. Importantly, this model provides an effective and simple screening kit for anti-FGF1 drug compounds for lung cancer treatment and a tool for understanding the molecular mechanisms of the FGFR1 signaling pathway in lung cancer. Furthermore, this toolkit based on a FGFR1 lentiviral construct model is transferrable to study FGFR1 signaling in any type of cancer cell.

T helper cells type 17 (Th17) are thought to be critically involved in development of rheumatoid arthritis (RA) as well as in collagen-induced arthritis (CIA), a mouse model of RA. Arthritis inducing functions of Th17 cells are mediated in part via production of IL-17A (a.k.a. IL-17), the signature cytokine of Th17 (1, 2). IL-17A belongs to a family of six cytokines (IL-17A-F) that signal via receptors composed of members of a family of 5 polypeptides (IL-17RA-RE), although the nature of these receptors is still poorly understood (3-6). IL-17A and IL-17F are closely related and produced by Th17 cells, but both are also secreted by other cells, including γδ T cells, iNK T cells, and lymphoid tissue inducers, among others (4-9). IL-17B, IL-17C and IL-17D appear to be generated mainly by non-hematopoietic cells (3, 4), while IL-17E (more commonly named IL-25) has been reported to be produced by a variety of cell types, including, among others, Th2 cells, mast cells, eosinophils and lung epithelial cells (3, 4, 10). IL-17A and IL-17F may signal largely via a heteromeric receptor formed by IL-17RA and IL-17RC chains (4, 8), while IL-25 (IL-17E) may signal via a heteromeric receptor formed by IL-17RA and IL-17RB, with IL-17RB providing the primary binding surface for IL-25 (4, 11, 12). Nevertheless, the precise nature of the signaling receptors for IL-17A/F and IL-25 remains to be determined and very little is known about the receptors for the remaining members of this cytokine family. CIKS (Connection to IKK and SAPK/JNK; a.k.a. Act1) (13, 14) is an adaptor protein required for signaling by IL-17A (15-17). CIKS and all members of the IL-17 receptor family contain so-called SEFIR domains (similar expression to fibroblast growth factor [SEF]/IL-17 receptor domain); SEFIR domains are distantly related to TIR domains present on Toll and IL-1 receptors and their adaptors, such as MyD88. Upon signaling by IL-17A CIKS is recruited to the IL-17 receptor complex via heterotypic SEFIR domain-mediated interactions (16, 18) which initiates a cascade of events culminating in activation of downstream effectors regulating gene expression, including MAP kinases, NF-κB and c/EBPs (4, 13, 14). Recent evidence indicates that CIKS is also required for IL-25 signaling (17, 19) and while relatively little is known about the remaining members of the IL-17 cytokine and receptor families, it is reasonable to assume that CIKS is similarly important for their signaling as well. Much evidence implicates IL-17A as an important mediator of pathogenesis in the CIA model in mice as well as in rheumatoid arthritis patients (2). IL-17A has been identified in RA synovial biopsies (20). Furthermore, mice lacking IL-17A are partially resistant to CIA (21), and are impaired in the development of spontaneous arthritis on an IL-1Ra-deficient background (22). Blocking IL-17A with neutralizing antibodies reduces the severity of CIA (23) and improves signs and symptoms of RA (24). In addition, IL-17F may contribute to arthritis incidence, albeit modestly (25). IL-17B and IL-17C have been reported to contribute to TNFα production and to exacerbate pathology in the CIA model (26). Since all four of these cytokines are likely to signal via CIKS, this adaptor and the pathways it activates may provide a particularly useful target to combat RA. On the other hand, interfering with IL-17 cytokine signaling could critically impair host defense and render animals susceptible to infections. Furthermore, interference with CIKS function could also impair signaling by IL-25, a Th2 response-associated cytokine that can function to delimit the generation of Th17 cells (17, 27). Impaired IL-25 signaling could conceivably enhance Th17-associated functions not related to IL-17A/F, thus possibly exacerbating arthritis. Aside from its role in IL-17 cytokine family signaling, Act1/CIKS has also been proposed to negatively regulate CD40- and BAFF-mediated B cell functions and survival. Loss of Act1 was reported to trigger B cell hyper-reactivity, leading to autoantibody production and even outright autoimmune disease as mice age (15, 28). Therefore, loss of Act1/CIKS might exacerbate autoantibody production and thus pathology in CIA. However, the aforementioned blatant B cell hyper-reactivity and resulting autoimmune conditions were not apparent in an independently generated CIKS-deficient mouse model, possibly due to subtle strain and/or environmental differences, as discussed previously (17). Given these possible scenarios the physiologic role of CIKS in the pathogenesis of CIA remains on open question. The present study seeks to address the relevance of CIKS in the CIA model, especially as this will also help determine whether CIKS-mediated signaling could be a possible target for therapeutic intervention in RA. We have applied the CIA model to CIKS deficient and CIKS sufficient mice that had either an otherwise wild-type background or were also lacking FcγRIIb, with the latter mice displaying exacerbated arthritis pathology (29). We show that CIKS was absolutely necessary for the development of pathology in the CIA model on both genetic backgrounds. In contrast to CIA, CIKS had no role in the acute arthritis condition induced by administration of anti-collagen type II antibodies. In sum these data suggest that CIKS-mediated signaling should be considered as a therapeutic target for rheumatoid arthritis.