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BACKGROUND: China has low seasonal influenza vaccination rates among priority populations. In this study, we aimed to evaluate a pay-it-forward strategy to increase influenza vaccine uptake in rural, suburban, and urban settings in China. METHODS: We performed a quasi-experimental pragmatic trial to examine the effectiveness of a pay-it-forward intervention (a free influenza vaccine and an opportunity to donate financially to support vaccination of other individuals) to increase influenza vaccine uptake compared with standard-of-care user-paid vaccination among children (aged between 6 months and 8 years) and older people (≥60 years) in China. Recruitment took place in the standard-of-care group until the expected sample size was reached and then in the pay-it-forward group in primary care clinics from a rural site (Yangshan), a suburban site (Zengcheng), and an urban site (Tianhe). Participants were introduced to the influenza vaccine by project staff using a pamphlet about influenza vaccination and were either asked to pay out-of-pocket at the standard market price (US$8·5-23·2; standard-of-care group) or to donate any amount anonymously (pay-it-forward group). Participants had to be eligible to receive an influenza vaccine and to have not received an influenza vaccine in the past year. The primary outcome was vaccine uptake. Secondary outcomes were vaccine confidence and costs (from the health-care provider perspective). Regression methods compared influenza vaccine uptake and vaccine confidence between the two groups. This trial is registered with ChiCTR, ChiCTR2000040048. FINDINGS: From Sept 21, 2020, to March 3, 2021, 300 enrolees were recruited from patients visiting three primary care clinics. 55 (37%) of 150 people in the standard-of-care group (40 [53%] of 75 children and 15 [20%] of 75 older adults) and 111 (74%) of 150 in the pay-it-forward group (66 [88%] of 75 children and 45 [60%] of 75 older adults) received an influenza vaccine. People in the pay-it-forward group were more likely to receive an influenza vaccine compared with those in the standard-of-care group (adjusted odds ratio [aOR] 6·7 [95% CI 2·7-16·6] among children and 5·0 [2·3-10·8] among older adults). People in the pay-it-forward group had greater confidence in vaccine safety (aOR 2·2 [95% CI 1·2-3·9]), importance (3·1 [1·6-5·9]), and effectiveness (3·1 [1·7-5·7]). In the pay-it-forward group, 107 (96%) of 111 participants donated money for subsequent vaccinations. The pay-it-forward group had a lower economic cost (calculated as the cost without subtraction of donations) per person vaccinated (US$45·60) than did the standard-of-care group ($64·67). INTERPRETATION: The pay-it-forward intervention seemed to be effective in improving influenza vaccine uptake and community engagement. Our data have implications for prosocial interventions to enhance influenza vaccine uptake in countries where influenza vaccines are available for a fee. FUNDING: Bill & Melinda Gates Foundation and the UK National Institute for Health Research. ispartof: LANCET INFECTIOUS DISEASES vol:22 issue:10 pages:1484-1492 ispartof: location:United States status: published

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.

Non-small cell lung cancer (NSCLC) is responsible for the highest number of cancer-associated mortalities worldwide, and the five-year survival rate is

© 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.

BACKGROUND microRNAs (miRNAs) are involved in the regulation of various cellular processes, such as differentiation, proliferation, metabolism, and apoptosis, and they have been implicated in several diseases, including cancers. METHODS To assess the role of miRNA in the progression of breast cancer, we performed TaqMan-based miRNA profiling for plasma from patients with breast cancer (n = 53), unrelated diseases (n = 40), or matched healthy controls (n = 40), and for breast tumors or adjacent non-tumors (n = 41). RESULTS We selected 18 miRNAs with predicted roles in breast cancer and demonstrated that let-7i (p = 0.019), let-7a (p = 0.02), and miR-650 (p = 0.008) were significantly up-regulated in plasma; miR-21 (p < 0.001) is up-regulated in breast cancer tissue, and miR-30e was down-regulated in both plasma (p < 0.001) and breast cancer tissues (p = 0.004). Plasma miR-30e expression was shown to be statistically associated with age (p = 0.0402) and clinical stage (p = 0.007). However, receiver-operating characteristic curve analyses suggested that miR-30e expression cannot significantly differentiate breast cancer from healthy tissue or plasma. Consistent with a potential role for miR-30e in breast cancer, three predicted targets of miR-30e (RAB11A, BNIP3L, and RAB32) are up-regulated in breast cancer tissue. CONCLUSIONS These findings suggest that reduced miR-30e correlates with the clinical stage of breast cancer. It is worthwhile to further explore that the potential role of miR-30e as a tumor suppressor in breast cancer, as well as its potential therapeutic utility.

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.

Background E2F-1 is a transcription factor that stimulates cellular proliferation and cell cycle progression. E2F-1 alone is sufficient to stimulate cells to initiate DNA synthesis, and this unscheduled entry into S phase is a potent trigger of apoptosis. Gemcitabine, a novel pyrimidine analogue with structural and metabolic similarities to cytarabine, also can efficiently induce apoptosis, especially for cancer cells that are already in S phase. Gemcitabine has established antitumor activity against solid tumors, including head and neck, ovarian, and non-small cell lung cancers. Therefore, we hypothesized that exogenous E2F-1 expression could accumulate cells in the S phase and thus sensitize them to gemcitabine. Methods We constructed an adenoviral vector (AdCMVE2F-1) to transduce the exogenous E2F-1 gene into human cancer cells. Infection of human colon cancer cells with AdCMVE2F-1 resulted in the overexpression of E2F-1 mRNA and protein in a dose-dependent manner and consequently induced accumulation in S phase as measured by FACS analysis. To assess the synergistic antitumor effect of AdCMVE2F-1 and gemcitabine, the human colon cancer cel lines SW620, DLD-1, and LoVo were infected with AdCMVE2F-1 at various multiplicities of infection and then exposed to various concentrations of gemcitabine 24 hours after infection. Result Isobologram analysis showed that E2F-1-transduced cancer cells exhibited higher sensitivity to gemcitabine treatment compared to control virus-infected cells. Treatment with AdCMVE2F-1 plus gemcitabine enhanced endogenous p53 expression in LoVo cells, which contain wild-type p53; however, the finding that the synergistic effect can also be observed in mutant p53-expressing SW620 and DLD-1 cells suggests that wild-type p53 function may not be necessary for the therapeutic effects of this drug combination. Conclusions: Our data demonstrate that overexpression of ectopic E2F-1 protein may render cels more sensitive to gemcitabine-mediated apoptosis, an outcome that has important general implications for the treatment of human cancer.

BACKGROUND MicroRNAs (miRNAs) exist stably and reproducibly in plasma and may be used as biomarkers for various diseases. Little is known about circulating miRNAs in the peripheral blood of juvenile patients with asthma. METHODS In this study, we used hybridization arrays to compare the miRNA expression profiles among 6 juvenile patients with or without asthma. Using quantitative PCR (qPCR), we verified the expression levels of these miRNAs in plasma from patients with asthma (n = 40) and healthy subjects (n = 14). RESULTS Our results showed that the levels of plasma miR-Let7C, miR-486, and miR-1260a in childhood asthma patients were significantly higher than in healthy controls (p < 0.01). Additionally, miR-1260a is correlated with the treatment schedule of these patients and patients with long treatment times had higher expression of miR-1260a than short treatment times; miR494 was significantly associated with challenge, and miR-3162-3p was significantly associated with MEF25 in asthma patients suggesting a potential correlation of miRNA levels with clinical disease parameters. Receiver operator characteristic analysis confirmed that the levels of miR-3162-3p could be used to discriminate childhood asthma patients from healthy subjects (area under the curve of 0.821), suggesting it may be a potential diagnostic biomarker. CONCLUSIONS These results indicate that circulating miR-3162-3p and miR-1260a should be further evaluated as potential non-invasive biomarkers in diagnosis and treatment for childhood asthma.

The aim is to investigate the molecular mechanisms underlying the PM2.5-induced autophagy in human lung cancer epithelial cells (A549). The effects of the PM2.5 on morphological and biochemical markers of autophagy in A549 were analyzed by electron microscopy, GFP-LC3 puncta was observed by confocal fluorescence microscope. The effects of phosphorylation of AMPK, mTOR, AKT, ERK, JNK, and p53 on LC3II in A549 were observed following PM2.5 exposure; the role of autophagy in PM2.5-induced apoptosis was examined using 3-methyladenine and rapamycin. PM2.5 induced morphological and biochemical markers of autophagy in A549. Phosphorylation of AMPK and dephosphorylation of mTOR were observed following PM2.5 treatment, and AMPK inhibitor blocked LC3B-II expression. In addition, we demonstrated that PM2.5-induced autophagy confers a pro-survival role in host defense.

Collagen-induced arthritis (CIA) is a widely used animal model for human rheumatoid arthritis (RA). Th17 cells are thought to be critical for development of RA and CIA, mediated in part via production of IL-17. CIKS/Act1 is an important adaptor molecule for signaling by IL-17 and related cytokines. Although evidence suggests a role for IL-17 in RA, the physiologic relevance of CIKS/Act1 in RA and the CIA model has not been evaluated. We have applied the CIA model to CIKS deficient and wild-type (WT) B6 mice. Based on clinical scores and histochemical analyses, arthritis could be induced in WT, but not CIKS deficient mice. The production of collagen type 2-specific antibodies (CII-Abs) and neutrophil recruitment to the joint were also blocked in CIKS deficient mice. We also performed CIA model studies in mice with compound deficiency in CIKS and FcgammaRIIb (B6). Although the loss of FcgammaRIIb greatly exacerbated arthritis in the CIA model in CIKS-sufficient mice, arthritis and production of CII-Abs were still blocked in the absence of CIKS. In addition we determined that CIKS is not required in the collagen antibody-induced arthritis (CAIA) model, in contrast to this adaptor’s role in CIA. These data suggest a crucial role of CIKS during the generation of CII-Abs and clearly implicate the CIKS adaptor as essential for development of CIA and thus a potential therapeutic target in RA.