The benefit of making voluntary choices generalizes across multiple effectors.

It has been shown that cognitive performance could be improved by expressing volition (e.g., making voluntary choices), which necessarily involves the execution of action through a certain effector. However, it is unclear if the benefit of expressing volition can generalize across different effectors. In the present study, participants made a choice between two pictures either voluntarily or forcibly, and subsequently completed a visual search task with the chosen picture as a task-irrelevant background. The effector for choosing a picture could be the hand (pressing a key), foot (pedaling), mouth (commanding), or eye (gazing), whereas the effector for responding to the search target was always the hand. Results showed that participants responded faster and had a more liberal response criterion in the search task after a voluntary choice (vs. a forced choice). Importantly, the improved performance was observed regardless of which effector was used in making the choice, and regardless of whether the effector for making choices was the same as or different from the effector for responding to the search target. Eye-movement data for oculomotor choice showed that the main contributor to the facilitatory effect of voluntary choice was the post-search time in the visual search task (i.e., the time spent on processes after the target was found, such as response selection and execution). These results suggest that the expression of volition may involve the motor control system in which the effector-general, high-level processing of the goal of the voluntary action plays a key role.

The efficacy of Facebook's vaccine misinformation policies and architecture during the COVID-19 pandemic.

Online misinformation promotes distrust in science, undermines public health, and may drive civil unrest. During the coronavirus disease 2019 pandemic, Facebook-the world's largest social media company-began to remove vaccine misinformation as a matter of policy. We evaluated the efficacy of these policies using a comparative interrupted time-series design. We found that Facebook removed some antivaccine content, but we did not observe decreases in overall engagement with antivaccine content. Provaccine content was also removed, and antivaccine content became more misinformative, more politically polarized, and more likely to be seen in users' newsfeeds. We explain these findings as a consequence of Facebook's system architecture, which provides substantial flexibility to motivated users who wish to disseminate misinformation through multiple channels. Facebook's architecture may therefore afford antivaccine content producers several means to circumvent the intent of misinformation removal policies.

Cytokine profiles in patients with newly diagnosed diffuse large B-cell lymphoma: IL-6 and IL-10 levels are associated with adverse clinical features and poor outcomes.

BACKGROUND: The development of diffuse large B-cell lymphoma (DLBCL), a prevalent subgroup of non-Hodgkin lymphoma (NHL), potentially involves various cytokines. We aimed to determine the correlation between deregulated serum levels of cytokines and clinical features and investigate their impact on the prognosis of patients with DLBCL. METHODS: We conducted a retrospective study of 77 patients with newly diagnosed DLBCL to explore the relationships between different cytokines, adverse clinical features, and poor outcomes. The Mann-Whitney U test was used to compare the cytokine profiles between patients with DLBCL and healthy controls. The Kaplan-Meier method was used to analyze the probability of survival, and the log-rank tests were used to evaluate the differences between survival curves. The Cox proportional hazards regression model was used to performed univariate and multivariate analyses to evaluate prognostic variables for survival analyze. RESULTS: Serum levels of interleukin-2 (IL-2), tumor necrosis factor (TNF)-α, IL-6, IL-10, and IFN-γ were significantly elevated in patients with untreated DLBCL. Serum levels of IL-6 and IL-10 were significantly higher in patients with an International Prognostic Index (IPI) of 3-5, bone marrow involvement, serum levels of LDH ≥ 250 U/L, and ß2-microglobulin (ß2-MG) levels ≥ 2.3 mg/L. Patients with B symptoms only had higher serum IL-10 levels, whereas patients with a partial response or no response to treatment had significantly elevated serum levels of IL-6 as well as IL-10. Significant positive correlations were observed between the levels of IL-6 and IL-10 with those of ß2-MG and LDH. Patients with levels of IL-6 ≥ 4.5 or IL-10 ≥ 5.0 pg/mL, as well as combined elevated IL-6 and IL-10 levels, exhibited shorter progression-free survival and overall survival. Additionally, univariate and multivariate analyses revealed that serum levels of IL-6 ≥ 4.5 pg/mL and IL-10 ≥ 5.0 pg/mL and IPI 3-5 were independent prognostic factors for relapse and survival in patients with DLBCL. CONCLUSIONS: Pre-treatment serum IL-6 and IL-10 levels in patients with newly diagnosed DLBCL might be powerful markers for determining treatment response and predicting the prognosis of DLBCL.

Cerebrospinal fluid interleukin-6 is a potential diagnostic biomarker for central nervous system involvement in adult acute myeloid leukemia.

Objective: We evaluated the correlation between cerebrospinal fluid (CSF) cytokine levels and central nervous system (CNS) involvement in adult acute myeloid leukemia (AML). Methods: The study sample consisted of 90 patients diagnosed with AML and 20 with unrelated CNS involvement. The AML group was divided into two sub-groups: those with (CNS+, n=30) and without CNS involvement (CNS-, n=60). We used a cytometric bead assay to measure CSF interleukin (IL)-2, IL-4, IL-6, and IL-10, tumor necrosis factor-α, interferon-γ, and IL-17A. We used receiver operating characteristic curves to evaluate the ability of CSF cytokine levels to identify CNS involvement in adult AML. Results: CSF IL-6 levels were significantly higher in CNS+adult AML patients and positively correlated with the lactate dehydrogenase levels (r=0.738, p<0.001) and white blood cell (WBC) count (r=0.455, p=0.012) in the blood, and the protein (r=0.686, p<0.001) as well as WBC count in the CSF (r=0.427, p=0.019). Using a CSF IL-6 cut-off value of 8.27 pg/ml yielded a diagnostic sensitivity and specificity was 80.00% and 88.46%, respectively (AUC, 0.8923; 95% CI, 0.8168-0.9678). After treating a subset of tested patients, their CSF IL-6 levels decreased. Consequently, the elevated CSF IL-6 levels remaining in CNS+ adult AML patients post-treatment were associated with disease progression. Conclusion: CSF IL-6 is a promising marker for the diagnosis of adult AML with CNS involvement and a crucial dynamic indicator for therapeutic response.

The impact of Facebook's vaccine misinformation policy on user endorsements of vaccine content: An interrupted time series analysis.

OBJECTIVES: To evaluate the impact of Facebook's vaccine misinformation policy in March 2019 on user endorsements of vaccine content on its platform. METHODS: We identified 172 anti- and pro-vaccine Facebook Pages and collected posts from these Pages six months before and after the policy. Using interrupted time series regression models, we evaluated the policy impact on user endorsements (i.e., likes) of anti- and pro-vaccine posts on Facebook. RESULTS: The number of likes for posts on anti-vaccine Pages had decreased after the policy implementation (policy = 153.2, p < 0.05; policy*day = -0.838, p < 0.05; marginal effect at the mean = -22.74, p < 0.01; marginal effect at the median = -24.56, p < 0.01). When the number of subscribers was considered, the policy effect on the number of likes for anti-vaccine posts was much smaller, but still statistically significant (policy = 4.849, p < 0.05; policy*day = -0.027, p < 0.05; marginal effect at the mean = -0.742, p < 0.01; marginal effect at the median = -0.800, p < 0.01). There was no policy effect observed for posts on pro-vaccine Pages. CONCLUSIONS: Our analysis suggested that Facebook's March 2019 vaccine misinformation policy moderately impacted the number of endorsements of anti-vaccine content on its platform. Social media companies can take measures to limit the popularity of anti-vaccine content by reducing their reach and visibility. Future research efforts should focus on evaluating additional policies and examining policies across platforms.

Making a saccade enhances Stroop and Simon conflict control.

Cognitive control is an important ability instantiated in many situations such as conflict control (e.g., Stroop/Simon task) and the control of eye movements (e.g., saccades). However, it is unclear whether eye movement control shares a common cognitive control system with the conflict control. In Experiment 1, we asked participants to make a prosaccade or antisaccade and then to identify the color of a lateralized color word (i.e., a Stroop-Simon stimulus). The stimulus onset asynchrony (SOA) between the saccadic cue and the Stroop-Simon stimulus was manipulated to be either short (200 ms) or long (600 ms). Results showed that the Stroop effect at the response level and the (negative) Simon effect were smaller when the SOA was short than long, demonstrating a decline of response control over time after making a saccade. Moreover, this temporal change of the Simon effect was more pronounced in the antisaccade session than in the prosaccade session. Furthermore, individuals who had better performance in the antisaccade task performed better in the response control of Stroop interference. When the saccade task was removed in Experiment 2, the temporal declines of the response control observed in Experiment 1 were absent. Experiment 3 replicated the key results of Experiment 1 by replacing the Stroop-Simon task with a typical Simon task and separately testing the typical Stroop and Simon tasks. Overall, our findings suggest that a common system is shared between the control of eye movements and the conflict control at the response level.

An Investigation of Influential Users in the Promotion and Marketing of Heated Tobacco Products on Instagram: A Social Network Analysis.

While an increasing body of the literature has documented the exposure to emerging tobacco products including heated tobacco products (HTPs) on social media, few studies have investigated the various stakeholders involved in the generation of promotional tobacco content. This study constructed a social network of Instagram users who posted IQOS content, a leading HTP brand, between 1 January and 5 April 2021 and identified users who positioned near the center of the network. We identified 4526 unique Instagram users who had created 19,951 IQOS-related posts during the study period. Nearly half of the users (42.1%) were business accounts authorized by Instagram, among which 59.0% belonged to Personal Goods and General Merchandise Stores and 18.1% belonged to Creators and Celebrities. For users with higher in-degree, out-degree, betweenness, and closeness centrality in the network, the majority of them were accounts directly associated with IQOS (e.g., containing "iqos" in username) or related to tobacco business as self-identified in the bio. Our findings further refine the social media marketing presence of tobacco products and suggest that the current self-regulatory efforts led by social media platforms are far from enough.

A qualitative investigation of the need for and feasibility of weight loss programs on university campuses.

BACKGROUND: Despite the public health significance of overweight and obesity, weight management has remained a low priority for health-related programming on university campuses. OBJECTIVE: Investigate the need for and feasibility of implementing university-based weight loss programs. METHODS: The Practical, Robust Implementation and Sustainability Model (PRISM) was used as a framework. Semi-structured individual interviews were conducted with fifteen university staff and students from two large U.S. universities in the Northeast and Mid-Atlantic. Interviews aimed to assess readiness, preferences, characteristics, barriers and facilitators in each of the four adapted PRISM domains: (1) Organizational and Recipient (Student) Perspectives on the Intervention, (2) Recipient (Student) Characteristics, (3) Internal Environment (organizational characteristics and infrastructure), and (4) External Environment. Verbatim transcriptions were analyzed using inductive and deductive thematic analyses. Themes were extracted as outlined by Consensual Qualitative Research. RESULTS: Participants supported university-based weight loss programs, but recognized barriers of resources, coordination across entities, and competing health issues taking priority for school programming. Campus built environment and students' busy schedules were identified as barriers to maintaining healthy weight and participation in weight loss programs. Recommendations included designing weight loss programming with a positive and holistic approach, minimizing weight-stigma, ensuring support from university leaders and students, and securing external funding. CONCLUSIONS: The identified themes provide recommendations for universities looking to develop and implement weight loss programming.

HADLN: Hybrid Attention-Based Deep Learning Network for Automated Arrhythmia Classification.

In recent years, with the development of artificial intelligence, deep learning model has achieved initial success in ECG data analysis, especially the detection of atrial fibrillation. In order to solve the problems of ignoring the correlation between contexts and gradient dispersion in traditional deep convolution neural network model, the hybrid attention-based deep learning network (HADLN) method is proposed to implement arrhythmia classification. The HADLN can make full use of the advantages of residual network (ResNet) and bidirectional long-short-term memory (Bi-LSTM) architecture to obtain fusion features containing local and global information and improve the interpretability of the model through the attention mechanism. The method is trained and verified by using the PhysioNet 2017 challenge dataset. Without loss of generality, the ECG signal is classified into four categories, including atrial fibrillation, noise, other, and normal signals. By combining the fusion features and the attention mechanism, the learned model has a great improvement in classification performance and certain interpretability. The experimental results show that the proposed HADLN method can achieve precision of 0.866, recall of 0.859, accuracy of 0.867, and F1-score of 0.880 on 10-fold cross-validation.

Mobile phone-based messaging for tobacco cessation in low and middle-income countries: A systematic review.

INTRODUCTION: Mobile phone-based tobacco cessation (mCessation) interventions are effective in high-income countries but their effectiveness in low and middle-income countries (LMICs) is unclear. We aimed to assess the evidence-base for mCessation interventions in LMICs by synthesizing study characteristics and to describe intervention characteristics and content. METHODS: Studies were included in this review if they evaluated an intervention that targeted tobacco users, were conducted in an LMIC, measured tobacco cessation as a primary or secondary outcome, and were primarily delivered using mobile phone (text or app-based) messaging. Data were extracted on fields pertaining to study and intervention characteristics and study quality was assessed using the Effective Public Health Practice Project tool. Screening, extraction and quality assessment were conducted by two independent reviewers. RESULTS: Of 606 unique records, 12 articles were included. The majority of studies were methodologically weak. Methodological limitations included small sample sizes, short follow-up durations and use of self-reported outcomes. Most evaluations were conducted in upper middle-income countries with urban, adult smokers intending to quit smoking. Approximately half the interventions were bidirectional (enabled two-way messaging) and fully automated. Almost all interventions were delivered via SMS. Treatment offerings of the intervention and control groups varied widely. CONCLUSIONS: More rigorous large-scale randomized controlled trials are needed to conclusively establish the efficacy of mCessation interventions in LMICs. Interventions also need to be tested across more diverse populations and settings. Future studies should test the relative effectiveness of different intervention characteristics.

Cytokine profiles in patients with newly diagnosed multiple myeloma: Survival is associated with IL-6 and IL-17A levels.

BACKGROUND: Identifying specific risk factors associated with multiple myeloma (MM) remains a significant issue. Different cytokines take part in the pathogenesis, progression, and prognosis of MM. Therefore, this study aimed to investigate the correlations between serum cytokine levels and clinical characteristics and determine their effects on disease progression and survival of MM patients. METHODS: We retrospectively analyzed the serum levels of 7 cytokines in 105 patients with newly diagnosed MM and in 20 healthy subjects. Interleukin (IL)-2, IL-4, IL-6, IL-10, and IL-17A, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were quantitatively determined by cytometric bead assay techniques. The concentrations of each cytokine were compared between the MM patients and healthy subjects using the Mann-Whitney U test. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). RESULTS: Serum IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α, and IFN-γ levels were higher in patients with newly diagnosed MM than in healthy controls. Positively significant correlations were found between IL-6, IL-10, IL-17A, and ß2-microglobulin. Significant correlations were also observed between IL-6 and IL-10, and lactate dehydrogenase. The overall response rate of low-IL-6 and IL-17A patients was significantly higher than that of high-IL-10 and IL-17A patients (P < 0.01). Univariate and multivariate analyses revealed that serum IL-6 levels were >3 pg/mL, serum IL-17A levels were >4 pg/mL, and treatment regimens were independent prognostic factors for PFS and OS. CONCLUSIONS: Cytokine deregulation, especially that of IL-6 and IL-17A, may be a powerful predictor of clinical prognosis for MM patients.

Peer-to-Peer Social Media as an Effective Prevention Strategy: Quasi-Experimental Evaluation.

BACKGROUND: Substance use by adolescents remains to be at unacceptably high levels, and there is evidence that teens' social norms are becoming more favorable toward recreational use and perceived safety of substances such as marijuana and prescription opioids. Social media offer a low-cost, potentially high-impact approach to disseminate prevention messages. OBJECTIVE: Living the Example (LTE) is a program that trains adolescent youth ambassadors to develop and disseminate prevention messages within their own social media networks and through in-school activities. This study aimed to evaluate the effects of exposure to LTE-based social media on students in the youth ambassadors' networks. METHODS: The George Washington (GW) University designed and implemented a quasi-experimental evaluation of the LTE program in 3 Maryland high schools. Before program launch, a sample of 826 students (wave 1) at the 3 schools, drawn from a census of freshmen enrolled in a class attended by all students at the grade level, completed a survey. A total of 584 students were surveyed at the wave 2 program midpoint and 542 at the wave 3 endpoint. The survey contained questions on drug use-related attitudes, beliefs, intentions, and behaviors, all based on validated measures. We evaluated the effects of LTE on the intended next 30-day drug use, and controlling for LTE self-reported exposure, age, and gender from waves 2 and 3 was appended into a single dataset. We first conducted ordinal logistic regressions for each drug use intention in wave 3 (ie, sell or distribute illegal drugs, smoke cigarettes, drink beer/wine/hard liquor when parents do not know about it, use marijuana, use lysergic acid diethylamide, cocaine, amphetamines or other illegal drugs, use heroin, use synthetic drugs, and use any prescription pills without a prescription) to examine the association between LTE exposure and drug use intentions. We included an interaction term for the study wave to examine intervention effects. RESULTS: We found a significant positive effect of LTE exposure on all 8 measured drug use intentions: sell/distribute illegal drugs; smoke cigarettes; drink beer, wine, or liquor when my parents do not know about it; use marijuana; use cocaine, amphetamines, or other illegal drug; use heroin; use synthetic drugs; use any prescription pills without a prescription (all P<.05; odds ratios ranging from 2.12 to 3.71). We also found that boys were more likely than girls to exhibit reduced drug use intentions. We also found reductions in 30-day intentions between the second and third survey waves for all 8 measured drug use variables. CONCLUSIONS: Overall, the results are consistent with and indicate a stronger LTE effect in this study compared with a previous pilot study. LTE appears to offer a protective effect, with exposure to program messages leading to reduced/improved drug use intentions.

Evaluating the Training of Chinese-Speaking Community Health Workers to Implement a Small-Group Intervention Promoting Mammography.

This study evaluated the training of Chinese American Community Health Workers (CHWs) to implement a small-group mammography video and discussion program as part of a randomized controlled trial that had the goal to increase adherence to mammography screening guidelines among Chinese American women. A total of 26 Chinese American CHWs in the metropolitan Washington DC area, Southern California, and New York City participated in a 4-h training workshop and completed surveys before and after the workshop to assess their knowledge regarding mammography screening guidelines and human subjects protection rules. The results showed significantly increased knowledge of mammography screening guidelines and human subjects protection rules (both p < 0.01) after the training. CHWs were also trained to lead a discussion of the video, including screening benefits and misconceptions. Forty-three audio recordings of discussions led by 13 active CHWs were transcribed and qualitatively analyzed to assess implementation fidelity. Ten out of 13 active CHWs fully addressed about 3 of the 5 benefit items, and 11 out of 13 CHWs fully addressed more than 5 of the 9 misconception items. Chinese CHWs can be trained to implement research-based intervention programs. However, a one-time training resulted in moderate adherence to the discussion protocol. Ongoing or repeat trainings throughout the intervention period may be needed to enhance implementation fidelity.

MicroRNA-411 Downregulation Enhances Tumor Growth by Upregulating MLLT11 Expression in Human Bladder Cancer.

Although several previous studies have reported the implication of various microRNAs (miRNAs) in regulation of human bladder cancer (BC) development, alterations and function of many miRNAs in bladder cancer growth are not explored yet at present. Here, we screened 1,900 known miRNAs and first discovered that miR-411 was one of the major miRNAs, which was down-regulated in n-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced BCs. This miR-411 down-regulation was also observed in human BC tissues and cell lines. The results from evaluating the relationship between miR-411 and patient survival in BC using the TCGA (The Cancer Genome Atlas) database indicated that miR-411 was positively correlated with DFS (disease-free survival). Our studies also showed that miR-411 inhibited tumor growth of human BC cells in a xenograft animal model. Mechanistic studies revealed that overexpression of miR-411 repressed the expression of ALL1-fused gene from the chromosome 1q (AF1q) (MLLT11) by binding to the 3' untranslated region (UTR) of mllt11 mRNA and in turn induced p21 expression and caused cell cycle arrest at the G2/M phase, further inhibiting BC tumor growth. Collectively, our results improve our understanding of the role of miR-411 in BC tumor growth and suggest miR-411 and MLLT11 as potential new targets for the treatment of BC patients.

XIAP overexpression promotes bladder cancer invasion in vitro and lung metastasis in vivo via enhancing nucleolin-mediated Rho-GDIß mRNA stability.

Our recent studies demonstrate that X-linked inhibitor of apoptosis protein (XIAP) is essential for regulating colorectal cancer invasion. Here, we discovered that RhoGDIß was a key XIAP downstream effector mediating bladder cancer (BC) invasion in vitro and in vivo. We found that both XIAP and RhoGDIß expressions were consistently elevated in BCs of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-treated mice in comparison to bladder tissues from vehicle-treated mice and human BCs in comparison to the paired adjacent normal bladder tissues. Knockdown of XIAP attenuated RhoGDIß expression and reduced cancer cell invasion, whereas RhoGDIß expression was attenuated in BBN-treated urothelium of RING-deletion knockin mice. Mechanistically, XIAP stabilized RhoGDIß mRNA by its positively regulating nucleolin mRNA stability via Erks-dependent manner. Moreover, ectopic expression of GFP-RhoGDIß in T24T(shXIAP) cells restored its lung metastasis in nude mice. Our results demonstrate that XIAP-regulated Erks/nucleolin/RhoGDIß axis promoted BC invasion and lung metastasis.

ATG7 Overexpression Is Crucial for Tumorigenic Growth of Bladder Cancer In Vitro and In Vivo by Targeting the ETS2/miRNA196b/FOXO1/p27 Axis.

Human bladder cancer (BC) is the fourth most common cancer in the United States. Investigation of the strategies aiming to elucidate the tumor growth and metastatic pathways in BC is critical for the management of this disease. Here we found that ATG7 expression was remarkably elevated in human bladder urothelial carcinoma and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse invasive BC. Knockdown of ATG7 resulted in a significant inhibitory effect on tumorigenic growth of human BC cells both in vitro and in vivo by promoting p27 expression and inducing cell cycle arrest at G2/M phase. We further demonstrated that knockdown of ATG7 upregulated FOXO1 (forkhead box protein O 1) expression, which specifically promoted p27 transcription. Moreover, mechanistic studies revealed that inhibition of ATG7 stabilized ETS2 mRNA and, in turn, reduced miR-196b transcription and expression of miR-196b, which was able to bind to the 3' UTR of FOXO1 mRNA, consequently stabilizing FOXO1 mRNA and finally promoting p27 transcription and attenuating BC tumorigenic growth. The identification of the ATG7/FOXO1/p27 mechanism for promoting BC cell growth provides significant insights into understanding the nature of BC tumorigenesis. Together with our most recent discovery of the crucial role of ATG7 in promoting BC invasion, it raises the potential for developing an ATG7-based specific therapeutic strategy for treatment of human BC patients.

Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells.

Chronic lung inflammation is accepted as being associated with the development of lung cancer caused by nickel exposure. Therefore, identifying the molecular mechanisms that lead to a nickel-induced sustained inflammatory microenvironment that causes transformation of human bronchial epithelial cells is of high significance. In the current studies, we identified SQSTM1/p62 as a novel nickel-upregulated protein that is important for nickel-induced inflammatory TNF expression, subsequently resulting in transformation of human bronchial epithelial cells. We found that nickel exposure induced SQSTM1 protein upregulation in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The SQSTM1 upregulation was also observed in human lung squamous cell carcinoma. Further studies revealed that the knockdown of SQSTM1 expression dramatically inhibited transformation of human lung epithelial cells upon chronic nickel exposure, whereas ectopic expression of SQSTM1 promoted such transformation. Mechanistic studies showed that the SQSTM1 upregulation by nickel was the compromised result of upregulating SQSTM1 mRNA transcription and promoting SQSTM1 protein degradation. We demonstrated that nickel-initiated SQSTM1 protein degradation is mediated by macroautophagy/autophagy via an MTOR-ULK1-BECN1 axis, whereas RELA is important for SQSTM1 transcriptional upregulation following nickel exposure. Furthermore, SQSTM1 upregulation exhibited its promotion of nickel-induced cell transformation through exerting an impetus for nickel-induced inflammatory TNF mRNA stability. Consistently, the MTOR-ULK1-BECN1 autophagic cascade acted as an inhibitory effect on nickel-induced TNF expression and cell transformation. Collectively, our results demonstrate a novel SQSTM1 regulatory network that promotes a nickel-induced tumorigenic effect in human bronchial epithelial cells, which is negatively controlled by an autophagic cascade following nickel exposure.

Isorhapontigenin (ISO) Inhibits Invasive Bladder Cancer Formation In Vivo and Human Bladder Cancer Invasion In Vitro by Targeting STAT1/FOXO1 Axis.

Although our most recent studies have identified Isorhapontigenin (ISO), a novel derivative of stilbene that isolated from a Chinese herb Gnetum cleistostachyum, for its inhibition of human bladder cancer growth, nothing is known whether ISO possesses an inhibitory effect on bladder cancer invasion. Thus, we addressed this important question in current study and discovered that ISO treatment could inhibit mouse-invasive bladder cancer development following bladder carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) exposure in vivo We also found that ISO suppressed human bladder cancer cell invasion accompanied by upregulation of the forkhead box class O 1 (FOXO1) mRNA transcription in vitro Accordingly, FOXO1 was profoundly downregulated in human bladder cancer tissues and was negatively correlated with bladder cancer invasion. Forced expression of FOXO1 specifically suppressed high-grade human bladder cancer cell invasion, whereas knockdown of FOXO1 promoted noninvasive bladder cancer cells becoming invasive bladder cancer cells. Moreover, knockout of FOXO1 significantly increased bladder cancer cell invasion and abolished the ISO inhibition of invasion in human bladder cancer cells. Further studies showed that the inhibition of Signal transducer and activator of transcription 1 (STAT1) phosphorylation at Tyr701 was crucial for ISO upregulation of FOXO1 transcription. Furthermore, this study revealed that metalloproteinase-2 (MMP-2) was a FOXO1 downstream effector, which was also supported by data obtained from mouse model of ISO inhibition BBN-induced mouse-invasive bladder cancer formation. These findings not only provide a novel insight into the understanding of mechanism of bladder cancer's propensity to invasion, but also identify a new role and mechanisms underlying the natural compound ISO that specifically suppresses such bladder cancer invasion through targeting the STAT1-FOXO1-MMP-2 axis. Cancer Prev Res; 9(7); 567-80. ©2016 AACR.

Induction of miR-137 by Isorhapontigenin (ISO) Directly Targets Sp1 Protein Translation and Mediates Its Anticancer Activity Both In Vitro and In Vivo.

Our recent studies found that isorhapontigenin (ISO) showed a significant inhibitory effect on human bladder cancer cell growth, accompanied with cell-cycle G0-G1 arrest as well as downregulation of Cyclin D1 expression at transcriptional level via inhibition of Sp1 transactivation in bladder cancer cells. In the current study, the potential ISO inhibition of bladder tumor formation has been explored in a xenograft nude mouse model, and the molecular mechanisms underlying ISO inhibition of Sp1 expression and anticancer activities have been elucidated both in vitro and in vivo. Moreover, the studies demonstrated that ISO treatment induced the expression of miR-137, which in turn suppressed Sp1 protein translation by directly targeting Sp1 mRNA 3'-untranslated region (UTR). Similar to ISO treatment, ectopic expression of miR-137 alone led to G0-G1 cell growth arrest and inhibition of anchorage-independent growth in human bladder cancer cells, which could be completely reversed by overexpression of GFP-Sp1. The inhibition of miR-137 expression attenuated ISO-induced inhibition of Sp1/Cyclin D1 expression, induction of G0-G1 cell growth arrest, and suppression of cell anchorage-independent growth. Taken together, our studies have demonstrated that miR-137 induction by ISO targets Sp1 mRNA 3'-UTR and inhibits Sp1 protein translation, which consequently results in reduction of Cyclin D1 expression, induction of G0-G1 growth arrest, and inhibition of anchorage-independent growth in vitro and in vivo. Our results have provided novel insights into understanding the anticancer activity of ISO in the therapy of human bladder cancer.

p85α promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation.

p85α is a regulatory subunit of phosphatidylinositol 3-kinase (PI3K) that is a key lipid enzyme for generating phosphatidylinositol 3, 4, 5-trisphosphate, and subsequently activates signaling that ultimately regulates cell cycle progression, cell growth, cytoskeletal changes, and cell migration. In addition to form a complex with the p110 catalytic subunit, p85α also exists as a monomeric form due to that there is a greater abundance of p85α than p110 in many cell types. Our previous studies have demonstrated that monomeric p85α exerts a pro-apoptotic role in UV response through induction of TNF-α gene expression in PI3K-independent manner. In current studies, we identified a novel biological function of p85α as a positive regulator of epidermal growth factor receptor (EGFR) expression and cell malignant transformation via nucleolin-dependent mechanism. Our results showed that p85α was crucial for EGFR and nucleolin expression and subsequently resulted in an increase of malignant cellular transformation by using both specific knockdown and deletion of p85α in its normal expressed cells. Mechanistic studies revealed that p85α upregulated EGFR protein expression mainly through stabilizing its mRNA, whereas nucleolin (NCL) was able to bind to egfr mRNA and increase its mRNA stability. Consistently, overexpression of NCL in p85α-/- cells restored EGFR mRNA stabilization, protein expression and cell malignant transformation. Moreover, we discovered that p85α upregulated NCL gene transcription via enhancing C-Jun activation. Collectively, our studies demonstrate a novel function of p85α as a positive regulator of EGFR mRNA stability and cell malignant transformation, providing a significant insight into the understanding of biomedical nature of p85α protein in mammalian cells and further supporting that p85α might be a potential target for cancer prevention and therapy.