Association between health-related social media use and E-cigarette use among current cigarette users: the roles of anti-tobacco messages and harm perception.

BACKGROUND: The popularity of e-cigarettes is on the rise among current cigarette users. Therefore, there are concerns about their health implications. This study examined the impact of health-related social media use on e-cigarette use among current cigarette users. It assesses the mediating influence of online anti-tobacco messages and the moderating role of the harm perception of e-cigarettes. METHODS: This study was focused on 563 current cigarette users from the 2022 Health Information National Trends Survey (HINTS). Three tasks were performed: (1) assessing the direct and indirect impacts of health-related social media use on e-cigarette use among current cigarette users, (2) exploring the mediating role of exposure to online anti-tobacco messages, and (3) examining the moderating influence of e-cigarette harm perception on the path from anti-tobacco messages to e-cigarette use. RESULTS: Health-related social media use was positively associated with current cigarette users' e-cigarette use directly (bp = 0.183, p < .01) and indirectly through exposure to online anti-tobacco messages (bp = 0.023, 95% CI: [0.001, 0.051]). Harm perception of e-cigarettes moderated the relationship between online exposure to anti-tobacco messages and e-cigarette use (bp=-0.467, p < .01). The relationship appeared weaker for individuals who perceived greater harm from e-cigarettes. CONCLUSIONS: Health-related social media use positively correlates with e-cigarette use among current cigarette users through exposure to online anti-tobacco messages. The perceived harm of e-cigarettes moderates this indirect path. These findings have implications for public health interventions aimed at smoking cessation.

"I Saw it Incidentally but Frequently": Exploring the Effects of Online Health Information Scanning on Lung Cancer Screening Behaviors Among Chinese Smokers.

In China, lung cancer is the most common cancer with high mortality. While prior research suggests that health information scanning influences cancer screening within the general population, a deeper exploration of the underlying mechanisms is imperative. This study specifically targets smokers, aiming to investigate whether online health information scanning can effectively encourage lung cancer screening and elucidate the mechanisms driving this association. Data were extracted from a Chinese national survey conducted between January and September 2023, exclusively involving current smokers (N = 992). A moderated mediation model was employed to examine a cognitive-affective sequential chain of mediation through risk perceptions and cancer worry. Results showed that 99.1% of Chinese smokers reported online health information scanning, which possessed significant influence. Online health information scanning was positively associated with effective lung cancer screening among smokers directly (OR = 1.927, p < .01) and indirectly (OR = .065, p < .001). The perceived threat of smoking and cancer worry served as the cognitive and affective mediating mechanisms. Furthermore, a moderating effect of eHealth literacy was observed (OR = 6.292, p < .05). Smokers with higher eHealth literacy are more inclined to undergo effective lung cancer screening. Based on these findings, public health sectors should leverage online platforms to disseminate tailored cancer screening education and implement initiatives to enhance public eHealth literacy.

A four-year longitudinal analysis examining the effects of e-cigarette advertisements and disparities among youth with internalizing problems.

BACKGROUND: Prior research indicates a direct, short-term effect of e-cigarette advertising on e-cigarette use among youth. This study seeks to investigate the long-term effects of e-cigarette advertisements and disparities in exposure among adolescents with different levels of internalizing problems. METHODS: Panel data of the Population Assessment of Tobacco and Health (PATH) Study Waves 3-5 (2015-2019) were analyzed. Youth aged 12-17 who were non-e-cigarette users at the time of Wave 3 were included (n = 4,678). A moderated mediation model was employed to examine the mediating role of perceived harm of e-cigarettes and the moderating effect of internalizing problems. RESULTS: Exposure to e-cigarette advertisements in Wave 3 predicted lower harm perception of e-cigarette in Wave 4 (bp = -0.055, p <.01), leading to more e-cigarette use in Wave 5 (bp = -0.042, p <.001). While e-cigarette advertisements exhibited a lasting indirect effect (bp = 0.002, p <.05), there was no long-term direct effect (bp = 0.017, p >.05) on youth e-cigarette use. Furthermore, a moderating effect of internalizing problems was observed (bp = 0.107, p <.05). CONCLUSIONS: E-cigarette advertisements can exert a lasting influence indirectly by diminishing harm perception, particularly among those with lower internalizing problems. Adolescents with higher internalizing problems exhibit lower susceptibility to advertisement influence, yet their perceived harm of e-cigarettes is notably lower than their peers with fewer internalizing problems. These disparities underscore the need for tailored prevention strategies: implementing anti-e-cigarette education programs for adolescents with low internalizing problems and providing mental health care for those facing internalizing challenges. Regulatory measures targeting e-cigarette advertising are also crucial.

The distribution characteristics of strabismus surgery types in a tertiary hospital in the Central Plains region during the COVID-19 epidemic.

OBJECTIVE: This study aimed to analyze the distribution of different types of strabismus surgery in a tertiary hospital in Central China during the three-year period of the COVID-19 pandemic. METHODS: A retrospective analysis was conducted on the clinical data of strabismus patients who underwent surgery and were admitted to the Department of Strabismus and Pediatric Ophthalmology at the First Affiliated Hospital of Zhengzhou University between January 2020 and December 2022. RESULTS: A total of 3939 strabismus surgery patients were collected, including 1357 in 2020, 1451 in 2021, and 1131 in 2022. The number of surgeries decreased significantly in February 2020, August 2021, and November and December 2022. Patients aged 0-6 years accounted for 37% of the total number of strabismus surgery patientsr. The majority (60%) of all strabismus surgery patients were diagnosed with exotropia, with intermittent exotropia accounting for the highest proportion (53%). There was no statistically significant difference in the proportion of intermittent exotropia and constant exotropia during the three-year period (χ2 = 2.642, P = 0.267 and χ2 = 3.012, P = 0.221, respectively). Among patients with intermittent exotropia, insufficient convergence type was the most common form of strabismus (accounting for over 70%). Non-accommodative esotropia accounted for more than 50% of all internal strabismus cases. CONCLUSION: During the period from 2020 to 2022, the total number of strabismus surgeries in our hospital did not show significant fluctuations, but there was a noticeable decrease in the number of surgeries during months affected by the pandemic. Exotropia accounted for the highest proportion among strabismus surgery patients. Intermittent exotropia was the most common type among patients undergoing surgery for exotropia, and the most prevalent subtype was the insufficient convergence type. The age distribution of patients varied in different months, with a concentration of surgeries for strabismus patients in the 7-12 years old age group during the months of July and August each year.

How does health communication on social media influence e-cigarette perception and use? A trend analysis from 2017 to 2020.

OBJECTIVE: E-cigarettes have achieved a high prevalence rapidly. While social media is among the most influential platforms for health communication, its impact on attitudes and behaviors of e-cigarettes and its changes over time remain underexplored. This study aims to address the gap. METHODS: Four years of data (2017-2020) were derived from the U.S. Health Information National Trends Survey (HINTS) (aged 18-64 years, n = 9,914). Initially, key variables were compared across years. Furthermore, guided by the health belief model, we employed a moderated mediation model to examine the influence of social media health communication on the public's perceptions and behaviors related to e-cigarettes, distinguishing between smokers and non-smokers throughout the four-year period. RESULTS: The evidence shows a process of dynamic interaction between communication, perception, and behavior. (1) We observed an increasing trend of social media health communication (SMH) and perceived relative harm of e-cigarettes (PHE). (2) Higher SMH was associated with more e-cigarette use directly in 2019. (3) Higher SMH was associated with less e-cigarette use indirectly through PHE in 2020. (4) Smokers consistently displayed heightened sensitivity in responding to harm perception compared to non-smokers. CONCLUSIONS: The findings support two mechanisms underlying the association between SMH and e-cigarette use: direct and indirect. The changes in the pathways during the timespan may have been influenced by increased e-cigarette information on social media and public health events like COVID-19. Stricter regulations for unverified e-cigarette advertisements and anti-e-cigarette education on social media are called for to curtail e-cigarette use.

Longitudinal relationship between social media and e-cigarette use among adolescents: the roles of internalizing problems and academic performance.

BACKGROUND: Prior research has investigated the influence of social media on e-cigarette use among adolescents, predominantly through the display of e-cigarette content and advertisements. However, the psychological mechanism underlying this relationship remains underexplored. This study aims to address the mediating effect of youths internalizing problems and elucidate the moderating effect of academic performance from a longitudinal perspective. METHODS: Panel data from the Public Assessment of Tobacco and Health (PATH) Study Waves 3-5 (2015-2019) were utilized in this study. The sample consisted of 3,975 youths between the ages of 12 and 17 years old. A moderated mediation model was utilized for analyses. RESULTS: Adolescents using social media more frequently in Wave 3 reported higher odds of internalizing problems in Wave 4 (bp = 0.061, p < .01), which led to more e-cigarette use in Wave 5 (bp = 0.029, p < .01). A negative moderating effect of academic performance was found in the association between internalizing problems and e-cigarette use (bp=-0.088, p < .05). CONCLUSIONS: Frequent social media use among young individuals leads to an increase in e-cigarette use through enhanced internalizing problems. However, adolescents who perform well academically exhibit higher resistance to e-cigarette use. Based on our findings, we recommend that tailored anti-e-cigarette campaigns and mental health interventions be used to target frequent social media users and academically struggling adolescents to prevent adverse health outcomes.

Synthesis, Biological Evaluation and Action Mechanism Study of New Mitochondria-Targeted Curcumin Derivative as Potential Antitumor Drugs.

Mitochondria have emerged as important targets in cancer therapy due to their key role in regulating energy supply, maintaining redox homeostasis, and intrinsic apoptosis. Curcumin (CUR) has shown promise in inhibiting the proliferation and metastasis of cancer cells by inducing apoptosis and arresting cell cycle. However, the clinical application of CUR has been limited by its low stability and poor tumor selectivity. To address these issues, the novel mitochondria-targeted curcumin derivatives were synthesized through the unilateral coupling (CUR-T) or bilateral coupling (CUR-2T) of curcumin's phenolic hydroxy groups with triphenyl phosphorus via ester bond. The aim was to achieve better stability, higher tumor selectivity, and stronger curative efficacy. The results of stability and biological experiments indicated that both stability and cytotoxicity were arranged in descending order of CUR-2T>CUR-T>CUR. In ovarian cancer cells (A2780 cells), CUR-2T showed well-defined preferential selectivity towards cancer cells and exhibited efficient anticancer efficacy due to its superior mitochondria accumulation ability. Subsequently, the mitochondrial redox balance was disrupted, accompanied by increased ROS levels, decreased ATP levels, dissipated MMP, and increased G0 /G1 phase arrest, leading to a higher apoptotic rate. In summary, the results of this study suggest that CUR-2T holds substantial promise for further development as a potential agent for the treatment of ovarian cancer.

Formulation and evaluation of a two-stage targeted liposome coated with hyaluronic acid for improving lung cancer chemotherapy and overcoming multidrug resistance.

Multidrug resistance (MDR) has emerged as a prominent challenge contributing to the ineffectiveness of chemotherapy in treating non-small cell lung cancer (NSCLC) patients. Currently, mitochondria of cancer cells are identified as a promising target for overcoming MDR due to their crucial role in intrinsic apoptosis pathway and energy supply centers. Here, a two-stage targeted liposome (HA/TT LP/PTX) was successfully developed via a two-step process: PTX-loaded cationic liposome (TT LP/PTX) were formulated by lipid film hydration & ultrasound technique, followed by further coating with natural anionic polysaccharide hyaluronic acid (HA). TT, an amphipathic polymer conjugate of triphenylphosphine (TPP)-tocopheryl polyethylene glycol succinate (TPGS), was used to modify the liposomes for mitochondrial targeting. The average particle size, zeta potential and encapsulation efficiency (EE%) of HA/TT LP/PTX were found to be 153 nm, -30.3 mV and 92.1% based on the optimal prescription of HA/TT LP/PTX. Compared to cationic liposome, HA-coated liposomes showed improved stability and safety, including biological stability in serum, cytocompatibility, and lower hemolysis percentage. In drug-resistant A549/T cells, HA was shown to improve the cellular uptake of PTX through CD44 receptor-mediated endocytosis and subsequent degradation by hyaluronidase (HAase) in endosomes. Following this, the exposure of TT polymer facilitated the accumulation of PTX within the mitochondria. As a result, the function of mitochondria in A549/T cells was disturbed, leading to an increased ROS level, decreased ATP level, dissipated MMP, and increased G2/M phase arrest. This resulted in a higher apoptotic rate and stronger anticancer efficacy.

Appraising co-composting efficiency of biodegradable plastic bags and food wastes: Assessment microplastics morphology, greenhouse gas emissions, and changes in microbial community.

Biodegradable plastic bags (BPBs) to collect food waste and microplastics (MPs) produced from their biodegradation have received considerable scientific attention recently. Therefore, the current study was carried out to assess the co-composting efficiency of biodegradable plastic bags (polylactic acid (PLA) + polybutylene terephthalate (PBAT) + ST20 and PLA + PBAT+MD25) and food waste. The variations in greenhouse gas (GHG) emissions, microbial community and compost fertility were likewise assessed. Compared with the control, PLA + PBAT+ST20 and PLA + PBAT+MD25 both accelerated organic matter degradation and increased temperature. Moreover, PLA + PBAT+ST20 aggravated CH4 and CO2 emissions by 12.10 % and 11.01 %, respectively. PLA + PBAT+MD25 decreased CH4 and CO2 emissions by 5.50 % and 9.12 %, respectively. Meanwhile, compared with PLA + PBAT+ST20, the combined effect of plasticizer and inorganic additive in PLA + PBAT+MD25, reduced the NO3--N contents, seed germination index (GI) and compost maturity. Furthermore, adding BPBs changed the richness and diversity of the bacterial community (Firmicutes, Proteobacteria and Bacteroidetes). Likewise, redundancy analysis (RDA) showed that the co-compost system of BPBs and food waste accelerated significantly bacterial community succession from Firmicutes and Bacteroidetes at the initial stage to Proteobacteria and Actinobacteria at the mature stage, increased co-compost temperature to over 64 °C and extended thermophilic composting phase, and promoted the degradation of MPs. Additionally, according to structural equation model quantification results, the inorganic additive of PLA + PBAT+MD25 had more serious toxicity to microorganisms and had significantly adverse effects on GI through CO2-C (λ = -0.415, p < 0.05) and NO3--N (λ = -0.558, p < 0.001), thus reduced compost fertility and quality. The results also indicated that the BPBs with ST20 as an additive could be more suitable for industrial composting than the BPBs with MD25 as an additive. This study provided a vital basis for understanding the potential environmental and human health risks of the MPs' generated by the degradation of BPBs in compost.

Food Waste Management Employing UV-Induced Black Soldier Flies: Metabolomic Analysis of Bioactive Components, Antioxidant Properties, and Antibacterial Potential.

Food waste, as a major part of municipal solid waste, has been increasingly generated worldwide. Efficient and feasible utilization of this waste material for biomanufacturing is crucial to improving economic and environmental sustainability. In the present study, black soldier flies (BSF) larvae were used as carriers to treat and upcycle food waste. Larvae of the BSF were incubated with UV light for 10, 20, and 30 min at a wavelength of 257.3 nm and an intensity of 8 W. The food waste utilization efficiency, antioxidant assays, antibacterial activity, and bioactive metabolites without and with UV treatment were determined and compared. Results showed that the BSF larvae feed utilization rate was around 75.6%, 77.7%, and 71.2% after UV treatment for 10, 20, and 30 min respectively, contrasting with the non-UV induced group (73.7%). In addition, it was perceived that the UV exposure enhanced antioxidant and antimicrobial properties of BSF extracts, and the maximum values were observed after 20 min UV induction time. Moreover, UV-induced BSF extracts showed an improved metabolic profile than the control group, with a change in the amino acids, peptides, organic acids, lipids, organic oxides, and other derivatives. This change in metabolomics profile boosted environmental signaling, degradation of starch, amino acids, sugars, and peptide metabolism. It was concluded that the bioconversion of food wastes using UV-induced BSF larvae can enhance the generation of a variety of functional proteins and bioactive compounds with potent antioxidant and antimicrobial activity. However, more studies are required to exploit the efficiency of UV treatment in improving BSF's potential for upcycling of food wastes.

Characterization of the ERG-regulated Kinome in Prostate Cancer Identifies TNIK as a Potential Therapeutic Target.

Approximately 50% of prostate cancers harbor the TMPRSS2:ERG fusion, resulting in elevated expression of the ERG transcription factor. Despite the identification of this subclass of prostate cancers, no personalized therapeutic strategies have achieved clinical implementation. Kinases are attractive therapeutic targets as signaling networks are commonly perturbed in cancers. The impact of elevated ERG expression on kinase signaling networks in prostate cancer has not been investigated. Resolution of this issue may identify novel therapeutic approaches for ERG-positive prostate cancers. In this study, we used quantitative mass spectrometry-based kinomic profiling to identify ERG-mediated changes to cellular signaling networks. We identified 76 kinases that were differentially expressed and/or phosphorylated in DU145 cells engineered to express ERG. In particular, the Traf2 and Nck-interacting kinase (TNIK) was markedly upregulated and phosphorylated on multiple sites upon ERG overexpression. Importantly, TNIK has not previously been implicated in prostate cancer. To validate the clinical relevance of these findings, we characterized expression of TNIK and TNIK phosphorylated at serine 764 (pS764) in a localized prostate cancer patient cohort and showed that nuclear enrichment of TNIK (pS764) was significantly positively correlated with ERG expression. Moreover, TNIK protein levels were dependent upon ERG expression in VCaP cells and primary cells established from a prostate cancer patient-derived xenograft. Furthermore, reduction of TNIK expression and activity by silencing TNIK expression or using the TNIK inhibitor NCB-0846 reduced cell viability, colony formation and anchorage independent growth. Therefore, TNIK represents a novel and actionable therapeutic target for ERG-positive prostate cancers that could be exploited to develop new treatments for these patients.

Characterization of the Src-regulated kinome identifies SGK1 as a key mediator of Src-induced transformation.

Despite significant progress, our understanding of how specific oncogenes transform cells is still limited and likely underestimates the complexity of downstream signalling events. To address this gap, we use mass spectrometry-based chemical proteomics to characterize the global impact of an oncogene on the expressed kinome, and then functionally annotate the regulated kinases. As an example, we identify 63 protein kinases exhibiting altered expression and/or phosphorylation in Src-transformed mammary epithelial cells. An integrated siRNA screen identifies nine kinases, including SGK1, as being essential for Src-induced transformation. Accordingly, we find that Src positively regulates SGK1 expression in triple negative breast cancer cells, which exhibit a prominent signalling network governed by Src family kinases. Furthermore, combined inhibition of Src and SGK1 reduces colony formation and xenograft growth more effectively than either treatment alone. Therefore, this approach not only provides mechanistic insights into oncogenic transformation but also aids the design of improved therapeutic strategies.

miR106b regulates retinoblastoma Y79 cells through Runx3.

MicroRNAs are increasingly recognized as important regulators of cancer. The aim of the present study was to investigate the role of miR-106b in the regulation of Y79 retinoblastoma. Y79 cells were transfected with antisense oligonucleotides (ASO) against miR-106b (ASO-miR-106b) or ASO-control. After transfection, the levels of miR-106b were monitored with real-time PCR (RT-PCR). The effects of ASO-miR-106b transfection on cell viability was evaluated by Cell Counting Kit-8 (CCK-8) analysis at 24, 48 and 72 h after transfection. Subsequently, the cells were stained with Annexin V-FITC and propidium iodide (PI) and subjected to flow cytometry to assess cell apoptosis. Transwell assay was used to analyze cell migration. Changes in Runt-related transcription factor 3 (Runx3) mRNA and proteins levels were also evaluated. miR-106b was downregulated by ASO-miR-106b at 48 and 72 h after transfection, accompanied by a decrease in cell viability and proliferation, as well as an increase in cell apoptosis. Transwell analysis indicated that cells treated with ASO-miR-106b exhibited significantly lower cell migratory abilities. The mRNA and protein level of Runx3 were upregulated after transfection. These results demonstrated that suppression of miR-106b inhibited Y79 cell proliferation and migration. The upregulation of Runx3 after miR-106b suppression ascertained that Runx3 is a tumor-suppressor in retinoblastoma and is a target of miR-106b.

The kinome 'at large' in cancer.

Over the past decade, rapid advances in genomics, proteomics and functional genomics technologies that enable in-depth interrogation of cancer genomes and proteomes and high-throughput analysis of gene function have enabled characterization of the kinome 'at large' in human cancers, providing crucial insights into how members of the protein kinase superfamily are dysregulated in malignancy, the context-dependent functional role of specific kinases in cancer and how kinome remodelling modulates sensitivity to anticancer drugs. The power of these complementary approaches, and the insights gained from them, form the basis of this Analysis article.

The pseudokinase SgK223 promotes invasion of pancreatic ductal epithelial cells through JAK1/Stat3 signaling.

BACKGROUND: Characterization of molecular mechanisms underpinning development of pancreatic ductal adenocarcinoma (PDAC) may lead to the identification of novel therapeutic targets and biomarkers. SgK223, also known as Pragmin, is a pseudokinase and scaffolding protein closely related to SgK269/PEAK1. Both proteins are implicated in oncogenic tyrosine kinase signaling, but their mechanisms and function remain poorly characterized. METHODS: Expression of SgK223 in PDAC and PDAC cell lines was characterized using gene expression microarrays, mass spectrometry (MS)-based phosphoproteomics and Western blotting. SgK223 was overexpressed in human pancreatic ductal epithelial (HPDE) cells via retroviral transduction, and knocked down in PDAC cells using siRNA. Cell proliferation was determined using a colorimetric cell viability assay, and cell migration and invasion using transwells. Expression of markers of epithelial-mesenchyme transition (EMT) was assayed by quantitative PCR. SgK223 and Stat3 signaling was interrogated by immunoprecipitation, Western blot and gene reporter assays. The functional role of specific kinases and Stat3 was determined using selective small molecule inhibitors. RESULTS: Elevated site-selective tyrosine phosphorylation of SgK223 was identified in subsets of PDAC cell lines, and increased expression of SgK223 detected in several PDAC cell lines compared to human pancreatic ductal epithelial (HPDE) cells and in PDACs compared to normal pancreas. Expression of SgK223 in HPDE cells at levels comparable to those in PDAC did not alter cell proliferation but led to a more elongated morphology, enhanced migration and invasion and induced gene expression changes characteristic of a partial EMT. While SgK223 overexpression did not affect activation of Erk or Akt, it led to increased Stat3 Tyr705 phosphorylation and Stat3 transcriptional activity, and SgK223 and Stat3 associated in vivo. SgK223-overexpressing cells exhibited increased JAK1 activation, and use of selective inhibitors determined that the increased Stat3 signaling driven by SgK223 was JAK-dependent. Pharmacological inhibition of Stat3 revealed that Stat3 activation was required for the enhanced motility and invasion of SgK223-overexpressing cells. CONCLUSIONS: Increased expression of SgK223 occurs in PDAC, and overexpression of SgK223 in pancreatic ductal epithelial cells promotes acquisition of a migratory and invasive phenotype through enhanced JAK1/Stat3 signaling. This represents the first association of SgK223 with a particular human cancer, and links SgK223 with a major signaling pathway strongly implicated in PDAC progression.

Profiling the tyrosine phosphoproteome of different mouse mammary tumour models reveals distinct, model-specific signalling networks and conserved oncogenic pathways.

INTRODUCTION: Although aberrant tyrosine kinase signalling characterises particular breast cancer subtypes, a global analysis of tyrosine phosphorylation in mouse models of breast cancer has not been undertaken to date. This may identify conserved oncogenic pathways and potential therapeutic targets. METHODS: We applied an immunoaffinity/mass spectrometry workflow to three mouse models: murine stem cell virus-Neu, expressing truncated Neu, the rat orthologue of human epidermal growth factor receptor 2, Her2 (HER2); mouse mammary tumour virus-polyoma virus middle T antigen (PyMT); and the p53-/- transplant model (p53). Pathways and protein-protein interaction networks were identified by bioinformatics analysis. Molecular mechanisms underpinning differences in tyrosine phosphorylation were characterised by Western blot analysis and array comparative genomic hybridisation. The functional role of mesenchymal-epithelial transition factor (Met) in a subset of p53-null tumours was interrogated using a selective tyrosine kinase inhibitor (TKI), small interfering RNA (siRNA)-mediated knockdown and cell proliferation assays. RESULTS: The three models could be distinguished on the basis of tyrosine phosphorylation signatures and signalling networks. HER2 tumours exhibited a protein-protein interaction network centred on avian erythroblastic leukaemia viral oncogene homologue 2 (Erbb2), epidermal growth factor receptor and platelet-derived growth factor receptor α, and they displayed enhanced tyrosine phosphorylation of ERBB receptor feedback inhibitor 1. In contrast, the PyMT network displayed significant enrichment for components of the phosphatidylinositol 3-kinase signalling pathway, whereas p53 tumours exhibited increased tyrosine phosphorylation of Met and components or regulators of the cytoskeleton and shared signalling network characteristics with basal and claudin-low breast cancer cells. A subset of p53 tumours displayed markedly elevated cellular tyrosine phosphorylation and Met expression, as well as Met gene amplification. Treatment of cultured p53-null cells exhibiting Met amplification with a selective Met TKI abrogated aberrant tyrosine phosphorylation and blocked cell proliferation. The effects on proliferation were recapitulated when Met was knocked down using siRNA. Additional subtypes of p53 tumours exhibited increased tyrosine phosphorylation of other oncogenes, including Peak1/SgK269 and Prex2. CONCLUSION: This study provides network-level insights into signalling in the breast cancer models utilised and demonstrates that comparative phosphoproteomics can identify conserved oncogenic signalling pathways. The Met-amplified, p53-null tumours provide a new preclinical model for a subset of triple-negative breast cancers.

Involvement of Lyn and the atypical kinase SgK269/PEAK1 in a basal breast cancer signaling pathway.

Basal breast cancer cells feature high expression of the Src family kinase Lyn that has been implicated in the pathogenicity of this disease. In this study, we identified novel Lyn kinase substrates, the most prominent of which was the atypical kinase SgK269 (PEAK1). In breast cancer cells, SgK269 expression associated with the basal phenotype. In primary breast tumors, SgK269 overexpression was detected in a subset of basal, HER2-positive, and luminal cancers. In immortalized MCF-10A mammary epithelial cells, SgK269 promoted transition to a mesenchymal phenotype and increased cell motility and invasion. Growth of MCF-10A acini in three-dimensional (3D) culture was enhanced upon SgK269 overexpression, which induced an abnormal, multilobular acinar morphology and promoted extracellular signal-regulated kinase (Erk) and Stat3 activation. SgK269 Y635F, mutated at a major Lyn phosphorylation site, did not enhance acinar size or cellular invasion. We show that Y635 represents a Grb2-binding site that promotes both Stat3 and Erk activation in 3D culture. RNA interference-mediated attenuation of SgK269 in basal breast cancer cells promoted acquisition of epithelial characteristics and decreased anchorage-independent growth. Together, our results define a novel signaling pathway in basal breast cancer involving Lyn and SgK269 that offers clinical opportunities for therapeutic intervention.

Targeting the human kinome for cancer therapy: current perspectives.

As highlighted by other articles in this review issue, great progress has been made in the development of targeted treatment modalities directed against particular oncogenic kinases, and the translation of these therapies into the clinic. However, recent data from cancer genome sequencing projects indicate that the spectrum of kinases that contribute to cancer progression is wider than previously imagined, and as international projects in this area gather momentum, it appears likely that further kinase oncogenes will be identified, and the roles of previously characterized ones will be extended to subsets of additional cancers. In addition, complementary approaches such as functional genomics and mass spectrometry (MS)-based proteomics are providing important insights into the functional roles played by specific kinases in particular cancers, the dependency of these roles on genetic background, how altered kinase regulation perturbs intracellular signaling networks, and how the latter respond to targeted agents that target the kinase in question. While other articles in this issue focus on individual cancer-associated kinases and their therapeutic targeting, the aim of this review is to take a broader perspective regarding our current knowledge of the cancer kinome and how this can be expanded and exploited for clinical utility.

Tyrosine phosphorylation profiling reveals the signaling network characteristics of Basal breast cancer cells.

To identify therapeutic targets and prognostic markers for basal breast cancers, breast cancer cell lines were subjected to mass spectrometry-based profiling of protein tyrosine phosphorylation events. This revealed that luminal and basal breast cancer cells exhibit distinct tyrosine phosphorylation signatures that depend on pathway activation as well as protein expression. Basal breast cancer cells are characterized by elevated tyrosine phosphorylation of Met, Lyn, EphA2, epidermal growth factor receptor (EGFR), and FAK, and Src family kinase (SFK) substrates such as p130Cas. SFKs exert a prominent role in these cells, phosphorylating key regulators of adhesion and migration and promoting tyrosine phosphorylation of the receptor tyrosine kinases EGFR and Met. Consistent with these observations, SFK inhibition attenuated cellular proliferation, survival, and motility. Basal breast cancer cell lines exhibited differential responsiveness to small molecule inhibitors of EGFR and Met that correlated with the degree of target phosphorylation, and reflecting kinase coactivation, inhibiting two types of activated network kinase (e.g., EGFR and SFKs) was more effective than single agent approaches. FAK signaling enhanced both proliferation and invasion, and Lyn was identified as a proinvasive component of the network that is associated with a basal phenotype and poor prognosis in patients with breast cancer. These studies highlight multiple kinases and substrates for further evaluation as therapeutic targets and biomarkers. However, they also indicate that patient stratification based on expression/activation of drug targets, coupled with use of multi-kinase inhibitors or combination therapies, may be required for effective treatment of this breast cancer subgroup.

In vivo protective effect of Porphyra yezoensis polysaccharide against carbon tetrachloride induced hepatotoxicity in mice.

To study the protective effect and possible mechanism of Porphyra yezoensis polysaccharide (PYP) in hepatotoxicity mice, acute liver injury was successfully induced by injecting 0.2% carbon tetrachloride (CCl(4)) intraperitoneally. Levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum and liver homogenate, content of malondialdehyde (MDA), activities of total superoxide dismutase (T-SOD) in liver were measured by biochemical methods. Liver index was calculated and pathological changes of the liver tissue were observed microscopically. PYP was found to significantly decrease the activities of ALT and AST (P<0.05), to remarkably lower the liver indexes and MDA level in hepatical tissues in mice (P<0.05), and to upregulated the lower T-SOD level in liver homogenate (P<0.01). Furthermore, histologic examination showed that PYP could attenuate and the extent of necrosis, reduce the immigration of inflammatory cells. PYP plays a protective action against hepatotoxicity induced by CCl(4) in mice, and its mechanisms may be related to free radical scavenging, increasing SOD activities and anti-lipid peroxide.