Lipopolysaccharide Triggers Luminal Acidification to Promote Defense Against Bacterial Infection in Vaginal Epithelium.

The vaginal epithelium plays pivotal roles in host defense against pathogen invasion, contributing to the maintenance of an acidic microenvironment within the vaginal lumen through the activity of acid-base transport proteins. However, the precise defense mechanisms of the vaginal epithelium after a bacterial infection remain incompletely understood. This study showed that bacterial lipopolysaccharide (LPS) potentiated net proton efflux by up-regulating the expression of Na+-H+ exchanger 1 (NHE1) without affecting other acid-base transport proteins in vaginal epithelial cells. Pharmacologic inhibition or genetic knockdown of Toll-like receptor-4 and the extracellular signal-regulated protein kinase signaling pathway effectively counteracted the up-regulation of NHE1 and the enhanced proton efflux triggered by LPS in vaginal epithelial cells. In vivo studies revealed that LPS administration led to luminal acidification through the up-regulation of NHE1 expression in the rat vagina. Moreover, inhibition of NHE exhibited an impaired defense against acute bacterial infection in the rat vagina. These findings collectively indicate the active involvement of vaginal epithelial cells in facilitating luminal acidification during acute bacterial infection, offering potential insights into the treatment of bacterial vaginosis.

Linc-NSC affects cell differentiation, apoptosis and proliferation in mouse neural stem cells and embryonic stem cells in vitro and in vivo.

BACKGROUND: Stem cell therapy is a promising therapeutic strategy. In a previous study, we evaluated tumorigenicity by the stereotactic transplantation of neural stem cells (NSCs) and embryonic stem cells (ESCs) from experimental mice. Twenty-eight days later, there was no evidence of tumor formation or long-term engraftment in the NSCs transplantation group. In contrast, the transplantation of ESCs caused tumor formation; this was due to their high proliferative capacity. Based on transcriptome sequencing, we found that a long intergenic non-coding RNA (named linc-NSC) with unknown structure and function was expressed at 1100-fold higher levels in NSCs than in ESCs. This finding suggested that linc-NSC is negatively correlated with stem cell pluripotency and tumor development, but positively correlated with neurogenesis. In the present study, we investigated the specific role of linc-NSC in NSCs/ESCs in tumor formation and neurogenesis. METHODS: Whole transcriptome profiling by RNA sequencing and bioinformatics was used to predict lncRNAs that are widely associated with enhanced tumorigenicity. The expression of linc-NSC was assessed by quantitative real-time PCR. We also performed a number of in vitro methods, including cell proliferation assays, differentiation assays, immunofluorescence assays, flow cytometry, along with in vivo survival and immunofluorescence assays to investigate the impacts of linc-NSC on tumor formation and neurogenesis in NSCs and ESCs. RESULTS: Following the knockdown of linc-NSC in NSCs, NSCs cultured in vitro and those transplanted into the cortex of mice showed stronger survival ability (P < 0.0001), enhanced proliferation(P < 0.001), and reduced apoptosis (P < 0.05); the opposite results were observed when linc-NSC was overexpressed in ESCs. Furthermore, the overexpression of linc-NSC in ECSs induced enhanced apoptosis (P < 0.001) and differentiation (P < 0.01), inhibited tumorigenesis (P < 0.05) in vivo, and led to a reduction in tumor weight (P < 0.0001). CONCLUSIONS: Our analyses demonstrated that linc-NSC, a promising gene-edited target, may promote the differentiation of mouse NSCs and inhibit tumorigenesis in mouse ESCs. The knockdown of linc-NSC inhibited the apoptosis in NSCs both in vitro and in vivo, and prevented tumor formation, revealing a new dimension into the effect of lncRNA on low survival NSCs and providing a prospective gene manipulation target prior to transplantation. In parallel, the overexpression of linc-NSC induced apoptosis in ESCs both in vitro and in vivo and attenuated the tumorigenicity of ESCs in vivo, but did not completely prevent tumor formation.

Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease.

Phenotypic screening has yielded small-molecule inhibitors of prion replication that are effective in vivo against certain prion strains but not others. Here, we sought to test the small molecule anle138b in multiple mouse models of prion disease. In mice inoculated with the RML strain of prions, anle138b doubled survival and durably suppressed astrogliosis measured by live-animal bioluminescence imaging. In knock-in mouse models of the D178N and E200K mutations that cause genetic prion disease, however, we were unable to identify a clear, quantifiable disease endpoint against which to measure therapeutic efficacy. Among untreated animals, the mutations did not impact overall survival, and bioluminescence remained low out to >20 months of age. Vacuolization and PrP deposition were observed in some brain regions in a subset of mutant animals but appeared to be unable to carry the weight of a primary endpoint in a therapeutic study. We conclude that not all animal models of prion disease are suited to well-powered therapeutic efficacy studies, and care should be taken in choosing the models that will support drug development programs. IMPORTANCE There is an urgent need to develop drugs for prion disease, a currently untreatable neurodegenerative disease. In this effort, there is a debate over which animal models can best support a drug development program. While the study of prion disease benefits from excellent animal models because prions naturally afflict many different mammals, different models have different capabilities and limitations. Here, we conducted a therapeutic efficacy study of the drug candidate anle138b in mouse models with two of the most common mutations that cause genetic prion disease. In a more typical model where prions are injected directly into the brain, we found anle138b to be effective. In the genetic models, however, the animals never reached a clear, measurable point of disease onset. We conclude that not all prion disease animal models are ideally suited to drug efficacy studies, and well-defined, quantitative disease metrics should be a priority.

A novel sub-regional radiomics model to predict immunotherapy response in non-small cell lung carcinoma.

BACKGROUND: Identifying precise biomarkers of immunotherapy response for non-small cell lung carcinoma (NSCLC) before treatment is challenging. This study aimed to construct and investigate the potential performance of a sub-regional radiomics model (SRRM) as a novel tumor biomarker in predicting the response of patients with NSCLC treated with immune checkpoint inhibitors, and test whether its predictive performance is superior to that of conventional radiomics, tumor mutational burden (TMB) score and programmed death ligand-1 (PD-L1) expression. METHODS: We categorized 264 patients from retrospective databases of two centers into training (n = 159) and validation (n = 105) cohorts. Radiomic features were extracted from three sub-regions of the tumor region of interest using the K-means method. We extracted 1,896 features from each sub-region, resulting in 5688 features per sample. The least absolute shrinkage and selection operator regression method was used to select sub-regional radiomic features. The SRRM was constructed and validated using the support vector machine algorithm. We used next-generation sequencing to classify patients from the two cohorts into high TMB (≥ 10 muts/Mb) and low TMB (< 10 muts/Mb) groups; immunohistochemistry was performed to assess PD-L1 expression in formalin-fixed, paraffin-embedded tumor sections, with high expression defined as ≥ 50% of tumor cells being positive. Associations between the SRRM and progression-free survival (PFS) and variant genes were assessed. RESULTS: Eleven sub-regional radiomic features were employed to develop the SRRM. The areas under the receiver operating characteristic curve (AUCs) of the proposed SRRM were 0.90 (95% confidence interval [CI] 0.84-0.96) and 0.86 (95% CI 0.76-0.95) in the training and validation cohorts, respectively. The SRRM (low vs. high; cutoff value = 0.936) was significantly associated with PFS in the training (hazard ratio [HR] = 0.35 [0.24-0.50], P < 0.001) and validation (HR = 0.42 [0.26-0.67], P = 0.001) cohorts. A significant correlation between the SRRM and three variant genes (H3C4, PAX5, and EGFR) was observed. In the validation cohort, the SRRM demonstrated a higher AUC (0.86, P < 0.001) than that for PD-L1 expression (0.66, P = 0.034) and TMB score (0.54, P = 0.552). CONCLUSIONS: The SRRM had better predictive performance and was superior to conventional radiomics, PD-L1 expression, and TMB score. The SRRM effectively stratified the progression-free survival (PFS) risk among patients with NSCLC receiving immunotherapy.

Adenosine kinase protects against acetaminophen-induced acute liver injury by activating autophagy in hepatocytes.

Acute liver injury (ALI) is a common life-threatening condition with a high mortality rate due to liver disease-related death. However, current therapeutic interventions for ALI remain ineffective, and the development of effective novel therapies is urgently needed. Liver samples from patients with drug-induced ALI were collected to detect adenosine kinase (ADK) expression. Male C57BL/6 J mice, hepatocyte-specific ADK knockout (ADKHKO) mice, and their controls (ADKf/f) were exposed to acetaminophen (APAP) and other treatments to investigate the mechanisms of APAP-related ALI. ADK expression was significantly decreased in APAP-injured livers. Hepatocyte-specific ADK deficiency exacerbated APAP-induced ALI, while a gain-of-function approach delivering AAV-ADK, markedly alleviated APAP-induced ALI, as indicated by changes in alanine aminotransferases (ALT) levels, aspartate aminotransferase (AST) levels, neutrophil infiltration and hepatocyte death. This study showed that ADK played a critical role in ALI by activating autophagy through two signaling pathways, the adenosine monophosphate-activated protein kinase (AMPK)-mTOR pathway and the adenosine receptor A1 (ADORA1)-Akt-mTOR pathway. Furthermore, we found that metformin upregulated ADK expression in hepatocytes and protected against APAP-induced ALI. These results demonstrate that ADK is critical in protecting against APAP-induced ALI and that developing therapeutics targeting ADK-adenosine-ADORA1 is a new approach for ALI treatment. Metformin is a potential candidate for preventing ALI by upregulating ADK.

Non-linear associations between noise level and people's short-term noise annoyance in different activity contexts.

Recent research has become increasingly interested in the on-linear associations between noise levels and people's short-term noise annoyance. However, there has been limited investigation into measuring short-term noise annoyance and how different activity contexts may affect these non-linear associations. To address this research gap, this study measured people's short-term noise annoyance using real-time Ecological Momentary Assessment (EMA) data and the Day Reconstruction Method's (DRM) recalled data. Corresponding noise levels were captured using Global Positioning Systems and portable noise sensors. Employing the Shapley additive explanations method, we examined the non-linear associations between noise level and people's real-time and recalled noise annoyance across different activity contexts. The results indicated that 1) People had greater sensitivity to noise levels in real-time annoyance (non-linear association threshold: 60 dB) compared to recalled annoyance, which had a higher non-linear association threshold of 70 dB. 2) The non-linear associations between noise level and people's real-time/recalled noise annoyance varied between different activity contexts. People tended to be more sensitive to noise in real-time annoyance than recalled annoyance on travel routes and at workplaces. 3) Among the factors examined, the contribution of noise level varied across activity contexts. Noise level contributed more significantly to people's real-time noise annoyance in outdoor recreational sites and on travel routes. These findings enhance our understanding of the non-linear association between noise level and people's short-term noise annoyance, moving beyond the linear paradigm. Policymakers should consider the non-linear relationships and different activity contexts when implementing noise control measures.

Impact of migration on oral health outcomes of children in multi-beneficial kindergartens in Nanning, Southern China: a cross-sectional study.

OBJECTIVE: To explore the effect of children's migration on their oral health outcomes in multi-beneficial kindergartens in Jiangnan District, Nanning, China, and to provide a basis for improving the oral health of migrant children. METHODS: A cross-sectional study was conducted among 470 children aged 5 years in Jiangnan District, Nanning, Guangxi. A questionnaire was used to collect information on their demographic and socioeconomic background, migration experience, eating habits, oral hygiene behaviours and utilization of dental care services. Dental caries of primary teeth was examined using the decayed, missing, and filled teeth (dmft) index recommended by the World Health Organization. Dental caries experience and oral health-related behaviours were compared between migrant and resident children. The impact of children's migration attributes on their oral health outcomes was examined by univariate and multivariate analyses. RESULTS: Among the examined children, 52.3% were migrant children. The prevalence of caries among the children in multi-beneficial kindergartens was 78.3%, and the mean number of dmft was 5.73 ± 5.00. The prevalence of caries was 81.7% for migrant children and 74.6% for resident children (p = 0.060). No significant difference was found in the mean numbers of DMFT between migrant children and resident children (5.96 ± 4.81 vs. 5.47 ± 5.20, p = 0.139). There were significant differences in the frequency of tooth brushing (p = 0.023) and parental help with tooth brushing (p = 0.008), typical use of fluoride (p = 0.012), regular dental check-ups (p = 0.003) and experience of dental fillings for caries (p < 0.001) between migrant and resident children. The multivariate logistic regression analysis showed that among the children with caries, the proportion of resident children who had regular dental check-ups was 1.720 times higher than that of migrant children (95% CI = 1.155 ~ 2.560), and resident children were more likely to have caries filled than migrant children (OR = 3.313, 95% CI = 1.585 ~ 6.927). CONCLUSION: Oral health status and oral health behaviours were poor among children in multi-beneficial kindergartens in Nanning, China, and migration might be a significant predictive indicator for the poor utilization of dental care services by children. The government departments should make special policy to promote the children's oral health in multi-beneficial kindergartens, and invest more to cover the migrant children's utilization of oral health services.

Guide Positioning Sequencing identifies aberrant DNA methylation patterns that alter cell identity and tumor-immune surveillance networks.

Aberrant DNA methylation is a distinguishing feature of cancer. Yet, how methylation affects immune surveillance and tumor metastasis remains ambiguous. We introduce a novel method, Guide Positioning Sequencing (GPS), for precisely detecting whole-genome DNA methylation with cytosine coverage as high as 96% and unbiased coverage of GC-rich and repetitive regions. Systematic comparisons of GPS with whole-genome bisulfite sequencing (WGBS) found that methylation difference between gene body and promoter is an effective predictor of gene expression with a correlation coefficient of 0.67 (GPS) versus 0.33 (WGBS). Moreover, Methylation Boundary Shift (MBS) in promoters or enhancers is capable of modulating expression of genes associated with immunity and tumor metabolism. Furthermore, aberrant DNA methylation results in tissue-specific enhancer switching, which is responsible for altering cell identity during liver cancer development. Altogether, we demonstrate that GPS is a powerful tool with improved accuracy and efficiency over WGBS in simultaneously detecting genome-wide DNA methylation and genomic variation. Using GPS, we show that aberrant DNA methylation is associated with altering cell identity and immune surveillance networks, which may contribute to tumorigenesis and metastasis.

Sociodemographic moderation of the association between depression and stroke incidence in a retrospective cohort of 0.4 million primary care recipients with hypertension.

BACKGROUND: Previous research has suggested an association between depression and subsequent acute stroke incidence, but few studies have examined any effect modification by sociodemographic factors. In addition, no studies have investigated this association among primary care recipients with hypertension. METHODS: We examined the anonymized records of all public general outpatient visits by patients aged 45+ during January 2007-December 2010 in Hong Kong to extract primary care patients with hypertension for analysis. We took the last consultation date as the baseline and followed them up for 4 years (until 2011-2014) to observe any subsequent acute hospitalization due to stroke. Mixed-effects Cox models (random intercept across 74 included clinics) were implemented to examine the association between depression (ICPC diagnosis or anti-depressant prescription) at baseline and the hazard of acute stroke (ICD-9: 430-437.9). Effect modification by age, sex, and recipient status of social security assistance was examined in extended models with respective interaction terms specified. RESULTS: In total, 396 858 eligible patients were included, with 9099 (2.3%) having depression, and 10 851 (2.7%) eventually hospitalized for stroke. From the adjusted analysis, baseline depression was associated with a 17% increased hazard of acute stroke hospitalization [95% confidence interval (CI) 1.03-1.32]. This association was suggested to be even stronger among men than among women (hazard ratio = 1.29, 95% CI 1.00-1.67). CONCLUSION: Depression is more strongly associated with acute stroke incidence among male than female primary care patients with hypertension. More integrated services are warranted to address their needs.

Bufalin inhibits peritoneal dissemination of gastric cancer through endothelial nitric oxide synthase-mitogen-activated protein kinases signaling pathway.

Peritoneal dissemination threatens the survival of patients with gastric cancer (GC). Bufalin is an extract of traditional Chinese medicine, which has been proved to have anticancer effect. The target of bufalin in suppressing gastric cancer peritoneal dissemination (GCPD) and the underlying mechanism are still unclear. In this research, GC cell line MGC-803 and high-potential peritoneal dissemination cell line MKN-45P were treated with bufalin or L-NAME. Malignant biological behavior and protein level of GC cell lines were detected with MTT, wound healing, transwell, adhesion, and western blotting. Bioinformatics analysis and patient tissues were used to verify the role of endothelial nitric oxide synthase (NOS3) in GC. Mice model was used to assess the effect of bufalin and role of NOS3 in vivo. We found that bufalin inhibited the proliferation, invasion, and migration in GC cell lines. NOS3, which was an independent prognostic factor of GC patients, was predicted to be a potential target of bufalin. Further experiments proved that bufalin reduced the phosphorylation of NOS3, thereby inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway, and ultimately suppressed GCPD by inhibiting EMT process. In conclusion, NOS3 was a potential therapeutic target and prognostic biomarker of GC. Bufalin could suppress GCPD through NOS3-MAPK signaling pathway, which provided more evidence support for intraperitoneal perfusion of bufalin to treat GCPD.

Screen time and health issues in Chinese school-aged children and adolescents: a systematic review and meta-analysis.

BACKGROUNDS: Many literature reviews summarized relationships between screen time and child health, but they only included a few studies conducted in Chinese children and adolescents. The potential influence of screen time may vary by social context. The current systematic review and meta-analysis aimed to evaluate relationships between screen time and health issues among Chinese school-aged children and adolescents. METHODS: Peer-reviewed articles written in Chinese and English were retrieved from CNKI, Wanfang, PubMed, Embase, and Web of Science from inception to June 2020. The Downs & Black checklist was applied to assess study quality. Meta analyses used random effect models and mixed effects model to calculate pooled adjusted odds ratios and 95% confidence intervals. Heterogeneity, sensitivity, and publication bias were assessed using Q and I2 statistics, "one-study removed" analysis, the funnel plot, trim and fill analysis, and classical fail-safe N, respectively. RESULTS: In total, we identified 252 articles reporting 268 studies with unique samples. These studies investigated relationships between screen time and health issues of adiposity, myopia, psycho-behavioral problems, poor academic performance, cardiometabolic disease risks, sleep disorder, poor physical fitness, musculoskeletal injury, sub-health, and miscellaneous issues of height and pubertal growth, injury, sick leave, and respiratory symptoms. Proportions of studies reporting positive relationships with screen time were lowest in adiposity (50.6%) and higher in myopia (59.2%) and psycho-behavioral problems (81.8%). Other health issues were examined in 10 or less studies, all of which had more than half showing positive relationships. The pooled odds ratio from 19 studies comparing health risks with the screen time cutoff of 2 hours per day was 1.40 (95% CI: 1.31 to 1.50, I2 = 85.9%). The pooled effect size was 1.29 (95% CI: 1.20 to 1.39) after trimming 7 studies for publication bias adjustments. CONCLUSIONS: Findings exclusively generated from Chinese school-aged children and adolescents resonate those mainly from western countries. Evidence suggests that higher levels of screen time are related with greater risks of various health issues, although the relationships appear to be weak and intertwined with other confounding factors. Future studies need to investigate health-specific dose effects and mechanisms of screen time.

Study on the autophagy-related mechanism of puerarin in improving the cognitive impairment induced by alcohol in female mice.

PRIMARY OBJECTIVE: This study aimed to investigate the effects of low-, medium-, and high-dose puerarin on cognitive impairment induced by 50% alcohol in mice and revealed the role of autophagy-related signaling pathways (mTOR and JNK pathways) in this process. RESEARCH DESIGN: The alcohol-induced brain injury model was treated with different concentrations of puerarin. The cognitive function of mice was evaluated by the behavioral test, and the changes of target proteins in hippocampus of each experimental group were detected. METHODS AND PROCEDURES: 40 female Kunming mice were randomly divided into 5 groups. The cognitive ability of mice was tested by Morris water maze, the morphological changes in the CA1 area of hippocampus were observed by HE staining, and the target proteins in hippocampus were measured by WB and IHC. MAIN OUTCOMES AND RESULTS: Compared with the 50% alcohol group, the expression of p-mTOR/mTOR and p-4E-BP1/4E-BP1 in hippocampus was significantly decreased, while the expression of p-JNK/JNK, Beclin1, and LC3 was significantly increased in the medium- and high-dose puerarin groups. CONCLUSIONS: Puerarin could improve the cognitive impairment induced by 50% alcohol. The mTOR and JNK pathways related to autophagy might be involved in this process.

Bufalin inhibits human diffuse large B-cell lymphoma tumorigenesis by inducing cell death through the Ca2+/NFATC1/cMYC pathway.

The 5-year survival rate of diffuse large B-cell lymphoma (DLBCL) can reach 60%. However, nearly half of patients undergo relapse/refractory issues with a survival period of less than 2 years. New therapeutic approaches are therefore needed to improve chemotherapy efficacy and patient survival. Bufalin (BF), isolated from the traditional Chinese medicine Chansu, has been reported to play an anticancer role in multiple cancer cell types. However, there are few reports of the effects of BF on the growth of DLBCL. In the present study, we demonstrated that BF exerts antitumor activity in DLBCL cells, both in vitro and in vivo. Treatment of DLBCL cells with BF resulted in increased proliferation and apoptosis in a dose- and time-dependent manner. Daily intraperitoneal injection of 1.5 mg/kg BF significantly delayed DLBCL xenograft growth in NOD/SCID mice without affecting body weight. Bioinformatics analysis showed that BF may regulate NFATC1 protein and affect expression of its downstream gene, cMYC. Our results suggest that BF can attenuate NFATC1 translocation by reducing the intracellular calcium concentration; BF may also have a low synergistic effect with cyclosporin A. In conclusion, we demonstrated that BF exerts antitumor activity that is mediated at least in part by the Ca2+/NFATC1/cMYC pathway. Our findings suggest that BF can be effectively applied as a novel potential therapeutic agent for DLBCL.

Controllable scattering of a single photon inside a one-dimensional coupled resonator waveguide with second-order nonlinearity.

We note that most of the studies of the single photon scattering inside a one-dimensional coupled resonator waveguide are based on the waveguide coupling with the atom systems. In this paper, we will study the single photon scattering enabled by another system, i.e., the second-order nonlinearity, which can act as a single photon switch to control the single photon transmission and reflection inside the one-dimensional coupled resonator waveguide. The transmission rate is calculated to analyze the single-photon scattering properties. In addition, a more complicated second-order nonlinear form, i.e., three-wave mixing, is discussed to control single photon transmission inside the one-dimensional coupled resonator waveguide.

Lymecycline reverses acquired EGFR-TKI resistance in non-small-cell lung cancer by targeting GRB2.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were first-line treatments for NSCLC patients with EGFR-mutations. However, about 30 % of responders relapsed within six months because of acquired resistance. In this study, we used Connectivity Map (CMap) to discover a drug capable of reversing acquired EGFR-TKIs resistance. To investigate Lymecycline's ability to reverse acquired EGFR-TKIs resistance, two Icotinib resistant cell lines were constructed. Lymecycline's ability to suppress the proliferation of Icotinib resistant cells in vitro and in vivo was then evaluated. Molecular targets were predicted using network pharmacology and used to identify the molecular mechanism. Growth factor receptor-bound protein 2 (GRB2) is an EGFR-binding adaptor protein essential for EGFR phosphorylation and regulation of AKT/ERK/STAT3 signaling pathways. Lymecycline targeted GRB2 and inhibited the resistance of the cell cycle to EGFR-TKI, arresting disease progression and inducing apoptosis in cancer cells. Combined Lymecycline and Icotinib treatment produced a synergistic effect and induced apoptosis in HCC827R5 and PC9R10 cells. Cell proliferation in resistant cancer cells was significantly inhibited by the combined Lymecycline and Icotinib treatment in mouse models. Lymecycline inhibited the resistance of the cell cycle to EGFR-TKI and induced apoptosis in NSCLC by inhibiting EGFR phosphorylation and GRB2-mediated AKT/ERK/STAT3 signaling pathways. This provided strong support that Lymecycline when combined with EGFR targeting drugs, enhanced the efficacy of treatments for drug-resistant NSCLC.

Prosaposin is a biomarker of mesenchymal glioblastoma and regulates mesenchymal transition through the TGF-ß1/Smad signaling pathway.

Mesenchymal glioblastoma (GBM) is the most aggressive subtype of GBM. Our previous study found that neurotrophic factor prosaposin (PSAP) is highly expressed and secreted in glioma and can promote the growth of glioma. The role of PSAP in mesenchymal GBM is still unclear. In this study, bioinformatic analysis, western blotting and RT-qPCR were used to detect the expression of PSAP in different GBM subtypes. Human glioma cell lines and patient-derived glioma stem cells were studied in vitro and in vivo, revealing that mesenchymal GBM expressed and secreted the highest level of PSAP among four subtypes of GBM, and PSAP could promote GBM invasion and epithelial-mesenchymal transition (EMT)-like processes in vivo and in vitro. Bioinformatic analysis and western blotting showed that PSAP mainly played a regulatory role in GBM invasion and EMT-like processes via the TGF-ß1/Smad signaling pathway. In conclusion, the overexpression and secretion of PSAP may be an important factor causing the high invasiveness of mesenchymal GBM. PSAP is therefore a potential target for the treatment of mesenchymal GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Piperlongumine inhibits head and neck squamous cell carcinoma proliferation by docking to Akt.

Piperlongumine (PL) is a biologically active alkaloid isolated from the long pepper roots and widely used as a traditional medicine in Ayurvedic medicine. However, the mechanism of PL's effect on head and neck squamous cell carcinoma (HNSCC) is not well understood. We performed cell experiments to confirm PL's inhibitory effect on HNSCC and employing cisplatin as positive control. Next, we conducted bioinformatics to predict PL's potential targets and verified by western blotting. Molecular docking, Biacore experiment and kinase activity assays were applied to elucidate the mechanism by which PL inhibited target activity. In vivo efficacy was verified by xenotransplantation and immunohistochemistry. PL inhibited proliferation, promoted late apoptosis, arrested cell cycle and inhibited DNA replication of the HEp-2 and FaDu cell lines. Employing bioinformatics, we found that PL's target was Akt and PL attenuated Akt phosphorylation. We found from molecular docking, Biacore experiment and kinase activity assay that PL inhibited Akt activation by docking to Akt to restrain its activity. In addition, PL significantly inhibited the growth of xenograft tumors by down regulating the expression of p-Akt in vivo. This study provides new insights into the molecular functions of PL and indicate its potential as a therapeutic agent for HNSCC.

Clinicopathological implications of TIM3+ tumor-infiltrating lymphocytes and the miR-455-5p/Galectin-9 axis in skull base chordoma patients.

Chordoma is difficult to eradicate due to high local recurrence rates. The immune microenvironment is closely associated with tumor prognosis; however, its role in skull base chordoma is unknown. The expression of Galectin-9 (Gal9) and tumor-infiltrating lymphocyte (TIL) markers was assessed by immunohistochemistry. Kaplan-Meier and multivariate Cox analyses were used to assessing local recurrence-free survival (LRFS) and overall survival (OS) of patients. MiR-455-5p was identified as a regulator of Gal9 expression. Immunopositivity for Gal9 was associated with tumor invasion (p = 0.019), Karnofsky performance status (KPS) score (p = 0.017), and total TIL count (p < 0.001); downregulation of miR-455-5p was correlated with tumor invasion (p = 0.017) and poor prognosis; and the T-cell immunoglobulin and mucin-domain 3 (TIM3)+ TIL count was associated with chordoma invasion (p = 0.010) and KPS score (p = 0.037). Furthermore, multivariate analysis indicated that only TIM3+ TIL density was an independent prognostic factor for LRFS (p = 0.010) and OS (p = 0.016). These results can be used to predict clinical outcome and provide a basis for immune therapy in skull base chordoma patients.

Role of abnormal microRNA expression in Helicobacter pylori associated gastric cancer.

Epidemiological studies have shown that Helicobacter pylori (HP) infection is a risk factor for gastric cancer (GC). HP infection may induce the release of pro-inflammatory mediators, and abnormally increase the level of reactive oxygen species (ROS), nitric oxide (NO), and cytokines in mucosal epithelial cells of the stomach. However, the specific mechanism underlying the pathogenesis of HP-associated GC is still poorly understood. Recent studies have revealed that abnormal microRNA expression may affect the proliferation, differentiation, and apoptosis of mucosal epithelial cells of the stomach to further influence GC occurrence, development, and metastasis. Herein, we summarize the role of abnormal microRNAs in the regulation of HP-associated GC progression. Abnormal microRNA expression in HP-positive GC may be a biomarker for GC diagnosis, occurrence, and development as well as its targeted treatment and prognosis.

Molecular Model of Dye Sensitized Titanium Oxides Based on Aryl-Amine Dye Anchored Titanium Oxo Clusters.

Model studies on dye sensitized titanium oxides have attracted wide interest with respect to their importance in understanding photoelectric and photophysical processes. Ligand modified titanium oxo clusters (TOCs) have been considered as the most appropriate models for dye sensitized solar cells (DSSCs) on the basis of their atomically precise structures. However, the ligands used previously in TOC models were seldom the dyes that really applied in DSSCs due to the difficulty with which the crystals of the dye anchored TOCs are obtained. We report herein a series of TOCs with the popularly used arylamine-cyanoacrylate dyes. As the closest model of DSSCs, the TOCs were studied by DFT calculations based on their accurate structural information. They have also been applied to photoelectric conversion evaluation by a solar cell device. Both the theoretical and application results showed that the synergistic effect of intradye molecular charge transfer (ICT) and dye to TiO cluster charge transfer (LMCT) is important in increasing the power conversion efficiency.