Individual and Community level Developmental Adversities: Associations with Marijuana and Alcohol Use in Late-Adolescents and Young Adults.

Exposure to community and individual level stressors during adolescence has been reported to be associated with increased substance use. However, it remains unclear what the relative contribution of different community- and individual-level factors play when alcohol and marijuana use become more prevalent during late adolescence. The present study uses a large longitudinal sample of adolescents (Wave 1: N = 2017; 55% Female; 54.5% White, 22.3% Black, 8% Hispanic, 15% other) to evaluate the association and potential interactions between community- and individual-level factors and substance use from adolescence to young adulthood (Wave 1 to Wave 3 Age Mean [SD]: 16.7 [1.1], 18.3 [1.2], 19.3 [1.2]). Across three waves of data, multilevel modeling (MLM) is used to evaluate the association between community affluence and disadvantage, individual household socioeconomic status (SES, measured as parental level of education and self-reported public assistance) and self-reported childhood maltreatment with self-reported 12-month alcohol and 12-month marijuana use occasions. Sample-selection weights and attrition-adjusted weights are accounted for in the models to evaluate the robustness of the estimated effects. Across the MLMs, there is a significant positive association between community affluence and parental education with self-reported alcohol use but not self-reported marijuana use. In post hoc analyses, higher neighborhood affluence in older adolescents is associated with higher alcohol use and lower use in younger adolescents; the opposite association is found for neighborhood disadvantage. Consistent with past literature, there is a significant positive association between self-reported childhood maltreatment and self-reported 12-month alcohol and 12-month marijuana use. Results are largely consistent across weighted and unweighted analyses, however, in weighted analyses there is a significant negative association between community disadvantage and self-reported 12-month alcohol use. This study demonstrates a nuanced relationship between community- and individual-level factors and substance use during the transitional window of adolescence which should be considered when contextualizing and interpreting normative substance use during adolescence.

Overexpression of Bruton Tyrosine Kinase Inhibits the Proliferation, Migration, and Invasion of Non-Small Cell Lung Cancer Cells.

Lung cancer is one of the most lethal malignant tumors in the world. Non-small cell lung cancer (NSCLC) is the most common pathological subtype. However, the molecular mechanism of NSCLC progress is still unclear. We extracted the expression data of the Bruton's tyrosine kinase (BTK) gene in NSCLC tissues from the TCGA database. The results of paired t-test showed that the BTK gene was significantly underexpressed in NSCLC tissues. To further verify the above results, we detected the expression of the BTK gene in NSCLC cell lines A549, H1299, and H1650 at the RNA and protein levels by real-time fluorescent quantitative polymerase chain reaction and Western Blot analysis, respectively. The results showed that BTK was low expressed in NSCLC tissues and cells. More importantly, the expression of the BTK gene is also significantly related to the patient's age, gender, tumor range (T), lymph node invasion (N), tumor stage, and prognosis, and its expression level gradually decreases with the progress of the disease. It is speculated that BTK may be an independent prognostic factor of NSCLC. Our experimental results are consistent with the above clinical correlation analysis results. Overexpression of BTK can significantly inhibit the proliferation, migration, and invasion of NSCLC cells and can block the G0/G1 tumor cell cycle, indicating that overexpression of BTK can inhibit the growth, migration, and invasion of NSCLC cells.

LINC01117 inhibits invasion and migration of lung adenocarcinoma through influencing EMT process.

BACKGROUND: Studying the mechanism of action of LncRNAs in lung adenocarcinoma (LUAD) is of great importance for an in-depth understanding of the molecular mechanism of lung adeno carcinogenesis and development. OBJECTIVE: The aim is to identify a long non-coding RNA LINC01117 that is specifically and highly expressed in LUAD cells and to investigate its biological functions and molecular mechanisms in LUAD cells, providing a new potential target for targeting LUAD therapy. METHODS: This study used publicly available data downloaded from The Cancer Genome Atlas (TCGA) database. Construction of siRNA and overexpression plasmid-packed lentiviral constructs were used to knock down and increase the expression of LINC01117 in LUAD cells. The effect of LINC01117 on LUAD cell migration and invasion was verified by scratch assays and Transwell assays. Western blot assays were performed to verify the effect of knocking down LINC01117 expression on key proteins of the EMT process. The effect of overexpression and knockdown LINC01117 expression on key proteins of the EMT process and the nuclear and cytoplasmic distribution of YAP1, a key effector molecule of the Hippo pathway, was verified by Western blot assays. RESULTS: LINC01117 expression was upregulated in LUAD tissues and cell lines. Clinical correlation and prognostic analyses showed that LINC01117 was associated with poorer clinical features (staging and N classification) and poorer prognosis and could be analyzed as an independent prognostic factor. Cell migration and invasion were significantly inhibited in the knockdown group compared to the control group; in contrast, cell migration and invasion were promoted in the overexpression group. Overexpression of LINC01117 resulted in down-regulation of E-cadherin expression and increased expression levels of N-cadherin, vimentin, ZEB1, snail and slug; in contrast, knockdown of LINC01117 appeared to have the opposite effect. Furthermore, knockdown of LINC01117 increased the enrichment of YAP1 protein in the cytoplasm and reduced its level in the nucleus; overexpression of LINC01117 produced the opposite intracellular distribution results. CONCLUSIONS: LINC01117 was highly expressed in LUAD, and knockdown of LINC01117 significantly inhibited the migration and invasion of LUAD cells, while overexpression of LINC01117 significantly promoted the migration and invasion of LUAD cells, and affected the EMT process, and was able to alter the distribution of YAP1 in the nucleus and cytoplasm. This suggests that LINC01117 may regulate the activity of the Hippo pathway by altering the nuclear and cytoplasmic distribution of YAP1, which in turn induces the EMT process in lung adenocarcinoma cells and thus exerts a pro-cancer effect. It suggests that LINC01117 may play a key role in the occurrence and development of LUAD.

The relationship of platelet-to-lymphocyte ratio with cognitive decline in T2DM.

PURPOSE: We aimed to investigate the role of platelet-to-lymphocyte ratio (PLR) in cognitive decline in patients with type 2 diabetes mellitus (T2DM). METHODS: A total number of 261 T2DM patients were enrolled in this study. The T2DM patients were divided into two groups according to the median of PLR (PLR < 96.5, n = 130; PLR ≥ 96.5, n = 131). Cognitive impairment was defined as Mini-mental State Examination score ≤ 26. Student's t test and Chi-square test were used to test the difference between the groups, and logistics regression analysis were performed to verify whether high PLR was an independent factor for cognitive impairment. RESULTS: T2DM patients with cognitive impairment had significantly higher PLR level when compared with the simple diabetes group (p = 0.003). Incidence of cognitive impairment was higher in the high PLR group, compared to low PLR group (p = 0.040). Multivariate logistic regression analysis suggested that PLR was a risk biomarker of cognitive decline in T2DM patients (odds ratio [OR] = 1.010, 95% CI: 1.001-1.018, p = 0.013). CONCLUSIONS: We demonstrated that a higher PLR was associated with cognitive decline in T2DM patients. The PLR may help to identify high-risk patients in time and provide clues for further prevention of cognitive dysfunction in T2DM patients.

Optimized terbium doped Ti/PbO2 dimensional stable anode as a strong tool for electrocatalytic degradation of imidacloprid waste water.

The presence of pesticides in water has emerged as a momentous environmental issue over the past decades. Herein, a terbium doped Ti/PbO2 (denoted as Ti/PbO2-Tb) dimensionally stable Ti/PbO2-Tb anode has been successfully prepared by one-step electrodeposition path for electrocatalytic degradation of imidacloprid (IMD) wastewater with high efficiency. Ti/PbO2-Tb electrode presents higher oxygen evolution potential, lower charge transfer resistance, stronger stability, longer service lifetime and outstanding electrocatalytic activity than Ti/PbO2 electrode. The optimum condition for IMD oxidation is obtained by analyzing the effects of some critical operating parameters including temperature, initial pH, current density and electrolyte concentration. It is proved that 70.05% of chemical oxygen demand and 76.07% of IMD are removed after 2.5 h of degradation under current density of 8 mA cm-2, pH 9, temperature 30 °C and 7.0 g L-1 NaCl electrolyte. In addition, the electrode displays commendable energy saving property as well as favorable reusability. The degradation mechanism of IMD is proposed by analyzing the intermediates identified by LC-MS. The present research provides a feasible strategy to degrade IMD wastewater by Ti/PbO2-Tb electrode.

Simultaneous voltammetric determination of guanine and adenine by using a glassy carbon electrode modified with a composite consisting of carbon quantum dots and overoxidized poly(2-aminopyridine).

A composite consisting of carbon quantum dots (CQDs) and overoxidized poly(2-aminopyridine) (PAPox) was deposited on a glassy carbon electrode (GCE) through electrochemical polymerization and electrochemical oxidation. The modified GCE was used for the simultaneous determination of guanine and adenine. Electrochemical responses to guanine and adenine were investigated by cyclic voltammetry and differential pulse voltammetry. Owing to the synergistic effect of CQDs and PAPox, two oxidation peaks can be observed, with peaks at 0.81 and 1.13 V (vs. SCE) for guanine and adenine, respectively. The current at the respective peaks has a linear dependence on the concentrations of guanine in the range from 1.0 to 65 µM, and of adenine in the range from 2.0 to 70 µM. The respective detection limits are 0.51 and 0.39 µM (at an S/N ratio of 3). The modified GCE is selective, reproducible and stable. Graphical abstract Schematic of the preparation of a glassy carbon electrode modified with carbon quantum dots and overoxidized poly(2-aminopyridine (CQD/PAPox/GCE), and its application for the simultaneous determination of guanine and adenine.

Association of fibroblast growth factor receptor 1 gene amplification with poor survival in patients with esophageal squamous cell carcinoma.

PURPOSE: To investigate whether FGFR1 gene amplification is associated with clinicopathologic characteristics and its potential impact on survival in patients with resected esophageal squamous cell carcinoma (ESCC). METHODS: Five hundred fifty-six ESCC patients undergoing curative resection of ESCC were retrospectively studied. FGFR1 gene copy number was determined in microarrayed tumor samples using fluorescent in situ hybridization (FISH) analysis. FGFR1 gene amplification status was prespecified as copy number ≥ 6 or FGFR1/CEN 8 ratio ≥ 2.2. FGFR1 expression was evaluated by immunohistochemistry. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method followed by the log rank test. Correlation with survival was examined using multivariate Cox regression. RESULTS: FGFR1 amplification was identified in 67 (12.1%) patients; these patients had significantly shorter OS (50.0 vs 32.0 months; log rank; P<0.001) as well as shorter DFS (47.0 vs 28.0 months; log rank; P<0.001) than those without FGFR1 amplification. Under a Cox proportional hazard model, FGFR1 amplification was associated with significantly shorter OS (adjusted hazard ratio [AHR]=1.61; 95% CI, 1.10-2.43, P=0.004) and DFS (AHR=1.72; 95%CI, 1.15-2.48; P<0.001). Moreover, cases with high intratumoral FGFR1 expression showed significantly shorter OS and DFS than those with low FGFR1 expression. The frequency of FGFR1 amplification was significantly higher in heavy drinkers than in moderate and light drinkers. CONCLUSION: FGFR1 amplification is an independent adverse prognostic factor in surgically resected ESCC. FGFR1 may be a promising therapeutic target in patients with ESCC.

VEGF-D-enhanced lymph node metastasis of ovarian cancer is reversed by vesicular stomatitis virus matrix protein.

Lymphatic metastasis is a poor prognostic factor in ovarian cancer, which correlates to the majority of cancer deaths. Matrix protein (MP) of vesicular stomatitis virus (VSV) exhibits potent antitumor and antiangiogenic activities through inducing apoptosis and inhibiting angiogenesis. In this study, the antitumor and antimetastatic effects of MP were further investigated. Wild-type SKOV3 (WT-SK) cells were successfully transfected with empty vector pcDNA3.1 plasmid, or pcDNA3.1-VEGF-D recombinant plasmid to construct cell lines named EV-SK, and VEGFD-SK, respectively. Inhibition of VEGFD-SK cell migration and invasion was detected by Transwell and wound healing assay. Then, lymphogenous metastatic model of ovarian cancer was established by injecting VEGFD-SK cells subcutaneously into the left hindlimb claw pad of nude mice. The inducted apoptotic effect of MP on VEGFD-SK cells were assessed by flow analysis and Hoechst-33258 staining, respectively, in vitro. The in vivo antitumor and antiangiogenic activities of MP gene were evaluated with lymphogenous metastatic model of ovarian cancer. Tumor volume and lymphatic metastasis rates were measured. Lymphatic vessels were delineated using Evan's blue and LYVE-1 staining. Expression of VEGF-D and MMP-2 were evaluated by immunostaining. Apoptosis of tumor cells was analyzed by Hoechst-33258 staining. Mice bearing VEGFD-SK tumor cells displayed more rapid tumorigenesis, higher lymphogenous metastatic tendency and increased lymphatic vessel density compared with the mice bearing WT-SK or EV-SK cells. However, VEGF-D-enhanced metastasis was evidently reversed by MP. MP significantly reduced the invasion of VEGFD-SK cells, tumor volume, lymphatic metastasis rates and lymphatic vessel density compared with control groups (P<0.05), accompanied with down-expression of VEGF-D and MMP-2 and increased apoptosis. Our data indicate that MP has strong antitumor and antimetastatic abilities, and it may be a promising therapeutic strategy against the lymphatic metastasis of human ovarian cancer.

Esophagectomy for a rapidly progressing esophageal duplication cyst.

Esophageal duplication cysts are rare and frequently asymptomatic anomalies of the adult gastrointestinal tract that are often misdiagnosed in clinical practice. Identifying the unique features of esophageal duplication cysts is therefore important. We report a unique case of esophageal duplication cyst in a 52-year-old woman with rapidly progressing chest pain and dysphagia. The cyst was found to share, in part, a remarkably inflammatory and edematous inner lining with the esophagus. Enucleation was not feasible, and therefore, esophagectomy was performed. The only long-term side effect that occurred after 44 months of follow-up examinations was slight acid reflux esophagitis.

Low-dose paclitaxel improves the therapeutic efficacy of recombinant adenovirus encoding CCL21 chemokine against murine cancer.

Secondary lymphoid tissue chemokine (SLC/CCL21), one of the CC chemokines, exerts potent antitumor immunity by co-localizing T cells and dendritic cells at the tumor site and is currently tested against human solid tumors. Here, we investigated whether the combination of recombinant adenovirus encoding murine CCL21 (Ad-mCCL21) with low-dose paclitaxel would improve therapeutic efficacy against murine cancer. Immunocompetent mice bearing B16-F10 melanoma or 4T1 breast carcinoma were treated with either Ad-mCCL21, paclitaxel, or both agents together. Our results showed that Ad-mCCL21 + low-dose paclitaxel more effectively reduced the growth of tumors as compared with either treatment alone and significantly prolonged survival time of the tumor-bearing animals. These antitumor effects of the combined therapy were linked to altered cytokine network at the tumor site, enhanced apoptosis of tumor cells, and decreased formation of new vessels in tumors. Importantly, the combined therapy elicited a strong therapeutic antitumor immunity, which could be partly abrogated by the depletion of CD4(+) or CD8(+) T lymphocytes. Collectively, these preclinical evaluations may provide a combined strategy for antitumor immunity and should be considered for testing in clinical trials.

VEGF-D-induced draining lymphatic enlargement and tumor lymphangiogenesis promote lymph node metastasis in a xenograft model of ovarian carcinoma.

BACKGROUND: Vascular endothelial growth factor (VEGF)-D has been shown to promote lymph node metastasis in several cancers. Although generally overexpressed in ovarian carcinoma, its role in nodal dissemination of this cancer is unclear. To clarify the role of VEGF-D and the underlying molecular mechanisms, we investigated the function of VEGF-D using a mouse xenograft model of ovarian cancer. METHODS: Human ovarian serous adenocarcinoma SKOV3 cells were transfected with VEGF-D recombinant plasmid DNA, or with control vectors. The cells were injected subcutaneously into the footpads of nude mice. Tumor growth was evaluated weekly. Draining lymphatics were observed grossly with Evan's blue lymphangiography. Tumoral lymphatics were delineated with both Evan's blue and LYVE-1 immunostaining. Tumor metastases to lymph nodes were evaluated by H&E and CA125/CD40 staining. Expression of VEGF-D in primary tumors and levels of CA125 in involved lymph nodes were examined by immunohistochemistry. Tumor cell apoptosis was analyzed by Hoechst dyeing. RESULTS: Mice bearing VEGF-D overexpressing xenografts showed a significantly higher rate of lymph node metastasis and markedly greater tumor volume compared with the controls. The functional lymphatic vessels were denser and enlarged in marginal and central tumor portions. Additionally, higher CA125 expression was observed in the involved lymph nodes. Mice bearing VEGF-D overexpressing xenografts also exhibited a markedly lower apoptotic index compared with the controls. CONCLUSIONS: Our data demonstrate the important role of VEGF-D in promoting lymph node metastasis by increasing tumor lymphangiogenesis, stimulating draining lymphatic vessel formation, and enhancing tumor invasiveness. Our findings show that VEGF-D can be a promising therapeutic target for ovarian cancer.

Receptor tyrosine kinase alterations and therapeutic opportunities in squamous cell carcinoma of the lung.

PURPOSE: Targeted therapy has greatly improved the treatment for adenocarcinoma of the lung, but not squamous cell carcinoma (SCC) of the lung. The current paper describes the abnormalities of receptor tyrosine kinases (RTK) in lung SCC in a hope to stimulate the development of therapeutics that can have clinical impact. METHODS: We reviewed both clinical and preclinical studies published in English regarding RTK abnormalities and/ or RTK-targeting treatment for SCC of the lung. RESULTS: RTK alterations have been demonstrated as biological signature for SCC of the lung. A number of clinical trials of RTK-targeting therapy have been carried out or are ongoing, with encouraging results. CONCLUSIONS: SCC of the lung should be treated as an independent disease with unique treatment options based on molecular changes, particularly RTK.

Zeolite A functionalized with copper nanoparticles and graphene oxide for simultaneous electrochemical determination of dopamine and ascorbic acid.

A novel Cu-zeolite A/graphene modified glassy carbon electrode for the simultaneous electrochemical determination of dopamine (DA) and ascorbic acid (AA) has been described. The Cu-zeolite A/graphene composites were prepared using Cu(2+) functionalized zeolite A and graphene oxide as the precursor, and subsequently reduced by chemical agents. The composites were characterized by X-ray diffraction, Fourier transform infrared spectra and scanning electron microscopy. Based on the Cu-zeolite A/graphene-modified electrode, the potential difference between the oxidation peaks of DA and AA was over 200mV, which was adequate for the simultaneous electrochemical determination of DA and AA. Also the proposed Cu-zeolite/graphene-modified electrode showed higher electrocatalytic performance than zeolite/graphene electrode or graphene-modified electrode. The electrocatalytic oxidation currents of DA and AA were linearly related to the corresponding concentration in the range of 1.0×10(-7)-1.9×10(-5)M for DA and 2.0×10(-5)-2.0×10(-4)M for AA. Detection limits (S/N=3) were estimated to be 4.1×10(-8)M for DA and 1.1×10(-5)M for AA, respectively.

The antitumor and antimetastatic effects of N-trimethyl chitosan-encapsulated camptothecin on ovarian cancer with minimal side effects.

Lymphatic metastasis plays a critical role in ovarian cancer, indicates poor prognoses and correlates to the majority of cancer deaths. Camptothecin derivatives exhibit promising activity for the treatment of solid tumors because of its specific inhibition of eukaryotic DNA topoisomerase I. Yet, its application is hindered due to extreme water insolubility and severe side effects. It is essential to establish an efficient and safe protocol for the administration of camptothecin versus tumor metastasis and growth. In the current research, we encapsulated camptothecin with N-trimethyl chitosan (CPT-TMC) to increase its water-solubility and lower its side effects, and tested it on a high potential lymphogenous metastatic model of human ovarian cancer. In the prophase study, we successfully transfected SKOV3 cells with VEGF-D recombinant plasmid DNA (pcDNA3.1(+)/VEGF-D) to construct a cell line named SKOV3/VEGF-D and establish a feasible lymphogenous metastatic model. The antitumor and antimetastatic activities of CPT-TMC were evaluated in nude mice subcutaneously inoculated with SKOV3/VEGF-D cells at the left hindlimb claw pad. The tumor-bearing mice were divided randomly into four groups and treated twice per week for three weeks. Evan's Blue Dye was used to delineate functional lymphatic vessels. Lymphatic metastasis rates were detected by hematoxylin and eosin (HE) staining. Expression of VEGF-D and MMP-9 were investigated by immunohistochemistry. In contrast to controls, administration of CPT-TMC achieved effective inhibition in primary tumor volume and lymphogenous metastasis, yet without apparent systemic toxic effects. These effects were associated with simultaneously down-regulated VEGF-D and MMP-9 expression, significantly decreased tumor-associated lymphatic and blood sprouts, tremendously reduced systemic toxic effects, dramatically increased tumor apoptotic index. Our data indicate that CPT-TMC is superior to CPT by maximizing its anticancer and antimetastatic activities with minimal toxicity on hosts. CPT-TMC may become a potentially therapeutic strategy against human advanced ovarian cancer.

A tumor-selective biotherapy with prolonged impact on established metastases based on cytokine gene-engineered MSCs.

The poor prognosis for patients with advanced malignancy relates partly to the inability to reverse cancer metastasis. In this study we have investigated an integrated immunotherapy method against pre-established metastases in three kinds of advanced cancer models including B16 melanoma, 4T1 breast tumor, and Hca hepatoma. The progression of metastases into multistep lymph nodes (LN) and internal organs was, markedly impeded in the midway stage and reversed in the ultimate stage following a 20-day course of intravenous immunotherapy [with interleukin-12 (IL-12) gene-engineered mesenchymal stem cells (MSCs), administered once every 5 days P < 0.05)]; the therapy was without systemic toxic effects. As the control, obvious systemic toxicity was observed in the free AdIL-12 group, yet metastasis was partly delayed only in the midway stage but not in the ultimate stage. Enzyme-linked immunosorbent assay (ELISA) showed that the intratumoral expression levels of IL-12 were enhanced by cytokine-engineered MSCs to be tenfold greater than that of free AdIL-12 groups in the ultimate stage; conversely, free AdIL-12 groups showed elevated serum, but not intratumoral levels of IL-12, during the midway stage. Furthermore, histomorphometric analysis revealed a reductive tendency toward reversion of tumor-associated lymphatic sprouts and an increased tumor apoptosis index in engineered MSC groups (P < 0.05). These data indicate the potential of cytokine-engineered MSCs to be considered as an integrated therapeutic weapon for targeting advanced malignancies.