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Objectives: To investigate epidemiological features and trends of influenza incidence with 1,173,640 cases in mainland China from 2005 to 2015. Methods: Incidence and mortality data for influenza from 2005 to 2015 were provided by the data-center of China public health science and covered a population of about 1.3 billion people from 31 provinces and regions in mainland China. Joinpoint regression and exploratory spatial data analyses were used to examine the incidence trends from 2005 to 2015. Results: The first upsurge in influenza cases occurred in 2009, and the highest incidence of influenza occurred in 2014 (15.9045 cases/100,000 people). The average incidence per year from 2009 to 2015 was threefold higher than that from 2005 to 2008 (10.5308 vs 3.4589 cases/100,000 people; incidence rate ratio = 3.0446). The joinpoint regression results showed that there was an increasing influenza incidence trend from 2005 to 2015 (annual change in percentage = 13.6%, 95%CI 2.2–26.3, p = 0.0236). The seasonal pattern analysis showed that influenza typically occurred in winter and spring during each monitoring year, peaking from November to March the next year. Conclusions: This study will help governments to make valuable decisions in allocating scarce resources and providing strategies to limit the spread of influenza. Keywords: Influenza, Epidemiology, Mainland China, Incidence, Seasonal pattern

Previous studies have confirmed that protein tyrosine phosphatase 1B (PTP1B) can promote tumour progression in non-small cell lung cancer (NSCLC). Vanadyl alginate oligosaccharides (VAOS) is a new coordination compounds that possesses a good PTP1B inhibitory activity. However, the potent anticancer efficacy of VAOS in human NSCLC requires further study. In this study, VAOS exhibited effective inhibitory effects in NSCLC both in cultured cells and in a xenograft mouse model. VAOS was further identified to induce NSCLC cell apoptosis through activating protein kinase B (AKT) to elevate intracellular reactive oxygen species (ROS) levels by increasing in oxygen consumption and impairing the ROS-scavenging system. Neither silencing of PTP1B by siRNA nor transient overexpression of PTP1B had an effect on the AKT phosphorylation triggered by VAOS, indicating that PTP1B inhibition was not involved in VAOS-induced apoptosis. Through phosphorus colorimetric assay, we demonstrated that VAOS notably inhibited phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylation activity, another member of the protein tyrosine phosphatases (PTPases)-upstream factor of AKT. Interestingly, PTEN knockdown sensitized cells to VAOS, whereas ectopic expression of PTEN markedly rescued VAOS-mediated lethality. In vivo, VAOS treatment markedly reduced PTEN activity and tumour cell burden with low systemic toxicity. Thus, our data not only provided a new therapeutic drug candidate for NSCLC, but presented new understanding into the pharmacological research of VAOS.

Non-coding RNAs (ncRNAs) involve in diverse biological processes by post-transcriptional regulation of gene expression. Emerging evidence shows that miRNA-4293 plays a significant role in the development of non-small cell lung cancer. However, the oncogenic functions of miR-4293 have not been studied. Our results demonstrated that miR-4293 expression is markedly enhanced in lung carcinoma tissue and cells. Moreover, miR-4293 promotes tumor cell proliferation and metastasis but suppresses apoptosis. Mechanistic investigations identified mRNA-decapping enzyme 2 (DCP2) as a target of miR-4293 and its expression is suppressed by miR-4293. DCP2 can directly or indirectly bind to WFDC21P and downregulates its expression. Consequently, miR-4293 can further promote WFDC21P expression by regulating DCP2. With a positive correlation to miR-4293 expression, WFDC21P also plays an oncogenic role in lung carcinoma. Furthermore, knockdown of WFDC21P results in functional attenuation of miR-4293 on tumor promotion. In vivo xenograft growth is also promoted by both miR-4293 and WFDC21P. Overall, our results establish oncogenic roles for both miR-4293 and WFDC21P and demonstrate that interactions between miRNAs and lncRNAs through DCP2 are important in the regulation of carcinoma pathogenesis. These results provided a valuable theoretical basis for the discovery of lung carcinoma therapeutic targets and diagnostic markers based on miR-4293 and WFDC21P.

Peritrophic membrane (PM) refers to a vital physical barrier enabling shrimp to resist pathogen invasion. It primarily consists of chitin and proteins, mostly chitin-binding protein (CBP). CBPs have been identified from microorganisms to higher organisms. In the present study, a CBP, designated MjCBP, was reported from Marsupenaeus japonicus. The open reading frame of MjCBP was 1854 bp, encoding a protein with 618 amino acids (MH544098). To be specific, the theoretical pI and molecular mass of mature MjCBP reached 5.43 and 66064.00 Da, respectively. MjCBP consisted of seven type Ⅱ chitin-binding domains (ChtB D2), which was up-regulated after being challenged with Vibrio anguillarum and then agglutinating several bacteria. In addition, MjCBP and the first chitin-binding domain (CBD1) could bind to several Gram-positive and Gram-negative bacteria via the binding process to lipopolysaccharides and peptidoglycans, whereas CBD1 was not capable of agglutinating bacteria. Moreover, the anterior and posterior segments of CBD1 were synthesized in vitro, and the posterior segment could bind to lipopolysaccharides. However, both segments fail to agglutinate bacteria. Furthermore, MjCBP and CBD1 facilitated the clearance of V. anguillarum in vivo, and the silencing of MjCBP via RNA interference reduced the ability of bacterial clearance. As revealed from the mentioned results, MjCBP acts as an opsonin or pattern recognition receptor to achieve antibacterial immune response in shrimp.

Chronic myeloid leukemia (CML) is a malignant hematological disease, and drug resistance is often related to poor prognosis. MicroRNAs (miRNA) play a pivotal role in transcriptional regulation, cell development, and chemotherapy resistance. Here, we describe the effect of let-7b on resistant leukemia cells and examine the relevance of let-7b as a biomarker for adriamycin resistance. Results showed that let-7b was downregulated in K562/ADM (KA) cells, and the downregulation of let-7b in K562 and KA cells increased ADM resistance. The inhibition of let-7b subsequently induced the upregulation of AURKB. Finally, results proved that the Pi3k/Akt/Erk pathway was related to AURKB-activated resistance. Our research indicated that the underexpression of let-7b and overexpression of AURKB contributed to the resistance of CML, and its function is partly regulated by the Pi3k/Akt/Erk pathway. Thus, our further understand of its inhibitory effect may promise a new therapeutic strategy to overcome chemotherapeutic resistance in CML.

Objectives and methodsWith 432 513 samples from UK Biobank dataset, multivariable linear/logistic regression were used to estimate the relationship between psoriasis/psoriatic arthritis (PsA) and estimated bone mineral density (eBMD)/osteoporosis, controlling for potential confounders. Here, confounders were set in three ways: model0 (including age, height, weight, smoking and drinking), model1 (model0 +regular physical activity) and model2 (model1 +medication treatments). The eBMD was derived from heel ultrasound measurement. And 4904 patients with psoriasis and 847 patients with PsA were included in final analysis. Mendelian randomisation (MR) approach was used to evaluate the causal effect between them.ResultsLower eBMD were observed in patients with PsA than in controls in both model0 (β-coefficient=−0.014, p=0.0006) and model1 (β-coefficient=−0.013, p=0.002); however, the association disappeared when conditioning on treatment with methotrexate or ciclosporin (model2) (β-coefficient=−0.005, p=0.28), mediation analysis showed that 63% of the intermediary effect on eBMD was mediated by medication treatment (pConclusionsThe effect of PsA on osteoporosis was secondary (eg, medication) but not causal. Under this hypothesis, psoriasis without arthritis was not a risk factor for osteoporosis.

Background Long noncoding (lncRNA) single‐nucleotide polymorphisms (SNPs) are associated with the susceptibility to the development of various malignant tumors. The aim of this study was to investigate the roles of HOX transcript antisense intergenic RNA (HOTAIR) and its SNPs in lung cancer. Methods Initially, the expression of HOTAIR in different tumors was investigated using the online Gene Expression Profiling Interactive Analysis (GEPIA) resource. Three SNPs (rs920778, rs1899663, and rs4759314) of HOTAIR were identified using the MassArray system. Following this, the relationship between these SNPs and susceptibility to lung cancer was investigated. Results Expression of HOTAIR was found to increase in a variety of cancers, including nonsmall cell lung cancer (NSCLC). We found that the genotypes of these SNPs (rs920778, rs1899663, and rs4759314) were not significantly associated with lung cancer type, family history, lymph node metastasis, or lung cancer stage. In gender stratification, the results of rs920778 genotypes showed that, compared to genotype AA, the AG (OR = 0.344, 95% CI: 0.133–0.893, p = .028) and AG + GG (OR = 0.378, 95% CI: 0.153–0.932, p = .035) genotypes of rs920778 are protective factors against NSCLC in females. In smoking stratification, compared with AA of rs920778, the genotype AG + GG (OR = 0.507, 95% CI: 0.263–0.975, p = .042) was a protective factor against NSCLC in nonsmoking people. No statistical differences were observed in the classifications of rs1899663 and rs4759314 genotypes. Linkage disequilibrium analysis revealed a high linkage disequilibrium between the rs920778 and rs1899663 (D′ = 0.99, r 2 = .74), rs920778 and rs4759314 (D′ = 0.85, r 2 = .13), and rs1899663 and rs4759314 (D′ = 0.79, r 2 = .00). Conclusion Our study demonstrated that HOTAIR expression increased in NSCLC, and that the genotypes of rs920778 could be useful in the diagnosis and prognosis of lung cancer., This study investigated the roles of HOTAIR and its SNPs in lung cancer. We found that HOTAIR increased in nonsmall cell lung cancer, and the genotypes of rs920778 are protective factors for female patients and nonsmoking people, which are useful for screening and prognosis for lung cancer.

HOX transcript antisense intergenic RNA (HOTAIR) is considered a diagnostic biomarker for cancer; however, results of previous studies on HOTAIR are inconsistent. In this meta-analysis, we aimed to investigate the role of HOTAIR in cancer diagnosis. Medline, PubMed, Embase, Ovid, Web of Science and Cochrane databases were searched for relevant literature up to May 2019. Over all, we included 20 studies from 17 articles on the role of HOTAIR in cancer diagnosis (individual diagnosis) and 7 studies from 6 articles on the role of HOTAIR along with other biomarkers in cancer diagnosis (combinative diagnosis). The sensitivity and specificity of HOTAIR-mediated individual diagnosis of cancers were 0.80 (95% confidence interval [CI], 0.74-0.85) and 0.74 (95% CI, 0.66-0.81), respectively. The sensitivity and specificity of HOTAIR-mediated combinative diagnosis of cancer were 0.82 (95% CI, 0.77-0.87) and 0.86 (95% CI, 0.80-0.91), respectively. The areas under the receiver operating characteristic curve for individual and combinative diagnoses was 0.84 (95% CI, 0.81-0.87) and 0.91 (95% CI, 0.88-0.93), respectively, indicating that a combinative diagnosis has a relatively better diagnostic accuracy (z = -2.22, P = 0.01) than individual diagnosis. In conclusion, HOTAIR levels might be a promising biomarker in cancer diagnosis. In addition, using HOTAIR in combination with other biomarkers showed a relatively better diagnostic accuracy than HOTAIR alone.

Seasonal influenza is one of the mandatorily monitored infectious diseases, in China. Making full use of the influenza surveillance data helps to predict seasonal influenza. In this study, a seasonal autoregressive integrated moving average (SARIMA) model was used to predict the influenza changes by analyzing monthly data of influenza incidence from January 2005 to December 2018, in China. The inter-annual incidence rate fluctuated from 2.76 to 55.07 per 100,000 individuals. The SARIMA (1, 0, 0) &times, (0, 1, 1) 12 model predicted that the influenza incidence in 2018 was similar to that of previous years, and it fitted the seasonal fluctuation. The relative errors between actual values and predicted values fluctuated from 0.0010 to 0.0137, which indicated that the predicted values matched the actual values well. This study demonstrated that the SARIMA model could effectively make short-term predictions of seasonal influenza.

Aims Active immunization with human vascular endothelial growth factor (hVEGF) vaccines provides a therapeutic option instead of bevacizumab therapy. However, the immunity to self-molecule is difficult to elicit due to immune tolerance. A bioactive peptide of two tandem repeats of mHSP70407–426 (M2) has exhibited potent adjuvant ability in our previous study, and the aim of this study was to explore whether M2 could assist hVEGF to display enhanced therapeutic anti-tumor effects. Main methods The anti-tumor effects of hVEGF-M2 vaccine were evaluated in both H22 hepatocellular carcinoma and Lewis lung tumor models. CD31 analysis of excised tumors was used to evaluate anti-angiogenesis effects. The titers of anti-VEGF antibody was detected by ELISA and verified by western blot analyses, and the effects of immune sera on HUVEC differentiation were investigated by tube formation assay. Key findings M2 could assist hVEGF to exhibit more favorable therapeutic anti-tumor growth and metastasis effects than hVEGF. Meanwhile, high titer of anti-VEGF antibody was detected in hVEGF-M2 immunized mice sera by ELISA and verified by western blot analysis. Sera from hVEGF-M2 immunized mice could more significantly inhibit HUVEC tube formation than hVEGF immune serum. The hVEGF-M2-immune sera could more effectively inhibit H22 tumor growth and extend the survival rates of H22 tumor bearing mice than hVEGF-immune sera. CD31 analysis of the excised tumors verified a significant reduction in vessel density after hVEGF-M2 vaccination. Significance M2 could assist hVEGF to display enhanced anti-tumor effects, which are important for the further application of M2 to enhance antigen-specific immune responses.

PurposeThe Westlake BioBank for Chinese (WBBC) pilot cohort is a population-based prospective study with its major purpose to better understand the effect of genetic and environmental factors on growth and development from adolescents to adults.ParticipantsA total of 14 726 participants (4751 males and 9975 females) aged 14–25 years were recruited and the baseline survey was carried out from 2017 to 2019. The pilot cohort contains rich range of information regarding of demographics and anthropometric measurements, lifestyle and sleep patterns, clinical and health outcomes. Visit the WBBC website for more information (https://wbbc.westlake.edu.cn/index.html).Findings to dateThe mean age of the study samples were 18.6 years for males and 18.5 years for females, respectively. The mean height and weight were 172.9 cm and 65.81 kg for males, and 160.1 cm and 52.85 kg for females. Results indicated that the prevalence of underweight in female was much higher than male, but the prevalence of overweight and obesity in female was lower than male. The mean serum 25(OH)D level in the 14 726 young participants was 22.4±5.3 ng/mL, and male had a higher level of serum 25(OH)D than female, overall, 33.5% of the participants had vitamin D deficiency and even more participants suffered from vitamin D insufficiency (58.2%). The proportion of deficiency in females was much higher than that in males (41.8 vs 16.4%). The issue of underweight and vitamin D deficiency in young people should be paid attention, especially in females. These results reflected the fact that thinness and paler skin are preferred in modern aesthetics of Chinese culture.Future plansWBBC pilot is designed as a prospective cohort study and provides a unique and rich data set analysing health trajectories from adolescents to young adults. WBBC will continue to collect samples with old age.

We performed this meta-analysis to analyze the cancer risk to individuals carrying the rs701848 and rs2735343 single nucleotide polymorphisms (SNPs) in the phosphatase and tensin homolog (PTEN) gene. We searched the PubMed, EMBASE, Cochrane library and the national knowledge infrastructure of China (CNKI) databases and identified 18 eligible case-control studies with 5458 cases and 6003 controls for rs701848 as well as 5490 cases and 6209 controls for rs2735343. Our analyses demonstrated that cancer risk was associated with rs701848 in the recessive model (CC vs. CT+TT, OR=1.169, 95% CI: 1.061-1.288) and with rs2735343 in the dominant model (GC+CC vs. GG, OR=0.758, 95% CI: 0.590-0.972). Subgroup analysis showed that in Asian subjects, carrying the C allele of rs701848 or GG genotype of rs2735343 was associated with increased cancer risk. Moreover, Asian subjects carrying the TC/CC genotype or C allele of rs701848 were associated with increased risk of esophageal squamous cell cancer. This meta-analysis indicates that the PTEN rs701848 (CC) and rs2735343 (GG) polymorphisms are associated with increased cancer risk in Asian subjects.

Several studies have demonstrated that cancer radiosensitivity is associated with the deregulation of c‑Myc, but the relationship between c‑Myc and Fas in radioresistance of lung adenocarcinoma remains unclear. In this study, we established radiation-resistant A549 cell model (A549/R), and investigated the roles of c‑Myc and Fas in radiation-induced cytotoxicity of A549 cells. Apoptosis detection showed that there were fewer apoptotic cells in A549/R cells treated with radiation than in A549 cells. Western blotting results demonstrated the inverse expression pattern of c‑Myc and Fas in A549 and A549/R cells. Suppression of c‑Myc expression by small interfering RNA (siRNA) displayed enhancement of Fas-mediated apoptosis in A549/R cells, accompanying a significant decrease of Bid, Bcl‑2, pro‑caspase‑8, -9 and -3 and increase of Bax. In contrast, Fas-mediated apoptosis was attenuated while Fas expression was suppressed by ectopic expression of c‑Myc in A549 cells. Moreover, decreased cell viability and increased induction of apoptosis were observed in A549/R cells followed by combinational treatment of c‑Myc siRNA and irradiation, whereas, upregulation of c‑Myc reduced the sensitivity of A549 cells to irradiation. These results indicated that c‑Myc and Fas regulated the sensitivity of A549 cells to irradiation by regulating caspase‑8-mediated Bid activation and the subsequent association with the mitochondrial pathway of apoptosis.

// Ping-Yu Wang 1, 2 , Jing-Hua Li 2 , Yue-Mei Liu 1 , Qing Lv 1 , Ning Xie 3 , Han-Han Zhang 1 , Shu-Yang Xie 1 1 Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong, 264003, P.R.China 2 Department of Epidemiology, Binzhou Medical University, YanTai, ShanDong, 264003, P.R.China 3 Department of Chest Surgery, YanTaiShan Hospital, YanTai, ShanDong, 264000, P.R.China Correspondence to: Shu-Yang Xie, email: shuyangxie@bzmc.edu.cn Keywords: ZNRD1-AS1, single nucleotide polymorphism, cancer, meta-analysis, lncRNA Received: August 12, 2016 Accepted: December 01, 2016 Published: December 28, 2016 ABSTRACT Single nucleotide polymorphisms (SNPs) in human zinc ribbon domain containing 1 antisense RNA 1 ( ZNRD1-AS1 ) have been associated with cancer development. In this meta-analysis, we more precisely estimated the associations between three expression quantitative trait loci SNPs in ZNRD1-AS1 (rs3757328, rs6940552, and rs9261204) and cancer susceptibility. The data for three SNPs were extracted from eligible studies, which included 5,293 patients and 5,440 controls. Overall, no significant associations between SNPs in ZNRD1-AS1 (rs3757328, rs6940552, and rs9261204) and cancer risk were observed. However, in further subgroup analyses based on cancer type, we found that the A allele of rs3757328 increased the risk of some cancer in both allele contrast (OR = 1.15, 95% CI = 1.05 – 1.25) and recessive models (OR = 1.79; 95% CI = 1.33 – 2.41). The A allele of rs6940552 and the G allele of rs9261204 also increased the risk of some cancer in an Asian population in allele contrast (OR = 1.17, 95% CI = 1.08 – 1.26, and OR = 1.25, 95% CI = 1.16 – 1.34, respectively) and recessive models (OR = 1.44, 95% CI = 1.18 – 1.77, and OR = 1.49; 95% CI = 1.23 – 1.80, respectively). Thus, rs3757328, rs6940552, and rs9261204 in ZNRD1-AS1 are all associated with increased some cancer risk in an Asian population.

Nuciferine, a major aporphine alkaloid constituent of lotus leaves, is a raw material for obesity treatment. Extensive studies have revealed that obesity is associated with pancreatic cancer (PC). However, it has not been clarified whether nuciferine could be used in PC treatment or prevention. Here, we show that nuciferine could enhance the sensitivity of PC cells to gemcitabine in both cultured cells and the xenograft mouse model. The mechanism study demonstrated that nuciferine induced YAP Ser127 phosphorylation [pYAP(Ser127)] through AMPK-mediated 3-hydroxy-3-methyl-glutaryl-coA reductase (HMGCR) downregulation. Remarkably, wild-type YAP overexpression or YAP Ser127 mutant could resist to nuciferine and no longer sensitize PC cells to gemcitabine. Knockdown of AMPK attenuated pYAP(Ser127) induced by nuciferine. Moreover, knockdown of AMPK reversed nuciferine-mediated HMGCR downregulation. Notably, HMGCR inhibiting could restrain YAP by phosphorylation Ser 127, and therefore enhance the efficiency of gemcitabine in PC cells. In line with this consistent, overexpression of HMGCR reduced growth inhibition caused by nuciferine and/or gemcitabine treatment in PC cells. In summary, these results provide an effective supplementary agent and suggest a therapeutic strategy to reduce gemcitabine resistance in PC.

MicroRNAs (miRNAs/miRs) serve important roles in the chemotherapeutic effect of anticancer drugs. To investigate the roles of miRNAs in cisplatin‑induced suppression of lung adenocarcinoma cell proliferation, A549 cells were treated with different concentrations of cisplatin. An MTT assay demonstrated that cisplatin inhibited A549 cell proliferation in a dose‑dependent manner. Cisplatin induced cell apoptosis and inhibited cell migration by increasing the levels of miR‑93, miR‑26a and miR‑26b. Furthermore, as an upstream factor, miR‑93 was proposed to regulate cyclin D2 expression in miR‑93‑transfected A549 cells. Cisplatin also induced Bcl‑2‑associated X protein expression, and decreased that of Bcl‑2 and c‑Myc in lung adenocarcinoma cells. In vivo analysis further supported that cisplatin inhibited lung adenocarcinoma cell growth by regulating cyclin D2 and miR‑93 expression. In conclusion, our findings demonstrated that cisplatin could effectively inhibit lung adenocarcinoma cell proliferation by decreasing cyclin D2 expression via miR‑93.

L-type lectins (LTLs) belong to the lectin family and are characterized by a conserved structural motif in their carbohydrate recognition domain. LTLs are homologous to leguminous lectins. In this study, we identified and functionally characterized an LTL from kuruma shrimp Marsupenaeus japonicus. We designated this LTL as MjLTL2. MjLTL2 contains a signal peptide, a Lectin_leg domain, a coiled coil, and transmembrane domain. MjLTL2 is distributed in hemocytes, heart, hepatopancreas, gill, stomach, and intestine; higher expression levels are seen in hemocytes and the hepatopancreas than in other tissues. MjLTL2 was upregulated following challenge of shrimp with Vibrio anguillarum and white spot syndrome virus (WSSV). MjLTL2 can agglutinate several bacteria without Ca2+. In addition, MjLTL2 could bind to several Gram-positive and -negative bacteria by binding to their lipopolysaccharide and peptidoglycan. However, MjLTL2 could not enhance the clearance of V. anguillarum in vivo. In the presence of WSSV infection, MjLTL2 knockdown by RNA interference resulted in a 7-day lower cumulative mortality of M. japonicus. Moreover, less VP19, VP24, VP26, and VP28 mRNAs were extracted from the hemocytes of MjLTL2 knockdown shrimp than from the control. These results suggest that MjLTL2 is involved in immune responses in shrimp., Highlights • MjLTL2 could agglutinate several Gram-positive and -negative bacteria. • MjLTL2 could bind to several Gram-positive and -negative bacteria. • MjLTL2 could bind to lipopolysaccharide and peptidoglycan. • MjLTL2 knockdown resulted in a lower cumulative mortality of M. japonicus in the presence of WSSV infection. • MjLTL2 knockdown resulted in a lower VP19, VP24, VP26, and VP28 expression levels.

In treating eye diseases, topical administration on the ocular surface is the most convenient and acceptable route. However, the intraocular efficiency of non-invasive drug delivery systems is still considerably hampered by the eye's defense barriers. In this work, cell-penetrating peptide TAT-functionalized, flurbiprofen-loaded liposomes (TAT-FB-Lip) were designed to enable transcorneal drug delivery and prolong ocular surface retention. The corneal penetration-promoting properties of TAT-functionalized liposomes (TAT-Lip) were confirmed in vitro using a corneal permeability assay and the HCE-T cell sphere model and in vivo by aqueous humor pharmacokinetics assessment. TAT-Lip induced an increase in intracellular calcium ion concentration and membrane potential depolarization. F-actin images of HCE-T cells treated with TAT-Lip show the tight junctions between cells partly opened. The cellular internalization pathway mainly depended on the electrostatic interaction between TAT-Lip and the cell membrane, and there is a certain degree of energy dependence. The pharmacokinetics of flurbiprofen in tears demonstrated TAT-Lip could reduce the drug loss rate. Moreover, the anti-inflammatory effect of TAT-FB-Lip was enhanced by markedly suppressing PGE2, IL-6, and TNF-α production in tears and aqueous humor in a rabbit conjunctivitis model. In conclusion, this work demonstrates that TAT-Lip is an effective ocular drug carrier system that facilitates transcorneal delivery.

Multidrug resistance (MDR) of leukemia cells is a major obstacle in chemotherapeutic treatment. The high expression and constitutive activation of P-glycoprotein (P-gp) and multidrug resistance protein-1 (MRP-1) have been reported to play a vital role in enhancing cell resistance to anticancer drugs in many tumors. The present study aimed to investigate the reversal of MDR by silencing homeobox A10 (HOXA10) in adriamycin (ADR)-resistant human chronic myelogenous leukemia (CML) K562/ADM cells by modulating the expression of P-gp and MRP-1. K562/ADM cells were stably transfected with HOXA10-targeted short hairpin RNA (shRNA). The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis showed that the mRNA and protein expression of HOXA10 was markedly suppressed following transfection with a shRNA-containing vector. The sensitivity of the K562/ADM cells to ADR was enhanced by the silencing of HOXA10, due to the increased intracellular accumulation of ADR. The accumulation of ADR induced by the silencing of HOXA10 may be due to the downregulation of P-gp and MRP-1. Western blot analysis revealed that downregulating HOXA10 inhibited the protein expression of P-gp and MRP-1. Taken together, these results suggest that knockdown of HOXA10 combats resistance and that HOXA10 is a potential target for resistant human CML.

We would like to thank the interests and comments from Cui et al 1 on our study2 entitled ‘Systemic evaluation of the relationship between psoriasis, psoriatic arthritis and osteoporosis: observational and Mendelian randomization study’. Here, we responded the comments point by point. First, the potential confounders we included were age, sex, height, weight, smoking status, drinking status, regular physical activity and mediation treatment. The selected confounders were known potentially to have effect on the outcome (bone mineral density, BMD),3 and were typically recorded in UK Biobank dataset. The mediation analysis suggested that 63% of the effect of psoriatic arthritis (PsA) on BMD were mediated by treatment with methotrexate or ciclosporin; thus, there were many other unmeasured confounders to be discovered. In addition, we excluded participants …

MicroRNAs (miRNAs or miRs) have recently become a popular focus of cancer research due to their ability to act as oncogenes or tumor suppressors. In the present study, miR‑33a‑5p expression was identified to be downregulated in lung adenocarcinoma samples compared with normal, which suggested that miR‑33a‑5p may serve as a tumor suppressor gene. Transfection with miR‑33a‑5p mimics inhibited the proliferation and migration of A549 and LTEP‑a‑2 cells and increased cellular apoptosis. A luciferase reporter assay confirmed that miR‑33a‑5p targets the 3'‑untranslated region of the mechanistic target of rapamycin (mTOR) gene. mTOR expression was decreased in A549 and LTEP‑a‑2 cells treated with miR‑33a‑5p mimics, as well as the expression of its downstream effectors phosphorylated (p)‑p70 ribosomal protein S6 kinase (p70S6K) and p‑eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). Following treatment with celastrol, miR‑33a‑5p expression was upregulated, and miR‑33a‑5p could enhance cellular sensitivity to celastrol. Western blot analysis revealed that the expression of mTOR, p‑p70S6K and p‑4EBP1 decreased following celastrol treatment. These results suggested that mTOR was involved in the mechanism by which miR‑33a‑5p enhanced the sensitivity of lung adenocarcinoma cells to celastrol. Furthermore, LTEP‑a‑2 cells were xenografted subcutaneously into nude mice, to examine the effect of celastrol and miR‑33a‑5p on the growth of LTEP‑a‑2 cells in vivo. The results demonstrated that tumor growth in the celastrol‑treated or miR‑33a‑5p‑treated group was attenuated compared with the control group. Notably, tumor growth in the combination treatment group was almost arrested after 2 weeks. In addition, celastrol upregulated the expression of miR‑33a‑5p, and high expression of miR‑33a‑5p inhibited mTOR and its downstream effectors. In summary, miR‑33a‑5p inhibited the proliferation of lung adenocarcinoma cells, enhanced the antitumor effect of celastrol, and improved sensitivity to celastrol by targeting mTOR in lung adenocarcinoma in vitro and in vivo.

Cumulative evidence has indicated that celastrol may suppress cancer growth; however, the underlying mechanism requires further investigation. In the present study, A549 cells were treated with various concentrations of celastrol. Lung cancer cell proliferation was evaluated using an MTT assay and observed under a microscope. Cell apoptosis was detected by Annexin V fluorescein isothiocyanate/propidium iodide double-labeled flow cytometry. The results demonstrated that celastrol suppressed proliferation and induced apoptosis in a dose-independent manner. Celastrol may also decrease the phosphorylation levels of signal transducer and activator of transcription 3 (STAT3) and the B cell lymphoma-2 (Bcl-2)/Bcl-2 associated C protein (Bax) ratio. As microRNA (miR-24 and miR-181b) were predicated to target STAT3, STAT3 activation was inhibited in miR-24-or miR-181b-treated A549 cells compared with the control treatment. The ratio of Bcl-2/Bax was further reduced in miR-24 or miR-181b-treated A549 cells. The results were further confirmed by detecting in another lung adenocarcinoma cell line, LTEP-a-2. In summary, the results of the present study demonstrated that celastrol treatment suppressed the proliferation and induced apoptosis by regulating the expression levels of miR-24 and miR-181b.

Background: Many studies manifested miRNA-628 (miR-628) was deregulated in various cancers, indicating that miR-628 might serve as a novel biomarker of cancer diagnosis and prognosis, but it's role was still uncertain. This study aimed to evaluate the value of miR-628 in various cancers for diagnosis and prognosis, as well as its predictive power in combination biomarkers. Materials and Methods: A literature search was performed using Medline (via PubMed), Embase, Web of Science databases, and Ovid platform up to November 2017. Meta-analysis was performed to provide summative outcomes. Quality assessment of each included study was performed. Results: Twelve articles with 20 studies were included in our meta-analysis, including 8 articles with 15 studies for diagnostic meta-analysis and 4 articles with 5 studies for prognostic meta-analysis. For the diagnostic meta-analysis of miR-628 alone, the overall pooled results for sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristic (SROC) curve (AUC) were 0.81 (95% CI: 0.62-0.91), 0.72 (95% CI: 0.48-0.88), 2.90 (95% CI: 1.50-5.40), 0.27 (95% CI: 0.14-0.50), 11.0 (95% CI: 4.00-25.00), and 0.84 (95% CI: 0.80-0.87), respectively. For the diagnostic meta-analysis of miR-628-related combination biomarkers, the above six parameters were 0.89 (95% CI: 0.84-0.92), 0.93 (95% CI: 0.82-0.97), 12.30 (95% CI: 4.70-32.50), 0.12 (95% CI: 0.08-0.19), and 100.00 (95% CI: 28.00-354.00), 0.93 (95% CI: 0.90-0.95), respectively. For the prognostic meta-analysis, patients with lower miR-628 had significant shorter overall survival than high expression of miR-628 (HR = 1.553, 95% CI: 1.041-2.318, z = 2.16, P = 0.031). Conclusions: This study confirms that miR-628 may be a promising biomarker for cancer diagnosis and prognosis. Expertly, microRNAs combination biomarkers could be a new alternative for clinical application.

Activating transcription factor 6 (ATF6) pathway is the key branch of unfolded protein response (UPR). In this study, a homolog of ATFα from Marsupenaeus japonicus (MjATF6) was identified using genome sequencing and characterized, so as to investigate the role of ATF6 pathway in anti-viral immunity of M. japonicus. The cDNA of MjATF6 obtained was 1008 bp in length, with an open reading frame (ORF) of 849bp, which had encoded a putative of 283 amino acid proteins. Results of qRT-PCR showed that MjATF6 was distributed in all the six tested tissues, with the higher expression level being seen in hemocytes and hepatopancreas. Furthermore, MjATF6 expression would be up-regulated from 1 day to 7 day under white spot syndrome virus (WSSV) challenge. In comparison, RNA interference-induced MjATF6 knockdown had resulted in a lower 7-day cumulative mortality of M. japonicus in the presence of WSSV infection. Additionally, our results also revealed that less VP28 mRNA was extracted from hemocytes or hepatopancreas of MjATF6 knockdown shrimp than that from the control. Taken together, these results have confirmed that ATF6 pathway is vital for WSSV replication, and that UPR in M. japonicus may facilitate WSSV infection.

Aims/Introduction Some previous studies reported no significant association of consuming fruit or vegetables, or fruit and vegetables combined, with type 2 diabetes. Others reported that only a greater intake of green leafy vegetables reduced the risk of type 2 diabetes. To further investigate the relationship between them, we carried out a meta-analysis to estimate the independent effects of the intake of fruit, vegetables and fiber on the risk of type 2 diabetes. Materials and Methods Searches of MEDLINE and EMBASE for reports of prospective cohort studies published from 1 January 1966 to 21 July 2014 were carried out, checking reference lists, hand-searching journals and contacting experts. Results The primary analysis included a total of 23 (11 + 12) articles. The pooled maximum-adjusted relative risk of type 2 diabetes for the highest intake vs the lowest intake were 0.91 (95% confidence interval [CI] 0.87–0.96) for total fruits, 0.75 (95% CI 0.66–0.84) for blueberries, 0.87 (95% CI 0.81–0.93) for green leafy vegetables, 0.72 (95% CI 0.57–0.90) for yellow vegetables, 0.82 (95% CI 0.67–0.99) for cruciferous vegetables and 0.93 (95% CI 0.88–0.99) for fruit fiber in these high-quality studies in which scores were seven or greater, and 0.87 (95% CI 0.80–0.94) for vegetable fiber in studies with a follow-up period of 10 years or more. Conclusions A higher intake of fruit, especially berries, and green leafy vegetables, yellow vegetables, cruciferous vegetables or their fiber is associated with a lower risk of type 2 diabetes.

Lung cancer is the most common cause of cancer-associated mortality. MicroRNAs (miRNAs), as oncogenes or tumor suppressor genes, serve crucial roles not only in tumorigenesis, but also in tumor invasion and metastasis. Although miRNA-let-7a (let-7a) has been reported to suppress cell growth in multiple cancer types, the biological mechanisms of let-7a in lung adenocarcinoma are yet to be fully elucidated. In the present study, the molecular roles of let-7a in lung adenocarcinoma were investigated by detecting its expression in lung adenocarcinoma tissues and exploring its roles in the regulation of lung cancer cell proliferation. Let-7a expression was identified to be downregulated in lung adenocarcinoma tissues compared with normal tissues. Overexpression of let-7a effectively suppressed cancer cell proliferation, migration and invasion in H1299 and A549 cells. Let-7a also induced cell apoptosis and cell cycle arrest. Furthermore, let-7a significantly inhibited cell growth by directly regulating cyclin D1 signals. This novel regulatory mechanism of let-7a in lung adenocarcinoma provides possible avenues for future targeted therapies of lung cancer.

Acquired resistance to chemotherapy plays a critical role in human drug treatment failure in many tumor types. Multidrug resistance (MDR) to Adriamycin (ADM) also limits the efficacy of therapy in human chronic myelogenous leukemia (CML). The overexpression of drug efflux transporters is one mechanism uderlying MDR. In particular, the consistent activation of MDR1 and MDR‑associated protein 1 (MRP1) is involved in drug resistance. In the present study, ADM‑resistant human CML K562/ADM cells were stably transfected with a Tribbles homolog 2 (TRIB2)‑targeted vector. A CCK‑8 assay showed that the half maximal inhibitory concentration (IC50) of ADM and the cell proliferation were lower in the transfected cells compared with that in the parental K562/ADM cells. The mRNA and protein expression levels of MDR1 and MRP1 were determined by reverse transcription‑polymerase chain reaction (RT‑PCR), RT‑quantitative PCR and western blot analysis. The results showed that the expression of MDR1 and MRP1 was significantly reduced in K562/ADM cells transfected with pGPU6/GFP/Neo‑TRIB2. Due to the downregulation of MDR1 and MRP1, the intracellular accumulation of ADM was increased in the transfected cells compared with that in the parental K562/ADM cells. Therefore, the sensitivity of the K562/ADM cells to ADM was enhanced and proliferation was inhibited. Our research revealed that protein expression of the ERK signaling pathway was inhibited by downregulating TRIB2, indicating that the ERK pathway was involved in cell drug resistance and proliferation. Furthermore, we used the ERK‑specific blocker U0126 to demonstrate this phenomenon. In summary, our research suggested that knockdown of TRIB2 could slow cell growth and reverse resistance, implying that TRIB2 is a potential therapy target for resistant human CML.

// Jing-Hua Li 1, 2 , Shan-Shan Sun 1 , Ning Li 1 , Peng Lv 1 , Shu-Yang Xie 2 and Ping-Yu Wang 1, 2 1 Department of Epidemiology, Binzhou Medical University, YanTai, ShanDong 264003, P.R. China 2 Key Laboratory of Tumor Molecular Biology in Binzhou Medical University, Department of Biochemistry and Molecular Biology, Binzhou Medical University, YanTai, ShanDong 264003, P.R. China Correspondence to: Shu-Yang Xie, email: shuyangxie@aliyun.com Ping-Yu Wang, email: wpingyugirl@163.com Keywords: biomarker, miR-205, lung cancer, diagnosis, prognosis Received: May 26, 2017 Accepted: July 13, 2017 Published: August 14, 2017 ABSTRACT MicroRNA-205 (miR-205) was revealed as a novel diagnostic and prognostic biomarker for lung cancer, but the results in the published papers were inconsistent. This meta-analysis aimed to investigate the diagnostic and prognostic roles of miR-205 in patients with lung cancer. Totally, 16 eligible articles were included, among which 10 articles investigated the diagnostic value of miR-205, 5 articles examined its prognostic values, and 1 article studied both diagnostic and prognostic values. For the diagnostic meta-analysis, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the overall area under the curve of miR-205 for patients with lung cancer were 0.88 (95% CI = 0.78 – 0.94), 0.78 (95% CI = 0.66 – 0.86), 4.00 (95% CI = 2.47 – 6.49), 0.16 (95% CI = 0.08 – 0.30), 25.86 (95% CI = 9.29 – 71.95), and 0.90 (95% CI = 0.87 – 0.92), respectively, indicating that miR-205 is a useful biomarker for diagnostic of lung cancer. The subgroup analysis further demonstrated that miR-205 had an excellent overall accuracy for detection with tissue samples compare with blood samples. For the prognostic meta-analysis, the pooled outcome of the disease-free survival and recurrence-free survival analyses revealed that increased miR-205 levels had a protective role in the prognosis of patients with lung cancer (pooled HR = 0.86, 95% CI: 0.78-0.96, z = 2.83, P = 0.005). In conclusion, miR-205 may be a promising biomarker for detection, predicting the recurrence of patients with lung cancer.

MicroRNAs play important roles in tumorigenesis of various types of cancers. MiR-320a can inhibits cell proliferation of some cancers, but the biologic roles of miR-320a in lung cancer need to be further studied. Here, we investigated the roles of miR-320a in suppressing the proliferation of lung adenocarcinoma cells. MiR-320a treatment was found to effectively suppress LTEP-a-2 and A549 cell proliferation, and induce more apoptotic cells with irradiation treatment compared with control treatment. Our results also showed that miR-320a, as a novel miRNA, directly regulated signal transducer and activator of transcription 3 (STAT3) and its signals, such as Bcl-2, Bax, and Caspase 3. The siRNA-inhibited STAT3 levels further proved its roles in regulating STAT3 signals. Moreover, miR-320a treatment effectively suppressed cancer cell growth in mice xenografts compared with controls, and significantly inhibited cell migration in vitro and in vivo. Our findings collectively demonstrated that miR-320a, by directly regulating STAT3 signals, not only suppressed cell proliferation and metastasis, but also enhanced irradiation-induced apoptosis of adenocarcinomia cells.

Cyclin D2 is involved in the pathology of vascular complications of type 2 diabetes mellitus (T2DM). This study investigated the role of cyclin‐D2‐regulated miRNAs in endothelial cell proliferation of T2DM. Results showed that higher glucose concentration (4.5 g/l) significantly promoted the proliferation of rat aortic endothelial cells (RAOECs), and significantly increased the expression of cyclin D2 and phosphorylation of retinoblastoma 1 (p‐RB1) in RAOECs compared with those under low glucose concentration. The cyclin D2‐3′ untranslated region is targeted by miR‐98, as demonstrated by miRNA analysis software. Western blot also confirmed that cyclin D2 and p‐RB1 expression was regulated by miR‐98. The results indicated that miR‐98 treatment can induce RAOEC apoptosis. The suppression of RAOEC growth by miR‐98 might be related to regulation of Bcl‐2, Bax and Caspase 9 expression. Furthermore, the expression levels of miR‐98 decreased in 4.5 g/l glucose‐treated cells compared with those treated by low glucose concentration. Similarly, the expression of miR‐98 significantly decreased in aortas of established streptozotocin (STZ)‐induced diabetic rat model compared with that in control rats; but cyclin D2 and p‐RB1 levels remarkably increased in aortas of STZ‐induced diabetic rats compared with those in healthy control rats. In conclusion, this study demonstrated that high glucose concentration induces cyclin D2 up‐regulation and miR‐98 down‐regulation in the RAOECs. By regulating cyclin D2, miR‐98 can inhibit human endothelial cell growth, thereby providing novel therapeutic targets for vascular complication of T2DM.

MicroRNAs (miRNAs) and Smad3, as key transcription factors in transforming growth factor-β1 (TGF-β1) signaling, help regulate various physiological and pathological processes. We investigated the roles of Smad3-regulated miRNAs with respect to lung adenocarcinoma cell apoptosis, proliferation, and metastasis. We observed that Smad3 and phospho-SMAD3 (p-Smad3) were decreased in miR-206- (or miR-140)-treated cells and there might be a feedback loop between miR-206 (or miR-140) and TGF-β1 expression. Smad3-related miRNAs affected tribbles homolog 2 (TRIB2) expression by regulating trib2 promoter activity through the CAGACA box. MiR-206 and miR-140 inhibited lung adenocarcinoma cell proliferation in vitro and in vivo by suppressing p-Smad3/Smad3 and TRIB2. Moreover, lung adenocarcinoma data supported a suppressive role for miR-206/miR-140 and an oncogenic role for TRIB2—patients with higher TRIB2 levels had poorer survival. In summary, miR-206 and miR-140, as tumor suppressors, induced lung adenocarcinoma cell death and inhibited cell proliferation by modifying oncogenic TRIB2 promoter activity through p-Smad3. MiR-206 and miR-140 also suppressed lung adenocarcinoma cell metastasis in vitro and in vivo by regulating EMT-related factors.