A Baseline Cellular Antiviral State Is Maintained by cGAS and Its Most Frequent Naturally Occurring Variant rs610913.

Upon recognition of aberrantly located DNA, the innate immune sensor cyclic GMP-AMP synthase (cGAS) activates stimulator of IFN genes (STING)/IFN regulatory factor (IRF)3-driven antiviral responses. In this study, we characterized the ability of a specific variant of the human cGAS-encoding gene MB21D1, rs610913, to alter cGAS-mediated DNA sensing and viral infection. rs610913 is a frequent G>T polymorphism resulting in a P261H exchange in the cGAS protein. Data from the International Collaboration for the Genomics of HIV suggested that rs610913 nominally associates with HIV-1 acquisition in vivo. Molecular modeling of cGAS(P261H) hinted toward the possibility for an additional binding site for a potential cellular cofactor in cGAS dimers. However, cGAS(wild-type [WT]) or cGAS(P261H)-reconstituted THP-1 cGAS knockout cells shared steady-state expression of IFN-stimulated genes, as opposed to cells expressing the enzymatically inactive cGAS(G212A/S213A). Accordingly, cGAS(WT) and cGAS(P261H) cells were less susceptible to lentiviral transduction and infection with HIV-1, HSV-1, and Chikungunya virus as compared with cGAS knockout or cGAS(G212A/S213A) cells. Upon DNA challenge, innate immune activation appeared to be mildly reduced upon expression of cGAS(P261H) compared with cGAS(WT). Finally, DNA challenge of PBMCs from donors homozygously expressing rs610913 provoked a trend toward a slightly reduced type I IFN response as compared with PBMCs from GG donors. Taken together, the steady-state activity of cGAS maintains a baseline antiviral state rendering cells more refractory to IFN-stimulated gene-sensitive viral infections. rs610913 failed to grossly differ phenotypically from the WT gene, suggesting that cGAS(P261H) and WT cGAS share a similar ability to sense viral infections in vivo.

Physical symptoms and anxiety and depression in older patients with advanced cancer in China: a network analysis.

BACKGROUND: Little is understood about the association between psychosomatic symptoms and advanced cancer among older Chinese patients. METHODS: This secondary analysis was part of a multicenter cross-sectional study based on an electronic patient-reported outcome platform. Patients with advanced cancer were included between August 2019 and December 2020 in China. Participants (over 60 years) completed the MD Anderson Symptom Inventory (MDASI) and Hospital Anxiety and Depression Scale (HADS) to measure symptom burden. Network analysis was also conducted to investigate the network structure, centrality indices (strength, closeness, and betweenness) and network stability. RESULTS: A total of 1022 patients with a mean age of 66 (60-88) years were included; 727 (71.1%) were males, and 295 (28.9%) were females. A total of 64.9% of older patients with advanced cancer had one or more symptoms, and up to 80% had anxiety and depression. The generated network indicated that the physical symptoms, anxiety and depression symptom communities were well connected with each other. Based on an evaluation of the centrality indices, 'distress/feeling upset' (MDASI 5) appears to be a structurally important node in all three networks, and 'I lost interest in my own appearance' (HADS-D4) had the lowest centrality indices. The network stability was relatively high (> 0.7). CONCLUSION: The symptom burden remains high in older patients with advanced cancer in China. Psychosomatic symptoms are highly interactive and often present as comorbidities. This network can be used to provide targeted interventions to optimize symptom management in older patients with advanced cancer in China. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1900024957), registered on 06/12/2020.

Phytophthora sojae effector PsAvh113 associates with the soybean transcription factor GmDPB to inhibit catalase-mediated immunity.

Phytophthora species are the most destructive plant pathogens worldwide and the main threat to agricultural and natural ecosystems; however, their pathogenic mechanism remains largely unknown. Here, we show that Avh113 effector is required for the virulence of Phytophthora sojae and is important for development of Phytophthora root and stem rot (PRSR) in soybean (Glycine max). Ectopic expression of PsAvh113 enhanced viral and Phytophthora infection in Nicotiana benthamiana. PsAvh113 directly associated with the soybean transcription factor GmDPB, inducing its degradation by the 26S proteasome. The internal repeat 2 (IR2) motif of PsAvh113 was important for its virulence and interaction with GmDPB, while silencing and overexpression of GmDPB in soybean hairy roots altered the resistance to P. sojae. Upon binding to GmDPB, PsAvh113 decreased the transcription of the downstream gene GmCAT1, which acts as a positive regulator of plant immunity. Furthermore, we revealed that PsAvh113 suppressed the GmCAT1-induced cell death by associating with GmDPB, thereby enhancing plant susceptibility to Phytophthora. Together, our findings reveal a vital role of PsAvh113 in inducing PRSR in soybean and offer a novel insight into the interplay between defence and counter-defence during the P. sojae infection of soybean.

The Impact of Customized Short Message Service on High-Risk Behaviors Among MSM in China, a Randomized Controlled Trial Study.

An individual based randomized controlled trial (RCT) was designed to evaluate the impact of a customized short message service (SMS) intervention on HIV-related high-risk behaviors among Men who have sex with men (MSM). In total, 631 HIV-negative MSM were enrolled at baseline and divided into intervention and control groups randomly. Nine months later, the intervention group who received additional customized SMS intervention reported significantly lower rates of multiple partners, unclear partner infection status and condomless anal intercourse compared to the control group who received the routine intervention only. Six months post stopping the SMS intervention, the rates of unclear partner infection status and condomless anal intercourse still remained lower report in the intervention group. Our study shown that the customized SMS interventions can significantly reduce the HIV-related high-risk behaviors among MSM and with sustained effects over a period of time.

Identification of potential druggable targets of cell cycle with small-molecule inhibitors in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors worldwide and there are few crucial regulators and druggable targets for early diagnosis. Therefore, the identification of biomarkers for the early diagnosis and druggable targets of OSCC is imminent. In this study, we integrated gene set enrichment analysis, differential gene expression analysis based on the negative binomial distribution, weighted correlation network analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes into analyzing the OSCC cohort downloaded from The Cancer Genome Atlas, and found that cell cycle and related biologic processes are significantly enriched. Then, we constructed the core gene network of OSCC, which showed the connection of encode human Cyclin-A2 protein, encode RAD51-associated protein 1, encode human centromere-associated protein E (CENPE), encode humans centromere protein I (CENPI) and encode polo-like kinase 1 (PLK1) to several cell cycle-related genes. Survival analysis further showed that low expression of these genes was associated with a better prognosis. Furthermore, we utilized a high-throughput virtual screening to find new CENPE and PLK1 inhibitors, and one of the CENPE inhibitor DB04517 suppressed the proliferation of OSCC cells by cell cycle arrest of cell cycle. Taken together, these candidate regulators could serve as the candidate diagnostic and prognostic biomarkers for OSCC, and specific suppression of these genes may be a potential approach to prevent and treat OSCC with the candidate inhibitors.

Suicidal ideation in advanced cancer patients without major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) is associated with an increased risk of suicide and suicide attempt among cancer patients. However, we do not know how many cancer patients without MDD have suicidal ideation (SI). OBJECTIVES: This study aimed to investigate the prevalence, characteristics and correlated factors of SI among advanced cancer patients without MDD. METHODS: This is a multi-center, cross-sectional study based on an electronic patient-reported outcome systems in patients who were diagnosed with advanced lung, liver, gastric, esophageal, colorectal or breast cancer, the top six prevalent cancers in China. A total of 2930 advanced cancer patients were recruited from 10 regional representative cancer centers across China from August 2019 to December 2020. Patients completed the Patient Health Questionnaire-9 regarding if they had thoughts of being better off dead or of hurting themselves in some way in the previous 2 weeks. Patients also completed the symptom inventory and quality of life assessment. Generalized estimating equation model was performed to explore the correlated factors associated with SI among the patients without MDD. RESULTS: The overall prevalence of SI among advanced cancer patients without MDD was 13.1%. The prevalence was higher in older patients. After adjusted for existing conditions, patients with vomiting symptom (p < 0.001), poorer life quality (p < 0.001), and middle education level (p = 0.031) were correlated factors of SI. CONCLUSIONS: The suicidal ideation is common in advanced cancer patients without MDD. Patients with vomiting, poor quality of life, and middle education level should be screened and monitored for suicidal ideation even without MDD. CLINICAL TRIAL INFORMATION: ChiCTR1900024957.

Fine-tuning grain amylose contents by genome editing of Waxy cis-regulatory region in rice.

Rice grain amylose contents (ACs) is a key quantitative trait influencing eating and cooking quality. Regulating the expression level of Waxy, a key gene controlling ACs, and in turn fine-tuning the grain ACs, is an ideal approach to improve grain quality of rice varieties. Based on CRISPR/Cas9 genome editing technology, we designed eight targets in the cis-regulatory region of Wxa background, screened phenotypic changes of the transgenic lines and generated eight novel Waxy alleles with altered grain ACs. Among the eight alleles, we found that a 407-bp non-homologous substitution (NHS) in the 5'UTR-intron caused by genome editing regulated Waxy expression and decreased grain ACs by 2.9%. Moreover, embedding the 407-bp NHS into the cis-regulatory region of Wxb allele can also affect gene activity. Our work suggested the effect of 5'UTR-intron on Waxy gene expression regulation, and provided a potentially useful allele in breeding that can finely adjust rice grain ACs.

Sagittal imaging study of the lumbar spine with the short rod technique.

PURPOSE: The short rod technique (SRT) is a novel method for lumbar pedicle screw placement to reduce surgical trauma and avoid damage to the facet joint and articular surface. The core concept is to change the entry point and angle of the screw on the vertebrae at both ends in the sagittal plane to shorten the length of the longitudinal rods. The purpose of this study is to determine the sagittal screw angle (SSA) and its safe Maximum (MAX) value on each lumbar vertebra for the SRT and to observe the shortening effect on the longitudinal rods. METHODS: A total of 152 healthy adults were investigated by measuring the lumbar spine lateral view images. The SSA and MAX-SSA were measured with SRT as reference to the conventional placement technique method. The distance between the entry points of the proximal and distal vertebrae was measured to compare the changes in the length of the longitudinal rods using the two screw placement techniques. RESULTS: + SSA increased from L1 to L4, and -SSA increased from L2 to L5, in which the -SSA of L2, L3, and L4 were significantly greater than those of + SSA (P < 0.05). + MAX-SSA at L1-L4 was 23.26 ± 3.54°, 23.68 ± 3.37°, 24.12 ± 3.29°, and 24.26 ± 3.42°, respectively. -MAX-SSA at L2-L5 was 36.25 ± 3.26°, 38.26 ± 3.73°, 38.62 ± 3.63° and 37.33 ± 3.31°, respectively. Theoretical reductions by calculation for the 2-segment lumbar pedicles were: L1-2: 9 mm, L2-3: 9.29 mm, L3-4: 6.23 mm, and L4-5: 7.08 mm; And the 3-segment lumbar pedicles were: L1-3: 16.97 mm, L2-4: 16.73 mm, L3-5, and 18.24 mm, respectively. CONCLUSIONS: The application of the SRT to lumbar pedicles is a safe screw placement method that can significantly shorten the length of the used longitudinal rods.

Image Security Based on Three-Dimensional Chaotic System and Random Dynamic Selection.

Image encryption based on a chaos system can effectively protect the privacy of digital images. It is said that a 3D chaotic system has a larger parameter range, better unpredictability and more complex behavior compared to low-dimension chaotic systems. Motivated by this fact, we propose a new image cryptosystem that makes use of a 3D chaotic system. There are three main steps in our scheme. In the first step, the chaotic system uses the hash value of the plaintext image to generate three sequences. In step two, one of the sequences is used to dynamically select confusion and diffusion methods, where confusion and diffusion have three algorithms, respectively, and will produce 32n (n > 100) combinations for encryption. In step three, the image is divided into hundreds of overlapping subblocks, along with the other two sequences, and each block is encrypted in the confusion and diffusion process. Information entropy, NPCR, UACI results and various security analysis results show that the algorithm has a better security performance than existing, similar algorithms, and can better resist clipping, noise, statistical analysis and other attacks.

Extracellular vesicles derived from CD73 modified human umbilical cord mesenchymal stem cells ameliorate inflammation after spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is an inflammatory condition, and excessive adenosine triphosphate (ATP) is released into the extracellular space, which can be catabolized into adenosine by CD73. Extracellular vesicles have been designed as nano drug carriers in many diseases. However, their impacts on delivery of CD73 after SCI are not yet known. We aimed to construct CD73 modified extracellular vesicles and explore the anti-inflammatory effects after SCI. METHODS: CD73 engineered extracellular vesicles (CD73+ hucMSC-EVs) were firstly established, which were derived from human umbilical cord mesenchymal stem cells (hucMSCs) transduced by lentiviral vectors to upregulate the expression of CD73. Effects of CD73+ hucMSC-EVs on hydrolyzing ATP into adenosine were detected. The polarization of M2/M1 was verified by immunofluorescence. Furthermore, A2aR and A2bR inhibitors and A2bR knockdown cells were used to investigate the activated adenosine receptor. Biomarkers of microglia and levels of cAMP/PKA were also detected. Repetitively in vivo study, morphology staining, flow cytometry, cytokine analysis, and ELISA assay, were also applied for verifications. RESULTS: CD73+ hucMSC-EVs reduced concentration of ATP and promoted the level of adenosine. In vitro experiments, CD73+ hucMSC-EVs increased macrophages/microglia M2:M1 polarization, activated adenosine 2b receptor (A2bR), and then promoted cAMP/PKA signaling pathway. In mice using model of thoracic spinal cord contusion injury, CD73+ hucMSC-EVs improved the functional recovery after SCI through decreasing the content of ATP in cerebrospinal fluid and improving the polarization from M1 to M2 phenotype. Thus, the cascaded pro-inflammatory cytokines were downregulated, such as TNF-α, IL-1ß, and IL-6, while the anti-inflammatory cytokines were upregulated, such as IL-10 and IL-4. CONCLUSIONS: CD73+ hucMSC-EVs ameliorated inflammation after spinal cord injury by reducing extracellular ATP, promoting A2bR/cAMP/PKA pathway and M2/M1 polarization. CD73+ hucMSC-EVs might be promising nano drugs for clinical application in SCI therapy.

Genome-Wide Identification and Characterization of Wheat 14-3-3 Genes Unravels the Role of TaGRF6-A in Salt Stress Tolerance by Binding MYB Transcription Factor.

14-3-3 proteins are a large multigenic family of general regulatory factors (GRF) ubiquitously found in eukaryotes and play vital roles in the regulation of plant growth, development, and response to stress stimuli. However, so far, no comprehensive investigation has been performed in the hexaploid wheat. In the present study, A total of 17 potential 14-3-3 gene family members were identified from the Chinese Spring whole-genome sequencing database. The phylogenetic comparison with six 14-3-3 families revealed that the majority of wheat 14-3-3 genes might have evolved as an independent branch and grouped into ε and non-ε group using the phylogenetic comparison. Analysis of gene structure and motif indicated that 14-3-3 protein family members have relatively conserved exon/intron arrangement and motif composition. Physical mapping showed that wheat 14-3-3 genes are mainly distributed on chromosomes 2, 3, 4, and 7. Moreover, most 14-3-3 members in wheat exhibited significantly down-regulated expression in response to alkaline stress. VIGS assay and protein-protein interaction analysis further confirmed that TaGRF6-A positively regulated slat stress tolerance by interacting with a MYB transcription factor, TaMYB64. Taken together, our findings provide fundamental information on the involvement of the wheat 14-3-3 family in salt stress and further investigating their molecular mechanism.

Phenols and γ-Lactams from the Aerial Part of Pseudolysimachion linariifolium subsp. dilatatum.

Linariifolioside II (1) and (2S)-2-hydroxy-5-oxoproline methyl ester (2), two new compounds along with 13 known compounds were obtained from the aerial part of Pseudolysimachion linariifolium Holub subsp. dilatatum (Nakai & Kitag.) D.Y. Hong. Their chemical structures were revealed mainly through NMR and MS data. The absolute configuration of 2 was deduced by comparing its experimental CD with the calculated ECD spectra. At a concentration of 1 mm, total antioxidant capacities of compounds 1-15 were measured using a rapid ABTS method in vitro. Compounds 1, 3-5, and 11-14 exhibited approximately equal antioxidant capacity to that of vitamin C (Vc).

Libertellenones O-S and Eutypellenones A and B, Pimarane Diterpene Derivatives from the Arctic Fungus Eutypella sp. D-1.

Seven new pimarane-type diterpene derivatives, libertellenones O-S (1-5) and eutypellenones A and B (6 and 7), together with two known compounds (8 and 9), were isolated from the culture of Eutypella sp. D-1 obtained from high-latitude soil of the Arctic. Their structures were elucidated from spectroscopic data, as well as experimental and calculated electronic circular dichroism (ECD) analysis. Structurally, compounds 1-5 possess a cyclopropyl-fused pimarane diterpene moiety, whereas compounds 6 and 7 share an unusual cyclobutyl-fused pimarane diterpene skeleton. Compounds 1-9 exhibited cytotoxicities against HeLa, MCF-7, HCT-116, PANC-1, and SW1990 cells, with IC50 values in the range of 0.3 to 29.4 µM. Compounds 6 and 7 could dose-dependently inhibit the activity of NF-κB and exhibited significantly inhibitory effects on nitric oxide production induced by lipopolysaccharide.

Conductance Measurement of Pyrazine Molecular Junction with Cu and Ag Electrodes.

We have measured the conductance of pyrazine molecular junction contacting with Cu and Ag electrodes by using an electrochemical jump-to-contact based scanning tunneling microscopy break junction (ECSTM-BJ). While conductance values of 10-2.8 and 10-3.7 G0 are measured for pyrazineCu electrode, 10-2.1 and 10-3.3 G0 are found for pyrazine-Ag contact. The result shows that the conductance of pyrazine with Ag electrode is larger than that with Cu electrode, which can contribute to the different efficiency of electron transport along the molecular junction between Ag and Cu electrodes. The current work shows the important role for the electrode material in electron transport.

Efficacy of carbon dioxide treatments for the control of the two-spotted spider mite, Tetranychus urticae, and treatment impact on plant seedlings.

To develop a new control method for the two-spotted spider mite (TSSM), Tetranychus urticae, we investigated the effect of controlled atmospheres of carbon dioxide (CO2) on TSSM mortality under different concentrations and treatment periods, and evaluated the impact of treatments on seedlings of five host plants of TSSM. Egg hatching rate of TSSM was reduced to 37.7, 5.4 or 0% after 24 h treatment involving concentrations of 16.7, 33.3 or 50%, respectively. Mobile stages (nymphs and adult) of TSSM were completely controlled after 24 h treatment at concentrations higher than 33.3%. After 4 h at concentrations of 33.3 or 50%, 1st-day survival rate for all mobile stages was 45.3 or 36.0%, respectively, whereas after 8 or 16 h treatments, all values were decreased to zero. Seedlings of four major host plants of TSSM (cucumber, eggplant, rape, green peppers) were damaged to varying degrees after 24 h at the three concentrations, but strawberry, another host plant, was not damaged. Cucumber suffered the most serious damage, resulting in wilting and death. In conclusion, controlled atmospheres of CO2 can kill TSSM, particularly at high concentrations and with long treatment times. It can be used to control TSSM on strawberry, but should be used cautiously on other host plants.

Cross-cultural validation of simplified Chinese version of spine functional index.

BACKGROUND: No effective constructs were available in mainland China to assess the whole spine function. The SFI was developed to evaluate spinal function based on the concept of a single kinetic chain concept for whole spine. The SFI has been translated to Spanish and Turkish with accepted psychometric properties. It is imperative to introduce the SFI in mainland China and further to explore the measurement properties. METHODS: The English versions of the SFI was cross-culturally translated according to international guidelines. Measurement properties (content validity, construct validity and reliability) were tested in accordance with the COSMIN checklists. A total of 271 patients were included in this study, and 61 participants with neck pain and 64 participants with back pain paid a second visit three to seven days later. Confirmatory factor analysis (CFA) and principal factor analysis (PCA) were applied to test the factor structure. The Functional Rating Index (FRI), Neck Disability Index (NDI), Oswestry Disability Index (ODI), SF-12 and a Visual Analogue Scale (VAS) were employed to evaluate the construct validity. Cronbach's alpha and an intra-class correlation coefficient (ICC) were calculated for internal consistency and reproducibility. RESULTS: The means score of SC-SFI was 63.60 in patients with spinal musculoskeletal disorders. A high response rate was acquired (265/271). No item was removed due to abnormal distribution or low item-total correlation. Results of CFA did not support that one-factor structure was in goodness of fit (CMIN/DF = 3.306, NNFI = 0.687, CFI = 0.756, GFI = 0.771 and RMSEA = 0.092). Yet, PCA suggested a one-factor structure was the best, accounting for 32% of the total variance. For structural validity, the SC-SFI correlated highly with the FRI, NDI, ODI, and PF, BP in SF-12 (r = 0.661, 0.610, 0.750, 0.709, 0.605, respectively). All the a priori hypotheses were verified. The Cronbach's alpha for the SC-SFI was 0.91, and ICC was 0.96 (95% CI, 0.94-0.98). Bland-Altman plot also confirmed excellent test-retest reliability. CONCLUSIONS: The SFI has been culturally adapted into SC-SFI with remarkable clinical acceptance, excellent internal consistency, reproducibility, and construct validity when applied to patients with spinal musculoskeletal disorders. The results of current study suggest that SC-SFI can be applied by physicians and researchers to measure whole-spine functional status in mainland China.

Autophagy induction contributes to GDC-0349 resistance in head and neck squamous cell carcinoma (HNSCC) cells.

Dysregulation of mammalian target of rapamycin (mTOR) signaling contributes to head and neck squamous cell carcinoma (HNSCC) tumorigenesis and progression. In the current study, we tested the anti-HNSCC cell activity by GDC-0349, a selective ATP-competitive inhibitor of mTOR. We showed that GDC-0349 inhibited proliferation of established and primary human HNSCC cells bearing high-level of p-AKT/p-S6K. Further, it induced caspase-dependent apoptosis in the HNSCC cells. GDC-0349 blocked mTORC1 and mTORC2 activation, yet it simultaneously induced autophagy activation in HNSCC cells. The latter was evidenced by induction of LC3B-II, Beclin-1 and Autophagy-related (ATG)-7, as well as downregulation of p62. Autophagy inhibitors (3-methyladenine and bafilomycin A1) or ATG-7 siRNA dramatically potentiated GDC-0349's cytotoxicity against HNSCC cells. Intriguingly, we showed that ceramide (C14), a pro-apoptotic sphingolipid, also induced ATG-7 degradation, and sensitized HNSCC cells to GDC-0349. Collectively, the preclinical study provided evidences to support GDC-0349 as a promising anti-HNSCC agent. GDC-0349 sensitization may be achieved via autophagy inhibition.

Follicular thyroid carcinoma but not adenoma recruits tumor-associated macrophages by releasing CCL15.

BACKGROUND: The differential diagnosis of follicular thyroid carcinoma (FTC) and follicular adenoma (FA) before surgery is a clinical challenge. Many efforts have been made but most focusing on tumor cells, while the roles of tumor associated macrophages (TAMs) remained unclear in FTC. Here we analyzed the differences between TAMs in FTC and those in FA. METHODS: We first analyzed the density of TAMs by CD68 immunostaining in 59 histologically confirmed FTCs and 47 FAs. Cytokines produced by FTC and FA were profiled using antibody array, and validated by quantitative PCR. Chemotaxis of monocyte THP-1 was induced by condition medium of FTC cell lines (FTC133 and WRO82-1) with and without anti-CCL15 neutralizing antibody. Finally, we analyzed CCL15 protein level in FTC and FA by immunohistochemistry. RESULTS: The average density of CD68(+) cells was 9.5 ± 5.4/field in FTC, significantly higher than that in FA (4.9 ± 3.4/field, p < 0.001). Subsequently profiling showed that CCL15 was the most abundant chemokine in FTC compared with FA. CCL15 mRNA in FTC was 51.4-folds of that in FA. CM of FTC cell lines induced THP-1 cell chemotaxis by 33 ~ 77%, and anti-CCL15 neutralizing antibody reduced THP-1 cell migration in a dose-dependent manner. Moreover, we observed positive CCL15 immunostaining in 67.8% of FTCs compared with 23.4% of FAs. CONCLUSION: Our study suggested FTC might induce TAMs infiltration by producing CCL15. Measurement of TAMs and CCL15 in follicular thyroid lesions may be applied clinically to differentiate FTC from FA pre-operation.

MiR-564 functions as a tumor suppressor in human lung cancer by targeting ZIC3.

Although miR-564 was reported to be dysregulated in human malignancy, the function and mechanism of miR-564 in tumorigenesis remains unknown. In the present study, we found that miR-564 frequently downregulated in lung cancer cells and significantly inhibited cell proliferation, cell cycle progression, motility, and the tumorigenicity of lung cancer cells. Moreover, we identified zic family member 3 (ZIC3) as a direct target of miR-564. ZIC3 overexpression impaired the suppressive effects of miR-564 on the capacity of lung cancer cells for proliferation and motility. Finally, we detected the expression level of miR-564 and ZIC3 protein in tissue specimens, and found a significant negative correlation between them. Patients with low levels of miR-564 showed a poorer overall survival. Taken together, our present study revealed the tumor suppressor role of miR-564, indicating restoration of miR-564 as a potential therapeutic strategy for the treatment of lung cancer.

The anti-esophageal cancer cell activity by a novel tyrosine/phosphoinositide kinase inhibitor PP121.

Here we explored the potential effect of PP121, a novel dual inhibitor of tyrosine and phosphoinositide kinases, against human esophageal cancer cells. We showed that PP121 exerted potent cytotoxic effect in primary (patient-derived) and established (Eca-109, TE-1 and TE-3 lines) esophageal cancer cells, possibly through activating caspase-3-dependnent apoptosis. PP121 was, however, non-cytotoxic to the normal human esophageal epithelial cells (EECs). At the molecular level, we showed that PP121 blocked Akt-mTOR (mammalian target of rapamycin) activation in esophageal cancer cells, which was restored by introducing a constitutively-active Akt (CA-Akt). Yet, CA-Akt only partly inhibited cytotoxicity by PP121 in Eca-109 cells. Importantly, we showed that PP121 inhibited nuclear factor kappa B (NFκB) signaling activation in esophageal cancer cells, which appeared independent of Akt-mTOR blockage. In vivo, oral administration of PP121 remarkably inhibited Eca-109 xenograft growth in nude mice, and significantly improved mice survival. Further, the immunohistochemistry (IHC) and Western blot assays analyzing xenografted tumors showed that PP121 inhibited Akt-mTOR and NFκB activations in vivo. Together, we demonstrate that PP121 potently inhibits esophageal cancer cells in vitro and in vivo, possibly through concurrently inhibiting Akt-mTOR and NFκB signalings.