Value of dual-layer spectral detector CT in predicting lymph node metastasis of non-small cell lung cancer.

Background: The accurate assessment of lymph node metastasis (LNM) is crucial for the staging, treatment, and prognosis of lung cancer. In this study, we explored the potential value of dual-layer spectral detector computed tomography (SDCT) quantitative parameters in the prediction of LNM in non-small cell lung cancer (NSCLC). Methods: In total, 91 patients presenting with solid solitary pulmonary nodules (8 mm < diameter ≤30 mm) with pathologically confirmed NSCLC (57 without LNM, and 34 with LNM) were enrolled in the study. The patients' basic clinical data and the SDCT morphological features were analyzed using the chi-square test or Fisher's exact test. The Mann-Whitney U-test and independent sample t-test were used to analyze the differences in multiple SDCT quantitative parameters between the non-LNM and LNM groups. The diagnostic efficacy of the corresponding parameters in predicting LNM in NSCLC was evaluated by plotting the receiver operating characteristic (ROC) curves. A multivariate logistic regression analysis was conducted to determine the independent predictive factors of LNM in NSCLC. Interobserver agreement was assessed using intraclass correlation coefficients (ICCs) and Bland-Altman plots. Results: There were no significant differences between the non-LNM and LNM groups in terms of age, sex, and smoking history. Lesion size and vascular convergence sign differed significantly between the two groups (P<0.05), but there were no significant differences in the six tumor markers. The SDCT quantitative parameters [SAR40keV, SAR70keV, Δ40keV, Δ70keV, CER40keV, CER70keV, NEF40keV, NEF70keV, λ, normalized iodine concentration (NIC) and NZeff] were significantly higher in the non-LNM group than the LNM group (P<0.05). The ROC analysis showed that CER40keV, NIC, and CER70keV had higher diagnostic efficacy than other quantitative parameters in predicting LNM [areas under the curve (AUCs) =0.794, 0.791, and 0.783, respectively]. The multivariate logistic regression analysis showed that size, λ, and NIC were independent predictive factors of LNM. The combination of size, λ, and NIC had the highest diagnostic efficacy (AUC =0.892). The interobserver repeatability of the SDCT quantitative and derived quantitative parameters in the study was good (ICC: 0.801-0.935). Conclusions: The SDCT quantitative parameters combined with the clinical data have potential value in predicting LNM in NSCLC. The size + λ + NIC combined parameter model could further improve the prediction efficacy of LNM.

Resveratrol prevents Ang II-induced cardiac hypertrophy by inhibition of NF-κB signaling.

BACKGROUND: Pathological cardiac hypertrophy is a hallmark of various cardiovascular diseases (CVD) including chronic heart failure (HF) and an important target for the treatment of these diseases. Aberrant activation of Angiotensin II (Ang II)/AT1R signaling pathway is one of the main triggers of cardiac hypertrophy, which further gives rise to excessive inflammation that is mediated by the key transcription factor NF-κB. Resveratrol (REV) is a natural polyphenol with multiple anti-inflammatory and anti-oxidative effects, however the ability of REV in preventing Ang II-induced cardiac hypertrophy in combination with NF-κB signaling activation remains unclear. METHODS: Murine models of cardiac hypertrophy was conducted via implantation of Ang II osmotic pumps. Primary neonatal rat cardiomyocyte and heart tissues were examined to determine the effect and underlying mechanism of REV in preventing Ang II-induced cardiac hypertrophy. RESULTS: Administrations of REV significantly prevented Ang II-induced cardiac hypertrophy, as well as robustly attenuated Ang II-induced cardiac fibrosis, and cardiac dysfunction. Furthermore, REV not only directly prevented Ang II/AT1R signal transductions, but also prevented Ang II-induced expressions of pro-inflammatory cytokines and activation of NF-κB signaling pathway. CONCLUSIONS: Our study provides important new mechanistic insight into the cardioprotective effects of REV in preventing Ang II-induced cardiac hypertrophy via inhibiting adverse NF-κB signaling activation. Our findings further suggest the therapeutic potential of REV as a promising drug for the treatment of cardiac hypertrophy and heart failure.

Estrodiol-17ß and aromatase inhibitor treatment induced alternations of genome-wide DNA methylation pattern in Takifugu rubripes gonads.

Estradiol-17ß (E2) and aromatase inhibitor (AI) exposure can change the phenotypic sex of fish gonads. To investigated whether alterations in DNA methylation is involved in this process, the level of genome-wide DNA methylation in Takifugu rubripes gonads was quantitatively analyzed during the E2-induced feminization and AI-induced masculinization processes in this study. The methylation levels of the total cytosine (C) in control-XX(C-XX), control-XY (C-XY), E2-treated-XY (E-XY) and AI-treated-XX (AI-XX) were 9.11%, 9.19%, 8.63% and 9.23%, respectively. In the C-XX vs C-XY comparison, 4,196 differentially methylated regions (DMRs) overlapped with the gene body of 2,497 genes and 608 DMRs overlapped with the promoter of 575 genes. In the E-XY vs C-XY comparison, 6,539 DMRs overlapped with the gene body of 3,416 genes and 856 DMRs overlapped with the promoter of 776 genes. In the AI-XX vs C-XX comparison, 2,843 DMRs overlapped with the gene body of 1,831 genes and 461 DMRs overlapped with the promoter of 421 genes. Gonadal genomic methylation mainly occurred at CG sites and the genes that overlapped with DMRs on CG context were most enriched in the signaling pathways related to gonad differentiation, such as the Wnt, TGF-ß, MAPK, CAM and GnRH pathways. The DNA methylation levels of steroid synthesis genes and estrogen receptor genes promoter or gene body were negative correlated with their expression. After bisulfite sequencing verification, the DNA methylation level of the amhr2 promoter in XY was increased after E2 treatment, which consistent with the data from the genome-wide DNA methylation sequencing. In C-XY group, the expression of amhr2 was significantly higher than that in E-XY (p < 0.05). Additionally, dnmt1, which is responsible for methylation maintenance, expressed at similar level in four groups (p > 0.05). dnmt3, tet2, and setd1b, which were responsible for methylation modification, expressed at significantly higher levels in E-XY compared to the C-XY (p < 0.05). Dnmt3 and tet2 were expressed at significantly higher levels in AI-XX than that in C-XX (p < 0.05). These results indicated that E2 and AI treatment lead to the aberrant genome-wide DNA methylation level and expression level of dnmt3, tet2, and setd1b in T. rubripes gonad.

Influence of Material Removal Strategy on Machining Deformation of Aluminum Plates with Asymmetric Residual Stresses.

In this paper, the effects of material removal strategies and initial stress states on the machining deformation of aluminum alloy plates were investigated through a combination of finite element simulation and experiments. We developed different machining strategies described by Tm+Bn, which removal m mm materials form top and n mm materials from the bottom of the plate. The results demonstrate that the maximum deformation of structural components with the T10+B0 machining strategy could reach 1.94 mm, whereas with the T3+B7 machining strategy was only 0.065 mm, decreasing by more than 95%. The asymmetric initial stress state had a significant impact on the machining deformation of the thick plate. The machined deformation of thick plates increased with the increase in the initial stress state. The concavity of the thick plates changed with the T3+B7 machining strategy due to the asymmetry of the stress level. The deformation of frame parts was smaller when the frame opening was facing the high-stress level surface during machining than when it was facing the low-stress level. Moreover, the modeling results for the stress state and machining deformation were accurate and in good accordance with the experimental findings.

Low Expression of CLEC2B Indicates Poor Prognosis in Melanoma.

Background: Melanoma is a highly malignant skin tumor with a poor prognosis. Identification of novel biomarkers might potentially reveal the underlying mechanisms of melanoma progression. Methods: We demonstrated the relationship between pan-cancer CLEC2B expression and melanoma samples in The Cancer Genome Atlas (TCGA) database. Next, the Kaplan-Meier plot and Cox regression analysis determined the prognostic value of CLEC2B in melanoma. Biological pathway enrichment was screened by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), enabling the correlation analysis between the immune infiltration level and CLEC2B expression in melanoma. Our final claim was validated using qPCR, immunohistochemistry, Western blot, cell colony formation assays, ethynyldeoxyuridine (Edu) analysis, and cell Invasion assays. Results: Our study revealed that the high CLEC2B expression correlates with poor overall survival of melanoma patients. Moreover, a low expression of CLEC2B was found in the A375 cell line. In addition, CLEC2B has significant prognostic value in melanoma diagnosis, with an AUC of 0.896. Prognostic analysis showed the low expression of CLEC2B to be independently associated with melanoma patients. Moreover, the expression of CLEC2B was significantly correlated with B cells, eosinophils, macrophages, neutrophils, NK cells, T helper cells, Tregs, Th1 cells, Th17 cells, and Th2 cells. PCR and immunohistochemistry indicated CLEC2B to be significantly downregulated in melanoma. The cell colony formation assay showed CLEC2B knockout increased the proliferation of A375 cells. Conclusion: Our study established low levels of CLEC2B to be poor prognostic markers, enabling immunosuppressive cell infiltration in melanoma.

[Hepatic fibrosis aggravation in nuclear autoantigenic sperm protein (NASP) mutant mice induced by concanavalin A].

Objective To investigate how mutation of nuclear autoantigenic sperm protein (NASP) gene affects mouse liver fibrosis induced by concanavalinA (ConA) and its mechanism. Methods The wild-type B6 (B6-WT) mice were used as a control group, and the NASP mutant B6 (B6-NASPM) mice as an experimental group. The mice were injected with ConA via tail vein once a week for 8 weeks to establish the model of liver fibrosis. The histopathological changes were observed by HE staining, the collagen fiber deposition by Masson staining, smooth muscle alpha-actin (α-SMA) expression in liver tissue by immunohistochemical staining. The levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by microplate assay. The serum tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) were measured by ELISA. The mRNA expressions of type I collagen (Col1) and Col3 in liver tissue were determined by real-time quantitative PCR, and the changes of T lymphocyte subsets in liver tissue were detected by flow cytometry. Results Compared with the B6-WT group, B6-NASPM group had disordered liver structure and no significant changes in mRNA expression of Col 1 and Col3, but the collagen fiber hyperplasia and α-SMA expression in liver tissue were more obvious, and the levels of serum ALT and TNF-α were significantly increased. In addition, the proportion and number of CD4+CD44hi T lymphocyte subsets in liver tissue were markedly decreased. Conclusion Mutation of NASP gene aggravates mouse liver fibrosis by increasing the release of TNF-α, changing the proportion of T lymphocyte subsets in liver tissue and promoting the activation of hepatic stellate cells.

γ-Glutamyl transpeptidase-activated indole-quinolinium based cyanine as a fluorescence turn-on nucleolus-targeting probe for cancer cell detection and inhibition.

A nucleolus as a prominent sub-nuclear, membraneless organelle plays a crucial role in ribosome biogenesis, which is in the major metabolic demand in a proliferating cell, especially in aggressive malignancies. We develop a γ-glutamyltranspeptidase (GGT)-activatable indole-quinolinium (QI) based cyanine consisting of a novel tripeptide fragment (Pro-Gly-Glu), namely QI-PG-Glu as a turn-on red fluorescent probe for the rapid detection of GGT-overexpressed A549 cancer cells in vivo. QI-PG-Glu can be triggered by GGT to rapidly release an activated fluorophore, namely HQI, in two steps including the cleavage of the γ-glutamyl group recognized by GGT and the rapid self-driven cyclization of the Pro-Gly linker. HQI exhibits dramatically red fluorescence upon binding to rRNA for imaging of nucleolus in live A549 cells. HQI also intervenes in rRNA biogenesis by declining the RNA Polymerase I transcription, thus resulting in cell apoptosis via a p53 dependent signaling pathway. Our findings may provide an alternative avenue to develop multifunctional cancer cell-specific nucleolus-targeting fluorescent probes with potential anti-cancer effects.

Profile of gene expression changes during estrodiol-17ß-induced feminization in the Takifugu rubripes brain.

BACKGROUND: As the critical tissue of the central nervous system, the brain has been found to be involved in gonad development. Previous studies have suggested that gonadal fate may be affected by the brain. Identifying brain-specific molecular changes that occur during estrodiol-17ß (E2) -induced feminization is crucial to our understanding of the molecular control of sex differentiation by the brains of fish. RESULTS: In this study, the differential transcriptomic responses of the Takifugu rubripes larvae brain were compared after E2 treatment for 55 days. Our results showed that 514 genes were differentially expressed between E2-treated-XX (E-XX) and Control-XX (C-XX) T. rubripes, while 362 genes were differentially expressed between E2-treated-XY (E-XY) and Control-XY (C-XY). For example, the expression of cyp19a1b, gnrh1 and pgr was significantly up-regulated, while st, sl, tshß, prl and pit-1, which belong to the growth hormone/prolactin family, were significantly down-regulated after E2 treatment, in both sexes. The arntl1, bhlbe, nr1d2, per1b, per3, cry1, cipc and ciart genes, which are involved in the circadian rhythm, were also found to be altered. Differentially expressed genes (DEGs), which were identified between E-XX and C-XX, were significantly enriched in neuroactive ligand-receptor interaction, arachidonic acid metabolism, cytokine-cytokine receptor interaction and the calcium signaling pathway. The DEGs that were identified between E-XY and C-XY were significantly enriched in tyrosine metabolism, phenylalanine metabolism, arachidonic acid metabolism and linoleic acid metabolism. CONCLUSION: A number of genes and pathways were identified in the brain of E2-treated T. rubripes larvae by RNA-seq. It provided the opportunity for further study on the possible involvement of networks in the brain-pituitary-gonadal axis in sex differentiation in T. rubripes.

Targeting EGFR sensitizes 5-Fu-resistant colon cancer cells through modification of the lncRNA-FGD5-AS1-miR-330-3p-Hexokinase 2 axis.

5-Fluorouracil (5-Fu) is a widely applied anti-cancer agent against colorectal cancer (CRC), yet a number of CRC patients have developed resistance to 5-Fu-based chemotherapy. The epidermal growth factor receptor (EGFR) is recognized as an oncogene that promotes diverse cancer progresses. In addition, long noncoding RNAs (lncRNAs) are essential regulators of cancers. Here we report that EGFR and lncRNA-FGD5-AS1 promoted 5-Fu resistance of CRC. By establishing the 5-Fu-resistant CRC cell line, we detected that EGFR, FGD5-AS1, and glucose metabolism were significantly elevated in 5-Fu-resistant CRC cells. A microRNA-microarray analysis revealed that miR-330-3p functions as a downstream effector of FGD5-AS1. FGD5-AS1 directly sponged miR-330-3p to form a competing endogenous RNA (ceRNA) network, leading to inhibition of miR-330-3p expression. Furthermore, bioinformatics analysis revealed that Hexokinase 2 (HK2) was a potential target of miR-330-3p, which was validated by luciferase assay. Rescue experiments demonstrated that FGD5-AS1 promotes glycolysis through modulating the miR-330-3p-HK2 axis, leading to 5-Fu resistance of CRC cancer cells. Finally, in vitro and in vivo xenograft experiments consistently demonstrated that inhibition of EGFR by the specific inhibitor erlotinib effectively enhanced the anti-tumor toxicity of 5-Fu by targeting the EGFR-FGD5-AS1-miR-330-3p-HK2 pathway. In summary, this study demonstrates new mechanisms of the EGFR-modulated 5-Fu resistance through modulating the noncoding RNA network, contributing to development of new approaches against chemoresistant CRC.

Gene Expression of Takifugu rubripes Gonads During AI- or MT-induced Masculinization and E2-induced Feminization.

Elucidating the global molecular changes that occur during aromatase inhibitor (AI)- or 17α-methyltestosterone (MT)-induced masculinization and estradiol-17ß (E2)-induced feminization is critical to understanding the roles that endocrine and genetic factors play in regulating the process of sex differentiation in fish. Here, fugu larvae were treated with AI (letrozole), MT, or E2 from 25 to 80 days after hatching (dah), and gonadal transcriptomic analysis at 80 dah was performed. The expression of dmrt1, gsdf, foxl2, and other key genes (star, hsd3b1, cyp11c1, cyp19a1a, etc.) involved in the steroid hormone biosynthesis pathway were found be altered. The expression of dmrt1, gsdf, cyp19a1a, and foxl2 was further verified by quantitative polymerase chain reaction. In the control group, the expression of dmrt1 and gsdf was significantly higher in XY larvae than in XX larvae, while the expression of foxl2 and cyp19a1a was significantly higher in XX larvae than in XY larvae (P < .05). AI treatment suppressed the expression of foxl2 and cyp19a1a, and induced the expression of dmrt1 and gsdf in XX larvae. MT treatment suppressed the expression of foxl2, cyp19a1a, dmrt1, and gsdf in XX larvae. E2 treatment suppressed the expression of dmrt1 and gsdf, but did not restore the expression of foxl2 and cyp19a1a in XY larvae. The shared response following AI, MT, and E2 treatment suggested that these genes are essential for sex differentiation. This finding offers some insight into AI or MT-induced masculinization, and E2-induced femininization in fugu.

Helicobacter pylori CagA Protein Attenuates 5-Fu Sensitivity of Gastric Cancer Cells Through Upregulating Cellular Glucose Metabolism.

INTRODUCTION: Gastric cancer (GC) is one of the most malignancies leading to human mortality due to its development, progress, metastasis and poor prognosis, despite the development of remarkable chemotherapy and surgery. The 5-fluorouracil (5-Fu) is an effective anti-gastric cancer agent. However, a fraction of GC patients acquire 5-Fu chemoresistance. METHODS: In this study, the CagA protein was detected from CagA-positive gastric cancer patients by qRT-PCR and immunohistochemistry. The 5-Fu resistant gastric cancer cell line was generated from MKN45-CagA cells which was transfected with CagA overexpression vector. Cellular glucose metabolism was determined by measurements of glucose uptake, lactate product and glycolysis enzymes. RESULTS: We report that the Helicobacter pylori (H. pylori)-secreted Cytotoxin-associated gene A (CagA) oncoprotein is positively correlated with 5-Fu resistance of gastric cancer. From totally 72 CagA-positive gastric cancer patients, CagA high-expressed patients showed more resistance to 5-Fu than CagA low-expressed patients. Moreover, statistical analysis revealed that CagA mRNA and protein expressions were significantly upregulated in 5-Fu resistant gastric cancer patients. We observed that CagA protein is upregulated in 5-Fu resistant gastric cancer cells compared with sensitive cells. Interestingly, cellular glucose metabolism was upregulated; the glucose uptake and lactate production were significantly higher in 5-Fu resistant gastric cancer cells. The Akt phosphorylation and expressions of glycolysis key enzymes, Hexokinase 2 and LDHA, were significantly upregulated in 5-Fu resistant gastric cancer cells. On the other way, inhibition of glycolysis or Akt pathway effectively overcame 5-Fu resistance from both in vitro and in vivo models. Finally, we report that the combination of Akt or glycolysis inhibitor with 5-Fu could synergistically enhance the cytotoxicity of 5-Fu to CagA-overexpressed gastric cancer cells. DISCUSSION: In summary, our study demonstrated a CagA-Akt-glycolysis-5-Fu resistance axis, contributing to the development of new therapeutic agents against chemoresistant human gastric cancer.

IGFBP-4 enhances VEGF-induced angiogenesis in a mouse model of myocardial infarction.

Vascular endothelial growth factor (VEGF) is a well-known angiogenic factor, however its ability in promoting therapeutic angiogenesis following myocardial infarction (MI) is limited. Here, we aimed to investigate whether dual treatment with insulin-like growth factor binding protein-4 (IGFBP-4), an agent that protects against early oxidative damage, can be effective in enhancing the therapeutic effect of VEGF following MI. Combined treatment with IGFBP-4 enhanced VEGF-induced angiogenesis and prevented cell damage via enhancing the expression of a key angiogenic factor angiopoietin-1. Dual treatment with the two agents synergistically decreased cardiac fibrosis markers collagen-I and collagen-III following MI. Importantly, while the protective action of IGFBP-4 occurs at an early stage of ischemic injury, the action of VEGF occurs at a later stage, at the onset angiogenesis. Our findings demonstrate that VEGF treatment alone is often not enough to protect against oxidative stress and promote post-ischemic angiogenesis, whereas the combined treatment with IGFBP4 and VEGF can utilize the dual roles of these agents to effectively protect against ischemic and oxidative injury, and promote angiogenesis. These findings provide important insights into the roles of these agents in the clinical setting, and suggest new strategies in the treatment of ischemic heart disease.

A retrospective study on the clinical characteristics and radiological features of primary pulmonary lymphoma.

BACKGROUND: The retrospective study was mainly performed to determine the clinical symptoms and radiological characteristics of primary pulmonary lymphoma (PPL) to improve the recognition and diagnosis of the disease. METHODS: Between June 2007 and June 2019, the clinical data and radiological images of the 16 patients with PPL confirmed by pathology were retrospectively analyzed. RESULTS: Among the 16 patients with PPL (6 males and 10 females, aged 32 to 72 years, with a median age of 55.13 years), 9 patients were mucosa-associated lymphoid tissue lymphoma (MALT) and 7 patients were diffuse large B-cell lymphoma (DLBCL); all of the patients did not suffer from autoimmune disease [such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or Sjogren's syndrome (SSS)]; and 11 patients had a long-term smoking history from 10 to 40 years. The common clinical symptoms were as follows: chest discomfort (n=8), cough (n=10), chest pain (n=7), fever (n=6), apnea (n=1), fatigue (n=4) and weight loss (n=3), however, 6 cases did not show clear symptoms at the time of diagnosis. Blood tests revealed anemia (n=6), thrombocytopenia (n=2), lactate dehydrogenase (LDH) level (n=7), C-reactive protein (CRP) (n=9), erythrocyte sedimentation rate (ESR) (n=8) and no tumor-related indexes were detected abnormal. The chest radiological images showed a total of 8 cases with multiple masses, 2 cases with different types of nodes, 4 cases with patchy infiltration or consolidation shadow, with or without an air bronchogram, and 2 cases with a mixed manifestation. All the lesions were only involved in unilateral lung (13 right, 3 left), none of them located on bilateral lung fields. At the time of admission, the patients were misdiagnosed as lung cancer (n=9), pneumonia (n=5), tuberculosis (n=1), and diffuse interstitial lung disease (n=1). Then final pathological diagnosis was confirmed by surgery (n=9), percutaneous lung biopsy (n=5), and bronchoscopic biopsy (n=2). CONCLUSIONS: PPL is a rare disease, though clinical symptoms and radiological characteristics are not typical, they serve as significant clues for the diagnosis and differential diagnosis. Accurate diagnosis mainly depends on histopathological examination, however, conducting a retrospectively study could improve and enrich our knowledge to the disease and reduce inappropriate treatments.

A decade retrospective study of light/laser devices in treating nasal rosacea.

Background: Large-scale retrospective studies of light/laser in treating nasal rosacea were lacking.Objective: The study was aimed to perform a decade retrospection of the patients with nasal rosacea who were treated with light/laser devices.Methods: A study between 2008 and 2017 was performed retrospectively. Categorization of rosacea type (erythema/telangiectasia, ET; papules/pustules, PP; rhinophyma, RP) was made according to the photographs. Device settings, treatment regimens and treatment sessions of light/laser facilities were summarized. Efficacy was evaluated using a grading scale.Results: In all, 807 patients received light/laser treatments. The subtypes of nasal rosacea were ET (n = 196), PP (n = 95), RP (n = 42), ET + PP (n = 334), ET + RP (n = 15), PP + RP (n = 88), and ET + PP + RP (n = 37). The lesions of ET or PP were mainly treated with noninvasive devices (Intense pulsed light, IPL; Dye pulse light, DPL; Dual wavelength laser system, DW) and those of RP were treated with the Fractional carbon dioxide (FCO2) laser. For the mixed subtypes, the general disposal orders of lesions were ET, PP, and later RP, and the fundamental orders of devices application were IPL, DPL, DW, and FCO2 laser. For all types of rosacea except for RP (2-4 sessions), most of the patients received 4-6 sessions of treatments. Of all subtypes of ET, PP, RP, ET + PP, ET + RP, PP + RP, and ET + PP + RP, the patients who achieved more than 50% improvement accounted for 74.5%, 58.3%, 83.3%, 69.2%, 73.3%, 61.4%, and 51.4%, respectively.Conclusion: The multiple, sequential light/laser devices can be safely used in nasal rosacea with various degrees efficacies based on different types.

Association between FAS gene -670 A/G and -1377 G/A polymorphisms and the risk of autoimmune diseases: a meta-analysis.

OBJECTIVES: FAS plays a critical role in the extrinsic apoptosis pathway in autoimmune diseases. Previous studies investigating the association between FAS gene -670 A/G and -1377 G/A polymorphisms and the risk of autoimmune diseases reported controversial results. We performed the meta-analysis to evaluate the possible association. METHODS: Relevant studies were identified by searching the PubMed, Embase, CNKI, and Wanfang databases up to December 2018. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to determine the association. RESULTS: A total of 43 articles including 67 studies (52 studies for FAS -670 A/G and 15 studies for -1377 G/A) were included in the meta-analysis. Our meta-analysis showed that the FAS -670 A/G polymorphism was associated with the risk of autoimmune diseases (GG vs. GA: OR = 1.079, 95% CI = 1.004-1.160, P=0.038), especially in Caucasians (GG vs. GA: OR = 1.12, 95% CI = 1.03-1.23, P=0.012), Asians (G vs. A: OR = 0.89, 95% CI = 0.83-0.96, P=0.002), systemic lupus erythematosus (SLE) (G vs. A: OR = 0.85, 95% CI = 0.77-0.94, P=0.001), multiple sclerosis (MS) (GG+GA vs. AA: OR = 0.83, 95% CI = 0.70-0.99, P=0.043), systemic sclerosis (SSc) (GG vs. GA: OR = 1.20, 95% CI = 1.07-1.36, P=0.003) and Hashimoto's thyroiditis (HT) (G vs. A: OR = 1.45, 95% CI = 1.10-1.90, P=0.008); the FAS -1377 G/A polymorphism was associated with the risk of autoimmune diseases (A vs. G: OR = 1.11, 95% CI = 1.03-1.20, P=0.008), especially in Asians (A vs. G: OR = 1.15, 95% CI = 1.05-1.25, P=0.002) and high quality studies (A vs. G: OR = 1.14, 95% CI = 1.05-1.24, P=0.002). CONCLUSION: This meta-analysis demonstrated that the FAS -670A/G and -1377 G/A polymorphisms were associated with the risk of autoimmune diseases.

Deletion of low-density lipoprotein-related receptor 5 inhibits liver Cancer cell proliferation via destabilizing Nucleoporin 37.

BACKGROUND: LRP5/6 are co-receptors in Wnt/ß-catenin pathway. Recently, we discovered multiple ß-catenin independent functions of LRP5/6 in tumor cells and in the diseased heart. Nucleoporin 37 (NUP37) is an important component of the nuclear pore complex (NPC), whose elevated expression is associated with worsened prognosis in liver cancer. Previous studies have shown that NUP37 interacted with YAP and activated YAP/TEAD signaling in liver cancer. Our preliminary findings showed a nuclear location of LRP5. We thus tested the hypothesis that LRP5 may act as a genuine regulator of YAP/TEAD signaling via modulating NUP37 in a ß-catenin-independent way. METHODS: We performed siRNA knockdown of LRP5, LRP6, or ß-catenin in liver cancer HepG2 cells to determine the effect on tumor cell proliferation. Protein expressions and interaction between LRP5 and NUP37 were determined using immunoprecipitation and western blot analyses. RESULTS: HepG2 cell proliferation was markedly inhibited by knockdown of LRP5 but not LRP6 or ß-catenin, suggesting that LRP5 has a specific, ß-catenin-independent role in inhibiting HepG2 cell proliferation. Knockdown of NUP37 by siRNA inhibited the proliferation of HepG2 cells, whereas overexpression of NUP37 reversed the decrease in cell proliferation induced by LRP5 knockdown. Immunoprecipitation assays confirmed that LRP5 bound to NUP37. Furthermore, LRP5 overexpression restored NUP37 knockdown-induced downregulation of YAP/TEAD pathway. CONCLUSIONS: LRP5 deletion attenuates cell proliferation via destabilization of NUP37, in a ß-catenin-independent manner. LRP5 therefore acts as a genuine regulator of YAP/TEAD signaling via maintaining the integrity of the NPC, and implicates a therapeutic strategy in targeting LRP5 for inhibiting liver cancer cell proliferation.

LRP6 Ectodomain Prevents SDF-1/CXCR4-Induced Breast Cancer Metastasis to Lung.

PURPOSE: Lung metastasis is an important cause of breast cancer-related deaths, in which SDF-1/CXCR4 signaling pathway plays a critical role. Single transmembrane protein LRP6 is viewed as an oncogene via activating the Wnt/ß-catenin signaling pathway. Our work aims to investigate the relationship between SDF-1/CXCR4 and LRP6 in breast cancer lung metastasis. EXPERIMENTAL DESIGN: We examined the expressions and functions of SDF-1/CXCR4 and LRP6 as well as their relationship in breast cancer in vitro and in vivo. RESULTS: LRP6 ectodomain (LRP6N) directly bound to CXCR4 and competitively prevented SDF-1 binding to CXCR4. LRP6N prevented SDF-1/CXCR4-induced metastasis to lung and prolonged survival in mice bearing breast tumors, whereas LRP6 knockdown activated SDF-1/CXCR4 signal transduction and promoted lung metastasis and tumor death. Furthermore, patients with breast cancer with high CXCR4 expression had poor prognosis, which was exacerbated by low LRP6 expression but improved by high LRP6 expression. Interestingly, a secreted LRP6N was found in the serum of mice and humans, which was downregulated by the onset of cancer metastasis in both mice bearing breast cancer as well as in patients with breast cancer. CONCLUSIONS: LRP6N might be a promising diagnostic marker for the early detection of breast cancer metastasis as well as an inhibitor of SDF-1/CXCR4-induced breast cancer metastasis. LRP6N also provides an interesting link between Wnt signaling and SDF-1/CXCR4 signaling, the two key pathways involved in cancer development.

The promising antitumour drug disulfiram inhibits viability and induces apoptosis in cardiomyocytes.

Disulfiram (DSF), widely used for treating alcohol abuse, is a promising antitumour drug that inhibits tumour cell viability, reverses cancer drug resistance and induces apoptosis. However, its potential side effects on cardiomyocytes remain unknown. This study demonstrated that DSF can not only inhibit cardiomyocyte viability and activity but also promote cell apoptosis. Furthermore, we revealed that cardiomyocytes were more sensitive to DSF than cancer cells. Moreover, the expression of STAT3, a key regulator of cardiomyocyte viability, was significantly down-regulated in cardiomyocytes treated with DSF. Finally, we also used experimental comparisons to indicate that PEG is a promising solvent for decreasing the adverse side effects of DSF, thereby expanding its potential range of clinical applications.