ASPM promotes migration and invasion of anaplastic thyroid carcinoma by stabilizing KIF11.

Abnormal spindle-like microcephaly-associated (ASPM) protein is crucial to the mitotic spindle function during cell replication and tumor progression in multiple tumor types. However, the effect of ASPM in anaplastic thyroid carcinoma (ATC) has not yet been understood. The present study is to elucidate the function of ASPM in the migration and invasion of ATC. ASPM expression is incrementally upregulated in ATC tissues and cell lines. Knockout (KO) of ASPM pronouncedly attenuates the migration and invasion of ATC cells. ASPM KO significantly reduces the transcript levels of Vimentin, N-cadherin, and Snail and increases E-cadherin and Occludin, thereby inhibiting epithelial-to-mesenchymal transition (EMT). Mechanistically, ASPM regulates the movement of ATC cells by inhibiting the ubiquitin degradation of KIF11 and thus stabilizing it via direct binding to it. Moreover, xenograft tumors in nude mice proved that KO of ASPM could ameliorate tumorigenesis and tumor growth accompanied by a decreased protein expression of KIF11 and an inhibition of EMT. In conclusion, ASPM is a potentially useful therapeutic target for ATC. Our results also reveal a novel mechanism by which ASPM inhibits the ubiquitin process in KIF11.

Correction to: Analysis of dynamic molecular networks for pancreatic ductal adenocarcinoma progression.

[This corrects the article DOI: 10.1186/s12935-018-0718-5.].

Inhibition of myeloid differentiation factor-2 attenuates obesity-induced cardiomyopathy and fibrosis.

Obesity causes cardiovascular diseases, including cardiac hypertrophy and remodeling, via chronic tissue inflammation. Myeloid differentiation factor-2 (MD2), a binding protein of lipopolysaccharide, is functionally essential for the activation of proinflammatory pathways in endotoxin-induced acute inflammatory diseases. Here we tested the hypothesis that MD2 plays a central role in obesity-induced cardiomyopathy. Wildtype or MD2 knockout mice were fed with a high fat diet (HFD) or normal diet (Control) for total 16weeks, and MD2 inhibitor L6H21 (20mg/kg) or vehicle (1% CMC-Na) were administered from the beginning of the 9th week. HFD induced significant weight gain and cardiac hypertrophy, with increased cardiac fibrosis and inflammation. L6H21 administration or MD2 knockout attenuated HFD-induced obesity, inflammation and cardiac remodeling. In vitro exposure of H9C2 cells to high lipids induced cell hypertrophy with activated JNK/ERK and NF-κB pathways, which was abolished by pretreatment of MD2 inhibitor L6H21. Our results demonstrate that MD2 is essential to obesity-related cardiac hypertrophy through activating JNK/ERK and NF-κB-dependent cardiac inflammatory pathways. Targeting MD2 would be a therapeutic approach to prevent obesity-induced cardiac injury and remodeling.

An anti-inflammatory chalcone derivative prevents heart and kidney from hyperlipidemia-induced injuries by attenuating inflammation.

Obesity is a growing pandemic in both developed and developing countries. Lipid overload in obesity generates a chronic, low-grade inflammation state. Increased inflammation in heart and renal tissues has been shown to promote the progression of heart and renal damage in obesity. Previously, we found that a novel chalcone derivative, L6H21, inhibited lipopolysaccharide-induced inflammatory response. In the present study, we investigated the effects of L6H21 on inflammatory responses in culture and in animal models of lipid overload. We utilized palmitic acid (PA) challenging in mouse peritoneal macrophages and apolipoprotein E knockout (ApoE-/-) mice fed a high fat diet (HFD) to study whether L6H21 mitigates the inflammatory response. Our studies show that L6H21 significantly reduced PA-induced expression of inflammatory cytokines in macrophages by inhibiting mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NFκB) signaling pathways. L6H21 also reduced fibrosis in the kidney and heart tissues, and indices of inflammatory response in the ApoE-/- mice fed a HFD. These effects in vivo were also associated with inhibition of MAPK and NFκB signaling by L6H21. These findings strongly suggest that L6H21 may be a potential agent for high fat diet-induced injuries in heart and kidney.

Analysis of dynamic molecular networks for pancreatic ductal adenocarcinoma progression.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors. The rapid progression of PDAC results in an advanced stage of patients when diagnosed. However, the dynamic molecular mechanism underlying PDAC progression remains far from clear. METHODS: The microarray GSE62165 containing PDAC staging samples was obtained from Gene Expression Omnibus and the differentially expressed genes (DEGs) between normal tissue and PDAC of different stages were profiled using R software, respectively. The software program Short Time-series Expression Miner was applied to cluster, compare, and visualize gene expression differences between PDAC stages. Then, function annotation and pathway enrichment of DEGs were conducted by Database for Annotation Visualization and Integrated Discovery. Further, the Cytoscape plugin DyNetViewer was applied to construct the dynamic protein-protein interaction networks and to analyze different topological variation of nodes and clusters over time. The phosphosite markers of stage-specific protein kinases were predicted by PhosphoSitePlus database. Moreover, survival analysis of candidate genes and pathways was performed by Kaplan-Meier plotter. Finally, candidate genes were validated by immunohistochemistry in PDAC tissues. RESULTS: Compared with normal tissues, the total DEGs number for each PDAC stage were 994 (stage I), 967 (stage IIa), 965 (stage IIb), 1027 (stage III), 925 (stage IV), respectively. The stage-course gene expression analysis showed that 30 distinct expressional models were clustered. Kyoto Encyclopedia of Genes and Genomes analysis indicated that the up-regulated DEGs were commonly enriched in five fundamental pathways throughout five stages, including pathways in cancer, small cell lung cancer, ECM-receptor interaction, amoebiasis, focal adhesion. Except for amoebiasis, these pathways were associated with poor PDAC overall survival. Meanwhile, LAMA3, LAMB3, LAMC2, COL4A1 and FN1 were commonly shared by these five pathways and were unfavorable factors for prognosis. Furthermore, by constructing the stage-course dynamic protein interaction network, 45 functional molecular modules and 19 nodes were identified as featured regulators for all PDAC stages, among which the collagen family and integrins were considered as two main regulators for facilitating aggressive progression. Additionally, the clinical relevance analysis suggested that the stage IV featured nodes MLF1IP and ITGB4 were significantly correlated with shorter overall survival. Moreover, 15 stage-specific protein kinases were identified from the dynamic network and CHEK1 was particularly activated at stage IV. Experimental validation showed that MLF1IP, LAMA3 and LAMB3 were progressively increased from tumor initiation to progression. CONCLUSIONS: Our study provided a view for a better understanding of the dynamic landscape of molecular interaction networks during PDAC progression and offered potential targets for therapeutic intervention.

[Identification of key pathways and drug repurposing for anaplastic thyroid carcinoma by integrated bioinformatics analysis].

OBJECTIVE: To identify hub genes and key pathways associated with anaplastic thyroid carcinoma (ATC), and to explore possible intervention strategy. METHODS: The differentially expressed genes (DEGs) in ATC were identified by Gene Expression Omnibus (GEO) combined with using R language; the pathway enrichment of DEGs were performed by using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). The protein-protein interaction (PPI) network of DEGs was constructed by STRING database and visualized by Cytoscape. Furthermore, the hub genes and key nodes were calculated by MCODE. Finally, the drug repurposing was performed by L1000CDS2. RESULTS: A total of 2087 DEGs were identified. The DEGs were clustered based on functions and pathways with significant enrichment analysis, among which PI3K-Akt signaling pathway, p53 signaling pathway, inflammatory response, extracellular matrix organization were significantly upregulated. The PPI network was constructed and the most significant three modules and nine genes were filtered. Twenty-two potential compounds were repurposed for ATC treatment. CONCLUSIONS: Using integrated bioinformatics analysis, we have identified hub genes and key pathways in ATC, and provide novel strategy for the treatment of ATC.

Blockade of myeloid differentiation protein 2 prevents obesity-induced inflammation and nephropathy.

Obesity is a major and independent risk factor of kidney diseases. The pathogenic mechanisms of obesity-associated renal injury are recognized to at least involve a lipid-rich and pro-inflammatory state of the renal tissues, but specific mechanisms establishing causal relation remain unknown. Saturated fatty acids are elevated in obesity, and known to induce chronic inflammation in kidneys. Myeloid differentiation protein 2 (MD2) is an important protein in lipopolysaccharide-induced innate immunity response and inflammation. We suggested that obesity-associated renal injury is regulated by MD2 thereby driving an inflammatory renal injury. The used three mouse models for in vivo study: MD2 knockout mice (KO) maintained on high fat diet (HFD), wild-type mice on HFD plus L6H21, a specific MD2 inhibitor and KO mice given palmitic acid (PA) by IV injection. The in vitro studies were carried out in cultured renal tubular epithelial cells, mouse mesangial cells and primary macrophages, respectively. The HFD mice presented with increased hyperlipidemia, serum creatinine and proteinuria. Renal tissue from HFD mice had increased fibrosis, inflammatory cytokines, macrophage infiltration, and activation of NF-κB and MAPKs. This HFD-induced renal injury profile was not observed in KO mice or L6H21-treated mice. Mice given PA mimmicked the HFD-induced renal injury profiles, which were prevented by MD2 knockout. The in vitro data further confirmed MD2 mediates PA-induced inflammation. MD2 is causally related with obesity-associated renal inflammatory injury. We believe that MD2 is an attractive target for future therapeutic strategies in obesity-associated kidney diseases.

Blockage of ROS and NF-κB-mediated inflammation by a new chalcone L6H9 protects cardiomyocytes from hyperglycemia-induced injuries.

Increased oxidative stress and cardiac inflammation have been implicated in the pathogenesis of diabetic cardiomyopathy (DCM). We previously found that a novel chalcone derivative, L6H9, was able to reduce LPS-induced inflammatory response in macrophages. This study was designed to investigate its protective effects on DCM and the underlying mechanisms. H9C2 cells were cultured with DMEM containing 33 mmol/L of glucose in the presence or absence of L6H9. Pretreatment with L6H9 significantly reduced high glucose-induced inflammatory cytokine expression, ROS level increase, mitochondrial dysfunction, cell apoptosis, fibrosis, and hypertrophy in H9c2 cells, which may be mediated by NF-κB inhibition and Nrf2 activation. In mice with STZ-induced diabetes, oral administration of L6H9 at 20 mg/kg/day for 8 weeks significantly decreased the cardiac cytokine and ROS level, accompanied by decreasing cardiac apoptosis and hypertrophy, and, finally, improved histological abnormalities and fibrosis, without affecting the hyperglycemia. L6H9 also attenuated the diabetes-induced NF-κB activation and Nrf2 decrease in diabetic hearts. These results strongly suggest that L6H9 may have great therapeutic potential in the treatment of DCM via blockage of inflammation and oxidative stress. This study also provides a deeper understanding of the regulatory role of Nrf2 and NF-κB in DCM, indicating that they may be important therapeutic targets for diabetic complications.

Inhibition of mitogen-activated protein kinases/nuclear factor κB-dependent inflammation by a novel chalcone protects the kidney from high fat diet-induced injuries in mice.

The prevalence of obesity has increased dramatically worldwide leading to increases in obesity-related complications, such as obesity-related glomerulopathy (ORG). Obesity is a state of chronic, low-grade inflammation, and increased inflammation in the adipose and kidney tissues has been shown to promote the progression of renal damage in obesity. Current therapeutic options for ORG are fairly limited and, as a result, we are seeing increased rates of progression to end-stage renal disease. Chalcones are a class of naturally occurring compounds with various pharmacological properties. 1-(3,4-Dihydroxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one (L2H17) is a chalcone that we have previously synthesized and found capable of inhibiting the lipopolysaccharide-induced inflammatory response in macrophages. In this study, we investigated L2H17's effect on obesity-induced renal injury using palmitic acid-induced mouse peritoneal macrophages and high fat diet-fed mice. Our results indicate that L2H17 protects against renal injury through the inhibition of the mitogen-activated protein kinase/nuclear factor κB pathways significantly by decreasing the expression of proinflammatory cytokines and cell adhesion molecules and improving kidney histology and pathology. These findings lead us to believe that L2H17, as an anti-inflammatory agent, can be a potential therapeutic option in treating ORG.

Attenuation of inflammatory response by a novel chalcone protects kidney and heart from hyperglycemia-induced injuries in type 1 diabetic mice.

High glucose-induced inflammatory response in diabetic complications plays an important role in disease occurrence and development. With inflammatory cytokines and signaling pathways as important mediators, targeting inflammation may be a new avenue for treating diabetic complications. Chalcones are a class of natural products with various pharmacological activities. Previously, we identified L2H17 as a chalcone with good anti-inflammatory activity, inhibiting LPS-induced inflammatory response in macrophages. In this study, we examined L2H17's effect on hyperglycemia-induced inflammation both in mouse peritoneal macrophages and a streptozotocin-induced T1D mouse model. Our results indicate that L2H17 exhibits a strong inhibitory effect on the expression of pro-inflammatory cytokines, cell adhesion molecules, chemokines and macrophage adhesion via modulation of the MAPK/NF-κB pathway. Furthermore, in vivo oral administration of L2H17 resulted in a significant decrease in the expression of pro-inflammatory cytokines and cell adhesion molecules, contributing to a reduction of key markers for renal and cardiac dysfunction and improvements in fibrosis and pathological changes in both renal and cardiac tissues of diabetic mice. These findings provide the evidence supporting targeting MAPK/NF-κB pathway may be effective therapeutic strategy for diabetic complications, and suggest that L2H17 may be a promising anti-inflammatory agent with potential as a therapeutic agent in the treatment of renal and cardiac diabetic complications.

A novel chalcone derivative attenuates the diabetes-induced renal injury via inhibition of high glucose-mediated inflammatory response and macrophage infiltration.

Inflammation plays a central role in the development and progression of diabetic nephropathy (DN). Researches on novel anti-inflammatory agents may offer new opportunities for the treatment of DN. We previously found a chalcone derivative L6H21 could inhibit LPS-induced cytokine release from macrophages. The aim of this study was to investigate whether L6H21 could ameliorate the high glucose-mediated inflammation in NRK-52E cells and attenuate the inflammation-mediated renal injury. According to the results, L6H21 showed a great inhibitory effect on the expression of pro-inflammatory cytokines, cell adhesion molecules, chemokines, and macrophage adhesion via down-regulation of NF-κB/MAPKs activity in high glucose-stimulated renal NRK-52E cells. Further, in vivo oral administration with L6H21 at a dosage of 20 mg/kg/2 days showed a decreased expression of pro-inflammatory cytokines, cell adhesion molecules, which subsequently contributed to the inhibition on renal macrophage infiltration, the reduction of serum creatinine and BUN levels, and the improvement on the fibrosis and pathological changes in the renal tissues of diabetic mice. These findings provided that chalcone derived L6H21 may be a promising anti-inflammatory agent and have the potential in the therapy of diabetic nephropathy, and importantly, MAPK/NF-κB signaling system may be a novel therapeutic target for human DN in the future.

Inhibition of MAPK-mediated ACE expression by compound C66 prevents STZ-induced diabetic nephropathy.

A range of in vitro, experimental and clinical intervention studies have implicated an important role for hyperglycaemia-induced activation of the renin-angiotensin system (RAS) in the development and progression of diabetic nephropathy (DN). Blockade of RAS by angiotensin converting enzyme (ACE) inhibitors is an effective strategy in treating diabetic kidney diseases. However, few studies demonstrate the mechanism by which hyperglycaemia up-regulates the expression of ACE gene. Our previous studies have identified a novel curcumin analogue, (2E,6E)-2,6-bis(2-(trifluoromethyl)benzylidene)cyclohexanone (C66), which could inhibit the high glucose (HG)-induced phosphorylation of mitogen-activated protein kinases in mouse macrophages. In this study, we found that the renal protection of C66 in diabetic mice was associated with mitogen-activated protein kinase (MAPK) inactivation and ACE/angiotensin II (Ang II) down-regulation. Generally, MAPKs have been considered as a downstream signalling of Ang II and a mediator for Ang II-induced pathophysiological actions. However, using C66 and specific inhibitors as small molecule probes, in vitro experiments demonstrate that the MAPK signalling pathway regulates ACE expression under HG stimulation, which contributes to renal Ang II activation and the development of DN. This study indicates that C66 is a potential candidate of DN therapeutic agents, and more importantly, that reduction in ACE expression by MAPKs inhibition seems to be an alternative strategy for the treatment of DN.

Caffeic acid phenethyl ester suppresses metastasis of breast cancer cells by inactivating FGFR1 via MD2.

BACKGROUND: Tumor metastasis is the main cause of death for breast cancer patients. Caffeic acid phenethyl ester (CAPE) has strong anti-tumor effects with very low toxicity and may be a potential candidate drug. However, the anti-metastatic effect and molecular mechanism of CAPE on breast cancer need more research. METHODS: MCF-7 and MDA-MB-231 breast cancer cells were used here. Wound healing and Transwell assay were used for migration and invasion detection. Western blot and RT-qPCR were carried out for the epithelial-to-myofibroblast transformation (EMT) process investigation. Western blot and immunofluorescence were performed for fibroblast growth factor receptor1 (FGFR1) phosphorylation and nuclear transfer detection. Co-immunoprecipitation was used for the FGFR1/myeloid differentiation protein2 (MD2) complex investigation. RESULTS: Our results suggested that CAPE blocks the migration, invasion, and EMT process of breast cancer cells. Mechanistically, CAPE inhibits FGFR1 phosphorylation and nuclear transfer while overexpression of FGFR1 reduces the anti-metastasis effect of CAPE. Further, we found that FGFR1 is bound to MD2, and silencing MD2 inhibits FGFR1 phosphorylation and nuclear transfer as well as cell migration and invasion. CONCLUSION: This study illustrated that CAPE restrained FGFR1 activation and nuclear transfer through MD2/FGFR1 complex inhibition and showed good inhibitory effects on the metastasis of breast cancer cells.

Identification and validation of the microRNAs and hub genes for pancreatic ductal adenocarcinoma by an integrated bioinformatic analysis.

Background: In the progression of pancreatic ductal adenocarcinoma (PDAC), aberrant micro RNAs (miRNAs) expression plays a crucial role. This study sought to identify and validate the key miRNAs and potential target genes involved in PDAC. A bioinformatic analysis was conducted to determine their potential use as biomarkers and therapeutic targets. Methods: Gene profiling data sets (GSE41372 and GSE32688) were retrieved from the Gene Expression Omnibus database. Differentially expressed miRNAs (DEMs) with a P value <0.05, and |fold change| >2 was identified. The prognostic value of the DEMs was accessed using the online server Kaplan-Meier plotter. Further, gene ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed using DAVID 6.7. The protein-protein interaction analyses were conducted with STRING, and miRNA-hub gene networks were constructed using Cytoscape software. The PDAC cells were transfected with miRNA inhibitors or mimics. Cell Counting Kit-8 assays and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to examine cell proliferation and apoptosis, respectively. Wound-healing assays were performed to evaluate cell migration. Results: Three DEMs (hsa-miR-21-5p, hsa-miR-135b-5p, and hsa-miR-222-3p) were identified. High expression levels of hsa-miR-21-5p, hsa-miR-135b-5p, or hsa-miR-222-3p predicted poor overall survival in PDAC patients. The pathway analysis revealed that the predicted target genes of the DEMs were closely related to several signaling pathways (including 'pathways in cancer', 'miRNAs in cancer', 'platinum drug resistance', 'lipid and atherosclerosis', and 'MAPK signaling pathway'). The MYC proto-oncogene (MYC), phosphate and tensin homolog gene (PTEN), poly(ADP-ribose) polymerase 1 (PARP1), von Hippel-Lindau (VHL), and fork head box p3 (FOXP3) were identified as potential target genes. The inhibition of hsa-miR-21-5p, hsa-miR-135b-5p, or hsa-miR-222-3p expression decreased cell proliferation. The overexpression of hsa-miR-21-5p, hsa-miR-135b-5p, or hsa-miR-222-3p facilitated PDAC cell migration. Conclusions: This study constructed the miRNA-hub gene network, which provides novel insights into the PDAC progression. Although further research is required, our results offer clues for new potential prognostic markers and therapeutic targets of PDAC.

Cost-effectiveness of PARP inhibitors in malignancies: A systematic review.

OBJECTIVES: Poly (ADP-ribose) polymerase inhibitor (PARPi) have become a mainstay for the treatment of BRCA-mutant malignancies. PARPis are likely to be more effective but also bring an increase in costs. Thus, we aimed at evaluating the cost effectiveness of PARPis in the treatment of malignancies. METHODS: Studies of cost effectiveness of PARPis were searched from PubMed, Web of Science, and Cochrane Library. Key information was extracted from the identified studies and reviewed. Quality of the included studies was evaluated using Quality of Health Economic Studies (QHES) instrument. Modeling techniques, measurement of parameters and uncertainty analysis were analyzed across studies. Interventions and cost-effectiveness results were reported stratified by patient population. RESULTS: Among the 25 studies identified, we included 17 on ovarian cancer, 2 on breast cancer, 3 on pancreatic cancer, and 3 on prostate cancer that involved olaparib, niraparib, rucaparib, and talazoparib. All studies had a QHES score of above 75. In the maintenance therapy of ovarian cancer, additional administration of olaparib was cost-effective for newly diagnosed patients after first-line platinum-based chemotherapy but was not cost-effective for platinum-sensitive recurrent patients in majority studies. However, the economic value of other PARPis in ovarian cancer as well as all PARPis in other tumors remained controversial. Cost-effectiveness of PARPi was primarily impacted by the costs of PARPi, survival time, health utility and discount rate. Moreover, genetic testing improved the cost-effectiveness of PARPi treatment. CONCLUSIONS: PARPi is potentially cost-effective for patients with ovarian, pancreatic, or prostate cancer. Genetic testing can improve the cost-effectiveness of PARPi.

A Novel Risk Model Based on Autophagy-Related LncRNAs Predicts Prognosis and Indicates Immune Infiltration Landscape of Patients With Cutaneous Melanoma.

Cutaneous melanoma (CM) is a malignant tumor with a high incidence rate and poor prognosis. Autophagy plays an essential role in the development of CM; however, the role of autophagy-related long noncoding RNAs (lncRNAs) in this process remains unknown. Human autophagy-related genes were extracted from the Human Autophagy Gene Database and screened for autophagy-related lncRNAs using Pearson correlation. Multivariate Cox regression analysis was implemented to identify ten autophagy-related lncRNAs associated with prognosis, and a risk model was constructed. The Kaplan-Meier survival curve showed that the survival probability of the high-risk group was lower than that of the low-risk group. A novel predictive model was constructed to investigate the independent prognostic value of the risk model. The nomogram results showed that the risk score was an independent prognostic signature that distinguished it from other clinical characteristics. The immune infiltration landscape of the low-risk and high-risk groups was further investigated. The low-risk groups displayed higher immune, stromal, and ESTIMATE scores and lower tumor purity. The CIBERSORT and single sample gene set enrichment analysis (ssGSEA) algorithms indicated a notable gap in immune cells between the low- and high-risk groups. Ten autophagy-related lncRNAs were significantly correlated with immune cells. Finally, Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) results demonstrated that autophagy-related lncRNA-mediated and immune-related signaling pathways are crucial factors in regulating CM. Altogether, these data suggest that constructing a risk model based on ten autophagy-related lncRNAs can accurately predict prognosis and indicate the tumor microenvironment of patients with CM. Thus, our study provides a new perspective for the future clinical treatment of CM.

Luteolin attenuated cisplatin-induced cardiac dysfunction and oxidative stress via modulation of Keap1/Nrf2 signaling pathway.

Cardiovascular complications are a well-documented limitation of cancer chemotherapy. Cisplatin-induced cardiotoxicity threatens the health and life of patients, and limits the application of cisplatin. Oxidative stress is the main mechanism underlying cisplatin-induced cardiac toxicity. Luteolin (Lut) has been reported to possess cardioprotective properties by activating nuclear factor-E2-related factor 2 (Nrf2) -mediated antioxidant response. However, the effect of Lut on cisplatin-induced cardiac damage remains unclear. In this study, we revealed that Lut exerted a protective effect against cisplatin-induced cardiac dysfunction and injury in vivo. In HL-1 cells, Lut was observed to dramatically reduce cisplatin-induced apoptosis and oxidative stress by modulating the Kelch-like epichlorohydrin-associated protein 1 (Keap1)/Nrf2 pathway. Altogether, these findings suggested that Lut showed promise in attenuating cisplatin-induced cardiac injury and might be considered a protective drug candidate for chemotherapy-associated cardiovascular complications.

MD2 blockage prevents the migration and invasion of hepatocellular carcinoma cells via inhibition of the EGFR signaling pathway.

BACKGROUND: The toll-like receptor (TLR) is an emerging signaling pathway in tumor invasion and metastasis. The activation of TLRs requires specific accessory proteins, such as the small secreted glycoprotein myeloid differentiation protein 2 (MD2), which contributes to ligand responsiveness. However, the role of MD2 in tumorigenesis and metastasis has rarely been reported. This study aimed to investigate the effects and underlying mechanisms of MD2 on the proliferation, migration, and invasion of hepatocellular carcinoma (HCC). METHODS: Cell counting kit 8 (CCK8), cell colony formation, wound healing, and transwell assays were conducted to determine cell viability, proliferation, migration, and invasion, respectively. Quantitative real-time PCR (qRT-PCR) was performed to assess the expression of MD2 in HCC cell lines and human normal liver cell lines as well as the silencing efficiency of MD2 blockage. Western blot and qRT-PCR assays were performed to detect the protein and mRNA expression levels of epithelial mesenchymal transformation (EMT) markers and epidermal growth factor receptor (EGFR) signaling molecules. RESULTS: MD2 was highly expressed in HCC tissues and cell lines. High expression of MD2 was associated with poor prognosis of HCC patients. In addition, MD2 silencing slightly inhibited the proliferation of HepG2 and HCCLM3, and significantly suppressed cell migration and invasion. Furthermore, MD2 blockage could distinctly prevent the EMT process by increasing the protein and mRNA levels of E-cadherin and Occludin, and decreasing the levels of Vimentin, N-cadherin, and Snail. Finally, the phosphorylation level of EGFR as well as its downstream molecular Src, Akt, I-κBα, and p65 were downregulated in HCC cells with MD2 silencing. CONCLUSIONS: Our findings suggest that high expression of MD2 may affect the EMT, migration, and invasion via modulation of the EGFR pathway in HCC cells.

HN1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by interacting with STMN1.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies frequently associated with extrathyroidal extension and metastasis through pathways that remain unclear. Analysis of the cancer genome atlas (TCGA) database and an independent cohort showed that the expression of hematological and neurological expressed 1 (HN1) was higher in thyroid cancers than in normal tissues, and negatively correlated with progression-free survival. RT-PCR and immunohistochemistry revealed higher HN1 expression in ATC compared to healthy tissues and papillary thyroid carcinoma (PTC). HN1 knockdown attenuated migration and invasion of ATC cells, whereas HN1 overexpression increased migration and invasion of PTC cells. HN1 reduced the acetylation of α-tubulin and promoted progression through epithelial-mesenchymal transition of ATC cells and mouse xenografts. HN1 knockdown significantly attenuated TGF-ß-induced mesenchymal phenotype, and inhibited tumor formation and growth of ATC xenografts in nude mice. Loss of STMN1 decreased the malignant potential of HN1, whereas HN1 knockdown in combination with STMN1 overexpression restored the aggressive properties of ATC cells. HN1 increased STMN1 mRNA expression, and prevented STMN1 ubiquitination and subsequent degradation. These results demonstrate that HN1 interacts with STMN1 and drives ATC aggressiveness.

Cost-effectiveness of pembrolizumab for treatment of platinum-resistant recurrent or metastatic head and neck squamous cell carcinoma in China: an economic analysis based on a randomised, open-label, phase III trial.

BACKGROUND: Pembrolizumab was recently demonstrated to have survival benefit in patients with recurrent or metastatic head and neck squamous cell carcinoma (r/mHNSCC). However, the cost-effectiveness of pembrolizumab versus chemotherapy in China remains uncertain. OBJECTIVE: This analysis aimed to describe the cost-effectiveness of pembrolizumab versus standard-of-care (SOC) therapy in r/mHNSCC in China. DESIGN: A Markov model consisting of three health states (stable, progressive and dead) was developed to compare the cost and effectiveness of pembrolizumab with SOC in platinum-resistant r/mHNSCC. Model inputs for transition probabilities and toxicity were collected from the KEYNOTE-040 trial, while health utilities were estimated from a literature review. Cost data were acquired for the payer's perspective in China. Costs and outcomes were discounted at an annual rate of 3.0%. Sensitivity analyses were conducted to test the uncertainties surrounding model parameters. OUTCOME MEASURES: The primary outcome was incremental cost-effectiveness ratios (ICERs), which were calculated as the cost per quality-adjusted life years (QALYs). RESULTS: The total mean cost of pembrolizumab and SOC was US$45 861 and US$41 950, respectively. As for effectiveness, pembrolizumab yielded 0.31 QALYs compared with 0.25 QALYs for SOC therapy. The ICER for pembrolizumab versus SOC was US$65 186/QALY, which was higher than the willingness-to-pay threshold (WTP) of US$28 130/QALY in China. The univariate sensitivity analysis indicated that utility values for progressive state, probability from stable to progressive in the SOC group, as well as cost of pembrolizumab were the three most influential variables on ICER. The probabilistic sensitivity analysis demonstrated that standard therapy was more likely to be cost-effective compared with pembrolizumab at a WTP value of US$28 130/QALY. Results were robust across both univariate analysis and probabilistic sensitivity analysis. CONCLUSIONS: Pembrolizumab is not likely to be a cost-effective strategy compared with SOC therapy in patients with platinum-resistant r/mHNSCC in China. TRIAL REGISTRATION NUMBER: NCT02252042; Post-results.