Biochemical Targets and Molecular Mechanism of Matrine against Aging.

The aim of this study is to explore the potential targets and molecular mechanism of matrine (MAT) against aging. Bioinformatic-based network pharmacology was used to investigate the aging-related targets and MAT-treated targets. A total of 193 potential genes of MAT against aging were obtained and then the top 10 key genes (cyclin D1, cyclin-dependent kinase 1, Cyclin A2, androgen receptor, Poly [ADP-ribose] polymerase-1 (PARP1), histone-lysine N-methyltransferase, albumin, mammalian target of rapamycin, histone deacetylase 2, and matrix metalloproteinase 9) were filtered by the molecular complex detection, maximal clique centrality (MMC) algorithm, and degree. The Metascape tool was used for analyzing biological processes and pathways of the top 10 key genes. The main biological processes were response to an inorganic substance and cellular response to chemical stress (including cellular response to oxidative stress). The major pathways were involved in cellular senescence and the cell cycle. After an analysis of major biological processes and pathways, it appears that PARP1/nicotinamide adenine dinucleotide (NAD+)-mediated cellular senescence may play an important role in MAT against aging. Molecular docking, molecular dynamics simulation, and in vivo study were used for further investigation. MAT could interact with the cavity of the PARP1 protein with the binding energy at -8.5 kcal/mol. Results from molecular dynamics simulations showed that the PARP1-MAT complex was more stable than PARP1 alone and that the binding-free energy of the PARP1-MAT complex was -15.962 kcal/mol. The in vivo study showed that MAT could significantly increase the NAD+ level of the liver of d-gal-induced aging mice. Therefore, MAT could interfere with aging through the PARP1/NAD+-mediated cellular senescence signaling pathway.

The Correlation of Mouse Double Minute 4 (MDM4) Polymorphisms (rs4245739, rs1563828, rs11801299, rs10900598, and rs1380576) with Cancer Susceptibility: A Meta-Analysis.

BACKGROUND Mouse double minute 4 (MDM4) has been extensively investigated as a negative regulator of P53, its negative feedback loop, and the effect of its genetic polymorphisms on cancers. However, many studies showed varying and even conflicting results. Therefore, we employed meta-analysis to further assess the intensity of the connection between MDM4 polymorphisms and malignancies. MATERIAL AND METHODS We searched eligible articles in 5 databases (Cochrane Library, PubMed, Web of Science, Wan Fang Database, and China National Knowledge Infrastructure) up to August 2021. Odds ratios (ORs) and 95% confidence intervals (CIs) were utilized to probe the correlation of 5 MDM4 polymorphisms (rs4245739, rs1563828, rs11801299, rs10900598, and rs1380576) with carcinomas. We employed meta-regression and subgroup analysis to probe for sources of heterogeneity; Funnel plots, Begg's test, and Egger's test were used to evaluate publication bias. Sensitivity analysis was applied to assess the stability of the study. RESULTS Twenty-two studies, comprising 77 reports with 29 853 cases and 72 045 controls, were included in our meta-analysis. We found that rs4245739 polymorphism was a factor in reducing overall cancer susceptibility (dominant model, OR=0.85, 95% CI=0.76-0.95; heterozygous model, OR=0.86, 95% CI=0.78-0.96; additive model, OR=0.87, 95% CI=0.79-0.95), especially in Asian populations, and it also reduces the risk for esophageal squamous cell carcinoma (ESCC). The remaining 4 SNPs were not associated with cancers. CONCLUSIONS The rs4245739 polymorphism might reduce the risk of malignancies, especially in Asian populations, and it is a risk-reducing factor for ESCC incidence. However, rs1563828, rs11801299, rs10900598, and rs1380576 are not relevant to cancer susceptibility.

Vascular endothelial growth factor gene polymorphism (-634G/C) and breast cancer risk.

The aim of this meta-analysis was to assess if the -634G/C polymorphism represents a predisposition factor for the risk of breast cancer. We included eight published case-control studies, in which a total of 6,175 cancer cases and 6,421 cancer-free controls were included. Pooled ORs and 95 % CIs were calculated by the fixed effects model to evaluate the association of the -634G/C polymorphism and breast cancer risk. When all studies were pooled, we did not find statistical evidence of any significant association with overall breast cancer risk (ORBB vs. bb = 1.00, 95 % CI = 0.93-1.07, P = 0.999; ORBB + Bb vs. bb = 1.00, 95 % CI = 0.95-1.05, P = 0.999; ORBB vs. Bb + bb = 1.03, 95 % CI = 0.96-1.09, P = 0.984; ORallele B vs. allele b = 1.01, 95 % CI = 0.97-1.05, P = 0.998; ORBb vs. bb = 0.99, 95 % CI = 0.92-1.06, P = 0.992). In further stratified analyses by ethnicity and control source, no significant association was revealed. This study suggests that the -634G/C polymorphism does not appear to represent a risk factor for breast cancer.

CD243 gene polymorphism significantly associated with breast cancer susceptibility.

We aimed to obtain a summary risk estimate for CD243 gene polymorphism associated with breast cancer. A total of nine case-control studies, including 5,073 cancer patients and 7,498 control subjects, were pooled in our fixed effects meta-analysis of the association between CD243 gene polymorphism and risk of breast cancer. All data were analyzed by using Stata software (version 12.0). We found significant risk effects under TT vs. TC + CC genetic model [odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.01-1.18, P = 0.516], but not in other comparisons. Stratifying the pooled data by ethnicity and source of controls revealed that the association between the T allele and an increased risk of breast cancer was more pronounced among Asians (TT vs. CC: OR = 1.26, 95 % CI = 1.02-1.57, P = 0.720; TT vs. TC + CC: OR = 1.31, 95 % CI = 1.07-1.61, P = 0.708) and hospital-based studies (TT vs. CC: OR = 1.25, 95 % CI = 1.02-1.53, P = 0.877; TT vs. TC + CC: OR = 1.27, 95 % CI = 1.05-1.53, P = 0.540). No notable heterogeneity was indicated across studies. Our meta-analysis demonstrates that CD243 gene polymorphism may act as a predisposition factor for breast cancer, particularly in Asian populations.

Relay protection sensitivity integrated optimal placement and capacity of inverter interfaced distributed generators in distribution networks.

The relay protection sensitivity is one of the determined factors in the power system, however, it is often overlooked in current distribution network (DN) planning. The relay protection sensitivity can be decreased to below the minimum values, failing to meet the requirements for electrical installations. To address this challenge, a new optimization model integrated with the relay protection sensitivity to maximize the inverter interfaced distributed generator (IIDG) penetration level while minimizing IIDG investment was proposed in this paper. The IIDG effect on the relay protection sensitivity was analysed and the relay protection sensitivity re-evaluation method was developed. The relay protection sensitivity evaluation was integrated into the proposed model and the particle swarm optimization (PSO) algorithm was developed to solve the nonlinear issue. The proposed optimization method was tested on different cases, and results confirmed the effectiveness of the method. Furthermore, the relay sensitivity profiles obtained through the proposed method and the optimization without considering the relay sensitivity limits were compared. The proposed method improves the average and minimum sensitivity factors by 28.77 % and 51.76 %, respectively, when the DTO protection functions as the backup for the protected line in the thirty-three-node system. When DTO acts as the backup for the adjacent line, the average and minimum values increase by 29.91 % and 50.95 %, respectively. Comparative analysis confirms the efficacy of the proposed method. The new method extends the power system panning approaches and can be integrated into the DN planning tools to support the low-carbon initiatives.

Risk factors and prognosis of sentinel lymph node metastasis in breast-conserving breast cancer: A retrospective study based on the SEER database.

At present, the risk factors and prognosis of sentinel lymph node metastasis (SLNM) are analyzed based on the study of axillary lymph node metastasis, but whether there is a difference between the two is unclear. Therefore, an accurate and appropriate predictive model needs to be proposed to evaluate patients undergoing sentinel lymph node biopsy (SLNB) for breast cancer. We selected 16983 women with breast cancer from the Surveillance Epidemiology and End Results (SEER) database. They were randomly assigned to two cohorts, one for development (n = 11891) and one for validation (n = 5092). multi-factor logistics regression was used to distinguish risk factors affecting SLNM. The potential prognostic factors were identified using the COX regression analysis. The hazard ratio (HR) and 95% confidence interval (95%CI) were calculated for all results. Multiple Cox models are included in the nomogram, with a critical P value of .05. In order to evaluate the model's performance, Concordance index and receiver operating characteristic curves were used. Six independent risk factors affecting SLNM were screened out from the Logistic regression, including tumor location, number of regional lymph nodes (2-5), ER positive, PR positive, tumor size (T2-3), and histological grade (Grade II-III) are independent risk factors for SLNM in patients (P < .05). Eight prognostic factors were screened out in the multivariate COX regression analysis (P < .05): Age: Age 60 to 79 years, Age ≥ 80 years; Race; Histological grading: Grade II, Grade III; No radiotherapy; Tumor size: T2, T3; ER positive:, sentinel lymph node positive, married. Histological grade, tumor location, T stage, ER status, PR status and the number of SLNB are significantly correlated with axillary SLNM. Age, ethnicity, histological grade, radiotherapy, tumor size, ER status, SLN status, and marital status were independent risk factors for Breast cancer specific survival (BCSS). Moreover, the survival rate of patients with 3 positive SLNs was not significantly different from that with one or two positive SLNs, We concluded that patients with stage N1 breast cancer were exempt from axillary lymph node dissection, which is worthy of further study.

Artificial neural network based on strong track and square root UKF for INS/GNSS intelligence integrated system during GPS outage.

When INS/GNSS (inertial navigation system/global navigation satellite system) integrated system is applied, it will be affected by the insufficient number of visible satellites, and even the satellite signal will be lost completely. At this time, the positioning error of INS accumulates with time, and the navigation accuracy decreases rapidly. Therefore, in order to improve the performance of INS/GNSS integration during the satellite signals interruption, a novel learning algorithm for neural network has been presented and used for intelligence integrated system in this article. First of all, determine the input and output of neural network for intelligent integrated system and a nonlinear model for weighs updating during neural network learning has been established. Then, the neural network learning based on strong tracking and square root UKF (unscented Kalman filter) is proposed for iterations of the nonlinear model. In this algorithm, the square root of the state covariance matrix is used to replace the covariance matrix in the classical UKF to avoid the filter divergence caused by the negative definite state covariance matrix. Meanwhile, the strong tracking coefficient is introduced to adjust the filter gain in real-time and improve the tracking capability to mutation state. Finally, an improved calculation method of strong tracking coefficient is presented to reduce the computational complexity in this algorithm. The results of the simulation test and the field-positioning data show that the proposed learning algorithm could improve the calculation stability and robustness of neural network. Therefore, the error accumulation of INS/GNSS integration is effectively compensated, and then the positioning accuracy of INS/GNSS intelligence integrated system has been improved.

DSM and Optimization of Multihop Smart Grid Based on Genetic Algorithm.

Multihop smart grid is built on the basis of an integrated and high-speed communication network. Through the application of advanced sensing and measurement technology, equipment technology, control method, and advanced decision support system technology, the goal of reliable, safe, economic, efficient, environment-friendly, and safe use of the power grid is realized. In order to solve the problem of excessive demand for power supply, new energy power generation and demand response are proposed. According to the above background, the demand side economic scheduling problem is a complex optimization problem, which is difficult to be solved by ordinary algorithms. The adaptive global search algorithm based on a genetic algorithm can better solve complex optimization problems. The genetic algorithm proposed in this paper can effectively manage a large number of controllable loads in the selected area. The algorithm minimizes the cost and peak to the average ratio by changing the load. Home users can arrange their maximum load when the price is low. The peak load of residential buildings decreased from 98.5 kw/h to 90 kw/h, and the peak load decreased by about 7.53%. Through appropriate load dispatching, users minimize the daily electricity charge, which is reduced from 1352 yuan to 1245 yuan per day, and the daily electricity charge is reduced by about 7.25%. In addition, the advanced measurement, communication, and control means under the framework of the smart grid also play a key role in promoting all aspects of demand side management (DSM).

Analysis and fabrication of a small-scale radio-frequency balun for magnetic resonance imaging amplifier.

In this study, the authors report the design and fabrication of a small mixed-integrated balun for magnetic resonance imaging (MRI). The device was designed by using the positive anti-symmetric coupling method, which applies the lump surface-mount technology capacitors as well as mirror-symmetric coupling strips that were etched on the top and bottom layers of a printed circuit board. The capacitors reduced the length of the coupling strips and compensated for imbalances in the phase and gain due to errors in the fabrication process. The structure and equivalent even-odd circuit model of the device was modeled and examined using commercial software to optimize the design parameters. Following this, the device was fabricated and its performance was assessed through measurements using a network analyzer. The results showed that imbalances in the gain and phase were lower than 0.1 dB and 1°, respectively, and the insertion loss and the input voltage standing-wave ratio (VSWR) were lower than 0.4 dB and -25 dB, respectively. More importantly, the device was small, with dimensions of 50 × 60 × 1.5 mm. This makes it suitable for MRI applications involving highly integrated miniaturized systems. The proposed device was integrated into a 3.0 T radio-frequency power amplifier (RFPA) and reduced the dimensions of its power modules by 20% compared with the traditional balun. Finally, the RFPA module was used in an 3.0T MRI system for imaging experiments, and the results showed that the balun can help obtain high-quality scanning images.

The correlation of leukocyte-specific protein 1 (LSP1) rs3817198(T>C) polymorphism with breast cancer: A meta-analysis.

BACKGROUND: Multiple studies have investigated the correlation of single nucleotide polymorphisms (SNPs) in leukocyte-specific protein 1 (LSP1) with susceptibility to breast cancer (BC) and have yielded inconsistent conclusions, particularly rs3817198(T > C). Consequently, we performed a meta-analysis to estimate this relationship more comprehensively. METHODS: Four databases were utilized to locate eligible publications: PubMed, Embase, Web of Science, and China National Knowledge Infrastructure. This meta-analysis included 14 studies, including 22 reports of 33194 cases and 36661 controls. The relationship of rs3817198 polymorphism with breast cancer was estimated using odds ratios (ORs) with 95% confidence intervals (CIs). The LSP1 co-expression network was constructed by STRING, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using DAVIDE. Download TCGA breast cancer mRNA-seq data and analyze the relationship between LSP1 expression and breast cancer chemotherapy sensitivity. RESULTS: The results indicated that rs3817198(T > C) was positively correlated to with breast malignancy (dominant model: OR = 1.11, 95%CI = 1.06-1.17; recessive model: OR = 1.10, 95%CI = 1.04-1.15; heterozygous model: OR = 1.09, 95%CI = 1.04-1.15; homozygous model: OR = 1.18, 95%CI = 1.09-1.28; additive model: OR = 1.09, 95%CI = 1.05-1.13), among Caucasians and Asians. However, rs3817198(T > C) may reduce the risk of breast carcinoma in Africans. Rs3817198(T > C) might result in breast carcinoma in individuals with BRCA1 and BRCA2 variants and can contribute to estrogen receptor (ER)-positive breast carcinoma. The expression of LSP1 was inversely correlated with the IC50 of doxorubicin (P = 8.91e-15, Cor = -0.23), 5-fluorouracil (P = 1.18e-22, Cor = -0.29), and cisplatin (P = 1.35e-42, Cor = -0.40). CONCLUSION: Our study identified that LSP1 rs3817198 polymorphism might result in breast malignancy, particularly among Caucasians and Asians, but lower breast cancer susceptibility in African populations. The expression of LSP1 was negatively correlated with the IC50 of doxorubicin, 5-fluorouracil, and cisplatin.

The correlation of BTLA rs1982809 polymorphism with cancer susceptibility: A meta-analysis of 8634 participators.

BACKGROUND: The connection between B and T lymphocyte attenuator rs1982809 polymorphism and cancer risk has been investigated by several studies and yielded different results. Therefore, we adopted the meta-analysis method to assess the association of rs1982809 polymorphism with the susceptibility of cancers synthetically. METHODS: Eligible publications were gathered by retrieving PubMed, Web of Science, Embase, Wan Fang, and China National Knowledge Infrastructure. We utilized odds ratio (OR) and 95% confidence intervals (95% CI) to assess correlation intensity and performed subgroup analyses, sensitivity analyses, and publication bias assessments. RESULTS: Six researches that encompassed 3678 cases and 4866 controls were incorporated into our meta-analysis. The rs1982809 polymorphism was proved to be connected with cancer risk by the meta-analysis in the additive model (G vs A: OR = 1.11, 95% CI = 1.04-1.19, Pheterogeneity= .096). Subgroup analyses revealed that this SNP is regarded as a susceptible factor for cancers in the dominant, heterozygous, and additive model (AG + GG vs AA: OR = 1.46, 95% CI = 1.19-1.80, Pheterogeneity= .592; AG vs AA: OR = 1.47, 95% CI = 1.19-1.82, Pheterogeneity= .536; G vs A: OR = 1.32, 95% CI = 1.12-1.55, Pheterogeneity= .745) in Caucasians; And this SNP may increase the susceptibility to lung cancer (GG vs AG+AA: OR = 1.20, CI = 1.01-1.44, Pheterogeneity= .854; G vs A: OR = 1.17, CI = 1.02-1.33, Pheterogeneity= .232). CONCLUSION: The paper concludes that B and T lymphocyte attenuator rs1982809 polymorphism may contribute to cancers, especially in Caucasians, and it may associate with lung cancer.

Expression patterns and correlation analyses of muscle-specific genes in the process of sheep myoblast differentiation.

The purpose of this study was to establish a system for the isolation, culture, and differentiation of sheep myoblasts, and to explore the expression patterns as well as mutual relationships of muscle-specific genes. Sheep fetal myoblasts (SFMs) were isolated by two-step enzymatic digestion, purified by differential adhesion and identified using immunofluorescence techniques. Two percent horse serum was used to induce differentiation in SFMs. Real-time quantitative and Western blot analyses were respectively used to detect the mRNA and protein expressions of muscle-specific genes including MyoD, MyoG, Myf5, Myf6, PAX3, PAX7, myomaker, desmin, MYH1, MYH2, MYH4, MYH7, and MSTN during the differentiation of SFMs. Finally, the correlation between muscle-specific genes was analyzed by the Pearson correlation coefficient method. The results showed that the isolated and purified SFMs could form myotubes after the induction for differentiation. The marker factors including MyoD, MyoG, myomaker, desmin, and MyHC were positively stained in SFMs. The mRNA expressions of MyoD, MyoG, and myomaker increased and then decreased, while Myf5, PAX3, and PAX7 decreased; Myf6, desmin, MYH1, MYH2, MYH4, and MYH7 increased; and MSTN fluctuated up and down during the differentiation of SFMs. The expression patterns of protein were basically consistent with those of mRNA except MSTN. There existed significant or highly significant correlations at mRNA or protein level among some genes. Some transcription factor proteins (MyoD, Myf5, Myf6, PAX3, PAX7) showed significant or highly significant correlations with the mRNA level of some other genes and/or themselves. In conclusion, SFMs with good myogenic differentiation ability were successfully isolated, and the expression patterns and correlations of muscle-specific genes during SFM differentiation were revealed, which laid an important foundation for elucidating the gene regulation mechanism of sheep myogenesis.

A fast fault current calculation method for distribution networks connected with inverter interfaced distributed generators.

The integration of the inverter interfaced distributed generation (IIDG) challenges the conventional fault current calculation methods. The existing fault current calculation methods for distribution networks with IIDG connection generally use nodal admittance matrix and its implicit inverse, which take a longer calculation time and are not suitable for electrical engineering. To simplify the calculation process and reduce the calculation time, a new method was proposed. The new method can estimate fault currents of the feeders with IIDG connection with a higher computation speed, using fault current values obtained in networks without IIDG connection as the initial values in the procedure. The proposed method can obtain results without modifying the node impedance matrix and the calculation time was not affected by the nodes number, which can be used for fast short-circuit current calculation in radial distribution networks with IIDG connection. The new method can be conveniently integrated into software packages for power system analysis and relay protection evaluation.•The proposed method can estimate fault currents of the feeders with IIDG connection with a higher computation speed, which is beneficial for electrical engineering.•The new method has advantages in calculation time and accuracy of the results in comparison with the conventional bus-oriented methods.•The method proposed in this paper can be conveniently integrated into software packages for power system analysis and relay protection evaluation.

LncRNA NEAT1 accelerates breast cancer progression through regulating miR-410-3p/ CCND1 axis.

BACKGROUND: Breast cancer is the most common malignant tumor and usually occurs in women. Studies have shown that lncRNA nuclear enriched abundant transcript 1 (NEAT1) contributes to breast cancer progression. This study intends to further investigate the molecular mechanism of NEAT1 in breast cancer. METHODS: The expression levels of NEAT1, miR-410-3p and Cyclin D1 (CCND1) were detected by quantitative real-time PCR (qRT-PCR) in breast cancer tissues and cells. Kaplan-Meier analysis and the log-rank test were performed to determine the relationship between NEAT1 and overall survival. Cell Counting Kit-8 (CCK-8) assay analyzed cell proliferation. Transwell assay was performed to examine cell migration and invasion. The protein levels of CCND1 and epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, N-cadherin and Vimentin) were measured by western blot. The target relationship was predicted by bioinformatics analysis, and confirmed by luciferase reporter assay and RNA Immunoprecipitation (RIP) assay. Xenograft analysis was used to evaluate the tumor growth in vivo. RESULTS: NEAT1 and CCND1 were upregulated, while miR-410-3p was down-regulated in breast cancer tissues and cells. Higher NEAT1 expression level was associated with lower survival rate of breast cancer patients. Knockdown of miR-410-3p restored silenced NEAT1-mediated the inhibition of on proliferation, migration, invasion and EMT of breast cancer cells. In addition, NEAT1 regulated CCND1 expression by sponging miR-410-3p in breast cancer cells. NEAT1 knockdown blocked the tumor growth in vivo. CONCLUSION: NEAT1 induced breast cancer progression by regulating the miR-410-3p/CCND1 axis, indicating that NEAT1 may be a potential therapeutic target in breast cancer.

Histone Deacetylation 10 Alleviates Inflammation After Intracerebral Hemorrhage via the PTPN22/NLRP3 Pathway in Rats.

The NOD-like receptor family Pyrin domain-containing 3 (NLRP3) inflammasome has a crucial role in the inflammatory process that occurs during intracerebral hemorrhage (ICH)-induced injury. Histone deacetylase 10 (HDAC10) is a newly identified class II histone deacetylase involved in immune responses. However, how HDAC10 affects the inflammatory response after ICH remains unknown. In this study, we investigated whether HDAC10 relieves ICH injury by suppressing NLRP3 inflammasome activation through the protein tyrosine phosphatase, nonreceptor type 22 (PTPN22) pathway. We induced ICH in Sprague-Dawley rats (healthy, male adult) with a single infusion of autologous blood. To knockdown HDAC10, we injected siRNA into the rats. To further explore the mechanisms underlying the role of HDAC10 in ICH injury, PTPN22 was silenced. HDAC10 levels were upregulated after ICH in humans and rats, and reached peak levels 24 h after ICH induction in rats. HDAC10 silencing aggravated ICH injury, as demonstrated by increased modified neurological severity scores, brain water content, Evans blue extravasation, and number of myeloperoxidase (MPO) cells, and the results of Nissl and H&E staining. Furthermore, HDAC10 knockdown increased the expression of PTPN22 and accentuated inflammatory responses mediated by the NLRP3 inflammasome. HDAC10 silencing increased NLRP3 inflammasome activation, and this was effectively reversed by PTPN22 knockdown using siRNA. Furthermore, HDAC10 silencing also promoted the interaction of PTPN22 and NLRP3. Our study demonstrated that HDAC10 silencing aggravated NLRP3-mediated inflammatory responses after ICH in rats via the PTPN22 pathway. These results suggest that regulating the NLRP3 inflammasome may be a novel method to ameliorate ICH injury.

Diagnosis and Treatment of Rheumatic Adverse Events Related to Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have completely changed the treatment of cancer, and they also can cause multiple organ immune-related adverse reactions (irAEs). Among them, rheumatic irAE is less common, mainly including inflammatory arthritis, rheumatic myalgia/giant cell arteritis, inflammatory myopathy, and Sjogren's syndrome. For oncologists, rheumatism is a relatively new field, and early diagnosis and treatment is very important, and we need to work closely with experienced rheumatologists. In this review, we focused on the incidence, clinical characteristics, and treatment strategies of rheumatic irAE.

Intratumoral injection of dendritic cells overexpressing interleukin­12 inhibits melanoma growth.

The present study aimed to investigate the antitumor effects of an intratumoral injection of dendritic cells (DCs) overexpressing interleukin-12 (IL­12) on melanoma. DCs, isolated from mouse spleen, were gene­modified using an IL­12 overexpression vector. Melanoma B6 cells were injected into C57BL/6 mice to generate tumors. Thereafter, DCs overexpressing IL­12 were injected into the tumors, and tumor volume was subsequently measured. Pathological changes in tumor tissue were detected by hematoxylin and eosin staining. The expression of interleukin-4 (IL­4) and IL­12 in tumors was measured by enzyme­linked immunosorbent assay, real­time PCR and western blotting. DCs were successfully isolated and a lentivirus vector expressing IL­12 was constructed. After intratumoral injection of phosphate­buffered saline (control group), tumor cells exhibited malignant growth; whereas tumors injected with DCs (DC group) or DCs + empty vector (DC + vector group) exhibited a small amount of inflammatory cell infiltration and limited areas of tissue necrosis. In contrast, tumors injected with DCs overexpressing IL­12 (DC + IL­12 group) displayed severe tissue necrosis, loss of cell structure, and inflammatory cell infiltration. Compared with the control group, the tumor volumes were significantly lower in the DC, the DC + vector and the DC + IL­12 groups, while the expression of IL­12 and IL­4 in the tumors was significantly higher. Importantly, the most marked changes in tumor volume and IL­12 and IL­4 expression were in the DC + IL­12 group, which were significantly greater than those in tumors treated with unmodified DCs. Hence, intratumoral injection of DCs overexpressing IL­12 exerted strong antitumor effects in melanoma, and biotherapy with DCs overexpressing IL­12 is a potential treatment strategy for melanoma.

Differential Expression of microRNAs in Medulloblastoma and the Potential Functional Consequences.

AIM: To identify differentially expressed microRNAs in medulloblastoma, and to investigate their biological function. MATERIAL AND METHODS: Differentially expressed microRNAs were identified using gene chips, and significantly different microRNAs were selected for verification using real time quantitative PCR. Potential target genes and their biological pathways were predicted by bioinformatics software. RESULTS: Our analysis identified two microRNAs, hsa-miR-208a-3p and hsa-miR-1207-5p, which were significantly downregulated in medulloblastoma. Bioinformatics analysis identified potential target genes in the Wnt and MAPK signaling pathways, including NLK, RAPGEF2, CACNA2D1, DUSP3, MAPK8IP3. CONCLUSION: Downregulation of hsa-miR-208a-3p and hsa-miR-1207-5p may be involved in the occurrence of medulloblastoma, through modulations of the Wnt and MAPK signaling pathways.

PI3K/AKT/Afadin signaling pathway contributes to pathological vascularization in glioblastomas.

Glioblastomas are brain tumors with extensive vascularization that are associated with tumor malignancy. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is activated in endothelial cell tumors, although its exact function in glioblastoma neovascularization is poorly characterized. The present study identified that endothelial cells derived from human glioblastomas exhibit increased permeability and motility compared with normal brain vascular endothelial cells. Furthermore, the phosphorylation of AKT was significantly induced in glioblastoma-derived endothelial cells and glioblastoma vessels. To the best of our knowledge, the present study demonstrated for the first time that the cell-cell adhesion junction protein Afadin is phosphorylated and re-localized in glioblastoma-derived endothelial cells, and the phosphorylation and re-localization of Afadin is PI3K/AKT pathway-dependent. AKT-mediated phosphorylation and re-localization of Afadin may be critically involved in the modulation of brain endothelial permeability and migration. Therapies targeting the PI3K/AKT/Afadin pathway may therefore be beneficial for reducing the angiogenic potential of glioblastoma.

Taxotere-induced elevated expression of IL8 in carcinoma-associated fibroblasts of breast invasive ductal cancer.

Breast cancer is the most common malignant tumor in women worldwide, and accounts for an estimated 29% of new cases and 15% of cancer-associated mortalities each year. Invasive ductal carcinoma represents 70-80% of all breast cancer cases, which are responsible for the majority of breast cancer fatalities. Though great progress has been made in understanding the tumorigenesis and development of breast cancer, problems surrounding treatment persist. It was previously reported that carcinoma-associated fibroblasts (CAFs) may be closely associated with chemotherapy resistance. In the present study, primary-cultured CAFs from surgically resected breast invasive ductal cancer tissues were prepared and tested to clarify the change of gene expression profile following treatment with 20 ng/ml Taxotere® for 24 h through microarray analysis. In addition, quantitative polymerase chain reaction and western blotting were performed to compare the gene and protein expression of the candidate gene in CAFs prior to and following Taxotere treatment. Based on the obtained data, 35 differentially expressed genes were identified, including ACTA2, ACTC1, ACTG, ALDH1B1, AMY1A, C5orf13, CNN1, CXCR7, DDAH1, FGF1, PDLIM3, MAMLD1, MYH11, OXTR, PDLIM5, RARRES1, SERPINA3, TRIL, C14orf43, C1orf51, CXCL12, CXCL2, EGR2, EGR3, IER3, interleukin (IL)8, IRF1, JUNB, MMP1, NAV2, NFKBIA, NFKBIZ, TRIB1, WNT16 and ZC3H12A. It was observed that the expression of the candidate gene IL8 in the CAFs of breast invasive cancer following treatment with Taxotere was increased (P<0.05). Overall, elevated expression of IL8 induced by Taxotere in CAFs potentially supports the association between IL8 and chemotherapy response.