PRMT5-PAK1 Signaling Participates in Metastasis and Is Associated With Poor Prognosis in Human Esophageal Carcinoma.

BACKGROUND/AIM: Protein arginine methyltransferase 5 (PRMT5), a member of the arginine methyltransferases, is an enzyme catalyzing the methylation of arginine residuals of histones and non-histone proteins to serve as one of many critical posttranslational modifications (PTMs). Phosphorylated P21-activated kinase 1 (p-PAK1), a serine/threonine protein kinase family member, is a cytoskeletal protein that plays a critical role in metastasis. We examined the expression of PRMT5 and PAK1 in esophageal squamous cell carcinoma (ESCC) and evaluated the correlation between PRMT5/p-PAK1 and both clinicopathological parameters and prognosis of ESCC patients. MATERIALS AND METHODS: 106 tumor tissues collected from ESCC patients were assessed for PRMT5 and PAK1 expression using immunohistochemistry. Pearson's correlation and Kaplan-Meier analysis were used to estimate the correlation with the clinicopathological parameters and effect on patient survival. Western blot analysis was used to determine the PRMT5/p-PAK1 protein expression. The wound healing assay was performed to assess the effect of PRMT5 on the migration of ESCC cells. RESULTS: PRMT5 is upregulated in ESCC and the level of PRMT5 is correlated with metastasis and can serve as an independent prognostic factor for overall survival (OS). PRMT5 knockdown remarkably inhibited ESCC cell migration with concomitantly reduced levels of phosphorylated PAK1 (p-PAK1) but not total PAK1. Kaplan-Meier analysis showed that the OS of the subgroup of patients with PRMT5high/p-PAK1high is remarkably shorter than those of other subgroups (i.e., PRMT5high/p-PAK1low, PRMT5low/p-PAK1low and PRMT5low/p-PAK1high). CONCLUSION: PRMT5-PAK1 signaling participates in ESCC metastasis and can predict patients' outcomes.

Identification of solute carrier family genes related to the prognosis and tumor-infiltrating immune cells of pancreatic ductal adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) has persisted as one of the worst prognostic tumors with a 5-year survival rate of lower than 6%. Although many studies have investigated PDAC, new biomarkers are required to ensure early diagnosis and predict the prognosis of PDAC. Methods: In this study, we used bioinformatics methods to evaluate differences in the expression of solute carrier (SLC) family genes in tumors and non-tumors. A Kaplan-Meier analysis, least absolute shrinkage and selection operator (LASSO) analysis, and multivariate Cox proportional hazards regression analysis were used to evaluate the relationship between SLC genes and prognosis using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. The prognostic signature was constructed depending on the risk score to assess the impact of multiple genes on the prognosis, receiver operating characteristic (ROC) curves and forest plot was constructed to assess the ability to predict the prognosis and effects of clinical variables in both high- and low-risk groups. Tumor-infiltrating immune cells were evaluated using Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) in both high- and low-risk groups. Results: In 32 SLC genes, 9 were significantly associated with the OS after LASSO analysis. SLC19A3 (P=0.007), SLC25A39 (P=0.027), SLC39A11 (P=0.043) were significantly associated with prognosis and included into the prognostic model. CIBERSORT demonstrated that memory B cells (P=0.004), naive B cells (P=0.007), CD8 T cells (P=0.003), activated memory CD4 T cells (P=0.004), and activated NK cells (P=0.019) were significantly higher in the low-risk group. Gene set enrichment analysis (GSEA) showed that potential molecular mechanisms enriched in MYC and p53 signaling pathways. Conclusions: SLC19A3, SLC25A35, and SLC39A11 were significantly relative to the prognosis of PDAC and changed the tumor microenvironment, as well as the MYC and p53 signaling pathways. The SLC19A3 gene may represent a new tumor suppressor in PDAC.

Tumour budding is a novel marker in breast cancer: the clinical application and future prospects.

Breast cancer (BC) is a group of markedly heterogeneous tumours. There are many subtypes with different biological behaviours and clinicopathological characteristics, leading to significantly different prognosis. Despite significant advances in the treatment of BC, early metastatic is a critical factor for poor prognosis in BC patients. Tumour budding (TB) is considered as the first step process of tumour metastasis and is related to the epithelial-mesenchymal transition (EMT). TB has been observed in a variety of cancers, such as colorectal and gastric cancer, and had been considered as a distinct clinicopathological characteristics for early metastasis. However, TB evaluation standards and clinical application are not uniform in BC, as well as its molecular mechanism is not fully understood. Here, we reviewed the interpretation criteria, mechanism, clinicopathological characteristics and clinical application prospects of TB in BC. Key messagesCurrently, tumour budding is a poor prognosis for various solid tumours, also in breast cancer.Tumour budding is based on epithelial-mesenchymal transition and tumour microenvironment factors and is presumed to be an early step in the metastatic process.Breast cancer tumour budding still needs multi-centre experiments. We summarize the current research on breast cancer tumour budding, analyse the method of discriminating breast cancer tumour budding and explore the prognostic role and mechanism in breast cancer.

Clinical Impact of 11q13.3 Amplification on Immune Cell Infiltration and Prognosis in Breast Cancer.

Introduction: Amplification of the 11q13.3 locus has been observed in various tumors. This study sought to determine the correlation of gene amplification at the 11q13.3 locus with the immune status and survival of breast cancer. Methods: Amplification of the 11q13.3 locus was characterized by analyzing a publicly available database from the cBioPortal platform (TCGA). The correlation of amplified genes with immune cell infiltration in breast cancer was further analyzed using the TIMER2.0 platform. Immunohistochemical staining was used to determine the expression levels of Cyclin D1 (CCND1), Fas-associated death domain (FADD) and P53 in 156 clinical breast cancer samples. Results: This study revealed that amplification of the 11q13.3 amplicon in breast cancer is likely more frequently detected in luminal B breast cancer. Moreover, high expression or amplification of CCND1, fibroblast growth factor 3 (FGF3), fibroblast growth factor 4 (FGF4), fibroblast growth factor 19 (FGF19) and FADD was inversely correlated with the abundance of CD4+ T cells and dendritic cell infiltration in breast cancer (P < 0.05). Data analysis also demonstrated that high expression of CCND1, FGF4 and FADD mRNA levels was closely correlated with shorter recurrence-free survival (RFS) in patients with breast cancer (P < 0.05). The results of immunohistochemical staining from clinical samples further confirmed that high expression of CCND1 and FADD was frequently detected in luminal B and high-grade breast cancer with shorter metastasis-free survival times (P < 0.05). Conclusion: This study demonstrated that coamplification of genes located on the 11q13.3 amplicon is frequently detected in luminal B subtype breast cancer and is closely associated with worse survival in patients with breast cancer. Moreover, coamplification of the CCND1-FGF locus might decrease antitumor immune activity in breast cancer, indicating that coamplification of the 11q13.3 amplicon is likely to be a key determinant of therapeutic resistance and accelerate the aggressive evolution of breast cancer.

A comprehensive analysis of the expression and regulation network of lymphocyte-specific protein tyrosine kinase in breast cancer.

BACKGROUND: Lymphocyte-specific protein tyrosine kinase (LCK), an encoded Src family protein tyrosine kinase, performs a pivotal molecular signaling role in the selection and maturation processes during T-cell development. Although aberrant LCK expression is known to have a significant association with carcinogenesis, the underlying role of LCK in breast cancer (BC) is still obscure. METHODS: An analysis of the levels of LCK mRNA expression in BC was performed, and the value of LCK expression for predicting the prognosis of patients with BC was studied using various online data resources, which included Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), and UALCAN. The web-based NetworkAnalyst tool was utilized to investigate the functional network of differentially expressed LCK. LinkedOmics was employed to identify the genes with which LCK has correlations in BC, together with the kinases, microRNAs, and transcription factors (TFs) potentially targeted by LCK in BC. The expression levels of LCK and its significantly correlated genes in BC were investigated with the Human Protein Atlas (HPA). RESULTS: We observed a significant difference in the level of LCK mRNA expression between BC patients and healthy individuals, and a higher LCK expression was associated with poor overall survival (OS). The functional enrichment results revealed that the differential expression of LCK was mainly involved in the regulation of immune response and inflammatory response in BC. The expression of significantly related genes, such as inducible T-cell kinase (ITK), CD5, CD96, CD247, SH2 domain containing 1A (SH2D1A), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CD), Src-like-adaptor 2 (SLA2), and interleukin 2 receptor (IL2RG), was associated with poor OS in patients with BC. Regulatory network analysis found that LCK regulated immune cells, cancer progression, apoptosis, and cell cycle signal transduction through cancer-related kinases (ITK and MAPK3), miRNAs (miR-345 and miR-524), and TFs (AP1, SRF, and E2F1). CONCLUSIONS: This study presents new perspectives on the differential expression and prognostic value of LCK in BC. Our observations will provide a basis for further study on the oncogenic and regulatory roles of LCK in BC.

Classification and immune invasion analysis of breast cancer based on m6A genes.

BACKGROUND: Breast cancer (BRCA) shows genetic, epigenetic, and phenotypic diversity. Methylation of N6-methyladenosine (m6A) affects the occurrence, development, and therapeutic efficacy of BRCA. However, the characteristics and prognostic value of m6A in BRCA remain unclear. We aimed to classify and construct a scoring system for the m6A regulatory gene in BRCA, and to explore its potential mechanisms. METHODS: In this study, we selected 23 m6A regulatory genes and analyzed their genetic variation in BRCA, including copy number variation (CNV) data, expression differences, mutations, gene types, and correlations between genes. Survival curves were drawn by the Kaplan-Meier method, and a log-rank P<0.05 was considered statistically significant. The partitioning around medoids (PAM) algorithm was used for molecular subtype analysis of m6A, single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm was used to quantify the relative infiltration levels of various immune cell subgroups, and a scoring system was built based on principal component analysis (PCA). RESULTS: In BRCA, m6A regulatory gene mutation frequency is not high, while that of CNV mutation is high, which is related to gene expression and closely related to prognosis. In this study, we identified 3 different m6A subtypes, which are closely related to the level of immune cell infiltration. We further constructed an m6A score system, in which lower scores were correlated with low tumor mutation burden (TMB), later clinical staging, programmed cell death 1 ligand 1 (PD-L1) expression, and triple-negative breast cancer (TNBC). CONCLUSIONS: This study highlights the diversity and complexity of the role of m6A in BRCA. The classification of BRCA based on the m6A regulatory gene can help us understand the characteristics of BRCA and help develop individualized immunotherapy regimens.

Atractylodin may induce ferroptosis of human hepatocellular carcinoma cells.

BACKGROUND: It has been reported that atractylodin has a potential antitumor effect. This study aimed to investigate the effects of atractylodin on Huh7 and Hccm hepatocellular carcinoma (HCC) cells and its molecular mechanism. METHODS: Huh7 and Hccm cells were cultured in vitro, and their viability was detected by CCK-8 assay and the half inhibitory concentration (IC50) was calculated. The cells were treated with different concentrations of atractylodin, and the migration and invasion ability of cells was detected by scratch assay and Transwell assay. The cell cycle change and apoptosis rate were detected by flow cytometry. IlluminaHiSeq4000 platform was used for transcriptome sequencing, and the results were analyzed for gene differential expression, gene function, and signal pathway enrichment. Morphological changes of cells were detected by transmission electron microscopy, reactive oxygen species (ROS) levels were detected by DCFH-DA probe, and the expressions of ferroptosis related proteins GPX4, ACSL4, FTL, and TFR1 were detected by Western blot. RESULTS: The results showed that atractylodin could inhibit the proliferation, migration, and invasion of Huh7 and Hccm cells, regulate the cell cycle, and induce cell apoptosis and G1 phase cell cycle arrest. In addition, it could significantly induce the increase of intracellular ROS levels, decrease the expression of GPX4 and FTL proteins, and up-regulate the expression of ACSL4 and TFR1 proteins. CONCLUSIONS: Atractylodin can inhibit the proliferation, migration, and invasion of Huh7 and Hccm liver cancer cells, and induce cell apoptosis and cell cycle arrest. In addition, our results suggest that atractylodin may induce ferroptosis in HCC cells by inhibiting the expression of GPX4 and FTL proteins, and up-regulating the expression of ACSL4 and TFR1 proteins.

Laparoscopic versus open hepatectomy for hepatocellular carcinoma with cirrhosis: a single-center propensity score matching analysis.

BACKGROUND: Laparoscopic hepatectomy (LH) for hepatocellular carcinoma (HCC) remains controversial due to limited research. This study analyzed the oncology prognosis of patients who received LH treatment for HCC compared with conventional open hepatectomy (OH). METHODS: We conducted a retrospective analysis of patients with cirrhosis who underwent hepatectomy for HCC between 2012 and 2018. Patients were divided into LH and OH groups, and the oncology outcomes were compared before and after 1:1 propensity score matching (PSM). RESULTS: A total of 403 patients with HCC cirrhosis who received LH (n=112) and OH (n=291) were enrolled. After PSM, 106 pairs of patients were matched. Compared with OH before and after PSM, there was no significant difference in overall survival (OS) and relapse-free survival (RFS) between the two groups. Tumor stage, Child-Pugh classification, venous tumor thrombus, tumor size ≥5 cm, and microvascular invasion (MVI) were independent risk factors for postoperative OS in HCC patients with cirrhosis. Tumor size ≥5 cm and MVI were independent risk factors for RFS. CONCLUSIONS: Patients with HCC who underwent LH had a similar OS and RFS compared with those who received traditional open surgery. Therefore, LH can be used as a safe and feasible treatment for patients with HCC.

AQ-4, a deuterium-containing molecule, acts as a microtubule-targeting agent for cancer treatment.

The important physiological function of microtubules makes them an indispensable and clinically effective target of anti-tumor agents. Herein, we sought to design, synthesize, and evaluate a novel 4-anilinoquinazoline derivative and identify its anti-tumor activity in vitro and in vivo. The novel compound, N-(4-methoxyphenyl)-N-methyl-2-(methyl-d3)quinazolin-4-amine (AQ-4), was identified as a representative scaffold and potent microtubule-targeting agent. As a promising antimitotic agent, AQ-4 displayed remarkable anti-tumor activity with an average IC50 value of 19 nM across a panel of 14 human cancer cell lines. AQ-4 also exhibited nearly identical potent activities against drug-resistant cells, with no evidence of toxicity towards normal cells. A further target verification study revealed that AQ-4 targets the tubulin-microtubule system by significantly inhibiting tubulin polymerization and disrupting the intracellular microtubule spindle dynamics. According to the results of mechanism study, AQ-4 induced cell cycle arrest in the G2/M phase, promoting evident apoptosis and a collapses of mitochondrial membrane potential. The superior anti-tumor effect of AQ-4 in vivo suggests that it should be further investigated to validate its use for cancer therapy.

[Clinical study on modified sanmiao powder in treating chronic uric acid nephropathy].

OBJECTIVE: To investigate the clinical efficacy of modified Sanmiao Powder (SMP) in treating chronic uric acid nephropathy (CUAN). METHODS: Ninety-four patients with CUAN were equally randomized to the treated group and the control group. Conventional treatment was given to all patients and the treated group was administered with SMP additionally for 12 weeks. Changes of symptoms were observed, and laboratory indexes, as urinary protein quantity (UPro), urinary RBC count (URBC), urinary beta2 microglobulin (beta2-M), urinary beta-N-acetylglucosaminidase (NAG), blood urea nitrogen (BUN), serum creatine (SCr) and serum uric acid (SUA), were detected before and after treatment. RESULTS: The total effective rate in the treated group was 87.2% (41/47), and in the control group was 61.7% (21/47), showing significant difference between groups (P < 0.01); significant improvement of UPro, URBC, beta2-M, NAG, BUN, SCr and SUA were shown in the treated group (P < 0.05, P < 0.01); but in the control group, only URBC count was significantly decreased (P < 0.05), no statistically significant change of other indexes was found (P > 0.05). SUA decreased in both groups (P < 0.01), which was markedly lower in the treated group than in the control group (P < 0.05); SCr and BUN were also decreased in the treated group (P < 0.01). CONCLUSIONS: Combined therapy of SMP and conventional Western medicine shows a favorable effect in treating CUAN. It could not only reduce SUA, but also alleviate the albuminuria and hematuria, lower the urinary levels of beta2-M and NAG to improve renal function.

First-principles investigation of the interface magnetic anisotropy of Fe/SrTiO3.

Interface effects in magnetic nanostructures play a critical role in the magnetic properties. By using first-principles density functional theory calculations, we investigate the electronic and magnetic properties of Fe/SrTiO3 interfaces, in which both the nonpolar surface SrTiO3(0 0 1) and the polar surface SrTiO3(1 1 0) are considered. A particular emphasis is placed on the magnetic anisotropy energy (MAE). Comparing MAE of the Fe/SrTiO3 interfaces and the corresponding Fe monolayers, we find the Fe/SrTiO3(0 0 1) interface decreases MAE, while the Fe/SrTiO3(1 1 0) interface increases MAE. The interface orbital hybridization and orbital magnetic moments are analyzed in detail to understand the different interface magnetic anisotropy. Our investigation indicates that interface engineering can be an effective way to modulate the magnetic properties.

Ferroelectric control of Rashba spin orbit coupling at the GeTe(111)/InP(111) interface.

GeTe is a prototypical compound of a new class of multifunctional materials, i.e., ferroelectric Rashba semiconductors (FRS). In the present work, by combining the first-principles calculations and Rashba model analysis, we reexamine Rashba spin-orbit coupling (SOC) in a GeTe(111) crystal and clarify its linear Rashba SOC strength. We further investigate Rashba SOC at the interface of a GeTe(111)/InP(111) superlattice and demonstrate the ferroelectric manipulation of Rashba SOC in detail. A large modulation of Rashba SOC is obtained, and surprisingly, we find that Rashba SOC does not monotonically increase with the increase of ferroelectric displacement, due to the parabola opening reversal of Rashba splitting bands. In addition, a reversal of the spin texture is realized by tuning the ferroelectric polarization. Our investigation provides a deep insight into the ferroelectric control of Rashba SOC, which is of great importance in FRS spin field effect transistors.

Prevalence of psychological symptoms among Ebola survivors and healthcare workers during the 2014-2015 Ebola outbreak in Sierra Leone: a cross-sectional study.

The 2014-2015 Ebola epidemic was considered to be the largest and most complex outbreak, which caused 11,310 reported deaths. The epidemic disease can cause a mental health crisis, however, there is only a small amount of scientific literature available related to this health issue so far. We evaluated the psychological symptoms of 161 participants including Ebola survivors and healthcare workers in Sierra Leone, analyzed the impact of job classification, education level on psychological status. We found that the order of total general severity index (GSI) scores from high to low was EVD survivors, SL medical staff, SL logistic staff, SL medical students, and Chinese medical staff. There were 5 dimensions (obsession-compulsion, anxiety, hostility, phobic anxiety, and paranoid ideation) extremely high in EVD survivors. GSI were associated with university education negatively. We believed our information is necessary to develop the comprehensive emergency response plan for emerging infectious disease outbreak.

Clinical presentations and outcomes of patients with Ebola virus disease in Freetown, Sierra Leone.

BACKGROUND: Clinical and laboratory data were collected and analysed from patients with Ebola virus disease (EVD) in Jui Government Hospital in Freetown, Sierra Leone, where patients with EVD were received and/or treated from October 1, 2014 to March 21, 2015 during the West Africa EVD outbreak. METHODS: The study admitted 285 patients with confirmed EVD and followed them up till the endpoint (recovery or death). EVD was confirmed by quantitative RT-PCR assays detecting blood Ebola virus (EBOV). RESULTS: Among the 285 lab-confirmed EVD cases in Jui Government Hospital, 146 recovered and 139 died, with an overall survival rate of 51.23 %. Patients under the age of 6 years had a lower survival rate (37.50 %). Most non-survivors (79.86 %) died within 7 days after admission and the mean hospitalization time for non-survivors was 5.56 ± 6.11 days. More than half survivors (63.69 %) turned blood EBOV negative within 3 weeks after admission and the mean hospitalization time for survivors was 20.38 ± 7.58 days. High blood viral load (≥106 copies/ml) was found to be predictive of the non-survival outcome as indicated by the Receiver Operating Characteristic (ROC) curve analysis. The probability of patients' survival was less than 15 % when blood viral load was greater than 106 copies/ml. Multivariate analyses showed that blood viral load (P = 0.005), confusion (P = 0.010), abdominal pain (P = 0.003), conjunctivitis (P = 0.035), and vomiting (P = 0.004) were factors independently associated with the outcomes of EVD patients. CONCLUSIONS: Most death occurred within 1 week after admission, and patients at the age of 6 or younger had a lower survival rate. Most surviving patients turned blood EBOV negative within 1-4 weeks after admission. Factors such as high blood viral load, confusion, abdominal pain, vomiting and conjunctivitis were associated with poor prognosis for EVD patients.

Improvement of glucose and lipid metabolism with pegylated interferon-a plus ribavirin therapy in Chinese patients chronically infected with genotype 1b hepatitis C virus.

BACKGROUND: Many epidemiological studies have demonstrated a significant association between Type 2 diabetes mellitus and abnormal lipid profiles with chronic HCV genotype 1 (GT1) infection. We examined the impact on glucose and lipid profiles of treating Chinese patients using pegylated interferon (Peg-IFN)-a and ribavirin (RBV). METHODS: We conducted a hospital-based clinical study of Chinese patients chronically infected with GT1b HCV. All the patients were treated for 48 weeks (PR48) with Peg-IFN-a (180 micro g once per week) or Peg-IFN-a (1.5 micro g/kg once per week) plus RBV (15 mg/kg per day). Fasting blood glucose (FBG), postprandial blood glucose (PBG-2h), glycosylated hemoglobin (HbA1c), total cholesterol (TC) and triglyceride (TG) levels, were measured at baseline, during therapy, at the end of therapy and at follow-up. In addition, liver stiffness (LS) by transient elastography, HCV RNA and ALT levels were also measured. RESULTS: We enrolled 116 patients. At the end of treatment (EOT) (week 48), HCV RNA was negative in all patients, 77.6% (90/116) of patients achieved sustained virologic response (SVR) 24 weeks after EOT, and 22.4% (26/116) did not achieve SVR. All parameters associated with liver inflammation, liver fibrosis, glucose and lipid metabolism had decreased significantly compared with baseline (P < .05) in SVR patients. However, there were no obvious changes in lipid metabolism in non-SVR patients. CONCLUSION: PR48 therapy is still the primary treatment for Chinese patients with GT1b HCV infection and will remain so until oral anti-HCV agents are approved. It is beneficial in amelioration of liver histological status and glucose metabolism regardless of post-treatment virologic response.