Cytoplasmic localization of SETDB1­induced Warburg effect via c­MYC­LDHA axis enhances migration and invasion in breast carcinoma.

SET domain bifurcated 1 (SETDB1), a pivotal histone lysine methyltransferase, is transported to the cytoplasm via a chromosome region maintenance 1 (CMR1)­dependent pathway, contributing to non­histone methylation. However, the function and underlying mechanism of cytoplasmic SETDB1 in breast cancer remain elusive. In the present study, immunohistochemistry revealed that elevated cytoplasmic SETDB1 was correlated with lymph node metastasis and more aggressive breast cancer subtypes. Functionally, wound healing and Transwell assays showed that cytoplasmic SETDB1 is key for cell migration and invasion, as well as induction of epithelial­mesenchymal transition (EMT), which was reversed by leptomycin B (LMB, a CMR1 inhibitor) treatment. Furthermore, RNA­seq and metabolite detection revealed that cytoplasmic SETDB1 was associated with metabolism pathway and elevated levels of metabolites involved in the Warburg effect, including glucose, pyruvate, lactate and ATP. Immunoblotting and reverse transcription­quantitative PCR verified that elevation of cytoplasmic SETDB1 contributed to elevation of c­MYC expression and subsequent upregulation of lactate dehydrogenase A (LDHA) expression. Notably, gain­ and loss­of­function approaches revealed that LDHA overexpression in T47D cells enhanced migration and invasion by inducing EMT, while its depletion in SETDB1­overexpressing MCF7 cells reversed SETDB1­induced migration and invasion, as well as the Warburg effect and EMT. In conclusion, subcellular localization of cytoplasmic SETDB1 may be a pivotal factor in breast cancer progression. The present study offers valuable insight into the novel functions and mechanisms of cytoplasmic SETDB1.

Advancement and the existing landscape of forensic medicine in Africa: A comparison with developed countries.

This article explores the development and challenges of forensic medicine in Africa, comparing it to developed countries. It addresses limited resources, funding, and a shortage of trained professionals. The growth of forensic investigation capabilities and the challenges of funding and technology access are discussed. Training and education have improved, but disparities remain. Partnerships with developed countries and international organizations are crucial to bridge the gap. A comprehensive legal framework is important, but disparities exist among African countries. Harmonizing forensic laws would enhance cooperation. The role of forensic medicine in the criminal justice system is examined, emphasizing the need to build trust in forensic evidence. International collaboration and capacity building are key to advancing forensic medicine in Africa. Investments in infrastructure, funding, training, and legal frameworks are required. By leveraging partnerships, Africa can develop its forensic medicine capabilities for a fair and effective criminal justice system.

Integrated multi-omic analysis and experiment reveals the role of endoplasmic reticulum stress in lung adenocarcinoma.

BACKGROUND: Lung cancer is a highly prevalent malignancy worldwide and is associated with high mortality rates. While the involvement of endoplasmic reticulum (ER) stress in the development of lung adenocarcinoma (LUAD) has been established, the underlying mechanism remains unclear. METHODS: In this study, we utilized data from The Cancer Genome Atlas (TCGA) to identify differentially expressed endoplasmic reticulum stress-related genes (ERSRGs) between LUAD and normal tissues. We performed various bioinformatics analyses to investigate the biological functions of these ERSRGs. Using LASSO analysis and multivariate stepwise regression, we constructed a novel prognostic model based on the ERSRGs. We further validated the performance of the model using two independent datasets from the Gene Expression Omnibus (GEO). Additionally, we conducted functional enrichment analysis, immune checkpoint analysis, and immune infiltration analysis and drug sensitivity analysis of LUAD patients to explore the potential biological function of the model. Furthermore, we conducted a battery of experiments to verify the expression of ERSRGs in a real-world cohort. RESULTS: We identified 106 ERSRGs associated with LUAD, which allowed us to classify LUAD patients into two subtypes based on gene expression differences. Using six prognostic genes (NUPR1, RHBDD2, VCP, BAK1, EIF2AK3, MBTPS2), we constructed a prognostic model that exhibited excellent predictive performance in the training dataset and was successfully validated in two independent external datasets. The risk score derived from this model emerged as an independent prognostic factor for LUAD. Confirmation of the linkage between this risk model and immune infiltration was affirmed through the utilization of Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The q-PCR results verified significant differences in the expression of prognostic genes between cancer and paracancer tissues. Notably, the protein expression of NUPR1, as determined by immunohistochemistry (IHC), exhibited an opposite pattern compared to the mRNA expression patterns. CONCLUSION: This study establishes a novel prognostic model for LUAD based on six ER stress-related genes, facilitating the prediction of LUAD prognosis. Additionally, NUPR1 was identified as a potential regulator of stress in LUAD.

Circulating cell-free DNA correlate to disease activity and treatment response of patients with radiographic axial spondyloarthritis.

Microdamage and its related inflammation contribute to the development of radiographic axial spondyloarthritis (r-axSpA). Inflammation and cell death in damaged tissues are associated with cell-free DNA (cfDNA) release. Here we investigated whether circulating cfDNA could be a potential biomarker for evaluating disease activity and treatment response in r-axSpA. Circulating cfDNA was detected in the discovery and validation cohort with 79 and 60 newly diagnosed r-axSpA patients respectively and 42 healthy controls using the Quant-iT PicoGreen dsDNA reagent and kit. As a result, cfDNA levels were significantly higher in r-axSpA patients compared with healthy controls in the discovery and validation cohort. Moreover, cfDNA levels were positively correlated with CRP, ASDAS-CRP and neutrophil counts. Additionally, non-steroid anti-inflammatory drugs (NSAIDs) combined with disease-modifying anti-rheumatic drugs or tumor necrosis factor inhibitors but not NSAIDs alone could reduce cfDNA levels. Moreover, a decrease of cfDNA levels after treatment was associated with an effective therapeutic response. Intriguingly, patients with higher levels of cfDNA at diagnosis responded better to combination therapy rather than NSAIDs. However, patients with lower levels of cfDNA displayed similar responses to combination or mono-NSAID treatment. In conclusion, circulating cfDNA levels showed a significant correlation with disease activity as well as treatment efficacy in patients with r-axSpA. Moreover, cfDNA at diagnosis might predict the response to different therapy. Consequently, cfDNA may serve as a useful biomarker of inflammation in r-axSpA.

Actin filament-associated protein 1-antisense RNA1 promotes the development and invasion of tongue squamous cell carcinoma via the AFAP1-AS1/miR-133a-5p/ZIC2 axis.

BACKGROUND: The present study aimed to explore the biological role and underlying mechanism of the long non-coding RNA actin filament-associated protein 1-antisense RNA1 (lncRNA AFAP1-AS1) in the progression of tongue squamous cell carcinoma (TSCC). METHODS: A quantitative reverse transcriptase-PCR (RT-qPCR) was conducted to assess relative levels of the miR-133a-5p, lncRNAs AFAP1-AS1 and zinc finger family member 2 (ZIC2) in TSCC cell lines and specimens, whereas ZIC2 protein levels were measured using western blotting. After modifying the levels of expression of lncRNA AFP1-AS1, miR-133a-5p and ZIC2 using lentivirus or plasmid transfection, we examined AKT/epithelial-mesenchymal transition signaling pathway alterations, in vivo carcinogenesis of TSCC in nude mice and in vitro malignant phenotypes. A dual-luciferase reporter assay was conducted to confirm the targeting relationship between ZIC2 and miR-133a-5p, as well as between miR-133a-5p and lncRNA AFAP1-AS1. Based on The Cancer Genome Atlas (TCGA) database, we additionally validated AFP1-AS1. The potential biological pathway for AFP1-AS1 was investigated using gene set enrichment analysis (GSEA). We also evaluated the clinical diagnostic capacities of AFP1-AS1 and clustered the most potential biomarkers with the Mfuzz expression pattern. Finally, we also made relevant drug predictions for AFP1-AS1. RESULTS: In TSCC cell lines and specimens, lncRNA AFAP1-AS1 was upregulated. ZIC2 was upregulated in TSCC cells as a result of lncRNA AFAP1-AS1 overexpression, which also promoted TSCC cell migration, invasion, viability, and proliferation. Via the microRNA sponge effect, it was found that lncRNA AFAP1-AS1 could upregulate ZIC2 by competitively inhibiting miR-133a-5p. Interestingly, knockdown of ZIC2 reversed the biological roles of lncRNA AFAP1-AS1 with respect to inducing malignant phenotypes in TSCC cells. In addition, in vivo overexpression of lncRNA AFAP1-AS1 triggered subcutaneous tumor growth in nude mice implanted with TSCC cells and upregulated ZIC2 in the tumors. The TCGA database findings revealed that AFAP1-AS1 was significantly upregulated in TSCC specimens and had good clinical diagnostic value. The results of GSEA showed that peroxisome proliferator-activated receptor signaling pathway was significantly correlated with low expression of AFP1-AS1. Finally, the results of drug prediction indicated that the group with high AFAP1-AS1 expression was more sensitive to docetaxel, AZD4547, AZD7762 and nilotinib. CONCLUSIONS: The upregulation of lncRNA AFAP1-AS1, which increases TSCC cell viability, migration, proliferation and invasion via the AFAP1-AS1/miR-133a-5p/ZIC2 axis, aids in the progression of TSCC.

Novel Signaling Pathway and NSC689534 as a Potential Drug Candidate for Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy of the skin, and its incidence is increasing annually. Once cSCC becomes metastatic, its associated mortality rate is much higher than that of cSCC in situ. However, the current treatments for progressive cSCC have several limitations. The aim of this study was to suggest a potential compound for future research that may benefit patients with cSCC. METHODS: In this study, we screened the following differentially expressed genes from the Gene Expression Omnibus database: GSE42677, GSE45164, GSE66359, and GSE98767. Using strategies such as protein-protein interaction network analysis and the CYTOSCAPE plugin MCODE, key modules were identified and then verified by Western blotting. Subsequently, related signalling pathways were constituted in the SIGNOR database. Finally, molecular docking analyses and cell viability assay were used to identify a potential candidate drug and verify its growth inhibition ability to A431 cell line. RESULTS: Fifty-one common differentially expressed genes were screened and two key modules were identified. Among them, three core genes were extracted, constituting two signalling pathways, both of which belong to the module associated with mitotic spindles and cell division. A pathway involving CDK1, the TPX2-KIF11 complex, and spindle organization was validated in a series of analyses, including analyses for overall survival, genetic alteration, and molecular structure. Molecular docking analyses identified the pyridine 2-carbaldehyde thiosemicarbazone (NSC689534), which interacts with TPX2 and KIF11, as a potential candidate for the treatment of cSCC. CONCLUSIONS: NSC689534 might be a candidate drug for cSCC targeting TPX2 and KIF11, which are hub genes in cSCC.

ATRX is a predictive marker for endocrinotherapy and chemotherapy resistance in HER2-/HR+ breast cancer through the regulation of the AR, GLI3 and GATA2 transcriptional network.

Drug resistance in breast cancer (BC) is a clinical challenge. Exploring the mechanism and identifying a precise predictive biomarker for the drug resistance in BC is critical. Three first-line drug (paclitaxel, doxorubicin and tamoxifen) resistance datasets in BC from GEO were merged to obtain 1,461 differentially expressed genes for weighted correlation network analysis, resulting in identifying ATRX as the hub gene. ATRX is a chromatin remodelling protein, therefore, ATRX-associated transcription factors were explored, thereby identifying the network of AR, GLI3 and GATA2. GO and KEGG analyses revealed immunity, transcriptional regulation and endocrinotherapy/chemotherapy resistance were enriched. Moreover, CIBERSORT revealed immunity regulation was inhibited in the resistance group. ssGSEA showed a significantly lower immune status in the ATRX-Low group compared to the ATRX-High group. Furthermore, the peaks of H3K9me3 ChIP-seq on the four genes were higher in normal tissues than in BC tissues. Notably, the frequency of ATRX mutation was higher than BRCA in BC. Moreover, depressed ATRX revealed worse overall survival and disease-free survival in the human epidermal growth factor receptor 2 (HER2)-/hormone receptor (HR)+ BC. Additionally, depressed ATRX predicted poor results for patients who underwent endocrinotherapy or chemotherapy in the HER2-/HR+ BC subgroup. A nomogram based on ATRX, TILs and ER exhibited a significantly accurate survival prediction ability. Importantly, overexpression of ATRX significantly inhibited the IC50 of the three first-line drugs on MCF-7 cell. Thus, ATRX is an efficient predictive biomarker for endocrinotherapy and chemotherapy resistance in HER2-/HR+ BC and acts by suppressing the AR, GLI3 and GATA2 transcriptional network.

A novel tetraspanin-related gene signature for predicting prognosis and immune invasion status of lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD), the most common subtype of lung cancer, is the primary contributor to cancer-linked fatalities. Dysregulation in the proliferation of cells and death is primarily involved in its development. Recently, tetraspanins, a group of transmembrane proteins, have gained increasing attention for their potential role in the progression of LUAD. Hence, our endeavor involved the development of a novel tetraspanin-based model for the prognostication of lung cancer. METHODS: A comprehensive set of bioinformatics tools was utilized to evaluate the expression of tetraspanin-related genes and assess their significance regarding prognosis. Hence, a robust risk signature was established through machine learning. The prognosis-predictive value of the signature was evaluated in terms of clinical application, functional enrichment, and the immune landscape. RESULTS: The research first identified differential expression of tetraspanin genes in patients with LUAD via publicly available databases. The resulting data were indicative of the value that nine of them held regarding prognosis. Five distinct elements were utilized in the establishment of a tetraspanin-related model (TSPAN7, TSPAN11, TSPAN14, UPK1B, and UPK1A). Furthermore, as per the median risk scores, the participants were classified into high- and low-risk groups. The model was validated using inner and outer validation sets. Notably, consensus clustering and prognostic score grouping analysis revealed that tetraspanin-related features affect tumor prognosis by modulating tumor immunity. A nomogram based on the tetraspanin gene was constructed with the aim of enhancing the poor prognosis of high-risk groups and facilitating clinical application. CONCLUSION: Through machine learning algorithms and in vitro experiments, a novel tetraspanin-associated signature was developed and validated for survival prediction in patients with LUAD that reflects tumor immune infiltration. This could potentially provide new and improved measures for diagnosis and therapeutic interventions for LUAD.

The Role of Nomogram Based on the Combination of Ultrasound Parameters and Clinical Indicators in the Degree of Pathological Remission of Breast Cancer.

Background: The mortality rate of breast cancer (BC) ranks first among female tumors worldwide and presents a trend of younger age, which poses a great threat to women's health and life. Neoadjuvant chemotherapy (NAC) for breast cancer is defined as the first step of treatment for breast cancer patients without distant metastasis before planned surgical treatment or local treatment with surgery and radiotherapy. According to the current NCCN guidelines, patients with different molecular types of BC should receive neoadjuvant chemotherapy (NAC), which can not only achieve tumor downstaging, increase the chance of surgery, and improve the breast-conserving rate. In addition, it can identify new genetic pathways and drugs related to cancer, improve patient survival rate, and make new progress in breast cancer management. Objective: To explore the role of the nomogram established by the combination of ultrasound parameters and clinical indicators in the degree of pathological remission of breast cancer. Methods: A total of 147 breast cancer patients who received neoadjuvant chemotherapy and elective surgery in the Department of Ultrasound, Nantong Cancer Hospital, from May 2014 to August 2021 were retrospectively included. Postoperative pathological remission was divided into two groups according to Miller-Payne classification: no significant remission group (NMHR group, n = 93) and significant remission group (MHR group, n = 54). Clinical characteristics of patients were recorded and collected. The multivariate logistic regression model was used to screen the information features related to the MHR group, and then, a nomogram model was constructed; ROC curve area, consistency index (C-index, CI), calibration curve, and H-L test were used to evaluate the model. And the decision curve is used to compare the net income of the single model and composite model. Results: Among 147 breast cancer patients, 54 (36.7%) had pathological remission. Multivariate logistic regression showed that ER, reduction/disappearance of strong echo halo, Adler classification after NAC, PR + CR, and morphological changes were independent risk factors for pathological remission (P < 0.05). Based on these factors, the nomogram was constructed and verified. The area under the curve (AUC) and CI were 0.966, the sensitivity and specificity were 96.15% and 92.31%, and the positive predictive value (PPV) and negative predictive value (NPV) were 87.72% and 97.15%, respectively. The mean absolute error of the agreement between the predicted value and the real value is 0.026, and the predicted risk is close to the actual risk. In the range of HRT of about 0.0∼0.9, the net benefit of the composite evaluation model is higher than that of the single model. H-L test results showed that χ 2 = 8.430, P=0.393 > 0.05. Conclusion: The nomogram model established by combining the changes of ultrasound parameters and clinical indicators is a practical and convenient prediction model, which has a certain value in predicting the degree of pathological remission after neoadjuvant chemotherapy.

Predictive value of lactate dehydrogenase combined with the abbreviated burn severity index for acute kidney injury and mortality in severe burn patients.

BACKGROUND: Extensive burns are devastating trauma. This study aimed to explore the predictive value of early lactate dehydrogenase (LDH) level, the abbreviated burn severity index (ABSI) and their combination on acute kidney injury (AKI) and mortality after severe burns. METHODS AND RESULTS: 194 severe burn patients (TBSA ≥ 30%) were included. After multivariate analyses, early LDH value (first 24 h after admission) was an independent risk factor for early AKI (OR=1.095, CI,1.025-1.169,p = 0.007) and AKI (OR=1.452, CI,1.131-1.864, p = 0.003) in severe burn patients and was still a significant risk factor for mortality (OR=1.059, CI,1.006-1.115，p = 0.03). In ROC analysis, after combining LDH and ABSI, the AUC values were 0.925 for AKI, 0.926 for stage 3 AKI, and 0.904 for mortality. Based on cut-off values, patients were divided into different risk groups. The cumulative incidence of AKI (within 5 days, 30 days) and survival rate (within 60 days) were analyzed by the Kaplan-Meier method. The mortality, AKI incidence, and AKI staging showed a significant upward trend with the increasing risk level (P < 0.001). CONCLUSION: Early LDH level is an independent risk factor for early AKI and AKI. LDH combined with ABSI can better predict mortality and AKI than single indicators.

Psilocin suppresses methamphetamine-induced hyperlocomotion and acquisition of conditioned place preference via D2R-mediated ERK signaling.

AIM: Psilocin is an active metabolite form of psilocybin and exerts psychoactive effects. Recent studies suggest that psilocin may have regulatory effects on abuse drugs, but the mechanisms remain unclear. In this study, we want to explore the effects of psilocin on methamphetamine (METH)-induced alterations of behavior in mice and its molecular mechanisms. METHODS: Acute METH administration model and conditioned place preference (CPP) model were used to investigate the effects of psilocin on METH-induced alterations of behavior. Western blot was used to detect the expression of proteins. RESULTS: In the acute 2 mg/kg METH administration model, 1 mg/kg psilocin counteracted METH-induced elevation of activity. In the 1 mg/kg METH-induced CPP model, 1 mg/kg psilocin inhibited CPP formation during the acquisition phase. However, psilocin did not impact METH extinction and relapse. Molecular results showed that the regulatory effect of psilocin on METH was underscored by altered expression of dopamine 2 receptor (D2R) and phosphorylated extra-cellular signal-regulated kinase (p-ERK) in the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). Trifluoperazine (TFP)-2HCl is a D2R inhibitor, and SCH772984 is a selective extra-cellular signal-regulated kinase (ERK) inhibitor that effectively inhibits ERK1/2 phosphorylation. The results indicated that 2 mg/kg TFP-2HCl and 10 mg/kg SCH772984 blocked METH-induced hyperactivity and acquisition of METH-induced CPP. CONCLUSION: Psilocin has regulatory effects on METH-induced alterations of behavior in mice via D2R-mediated signal regulation of ERK phosphorylation.

Regulatory Fibroblast-Like Synoviocytes Cell Membrane Coated Nanoparticles: A Novel Targeted Therapy for Rheumatoid Arthritis.

Fibroblast-like synoviocytes (FLS) are the main cell component in the inflamed joints of patients with rheumatoid arthritis (RA). FLS intimately interact with infiltrating T cells. Fibroblasts have potent inhibitory effects on T cells, leading to the resolution of inflammation and immune tolerance. However, this "regulatory" phenotype is defect in RA, and FLS in RA instead act as "proinflammatory" phenotype mediating inflammation perpetuation. Signals that orchestrate fibroblast heterogeneity remain unclear. Here, it is demonstrated that different cytokines can induce distinct phenotypes of FLS. Interferon-gamma (IFN-γ) is pivotal in inducing the regulatory phenotype of FLS (which is termed FLSreg ) characterized by high expressions of several inhibitory molecules. Rapamycin enhances the effect of IFN-γ on FLS. Based on the characteristics of FLSreg , a novel biomimetic therapeutic strategy for RA is designed by coating cell membrane derived from FLSreg induced by IFN-γ and rapamycin on nanoparticles, which is called FIRN. FIRN show good efficacy, stability, and inflammatory joint targeting ability in an RA mouse model. The findings clarify how fibroblast phenotypes are modulated in the inflammatory microenvironment and provide insights into novel therapeutic designs for autoimmune diseases based on regulatory fibroblasts.

The roles of K+-dependent Na+/Ca2+ exchanger 2 (NCKX2) in methamphetamine-induced behavioral sensitization and conditioned place preference in mice.

Drug addiction, including methamphetamine (METH) addiction, is a significant public health and social issue. Perturbations in intracellular Ca2+ homeostasis are associated with drug addiction. K+-dependent Na+/Ca2+ exchanger 2 (NCKX2) is located on neuronal cell membranes and constitutes a Ca2+ clearance mechanism, with key roles in synaptic plasticity. NCKX2 is associated with motor learning, memory, and cognitive functions. However, the role of NCKX2 in METH addiction remains unclear. In this study, we investigated the expression levels of NCKX2 in four addiction-related brain regions: the prefrontal cortex (PFc), nucleus accumbens (NAc), dorsal striatum (DS), and hippocampus (Hip) in a C57/BL6 mouse model of METH-induced conditioned place preference (CPP) and behavioral sensitization. Levels of NCKX2 were unchanged in these brain regions in mice with METH-induced CPP but were decreased in the PFc and NAc of mice with METH-induced behavioral sensitization. Adeno-associated virus (AAV)-mediated overexpression of NCKX2 in the PFc attenuated the expression phase of METH-induced behavioral sensitization in mice, whereas AAV-mediated knockdown of NCKX2 enhanced the effects of METH. Collectively, our results suggest that NCKX2 is involved in METH-induced behavioral sensitization but does not affect conditioned reward-related memory, highlighting the potential of NCKX2 as a molecular target for studying the mechanisms underscoring METH addiction.

Association between antinuclear antibody and female infertility: A meta-analysis.

Autoimmunity is reported involving in reproductive failures, and antinuclear antibody (ANA) positivity has been regarded as a typical feature of autoimmunity. Published studies on the association of ANA with reproductive failures including infertility are controversial. The aim of this meta-analysis was to analyse whether the presence of ANA positivity increases the risk of infertility in women. We searched the PubMed and Embase databases for relevant literature without any restrictions prior to April 28, 2021. All analyses were performed using the RevMan 5.3 software. Twelve studies with 2734 participants, including 1482 patients with infertility, met the inclusion and exclusion criteria. The total positivity rate of ANA was 23.8% (353/1482) in all infertile patients and 8.5% (107/1252) in the control group. Infertile females had a significantly higher ANA positivity rate than the control group (odds ratio [OR] = 2.90, 95% confidence interval [CI]: 1.72-4.87, I2 = 65%, P < .0001). Several subgroup analyses were performed to reduce the heterogeneity. ANA positivity was associated with female infertility in studies either performed by indirect immunofluorescence (OR = 2.26, 95% CI:1.67-3.06, P < .00001) or by ELISA (OR = 10.76, 95% CI:1.82-63.64, P < .00001). ANA was significantly associated with increased risk of women infertility either after the definite exclusion of individuals with autoimmune diseases (AID) or without exclusion [(OR = 1.99, 95% CI:1.29-3.06, P = .002), (OR = 2.76, 95% CI:1.56-4.88, P = .0005), respectively]. This meta-analysis provides a comprehensive overview of the prevalence of antinuclear antibodies (ANA) in infertile women and suggests that ANA positivity increases the risk of infertility.

Identification and validation of novel biomarker TRIM8 related to cervical cancer.

Background: Cervical cancer, as a common gynecological disease, endangers female health. Give the lack of effective biomarkers for the diagnosis and treatment of cervical cancer, this paper aims to analyze the Gene Expression Omnibus (GEO) data sets using comprehensive bioinformatics tools, and to identify biomarkers associated with the cancer in patient samples. Methods: The bioinformatics methods were used to extract genes related to cervical cancer from GSE39001, while the GEO2R online tool to elaborate on differentially expressed genes (DEGs) in normal and cancer samples, and to clarify related genes and functions. The results were verified by IHC, WB, CCK-8, clone formation and flow cytometry experiments. Results: A total of 2,859 DEGs were identified in the GEO microarray dataset. We extracted genes associated with both ubiquitination and autophagy from the key modules of weighted gene co-expression network analysis (WGCNA), and the analysis showed that TRIM8 was of great significance for the diagnosis and prognosis of cervical cancer. Besides, experimental validation showed the high TRIM8 expression in cervical cancer, as well as its involvement in the proliferation of cervical cancer cells. Conclusion: We identified a biomarker (TRIM8) that may be related to cervical cancer through a series of analyses on the GEO dataset. Experimental verification confirmed the inhibition of cervical cancer cells proliferation by lowering TRIM8 expression. Therefore, TRIM8 can be adopted as a new biomarker of cervical cancer to develop new therapeutic targets.

Screening of the Key Genes for the Progression of Liver Cirrhosis to Hepatocellular Carcinoma Based on Bioinformatics.

Hepatocellular carcinoma (HCC), which is among the most globally prevalent cancers, is strongly associated with liver cirrhosis. Using a bioinformatics approach, we have identified and investigated the hub genes responsible for the progression of cirrhosis into HCC. We analyzed the Gene Expression Omnibus (GEO) microarray datasets, GSE25097 and GSE17549, to identify differentially expressed genes (DEGs) in these two conditions and also performed protein-protein interaction (PPI) network analysis. STRING database and Cytoscape software were used to analyze the modules and locate hub genes following which the connections between hub genes and the transition from cirrhosis to HCC, progression of HCC, and prognosis of HCC were investigated. We used the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis to detect the molecular mechanisms underlying the action of the primary hub genes. In all, 239 DEGs were obtained, with 94 of them showing evidence of upregulation and 145 showing evidence of downregulation in HCC tissues as compared to cirrhotic liver tissues. We identified six hub genes, namely, BUB1B, NUSAP1, TTK, HMMR, CCNA2, and KIF2C, which were upregulated and had a high diagnostic value for HCC. Besides, these six hub genes were positively related to immune cell infiltration. Since these genes may play a direct role in the progression of cirrhosis to HCC, they can be considered as potential novel molecular indicators for the onset and development of HCC.

Mechanisms underlying microRNA-222-3p modulation of methamphetamine-induced conditioned place preference in the nucleus accumbens in mice.

RATIONALE: MicroRNA (miRNA) control of post-transcription gene expression in the nucleus accumbens (NAc) has been implicated in methamphetamine (METH) dependence. Conditioned place preference (CPP) is a classical animal procedure that reflects the rewarding effects of addictive drugs. miR-222-3p has been reported to play a key role in various neurological diseases and is strongly associated with alcohol dependence. Nevertheless, the role of miR-222-3p in METH dependence remains unclear. OBJECTIVE: To explore the molecular mechanisms underlying the role of miR-222-3p in the NAc in METH-induced CPP. METHODS: miR-222-3p expression in the NAc of METH-induced CPP mice was detected by quantitative real-time (qPCR). Following adeno-associated virus (AAV)-mediated overexpression or knockdown of miR-222-3p in the NAc, mice were subjected to CPP to investigate the effects of miR-222-3p on METH-induced CPP. Target genes of mir-222-3p were predicted using bioinformatics analysis. Candidate target genes for METH-induced CPP were validated by qPCR. RESULTS: miR-222-3p expression in the NAc was decreased in CPP mice. Overexpression of miR-222-3p in the NAc blunted METH-induced CPP. Ppp3r1, Cdkn1c, Fmr1, and PPARGC1A were identified as target gene transcripts potentially mediating the effects of miR-222-3p on METH-induced CPP. CONCLUSION: Our results highlight miR-222-3p as a key epigenetic regulator in METH-induced CPP and suggest a potential role for miR-222-3p in the regulation of METH-induced reward-related changes in the brain.

Predictive value of indicator of CA125 combined with D-dimer (ICD) for lymph node metastasis in patients with ovarian cancer: A two center cohort study.

Background: The clinical serum markers CA125 and D-dimer have been reported to predict lymph node metastasis(LNM) in several malignant tumors, but the reports in ovarian cancer(OC) are still absent. The purpose of this study was to explore the value of indicator CA125 combined with D-dimer (ICD) in predicting LNM in patients with OC. Methods: A total of 447 patients diagnosed with OC from January 2008 to June 2019 were included in this retrospective study as the training set. A total of 284 patients were included in the validation set. The optimal cut-off critical value of ICD was evaluated by the receiver operating characteristic curve (ROC), and the maximum Youden index (sensitivity + specificity-1). Univariate and multivariate analysis were used to evaluate ICD as a predictor of LNM in OC. Results: According to ROC curve, area under curve (AUC) of ICD (AUC=0.706, p<0.001) was significantly larger than that of CA125 (AUC=0.671, p<0.001) and D-dimer (AUC=0.562, p=0.022) alone. Multivariate analysis showed that ICD (HR 2.651, 95% CI 1.273-5.520, p=0.009) was an independent predictor of LNM and overall survival (OS) in OC. It has also been verified in another medical center. Conclusion: ICD is an independent predictor of LNM in ovarian cancers, which is helpful for clinicians to draw up individual treatment plans.

Bioinspired membrane-based nanomodulators for immunotherapy of autoimmune and infectious diseases.

Autoimmune or infectious diseases often instigate the undesirable damages to tissues or organs to trigger immune-related diseases, which involve plenty of immune cells, pathogens and autoantibodies. Nanomedicine has a great potential in modulating immune system. Particularly, biomimetic nanomodulators can be designed for prevention, diagnosis and therapy to achieve a better targeted immunotherapy. With the development of materials science and bioengineering, a wide range of membrane-coated nanomodulators are available. Herein, we summarize recent advancements of bioinspired membrane-coated nanoplatform for systemic protection against immune-related diseases including autoimmune and infectious diseases. We also rethink the challenges or limitations in the progress of the therapeutic nanoplatform, and discuss the further application of the nanomodulators in the view of translational medicine for combating immune-related diseases.