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Chemoresistance in patients with glioblastoma multiforme (GBM) is a common reason hindering the success of treatment. Recently, ferroptosis has been reported to be associated with chemoresistance in different types of cancer, while the role of ferroptosis‐related genes in GBM have not been fully elucidated. This study aimed to demonstrate the roles and mechanism of ferroptosis‐related genes in chemoresistance and metastasis of GBM. First, two candidate genes, squalene epoxidase (SQLE) and FANCD2, were identified to be associated with ferroptosis‐related chemoresistance in GBM from three temozolomide (TMZ) therapeutic datasets and one ferroptosis‐related gene dataset. Then, comprehensive bio‐informatics data from different databases testified that SQLE was significantly downregulated both in GBM tissue and cells and displayed a better prognosis in GBM. Clinical data identified lower expression of SQLE was significantly associated with WHO grade and 1p/19q codeletion. Moreover, through in vitro experiments, SQLE was confirmed to suppress ERK‐mediated TMZ chemoresistance and metastasis of GBM cells. The KEGG analysis of SQLE‐associated co‐expressed genes indicated SQLE was potentially involved in the cell cycle. Furthermore, SQLE was found to have the most significant correlations with tumor‐infiltrating lymphocytes and immunomodulators. These findings highlighted that SQLE could be a potential target and a biomarker for therapy and prognosis of patients with GBM. [ABSTRACT FROM AUTHOR]

RET (rearranged during transfection), encoding a tyrosine kinase receptor, is a novel therapeutic target for cancers. The aberrations of RET are commonly found in cancers. Here, we profiled a comprehensive genomic landscape of RET mutations, copy number variants (CNVs), co-occurrence of RET and its mRNA expression and methylation levels in pan cancer, paving the way to the development of new RET-targeted therapies in clinic. Analysis of RET somatic mutations, CNVs, co-occurrence, mRNA expression and methylation were performed among 32 cancer types from The Cancer Genome Atlas (TCGA) dataset covering a total of 10,953 patients with 10,967 samples. RET aberrations were found in 3.0% of diverse cancers. The top two RET-altered tumors were skin cutaneous melanoma (SKCM) and uterine corpus endometrial carcinoma (UCEC) with dominant mutations in the other and PKinase_Tyr domains. RET-G823E and RET-S891L were most commonly found in SKCM and UCEC. Thyroid carcinoma (THCA) demonstrated the highest rate of coiled-coil domain containing 6 (CCDC6)-RET fusions, which constitutively activate RET kinase. Two FDA-approved RET inhibitors—pralsetinib and selpercatinib have been implied for the treatment of patients with RET S891L mutant UCEC and the treatment of patients with metastatic RET-fusion positive THCA and non-small cell lung cancer (NSCLC) at therapeutic level 1. We also identified four RET M918T-altered cases in patients with pheochromocytoma and paraganglioma (PCPG), which may induce drug resistance against multikinase inhibitors. Next, 273 co-occurring aberrations, most frequently in Notch signaling, TGF-β pathway, cell cycle, and Ras-Raf-MEK-Erk/JNK signaling, were uncovered among 311 RET altered cases. TP53 mutations (162 patients) leads to the most significant co-occurrence associated with RET aberrations. Furthermore, the RET expression was found most significantly increased in breast invasive carcinoma (BRCA) and neck squamous cell carcinoma (HNSC), as compared to their corresponding normal tissues. At last, patients with higher expression and sequence variant frequency have a worse prognosis, such as sarcoma patients. This work provided a profound and comprehensive analysis of RET and co-occurred alterations, RET mRNA expression and the clinical significance in pan cancer, offering new insights into targeted therapy for patients with RET anomalies. [ABSTRACT FROM AUTHOR]

The invasion capability of HCC cells was critically disrupted after the co-knockdown of BTBD7 and HIF-1 , and was moderately decreased when si-BTBD7 or si-HIF-1 was transfected separately (Figure S4). Luciferase assay proved that the transcriptional activity of BTBD7 was abolished under hypoxia by HRE2-mut (PGL3-BTBD7-581M) instead of HRE1-mut (PGL3-BTBD7-1000M) and HRE3-mut (PGL3-BTBD7-40M) (Figure 2C). Dear Editor, This study is the first to demonstrate that HIF-1 could activate BTBD7 under hypoxia, thus promoting HCC metastasis through tumor cell adhesion and EMT. Besides, the overexpression of BTBD7 or HIF-1 enhanced the invasion activity of HepG2 cells and exhibited a combined effect when BTBD7 and HIF-1 were co-overexpressed (Figure 2E). [Extracted from the article]

In the face of the batch, dynamic access data, or the flow of data that continuous changes over time, the traditional support vector machine algorithm cannot dynamically adjust the previous classification model. To overcome this shortcoming, the incremental support vector machine (ISVM) algorithm is proposed. However, many incremental support vector algorithms still have shortcomings such as low efficiency, memory limitation, and poor generalization. This paper puts forward the new ISVM algorithm, HDFC-ISVM ∗ algorithm, based on the high-dimensional distance and forgetting characteristics. This paper firstly proposes the original HDFC-ISVM algorithm that first learns the distribution characteristics of the samples according to the distance between the samples and the normative hyperplane. Then, it introduces the forgetting factor. In the incremental learning process, the classifier gradually accumulates the spatial distribution knowledge of samples, eliminates the samples that have no contributions to the classifier, and selectively forgets some useless samples according to the forgetting factor, which overcomes the shortcomings such as low efficiency and poor accuracy of some algorithms. But, the original HDFC-ISVM algorithm is sensitive to parameters, and different settings of the parameters have a great impact on the final classification accuracy of the algorithm. Therefore, on the basis of the original algorithm, an improved algorithm HDFC-ISVM ∗ based on the adjustments to the initialization strategy and updating rules of the forgetting factor is proposed. The initialization strategy and updating rules of the forgetting factor are adjusted to adapt datasets with different distributions in this improved algorithm. The rationality of the improved strategy about the forgetting factor is discussed theoretically. At the same time, the proposed algorithm has better classification accuracy, classification efficiency, and better generalization ability than other algorithms, which is verified by experiments. [ABSTRACT FROM AUTHOR]

Alterations of mitogen-activated protein kinase kinase 1 (MEK1) are commonly associated with tumorigenesis, and MEK1 is thought to be a suitable targeted therapy for various cancers. However, abnormal MEK1 alterations and their relevant clinical implications are unknown. Our research comprehensively analyzed the MEK1 alteration spectrum and provided novel insight for targeted therapies. There were 7694 samples covering 32 types of cancer from The Cancer Genome Atlas (TCGA) database. They were used to conduct an integrative analysis of MEK1 expression, alterations, functional impacts and clinical significance. There was a dramatic difference in the alteration frequency and distribution and clinical implications in 32 types of cancer from the TCGA. Skin cutaneous melanoma (SKCM) has the most alterations and has therapeutic targets located in the protein kinase domain, and the growing expression of SKCM is positively related to patient prognosis. MEK1 expression in lung adenocarcinoma (LUAD), kidney renal papillary cell carcinoma (KIRP), esophageal carcinoma (ESCA) and liver hepatocellular carcinoma (LIHC) is decreased, which is associated with better prognosis, while MEK1 expression in thymoma (THYM), stomach adenocarcinoma (STAD), kidney renal clear cell carcinoma (KIRC), testicular germ cell tumors (TGCTs) and head and neck squamous cell carcinoma (HNSC) is increased, which is associated with better prognosis. Mesothelioma (MESO) has the second highest alterations but has no therapy targets. This study provided a great and detailed interpretation of MEK1 expression, alterations and clinical implications in 32 types of cancer and reminded us to fill the gap in MEK1 research from a new perspective. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) function as critical regulators of gene expression and their deregulation is associated with the development and progression of various cancers. This study aimed to investigate the biological role and mechanism of miR-205 in ovarian cancer (OC). MiR-205 was upregulated in OC tissues and cells in comparison to the controls. Meanwhile, overexpression of miR-205 was significantly associated with poor overall survival of OC patients. Functional study indicated that ectopic expression of miR-205 significantly promoted cell proliferation, migration, invasion and chemoresistance of OC cells. SMAD4 and PTEN were identified as direct targets of miR-205 using luciferase reporter assays, real-time PCR (qRT-PCR), and western blot. Most interestingly, in vivo studies indicated that miR-205 markedly promoted the growth and metastasis of tumors and the expression of miR-205 was also found to be inversely correlated with that of SMAD4 and PTEN in nude mice. Overall, we suggest that miR-205 functions as an oncogenic miRNA by directly binding to SMAD4 and PTEN, providing a novel target for the molecular treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

CCN gene family members have recently been identified as multifunctional regulators involved in diverse biological functions, especially in vascular and skeletal development. In the present study, a comparative genomic and phylogenetic analysis was performed to show the similarities and differences in structure and function of CCNs from different organisms and to reveal their potential evolutionary relationship. First, CCN homologs of metazoans from different species were identified. Then we made multiple sequence alignments, MEME analysis, and functional sites prediction, which show the highly conserved structural features among CCN metazoans. The phylogenetic tree was further established, and thus CCNs were found undergoing extensive lineage-specific duplication events and lineage-specific expansion during the evolutionary process. Besides, comparative analysis about the genomic organization and chromosomal CCN gene surrounding indicated a clear orthologous relationship among these species counterparts. At last, based on these research results above, a potential evolutionary scenario was generated to overview the origin and evolution of the CCN gene family. [ABSTRACT FROM AUTHOR]

BRCA1 interacting helicase 1 (BRIP1) alteration was crucial in tumors and it was a potential therapeutic target in ovarian serous cystadenocarcinoma (OV). Although a small number of studies had focused on BRIP1, an extensive study of BRIP1 genetic mutation and its clinical application in different cancer types had not been analyzed. In the current study, we analyzed BRIP1 abnormal expression, methylation, mutation, and their clinical application via several extensive datasets, which covered over 10,000 tumor samples across more than 30 cancer types. The total mutation rate of BRIP1 was rare in pan cancer. Its alteration frequency, oncogenic effects, mutation, and therapeutic implications were different in each cancer. 242 BRIP1 mutations were found across 32 cancer types. UCEC had the highest alteration (mutation and CNV) frequency. In addition, BRIP1 was a crucial oncogenic factor in OV and BRCA. BRIP1 mutation in PRAD was targetable, and FDA had approved a new drug. Moreover, Kaplan–Meier curve analysis showed that BRIP1 expression and genetic aberrations were closely related to patient survival in several cancers, indicating their potential for application as new tumor markers and therapeutic targets. The current study profiled the total BRIP1 mutation spectrum and offered an extensive molecular outlook of BRIP1 in a pan cancer analysis. And it suggested a brand-new perspective for clinical cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer (OC) seriously threatens women's life. Ferroptosis plays an essential role in the initiation and development of OC. However, more molecular targets and mechanisms for ferroptosis in OC remain to be further elucidated.Methods: Several OC datasets were integrated in this study and three candidate genes including PRNP were further screened out as the ferroptosis-related gene which was differentially expressed in OC. Then, comprehensive evaluations concerning gene expression, clinical implication, in vitro validation of expression and functional experiments, prediction of downstream molecules and related signal pathways, and immune-modulating function were performed.Results: PRNP was the only downregulated ferroptosis-related gene with prognostic value for OC patients. The decreased mRNA and protein expression was verified in OC tissues and cell lines. PRNP was significantly correlated with cancer stages, primary therapy outcomes, and age in OC patients. Moreover, we found that overexpression of PRNP inhibited the proliferation, migration, and invasion ability of OC cells through in vitro experiments. PRNP was enriched to the Ras signaling pathway. PRNP expression was positively correlated with the infiltration of immune cells, such as mast cells, T effector memory cells, plasmacytoid DC cells, NK cells, and eosinophils. In addition, the association of PRNP with other immune signatures was also found.Conclusion: This study demonstrated for the first time showed that ferroptosis-related gene PRNP exerted a tumor suppressive role in OC and the aberrant expression and function of PRNP making it a potential novel biomarker for OC diagnosis, prognosis, and response to immunotherapies. [ABSTRACT FROM AUTHOR]

Previous studies in our laboratory have reported that miR-222-3p was a tumor-suppressive miRNA in OC. This study aims to further understand the regulatory role of miR-222-3p in OC and provide a new mechanism for its prevention and treatment. We first found that miR-222-3p inhibited the migration and proliferation of OC cells. Then, we observed CDK19 was highly expressed in OC and inversely correlated with miR-222-3p. Besides, we observed that miR-222-3p directly binds to the 3′-UTR of CDK19 and inhibits CDK19 translation, thus inhibiting OC cell migration and proliferation in vitro and repressed tumor growth in vivo. We also observed the inhibitory effect of Hotair on miR-222-3p in OC. In addition, Hotair could promote the proliferation and migration of OC cells in vitro and facilitate the growth and metastasis of tumors in vivo. Moreover, Hotair was positively correlated with CDK19 expression. These results suggest Hotair indirectly up-regulates CDK19 through sponging miR-222-3p, which enhances the malignant behavior of OC. This provides a further understanding of the mechanism of the occurrence and development of OC. [ABSTRACT FROM AUTHOR]

Background. All YTH domain family members are m6A reader proteins accounting for the methylation modulation involved in the process of tumorgenesis and tumor progression. However, the expression profiles and roles of the YTH domain family in lung adenocarcinoma (LUAD) remain to be further illustrated. Methods. GEPIA2 and TNMplot databases were used to generate the expression profiles of the YTH family. Kaplan-Meier plotter database was employed to analysis the prognostic value of the YTH family. Coexpression profiles and genetic alterations analysis of the YTH family were undertaken using the cBioPortal database. YTH family protein-associated protein-protein interaction (PPI) network was identified by using STRING. Functional enrichment analysis was performed with the help of the WebGestalt database. The correlation analysis between the YTH family and immune cell infiltration in LUAD was administrated by using the TIMER2.0 database. Results. mRNA expression of YTHDC1 and YTHDC2 was significantly lower in LUAD, whereas YTHDF1, YTHDF2, and YTHDF3 with apparently higher expression. YTHDF2 expression was observed to be the highest in the nonsmoker subgroup, and its expression gradually decreased with the increased severity of smoking habit. LUAD patients with low expression of YTHDC2, YTHDF1, and YTHDF2 were correlated with a better overall survival (OS) time. The YTHDF1 genetic alteration rate was 26%, which was the highest in the YTH family. The major cancer-associated functions of YTH family pointed in the direction of immunomodulation, especially antigen processing and presentation. Most of the YTH family members were significantly correlated with the infiltration of CD4+ T cells, CD8+ T cells, macrophages, and neutrophils, indicating the deep involvement of the YTH domain family in the immune cell infiltration in LUAD. Conclusion. The molecular and expression profiles of the YTH family were dysregulated in LUAD. YTH family members (especially YTHDC2) were promising biomarkers and potential therapeutic targets that may bring benefit for the patients with LUAD. [ABSTRACT FROM AUTHOR]

Highlights • Feeble effect of acute exposure to hypobaric hypoxia on learning and memory. • Increased antioxidative capacity appeared after simulation of hypobaric hypoxia. • Differences in expressions of NMDA receptors were related to altitude and duration. Abstract The present study aimed to observe the effects of acute exposure to hypobaric hypoxia on learning and memory in adult Sprague-Dawley (SD) rats as well as the changes in N-methyl-D-aspartate receptor (NMDAR) subunits. Learning and memory abilities were evaluated with Morris water maze following simulated hypoxia at 5000 m or 7000 m for 2, 4 or 6 days. The number of red blood cells, the level of hemoglobin, oxidative stress markers, the extent of neuronal damage in the hippocampal CA1, and the expression of NMDAR subunits were all measured. In place navigation test, the escape latency significantly increased only in the 5000 M 6Day (P < 0.05) group than the latency in the plain group on the fourth day. In the spatial probe test, the times of platform passing showed no significant difference between the hypoxia and plain groups. Polycythemia, an increased ratio of superoxide dismutase/malondialdehyde and degeneration of neurons appeared in an elevation-dependent and duration-dependent manner in those hypoxia groups. Furthermore, the protein expression of NR1 increased and the protein expression levels of NR2A, NR2B, and NR3A were all decreased in the 5000M 6Day and 7000M 6Day groups. In summary, the feeble effect of acute exposure to simulated hypobaric hypoxia on learning and memory in adult SD rats may be attributed to increased antioxidative capacities and decreased expression of NR3A. And moreover, differences in the expressions of NMDAR subunits were closely related to the altitude and duration. [ABSTRACT FROM AUTHOR]