The AAA-ATPase Yta4/ATAD1 interacts with the mitochondrial divisome to inhibit mitochondrial fission.

Mitochondria are in a constant balance of fusion and fission. Excessive fission or deficient fusion leads to mitochondrial fragmentation, causing mitochondrial dysfunction and physiological disorders. How the cell prevents excessive fission of mitochondria is not well understood. Here, we report that the fission yeast AAA-ATPase Yta4, which is the homolog of budding yeast Msp1 responsible for clearing mistargeted tail-anchored (TA) proteins on mitochondria, plays a critical role in preventing excessive mitochondrial fission. The absence of Yta4 leads to mild mitochondrial fragmentation in a Dnm1-dependent manner but severe mitochondrial fragmentation upon induction of mitochondrial depolarization. Overexpression of Yta4 delocalizes the receptor proteins of Dnm1, i.e., Fis1 (a TA protein) and Mdv1 (the bridging protein between Fis1 and Dnm1), from mitochondria and reduces the localization of Dnm1 to mitochondria. The effect of Yta4 overexpression on Fis1 and Mdv1, but not Dnm1, depends on the ATPase and translocase activities of Yta4. Moreover, Yta4 interacts with Dnm1, Mdv1, and Fis1. In addition, Yta4 competes with Dnm1 for binding Mdv1 and decreases the affinity of Dnm1 for GTP and inhibits Dnm1 assembly in vitro. These findings suggest a model, in which Yta4 inhibits mitochondrial fission by inhibiting the function of the mitochondrial divisome composed of Fis1, Mdv1, and Dnm1. Therefore, the present work reveals an uncharacterized molecular mechanism underlying the inhibition of mitochondrial fission.

IL-17 induces non-small cell lung cancer metastasis via GCN5-dependent SOX4 acetylation enhancing MMP9 gene transcription and expression.

Interleukin-17 (IL-17), a potent proinflammatory cytokine, can trigger the metastasis of non-small cell lung cancer (NSCLC). However, the underlying mechanism involved in IL-17-induced NSCLC cell metastasis remains unclear. In this study, we found that not only the expression of IL-17, IL-17RA, and/or general control nonrepressed protein 5 (GCN5), SRY-related HMG-BOX gene 4 (SOX4), and matrix metalloproteinase 9 (MMP9) was increased in the NSCLC tissues and in the IL-17-stimulated NSCLC cells, but also IL-17 treatment could enhance NSCLC cell migration and invasion. Further mechanism exploration revealed that IL-17-upregulated GCN5 and SOX4 could bind to the same region (-915 to -712 nt) of downstream MMP9 gene promoter driving its gene transcription. In the process, GCN5 could mediate SOX4 acetylation at lysine 118 (K118, a newly identified site) boosting MMP9 gene expression as well as cell migration and invasion. Moreover, the SOX4 acetylation or MMP9 induction and metastatic nodule number in the lung tissues of the BALB/c nude mice inoculated with the NSCLC cells stably infected by corresponding LV-shGCN5 or LV-shSOX4, LV-shMMP9 plus IL-17 incubation were markedly reduced. Overall, our findings implicate that NSCLC metastasis is closely associated with IL-17-GCN5-SOX4-MMP9 axis.

Sublytic C5b-9 triggers glomerular mesangial cell proliferation via enhancing FGF1 and PDGFα gene transcription mediated by GCN5-dependent SOX9 acetylation in rat Thy-1 nephritis.

Rat Thy-1 nephritis (Thy-1N) is an animal model of human mesangioproliferative glomerulonephritis (MsPGN), accompanied by glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) deposition. Although sublytic C5b-9 formed on GMC membrane could induce cell proliferation, the mechanism is still unclear. In this study, we first demonstrated that the level of SRY related HMG-BOX gene 9 (SOX9), general control nonderepressible 5 (GCN5), fibroblast growth factor 1 (FGF1) and platelet-derived growth factor α (PDGFα) was all elevated both in the renal tissues of Thy-1N rats (in vivo) and in the GMCs (in vitro) with sublytic C5b-9 stimulation. Then, we not only discovered that sublytic C5b-9 caused GMC proliferation through increasing SOX9, GCN5, FGF1 and PDGFα expression, but also proved that SOX9 and GCN5 formed a complex and combined with FGF1 and PDGFα promoters, leading to FGF1 and PDGFα gene transcription. More importantly, GCN5 could mediate SOX9 acetylation at lysine 62 (K62) to enhance SOX9 binding to FGF1 or PDGFα promoter and promote FGF1 or PDGFα synthesis and GMC proliferation. Besides, the experiments in vivo also showed that FGF1 and PDGFα expression, GMC proliferation and urinary protein secretion in Thy-1N rats were greatly reduced by silencing renal SOX9, GCN5, FGF1 or PDGFα gene. Furthermore, the renal tissues of MsPGN patients also exhibited positive expression of these genes mentioned above. Collectively, our findings indicate that GCN5, SOX9 and FGF1/PDGFα can form an axis and play an essential role in sublytic C5b-9-triggered GMC proliferation, which might provide a novel insight into the pathogenesis of Thy-1N and MsPGN.

De-differentiation associated with drop metastasis of a recurrent intracranial solitary fibrous tumor: a case report and literature review.

BACKGROUND: Central nervous system is a rare occurring location of solitary fibrous tumors (SFTs). SFTs have a potential for recurrence, which is the leading cause of death in patients with these disease entities. De-differentiation phenomenon combined with cerebrospinal fluid (CSF) dissemination through drop metastasis of STFs from intracranial to intraspinal has only been reported in extremely limited cases. CASE DESCRIPTION: Herein, we present a case of SFT in a 54-year old male. MRI showed characteristic of mixed high and low signal with 6.3 cm × 6.5 cm × 5.9 cm. After radical surgical resection, the pathology indicated benign SFT. However, MRI re-examination of 22 months later detected local recurrence, concomitant with spreading of intracranial and intraspinal through CSF dissemination. And interestingly, the second pathology found de-differentiation phenomenon and malignance of SFT, in which some areas transformed to rhabdomyosarcoma. CONCLUSION: This is the first case report of recurrent intracranial SFT de-differentiating to rhabdomyosarcoma concurrent with CSF pathway drop metastasis. Benign intracranial SFTs have the potential of de-differentiation, which may play an important role in its distant metastasis. The underlying molecular biological and pathological mechanisms of benign SFT malignance transformation still warrant further exploration.

Spontaneous acute epidural hematoma associated with chronic subdural hematoma due to dural metastasis of gastric carcinoma: a case report and literature review.

Background: Non-traumatic spontaneous acute epidural hematoma (EDH) happening to chronic subdural hematoma (SDH) caused by dural metastases is a rare entity. Pathogenesis can be derived from infection, coagulopathy, and inflammation. Malignant tumors metastasize to dura mater is one of the most infrequent causes. The exact mechanism remains elusive in spite of several possible speculations. The clinical manifestations, management and outcomes vary among reported cases.Case Description: A 45-year-old woman without history of trauma presented with headache, vomiting and disturbance of consciousness and developed brain hernia rapidly. On arival, she has lost into coma with Glasgow coma scale (GCS) score 5, bilateral pupils were not equal, with disappeared reflectance. Emergency imaging prompted large acute EDH, combined with SDH, arising from dural granular neoplasm confirmed intraoperatively. Four days after surgery, the bilateral pupils were equal in size and sensitive to light reflection.Conclusion: Dural metastases can cause EDH, chronic SDH can also be resulted from metastatic tumors of dura mater. When dealing with spontaneous non-traumatic hematoma around the dura mater, to make the precise diagnosis is sometimes doubtful and confusing. The stream of diagnostic thinking should be opened, including medical diseases such as liver and kidney disease, drug history, history of cancer and other possible clues. Thus, a detailed and purposeful systematic medical history review and physical examination is important in order to make more appropriate strategies for the clinic.

Analysis on the polymorphisms of site RS4977574, and RS1333045 in region 9p21 and the susceptibility of coronary heart disease in Chinese population.

BACKGROUND: Rs4977574 (A > G) and Rs1333045 (C > T) are both single nucleotide polymorphisms (SNPs) related with coronary artery disease, locating on chromosome 9p21.3. The study aimed to identify the correlation between rs4977574 and rs1333045 polymorphism genotypes and coronary heart disease (CHD) in a Chinese population. METHODS: Blood samples were collected from 855 subjects. A case-control study was used in this experiment, and 598 cases in the CHD group and 257 subjects in the control group were enrolled. Genotyping was identified by the Agena MassARRAY system. Statistical analysis was conducted by SPSS (Ver 16.0) and plink (Ver. 1.07, Shaun Purcell). Haplotype analysis was performed using Haploview software. RESULTS: Association analysis by plink indicated a significant difference in the allele distribution for single nucleotide polymorphisms between cases and controls (rs4977574 P = 0.003, rs1333045 P = 0.035). Fisher's exact test by plink proved that allele G may be associated with a higher risk of CHD (P = 0.003, odds ratio (OR) = 1.371) and the T allele was likely to reduce the risk of coronary events (P = 0.035, OR = 0.798). The serum levels of apolipoprotein A (ApoA) were higher in subjects with the AG + AA genotype of rs4977574 compared to those with the GG genotype (P = 0.028). In the dominant model of rs1333045, the levels of ApoA were higher and LDL levels were lower in the TC + TT genotype than in the CC genotype. CONCLUSIONS: The present study examined the association between the 9p21 chromosome rs4977574 and rs1333045 polymorphism genotypes and CHD in a population of Chinese patients. The G allele of rs4977574 and the C allele of rs1333045 are the susceptibility sites of CHD.

The effectiveness of quarantine of Wuhan city against the Corona Virus Disease 2019 (COVID-19): A well-mixed SEIR model analysis.

A novel coronavirus pneumonia, first identified in Wuhan City and referred to as COVID-19 by the World Health Organization, has been quickly spreading to other cities and countries. To control the epidemic, the Chinese government mandated a quarantine of the Wuhan city on January 23, 2020. To explore the effectiveness of the quarantine of the Wuhan city against this epidemic, transmission dynamics of COVID-19 have been estimated. A well-mixed "susceptible exposed infectious recovered" (SEIR) compartmental model was employed to describe the dynamics of the COVID-19 epidemic based on epidemiological characteristics of individuals, clinical progression of COVID-19, and quarantine intervention measures of the authority. Considering infected individuals as contagious during the latency period, the well-mixed SEIR model fitting results based on the assumed contact rate of latent individuals are within 6-18, which represented the possible impact of quarantine and isolation interventions on disease infections, whereas other parameter were suppose as unchanged under the current intervention. The present study shows that, by reducing the contact rate of latent individuals, interventions such as quarantine and isolation can effectively reduce the potential peak number of COVID-19 infections and delay the time of peak infection.

Sublytic C5b-9 Induces IL-23 and IL-36a Production by Glomerular Mesangial Cells via PCAF-Mediated KLF4 Acetylation in Rat Thy-1 Nephritis.

Sublytic C5b-9 formation on glomerular mesangial cells in rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis, is accompanied by the production of proinflammatory cytokines, but the relationship between sublytic C5b-9 and cytokine synthesis and the underlying mechanism remains unclear. To explore the problems mentioned above, in this study, we first examined the levels of proinflammatory ILs (e.g., IL-23 and IL-36a) as well as transcription factor (KLF4) and coactivator (PCAF) in the renal tissues of Thy-1N rats and in the glomerular mesangial cell line (HBZY-1) stimulated by sublytic C5b-9. Then, we further determined the role of KLF4 and PCAF in sublytic C5b-9-induced IL-23 and IL-36a production as well as the related mechanism. Our results showed that the levels of KLF4, PCAF, IL-23, and IL-36a were obviously elevated. Mechanistic investigation revealed that sublytic C5b-9 stimulation could increase IL-23 and IL-36a synthesis through KLF4 and PCAF upregulation, and KLF4 and PCAF could form a complex, binding to the IL-23 or IL-36a promoter in a KLF4-dependent manner, causing gene transcription. Importantly, KLF4 acetylation by PCAF contributed to sublytic C5b-9-induced IL-23 and IL-36a transcription. Besides, the KLF4 binding regions on IL-23 or IL-36a promoters and the KLF4 lysine site acetylated by PCAF were identified. Furthermore, silencing renal KLF4 or PCAF gene could significantly inhibit IL-23 or IL-36a secretion and tissue damage of Thy-1N rats. Collectively, these findings implicate that the KLF4/PCAF interaction and KLF4 acetylation by PCAF play a pivotal role in the sublytic C5b-9-mediated IL-23 and IL-36a production of Thy-1N rats.

Changes in oxidation-antioxidation function on the thymus of chickens infected with reticuloendotheliosis virus.

BACKGROUND: Reticuloendotheliosis virus (REV) is a retrovirus that causes severe immunosuppression in poultry. Animals grow slowly under conditions of oxidative stress. In addition, long-term oxidative stress can impair immune function, as well as accelerate aging and death. This study aimed to elucidate the pathogenesis of REV from the perspective of changes in oxidative-antioxidative function following REV infection. METHODS: A total of 80 one-day-old specific pathogen free (SPF) chickens were randomly divided into a control group (Group C) and an REV-infected group (Group I). The chickens in Group I received intraperitoneal injections of REV with 104.62/0.1 mL TCID50. Thymus was collected on day 1, 3, 7, 14, 21, 28, 35, and 49 for histopathology and assessed the status of oxidative stress. RESULTS: In chickens infected with REV, the levels of H2O2 and MDA in the thymus increased, the levels of TAC, SOD, CAT, and GPx1 decreased, and there was a reduction in CAT and Gpx1 mRNA expression compared with the control group. The thymus index was also significantly reduced. Morphological analysis showed that REV infection caused an increase in the thymic reticular endothelial cells, inflammatory cell infiltration, mitochondrial swelling, and nuclear damage. CONCLUSIONS: These results indicate that an increase in oxidative stress enhanced lipid peroxidation, markedly decreased antioxidant function, caused thymus atrophy, and immunosuppression in REV-infected chickens.

Association between circular RNA expression content and severity of coronary atherosclerosis in human coronary artery.

BACKGROUND: Circular RNAs (circRNAs) may act as biomarkers of coronary artery disease (CAD). However, the relationship between expression characteristics of circRNAs and coronary atherosclerosis has not been fully explored. The aim of this study was to determine and characterize the circRNAs from human coronary artery. METHODS: The coronary artery segments were obtained from an 81-year-old male patient with sudden death of myocardial infarction at autopsy. The coronary stenosis and atherosclerosis were evaluated by hematoxylin and eosin (H&E) staining, and the circRNAs expression profile was characterized by RNA sequencing (RNA-seq). The differentially expressed circRNAs were validated by qRT-PCR. RESULTS: The analysis of H&E staining indicated that coronary atherosclerosis grade and extent in the LM was more serious than that in other coronary arteries. Twenty-seven circRNAs were selected for expression validation in coronary artery. CircRNAs corresponding cyclization sites of 3 circRNAs (hsa_circ_0016868, hsa_circ_0001364, hsa_circ_0006731) have been verified by Sanger sequencing. CONCLUSION: The 3 circRNAs are suggested to play a pathological role underlying the coronary arteries atherosclerosis and may serve as a valuable resource as diagnostic or therapeutic targets against CAD.

Quantitative proteomics reveals the regulatory networks of circular RNA BTBD7_hsa_circ_0000563 in human coronary artery.

BACKGROUND: BTBD7_hsa_circ_0000563, which is located on chromosome 14, contains conserved binding sites with miR-155/130a and RNA-binding proteins according to bioinformatic prediction. We investigated the association of BTBD7_hsa_circ_0000563 expression in coronary artery segments with atherosclerotic stenosis and identified the proteome-wide BTBD7_hsa_circ_0000563-regulated proteins in human coronary artery. METHODS: The atherosclerotic grade and extent in coronary artery segments were determined by hematoxylin and eosin staining. BTBD7_hsa_circ_0000563 expression in eight coronary artery segments from one patient was quantified by RT-qPCR assay. A proteomic approach was adopted to reveal significant differences in protein expression between among four groups differing in their BTBD7_hsa_circ_0000563 expression levels. RESULTS: The RT-qPCR assay revealed that coronary artery segments with severe atherosclerotic stenosis had significantly low BTBD7_hsa_circ_0000563 levels. The proteomic analysis identified 49 differentially expressed proteins among the segment groups with different BTBD7_hsa_circ_0000563 expression levels, of which 10 were downregulated and 39 were upregulated with increases in the BTBD7_hsa_circ_0000563 level. The 10 downregulated proteins were P61626 (LYSC_HUMAN), P02760 (AMBP_HUMAN), Q02985 (FHR3_HUMAN), P01701 (LV151_HUMAN), P06312(KV401_HUMAN), P01624 (KV315_HUMAN), P13671 (CO6_HUMAN), P01700(LV147_HUMAN), Q9Y287(ITM2B_HUMAN), and A0A075B6I0 (LV861_HUMAN). The top 10 upregulated proteins were Q92552 (RT27_HUMAN), Q9UJY1(HSPB8_HUMAN), Q9Y235(ABEC2_HUMAN), P19022 (CADH2_HUMAN), O43837(IDH3B_HUMAN), Q9H479(FN3K_HUMAN), Q9UM22(EPDR1_HUMAN), P48681(NEST_HUMAN), Q9NRP0(OSTC_HUMAN), and Q15628(TRADD_HUMAN). CONCLUSION: BTBD7_hsa_circ_0000563 is involved in the atherosclerotic changes in human coronary artery segments. Verification, mechanistic, and function studies are needed to confirm whether patients with coronary artery disease would benefit from such personalized medicine in the future.

Sublytic C5b-9 induces proliferation of glomerular mesangial cells via ERK5/MZF1/RGC-32 axis activated by FBXO28-TRAF6 complex.

Mesangioproliferative glomerulonephritis (MsPGN) is characterized by the proliferation of glomerular mesangial cells (GMCs) and accumulation of extracellular matrix (ECM), followed by glomerulosclerosis and renal failure of patients. Although our previous studies have demonstrated that sublytic C5b-9 complex formed on the GMC membrane could trigger GMC proliferation and ECM expansion of rat Thy-1 nephritis (Thy-1N) as an animal model of MsPGN, their mechanisms are still not fully elucidated. In the present studies, we found that the levels of response gene to complement 32 (RGC-32), myeloid zinc finger 1 (MZF1), phosphorylated extracellular signal-regulated kinase 5 (phosphorylated ERK5, p-ERK5), F-box only protein 28 (FBXO28) and TNF receptor-associated factor 6 (TRAF6) were all markedly up-regulated both in the renal tissues of rats with Thy-1N (in vivo) and in the GMCs upon sublytic C5b-9 stimulation (in vitro). Further in vitro experiments revealed that up-regulated FBXO28 and TRAF6 could form protein complex binding to ERK5 and enhance ERK5 K63-ubiquitination and subsequent phosphorylation. Subsequently, ERK5 activation contributed to MZF1 expression and MZF1-dependent RGC-32 up-regulation, finally resulting in GMC proliferative response. Furthermore, the MZF1-binding element within RGC-32 promoter and the functions of FBXO28 domains were identified. Additionally, knockdown of renal FBXO28, TRAF6, ERK5, MZF1 and RGC-32 genes respectively markedly reduced GMC proliferation and ECM production in Thy-1N rats. Together, these findings indicate that sublytic C5b-9 induces GMC proliferative changes in rat Thy-1N through ERK5/MZF1/RGC-32 axis activated by the FBXO28-TRAF6 complex, which might provide a new insight into MsPGN pathogenesis.

Sublytic C5b-9 Induces Glomerular Mesangial Cell Apoptosis through the Cascade Pathway of MEKK2-p38 MAPK-IRF-1-TRADD-Caspase 8 in Rat Thy-1 Nephritis.

The apoptosis of glomerular mesangial cells (GMCs) in the early phase of rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis (MsPGN), is primarily triggered by sublytic C5b-9. However, the mechanism of GMC apoptosis induced by sublytic C5b-9 remains unclear. In this study, we demonstrate that expressions of TNFR1-associated death domain-containing protein (TRADD) and IFN regulatory factor-1 (IRF-1) were simultaneously upregulated in the renal tissue of Thy-1N rats (in vivo) and in GMCs under sublytic C5b-9 stimulation (in vitro). In vitro, TRADD was confirmed to be a downstream gene of IRF-1, because IRF-1 could bind to TRADD gene promoter to promote its transcription, leading to caspase 8 activation and GMC apoptosis. Increased phosphorylation of p38 MAPK was verified to contribute to IRF-1 and TRADD production and caspase 8 activation, as well as to GMC apoptosis induced by sublytic C5b-9. Furthermore, phosphorylation of MEK kinase 2 (MEKK2) mediated p38 MAPK activation. More importantly, three sites (Ser153/164/239) of MEKK2 phosphorylation were identified and demonstrated to be necessary for p38 MAPK activation. In addition, silencing of renal MEKK2, IRF-1, and TRADD genes or inhibition of p38 MAPK activation in vivo had obvious inhibitory effects on GMC apoptosis, secondary proliferation, and urinary protein secretion in rats with Thy-1N. Collectively, these findings indicate that the cascade axis of MEKK2-p38 MAPK-IRF-1-TRADD-caspase 8 may play an important role in GMC apoptosis following exposure to sublytic C5b-9 in rat Thy-1N.

Sublytic C5b-9 Induces Glomerular Mesangial Cell Apoptosis Through miR-3546/SOX4/Survivin Axis in Rat Thy-1 Nephritis.

BACKGROUND/AIMS: The activation of complement system and the formation of C5b-9 complex have been confirmed in the glomeruli of patients with mesangioproliferative glomerulonephritis (MsPGN). However, the role and mechanism of C5b-9-induced injury in glomerular mesangial cell (GMC) are poorly understood. Rat Thy-1N is an animal model for studying MsPGN. It has been revealed that the attack of C5b-9 to the GMC in rat Thy-1N is sublytic, and sublytic C5b-9 can cause GMC apoptosis, but the underlying mechanism is not fully elucidated. To explore the role and regulatory mechanism of C5b-9 in MsPGN lesion, we used rat Thy-1N model and first detected the change of microRNA (miRNA) profiles both in Thy-1N rat renal tissues (in vivo) and in the cultured GMCs with sublytic C5b-9 stimulation (in vitro). Then we determined the effect of miR-3546, which increased both in vivo and in vitro, on GMC apoptosis upon sublytic C5b-9 as well as the involved mechanism. METHODS: Rat Thy-1N model was established and GMCs were treated with sublytic C5b-9. The rat renal cortex and the stimulated GMCs were obtained for miRNA microarray detection. Subsequently, the increased miRNAs were verified by real-time PCR. Meanwhile, to ascertain the ability of some miRNAs to upregulate cleaved caspase 3 and induce GMC apoptosis, the corresponding miRNA mimics were transfected into GMCs, followed by western blotting (WB) and flow cytometry mesurement. Thereafter, the miR-3546-targeted gene (SOX4) was predicted using bioinformatics approaches, and SOX4 expression in Thy-1N tissues and in the GMCs upon sublytic C5b-9 stimulation or miR-3546 mimic/inhibitor transfection were detected using real-time PCR and WB. To prove that miR-3546 can affect SOX4 gene transcription and SOX4 can regulate survivin expression, dual luciferase reporter assay, real-time PCR, WB and chromatin immunoprecipitation (ChIP) assays were performed. Furthermore, the role of miR-3546/SOX4/survivin axis in the GMC apoptosis induced by sublytic C5b-9 was examined using WB and flow cytometry. RESULTS: Compared with normal renal tissues and untreated GMCs, there were 43 and 62 upregulated miRNAs (> 2-fold) in Thy-1N tissues and sublytic C5b-9-stimulated GMCs respectively. A total of 17 miRNAs were increased both in vivo and in vitro, 11 of which were validated by real-time PCR. Among them, miR-3546 could markedly promote GMC apoptosis and inhibit SOX4 or survivin expression in response to sublytic C5b-9, and either SOX4 or survivin overexpression markedly rescued the GMC apoptosis mediated by miR-3546 mimic. Additionally, SOX4 overexpression could reverse the survivin suppression by miR-3546 mimic, and SOX4 could bind to survivin promoter (-1,278 to -853 nt) and activate survivin gene transcription. CONCLUSION: MiR-3546/ SOX4/survivin axis has a promoting role in the GMC apoptosis triggered by sublytic C5b-9, and our findings may provide a new insight into the pathogenesis of rat Thy-1N and human MsPGN.

LINC01510 suppresses cell proliferation and invasion by inhibiting Wnt/ß-catenin signaling in renal cell carcinoma.

The role of long non-coding RNA in Renal cell carcinoma (RCC) tumorigenesis and progression remains largely unknown. Here, we found that LINC01510 functions as a tumor suppressor in RCC tumorigenesis. We screened TCGA database and then found that LINC01510 is significantly down-regulated in malignant RCC tissues, and the lower expression of LINC01510 predicts poor prognosis. Moreover, the down-regulated LINC01510 was further confirmed in our fresh tissues and cell lines. Biological functions assays shown that Ectopic expression of LINC01510 not only inhibits RCC cell proliferation both in vitro and in vivo, but also impairs cell invasion ability. Moreover, we found overexpression of LINC01510 inhibits the expression of CCND1 and CCNE1, as well as MMPs (MMP2, MMP7 and MMP9), and thus affecting RCC cell cycle and invasion. Meanwhile, Western blot assays revealed that the expression of ß-catenin is regulated by LINC01510; overexpression of ß-catenin could partly rescue the cell viability and invasion ability caused by ectopic expression of LINC01510. Taken together, we found that LINC01510 regulates cell proliferation and invasion by modulating Wnt/ß-catenin signaling in RCC.

Correlation of VEGF and EGFR in peripheral blood with clinical stage and pathological grade of renal cell carcinoma and analysis of prognosis.

PURPOSE: To detect the expression of VEGF and EGFR in peripheral blood and cancer tissues of patients with renal cell carcinoma (RCC), and to explore the correlations with clinical stage, pathological grade and prognosis of disease. METHODS: A total of 64 patients with RCC who were diagnosed and treated from June 2016 to August 2017 in our hospital were enrolled. Patients were divided into different clinical stages and pathological grades, and ELISA and immunohistochemistry were used to detect the expression of VEGF and EGFR in peripheral blood. Peripheral blood was also taken from 24 healthy individuals to serve as control group. Real-time fluorescence quantitative PCR (qRT-PCR) was used to detect the expression of VEGF and EGFR in RCC tissues and paracancer tissues. All patients were followed up after discharge to record their survival. RESULTS: Significant differences in the expression levels of VEGF and EGFR were found between stage III and IV (p<0.05), but not between stage I and II. Expressions level of VEGF and EGFR in serum of well-differentiated, moderatelydifferentiated, and poorly-differentiated RCC were all higher than those in the healthy control group, and significant differences were found between different pathological grades (p<0.05). Patients with higher expression levels of VEGF and EGFR showed shorter survival compared to patients with lower expression levels (p<0.05). CONCLUSION: VEGF and EGFR in peripheral blood can be used as one of the effective indicators of prognosis of RCC. Our study provided reference for clinical treatment and prediction of prognosis of RCC.

KLF15 Inhibits Cell Proliferation in Gastric Cancer Cells via Up-Regulating CDKN1A/p21 and CDKN1C/p57 Expression.

BACKGROUND: Krüppel-like factors (KLFs) have been identified in multi-cancers and act as oncogenes or tumor suppressors. The function of KLF15, one member of KLFs, has not been well elucidated, especially in gastric cancer (GC). AIMS: This study was designed to investigate the prognostic value and biological functions of KLF15 in GC. METHODS: KLF15 protein expression in GC patients was evaluated by immunohistochemistry assays in 50 paired GC tissues and adjacent normal tissues, and correlations between KLF15 expression and clinicopathological characteristics and prognosis were analyzed. Then, we investigated the over-expression of KLF15 on cell proliferation and its mechanism in GC cells. RESULTS: KLF15 expression levels were significantly down-regulated in GC tissues compared to adjacent normal tissues. And KLF15 expression was negatively correlated with clinical stage, lymphatic metastasis, and distant metastasis. Furthermore, KLF15 expression could predict prognosis in patients with GC. Moreover, over-expression of KLF15 could inhibit cell proliferation partly via regulating CDKN1A/p21 and CDKN1C/p57. CONCLUSION: These findings demonstrate that KLF15 plays a significant role in GC progression and could be a therapeutic target for GC.

Preoperative Computed Tomography Assessment for Perinephric Fat Invasion: Comparison With Pathological Staging.

OBJECTIVE: The aim of this study was to assess the accuracy of computed tomography (CT) imaging in diagnosing perinephric fat (PNF) invasion in patients with renal cell carcinoma. METHODS: We retrospectively reviewed the medical records and preoperative CT images of 161 patients (105 men and 56 women) for pT1-pT3a renal cell carcinoma. We analyzed the predictive accuracy of CT criteria for PNF invasion stratified by tumor size. We determined the predictive value of CT findings in diagnosing PNF invasion using logistic regression analysis. RESULTS: The overall accuracy of perinephric (PN) soft-tissue stranding, peritumoral vascularity, increased density of the PNF, tumoral margin, and contrast-enhancing soft-tissue nodule to predict PNF invasion were 56%, 59%, 35%, 80%, and 87%, respectively. Perinephric soft-tissue stranding and peritumoral vascularity showed high sensitivity but low specificity regardless of tumor size. A contrast-enhancing soft-tissue nodule showed low sensitivity but high specificity in predicting PNF invasion. Among tumors 4 cm or less, PN soft-tissue stranding showed 100% sensitivity and 70% specificity, and tumor margin showed 100% sensitivity and 98% specificity. Among CT criteria for PNF invasion, PN soft-tissue stranding was chosen as the only significant factor for assessing PNF invasion by logistic regression analysis. CONCLUSIONS: Computed tomography does not seem to reliably predict PNF invasion. However, PN soft-tissue stranding was shown to be the only significant factor for predicting PNF invasion, which showed good accuracy with high sensitivity and high specificity in tumors 4 cm or less.

Intestinal metaplasia of the bladder in 89 patients: a study with emphasis on long-term outcome.

BACKGROUND: Intestinal metaplasia of the bladder is an uncommon glandular proliferation. We examined a large series of intestinal metaplasia for the clinicopathological features and discuss the significance of this lesion. METHODS: All cases of intestinal metaplasia diagnosed in our institution between 1990 and 2014 were retrospectively reviewed. Patients with a history of urothelial carcinoma or concurrent adenocarcinoma were excluded. Patient characteristics, pathological features, and follow-up outcomes were obtained. RESULTS: We identified 89 patients with intestinal metaplasia during this period. Sixty seven were men and 22 were women. Mean age at diagnosis was 57 years (range 23-81). Common presenting complaints included haematuria (73 cases), mucosuria (13 cases), and irritative voiding symptoms (seven cases). The majority of intestinal metaplasias located on or near the trigone (67 cases). Eighty-two patients underwent transurethral resection of their lesions. Partial cystectomy was performed in the remaining seven patients. The mean follow-up of 78 patients was 105 months (range 6-255). One case of bladder adenocarcinoma was indentified 6 months later. The initial histologic findings had revealed intestinal metaplasia with severe dysplasia. Four patients presented recurrence during the follow-up, and this occurred 9, 13, 17 and 24 months after the surgery. CONCLUSIONS: Although intestinal metaplasia can be treated effectively by transurethral resection in most cases, its potential malignancy need to be taken into consideration after the evidence of recurrences and its association with bladder adenocarcinoma. Therefore, it is necessary to perform close surveillance following the surgery, particularly in patients with dysplastic changes.

Brusatol's anticancer activity and its molecular mechanism: a research update.

OBJECTIVE: Brusatol (BT) is a quassinoid compound extracted from Brucea javanica that is a traditional Chinese herbal medicine. Brusatol possesses biological and medical activity, including antitumor, antileukemia, anti-inflammatory, antitrypanosomal, antimalarial, and antitobacco mosaic virus activity. To summarize and discuss the antitumor effects of BT and its mechanisms of actions, we compiled this review by combining the extensive relevant literature and our previous studies. METHODS: We searched and retrieved the papers that reported the pharmacological effects of BT and the mechanism of BT antitumor activity from PubMed until July 2023. KEY FINDINGS: Numerous studies have shown that BT is a unique nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor that acts on various signaling pathways and has good antitumor properties. Brusatol shows great potential in cancer therapy by inhibiting cell proliferation, blocking the cell cycle, promoting tumor cell differentiation, accelerating tumor cell apoptosis, inducing autophagy, suppressing angiogenesis, inhibiting tumor invasion and metastasis, and reversing multidrug resistance. CONCLUSION: This review summarizes recent updates on the antitumor activity and molecular mechanisms of BT and provides references for future development and clinical translation of BT and its derivatives as antitumor drugs.