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BACKGROUND: Glioblastoma (GB) is recognized as one of the most aggressive brain tumors, with a median survival of 14.6 months. However, there are still some patients whose survival time was greater than 3 years, and the biological reasons behind this clinical phenomenon arouse our research interests. By conducting proteomic analysis on tumor tissues obtained from GB patients who survived over 3 years compared to those who survived less than 1 year, we identified a significant upregulation of SelK in patients with shorter survival times. Therefore, we hypothesized that SelK may be an important indicator related to the occurrence and progression of GBM. METHODS: Proteomics and immunohistochemistry from GB patients were analyzed to investigate the correlation between SelK and clinical prognosis. Cellular phenotypes were evaluated by cell cycle analysis, cell viability assays, and xenograft models. Immunoblots and co-immunoprecipitation were conducted to verify SelK-mediated ubiquitin-dependent degradation of CDK4. RESULTS: SelK was found to be significantly upregulated in GB samples from short-term survivors (≤ 1 year) compared to those from long-term survivors (≥ 3 years), and its expression levels were negatively correlated with clinical prognosis. Knocking down of SelK expression reduced GB cell viability, induced G0/G1 phase arrest, and impaired the growth of transplanted glioma cells in nude mice. Down-regulation of SelK-induced ER stress leads to a reduction in the expression of SKP2 and an up-regulation of ß-TrCP1 expression. Up-regulation of ß-TrCP1, thereby accelerating the ubiquitin-dependent degradation of CDK4 and ultimately inhibiting the malignant proliferation of the GB cells. CONCLUSION: This study discovered a significant increase in SelK expression in GB patients with poor prognosis, revealing a negative correlation between SelK expression and patient outcomes. Further mechanistic investigations revealed that SelK enhances the proliferation of GB cells by targeting the endoplasmic reticulum stress/SKP2/ß-TrCP1/CDK4 axis.
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Proliferación Celular , Quinasa 4 Dependiente de la Ciclina , Glioblastoma , Humanos , Glioblastoma/metabolismo , Glioblastoma/patología , Glioblastoma/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Animales , Ratones , Masculino , Femenino , Proteínas con Repetición de beta-Transducina/metabolismo , Proteínas con Repetición de beta-Transducina/genética , Ubiquitina/metabolismo , Línea Celular Tumoral , Proteolisis , Pronóstico , Ratones Desnudos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Persona de Mediana Edad , UbiquitinaciónRESUMEN
BACKGROUND: Phosphatase and tensin homolog deleted on chromosome ten (PTEN) serves as a powerful tumor suppressor, and has been found to be downregulated in human bladder cancer (BC) tissues. Despite this observation, the mechanisms contributing to PTEN's downregulation have remained elusive. METHODS: We established targeted genes' knockdown or overexpressed cell lines to explore the mechanism how it drove the malignant transformation of urothelial cells or promoted anchorageindependent growth of human basal muscle invasive BC (BMIBC) cells. The mice model was used to validate the conclusion in vivo. The important findings were also extended to human studies. RESULTS: In this study, we discovered that mice exposed to N-butyl-N-(4-hydroxybu-tyl)nitrosamine (BBN), a specific bladder chemical carcinogen, exhibited primary BMIBC accompanied by a pronounced reduction in PTEN protein expression in vivo. Utilizing a lncRNA deep sequencing high-throughput platform, along with gain- and loss-of-function analyses, we identified small nucleolar RNA host gene 1 (SNHG1) as a critical lncRNA that might drive the formation of primary BMIBCs in BBN-treated mice. Cell culture results further demonstrated that BBN exposure significantly induced SNHG1 in normal human bladder urothelial cell UROtsa. Notably, the ectopic expression of SNHG1 alone was sufficient to induce malignant transformation in human urothelial cells, while SNHG1 knockdown effectively inhibited anchorage-independent growth of human BMIBCs. Our detailed investigation revealed that SNHG1 overexpression led to PTEN protein degradation through its direct interaction with HUR. This interaction reduced HUR binding to ubiquitin-specific peptidase 8 (USP8) mRNA, causing degradation of USP8 mRNA and a subsequent decrease in USP8 protein expression. The downregulation of USP8, in turn, increased PTEN polyubiquitination and degradation, culminating in cell malignant transformation and BMIBC anchorageindependent growth. In vivo studies confirmed the downregulation of PTEN and USP8, as well as their positive correlations in both BBN-treated mouse bladder urothelium and tumor tissues of bladder cancer in nude mice. CONCLUSIONS: Our findings, for the first time, demonstrate that overexpressed SNHG1 competes with USP8 for binding to HUR. This competition attenuates USP8 mRNA stability and protein expression, leading to PTEN protein degradation, consequently, this process drives urothelial cell malignant transformation and fosters BMIBC growth and primary BMIBC formation.
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ARN Largo no Codificante , Neoplasias de la Vejiga Urinaria , Animales , Humanos , Ratones , Carcinogénesis/genética , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Ratones Desnudos , Músculos/metabolismo , Músculos/patología , Proteolisis , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , ARN Largo no Codificante/genética , ARN Mensajero/metabolismo , Regulación hacia Arriba , Neoplasias de la Vejiga Urinaria/inducido químicamente , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
Sensitivity to platinum-based combination chemotherapy is associated with a favorable prognosis in patients with non-small cell lung cancer (NSCLC). Here, our results obtained from analyses of the Gene Expression Omnibus database of NSCLC patients showed that cartilage acidic protein 1 (CRTAC1) plays a role in the response to platinum-based chemotherapy. Overexpression of CRTAC1 increased sensitivity to cisplatin in vitro, whereas knockdown of CRTAC1 decreased chemosensitivity of NSCLC cells. In vivo mouse experiments showed that CRTAC1 overexpression increased the antitumor effects of cisplatin. CRTAC1 overexpression promoted NFAT transcriptional activation by increasing intracellular Ca2+ levels, thereby inducing its regulated STUB1 mRNA transcription and protein expression, accelerating Akt1 protein degradation and, in turn, enhancing cisplatin-induced apoptosis. Taken together, the present results indicate that CRTAC1 overexpression increases the chemosensitivity of NSCLC to cisplatin treatment by inducing Ca2+-dependent Akt1 degradation and apoptosis, suggesting the potential of CRTAC1 as a biomarker for predicting cisplatin chemosensitivity. Our results further reveal that modulating the expression of CRTAC1 could be a new strategy for increasing the efficacy of cisplatin in chemotherapy of NSCLC patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Ratones , Calcio , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Cisplatino/farmacología , Cisplatino/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Platino (Metal) , HumanosRESUMEN
Colorectal cancer (CRC) is one of the most common malignant tumors in the gastrointestinal tract, and has been attracted a great deal attention and extensive investigation due to its high morbidity and mortality rates. The C4orf19 gene encodes a protein with uncharacterized function. Our preliminary exploration of the TCGA database indicated that C4orf19 is markedly downregulated in CRC tissues in comparison to that observed in normal colonic tissues, suggesting its potential association with CRC behaviors. Further studies showed a significant positive correlation between C4orf19 expression levels and CRC patient prognosis. Ectopic expression of C4orf19 inhibited the growth of CRC cells in vitro and tumorigenic ability in vivo. Mechanistic studies showed that C4orf19 binds to Keap1 at near the Lys615, which prevents the ubiquitination of Keap1 by TRIM25, thus protecting the Keap1 protein from degradation. The accumulated Keap1 results in USP17 degradation and in turn leading to the degradation of Elk-1, further attenuates its regulated CDK6 mRNA transcription and protein expression, as well as its mediated proliferation of CRC cells. Collectively, the present studies characterize function of C4orf19 as a tumor suppressor for CRC cell proliferation by targeting Keap1/USP17/Elk-1/CDK6 axis.
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Neoplasias Colorrectales , Factor 2 Relacionado con NF-E2 , Humanos , Línea Celular Tumoral , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Quinasa 6 Dependiente de la Ciclina/genética , Regulación Neoplásica de la Expresión Génica , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factores de Transcripción/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Proteínas de Neoplasias/metabolismoRESUMEN
We designed a four-arm randomized controlled trial to investigate the median effective concentration (EC50) of propofol in combination with different doses of esketamine inducing appropriate depth of anaesthesia during gastrointestinal endoscopy in adults. One hundred patients aged 18-65 years planning for gastrointestinal endoscopy were divided into four groups randomly: esketamine 0, 0.15, 0.25 and 0.5 mg/kg groups (n = 25). Propofol doses followed the Dixon and Massey up-and-down method with different starting between groups. The primary endpoint was the EC50 of propofol. Secondary outcomes included the cumulative dose of propofol, the duration of the procedure, recovery time, and adverse effects. The EC50 (median, 95% confidence interval) of propofol was significantly less in the esketamine 0.5 mg/kg group compared with the esketamine 0, 0.15, and 0.25 mg/kg groups [1.34 (1.15, 1.54) vs. 3.48 (3.25, 3.71), 2.82 (2.58, 3.07), and 2.36 (2.11, 2.61), respectively; p < 0.001]. The total dose of propofol (mean ± SD) required for the whole procedure was significantly less in the esketamine 0.5 mg/kg group compared with the esketamine 0, 0.15, and 0.25 mg/kg groups [95.5 ± 43.1 vs. 277.4 ± 49.0, 207.8 ± 31.6, and 135.1 ± 27.7, respectively; p < 0.001]. The recovery time was significantly longer in esketamine 0 and 0.5 mg/kg group compared with other two groups (p < 0.001). More patients in the esketamine 0.5 mg/kg group experienced visual disturbance compared with the other groups (p = 0.016). Additionally, the incidence of hypotensionin the esketamine 0 mg/kg group after inducation was higher compared with other groups (p < 0.001). In summary, the administration of esketamine significantly and dose-dependently reduced the dose of propofol required to accomplish procedures.
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SOX2, a member of the SRY-related HMG-box (SOX) family, is abnormally expressed in many tumors and associated with cancer stem cell-like properties. Previous reports have shown that SOX2 is a biomarker for cancer stem cells in human bladder cancer (BC), and our most recent study has indicated that the inhibition of SOX2 by anticancer compound ChlA-F attenuates human BC cell invasion. We now investigated the mechanisms through which SOX2 promotes the invasive ability of BC cells. Our studies revealed that SOX2 promoted SKP2 transcription and increased SKP2-accelerated Sp1 protein degradation. As Sp1 is a transcriptionally regulated gene, HUR transcription was thereby attenuated, and, in the absence of HUR, FOXO1 mRNA was degraded fast, which promoted BC cell invasion. In addition, SOX2 promoted BC invasion through the upregulation of nucleolin transcription, which resulted in increased MMP2 mRNA stability and expression. Collectively, our findings show that SOX2 promotes BC invasion through both SKP2-Sp1-HUR-FOXO1 and nucleolin-MMP2 dual axes.
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MicroARNs , Neoplasias de la Vejiga Urinaria , Humanos , Regulación hacia Abajo , Regulación hacia Arriba , Neoplasias de la Vejiga Urinaria/metabolismo , Metaloproteinasa 2 de la Matriz/genética , Metaloproteinasa 2 de la Matriz/metabolismo , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Línea Celular Tumoral , Biomarcadores , ARN Mensajero/genética , Invasividad Neoplásica/patología , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismoRESUMEN
Colorectal cancer (CRC) is the most common digestive tract malignancy, attributing to approximately 9.4% of global cancer-related deaths. However, the pathogenesis of CRC is poorly understood. The testis-expressed 11 (TEX11) gene is located on the X chromosome and is required for spermatogenesis, and is reported might serve as a biomarker for early onset CRC according to database analysis. However, the role played by TEX11 in cancer progression remains to be investigated. In this study, we show that TEX11 expression is significantly downregulated in CRC cell lines and clinical CRC tissue samples, and TEX11 expression correlates with poor prognosis in CRC patients. We further demonstrate that TEX11 can significantly inhibit the proliferative capacity of CRC cells in vitro and in vivo. Mechanistically, we demonstrate that TEX11 promotes transcription of COP1 by upregulating FOXO3a expression. This enhanced COP1 expression subsequently accelerates the degradation of the negative transcriptional regulator c-Jun, which, in turn, enhances p21 transcription inhibiting CRC cell cycle progression and proliferation. Overall, our findings suggest that TEX11 may be a valuable therapeutic target for the treatment of CRC.
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Neoplasias Colorrectales , Testículo , Humanos , Masculino , Regulación hacia Abajo , Testículo/metabolismo , Neoplasias Colorrectales/patología , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismoRESUMEN
To investigate the molecular mechanism of Xingnao Kaiqiao Pill in the treatment of perioperative neurocognitive disorder (PND) from the perspective of network pharmacology and molecular docking technology. Active ingredients of Xingnao Kaiqiao Pill were screened from the traditional Chinese medicine database and analysis platform, and the putative targets were predicted. The GeneCards database was searched to obtain PND-related targets. The genes corresponding to the targets were searched and annotated on the UniProt database. The VennDiagram package in R was employed to obtain common target genes. The overlap genes were introduced into STRING to obtain a protein-protein interaction (PPI) network; thus, key targets were screened. The target relationship network of "Xingnao Kaiqiao Pill-traditional Chinese medicine-compound-common target" was constructed by Cytoscape software. Using R language package Bioconductor, Gene Ontology (GO) and pathway enrichment analysis (Kyoto Encyclopedia of Genes and Genomes Pathway, KEGG Pathway) were performed on the common target genes. A total of 45 active ingredients of Xingnao Kaiqiao Pill were screened, with 182 potential targets, and 1,579 PND-related targets were retrieved from the GeneCards databases (Score ≥ 1). Using VennDiagram, 132 overlap genes were gotten. Xingnao Kaiqiao Pill mainly acted on targets, such as MAPK and JUN. GO enrichment analysis displayed G protein-coupled amine receptor activity, nuclear receptor activity, ligand-activated transcription factor activity, G protein-coupled neurotransmitter receptor activity, steroid hormone receptor activity, and cytokine receptor activity. KEGG enrichment analysis exhibited 157 signaling pathways. The regulation of interleukin 17, tumor necrosis factor, hypoxia-inducible factor-1, and MAPK signaling pathways affected central nervous system (CNS) inflammatory response, cellular immunity, tumor-related signaling pathways, protected neurons, and inhibited PND. The active ingredients of Xingnao Kaiqiao Pill adjust interleukin 17, tumor necrosis factor, hypoxia-inducible factor-1, and MAPK signaling pathways by acting on cell targets, such as JUN, MAPK, AKT1, etc., and finally exert a therapeutic effect on PND.
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Although our previous studies have identified that isorhapontigenin (ISO) is able to initiate autophagy in human bladder cancer (BC) cells by activating JNK/C-Jun/SESN2 axis and possesses an inhibitory effect on BC cell growth, association of autophagy directly with inhibition of BC invasion has never been explored. Also, upstream cascade responsible for ISO activating JNK remains unknown. Thus, we explored both important questions in the current study and discovered that ISO treatment initiated RAC1 protein translation, and its downstream kinase MKK7/JNK phosphorylation/activation, and in turn promoted autophagic responses in human BC cells. Inhibition of autophagy abolished ISO inhibition of BC invasion, revealing that autophagy inhibition was crucial for ISO inhibition of BC invasion. Consistently, knockout of RAC1 also attenuated induction of autophagy and inhibition of BC invasion by ISO treatment. Mechanistic studies showed that upregulation of RAC1 translation was due to ISO inhibition of miR-365a transcription, which reduced miR-365a binding to the 3'-UTR of RAC1 mRNA. Further study indicated that inhibition of miR-365a transcription was caused by downregulation of its transcription factor SOX2, while ISO-promoted Dicer protein translation increased miR-145 maturation, and consequently downregulating SOX2 expression. These findings not only provide a novel insight into the understanding association of autophagy induction with BC invasion inhibition by ISO, but also identify an upstream regulatory cascade, Dicer/miR145/SOX2/miR365a/RAC1, leading to MKK7/JNKs activation and autophagy induction.
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MicroARNs , Neoplasias de la Vejiga Urinaria , Regiones no Traducidas 3' , Autofagia/genética , Línea Celular Tumoral , ARN Helicasas DEAD-box , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Nucleares/metabolismo , Fosforilación , Biosíntesis de Proteínas , Ribonucleasa III , Factores de Transcripción SOXB1/metabolismo , Sestrinas , Estilbenos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo , Proteína de Unión al GTP rac1/genética , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Objective: Sepsis remains a major cause of neonatal death. To better characterize the inflammatory response during neonatal sepsis, we compared the differences in serum cytokines and chemokines between full-term neonates with sepsis and without infection. Methods: We enrolled 40 full-term neonates with sepsis and 26 full-term neonates without infection as controls between October 2016 and June 2018. Forty cytokines /chemokines in serum were analyzed using the Luminex Bead Immunoassay System. Results: Our results showed that serum IL-6, IL-8, TNF-α, IL-1ß, MIF, CXCL13, CXCL1, CXCL2, CXCL5, CXCL6, CXCL16, CCL27, CCL2, CCL8, CCL3, CCL20, CCL23, and CX3CL1 levels were significantly increased in neonates with sepsis compared to those in the control group (all p<0.05). The levels of serum CCL20, and IL-17 were higher in late-onset sepsis (LOS) than those in early-onset sepsis (EOS) (all p<0.05). Conversely, serum CXCL16 was lower in LOS than that in EOS (p<0.05). Conclusion: Our findings revealed that excessive pro-inflammatory cytokines might be involved in neonatal sepsis. In addition, chemokines significantly increased the recruitment of immune cells after infection to participate in the anti-infection defense of neonates, but this could lead to damage.
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Purpose: To clarify the distribution of pathogenic bacteria by analyzing the bacterial susceptibility characteristics and risk factors for adult sepsis in The Wenzhou city, Zhejiang province, China, and to aid early diagnosis, monitoring, and prognosis prediction in cases of bacterial sepsis. Patients and Methods: We retrospectively analyzed 329 patients with sepsis admitted to the Second Affiliated Hospital of Wenzhou Medical University between January 2018 and March 2021. Laboratory data were collected before and after treatment; moreover, the bacterial susceptibility characteristics and risk factors for sepsis were comprehensively analyzed using the Sequential Organ Failure Assessment (SOFA) score. Results: The SOFA score was negatively correlated with the prognosis (P < 0.05). We isolated 47 pathogenic strains from blood culture samples, including 29 gram-positive strains, 18 gram-negative strains. The most common gram-negative pathogens in blood cultures are Klebsiella pneumoniae and Escherichia coli, while the most common gram-positive pathogens are Staphylococcus aureus and Staphylococcus h omini s. Gram-negative pathogens had resistance rates of 77% and 62.5% to ciprofloxacin and ceftriaxone, respectively. Gram-positive bacteria had a high resistance to penicillin at 100%. Prognostic factors for sepsis included patients' consciousness, SOFA score, prothrombin time, international normalized ratio, fibrinogen, D-dimer, and aspartate aminotransferase (P < 0.05). Of these, the D-dimer level could predict the outcome of patients with sepsis (AUC = 0.661, P < 0.05). Conclusion: The pathogens detected in adult sepsis in Wenzhou are mainly Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, and Staphylococcus hominis. The pathogens exhibited differences in drug susceptibility. The optimal antibiotics should be chosen based on the principles of rational use and drug susceptibility. Combined with D-dimer levels, these parameters can be used to determine the optimal strategy for preventing and treating pathogenic bacteria.
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BACKGROUND: MicroRNAs (miRNAs), the key regulator of gene expression, and N6-methyladenosine (m6A) RNA modification play a significant role in tumour progression. However, regulation of m6A-modified mRNAs by miRNAs in colorectal cancer (CRC), and its effect on progression of CRC, remains to be investigated. METHODS: Expression of miR-6125 and YTH Domain-Containing Family Protein 2 (YTHDF2) was detected by western blotting and immunohistochemistry. The effects of miR-6125 and YTHDF2 on proliferative capacity of CRC cells were analysed using soft agar, ATP, CCK8 and EdU assays, and in animal experiments. RESULTS: MiR-6125 expression was downregulated markedly in CRC, and expression correlated negatively with tumour size and prognosis. MiR-6125 targeted the 3'-UTR of YTHDF2 and downregulated the YTHDF2 protein, thereby increasing the stability of m6A-modified glycogen synthase kinase 3 beta (GSK3ß) mRNA. Increased GSK3ß protein levels inhibited the expression of Wnt/ß-catenin/Cyclin D1 pathway-related proteins, leading to G0-G1 phase arrest and ultimately inhibiting the proliferation of CRC cells. CONCLUSIONS: MiR-6125 regulates YTHDF2 and thus plays a critical role in regulating the Wnt/ß-catenin pathway, thereby affecting the growth of CRC. Collectively, these results suggest that miR-6125 and YTHDF2 are potential targets for treatment of CRC.
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Adenosina/análogos & derivados , Neoplasias Colorrectales/genética , Regulación hacia Abajo/genética , Glucógeno Sintasa Quinasa 3 beta/genética , MicroARNs/genética , Proteínas de Unión al ARN/genética , Adenosina/genética , Adenosina/metabolismo , Animales , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Ratones , MicroARNs/metabolismo , Proteínas de Unión al ARN/metabolismoRESUMEN
Transcribed ultraconserved regions (T-UCRs) are a new type of long non-coding RNA, and the UCR has 481 segments longer than 200 base pairs that are 100% conserved between humans, rats, and mice. T-UCRs involved in colorectal cancer (CRC) have not been studied in detail. We performed T-UCR microarray analysis and found that uc.77- was significantly downregulated in CRC tissues and cell lines. Ectopic expression of uc.77- significantly inhibited the proliferation of CRC cells in vitro and the growth of xenograft tumors in nude mice in vivo. Mechanistic studies showed that uc.77- competed with FBXW8 mRNA for binding to microRNA (miR)-4676-5p through a competing endogenous RNA mechanism and inhibited the proliferation of CRC cells by negatively regulating CDK4. The present findings highlight the role of the uc.77-/miR-4676-5p/FBXW8 axis in CRC and identify uc.77- as a potential novel target for the treatment of CRC.
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OBJECTIVE: Central nervous system infections (CNSI) are serious diseases that endanger human health. Identifying pathogens and their susceptibility to antibiotics, and promptly using antibiotics under this guidance is essential for treatment. The purpose of this study is to investigate the pathogen characteristics of CNSI patients, which can help clinicians choose appropriate empiric antibiotic . METHODS: We retrospectively collected data on CNSI patients with cerebrospinal fluid (CSF) culture positive from 2012 to 2020, including demographic characteristics, laboratory data, pathogenic bacteria, and antimicrobial susceptibility test results. RESULTS: A total of 166 patients with 168 isolates out of 8188 patients were available for data analysis. Among the isolates, Gram-positive bacteria, Gram-negative bacteria and fungi accounted for 59.5%, 36.3%, and 4.2%, respectively. Among newborns, children under 12, and patients over 12, the most isolated strains were Streptococcus agalactiae (24/46, 52.2%), Streptococcus pneumoniae (21/68, 30.9%) and Staphylococcus epidermidis (10/54, 18.5%), respectively. Streptococcus agalactiae is more sensitive to linezolid and vancomycin. Streptococcus pneumoniae is more sensitive to vancomycin. Staphylococcus epidermidis is more sensitive to clindamycin and rifampicin. The sugar content in the CSF of Gram-negative bacteria of children ≤12 years old was significantly lower than that of Gram-positive bacteria (P<0.05). CONCLUSION: We comprehensively studied the etiological characteristics and antimicrobial resistance patterns of positive cerebrospinal fluid cultures in Wenzhou City, Zhejiang Province from 2012 to 2020, which can provide valuable strategies for preventing pathogens and improving evidence-based treatment.
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BACKGROUND: Previous studies concerning the effect of plasma hemoglobin (HB) and other factors that may modify the risk of death in people living with HIV/AIDS (PLHIV) treated with antiretroviral therapy (ART) are limited. RESULTS: Higher HB was independently linked to a lower death risk in PLHIV, with a decrease of 29% (13%, 43%) per standard deviation (SD) increment after adjusting for CD4, VL and other potential factors [hazard ratio (HR): 0.71, 95% confidence interval (CI): 0.57-0.87, P<0.001]. In addition, the addition of HB to the predictive model containing VL and CD4 significantly improved the C-index, by 0.69% (95% CI: 0.68%-0.71%), and net discrimination, by 0.5% (95% CI: 0.0%-1.6%, P=0.040), when predicting the death risk of PLHIV. CONCLUSIONS: A lower level of HB was an independent risk factor for HIV/AIDS-associated death in PLHIV. HB combined with VL and CD4 may be an appropriate predictive model of the death risk of PLHIV. MATERIALS AND METHODS: A propensity-score matching (PSM) approach was applied to select a total of 750 PLHIV (150 deceased and 600 living) from the AIDS prevention and control information system in the Wenzhou area from 2006 to 2018. Multivariable Cox proportional hazards regression models were formulated to estimate the effect of HB. The predictive performance improvement contributed by HB was evaluated using the C-index and net reclassification improvement.
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Síndrome de Inmunodeficiencia Adquirida/sangre , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Antirretrovirales/farmacología , Hemoglobinas/metabolismo , Adulto , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Masculino , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
BACKGROUND: Although miR-190 has been reported to be related to human diseases, especially in the development and progression of cancer, its expression in human bladder cancer (BC) and potential contribution to BC remain unexplored. METHODS: RT-qPCR was used to verify the expression level of miR-190 and CDKN1B. Flow cytometry (FCM) assays were performed to detect cell cycle. Soft agar assay was used to measure anchorage-independent growth ability. Methylation-Specific PCR, Dual-luciferase reporter assay and Western blotting were used to elucidate the potential mechanisms involved. RESULTS: Our studies revealed that downregulation of the p27 (encoded by CDKN1B gene) protein is an important event related to miR-190, promoting the malignant transformation of bladder epithelial cells. miR-190 binds directly to CDKN1B 3'-UTR and destabilizes CDKN1B mRNA. Moreover, miR-190 downregulates TET1 by binding to the TET1 CDS region, which mediates hypermethylation of the CDKN1B promoter, thereby resulting in the downregulation of CDKN1B mRNA. These two aspects led to miR-190 inhibition of p27 protein expression in human BC cells. A more in-depth mechanistic study showed that c-Jun promotes the transcription of Talin2, the host gene of miR-190, thus upregulating the expression of miR-190 in human BC cells. CONCLUSIONS: In this study, we found that miR-190 plays an important role in the development of BC. Taken together, these findings indicate that miR-190 may promote the malignant transformation of human urothelial cells by downregulating CDKN1B, which strengthens our understanding of miR-190 in regulating BC cell transformation.
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BACKGROUND: Lung adenocarcinoma (LUAD) metastasis significantly reduces patient survival; hence inhibiting the metastatic ability of lung cancer cells will greatly prolong patient survival. Alkaline phosphatase (ALPL), a homodimeric cell surface phosphohydrolase, is reported to play a controversial role in prostate cancer and ovarian cancer cell migration; however, the function of ALPL in LUAD and the related mechanisms remain unclear. METHODS: TCGA database was used to analysis the expression of ALPL, and further verification was performed in a cohort of 36 LUAD samples by qPCR and western blot. Soft-agar assay, transwell assay and lung metastasis assay were employed to detect the function of ALPL in LUAD progression. The qPCR, luciferase promoter reporter assay and western blot were used to clarify the molecular mechanisms of ALPL in promoting metastasis in LUAD. RESULTS: ALPL was downregulated in LUAD, and the disease-free survival rate of patients with low ALPL was significantly reduced. Further studies showed that overexpression of ALPL in LUAD cell lines did not significantly affect cell proliferation, but it did significantly attenuate lung metastasis in a mouse model. ALPL downregulation in LUAD led to a decrease in the amount of phosphorylated (p)-ERK. Because p-ERK promotes the classical c-Myc degradation pathway, the decrease in p-ERK led to the accumulation of c-Myc and therefore to an increase in RhoA transcription, which enhanced LUAD cell metastasis. CONCLUSION: ALPL specially inhibits the metastasis of LUAD cells by affecting the p-ERK/c-Myc/RhoA axis, providing a theoretical basis for the targeted therapy of clinical LUAD.
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BACKGROUND: LARGE1 plays a pivotal role in glycosylation of alpha-Dystroglycan (α-DG) and is aberrantly downregulated in cell lines originating from epithelium-derived cancers including lung cancer. However, the expression of LARGE1 and its clinical significance in NSCLC are not clear. MATERIALS AND METHODS: The data were collected from the TCGA database to investigate LARGE1 expression in stage I-III NSCLC and explore its associations with clinicopathological parameters and overall survival of patients. The prognostic role of LARGE1 was examined in subgroups according to clinical features and treatments. The results were validated in external cohorts from the NCBI GEO database. Gene Set Enrichment Analysis (GSEA) was performed to investigate the potential molecular mechanisms during LARGE1 alteration in NSCLC. RESULTS: LARGE1 was aberrantly downregulated in NSCLC compared with adjacent tissues and normal lung tissues and in tumors with advanced stage compared with early stage. There was only a trend of association between high LARGE1 with OS in multivariate analysis. Surprisingly, high LARGE1 was significantly associated with improved OS in a subgroup of the patients with adjuvant chemotherapy (ACT) and a significant interaction between LARGE1 expression and ACT was found. Improved OS after ACT was also found in patients with high LARGE1 compared to those with low LARGE1. When combining LARGE1 expression and ACT, compared with patients with non-ACT, HR of low LARGE1/ACT was 0.592 (95% CI=0.432-0.813, P=0.0012), and HR of high LARGE1/ACT was 0.124 (95% CI=0.031-0.505, P=0.0036). The results were verified in two external cohorts from the GEO database. GSEA indicated that LARGE1 might downregulate cell cycle pathway to improve ACT sensitivity and subsequently the prognosis in NSCLC. CONCLUSION: High LARGE1 can be used to identify the patients with resected stage I-III NSCLC most likely to benefit from adjuvant chemotherapy.
RESUMEN
Although MIR516A has been reported to be downregulated and act as a tumor suppressor in multiple cancers, its expression and potential contribution to human bladder cancer (BC) remain unexplored. Unexpectedly, we showed here that MIR516A was markedly upregulated in human BC tissues and cell lines, while inhibition of MIR516A expression attenuated BC cell monolayer growth in vitro and xenograft tumor growth in vivo, accompanied with increased expression of PHLPP2. Further studies showed that MIR516A was able to directly bind to the 3'-untranslated region of PHLPP2 mRNA, which was essential for its attenuating PHLPP2 expression. The knockdown of PHLPP2 expression in MIR516A-inhibited cells could reverse BC cell growth, suggesting that PHLPP2 is a MIR516A downstream mediator responsible for MIR516A oncogenic effect. PHLPP2 was able to mediate BECN1/Beclin1 stabilization indirectly, therefore promoting BECN1-dependent macroautophagy/autophagy, and inhibiting BC tumor cell growth. In addition, our results indicated that the increased autophagy by attenuating MIR516A resulted in a dramatic inhibition of xenograft tumor formation in vivo. Collectively, our results reveal that MIR516A has a novel oncogenic function in BC growth by directing binding to PHLPP2 3'-UTR and inhibiting PHLPP2 expression, in turn at least partly promoting CUL4A-mediated BECN1 protein degradation, thereby attenuating autophagy and promoting BC growth, which is a distinct function of MIR516A identified in other cancers.Abbreviation: ATG3: autophagy related 3; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG12: autophagy related 12; BAF: bafilomycin A1; BC: bladder cancer; CHX: cycloheximide; Co-IP: co-immunoprecipitation; CUL3: cullin 3; CUL4A: cullin 4A; CUL4B: cullin 4B; IF: immunofluorescence: IHC-p: immunohistochemistry-paraffin; MIR516A: microRNA 516a (microRNA 516a1 and microRNA 516a2); MS: mass spectrometry; PHLPP2: PH domain and leucine rich repeat protein phosphatase.
Asunto(s)
Autofagia/genética , Beclina-1/metabolismo , Carcinogénesis/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/metabolismo , Fosfoproteínas Fosfatasas/genética , Neoplasias de la Vejiga Urinaria/genética , Regiones no Traducidas 3'/genética , Secuencia de Bases , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas Cullin/metabolismo , Regulación hacia Abajo/genética , Humanos , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , MicroARNs/genética , Fosfoproteínas Fosfatasas/metabolismo , Unión Proteica , Proteolisis , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/ultraestructura , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Metastasis is the leading cause of death in patients with bladder cancer (BC). However, current available treatments exert little effects on metastatic BC. Moreover, traditional grading and staging have only a limited ability to identify metastatic BC. Accumulating evidence indicates that the aberrant expression of microRNA is intimately associated with tumor progression. So far, many miRNAs have been identified as molecular targets for cancer diagnosis and therapy. This study focused on the role of miR-516a-5p (miR-516a) in BC. METHODS: MiR-516a expression and its downstream signaling pathway were detected using molecular cell biology and biochemistry approaches and techniques. Fresh clinical BC tissue was used to study the clinicopathological characteristics of patients with different miR-516a expression. The biological functions of miR-516a in BC were tested both in vivo and in vitro. RESULTS: A more invasive BC phenotype was significantly and positively correlated with miR-516a overexpression in BC patients. MiR-516a inhibition significantly decreased BC cell invasion and migration in vitro and in vivo. Furthermore, miR-516a attenuated the expression of PH domain leucine-rich repeat-containing protein phosphatase 2 protein and inhibited SMAD-specific E3 ubiquitin protein ligase 1 transcription by activating the AKT/Forkhead box O3 signaling pathway, which stabilized MMP9 and slowed down its proteasomal degradation, ultimately promoting BC motility and invasiveness. CONCLUSIONS: Our findings reveal the crucial function of miR-516a in promoting BC metastasis, and elucidate the molecular mechanism involved, suggesting that miR-516a may be a promising novel diagnostic and therapeutic target for BC.