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Immunotherapies, such as chimeric antigen receptor (CAR) modified T cells and antibody-drug conjugates (ADCs), have revolutionized the treatment of cancer, especially of lymphoid malignancies. The application of targeted immunotherapy to patients with acute myeloid leukemia (AML) has been limited in particular by the lack of a tumor-specific target antigen. Gemtuzumab ozogamicin (GO), an ADC targeting CD33, is the only approved immunotherapeutic agent in AML. In our study, we introduce a CD33-directed third-generation CAR T-cell product (3G.CAR33-T) for the treatment of patients with AML. 3G.CAR33-T cells could be expanded up to the end-of-culture, that is, 17 days after transduction, and displayed significant cytokine secretion and robust cytotoxic activity when incubated with CD33-positive cells including cell lines, drug-resistant cells, primary blasts as well as normal hematopoietic stem and progenitor cells (HSPCs). When compared to second-generation CAR33-T cells, 3G.CAR33-T cells exhibited higher viability, increased proliferation and stronger cytotoxicity. Also, GO exerted strong antileukemia activity against CD33-positive AML cells. Upon genomic deletion of CD33 in HSPCs, 3G.CAR33-T cells and GO preferentially killed wildtype leukemia cells, while sparing CD33-deficient HSPCs. Our data provide evidence for the applicability of CD33-targeted immunotherapies in AML and its potential implementation in CD33 genome-edited stem cell transplantation approaches.
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Gemtuzumab/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Inmunoterapia Adoptiva , Leucemia Mieloide Aguda/terapia , Receptores Quiméricos de Antígenos/inmunología , Lectina 3 Similar a Ig de Unión al Ácido Siálico/inmunología , Edición Génica , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Leucemia Mieloide Aguda/patología , Lectina 3 Similar a Ig de Unión al Ácido Siálico/análisis , Lectina 3 Similar a Ig de Unión al Ácido Siálico/genéticaRESUMEN
Noncoding RNAs, including small nucleolar RNAs (snoRNAs), play important roles in leukemogenesis, but the relevant mechanisms remain incompletely understood. We performed snoRNA-focused CRISPR-Cas9 knockout library screenings that targeted the entire snoRNAnome and corresponding host genes. The C/D box containing SNORD42A was identified as an essential modulator for acute myeloid leukemia (AML) cell survival and proliferation in multiple human leukemia cell lines. In line, SNORD42A was consistently expressed at higher levels in primary AML patient samples than in CD34+ progenitors, monocytes, and granulocytes. Functionally, knockout of SNORD42A reduced colony formation capability and inhibited proliferation. The SNORD42A acts as a C/D box snoRNA and directs 2'-O-methylation at uridine 116 of 18S ribosomal RNA (rRNA). Deletion of SNORD42A decreased 18S-U116 2'-O-methylation, which was associated with a specific decrease in the translation of ribosomal proteins. In line, the cell size of SNORD42A deletion carrying leukemia cells was decreased. Taken together, these findings establish that high-level expression of SNORD42A with concomitant U116 18S rRNA 2'-O-methylation is essential for leukemia cell growth and survival.
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Proliferación Celular , Metilación de ADN , Leucemia Mieloide Aguda/patología , ARN Ribosómico 18S/genética , ARN Nucleolar Pequeño/metabolismo , Proteínas Ribosómicas/metabolismo , Sistemas CRISPR-Cas , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , ARN Ribosómico 18S/química , ARN Nucleolar Pequeño/genética , Proteínas Ribosómicas/antagonistas & inhibidores , Proteínas Ribosómicas/genética , Células Tumorales CultivadasRESUMEN
Pulmonary fibrosis is a progressive and fatal lung disease characterized by activation of lung fibroblasts and excessive deposition of collagen matrix. We show here that the concentrations of kindlin-2 and its binding partner PYCR1, a key enzyme for proline synthesis, are significantly increased in the lung tissues of human patients with pulmonary fibrosis. Treatment of human lung fibroblasts with TGF-ß1 markedly increased the expression of kindlin-2 and PYCR1, resulting in increased kindlin-2 mitochondrial translocation, formation of the kindlin-2-PYCR1 complex, and proline synthesis. The concentrations of the kindlin-2-PYCR1 complex and proline synthesis were markedly reduced in response to pirfenidone or nintedanib, two clinically approved therapeutic drugs for pulmonary fibrosis. Furthermore, depletion of kindlin-2 alone was sufficient to suppress TGF-ß1-induced increases of PYCR1 expression, proline synthesis, and fibroblast activation. Finally, using a bleomycin mouse model of pulmonary fibrosis, we show that ablation of kindlin-2 effectively reduced the concentrations of PYCR1, proline, and collagen matrix and alleviate the progression of pulmonary fibrosis in vivo. Our results suggest that kindlin-2 is a key promoter of lung fibroblast activation, collagen matrix synthesis, and pulmonary fibrosis, underscoring the therapeutic potential of targeting the kindlin-2 signaling pathway for control of this deadly lung disease.
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Proteínas del Citoesqueleto/metabolismo , Fibroblastos/metabolismo , Pulmón/metabolismo , Proteínas Musculares/metabolismo , Fibrosis Pulmonar/metabolismo , Transducción de Señal , Animales , Bleomicina/efectos adversos , Bleomicina/farmacología , Proteínas del Citoesqueleto/genética , Modelos Animales de Enfermedad , Fibroblastos/patología , Humanos , Pulmón/patología , Ratones , Ratones Transgénicos , Proteínas Musculares/genética , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/patologíaRESUMEN
Proline metabolic reprogramming is intimately involved in cancer progression. We recently identified a critical role of PINCH-1, a cell-extracellular matrix (ECM) adhesion protein whose expression is elevated in lung adenocarcinoma, in the promotion of proline biosynthesis, fibrosis and lung adenocarcinoma growth. How PINCH-1 promotes proline biosynthesis, however, was incompletely understood. In this study, we show that PINCH-1 promotes the expression of Δ1-pyrroline-5-carboxylate synthase (P5CS), a key enzyme that links glutamate metabolism to proline biosynthesis. Depletion of PINCH-1 from lung adenocarcinoma cells reduced the protein but not mRNA level of P5CS, resulting in down-regulation of the cellular level of P5C and cell proliferation. Treatment of the cells with protease inhibitor leupeptin effectively reversed PINCH-1 deficiency-induced reduction of the P5CS level. At the molecular level, PINCH-1, through its LIM2 domain, physically associated with P5CS in lung adenocarcinoma cells. Re-expression of wild type PINCH-1, but not that of the PINCH-1 LIM2 deletion mutant, in PINCH-1 deficient lung adenocarcinoma cells restored P5CS expression, proline biosynthesis and cell proliferation. Finally, P5CS expression, like that of PINCH-1, is elevated in human and mouse lung adenocarcinoma. Using a mouse model of lung adenocarcinoma in which PINCH-1 is conditionally ablated, we show that knockout of PINCH-1 from lung adenocarcinoma effectively reduced the P5CS level in vivo. Our results reveal an important role of PINCH-1 in the promotion of P5CS expression, which likely contributes to proline metabolic reprogramming and consequently lung adenocarcinoma progression.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenocarcinoma del Pulmón/metabolismo , Proteínas con Dominio LIM/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas de la Membrana/metabolismo , Prolina/metabolismo , Células A549 , Animales , Línea Celular Tumoral , Proliferación Celular/fisiología , Regulación hacia Abajo/fisiología , Humanos , Ratones , Ratones Transgénicos , ARN Mensajero/metabolismoRESUMEN
Malignant glioblastoma multiforme is one of the most aggressive human cancers, with very low survival rates. Recent studies have reported that glioma stem-like cells transdifferentiate into endothelial cells, indicating a new mechanism for tumor angiogenesis and potentially providing new therapeutic options for glioblastoma treatment. Glioma malignancy is strongly associated with altered expression of N-linked oligosaccharide structures on the cell surface. We have previously reported that ß1,4-galactosyltransferase V (ß1,4GalTV), which galactosylates the GlcNAcß1-6Man arm of the branched N-glycans, is highly expressed in glioma and promotes glioma cell growth in vitro and in vivo However, the mechanism by which ß1,4GalTV stimulates glioma growth is unknown. Here we demonstrate that short hairpin RNA-mediated ß1,4GalTV knockdown inhibits the tumorigenesis of glioma stem-like cells and reduces their transdifferentiation into endothelial cells. We also found that ß1,4GalTV overexpression increased glioma stem-like cell transdifferentiation into endothelial cells and that this effect required ß1,4GalTV galactosylation activity. Moreover, ß1,4GalTV promoted ß1,4-galactosylation of Notch1 and increased Notch1 protein levels. Of note, ectopic expression of activated Notch1 rescued the inhibitory effect of ß1,4GalTV depletion on glioma stem-like cell transdifferentiation. In summary, our findings indicate that ß1,4GalTV stimulates transdifferentiation of glioma stem-like cells into endothelial cells by activating Notch1 signaling. These detailed insights shed important light on the mechanisms regulating glioma angiogenesis.
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Transdiferenciación Celular , Glioma/patología , N-Acetil-Lactosamina Sintasa/fisiología , Receptor Notch1/metabolismo , Transducción de Señal , Células Endoteliales/patología , Humanos , Células Madre Neoplásicas/patología , Neovascularización PatológicaRESUMEN
The biological significance of a known normal and cancer stem cell marker CD133 remains elusive. We now demonstrate that the phosphorylation of tyrosine-828 residue in CD133 C-terminal cytoplasmic domain mediates direct interaction between CD133 and phosphoinositide 3-kinase (PI3K) 85 kDa regulatory subunit (p85), resulting in preferential activation of PI3K/protein kinase B (Akt) pathway in glioma stem cell (GSC) relative to matched nonstem cell. CD133 knockdown potently inhibits the activity of PI3K/Akt pathway with an accompanying reduction in the self-renewal and tumorigenicity of GSC. The inhibitory effects of CD133 knockdown could be completely rescued by expression of WT CD133, but not its p85-binding deficient Y828F mutant. Analysis of glioma samples reveals that CD133 Y828 phosphorylation level is correlated with histopathological grade and overlaps with Akt activation. Our results identify the CD133/PI3K/Akt signaling axis, exploring the fundamental role of CD133 in glioma stem cell behavior.
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Antígenos CD/metabolismo , Transformación Celular Neoplásica/metabolismo , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Glioma/fisiopatología , Glicoproteínas/metabolismo , Células Madre Neoplásicas/fisiología , Péptidos/metabolismo , Transducción de Señal/fisiología , Antígeno AC133 , Animales , Antígenos CD/genética , Western Blotting , Glioma/metabolismo , Glicoproteínas/genética , Humanos , Inmunoprecipitación , Ratones , Ratones Endogámicos NOD , Ratones SCID , Mutación Missense/genética , Células Madre Neoplásicas/metabolismo , Péptidos/genética , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
The feasibility of removing heavy metals and eliminating pathogens from pig slurry through bioleaching involving the fungus Galactomyces sp. Z3 and two acidophilic thiobacillus (A. ferrooxidans LX5 and A. thiooxidans TS6) was investigated. It was found that the isolated pig slurry dissolved organic matter (DOM) degrader Z3 was identified as Galactomyces sp. Z3, which could grow well at pH 2.5-7 and degrade pig slurry DOM from 1973 to 942 mg/l within 48 h. During the successive multi-batch bioleaching systems, the co-inoculation of pig slurry degrader Galactomyces sp. Z3 and the two Acidithiobacillus species could improve pig slurry bioleaching efficiency compared to the single system without Galactomyces sp. Z3. The removal efficiency of Zn and Cu exceeded 94% and 85%, respectively. In addition, the elimination efficiencies of pathogens, including both total coliform and faecal coliform counts, exceeded 99% after bioleaching treatment. However, the counts of Galactomyces sp. Z3 decreased with the fall of pH and did not restore to the initial level during successive multi-batch bioleaching systems, and it is necessary to re-inoculate Galactomyces sp. Z3 cells into the bioleaching system to maintain its role in degrading pig slurry DOM. Therefore, a bioleaching technique involving both Galactomyces sp. Z3 and Acidithiobacillus species is an efficient method for removing heavy metals and eliminating pathogens from pig slurry.
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Estiércol/microbiología , Metales Pesados/metabolismo , Saccharomycetales/aislamiento & purificación , Administración de Residuos , Acidithiobacillus/metabolismo , Animales , Enterobacteriaceae , Estudios de Factibilidad , Fertilizantes , Concentración de Iones de Hidrógeno , Compuestos Orgánicos/metabolismo , Saccharomycetales/crecimiento & desarrollo , Saccharomycetales/metabolismo , Sulfatos/metabolismo , PorcinosRESUMEN
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is involved in neural injury, neuroinflammation, microglia activation, and polarization, while its function in spinal cord injury (SCI) remains unclear. Thus, this study aimed to evaluate the role of MALT1 modification on SCI recovery and its underlying mechanism. SCI surgery or sham surgery was performed in Sprague-Dawley rats. Then, MALT1 knockdown or negative control lentivirus was injected into SCI rats. Subsequently, MALT1 expression, locomotor capability, neural injury, markers for microglia activation and polarization, inflammatory cytokine expressions, and nuclear factor (NF)-κB pathway were detected. SCI rats exhibited higher MALT1 expression, microglia activation and M1 polarization, neuroinflammation, and NF-κB pathway activation, while worse locomotor capacity compared to sham rats (all P < 0.05). In SCI rats, MALT1 knockdown alleviated Basso, Beattie, and Bresnahan score from 10 to 28 days and attenuated HE staining reflected neural injury (all P < 0.05). Besides, MALT1 knockdown declined the number of IBA1+ cells, IBA1+ iNOS+ cells, and IBA1+ CD86+ cells, while enhanced the number of IBA1+ Arg1+ cells and IBA1+ CD206+ cells in SCI rats (all P < 0.05). Meanwhile, MALT1 knockdown declined the expressions of IL-1ß, IL-6, and TNF-α in SCI (all P < 0.05), but did not affect IL-10 expression (P > 0.05). Furthermore, MALT1 knockdown suppressed NF-κB pathway activation validated by immunofluorescence staining and western blot assays (all P < 0.05). MALT1 knockdown improves functional recovery, attenuates microglia activation, M1 polarization, and neuroinflammation via inhibiting NF-κB pathway in SCI.
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Microglía , Traumatismos de la Médula Espinal , Animales , Ratas , Microglía/metabolismo , Enfermedades Neuroinflamatorias , FN-kappa B/metabolismo , Ratas Sprague-Dawley , Médula Espinal/patología , Traumatismos de la Médula Espinal/patologíaRESUMEN
Bacterial chemotaxis is the phenomenon in which bacteria migrate toward a more favorable niche in response to chemical cues in the environment. The methyl-accepting chemotaxis proteins (MCPs) are the principal sensory receptors of the bacterial chemotaxis system. Aerotaxis is a special form of chemotaxis in which oxygen serves as the signaling molecule; the process is dependent on the aerotaxis receptors (Aer) containing the Per-Arnt-Sim (PAS) domain. Over 40 MCPs are annotated on the genome of Vibrio cholerae; however, little is known about their functions. We investigated six MCPs containing the PAS domain in V. cholerae El Tor C6706, namely aer2, aer3, aer4, aer5, aer6, and aer7. Deletion analyses of each aer homolog gene indicated that these Aer receptors are involved in aerotaxis, chemotaxis, biofilm formation, and intestinal colonization. Swarming motility assay indicated that the aer2 gene was responsible for sensing the oxygen gradient independent of the other five homologs. When bile salts and mucin were used as chemoattractants, each Aer receptor influenced the chemotaxis differently. Biofilm formation was enhanced by overexpression of the aer6 and aer7 genes. Moreover, deletion of the aer2 gene resulted in better bacterial colonization of the mutant in adult mice; however, virulence gene expression was unaffected. These data suggest distinct roles for different Aer homologs in V. cholerae physiology.
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Vibrio cholerae , Animales , Ratones , Vibrio cholerae/genética , Vibrio cholerae/metabolismo , Células Quimiorreceptoras/metabolismo , Quimiotaxis/genética , Proteínas Portadoras/genética , Oxígeno/metabolismoRESUMEN
The estimation of a postmortem interval (PMI) is particularly important for forensic investigations. The aim of this study was to assess the succession of bacterial communities associated with the decomposition of mouse cadavers and determine the most important biomarker taxa for estimating PMIs. High-throughput sequencing was used to investigate the bacterial communities of gravesoil samples with different PMIs, and a random forest model was used to identify biomarker taxa. Redundancy analysis was used to determine the significance of environmental factors that were related to bacterial communities. Our data showed that the relative abundance of Proteobacteria, Bacteroidetes and Firmicutes showed an increasing trend during decomposition, but that of Acidobacteria, Actinobacteria and Chloroflexi decreased. At the genus level, Pseudomonas was the most abundant bacterial group, showing a trend similar to that of Proteobacteria. Soil temperature, total nitrogen, NH4+-N and NO3--N levels were significantly related to the relative abundance of bacterial communities. Random forest models could predict PMIs with a mean absolute error of 1.27 days within 36 days of decomposition and identified 18 important biomarker taxa, such as Sphingobacterium, Solirubrobacter and Pseudomonas. Our results highlighted that microbiome data combined with machine learning algorithms could provide accurate models for predicting PMIs in forensic science and provide a better understanding of decomposition processes.
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Background: As the most common female malignancy, the incidence and mortality of endometrial carcinoma (EC) continue to increase worldwide. The effects of traditional standard therapy are limited; thus, novel therapeutic strategies urgently need to be developed. We sought to provide prospective targeting insights into EC therapeutics by comprehensively examining and confirming the biological molecular characterization of EC genes. Methods: The molecular characterization of EC genes was integrated and analyzed using data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Project (GTEx) databases. The differentially expressed genes (DEGs) were identified, and the abnormal expression of some core cell-cycle proteins in the EC specimens was determined by examining and integrating the TCGA and GTEx data. The enriched signaling pathways involved in tumor progression were also examined. Results: Immunohistochemical staining data from the Human Protein Atlas database showed that the differential expression levels of the cyclin dependent kinase inhibitor 2A (CDKN2A) and tyrosine threonine kinase (TTK) molecules, and the high messenger ribonucleic acid (RNA) levels of CDKN2A and TTK were associated with a poor prognosis in EC patients. High TTK expression was also significantly correlated with the tumor progression associated signaling pathways, such as the cell-cycle, nucleolus, and RNA processing pathways. The inhibition of TTK expression by a TTK inhibitor (NTRC0066-0) significantly suppressed the proliferation of the EC cells and synergistically increased the sensitivity of the EN and AN3-CA EC cell lines. Conclusions: The findings suggest that the TTK inhibitor could be used in EC therapy. This study highlighted the potential predictive role of TTK molecules and showed that TTK molecules might serve as prospective targets for EC therapy.
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Azorhizobium caulinodans ORS571 contains an 87.6 kb integrative and conjugative element (ICEAc) that conjugatively transfers symbiosis genes to other rhizobia. Many hypothetical redundant gene fragments (rgfs) are abundant in ICEAc, but their potential function in horizontal gene transfer (HGT) is unknown. Molecular biological methods were employed to delete hypothetical rgfs, expecting to acquire a minimal ICEAc and consider non-functional rgfs as editable regions for inserting genes related to new symbiotic functions. We determined the significance of rgf4 in HGT and identified the physiological function of genes designated rihF1a (AZC_3879), rihF1b (AZC_RS26200), and rihR (AZC_3881). In-frame deletion and complementation assays revealed that rihF1a and rihF1b work as a unit (rihF1) that positively affects HGT frequency. The EMSA assay and lacZ-based reporter system showed that the XRE-family protein RihR is not a regulator of rihF1 but promotes the expression of the integrase (intC) that has been reported to be upregulated by the LysR-family protein, AhaR, through sensing host's flavonoid. Overall, a conservative module containing rihF1 and rihR was characterized, eliminating the size of ICEAc by 18.5%. We propose the feasibility of constructing a minimal ICEAc element to facilitate the exchange of new genetic components essential for symbiosis or other metabolic functions between soil bacteria.
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Azorhizobium caulinodans , Sesbania , Azorhizobium caulinodans/genética , Transferencia de Gen Horizontal , Sesbania/microbiología , Integrasas/metabolismo , Flavonoides/metabolismo , SueloRESUMEN
Tea plant is an economically important crop in China, but long-term monoculture and substantial chemical nitrogen fertilizer input cause soil acidification, which in turn affects the nutrient supply and tea quality. Intercropping has drawn more attention in tea gardens because this pattern is expected to improve soil fertility and tea quality and change the soil microbial community composition. However, the roles of some key microorganisms in rhizosphere soils have not been well characterized. Hereby, a "soybean in summer and smooth vetch in winter" mode was selected to investigate the effects of intercropped legumes in a tea garden on soil fertility, tea quality, and the potential changes in beneficial bacteria such as Bacillus. Our data showed that when soybeans were turned into soil, intercropping system exhibited higher soil organic matter (SOM), total nitrogen (TN), tea quality indices and the expression of Camellia sinensis glutamine synthetase gene (CsGS). Notably, intercropping significantly affected the bacterial communities and decreased the relative abundance of Bacillus but increased its absolute abundance. Bacillus amyloliquefaciens BM1 was isolated from intercropped soil and showed outstanding plant growth-promoting (PGP) properties when coinoculated with rhizobia. In winter, intercropping with smooth vetch had a beneficial effect on soil properties and tea quality. Comparably, coinoculation with strain BM1 and Rhizobium leguminosarum Vic5 on smooth vetch (Vicia villosa) showed huge improvements in SOM, TN and quality of tea leaves, accompanied by the highest level of amino acids and lowest levels of polyphenol and caffeine (p < 0.05). According to these results, our findings demonstrate that intercropping with some legumes in the tea garden is a strategy that increases SOM, TN and tea quality, and some PGP Bacillus species are optional to obtain an amplification effect.
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BACKGROUND: Atrial fibrillation (AF) is the most common type of clinical arrhythmia. An early diagnosis can be beneficial in the prevention of complications, such as heart failure (HF) and stroke. In this study, we revealed that ELABELA (ELA) acts as a protective factor in patients with arrhythmia and could serve as a prognostic marker for AF and its associated complication of HF. METHODS: We tested the expression level of potential biomarkers including matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and ELA with enzyme-linked immunosorbent assay (ELISA) in serum derived from 131 patients (patients with AF =103; patients with paroxysmal supraventricular tachycardia =28). The impact of clinical risk factors and biomarkers on AF occurrence was evaluated using binary logistic analysis. RESULTS: The ELA expression level was lower in AF patients than in the negative controls (P<0.0001). Expression of ELA was negatively correlated with brain natriuretic peptide (BNP) expression in all the samples. In the binary logistic analysis, high levels of BNP and lower levels of ELA were significantly associated with an increased risk of AF (P<0.0001) and could be used as prognostic markers for patients with AF. CONCLUSIONS: Expression of ELA showed a protective role in AF patients. The ELA level was negatively correlated with BNP levels, which has been shown to predict a high risk of HF independently and consistently. Additionally, lower levels of ELA were associated with a high risk of AF and HF in patients with arrhythmia. KEYWORDS: ELABELA (ELA); matrix metalloproteinase-9 (MMP-9); tissue inhibitor of metalloproteinase-1 (TIMP-1); atrial fibrillation (AF); brain natriuretic peptide (BNP).
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Relapse of acute myeloid leukemia (AML) has a very poor prognosis and remains a common cause of treatment failure in patients with this disease. AML relapse is partially driven by the chemoresistant nature of leukemia stem cells (LSCs), which remains poorly understood, and our study aimed at elucidating the underlying mechanism. Accumulating evidences show that long noncoding RNAs (lncRNAs) play a crucial role in AML development. Herein, the lncRNA, LINC00152, was identified to be highly expressed in CD34+ LSCs and found to regulate the self-renewal of LSCs derived from AML patients. Importantly, LINC00152 upregulation was correlated with the expression of 16 genes within a 17-gene LSC biomarker panel, which contributed to the accurate prediction of initial therapy resistance in AML. Knockdown of LINC00152 markedly increased the drug sensitivity of leukemia cells. Furthermore, LINC00152 expression was found to be correlated with poly (ADP-ribose) polymerase 1 (PARP1) expression in AML, whereas LINC00152 knockdown significantly decreased the expression of PARP1. Upregulation of LINC00152 or PARP1 was associated with poor prognosis in AML patients. Collectively, these data highlight the importance and contribution of LINC00152 in the regulation of self-renewal and chemoresistance of LSCs in AML.
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Breast cancer (BC) is the most frequent cancer among women worldwide and is the leading cause of cancer-related deaths in women. Cancer cells with stem cell-like features and tumor-initiating potential contribute to drug resistance, tumor recurrence, and metastasis. To achieve better clinical outcomes, it is crucial to eradicate both bulk BC cells and breast cancer stem cells (BCSCs). Salinomycin, a monocarboxylic polyether antibiotic isolated from Streptomyces albus, can precisely kill cancer stem cells (CSCs), particularly BCSCs, by various mechanisms, including apoptosis, autophagy, and necrosis. There is increasing evidence that salinomycin can inhibit cell proliferation, invasion, and migration in BC and reverse the immune-inhibitory microenvironment to prevent tumor growth and metastasis. Therefore, salinomycin is a promising therapeutic drug for BC. In this review, we summarize established mechanisms by which salinomycin protects against BC and discuss its future clinical applications.
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Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide underlining the urgent need for new biomarkers and therapeutic targets for this disease. Long noncoding RNAs are critical players in NSCLC but the role of small RNA species is not well understood. In the present study, we investigated the role of H/ACA box small nucleolar RNAs (snoRNAs) and snoRNA-bound ribonucleoproteins (snoRNPs) in the tumorigenesis of NSCLC. H/ACA box snoRNPs including the NOP10 core protein were highly expressed in NSCLC. High levels of either NOP10 mRNA or protein were associated with poor prognosis in NSCLC patients. Loss of NOP10 and subsequent reduction of H/ACA box snoRNAs and rRNA pseudouridylation inhibited lung cancer cell growth, colony formation, migration, and invasion. A focused CRISPR/Cas9 snoRNA knockout screen revealed that genomic deletion of SNORA65, SNORA7A, and SNORA7B reduced proliferation of lung cancer cells. In line, high levels of SNORA65, SNORA7A, and SNORA7B were observed in primary lung cancer specimens with associated changes in rRNA pseudouridylation. Knockdown of either SNORA65 or SNORA7A/B inhibited growth and colony formation of NSCLC cell lines. Our data indicate that specific H/ACA box snoRNAs and snoRNA-associated proteins such as NOP10 have an oncogenic role in NSCLC providing new potential biomarkers and therapeutic targets for the disease.
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Neoplasias Pulmonares/genética , ARN Nucleolar Pequeño/genética , Ribonucleoproteínas Nucleolares Pequeñas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Nucléolo Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , Pronóstico , Procesamiento Postranscripcional del ARN/genética , ARN Mensajero/genéticaRESUMEN
Sox2, a master transcription factor, contributes to the generation of induced pluripotent stem cells and plays significant roles in sustaining the self-renewal of neural stem cells and glioma-initiating cells. Understanding the functional differences of Sox2 between glioma-initiating cells and normal neural stem cells would contribute to therapeutic approach for treatment of brain tumors. Here, we first demonstrated that Sox2 could contribute to the self-renewal and proliferation of glioma-initiating cells. The following experiments showed that Sox2 was activated at translational level in a subset of human glioma-initiating cells compared with the normal neural stem cells. Further investigation revealed there was a positive correlation between Sox2 and eukaryotic initiation factor 4E (eIF4E) in glioma tissues. Down-regulation of eIF4E decreased Sox2 protein level without altering its mRNA level in glioma-initiating cells, indicating that Sox2 was activated by eIF4E at translational level. Furthermore, eIF4E was presumed to regulate the expression of Sox2 by its 5' untranslated region (5' UTR) sequence. Our results suggest that the eIF4E-Sox2 axis is a novel mechanism of unregulated self-renewal of glioma-initiating cells, providing a potential therapeutic target for glioma.
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Factor 4E Eucariótico de Iniciación/metabolismo , Glioma/metabolismo , Biosíntesis de Proteínas , Factores de Transcripción SOXB1/biosíntesis , Línea Celular Tumoral , Proliferación Celular , Glioma/patología , Humanos , Factores de Transcripción SOXB1/genéticaRESUMEN
Glioma results from unregulated expansion of a self-renewing glioma-initiating cell population. The regulatory pathways which are essential for sustaining the self-renewal of glioma-initiating cells remain largely unknown. Cell surface N-linked oligosaccharides play functional roles in determining cell fate and are associated with glioma malignancy. Previously, we have reported that beta1,4-galactosyltransferase V (beta1,4GalT V) effectively galactosylates the GlcNAcbeta1-->6Man arm of the highly branched N-glycans and positively regulates glioma cell growth. Here, we show that decreasing the expression of beta1,4GalT V by RNA interference in glioma cells attenuated the formation of polylactosamine and inhibited the ability of tumor formation in vivo. Down-regulation of beta1,4GalT V depleted CD133-positive cells in glioma xenograft, and inhibited the self-renewal capacity and the tumorigenic potential of glioma-initiating cells. These data reveal a critical role of beta1,4GalT V in the self-renewal and tumorigenicity of glioma-initiating cells, and indicate that manipulating beta1,4GalT V expression may have therapeutic potential for the treatment of malignant glioma.
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Galactosiltransferasas/fisiología , Glioma/patología , Células Madre Neoplásicas/patología , Amino Azúcares/metabolismo , Animales , Línea Celular Tumoral , Galactosiltransferasas/genética , Técnicas de Silenciamiento del Gen , Glioma/enzimología , Humanos , Ratones , Ratones Desnudos , Células Madre Neoplásicas/enzimología , Polisacáridos/metabolismo , ARN Interferente Pequeño/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Reprograming of proline metabolism is critical for tumor growth. Here we show that PINCH-1 is highly expressed in lung adenocarcinoma and promotes proline synthesis through regulation of mitochondrial dynamics. Knockout (KO) of PINCH-1 increases dynamin-related protein 1 (DRP1) expression and mitochondrial fragmentation, which suppresses kindlin-2 mitochondrial translocation and interaction with pyrroline-5-carboxylate reductase 1 (PYCR1), resulting in inhibition of proline synthesis and cell proliferation. Depletion of DRP1 reverses PINCH-1 deficiency-induced defects on mitochondrial dynamics, proline synthesis and cell proliferation. Furthermore, overexpression of PYCR1 in PINCH-1 KO cells restores proline synthesis and cell proliferation, and suppresses DRP1 expression and mitochondrial fragmentation. Finally, ablation of PINCH-1 from lung adenocarcinoma in mouse increases DRP1 expression and inhibits PYCR1 expression, proline synthesis, fibrosis and tumor growth. Our results identify a signaling axis consisting of PINCH-1, DRP1 and PYCR1 that regulates mitochondrial dynamics and proline synthesis, and suggest an attractive strategy for alleviation of tumor growth.