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Glioma is the most frequently diagnosed primary brain tumor and typically has a poor prognosis because of malignant proliferation and invasion. It is urgent to elucidate the mechanisms driving glioma tumorigenesis and develop novel treatments to address this deadly disease. Here, we first revealed that PDZK1 is expressed at high levels in gliomas. Promoter hypomethylation may cause high expression of PDZK1 in glioma. Knockdown of PDZK1 inhibits glioma cell proliferation and invasion in vitro. Mechanistically, further investigations revealed that the loss of PDZK1 expression by siRNA inhibited the activation of the AKT/mTOR signaling pathway, leading to cell cycle arrest and apoptosis. Clinically, high expression of PDZK1 predicts a poorer prognosis for glioma patients than low expression of PDZK1. Overall, our study revealed that PDZK1 acts as a novel oncogene in glioma by binding to AKT1 and maintaining the activation of the AKT/mTOR signaling pathway. Thus, PDZK1 may be a potential therapeutic target for glioma.
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Neoplasias Encefálicas , Metilação de DNA , Glioma , Proteínas de Membrana , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-akt , Humanos , Masculino , Apoptose/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glioma/metabolismo , Glioma/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genéticaRESUMO
Ferroptosis, a therapeutic strategy for tumours, is a regulated cell death characterised by the increased accumulation of iron-dependent lipid peroxides (LPO). Tumour-associated long non-coding RNAs (lncRNAs), when combined with traditional anti-cancer medicines or radiotherapy, can improve efficacy and decrease mortality in cancer. Investigating the role of ferroptosis-related lncRNAs may help strategise new therapeutic options for breast cancer (BC). Herein, we briefly discuss the genes and pathways of ferroptosis involved in iron and reactive oxygen species (ROS) metabolism, including the XC-/GSH/GPX4 system, ACSL4/LPCAT3/15-LOX and FSP1/CoQ10/NAD(P)H pathways, and investigate the correlation between ferroptosis and LncRNA in BC to determine possible biomarkers related to ferroptosis.
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Ferroptose , Neoplasias , RNA Longo não Codificante , Ferroptose/genética , RNA Longo não Codificante/genética , Ferro , Peróxidos Lipídicos , Espécies Reativas de OxigênioRESUMO
Salmonella is a globally prevalent foodborne bacterium, and ceftriaxone and azithromycin have been regarded as drugs of choice for treating Salmonella infections, particularly in children. With the growing incidence of ceftriaxone and azithromycin resistance in Salmonella, there is an urgent requirement for a rapid and dependable gene testing approach to enhance the efficacy of treating Salmonella infections. Utilizing the orange to green visible dye approach, this study developed loop-mediated isothermal amplification (LAMP) assays for the sensitive and specific detection of Salmonella, ceftriaxone and azithromycin resistance genes (including CTX-M-1 group, mph(A), and ermB genes) in stool and blood samples. The specificity and sensitivity of primers during the LAMP assays for detection of Salmonella, CTX-M-1 group, mph(A), and ermB genes were determined in this study. The detection threshold for Salmonella was found to be 1.5 × 103 colony-forming units (CFU)/mL, while it was 1.5 × 102 CFU/mL for CTX-M-1 group genes (including blaCTX-M-3, blaCTX-M-15, and blaCTX-M-55), 1.5 × 102 CFU/mL for mph(A), and 1.5 × 102 CFU/mL for ermB, showing 10-103-fold, 103-fold, and 105-fold increased sensitivity compared with the polymerase chain reaction assay, respectively. Results indicated that the LAMP primers designed for Salmonella, CTX-M-1 group, mph(A), and ermB genes possess high specificity (100%) and sensitivity (over 94%). This novel approach advocates its application in detecting Salmonella, CTX-M-1 group, mph(A), and ermB genes.
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INTRODUCTION: This study examined the cost-effectiveness of first-line toripalimab plus chemotherapy (TC) for patients with advanced non-small cell lung cancer (NSCLC), excluding patients with nonsquamous NSCLC and EGFR/ALK mutations. It further analyzed the cost-effectiveness of this strategy in biomarker-based subgroups, all within the context of the Chinese healthcare system. METHODS: Eighteen Markov models with 21-day Markov cycle lengths and 30-year time horizons were constructed in this study. Clinical effectiveness data were derived from the CHOICE-01 trial. Health state utilities and costs data were obtained from various sources. The primary outputs were the calculation of incremental cost-effectiveness ratios (ICERs), which were then compared to a willingness-to-pay (WTP) threshold of $17,961 per quality-adjusted life-year (QALY). This comparison was used to determine the treatment that offered greater cost-effectiveness. To account for uncertainty in the model, sensitivity analyses were conducted. RESULTS: For the overall patient population, the estimated ICER between first-line TC and placebo plus chemotherapy (PC) was $9445/QALY, significantly lower than the WTP threshold used in the model. In subgroups based on pathologic types, first-line TC had an ICER of $16,757/QALY for patients with nonsquamous NSCLC, slightly below the WTP threshold; first-line TC demonstrated dominance in patients with squamous NSCLC, indicating both better effectiveness and lower costs compared to first-line PC. In biomarkers-based subgroups, first-line TC was dominant over first-line PC in the subgroups with programmed cell death ligand 1 (PD-L1) expression ≥ 50% and SMARCA4 mutations. Moreover, first-line TC had ICERs lower than the WTP threshold in other subgroups, except for the subgroup with RB1 mutations. Sensitivity analysis confirmed the robustness of these findings. CONCLUSION: From the perspective of the Chinese healthcare system, this study's findings suggested that first-line TC represents a cost-effective strategy for patients with advanced NSCLC. However, the cost-effectiveness of first-line TC varied across different subgroups when considering predictive biomarkers.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Análise Custo-Benefício , Neoplasias Pulmonares/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , DNA Helicases , Proteínas Nucleares/uso terapêutico , Fatores de Transcrição/uso terapêuticoRESUMO
Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer-related death among females. Metastasis accounts for the majority of BC related deaths. One feasible strategy to solve this challenging problem is to disrupt the capabilities required for tumor metastasis. Herein, we verified a novel metastasis suppressive circRNA, circPOKE in BC. circPOKE was downregulated in primary and metastatic BC tissues and overexpression of circPOKE inhibited the metastatic potential but not the proliferative ability of BC cells in vitro and in vivo. Mechanistically, circPOKE competitively binds to USP10, and reduces its binding to Snail, a key transcriptional regulator of EMT, thereby inhibiting Snail stability via the protein-ubiquitination degradation pathway. In addition, we found that circPOKE could be secreted into the extracellular space via exosomes and that exosome-carried circPOKE significantly inhibited the invasive capabilities of BC cells in vitro and in vivo. Furthermore, the levels of circPOKE, USP10 and Snail are clinically relevant in BC, suggesting that circPOKE may be used as a potential therapeutic target for patients with BC metastasis.
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Neoplasias da Mama , Melanoma , MicroRNAs , Neoplasias Cutâneas , Feminino , Humanos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Melanoma/genética , Neoplasias Cutâneas/genética , Regulação Neoplásica da Expressão Gênica , Transição Epitelial-Mesenquimal/genética , MicroRNAs/genética , Metástase Neoplásica , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Melanoma Maligno CutâneoRESUMO
Phase separation is now acknowledged as an essential biologic mechanism wherein distinct activated molecules assemble into a different phase from the surrounding constituents of a cell. Condensates formed by phase separation play an essential role in the life activities of various organisms under normal physiological conditions, including the advanced structure and regulation of chromatin, autophagic degradation of incorrectly folded or unneeded proteins, and regulation of the actin cytoskeleton. During malignant transformation, abnormally altered condensate assemblies are often associated with the abnormal activation of oncogenes or inactivation of tumor suppressors, resulting in the promotion of the carcinogenic process. Thus, understanding the role of phase separation in various biological evolutionary processes will provide new ideas for the development of drugs targeting specific condensates, which is expected to be an effective cancer therapy strategy. However, the relationship between phase separation and cancer has not been fully elucidated. In this review, we mainly summarize the main processes and characteristics of phase separation and the main methods for detecting phase separation. In addition, we summarize the cancer proteins and signaling pathways involved in phase separation and discuss their promising future applications in addressing the unmet clinical therapeutic needs of people with cancer. Finally, we explain the means of targeted phase separation and cancer treatment.
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Cell death is a necessary event in life and is crucial for the regulation of organismal development, homeostasis, aging and pathological conditions. There are different modes of cell death, i.e., regulated and nonregulated. Cell death induced by programmed cell death (PCD) has gained increasing attention in recent years. Abnormal control of PCD plays an important role in tumorigenesis. For example, tumor cells are relatively resistant to apoptosis, and the induction of cell death is also an important mechanism underlying the antitumor effects of current clinical chemotherapeutic agents. Recently, studies have revealed that noncoding RNAs (ncRNAs) are involved in regulating multiple biological processes of breast cancer, including PCD. NcRNAs can exert both protumorigenic and antitumorigenic effects, depending on their expression patterns. Therefore, constructing ncRNA-based therapies to target PCD may be a promising therapeutic strategy for breast cancer. Herein, this review discusses the function of various ncRNAs in regulating the PCD of breast cancer cells. In addition, given the recent trend of utilizing ncRNAs as cancer therapeutics, we also discuss the great potential applications of ncRNAs as biomarkers or activators of PCD in breast cancer.
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Antineoplásicos , Neoplasias da Mama , RNA Longo não Codificante , Antineoplásicos/farmacologia , Apoptose/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , RNA Longo não Codificante/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismoRESUMO
Triple-negative breast cancer (TNBC), an aggressive histological subtype of breast cancer, exhibits a high risk of early recurrence rate and a poor prognosis, and it is primarily associated with the abundance of cancer stem cells (CSCs). At present, the strategies for effectively eradicating or inhibiting TNBC CSCs are still limited, which makes the development of novel drugs with anti-CSCs function be of great value for the treatment of TNBC, especially the refractory TNBC. In this study, we found that the small-molecule tyrosine kinase inhibitor DCC-2036 suppressed TNBC stem cells by inhibiting the tyrosine kinase AXL and the transcription factor KLF5. DCC-2036 downregulated the expression of KLF5 by decreasing the protein stability of KLF5 via the AXL-Akt-GSK3ß signal axis, and in turn, the downregulation of KLF5 further reduced the expression of AXL via binding to its promotor (-171 to -162 bp). In addition, p-AXL/AXL levels were positively correlated with KLF5 expression in human TNBC specimens. These findings indicated that DCC-2036 is able to suppress the CSCs in TNBC by targeting the AXL-KLF5 positive feedback loop. Moreover, our findings indicated that DCC-2036 increased the sensitivity of TNBC chemotherapy. Therefore, this study proposes a potential drug candidate and several targets for the treatment of refractory TNBC.
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Neoplasias de Mama Triplo Negativas , Linhagem Celular Tumoral , Proliferação de Células , Receptor DCC , Retroalimentação , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Células-Tronco Neoplásicas/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
BACKGROUND: Although major advances have been made in the histopathological diagnosis of high-grade astrocytoma (HGA), methods for effective and noninvasive diagnosis remain largely unknown. Exosomes can cross the blood-brain barrier and are readily accessible in human biofluids, making them promising biomarkers for HGA. Circular RNAs (circRNAs) have potential as tumor biomarkers owing to their stability, conservation, and tissue specificity. However, the landscape and characteristics of exosome circRNAs in HGA remain to be studied. METHODS: CircRNA deep sequencing and bioinformatics approaches were used to generate a circRNA profiling database and analyze the features of HGA cell circRNAs and HGA cell-derived exosome circRNAs. Exosome circRNA expression in the serum and tissues of healthy individuals and patients with HGA was detected using reverse transcription-quantitative PCR. Additionally, the receiver operating characteristic curve and overall survival curves were analyzed. RESULTS: By investigating the characteristics of HGA cell-derived exosome circRNAs and HGA cell circRNAs, we observed that exosomes were more likely to enrich short-exon and suppressor circRNAs than HGA cells. Moreover, a serum exosome circRNA panel including hsa_circ_0075828, hsa_circ_0003828, and hsa_circ_0002976 could be used to screen for HGA, whereas a good prognosis panel comprised high concentrations of hsa_circ_0005019, hsa_circ_0000880, hsa_circ_0051680, and hsa_circ_0006365. CONCLUSIONS: This study revealed a comprehensive circRNA landscape in HGA exosomes and cells. The serum exosome circexosome circRNA panel and tissue circRNAs are potentially useful for HGA liquid biopsy and prognosis monitoring. Exosome circRNAs as novel targets should facilitate further biomarker discovery and aid in HGA diagnosis and therapy monitoring.
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Astrocitoma , Exossomos , Astrocitoma/diagnóstico , Astrocitoma/genética , Biomarcadores Tumorais/genética , Exossomos/genética , Humanos , RNA/genética , RNA Circular/genética , Análise de Sequência de RNARESUMO
Breast cancer is a malignant tumor that occurs in the glandular epithelium of the breast, and more than 15% of the patients are triple-negative breast cancer (TNBC). Therefore, finding new targets and targeted therapeutic drugs for TNBC is urgent. Overexpression of the AXL is associated with motility and invasiveness of the TNBC cells, which is a potential target for breast cancer therapy. A compound Y041-5921 (IC50 = 6.069 µm for AXL kinase and IC50 = 4.1 µm for MDA-MB-231 cell line) was identified through structure-based virtual screening and bioassay test for the first time. The compound Y041-5921 could significantly inhibit the proliferation and invasion of the TNBC cells and the toxicity of Y041-5921 to normal immortalized breast epithelial cells was far lower than that of commonly used clinical chemotherapy drugs. Besides, it also had well inhibitory effect on the proliferation of many other malignant tumor cell lines (the IC50 value are 10.0 m, 7.1 m, 10.3 m, 11.4 m and 5.8 m for U251 cell, COLO cell, PC-9 cell, CAKI-1 cell and MG63 cell, respectively). The interaction mechanism between Y041-5921 and AXL was studied by molecular dynamics (MD) simulations and binding free energy calculation, and the key residues whose energy contribution mainly comes from non-polar solvation interaction (such as Ala565, Lys567, Met598, Leu620, Pro621, Met623, Lys624, Arg676, Asn677 and Met679) were identified. The small molecule inhibitors Y041-5921 targeting AXL reported in this work will lay a foundation and provide a theoretical basis for the development of the TNBC.
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Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/diagnóstico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Detecção Precoce de Câncer , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Receptor Tirosina Quinase AxlRESUMO
Mounting evidence reveals that dysregulation of circular RNAs (circRNAs) is involved in the development of glioblastoma. Leucine-rich repeat-containing 4 (LRRC4) has been shown to suppress tumors in glioblastoma. However, whether LRRC4 can regulate the formation of circRNA is not yet understood. In this study, LRRC4 was found to interact with SAM68. LRRC4 promoted the generation of circCD44 by inhibiting the binding between SAM68 and CD44 pre-mRNA. Moreover, downregulated expression of circCD44 was found in glioblastoma multiforme (GBM) tissues and GBM primary cells. Re-expression of circCD44 significantly suppressed the proliferation, colony formation, and invasion of GBM cells and inhibited tumor growth in vivo. Mechanistically, circCD44 could regulate the expression of SMAD6 via sponging miR-326 and miR-330-5p involved in the progression of GBM. Thus, the LRRC4/SAM68/circCD44/miR-326/miR-330-5p/SMAD6 signaling axis could be a potential target for GBM treatment.
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BACKGROUND: Leucine rich repeat containing 4 (LRRC4), also known as netrin-G ligand-2 (NGL-2), belongs to the superfamily of LRR proteins and serves as a receptor for netrin-G2. LRRC4 regulates the formation of excitatory synapses and promotes axon differentiation. Mutations in LRRC4 occur in Autism Spectrum Disorder (ASD) and intellectual disability. Multiple sclerosis (MS) is a chronic neuroinflammatory disease with spinal cords demyelination and neurodegeneration. Here, we sought to investigate whether LRRC4 is involved in spinal cords neuron-associated diseases. METHODS: LRRC4 was detected in the CNS of experimental autoimmune encephalomyelitis (EAE) mice by the use of real-time PCR and western blotting. LRRC4-/- mice were created and immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35-55. Pathological changes in spinal cords of LRRC4-/- and WT mice 15 days after immunization were examined by using hematoxylin and eosin (H&E), Luxol Fast Blue (LFB) staining and immunohistochemistry. The number of Th1/Th2/Th17/Treg cells in spleens and blood were measured with flow cytometry. Differential gene expression in the spinal cords from WT and LRRC4-/- mice was analyzed by using RNA sequencing (RNA-seq). Adeno-associated virus (AAV) vectors were used to overexpress LRRC4 (AAV-LRRC4) and were injected into EAE mice to assess the therapeutic effect of AAV-LRRC4 ectopic expression on EAE. RESULTS: We report that LRRC4 is mainly expressed in neuron of spinal cords, and is decreased in the spinal cords of the EAE mice. Knockout of LRRC4 have a disease progression quickened and exacerbated with more severe myelin degeneration and infiltration of leukocytes into the spinal cords. We also first found that Rab7b is high expressed in EAE mice, and the deficiency of LRRC4 induces the elevated NF-κB p65 by up-regulating Rab7b, and up-regulation of IL-6, IFN-γ and down-regulation of TNF-α, results in more severe Th1 immune response in LRRC4-/- mice. Ectopic expression of LRRC4 alleviates the clinical symptoms of EAE mice and protects the neurons from immune damages. CONCLUSIONS: We identified a neuroprotective role of LRRC4 in the progression of EAE, which may be used as a potential target for auxiliary support therapeutic treatment of MS.
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Encefalomielite Autoimune Experimental/genética , Proteínas do Tecido Nervoso/genética , Animais , Citocinas/genética , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neuroproteção , Proteínas Proto-Oncogênicas c-akt/metabolismo , Medula Espinal/metabolismoRESUMO
[This corrects the article DOI: 10.3389/fimmu.2018.01557.].
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Temozolomide (TMZ) insensitivity and resistance are major causes of treatment failure and poor prognosis for GBM patients. Here, we identify LRRC4 as a novel autophagy inhibitor that restores the sensitivity of GBMs to TMZ. LRRC4 was associated with the DEPTOR/mTOR complex, and this interaction resulted in autophagy inhibition. Further investigation demonstrated that the PDZ binding domain of LRRC4 binds to the PDZ domain of DEPTOR. This binding decreases the half-life of DEPTOR via ubiquitination, thus inhibiting GBM cell autophagy and increasing the TMZ treatment response of GBM. Combined LRRC4 expression and TMZ treatment prolonged the survival of mice with tumour xenografts. Furthermore, the levels of LRRC4, DEPTOR and autophagy are clinically relevant for GBM, indicating that LRRC4 is likely to have significant potential as a therapeutic marker and target for TMZ treatment in glioma patients.
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Antineoplásicos Alquilantes/farmacologia , Autofagia/genética , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Temozolomida/farmacologia , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/patologia , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Knockout , Domínios Proteicos/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Ubiquitinação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This corrects the article DOI: 10.21037/apm.2020.03.29.
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BACKGROUND: Chronic osteomyelitis is a serious complication of orthopedic trauma. Residual bacteria after incomplete debridement and/or bacterial colonization, bacterial biofilm formation, and generation of antibiotic-resistant bacterial strains in the microtubule system of compact bones due to irrational use of antibiotics often make the condition more prolonged, recurrent, and refractory. The passive immunotherapy targeting the protein components of bacteria has become an area of intense research interest, for which identifying the bacterial isolates in different areas at different time points remains a key step. Few multicenter randomized controlled trials have investigated the epidemiological data of pathogens in different areas, and there is a lack of timely and dynamic data that can inform clinical treatment. METHODS: A total of 5,268 patients with limb fractures were treated in our center from January 1, 2012, to December 31, 2015, among whom 108 were diagnosed with post-traumatic osteomyelitis (PTO) based on clinical manifestations, imaging findings, and pathology. Bacteria cultures showed positive results in 84 patients. The clinical manifestations (including the infection site) were analyzed. The distribution and drug resistance of pathogens were analyzed and summarized based on the M-100-S22 protocol [Clinical and Laboratory Standards Institute® (CLSI) 2012, USA]. RESULTS: The incidence of PTO in limbs was 2.1% (n=108), and the bacterial cultures were positive in 84 patients (84/108, 77.8%). The infection sites included the tibia and fibula (n=40, 47.6%), femur (n=20, 23.8%), ulna and radium (n=11, 13.1%), humerus (n=5, 6%), patella (n=5, 6%), and calcaneus (n=3, 3.6%). In total, 104 of the following bacterial strains were identified: 56 strains of gram-positive bacteria (53.9%), among which Staphylococcus aureus (n=39, 37.5%) and Staphylococcus epidermis (n=6, 5.8%) were the most dominant bacteria, with both being sensitive to ampicillin, quinupristin, linazolamide, tigarycline, nitrofurantoin, and vancomycin; 48 strains of gram-negative bacteria (46.1%), among which Escherichia coli (n=16, 15.4%) and Enterobacter cloacae (n=11, 10.6%) were the most common bacteria, with both being sensitive to thiomycin; mixed infections were detected in 18 cases (21.4%). CONCLUSIONS: The incidence of PTO in the Zunyi area is similar to the national level. The most common site of infection is the lower extremity. Bacterial infections (mainly infection caused by a single bacterial type) were observed in 77.8% of the cases. Staphylococcus aureus is the most common pathogenic bacteria, followed by Escherichia coli and Enterobacter cloacae. The antibiotic-resistant bacteria have characteristic distributions in different regions.
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Fraturas Ósseas/microbiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Osteomielite/microbiologia , Adulto , Antibacterianos/uso terapêutico , Feminino , Fraturas Ósseas/complicações , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Osteomielite/tratamento farmacológico , Resultado do TratamentoRESUMO
Epithelial ovarian cancer (EOC) is the most malignant gynecological carcinoma and is of a high incidence of death due to detection at late stages when metastasis already occurs. However, the mechanism underlying metastasis of EOC remains unclear. Analysis of the open database and experiments with immunochemistry showed that LRRC4 is lowly expressed in high-grade serous ovarian cancer (HGSC) cells and during EOC metastasis. The 3D cell culture system and the orthotopic ovarian xenograft model infected with LRRC4-containing adeno-associated virus serotype 9 (AAV9) were used to confirm collective invasion and metastasis of cells in vitro and in vivo. Phos-tag SDS-PAGE was used to detect the phosphorylation of LRRC4 and PIK3R1. A number of experiments with methods such as co-immunoprecipitation and immunoblotting were performed to explore the mechanism for the actions of LRRC4 and PIK3R1 in EOC metastasis. An inverse correlation between LRRC4 and E-cadherin expression was detected in the regions of invasion in primary EOC tissues and metastatic ascites. LRRC4 binds to the cSH2 domain of PIK3R1 and inhibits the activity of PIK3R1, without disrupting the physical interactions between PIK3R1 and PIK3CA. LRRC4 inhibits EOC metastasis by targeting E-cadherin-dependent collective cell invasion and does so by inhibiting the PIK3R1-mediated AKT/GSK3ß/ß-catenin signaling pathway. LRRC4 functions as a tumor suppressor gene to inhibit EOC collective invasion and metastasis in vitro and in vivo and does so by directly binding to the cSH2 domain of PIK3R1 to exert its regulatory function. Our findings provide a potential novel approach for metastasis prognosis and a new strategy for the treatment of EOC.
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The homeotic protein SIX3 is a transcription factor vital for neurogenesis and has a bivalent promoter. We previously showed that SIX3 can be transcriptionally silenced by DNA hypermethylation, functions as a tumor suppressor gene, and inhibits human glioblastoma transcriptionally. Here, we show that the activation of epidermal growth factor (EGFR) induces DNA methylation of SIX3 promoter through the MAPK pathway. ERK, when activated, binds with ZNF263, consequently abrogating the ubiquitination of ZNF263 and leading to its stabilization. ZNF263 binds to the core promoter region of SIX3 and recruits the KAP1/HATS/DNMT corepressor complex to induce transcriptional silencing of SIX3 through H3K27me3 and methylation of SIX3 promoter. Activation of the EGFR-ZNF263 signaling axis in phenotypically normal astrocytes or glioblastoma cells triggers or enhances tumorigenic activities, while elevated expression of the EGFR-ZNF263 signaling components in glioblastoma tissues is associated with poor prognosis of the patients. Together, our findings demonstrate that epigenetic silencing of SIX3 is controlled by a sophisticated and highly ordered oncogenic signaling pathway and therefore provide new insights into initiation and progression of glioblastoma.
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Neoplasias Encefálicas/genética , Proteínas de Ligação a DNA/genética , Proteínas do Olho/metabolismo , Glioblastoma/genética , Proteínas de Homeodomínio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Encéfalo/patologia , Encéfalo/cirurgia , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Carcinogênese/genética , Linhagem Celular Tumoral , Metilação de DNA , Progressão da Doença , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Glioblastoma/mortalidade , Glioblastoma/patologia , Glioblastoma/cirurgia , Histonas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases/genética , Prognóstico , Regiões Promotoras Genéticas/genética , Estabilidade Proteica , Ubiquitinação , Proteína Homeobox SIX3RESUMO
Long non-coding RNAs (lncRNAs) play a significant role in post-translational modifications of proteins, yet the importance of lncRNAs for SUMOylation is unknown. rhabdomyosarcoma 2 associated transcript (RMST) expression in glioma tissues and normal brain tissues was measured by quantitative real-time PCR and in situ hybridization. The functional roles of RMST in astrocytomas were demonstrated by a series of in vitro experiments. The potential mechanisms of RMST for SUMOylation were investigated by RNA immunoprecipitation, RNA pull-down, western blotting, and coimmunoprecipitation assays. We first demonstrated the oncogenic activity of lncRNA RMST by inhibiting glioma cells mitophagy. We also first determined that RMST is an enhancer of FUS SUMOylation, especially boosting SUMO1 modification at K333. SUMOylation induced by RMST contributes to the interaction between FUS and heterogeneous nuclear ribonucleoprotein D (hnRNPD) and stabilized their expression and cells mitophagy. Importantly, lncRNA RMST could serve as a promising prognostic factor for glioma patients. Our results demonstrated a previously unknown function of lncRNAs worked as an enhancer in FUS SUMOylation, and RMST will be a significant guide for the development of medications targeting gliomas.
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Galactomannan (GM), 1,3-ß-D-glucan (BDG) and aspergillus-lateral flow device (LFD) are recognized as diagnostic tools for invasive aspergillosis (IA). The combined performance of these assays, however, is inconsistent in various studies. We undertook a meta-analysis of 13 studies involving 1513 patients to evaluate the utility of GM in combination with BDG or LFD for diagnosing IA. The pooled SEN, SPE, PLR, NLR and diagnostic odds ratio (DOR) were calculated and constructed to summarize the overall combined performance. Combining both positive results of GM and BDG assays leaded to the pooled SEN 0.49 (95%CI 0.27-0.72), SPE 0.98 (95%CI 0.94-1.00), PLR 31.68 (95%CI 5.36-187.37), NLR 0.52 (95%CI 0.32-0.84) and DOR 61.23 (95%CI 6.96-538.90). Comparing with GM and BDG assays, both positive results of GM and LFD leaded to high SEN, similar SPE, low PLR and NLR. At least one positive result of GM or LFD conferred great SEN 0.93 and low NLR 0.08. Both positive results of GM and BDG or LFD assay were in favor of confirming the existence of IA. And both negative results of GM and LFD were beneficial to rule out IA. Further studies with sufficient sample size should focus on the diagnostic performance and cost-effectiveness of these combined tests in clinical setting.