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When a camera lens is directly faced with a strong light source, image flare commonly occurs, significantly reducing the clarity and texture of the photo and interfering with image processing tasks that rely on visual sensors, such as image segmentation and feature extraction. A novel flare removal network, the Sparse-UFormer neural network, has been developed. The network integrates two core components onto the UFormer architecture: the mixed-scale feed-forward network (MSFN) and top-k sparse attention (TKSA), creating the sparse-transformer module. The MSFN module captures rich multi-scale information, enabling the more effective addressing of flare interference in images. The TKSA module, designed with a sparsity strategy, focuses on key features within the image, thereby significantly enhancing the precision and efficiency of flare removal. Furthermore, in the design of the loss function, besides the conventional flare, background, and reconstruction losses, a structural similarity index loss has been incorporated to ensure the preservation of image details and structure while removing the flare. Ensuring the minimal loss of image information is a fundamental premise for effective image restoration. The proposed method has been demonstrated to achieve state-of-the-art performance on the Flare7K++ test dataset and in challenging real-world scenarios, proving its effectiveness in removing flare artefacts from images.
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BACKGROUND: T-LAK cell-oriented protein kinase (TOPK) strongly promotes the malignant proliferation of cancer cells and is recognized as a promising biomarker of tumor progression. Psoriasis is a common inflammatory skin disease featured by excessive proliferation of keratinocytes. Although we have previously reported that topically inhibiting TOPK suppressed psoriatic manifestations in psoriasis-like model mice, the exact role of TOPK in psoriatic inflammation and the underlying mechanism remains elusive. METHODS: GEO datasets were analyzed to investigate the association of TOPK with psoriasis. Skin immunohistochemical (IHC) staining was performed to clarify the major cells expressing TOPK. TOPK conditional knockout (cko) mice were used to investigate the role of TOPK-specific deletion in IMQ-induced psoriasis-like dermatitis in mice. Flow cytometry was used to analyze the alteration of psoriasis-related immune cells in the lesional skin. Next, the M5-induced psoriasis cell model was used to identify the potential mechanism by RNA-seq, RT-RCR, and western blotting. Finally, the neutrophil-neutralizing antibody was used to confirm the relationship between TOPK and neutrophils in psoriasis-like dermatitis in mice. RESULTS: We found that TOPK levels were strongly associated with the progression of psoriasis. TOPK was predominantly increased in the epidermal keratinocytes of psoriatic lesions, and conditional knockout of TOPK in keratinocytes suppressed neutrophils infiltration and attenuated psoriatic inflammation. Neutrophils deletion by neutralizing antibody greatly diminished the suppressive effect of TOPK cko in psoriasis-like dermatitis in mice. In addition, topical application of TOPK inhibitor OTS514 effectively attenuated already-established psoriasis-like dermatitis in mice. Mechanismly, RNA-seq revealed that TOPK regulated the expression of some genes in the IL-17 signaling pathway, such as neutrophils chemokines CXCL1, CXCL2, and CXCL8. TOPK modulated the expression of neutrophils chemokines via activating transcription factors STAT3 and NF-κB p65 in keratinocytes, thereby promoting neutrophils infiltration and psoriasis progression. CONCLUSIONS: This study identified a crucial role of TOPK in psoriasis by regulating neutrophils infiltration, providing new insights into the pathogenesis of psoriasis.
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Queratinócitos , Quinases de Proteína Quinase Ativadas por Mitógeno , Infiltração de Neutrófilos , Psoríase , Animais , Humanos , Camundongos , Modelos Animais de Doenças , Progressão da Doença , Imiquimode , Queratinócitos/patologia , Queratinócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/metabolismo , Neutrófilos/patologia , Psoríase/patologia , Psoríase/genética , Transdução de Sinais , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Regulação para Cima , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismoRESUMO
The early diagnosis of brain tumors is critical in the area of healthcare, owing to the potentially life-threatening repercussions unstable growths within the brain can pose to individuals. The accurate and early diagnosis of brain tumors enables prompt medical intervention. In this context, we have established a new model called MTAP to enable a highly accurate diagnosis of brain tumors. The MTAP model addresses dataset class imbalance by utilizing the ADASYN method, employs a network pruning technique to reduce unnecessary weights and nodes in the neural network, and incorporates Avg-TopK pooling method for enhanced feature extraction. The primary goal of our research is to enhance the accuracy of brain tumor type detection, a critical aspect of medical imaging and diagnostics. The MTAP model introduces a novel classification strategy for brain tumors, leveraging the strength of deep learning methods and novel model refinement techniques. Following comprehensive experimental studies and meticulous design, the MTAP model has achieved a state-of-the-art accuracy of 99.69%. Our findings indicate that the use of deep learning and innovative model refinement techniques shows promise in facilitating the early detection of brain tumors. Analysis of the model's heat map revealed a notable focus on regions encompassing the parietal and temporal lobes.
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Neoplasias Encefálicas , Humanos , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/diagnóstico , Redes Neurais de Computação , Aprendizado Profundo , Algoritmos , Diagnóstico por Computador/métodos , Imageamento por Ressonância Magnética/métodosRESUMO
Cancer is still a major cause of death worldwide. Unfortunately, the majority of current anticancer treatments suffer many limitations, mainly emergence of resistance and lack of selectivity which necessitate the search for new therapeutics. The TOPK enzyme emerges as a promising target due to its overexpression in many cancer types while being rarely detected in normal tissues. Therefore, targeting TOPK would affect the malignant activity of cancerous cells while sparing normal ones. Further, its vital role in cell division, particularly in cytokinesis, adds to its safety to normal non-multiplying cells. In this study, a combined ligand and structure-based approach was utilized to identify potential TOPK inhibitors. Previously, we identified TOPK inhibitors using a structure-based approach following the construction of a 3D homology model of the TOPK enzyme. Herein, the most active identified inhibitor (lead) was used as a search query to conduct similarity search against PubChem and ChemBridge databases. Retrieved hits were filtered using drug-like filters, docked into the ATP binding site of the enzyme, and finally, the binding free energies of all docked poses were calculated. Based on the computational scores, eight hits were selected as potential TOPK inhibitors. The predicted ADMET descriptors of the eight selected hits were generally favorable. Further, MD simulations of the top scoring hit were conducted to investigate its binding dynamics compared to the lead compound and OTS964 which agreed with the docking results and propose the selected hits as potential TOPK inhibitors. Yet, biochemical testing is still needed to validate these results.Communicated by Ramaswamy H. Sarma.
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T-LAK cell-oriented protein kinase (TOPK) potently promotes malignant proliferation of tumour cells and is considered as a maker of tumour progression. Psoriasis is a common inflammatory skin disease characterized by abnormal proliferation of keratinocytes. However, the role of TOPK in psoriasis has not been well elucidated. This study aims to investigate the expression and role of TOPK in psoriasis, and the role of TOPK inhibitor in psoriasis attenuation. Gene Expression Omnibus datasets derived from psoriasis patients and psoriatic model mice were screened for analysis. Skin specimens from psoriasis patients were collected for TOPK immunohistochemical staining to investigate the expression and localization of TOPK. Next, psoriatic mice model was established to further confirm TOPK expression pattern. Then, TOPK inhibitor was applied to investigate the role of TOPK in psoriasis progression. Finally, cell proliferation assay, apoptosis assay and cell cycle analysis were performed to investigate the potential mechanism involved. Our study showed that TOPK was upregulated in the lesions of both psoriasis patients and psoriatic model mice, and TOPK levels were positively associated with psoriasis progression. TOPK was upregulated in psoriatic lesions and expressed predominantly by epidermal keratinocytes. In addition, TOPK levels in epidermal keratinocytes were positively correlated with epidermal hyperplasia. Furthermore, topical application of TOPK inhibitor OTS514 obviously alleviated disease severity and epidermal hyperplasia. Mechanismly, inhibiting TOPK induces G2/M phase arrest and apoptosis of keratinocytes, thereby attenuating epidermal hyperplasia and disease progression. Collectively, this study identifies that upregulation of TOPK in keratinocytes promotes psoriatic progression, and inhibiting TOPK attenuates epidermal hyperplasia and psoriatic progression.
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Neoplasias , Psoríase , Humanos , Animais , Camundongos , Inibidores de Proteínas Quinases , Hiperplasia/patologia , Células Matadoras Ativadas por Linfocina/metabolismo , Células Matadoras Ativadas por Linfocina/patologia , Linfócitos T/metabolismo , Queratinócitos/metabolismo , Psoríase/metabolismo , Pontos de Checagem do Ciclo Celular , Apoptose/genética , Neoplasias/metabolismo , Proliferação de Células/genéticaRESUMO
T-lymphokine-activated killer cell-originated protein kinase (TOPK) is a serine-threonine kinase that is overexpressed in gastric cancer (GC) and promotes tumor progression. Polyphyllin VII (PPVII), a pennogenin isolated from the rhizomes of Paris polyphylla, shows anticancer effects. Here, we explored the antitumor activity and mechanism of PPVII in GC. Ferroptosis was detected by transmission electron microscope, malondialdehyde, and iron determination assays. Autophagy and its upstream signaling pathway were detected by Western blot, and gene alterations. The binding of PPVII and TOPK was examined through microscale thermophoresis and drug affinity responsive target stability assays. An in vivo mouse model was performed to evaluate the therapeutic of PPVII. PPVII inhibits GC by inducing autophagy-mediated ferroptosis. PPVII promotes the degradation of ferritin heavy chain 1, which is responsible for autophagy-mediated ferroptosis. PPVII activates the Unc-51-like autophagy-activating kinase 1 (ULK1) upstream of autophagy. PPVII inhibits the activity of TOPK, thereby weakening the inhibition of downstream ULK1. PPVII stabilizes the dimer of the inactive form of TOPK by direct binding. PPVII inhibits tumor growth without causing obvious toxicity in vivo. Collectively, this study suggests that PPVII is a potential agent for the treatment of GC by targeting TOPK to activate autophagy-mediated ferroptosis.
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Ferroptose , Neoplasias Gástricas , Humanos , Animais , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Células Matadoras Ativadas por Linfocina/metabolismo , Autofagia , Linhagem Celular TumoralRESUMO
In conversational query answering systems, context plays a significant role in accurately and meaningfully carrying it forward. In many chatbots, such as in Expedia, the discussion quickly degenerates into circling back to restarting the conversation or to inviting a live agent to intervene because the bot could not grasp the context. Contexts shorten interactions by way of implied query constraints to narrow search and to not repeat them in subsequent queries. In this paper, we introduce a novel way of viewing contexts as a distance function via the concept of query relaxation. We demonstrate that a typed domain distance function is sufficient to model context in a conversation. Our approach is based on the idea of non-monotonic constraint inheritance in a context hierarchy.
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Children with Group 3 medulloblastoma (G3 MB) have a very poor prognosis, and many do not survive beyond 5 years after diagnosis. A factor that may contribute to this is the lack of available targeted therapy. Expression of protein lin-28 homolog B (LIN28B), a regulator of developmental timing, is upregulated in several cancers, including G3 MB, and is associated with worse survival in this disease. Here, we investigate the role of the LIN28B pathway in G3 MB and demonstrate that the LIN28B-lethal-7 (let-7; a microRNA that is a tumor suppressor)-lymphokine-activated killer T-cell-originated protein kinase (PBK; also known as PDZ-binding kinase) axis promotes G3 MB proliferation. LIN28B knockdown in G3-MB-patient-derived cell lines leads to a significant reduction in cell viability and proliferation in vitro and in prolonged survival of mice with orthotopic tumors. The LIN28 inhibitor N-methyl-N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide (1632) significantly reduces G3 MB cell growth and demonstrates efficacy in reducing tumor growth in mouse xenograft models. Inhibiting PBK using HI-TOPK-032 also results in a significant reduction in G3 MB cell viability and proliferation. Together, these results highlight a critical role for the LIN28B-let-7-PBK pathway in G3 MB and provide preliminary preclinical results for drugs targeting this pathway.
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Neoplasias Cerebelares , Meduloblastoma , MicroRNAs , Humanos , Camundongos , Animais , Meduloblastoma/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proliferação de Células/genética , MicroRNAs/genética , Neoplasias Cerebelares/genética , Linhagem Celular Tumoral , Proteínas de Ligação a RNA/genéticaRESUMO
T-LAK cell originated protein kinase (TOPK) has been shown to regulate proliferation, invasion or migration of various cancer cells. However, the role of TOPK in follicle environments remains unknown. Here we reveal that TOPK inhibits TNF-α-induced human granulosa COV434 cell apoptosis. The expression of TOPK were increased in COV434 cells in response to TNF-α. TOPK inhibition also decreased TNF-α-induced SIRT1 expression but promoted TNF-α-induced p53 acetylation and expression of PUMA or NOXA. Accordingly, TOPK inhibition attenuated TNF-α-mediated SIRT1 transcriptional activity. In addition, SIRT1 inhibition augmented acetylation of p53 or expression of PUMA and NOXA in response to TNF-α, leading to COV434 cell apoptosis. We conclude that TOPK suppresses TNF-α-induced COV434 granulosa cell apoptosis via regulation of p53/SIRT1 axis, suggesting a potential role of TOPK in regulation of ovarian follicular development.
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Apoptose , Células da Granulosa , Fator de Necrose Tumoral alfa , Proteína Supressora de Tumor p53 , Feminino , Humanos , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células da Granulosa/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
KRAS mutation is the most frequent type of genetic mutation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma. However, KRAS mutation can affect many biological processes and the mechanisms underlying KRAS mutation-mediate carcinogenesis in NSCLC have not been fully understood. In this research, we found that KRASG12C mutation was associated with the upregulation of T-LAK cell-originated protein kinase (TOPK), which is a well-known serine/threonine MAPK-like protein kinase implicated in tumorigenesis. The overexpression of TOPK significantly promoted the malignant phenotype of A549 cells, and TOPK silencing impaired the malignant phenotype with KRASG12C mutation. Moreover, we demonstrated that TOPK level was regulated by MAPK/ERK signalling and the transcription factor Elk1. TOPK was also found to promote the activation of NF-κB signalling in A549 cells with KRASG12C mutation via facilitating the phosphorylation of TAK1. In the in vivo tumorigenesis model, the administration of TOPK inhibitor OTS514 enhanced the anticancer effect of 5-FU, and the combinatory use of OTS514 and KRASG12C inhibitor AMG510 showed synergistic anti-tumour effect. These results suggest that KRAS-TOPK axis contributes to the progression of NSCLC and targeting this axis could synergize with anticancer effect of the existing chemotherapeutics.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinogênese/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Matadoras Ativadas por Linfocina/metabolismo , Células Matadoras Ativadas por Linfocina/patologia , Neoplasias Pulmonares/patologia , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismoRESUMO
BACKGROUND: FYN is a nonreceptor tyrosine kinase that regulates diverse pathological processes. The pro-cancer role of FYN in multiple malignancies has been elucidated. However, the mechanisms that FYN promotes gastric cancer (GC) progression remain largely unknown. METHODS: In vitro and in vivo assays were used to investigate the function of FYN. FYN, TOPK, p-TOPK expression in GC specimens were detected by immunohistochemistry. Phosphoproteomics assays identify TOPK downstream substrate molecules. The molecular mechanism was determined using COIP assays, pull-down assays, immunofluorescence co-localization assays, western blotting, 32p-labeled isotope radioautography assays, vitro kinase assays, and TOPK knockout mice. RESULTS: FYN was found to be significantly upregulated in GC tissues as well as in GC cells. Knockdown of FYN expression markedly attenuated the malignant phenotype of GC cells in vitro and in vivo. Mechanistically, we identified TOPK/PBK as a novel downstream substrate of FYN, FYN directly phosphorylates TOPK at Y272. One phosphospecific antibodies against Y272 was developed to validate the phosphorylation of TOPK by FYN. Moreover, the TOPK-272F mutation impaired the interaction between TOPK and FYN, leading to disappeared TOPK phosphorylation. Consistently, human GC tissues displayed increased p-TOPK(Y272), which correlated with poor survival. Phosphoproteomics results showed a significant downregulation of both HSPB1 and p-HSPB1(ser15) in TOPK-knockdown cells, which was confirmed by TOPK-konckout mice. CONCLUSIONS: FYN directly binds to TOPK in GC cells and phosphorylates TOPK at the Y272, which leads to proliferation and metastasis of GC. FYN-TOPK axis facilitates GC progression by phosphorylating HSPB1. Collectively, our study elucidates the pivotal role of the FYN-TOPK-HSPB1 cascade in GC.
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Quinases de Proteína Quinase Ativadas por Mitógeno , Neoplasias Gástricas , Humanos , Animais , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Linhagem Celular Tumoral , Neoplasias Gástricas/genética , Fosforilação , Proliferação de Células/fisiologia , Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismoRESUMO
Xanthohumol is a principal prenylated chalcone isolated from hops. Previous studies have shown that xanthohumol was effective against various types of cancer, but the mechanisms, especially the direct targets for xanthohumol to exert an anticancer effect, remain elusive. Overexpression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) promotes tumorigenesis, invasion and metastasis, implying the likely potential for targeting TOPK in cancer prevention and treatment. In the present study, we found that xanthohumol significantly inhibited the cell proliferation, migration and invasion of non-small cell lung cancer (NSCLC) in vitro and suppressed tumor growth in vivo, which is well correlated with inactivating TOPK, evidenced by reduced phosphorylation of TOPK and its downstream signaling histone H3 and Akt, and decreased its kinase activity. Moreover, molecular docking and biomolecular interaction analysis showed that xanthohumol was able to directly bind to the TOPK protein, suggesting that TOPK inactivation by xanthohumol is attributed to its ability to directly interact with TOPK. The findings of the present study identified TOPK as a direct target for xanthohumol to exert its anticancer activity, revealing novel insight into the mechanisms underlying the anticancer activity of xanthohumol.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Células Matadoras Ativadas por Linfocina/metabolismo , Células Matadoras Ativadas por Linfocina/patologia , Linhagem Celular TumoralRESUMO
Although esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers, there are major bottlenecks in its therapeutic approaches, primarily the identification of clinically relevant targets and the lack of effective targeted therapeutics. Herein, we identified the hallmarks of ESCC, namely, high T-lymphokine-activated killer cell-originated protein kinase (TOPK) expression in human ESCC tumors and its correlation with poor patient prognosis and hypoxia in the tumor microenvironment. We developed hypoxia-sensitive nanoparticles encapsulating TOPK inhibitor OTS964 and photosensitizer chlorin e6 for the imaging-directed precision therapy of ESCC tumors. The sub-100 nm monodisperse nanoparticles efficiently delivered drugs into the human ESCC KYSE 150 cancer cells to kill the cells. The nanoparticles were selectively accumulated in the ESCC tumors after intravenous (i.v.) injection, thereby enabling the diagnosis and photoacoustic imaging-guided local laser irradiation of tumors. The combination of chemotherapy and photodynamic therapy effectively eradicated human ESCC KYSE 150 tumors and inhibited liver metastasis and recurrence by suppressing TOPK and inducing ESCC cell apoptosis. The nanoparticle-based therapies further stimulated high rates of natural killer cells in ESCC tumors, thereby exhibiting the potential of immunotherapy. This study identified important therapeutic targets of ESCC tumors and delineated an effective nanocarrier-based approach for tumor microenvironment and molecular targeted therapy.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Neoplasias Hepáticas , Humanos , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/tratamento farmacológico , Linhagem Celular Tumoral , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Imunoterapia , Microambiente TumoralRESUMO
Answer sorting and filtering are two closely related steps for determining the answer to a question. Answer sorting is designed to produce an ordered list of scores based on Top-k and contextual criteria. Answer filtering optimizes the selection according to other criteria, such as the range of time constraints the user expects. However, the unclear number of answers and time constraints, as well as the high score of false positive results, indicate that the traditional sorting and selection methods cannot guarantee the quality of answers to multi-answer questions. Therefore, this study proposes MATQA, a component based on multi-answer temporal question reasoning, using a re-validation framework to convert the Top-k answer list output by the QA system into a clear number of answer combinations, and a new multi-answer based evaluation index is proposed for this output form. First, the highly correlated subgraph is selected by calculating the scores of the boot node and the related fact node. Second, the subgraph attention inference module is introduced to determine the initial answer with the highest probability. Finally, the alternative answers are clustered at the semantic level and the time constraint level. Meanwhile, the candidate answers with similar types and high scores but do not satisfy the semantic constraints or the time constraints are eliminated to ensure the number and accuracy of final answers. Experiments on the multi-answer TimeQuestions dataset demonstrate the effectiveness of the answer combinations output by MATQA.
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BACKGROUND: PDZ-binding kinase/T-lymphokine-activated killer cell-derived protein kinase (PBK/TOPK) is a potential prognostic indicator for patients with breast cancer. The objective of the present study was to explore the relationship between PBK/TOPK expression and clinicopathological indicators as well as the survival of patients with breast cancer. METHODS: Immunohistochemical staining was used to detect the expression of PBK/TOPK in 202 cases of breast cancer tissues. The relationship between PBK/TOPK and clinicopathological parameters was evaluated using Spearman's rank-order correlation. The difference in PBK/TOPK expression among different molecular types was analyzed with the chi-square test. Kaplan-Meier analysis was used to create a survival curve and the log rank test was used to analyze the overall survival (OS) and disease-free survival (DFS). Prognostic correlation was assessed using univariate and multivariate Cox regression analyses. RESULTS: Among 202 breast cancer samples, PBK/TOPK was expressed ("+" and "++") in 182 samples (90.1%). In addition, the histological grade, TNM stages, lymph node metastasis, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 were positively associated with PBK/TOPK expression. With regard to the molecular type, the expression of PBK/TOPK is different. The expression level of PBK/TOPK was negatively correlated with both the OS and DFS of breast cancer patients. The difference in the above results is meaningful (P < 0.05). CONCLUSIONS: PBK/TOPK is overexpressed in breast cancer, and the expression is closely related to the clinicopathological characteristics of the disease. Breast cancer patients with high expression of PBK/TOPK have a poor prognosis. Therefore, healthcare providers can optimize breast cancer management using this indicator.
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Neoplasias da Mama , Receptores de Progesterona , Feminino , Humanos , Antígeno Ki-67 , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Prognóstico , Receptores de Estrogênio , Estudos RetrospectivosRESUMO
To overcome the severe side effects of cancer chemotherapy, it is vital to develop targeting chemotherapeutic delivery systems with the potent inhibition of tumour growth, angiogenesis, invasion and migration at low drug dosages. For this purpose, we co-loaded a conventional antiworm drug, albendazole (ABZ), and a TOPK inhibitor, OTS964, into lipid-coated calcium phosphate (LCP) nanoparticles for skin cancer treatment. OTS- and ABZ-loaded LCP (OTS-ABZ-LCP) showed a synergistic cytotoxicity against skin cancer cells through their specific cancerous pathways, without obvious toxicity to healthy cell lines. Moreover, dual-targeting the programmed death ligand-1 (PD-L1) and folate receptor overexpressed on the surface of skin cancer cells completely suppressed the skin tumour growth at low doses of ABZ and OTS. In summary, ABZ and OTS co-loaded dual-targeting LCP NPs represent a promising platform with high potentials against complicated cancers where PD-L1/FA dual targeting appears as an effective approach for efficient and selective cancer therapy.
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Burkitt lymphoma (BL), which is characterized by high invasiveness, is a subgroup of non-Hodgkin lymphoma. Although BL is regarded as a highly curable disease, especially for children, some patients unfortunately still do not respond adequately. The understanding of the etiology and molecular mechanisms of BL is still limited, and targeted therapies are still lacking. Here, we found that T-LAK cell-derived protein kinase (TOPK) and phosphorylated Janus kinase 2 (p-JAK2) are highly expressed in the tissues of BL patients. We report that TOPK directly binds to and is phosphorylated at Tyr74 by JAK2. Histone H3, one of the downstream targets of TOPK, is also phosphorylated in vivo and in vitro. Furthermore, we report that the phosphorylation of TOPK at Tyr74 by JAK2 plays a vital role in the proliferation of BL cells and promotes BL tumorigenesis in vivo. Phosphorylation of TOPK at Tyr74 by JAK2 enhances the stability of TOPK. Collectively, our results suggest that the JAK2/TOPK/histone H3 axis plays a key role in the proliferation of BL cells and BL tumorigenesis in vivo.
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Linfoma de Burkitt , Linfoma de Burkitt/genética , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Criança , Histonas/metabolismo , Humanos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , FosforilaçãoRESUMO
Androgen deprivation therapy (ADT) is a systemic therapy for advanced prostate cancer (PCa). Although most patients initially respond to ADT, almost all cancers eventually develop castration resistance. Castration-resistant PCa (CRPC) is associated with a very poor prognosis, and the treatment of which is a serious clinical challenge. Accumulating evidence suggests that abnormal expression and activation of various kinases are associated with the emergence and maintenance of CRPC. Many efforts have been made to develop small molecule inhibitors to target the key kinases in CRPC. These inhibitors are designed to suppress the kinase activity or interrupt kinase-mediated signal pathways that are associated with PCa androgen-independent (AI) growth and CRPC development. In this review, we briefly summarize the roles of the kinases that are abnormally expressed and/or activated in CRPC and the recent advances in the development of small molecule inhibitors that target kinases for the treatment of CRPC.
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Diffuse large B-cell lymphoma (DLBCL) is one of the most common causes of cancer death worldwide, and responds poorly to the existing treatments. Thus, identifying novel therapeutic targets of DLBCL is urgently needed. In this study, we found that T-lymphokine-activated killer cell-originated protein kinase (TOPK) was highly expressed in DLBCL cells and tissues. Data from the GEPIA database also indicated that TOPK was highly expressed in DLBCL tissues. The high expression levels of proteins were identified via Western blots and immunohistochemistry (IHC). TOPK knockdown inhibited cell growth and induced apoptosis of DLBCL cells with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) and flow cytometry. Further experiments demonstrated that acetylshikonin, a compound that targeted TOPK, could attenuate cell growth and aggravate cell apoptosis through TOPK/extracellular signal-regulated kinase (ERK)-1/2 signaling, as shown by MTS, flow cytometry and Western blots. In addition, we demonstrated that TOPK modulated the effect of acetylshikonin on cell proliferation and apoptosis in U2932 and OCI-LY8 cells using MTS, flow cytometry and Western blots. Taken together, the present study suggests that acetylshikonin suppresses the growth of DLBCL cells by attenuating TOPK signaling, and the targeted inhibition of TOPK by acetylshikonin may be a promising approach for the treatment of DLBCL.
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Antraquinonas/farmacologia , Linfoma Difuso de Grandes Células B , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Tecido Linfoide/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Immune checkpoint inhibitor therapy has proven efficacy in a subset of colon cancer patients featuring a deficient DNA mismatch repair system or a high microsatellite instability profile. However, there is high demand for more effective biomarkers to expand the colon cancer population responding to ICI therapy. PBK/TOPK, a serine/threonine kinase, plays a role in cell cycle regulation and mitotic progression. Here, we investigated the correlation between PBK/TOPK expression and tumor immunity and its prognostic value in colon cancer. Based on large-scale bioinformatics analysis, we discovered that elevated PBK/TOPK expression predicted a favorable outcome in patients with colon cancer and was positively associated with immune infiltration levels of CD8+ T cells, CD4+ T cells, natural killer cells, and M1 macrophages. In contrast, a negative correlation was found between PBK/TOPK expression and immune suppressor cells, including regulatory T cells and M2 macrophages. Furthermore, the expression of PBK/TOPK was correlated with the expression of T-cell cytotoxicity genes in colon cancer. Additionally, high PBK/TOPK expression was associated with mutations in DNA damage repair genes, and thus with increased tumor mutation and neoantigen burden. These findings suggest that PBK/TOPK may serve as a prognostic and predictive biomarker for immunotherapy in colon cancer.