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Objectives: Lung cancer is one of the malignant tumors that threaten human health seriously. Long non-coding RNA (lncRNA) is an important factor affecting tumorigenesis and development. However, the mechanism of lncRNA in lung cancer progression remains to be further explored. Methods: In this study, the TCGA database was analyzed, and LINC01572 was found to be increased in lung adenocarcinoma (LUAD) tissues. Thereafter, with the help of databases including lncBase, TargetScan, and mirDIP, as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, LINC01572/miRNA-338-5p/TTK regulatory axis and downstream p53 signaling pathway were excavated. qRT-PCR was adopted to detect levels of LINC01572, miRNA-338-5p, and TTK in LUAD cells. The role that LINC01572 played in LUAD cells was validated by CCK-8 assay, flow cytometry, colony formation, Transwell, and scratch healing assays. The binding ability between LINC01572/TTK and miRNA-338-5p was then verified by dual-luciferase and RIP analysis. Key findings: The results of this study demonstrated that LINC01572 was elevated in LUAD cells compared with normal cells. The overexpression of LINC01572 promoted the proliferative and migratory properties of LUAD cells but inhibited cell apoptosis. The inhibition of LINC01572 resulted in the opposite result. In addition, rescue experiments revealed that LINC01572, as a molecular sponge of miRNA-338-5p, targeted TTK to manipulate p53 for facilitating LUAD cell malignant progression. Apart from this, we constructed a mouse xenograft model and confirmed that the knockdown of LINC01572 hindered the growth of LUAD solid tumors in vivo. Conclusions: Our findings illuminated the molecular mechanism of LINC01572 influencing LUAD and provided new insights for targeted therapy of LUAD cells. [ABSTRACT FROM AUTHOR]

Abstract This review aims to outline mitotic kinase inhibitors’ roles as potential therapeutic targets and assess their suitability as a stand-alone clinical therapy or in combination with standard treatments for advanced-stage solid tumors, including triple-negative breast cancer (TNBC). Breast cancer poses a significant global health risk, with TNBC standing out as the most aggressive subtype. Comprehending the role of mitosis is crucial for understanding how TNBC advances from a solid tumor to metastasis. Chemotherapy is the primary treatment used to treat TNBC. Some types of chemotherapeutic agents target cells in mitosis, thus highlighting the need to comprehend the molecular mechanisms governing mitosis in cancer. This understanding is essential for devising targeted therapies to disrupt these mitotic processes, prevent or treat metastasis, and improve patient outcomes. Mitotic kinases like Aurora kinase A, Aurora Kinase B, never in mitosis gene A-related kinase 2, Threonine-Tyrosine kinase, and Polo-kinase 1 significantly impact cell cycle progression by contributing to chromosome separation and centrosome homeostasis. When these kinases go awry, they can trigger chromosome instability, increase cell proliferation, and activate different molecular pathways that culminate in a transition from epithelial to mesenchymal cells. Ongoing clinical trials investigate various mitotic kinase inhibitors as potential biological treatments against advanced solid tumors. While clinical trials against mitotic kinases have shown some promise in the clinic, more investigation is necessary, since they induce severe adverse effects, particularly affecting the hematopoietic system.

This review aims to outline mitotic kinase inhibitors' roles as potential therapeutic targets and assess their suitability as a stand-alone clinical therapy or in combination with standard treatments for advanced-stage solid tumors, including triple-negative breast cancer (TNBC). Breast cancer poses a significant global health risk, with TNBC standing out as the most aggressive subtype. Comprehending the role of mitosis is crucial for understanding how TNBC advances from a solid tumor to metastasis. Chemotherapy is the primary treatment used to treat TNBC. Some types of chemotherapeutic agents target cells in mitosis, thus highlighting the need to comprehend the molecular mechanisms governing mitosis in cancer. This understanding is essential for devising targeted therapies to disrupt these mitotic processes, prevent or treat metastasis, and improve patient outcomes. Mitotic kinases like Aurora kinase A, Aurora Kinase B, never in mitosis gene A-related kinase 2, Threonine-Tyrosine kinase, and Polo-kinase 1 significantly impact cell cycle progression by contributing to chromosome separation and centrosome homeostasis. When these kinases go awry, they can trigger chromosome instability, increase cell proliferation, and activate different molecular pathways that culminate in a transition from epithelial to mesenchymal cells. Ongoing clinical trials investigate various mitotic kinase inhibitors as potential biological treatments against advanced solid tumors. While clinical trials against mitotic kinases have shown some promise in the clinic, more investigation is necessary, since they induce severe adverse effects, particularly affecting the hematopoietic system. [ABSTRACT FROM AUTHOR]

BackgroundThreonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at the kinetochore, ensuring appropriate chromosome alignment and segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated in cancer patients; however, dual inhibitors have not yet been pursued. Here we present the in vitro and in vivo characterization of a first in class, dual TTK/PLK1 inhibitor (BAL0891).MethodsMechanism of action studies utilized biochemical kinase and proteomics-based target-engagement assays. Cellular end-point assays included immunoblot- and flow cytometry-based cell cycle analyses and SAC integrity evaluation using immunoprecipitation and immunofluorescence approaches. Anticancer activity was assessed in vitro using cell growth assays and efficacy was evaluated, alone and in combination with paclitaxel and carboplatin, using mouse models of triple negative breast cancer (TNBC).ResultsBAL0891 elicits a prolonged effect on TTK, with a transient activity on PLK1. This unique profile potentiates SAC disruption, forcing tumor cells to aberrantly exit mitosis with faster kinetics than observed with a TTK-specific inhibitor. Broad anti-proliferative activity was demonstrated across solid tumor cell lines in vitro. Moreover, intermittent intravenous single-agent BAL0891 treatment of the MDA-MB-231 mouse model of TNBC induced profound tumor regressions associated with prolonged TTK and transient PLK1 in-tumor target occupancy. Furthermore, differential tumor responses across a panel of thirteen TNBC patient-derived xenograft models indicated profound anticancer activity in a subset (~40%). Using a flexible dosing approach, pathologically confirmed cures were observed in combination with paclitaxel, whereas synergy with carboplatin was schedule dependent.ConclusionsDual TTK/PLK1 inhibition represents a novel approach for the treatment of human cancer, including TNBC patients, with a potential for potent anticancer activity and a favorable therapeutic index. Moreover, combination approaches may provide an avenue to expand responsive patient populations.

Abstract Background Threonine and tyrosine kinase (TTK) is associated with invasion and metastasis in various tumors. However, the prognostic importance of TTK and its correlation with immune infiltration in endometrial cancer (EC) remain unclear. Methods The expression profile of TTK was analyzed using data from The Cancer Genome Atlas (TCGA) and the Clinical Proteome Cancer Analysis Consortium (CPTAC). TTK protein and mRNA levels were verified in EC cell lines. Receiver operating characteristic (ROC) curve analysis was used to evaluate the ability of TTK to distinguish between normal and EC tissues. K-M survival analysis was also conducted to evaluate the impact of TTK on survival outcomes. Protein‒protein interaction (PPI) networks associated with TTK were explored using the STRING database. Functional enrichment analysis was performed to elucidate the biological functions of TTK. TTK mRNA expression and immune infiltration correlations were examined using the Tumor Immune Estimation Resource (TIMER) and the Tumor-Immune System Interaction Database (TISIDB). Results TTK expression was significantly greater in EC tissues than in adjacent normal tissues. Higher TTK mRNA expression was associated with tumor metastasis and advanced TNM stage. The protein and mRNA expression of TTK was significantly greater in tumor cell lines than in normal endometrial cell lines. ROC curve analysis revealed high accuracy (94.862%), sensitivity (95.652%), and specificity (94.894%) of TTK in differentiating EC from normal tissues. K-M survival analysis demonstrated that patients with high TTK expression had worse overall survival (OS) and disease-free survival (DFS) rates. Correlation analysis revealed that TTK mRNA expression was correlated with B cells and neutrophils. Conclusion TTK upregulation is significantly associated with poor survival outcomes and immune infiltration in patients with EC. TTK can serve as a potential biomarker for poor prognosis and a promising immunotherapy target in EC. Further investigation of the role of TTK in EC may provide valuable insights for therapeutic interventions and personalized treatment strategies.

Background: Threonine and tyrosine kinase (TTK) is associated with invasion and metastasis in various tumors. However, the prognostic importance of TTK and its correlation with immune infiltration in endometrial cancer (EC) remain unclear. Methods: The expression profile of TTK was analyzed using data from The Cancer Genome Atlas (TCGA) and the Clinical Proteome Cancer Analysis Consortium (CPTAC). TTK protein and mRNA levels were verified in EC cell lines. Receiver operating characteristic (ROC) curve analysis was used to evaluate the ability of TTK to distinguish between normal and EC tissues. K-M survival analysis was also conducted to evaluate the impact of TTK on survival outcomes. Protein‒protein interaction (PPI) networks associated with TTK were explored using the STRING database. Functional enrichment analysis was performed to elucidate the biological functions of TTK. TTK mRNA expression and immune infiltration correlations were examined using the Tumor Immune Estimation Resource (TIMER) and the Tumor-Immune System Interaction Database (TISIDB). Results: TTK expression was significantly greater in EC tissues than in adjacent normal tissues. Higher TTK mRNA expression was associated with tumor metastasis and advanced TNM stage. The protein and mRNA expression of TTK was significantly greater in tumor cell lines than in normal endometrial cell lines. ROC curve analysis revealed high accuracy (94.862%), sensitivity (95.652%), and specificity (94.894%) of TTK in differentiating EC from normal tissues. K-M survival analysis demonstrated that patients with high TTK expression had worse overall survival (OS) and disease-free survival (DFS) rates. Correlation analysis revealed that TTK mRNA expression was correlated with B cells and neutrophils. Conclusion: TTK upregulation is significantly associated with poor survival outcomes and immune infiltration in patients with EC. TTK can serve as a potential biomarker for poor prognosis and a promising immunotherapy target in EC. Further investigation of the role of TTK in EC may provide valuable insights for therapeutic interventions and personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) ranks among the most prevalent forms of cancer globally, and its late-stage survival outcomes are less than optimal. A more nuanced understanding of the underlying mechanisms behind CRC's development is crucial for enhancing patient survival rates. Existing research suggests that the expression of Cell Wall Biogenesis 43 C-Terminal Homolog (CWH43) is reduced in CRC. However, the specific role that CWH43 plays in cancer progression remains ambiguous. Our research seeks to elucidate the influence of CWH43 on CRC's biological behavior and to shed light on its potential as a therapeutic target in CRC management. Utilizing publicly available databases, we examined the expression levels of CWH43 in CRC tissue samples and their adjacent non-cancerous tissues. Our findings indicated lower levels of both mRNA and protein expressions of CWH43 in cancerous tissues. Moreover, we found that a decrease in CWH43 expression correlates with poorer prognoses for CRC patients. In vitro experiments demonstrated that the suppression of CWH43 led to increased cell proliferation, migration, and invasiveness, while its overexpression had inhibitory effects. Further evidence from xenograft models showed enhanced tumor growth upon CWH43 silencing. Leveraging data from The Cancer Genome Atlas (TCGA), our Gene Set Enrichment Analysis (GSEA) indicated a positive relationship between low CWH43 expression and the activation of the epithelial–mesenchymal Transition (EMT) pathway. We conducted RNA sequencing to analyze gene expression changes under both silenced and overexpressed CWH43 conditions. By identifying core genes and executing KEGG pathway analysis, we discovered that CWH43 appears to have regulatory influence over the TTK-mediated cell cycle. Importantly, inhibition of TTK counteracted the tumor-promoting effects caused by CWH43 downregulation. Our findings propose that the decreased expression of CWH43 amplifies TTK-mediated cell cycle activities, thus encouraging tumor growth. This newly identified mechanism offers promising avenues for targeted CRC treatment strategies. [ABSTRACT FROM AUTHOR]

Abstract Background While the increased screening, changes in lifestyle, and recent advances in treatment regimen have decreased colorectal cancer (CRC) mortality, metastatic disease and recurrence remains a major clinical challenge. In the era of precision medicine, the identification of actionable novel therapeutic targets could ultimately offer an alternative treatment strategy for CRC. Methods RNA-Seq was conducted using the illumina platform, while bioinformatics analyses were conducted using CLC genomics workbench and iDEP.951. Colony forming unit, flow cytometry, and fluorescent microscopy were used to assess cell proliferation, cell cycle distribution, and cell death, respectively. The growth potential of CRC cells under 3-dimensional (3D) conditions was assessed using Matrigel. STRING database (v11.5) and Ingenuity Pathway Analysis (IPA) tool were used for network and pathway analyses. CRISPR-Cas9 perturbational effects database was used to identify potential therapeutic targets for CRC, through integration with gene-drug interaction database. Structural modeling and molecular docking were used to assess the interaction between candidate drugs and their targets. Results In the current study, we investigated the therapeutic potential of targeting TPX2, TTK, DDX39A, and LRP8, commonly upregulated genes in CRC identified through differential expression analysis in CRC and adjacent non-cancerous tissue. Targeted depletion of TPX2 and TTK impaired CRC proliferation, cell cycle progression, and organoid formation under 3D culture conditions, while suppression of DDX39A and LRP8 had modest effects on CRC colony formation. Differential expression analysis and bioinformatics on TPX2 and TTK-deficient cells identified cell cycle regulation as the hallmark associated with loss of TPX2 and TTK. Elevated expression of TPX2 and TTK correlated with an oncogenic state in tumor tissue from patients with colon adenocarcinoma, thus corroborating an oncogenic role for the TPX2/TTK network in the pathogenesis of CRC. Gene set enrichment and pathway analysis of TPX2high/TTKhigh CRC identified numerous additional gene targets as integral components of the TPX2/TTK network. Integration of TPX2/TTK enriched network with CRISPR-Cas9 functional screen data identified numerous novel dependencies for CRC. Additionally, gene-drug interaction analysis identified several druggable gene targets enriched in the TPX2/TTK network, including AURKA, TOP2A, CDK1, BIRC5, and many others. Conclusions Our data has implicated an essential role for TPX2 and TTK in CRC pathogenesis and identified numerous potential therapeutic targets and their drug interactions, suggesting their potential clinical use as a novel therapeutic strategy for patients with CRC. Video Abstract

Background: While the increased screening, changes in lifestyle, and recent advances in treatment regimen have decreased colorectal cancer (CRC) mortality, metastatic disease and recurrence remains a major clinical challenge. In the era of precision medicine, the identification of actionable novel therapeutic targets could ultimately offer an alternative treatment strategy for CRC. Methods: RNA-Seq was conducted using the illumina platform, while bioinformatics analyses were conducted using CLC genomics workbench and iDEP.951. Colony forming unit, flow cytometry, and fluorescent microscopy were used to assess cell proliferation, cell cycle distribution, and cell death, respectively. The growth potential of CRC cells under 3-dimensional (3D) conditions was assessed using Matrigel. STRING database (v11.5) and Ingenuity Pathway Analysis (IPA) tool were used for network and pathway analyses. CRISPR-Cas9 perturbational effects database was used to identify potential therapeutic targets for CRC, through integration with gene-drug interaction database. Structural modeling and molecular docking were used to assess the interaction between candidate drugs and their targets. Results: In the current study, we investigated the therapeutic potential of targeting TPX2, TTK, DDX39A, and LRP8, commonly upregulated genes in CRC identified through differential expression analysis in CRC and adjacent non-cancerous tissue. Targeted depletion of TPX2 and TTK impaired CRC proliferation, cell cycle progression, and organoid formation under 3D culture conditions, while suppression of DDX39A and LRP8 had modest effects on CRC colony formation. Differential expression analysis and bioinformatics on TPX2 and TTK-deficient cells identified cell cycle regulation as the hallmark associated with loss of TPX2 and TTK. Elevated expression of TPX2 and TTK correlated with an oncogenic state in tumor tissue from patients with colon adenocarcinoma, thus corroborating an oncogenic role for the TPX2/TTK network in the pathogenesis of CRC. Gene set enrichment and pathway analysis of TPX2high/TTKhigh CRC identified numerous additional gene targets as integral components of the TPX2/TTK network. Integration of TPX2/TTK enriched network with CRISPR-Cas9 functional screen data identified numerous novel dependencies for CRC. Additionally, gene-drug interaction analysis identified several druggable gene targets enriched in the TPX2/TTK network, including AURKA, TOP2A, CDK1, BIRC5, and many others. Conclusions: Our data has implicated an essential role for TPX2 and TTK in CRC pathogenesis and identified numerous potential therapeutic targets and their drug interactions, suggesting their potential clinical use as a novel therapeutic strategy for patients with CRC. 8pAfbPjv5QF2m5WMY3QXvq Video Abstract [ABSTRACT FROM AUTHOR]

Abstract Background Cancer-testis antigens (CTAs) are often expressed in tumor and testicular tissues but not in other normal tissues. To date, there has been no comprehensive study of the expression and clinical significance of CTA genes associated with endometrial cancer (EC) development. Additionally, the clinical relevance, biological role, and molecular mechanisms of the CTA gene TTK protein kinase (TTK) in EC are yet to be fully understood. Methods Using bioinformatics methods, we comprehensively investigated the genomic, transcriptomic, and epigenetic changes associated with aberrant TTK overexpression in EC samples from the TCGA database. We further investigated the mechanisms of the lower survival associated with TTK dysregulation using single-cell data of EC samples from the GEO database. Cell functional assays were used to confirm the biological roles of TTK in EC cells. Results We identified 80 CTA genes that were more abundant in EC than in normal tissues, and high expression of TTK was significantly linked with lower survival in EC patients. Furthermore, ROC analysis revealed that TTK could accurately distinguish stage I EC tissues from benign endometrial samples, suggesting that TTK has the potential to be a biomarker for early EC detection. We found TTK overexpression was more prevalent in EC patients with high-grade, advanced tumors, serous carcinoma, and TP53 alterations. Furthermore, in EC tissue, TTK expression showed a strong positive correlation with EMT-related genes. With single-cell transcriptome data, we identified a proliferative cell subpopulation with high expression of TTK and known epithelial–mesenchymal transition (EMT)-related genes and transcription factors. When proliferative cells were grouped according to TTK expression levels, the overexpressed genes in the TTKhigh group were shown to be functionally involved in the control of chemoresistance. Utilizing shRNA to repress TTK expression in EC cells resulted in substantial decreases in cell proliferation, invasion, EMT, and chemoresistance. Further research identified microRNA-21 (miR-21) as a key downstream regulator of TTK-induced EMT and chemoresistance. Finally, the TTK inhibitor AZ3146 was effective in reducing EC cell growth and invasion and enhancing the apoptosis of EC cells generated by paclitaxel. Conclusion Our findings establish the clinical significance of TTK as a new biomarker for EC and an as-yet-unknown carcinogenic function. This present study proposes that the therapeutic targeting of TTK might provide a viable approach for the treatment of EC.

Dual specificity protein kinase threonine/Tyrosine kinase (TTK) is one of the mitotic kinases. High levels of TTK are detected in several types of cancer. Hence, TTK inhibition is considered a promising therapeutic anti‐cancer strategy. In this work, we used multiple docked poses of TTK inhibitors to augment training data for machine learning QSAR modeling. Ligand‐Receptor Contacts Fingerprints and docking scoring values were used as descriptor variables. Escalating docking‐scoring consensus levels were scanned against orthogonal machine learners, and the best learners (Random Forests and XGBoost) were coupled with genetic algorithm and Shapley additive explanations (SHAP) to determine critical descriptors for predicting anti‐TTK bioactivity and for pharmacophore generation. Three successful pharmacophores were deduced and subsequently used for in silico screening against the NCI database. A total of 14 hits were evaluated in vitro for their anti‐TTK bioactivities. One hit of novel chemotype showed reasonable dose‐response curve with experimental IC50 of 1.0 μM. The presented work indicates the validity of data augmentation using multiple docked poses for building successful machine learning models and pharmacophore hypotheses. [ABSTRACT FROM AUTHOR]

Abstract Molecular epidemiology evidence indicates racial and ethnic differences in the aggressiveness and survival of breast cancer. Hispanics/Latinas (H/Ls) and non-Hispanic Black women (NHB) are at higher risk of breast cancer (BC)-related death relative to non-Hispanic white (NHW) women in part because they are diagnosed with hormone receptor-negative (HR) subtype and at higher stages. Since the cell cycle is one of the most commonly deregulated cellular processes in cancer, we propose that the mitotic kinases TTK (or Mps1), TBK1, and Nek2 could be novel targets to prevent breast cancer progression among NHBs and H/Ls. In this study, we calculated levels of TTK, p-TBK1, epithelial (E-cadherin), mesenchymal (Vimentin), and proliferation (Ki67) markers through immunohistochemical (IHC) staining of breast cancer tissue microarrays (TMAs) that includes samples from 6 regions in the Southeast of the United States and Puerto Rico -regions enriched with NHB and H/L breast cancer patients. IHC analysis showed that TTK, Ki67, and Vimentin were significantly expressed in triple-negative (TNBC) tumors relative to other subtypes, while E-cadherin showed decreased expression. TTK correlated with all of the clinical variables but p-TBK1 did not correlate with any of them. TCGA analysis revealed that the mRNA levels of multiple mitotic kinases, including TTK, Nek2, Plk1, Bub1, and Aurora kinases A and B, and transcription factors that are known to control the expression of these kinases (e.g. FoxM1 and E2F1-3) were upregulated in NHBs versus NHWs and correlated with higher aneuploidy indexes in NHB, suggesting that these mitotic kinases may be future novel targets for breast cancer treatment in NHB women.

Abstract Background Temozolomide (TMZ) resistance remains the main therapy challenge in patients with glioblastoma multiforme (GBM). TTK Protein Kinase (TTK) contributes to the radioresistance and chemoresistance in many malignancies. However, the role of TTK in the TMZ resistance of GBM cells remains unknown. Methods The expression of TTK was measured by western blot. The proliferation of GBM cells was assessed through MTT assay and clonogenic assay. Cell apoptosis was evaluated using western blot. LC3B puncta were detected using immunohistochemistry staining. The mouse xenograft model was used to investigate the role of TTK in vivo. Results Knockdown of TTK increased the sensitivity of GBM cells to TMZ treatment, while overexpression of TTK induced TMZ resistance. Two specific TTK inhibitors, BAY-1217389 and CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ. In addition, the knockdown of TTK decreased the autophagy levels of GBM cells. Inhibition of TTK using specific inhibitors could also suppress the autophagy process. Blocking autophagy using chloroquine (CQ) abolished the TMZ resistance function of TTK in GBM cells and in the mouse model. Conclusions We demonstrated that TTK promotes the TMZ resistance of GBM cells by inducing autophagy in vitro and in vivo. The use of a TTK inhibitor in combination with TMZ might help to overcome TMZ resistance and improve therapy efficiency in GBM.

Colorectal cancer (CRC) ranks among the most prevalent forms of cancer globally, and its late-stage survival outcomes are less than optimal. A more nuanced understanding of the underlying mechanisms behind CRC’s development is crucial for enhancing patient survival rates. Existing research suggests that the expression of Cell Wall Biogenesis 43 C-Terminal Homolog (CWH43) is reduced in CRC. However, the specific role that CWH43 plays in cancer progression remains ambiguous. Our research seeks to elucidate the influence of CWH43 on CRC’s biological behavior and to shed light on its potential as a therapeutic target in CRC management. Utilizing publicly available databases, we examined the expression levels of CWH43 in CRC tissue samples and their adjacent non-cancerous tissues. Our findings indicated lower levels of both mRNA and protein expressions of CWH43 in cancerous tissues. Moreover, we found that a decrease in CWH43 expression correlates with poorer prognoses for CRC patients. In vitro experiments demonstrated that the suppression of CWH43 led to increased cell proliferation, migration, and invasiveness, while its overexpression had inhibitory effects. Further evidence from xenograft models showed enhanced tumor growth upon CWH43 silencing. Leveraging data from The Cancer Genome Atlas (TCGA), our Gene Set Enrichment Analysis (GSEA) indicated a positive relationship between low CWH43 expression and the activation of the epithelial–mesenchymal Transition (EMT) pathway. We conducted RNA sequencing to analyze gene expression changes under both silenced and overexpressed CWH43 conditions. By identifying core genes and executing KEGG pathway analysis, we discovered that CWH43 appears to have regulatory influence over the TTK-mediated cell cycle. Importantly, inhibition of TTK counteracted the tumor-promoting effects caused by CWH43 downregulation. Our findings propose that the decreased expression of CWH43 amplifies TTK-mediated cell cycle activities, thus encouraging tumor growth. This newly identified mechanism offers promising avenues for targeted CRC treatment strategies.

Background High expression levels of the TTK gene are closely related to tumor occurrence and poor prognosis, as confirmed by some studies. Our study explored the prognosis of lung adenocarcinoma (LUAD) patients with different TTK levels and the possible pathological mechanism of TTK in LUAD.Methods We extensively searched literature databases and high-throughput sequencing databases and included relevant literature or datasets in the meta-analysis according to the inclusion and exclusion criteria. Hazard ratios (HRs) and 95% confidence intervals (CIs) related to TTK expression were calculated, publication bias was assessed, and sensitivity tests were performed. We also compared the relationship between cancer immune infiltrating cells and tumor mutation burden (TMB) in patients with different TTK expression levels via bioinformatics analysis. The half maximal inhibitory concentration (IC50) of some chemotherapeutic and targeted therapy drugs were calculated. The potential biological functions or pathways associated with different TTK expression levels were determined by gene set enrichment analysis (GSEA).Results The meta-analysis revealed that higher TTK expression level was significantly associated with poor prognosis in LUAD patients, both in overall survival (OS) and progression-free survival (PFS). The expression level of TTK was significantly correlated with presence of some immune cells and TMB. Tumors with higher TTK expression levels were mostly enriched for the cell cycle, DNA replication and homologous recombination pathways. In addition, patients with different TTK expression levels were differently sensitive to some antitumor drugs.Conclusion TTK may be a promising prognostic biomarker for LUAD and is worthy of further investigation.

Molecular epidemiology evidence indicates racial and ethnic differences in the aggressiveness and survival of breast cancer. Hispanics/Latinas (H/Ls) and non-Hispanic Black women (NHB) are at higher risk of breast cancer (BC)-related death relative to non-Hispanic white (NHW) women in part because they are diagnosed with hormone receptor-negative (HR) subtype and at higher stages. Since the cell cycle is one of the most commonly deregulated cellular processes in cancer, we propose that the mitotic kinases TTK (or Mps1), TBK1, and Nek2 could be novel targets to prevent breast cancer progression among NHBs and H/Ls. In this study, we calculated levels of TTK, p-TBK1, epithelial (E-cadherin), mesenchymal (Vimentin), and proliferation (Ki67) markers through immunohistochemical (IHC) staining of breast cancer tissue microarrays (TMAs) that includes samples from 6 regions in the Southeast of the United States and Puerto Rico -regions enriched with NHB and H/L breast cancer patients. IHC analysis showed that TTK, Ki67, and Vimentin were significantly expressed in triple-negative (TNBC) tumors relative to other subtypes, while E-cadherin showed decreased expression. TTK correlated with all of the clinical variables but p-TBK1 did not correlate with any of them. TCGA analysis revealed that the mRNA levels of multiple mitotic kinases, including TTK, Nek2, Plk1, Bub1, and Aurora kinases A and B, and transcription factors that are known to control the expression of these kinases (e.g. FoxM1 and E2F1-3) were upregulated in NHBs versus NHWs and correlated with higher aneuploidy indexes in NHB, suggesting that these mitotic kinases may be future novel targets for breast cancer treatment in NHB women. [ABSTRACT FROM AUTHOR]

Background: Temozolomide (TMZ) resistance remains the main therapy challenge in patients with glioblastoma multiforme (GBM). TTK Protein Kinase (TTK) contributes to the radioresistance and chemoresistance in many malignancies. However, the role of TTK in the TMZ resistance of GBM cells remains unknown.Methods: The expression of TTK was measured by western blot. The proliferation of GBM cells was assessed through MTT assay and clonogenic assay. Cell apoptosis was evaluated using western blot. LC3B puncta were detected using immunohistochemistry staining. The mouse xenograft model was used to investigate the role of TTK in vivo.Results: Knockdown of TTK increased the sensitivity of GBM cells to TMZ treatment, while overexpression of TTK induced TMZ resistance. Two specific TTK inhibitors, BAY-1217389 and CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ. In addition, the knockdown of TTK decreased the autophagy levels of GBM cells. Inhibition of TTK using specific inhibitors could also suppress the autophagy process. Blocking autophagy using chloroquine (CQ) abolished the TMZ resistance function of TTK in GBM cells and in the mouse model.Conclusions: We demonstrated that TTK promotes the TMZ resistance of GBM cells by inducing autophagy in vitro and in vivo. The use of a TTK inhibitor in combination with TMZ might help to overcome TMZ resistance and improve therapy efficiency in GBM. [ABSTRACT FROM AUTHOR]

Background: Threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at the kinetochore, ensuring appropriate chromosome alignment and segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated in cancer patients; however, dual inhibitors have not yet been pursued. Here we present the in vitro and in vivo characterization of a first in class, dual TTK/PLK1 inhibitor (BAL0891)., Methods: Mechanism of action studies utilized biochemical kinase and proteomics-based target-engagement assays. Cellular end-point assays included immunoblot- and flow cytometry-based cell cycle analyses and SAC integrity evaluation using immunoprecipitation and immunofluorescence approaches. Anticancer activity was assessed in vitro using cell growth assays and efficacy was evaluated, alone and in combination with paclitaxel and carboplatin, using mouse models of triple negative breast cancer (TNBC)., Results: BAL0891 elicits a prolonged effect on TTK, with a transient activity on PLK1. This unique profile potentiates SAC disruption, forcing tumor cells to aberrantly exit mitosis with faster kinetics than observed with a TTK-specific inhibitor. Broad anti-proliferative activity was demonstrated across solid tumor cell lines in vitro . Moreover, intermittent intravenous single-agent BAL0891 treatment of the MDA-MB-231 mouse model of TNBC induced profound tumor regressions associated with prolonged TTK and transient PLK1 in-tumor target occupancy. Furthermore, differential tumor responses across a panel of thirteen TNBC patient-derived xenograft models indicated profound anticancer activity in a subset (~40%). Using a flexible dosing approach, pathologically confirmed cures were observed in combination with paclitaxel, whereas synergy with carboplatin was schedule dependent., Conclusions: Dual TTK/PLK1 inhibition represents a novel approach for the treatment of human cancer, including TNBC patients, with a potential for potent anticancer activity and a favorable therapeutic index. Moreover, combination approaches may provide an avenue to expand responsive patient populations., Competing Interests: EZ, NF-G, FB, PM, KB, AG, MR, MS and HL were all previous employees of Basilea Pharmaceutica International Ltd, Allschwil. AB, KL, LK and LB are current employees of Basilea Pharmaceutica International Ltd, Allschwil. MS, AB, KL, LK and HL are also Basilea Pharmaceutica International Ltd, Allschwil, stockholders. HL is also a consultant for SillaJen Inc. NW-S, HR and GZ are employees of Oncolines BV and previous Netherlands Translational Research Center NTRC B.V. employees. JM, D-VP and RB are employees of Crossfire Oncology BV formerly Netherlands Translational Research Center NTRC B.V. The studies presented in this manuscript were funded by Basilea Pharmaceutica International Ltd, Allschwil. The funder contributed to study design, as well as the collection, analysis, and interpretation of the results., (Copyright © 2024 Zanini, Forster-Gross, Bachmann, Brüngger, McSheehy, Litherland, Burger, Groner, Roceri, Bury, Stieger, Willemsen-Seegers, de Man, Vu-Pham, van Riel, Zaman, Buijsman, Kellenberger and Lane.)

High expression levels of the TTK gene are closely related to tumor occurrence and poor prognosis, as confirmed by some studies. Our study explored the prognosis of lung adenocarcinoma (LUAD) patients with different TTK levels and the possible pathological mechanism of TTK in LUAD. We extensively searched literature databases and high-throughput sequencing databases and included relevant literature or datasets in the meta-analysis according to the inclusion and exclusion criteria. Hazard ratios (HRs) and 95% confidence intervals (CIs) related to TTK expression were calculated, publication bias was assessed, and sensitivity tests were performed. We also compared the relationship between cancer immune infiltrating cells and tumor mutation burden (TMB) in patients with different TTK expression levels via bioinformatics analysis. The half maximal inhibitory concentration (IC50) of some chemotherapeutic and targeted therapy drugs were calculated. The potential biological functions or pathways associated with different TTK expression levels were determined by gene set enrichment analysis (GSEA). The meta-analysis revealed that higher TTK expression level was significantly associated with poor prognosis in LUAD patients, both in overall survival (OS) and progression-free survival (PFS). The expression level of TTK was significantly correlated with presence of some immune cells and TMB. Tumors with higher TTK expression levels were mostly enriched for the cell cycle, DNA replication and homologous recombination pathways. In addition, patients with different TTK expression levels were differently sensitive to some antitumor drugs. TTK may be a promising prognostic biomarker for LUAD and is worthy of further investigation. [ABSTRACT FROM AUTHOR]

Yudong Tian,1 Yanbin Guan,2 Yang Su,1 Wenjian Luo,1 Guo Yang,1 Yu Zhang1 1Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, People’s Republic of China; 2School of Pharmacy, Henan University of Traditional Chinese Medicine, Zhengzhou 450000, Henan, People’s Republic of ChinaCorrespondence: Yudong TianDepartment of Urology, The First Affiliated Hospital of Zhengzhou University, No. 1 Longhu Zhonghuan Road, Jinshui District, Zhengzhou 450000, Henan, People’s Republic of ChinaTel +86 150 371 83651Email tian_yd95@163.comBackground: Bladder cancer (BC) refers to the malignant growth found in the cells and tissues of the urinary bladder. While many studies have researched the progression of BC, scientists are yet to fully understand the mechanism of BC. This research aimed to explore the role of miR-582-5p and its target gene TTK in BC pathogenesis.Methods: The evaluation of miR-582-5p and TTK mRNA expression in BC tissues or cells was performed using qRT-PCR. TargetScan was then used to predict the binding site of miR-582-5p on TTK mRNA. Subsequently, dual-luciferase reporter and RNA pull-down assays were employed to validate the binding relationship between miR-582-5p and TTK mRNA. CCK-8, BrdU, flow cytometry, and caspase-3 activity assays were later conducted to evaluate the viability, proliferation, cell cycle, and apoptosis of BC cells.Results: Investigations revealed that miR-582-5p was downregulated in BC tissues and cells. Meanwhile, miR-582-5p inhibited the viability and proliferation of BC cells while stimulating the apoptosis and cycle arrest of the cells. TTK, the target gene of miR-582-5p, was later found to be over-expressed in BC tissues and cells. TTK, however, was observed to exhibit an opposite effect on miR-582-5p. Simply put, it stimulated BC cell malignant phenotypes, and this stimulation could be directly reversed by miR-582-5p.Conclusion: This research confirmed that miR-582-5p could restrain bladder carcinogenesis by inhibiting TTK expression.Keywords: bladder cancer, miR-582-5p, TTK, proliferation, apoptosis

TTK (also known as Mps1) is the core component of the spindle assembly checkpoint, which ensures proper distribution of chromosomes to daughter cells to maintain genome integrity and to balance growth and division. However, the function of TTK in tumorigenesis has not been extensively studied, especially in relation to the development of gastric cancer. In this study, survival and tumor recurrence data related to TTK expression level in gastric cancer patients were collected and analyzed. We observed that TTK expression was negatively correlated with survival and tumor recurrence in vivo. TTK was also upregulated in gastric cancer cells and was observed to be essential for the proliferation and survival of gastric cancer cells. Knockdown of TTK inhibited proliferation and increased apoptosis. Furthermore, we report that TTK regulates the proliferation and apoptosis of tumor cells through the Akt‐mTOR pathway. Knockdown of TTK inhibited activation of Akt‐mTOR signaling. In summary, our data indicate that TTK is involved in the regulation of gastric cancer proliferation and apoptosis.

The bioluminescent Leishmania infantum BALB/c mouse model was used to evaluate the parasiticidal drug action kinetics of the reference drugs miltefosine, paromomycin, sodium stibogluconate, and liposomal amphotericin B. Infected mice were treated for 5 days starting from 7 days post-infection, and parasite burdens were monitored over time via bioluminescence imaging (BLI). Using nonlinear regression analyses of the BLI signal, the parasite elimination half-life ( t 1/2 ) in the liver, bone marrow, and whole body was determined and compared for the different treatment regimens. Significant differences in parasiticidal kinetics were recorded. A single intravenous dose of 0.5 mg/kg liposomal amphotericin B was the fastest acting with a t 1/2 of less than 1 day. Intraperitoneal injection of paromomycin at 320 mg/kg for 5 days proved to be the slowest with a t 1/2 of about 5 days in the liver and 16 days in the bone marrow. To conclude, evaluation of the cidal kinetics of the different antileishmanial reference drugs revealed striking differences in their parasite elimination half-lives. This BLI approach also enables an in-depth pharmacodynamic comparison between novel drug leads and may constitute an essential tool for the design of potential drug combinations.

The monopolar spindle 1 ((hMps1/TTK) is a serine/threonine kinase that plays an important role in spindle assembly checkpoint signaling. To explore the possible relationship between TTK inhibition and radiosensitivity, we examined whether TTK inhibition influences cellular susceptibility of radiation. And we further revealed its mechanisms. We found that the expression of TTK was obviously higher in liver cancer tissues compared to the normal liver tissues. Kaplan-Meier Plotter demonstrated that patients with low TTK expression levels had a longer overall survival than patients with high TTK expression levels. TTK inhibitor AZ3146 could simulated liver cancer cells to accumulate in the G2/M phase, which ultimately enhances DNA damage with more γ-H2AX foci and more apoptosis and necrosis induced by radiation, which prompted that TTK inhibition sensitized liver cancer cells to radiation. In addition, TTK inhibition altered cell-cycle progression and exacerbated centrosome abnormalities, resulting in enhanced mitotic catastrophe (MC) induced by radiation in a p21-mediated manner. In this study, we present evidences that the TTK inhibitor promotes the radiosensitivity of liver cancer cells through regulating cell cycle in p21-mediated manner in vitro, indicating that TTK inhibitor may be an attractive radiosensitizer for the patients with liver cancer. • TTK acted as an oncogene in liver cancer and indicator of poor survival prognosis. • TTK inhibitor increase radiosensitivity in liver cancer. • TTK inhibitor promote liver cancer cells to accumulate in the G2/M phase. • TTK inhibitor enhances DNA damage with more γ-H2AX foci and more apoptosis and necrosis induced by radiation. • TTK inhibitor enhance mitotic catastrophe (MC) induced by radiation in a p21-mediated manner. [ABSTRACT FROM AUTHOR]

Despite progress in the application of checkpoint immunotherapy against various tumors, attempts to utilize immune checkpoint blockade (ICB) agents in triple negative breast cancer (TNBC) have yielded limited clinical benefits. The low overall response rate of checkpoint immunotherapy in TNBC may be attributed to the immunosuppressive tumor microenvironment (TME). In this study, we investigated the role of mitogen-associated kinase TTK in reprogramming immune microenvironment in TNBC. Notably, TTK inhibition by BAY-1217389 induced DNA damage and the formation of micronuclei containing dsDNA in the cytosol, resulting in elicition of STING signal pathway and promoted antitumor immunity via the infiltration and activation of CD8+ T cells. Moreover, TTK inhibition also upregulated the expression of PD-L1, demonstrating a synergistic effect with anti-PD1 therapy in 4T1 tumor-bearing mice. Taken together, TTK inhibition facilitated anti-tumor immunity mediated by T cells and enhanced sensitivity to PD-1 blockade, providing a rationale for the combining TTK inhibitors with immune checkpoint blockade in clinical trials. • Breast cancer, especially triple negative breast cancer, shows higher TTK expression than normal breast tissue. • Inhibition of TTK generates cytosolic dsDNA and activates STING signaling in TNBC cells. • TTK inhibitor suppresses 4T1 tumor growth dependent on CD8+ T cells and modulates tumor immune microenvironment. • Inhibition of TTK synergistically enhances the effectiveness of anti-PD1 therapy in subcutaneous 4T1 tumor model. [ABSTRACT FROM AUTHOR]

The main factor for the development of Cervical Cancer (CC) is infection by the high-risk human papillomavirus (HR-HPV). In exploring new molecular markers to identify women at high risk of developing cancer, the study of MAD2 and TTK is proposed. The aim of this study was to explore the expression levels and prognostic significance of MAD2 and TTK in CC using bioinformatics. Finally, the findings will be verified in samples of tumors and cell lines. MAD2 and TTK expression through GEPIA, PP interaction through STRING, as well as KEGG and survival analysis. Data was analyzed using UCSC Xena, to see its association with HPV. Expression levels of MAD2 and TTK were determined using RT-qPCR. Results showed the expression of the MAD2 and TTK genes was higher in tumor samples compared to control samples in both genes, having a statistically significant result (p < 0.005). in conclusion the expression analysis reveals that high expression of MAD2 and TTK may contribute to the development of cervical cancer and may serve as a potential diagnostic target for CC. [ABSTRACT FROM AUTHOR]

Copyright of Practical Oncology Journal is the property of Journal of Practical Oncology Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Basal-like breast cancers have the highest rates of locoregional recurrence after radiation. By correlating gene expression with early locoregional recurrence, we nominate TTK protein kinase as a mediator of radioresistance. TTK inhibition radiosensitizes in vitro and in vivo through a novel mechanism of impaired homologous recombination and represents a promising translational strategy.

TTK (also known as Mps1) is the core component of the spindle assembly checkpoint, which ensures proper distribution of chromosomes to daughter cells to maintain genome integrity and to balance growth and division. However, the function of TTK in tumorigenesis has not been extensively studied, especially in relation to the development of gastric cancer. In this study, survival and tumor recurrence data related to TTK expression level in gastric cancer patients were collected and analyzed. We observed that TTK expression was negatively correlated with survival and tumor recurrence in vivo. TTK was also upregulated in gastric cancer cells and was observed to be essential for the proliferation and survival of gastric cancer cells. Knockdown of TTK inhibited proliferation and increased apoptosis. Furthermore, we report that TTK regulates the proliferation and apoptosis of tumor cells through the Akt‐mTOR pathway. Knockdown of TTK inhibited activation of Akt‐mTOR signaling. In summary, our data indicate that TTK is involved in the regulation of gastric cancer proliferation and apoptosis. [ABSTRACT FROM AUTHOR]

In today's business world, managers have a growing awareness that psychological capital is the most important type of capital that brings productivity, reproductivity and profitability to their organizations. The dimensions of psychological capital, including self-efficacy, optimism, hope and psychological resilience, are the factors that bring success to organizations. The aim of this study is to determine psychological capital dimensions of the underground miners employed by the Turkish Hard Coal Enterprise (TCMC) - Kozlu Establishment (Türkiye Taş Kömürü Kurumu (TTK) - Kozlu Müessesesi). In order to determine the psychological capital dimensions of the miners, a questionnaire was applied to 344 underground miners. Analyzes were made by using SPSS 22 and AMOS 24 package programs. Exploratory factor analysis and confirmatory factor analysis were used to determine the psychological capital dimensions of miners. According to the results of analyze, the psychological capital factors of the miners appear as hope and self-efficacy. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the expression levels of TTK in clear cell renal cell carcinoma (ccRCC) tissues and its possible link with the clinical pathologic characteristics and the prognosis of patients suffering this disease, and to further explore the potential role of TTK in the progression of ccRCC. Immunohistochemical (IHC) assays were performed to detect the expression levels of TTK in 112 samples of ccRCC tissues and corresponding non-tumor tissues. According to the results of IHC assays, patients were divided into TTK high expression and low expression group. Clinical analysis related to the clinical features (age, gender, T stage), and the potential link between TTK expression levels and clinical features were analyzed. In addition, the effects of TTK on the proliferation and invasion of ccRCC cells were detected through colony formation assay and transwell assays, respectively. The possible effects of TTK on tumor growth and metastasis were measured in mice. We found a high expression level of TTK in human ccRCC tissues from patients who received surgical treatment. We also found its expression level was obviously associated with clinical characteristics, such as T stage (p=0.008) and lymphatic metastasis (p=0.023). We further confirmed that knockdown of TTK suppressed cell proliferation and invasion in 2 types of ccRCC cells, HTB-47 and CRL-1932 cells. Furthermore, TTK contributes to tumor growth and metastasis of ccRCC in mice. We found that TTK affected the progression of ccRCC and further mechanically confirmed it could be a novel therapeutic target for ccRCC treatment. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most common malignancies among females, and its prognosis is affected by a complex network of gene interactions. In this study, we constructed free-scale gene co-expression networks using weighted gene co-expression network analysis (WGCNA). The gene expression profiles of GSE25055 were downloaded from the Gene Expression Omnibus (GEO) database to identify potential biomarkers associated with breast cancer progression. GSE42568 was downloaded for validation. A total of 9 modules were established via the average linkage hierarchical clustering. We identified 3 hub genes (ASPM, CDC20, and TTK) in the significant module (R2 = 0.52), which were significantly correlated with poor prognosis both in test and validation datasets. In the datasets GSE25055 and GSE42568, higher expression levels of ASPM, CDC20, and TTK correlated with advanced tumor grades. Immunohistochemistry data from the Human Protein Atlas also demonstrated that their protein levels were higher in tumor samples. According to gene set enrichment analysis, 4 commonly enriched pathways were identified: cell cycle pathway, DNA replication pathway, homologous recombination pathway, and P53 signaling pathway. In addition, strong correlations were found among their expression levels. In conclusion, our WGCNA analysis identified candidate prognostic biomarkers for further basic and clinical researches.

The immunotherapy agent pembrolizumab has been approved for gastric cancer (GC) patients with recurrent or advanced disease who are PD-L1 positive. Mutations in the primary lesion may drive the expression of immune targets thereby priming the tumor to therapeutic sensitivity. In this study, we aimed to uncover mutations associated with elevated PD-L1 expression in GC patients. Data from 410 GC patients were available, including the mutational spectrum of 39,916 genes and expression values of 20,500 genes. PD-L1 gene expression was compared to the mutational status of each gene separately by using a Mann-Whitney U-test and a Receiver Operating Characteristic test. Only mutations with a prevalence over 5% were considered. Significance was accepted in cases of p < 1E-05 and a fold change over 1.44. Mutations in 209 genes were associated with increased PD-L1 expression. These mutations were enriched in genes related to microtubule-based movement (p = 3.4E-4), cell adhesion (p = 4.9E-4), response to DNA-damage (p = 6.9E-4), and double-strand break-repair (p = 1.6E-3). Mutations in TTK (p = 8.8E-10, AUC = 0.77), COL7A1 (p = 2.0E-9, AUC = 0.74), KIF15 (p = 2.5E-9, AUC = 0.75), and BDP1 (p = 3.3E-9, AUC = 0.74) had the strongest link to elevated PD-L1 expression. Finally, we established a decision tree based on mutations in PIK3CA, MEF2C, SLC11A1, and KIF15 capable to separate patient sub-cohorts with elevated PD-L1 expression. In summary, we identified mutations associated with elevated PD-L1 expression that facilitate the development of better prognostic biomarkers for GC, and might offer insight into the underlying tumor biology.

Objective: To investigate the role and clinical significance of threonine tyrosine kinase (TTK) in papillary thyroid cancer (PTC)., Methods: TTK expression in PTC and normal groups were compared using TCGA data and in vitro experiments. The prognostic value of TTK and its possible role in PTC dedifferentiation was evaluated. Next, TTK involvement in PTC occurrence and progression was analyzed via in vitro experiments. Subsequently, analyses of enrichment and immune cell infiltration were conducted to reveal the possible mechanism. Finally, we predicted the target miRNAs followed by performing a luciferase reporter experiment., Results: TTK upregulation was observed in PTC, and its elevated level was significantly related to an unfavorable prognosis ( P < 0.05). Interestingly, TTK negatively correlated with thyroid differentiation score (TDS), and patients with higher TDS showed longer survival (all P < 0.05). PTC cell growth, migration, and invasion were inhibited upon TTK knockdown. Besides, TTK was involved in metabolic processes and regulated cell adhesion molecules pathway. Its overexpression was positively associated with immune cell infiltrates ( P < 0.05). Moreover, miR-582-5p was an upstream target of TTK., Conclusion: TTK serves as a potential biomarker for tumorigenesis and prognosis in PTC, especially for those that may differentiate into more aggressive thyroid cancers.

Achieving the targeted level of productivity in organizations is an important issue. The influence of absenteeism and presenteeism behaviors is very high in organizations' productivity and performance indicators. Socio-demographic variables that are thought to have an effect on behaviors such as absenteeism and presenteeism are examined. The study was conducted on underground miners working in Zonguldak Turkish Hard Coal Foundation (TCMC). Analyzes were made on 607 underground miners using the SPSS 22 package program. One-way ANOVA tests were used to identify socio-demographic factors that may have a decisive influence on these behaviors. Within the analyzed socio-demographic factors; the differences between the study type, income group and health status were found to have a statistically significant effect on the variables of the performance indicators examined. [ABSTRACT FROM AUTHOR]

Copyright of Inonu University Law Review / İnönü Üniversitesi Hukuk Fakültesi Dergisi is the property of Inonu University Law Review (IULR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Breast cancer is one of the most common malignancies among females, and its prognosis is affected by a complex network of gene interactions. In this study, we constructed free-scale gene co-expression networks using weighted gene co-expression network analysis (WGCNA). The gene expression profiles of GSE25055 were downloaded from the Gene Expression Omnibus (GEO) database to identify potential biomarkers associated with breast cancer progression. GSE42568 was downloaded for validation. A total of 9 modules were established via the average linkage hierarchical clustering. We identified 3 hub genes (ASPM, CDC20, and TTK) in the significant module (R 2 = 0.52), which were significantly correlated with poor prognosis both in test and validation datasets. In the datasets GSE25055 and GSE42568, higher expression levels of ASPM, CDC20, and TTK correlated with advanced tumor grades. Immunohistochemistry data from the Human Protein Atlas also demonstrated that their protein levels were higher in tumor samples. According to gene set enrichment analysis, 4 commonly enriched pathways were identified: cell cycle pathway, DNA replication pathway, homologous recombination pathway, and P53 signaling pathway. In addition, strong correlations were found among their expression levels. In conclusion, our WGCNA analysis identified candidate prognostic biomarkers for further basic and clinical researches. [ABSTRACT FROM AUTHOR]

Monopolar spindle 1 (Mps1) is a dual‐specificity protein kinase, orchestrating faithful chromosome segregation during mitosis. All reported structures of the Mps1 kinase adopt the hallmarks of an inactive conformation, which includes a mostly disordered activation loop. Here, we present a 2.4 Å resolution crystal structure of an "extended" version of the Mps1 kinase domain, which shows an ordered activation loop. However, the other structural characteristics of an active kinase are not present. Our structure shows that the Mps1 activation loop can fit to the ATP binding pocket and interferes with ATP, but less so with inhibitors binding, partly explain the potency of various Mps1 inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: Esophageal cancer is a common disease in China with low survival rate due to no obvious early symptoms and lack of effective screening strategies. Traditional treatments usually do not produce desirable results in patients with advanced esophageal cancer, so immunotherapy which relies on tumor-related antigens is needed to combat low survival rates effectively. Cancer-testis antigens (CTA), a large family of tumor-related antigens, have a strong in vivo immunogenicity and tumor-restricted expressing patterns in normal adult tissues. These two characteristics are ideal features of anticancer immunotherapy targets and, therefore, promoted the development of some studies of CTA-based therapy. To provide ideas for the role of the cancer-testis antigens MAGE-A, NY-ESO-1, LAGE-1, and TTK in esophageal cancer, we summarized their expression, prognostic value, and development in immunotherapy.Methods: The relevant literature from PubMed is reviewed in this study.Results: In esophageal cancer, although the relationship between expression of MAGE-A, NY-ESO-1, LAGE-1, and TTK and prognosis value is still in a controversial situation, MAGE-A, NY-ESO-1, LAGE-1, and TTK are highly expressed and can induce specific CTL cells to produce particular killing effect on tumor cells, and some clinical trials have demonstrated that immunotherapy for esophageal cancer patients is effective and safe, which provides a new therapeutic strategy for the treatment of esophageal cancer in the future.Conclusion: In this review, we summarize expression and prognostic value of MAGE-A, NY-ESO-1, LAGE-1, and TTK in esophageal cancer and point out recent advances in immunotherapy about them. [ABSTRACT FROM AUTHOR]

Discovered in 1991 in a screen for genes involved in spindle pole body duplication, the monopolar spindle 1 (Mps1) kinase has since claimed a central role in processes that ensure error-free chromosome segregation. As a result, Mps1 kinase activity has become an attractive candidate for pharmaceutical companies in the search for compounds that target essential cellular processes to eliminate, for example, tumour cells or pathogens. Research in recent decades has offered many insights into the molecular function of Mps1 and its regulation. In this review, we integrate the latest knowledge regarding the regulation of Mps1 activity and its spatio-temporal distribution, highlight gaps in our understanding of these processes and propose future research avenues to address them.

Basal-like breast cancers have the highest rates of locoregional recurrence after radiation. By correlating gene expression with early locoregional recurrence, we nominate TTK protein kinase as a mediator of radioresistance. TTK inhibition radiosensitizes in vitro and in vivo through a novel mechanism of impaired homologous recombination and represents a promising translational strategy. [ABSTRACT FROM AUTHOR]

The present study has two main aims: the first aim is to reveal to what extent educational status of professional accountants in Turkey have changed from 1992, when the edict on accounting practices in Turkey was issued, up to beginning of 2018. The second aim of the study is to reveal to what extent the education-related regulations and activities for accounting professionals in Turkey are in accordance with the International Education Standards (IESs). For the purpose of the study, we investigated the current regulations and activities on education for professional accountants in Turkey by comparing them to the general framework of IESs for Professional Accountants issued by the International Federation of Accountants (IFAC). [ABSTRACT FROM AUTHOR]

Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies. [ABSTRACT FROM AUTHOR]

New targeted therapy approaches for certain subtypes of breast cancer, such as triple-negative breast cancers and other aggressive phenotypes, are desired. High levels of the mitotic checkpoint kinase Mps1/TTK have correlated with high histologic grade in breast cancer, suggesting a potential new therapeutic target for aggressive breast cancers (BC). Novel small molecules targeting Mps1 were designed by computer assisted docking analyses, and several candidate compounds were synthesized. These compounds were evaluated in anti-proliferative assays of a panel of 15 breast cancer cell lines and further examined for their ability to inhibit a variety of Mps1-dependent biological functions. The results indicate that the lead compounds have strong anti-proliferative potential through Mps1/TTK inhibition in both basal and luminal BC cell lines, exhibiting IC 50 values ranging from 0.05 to 1.0 μM. In addition, the lead compounds 1 and 13 inhibit Mps1 kinase enzymatic activity with IC 50 values from 0.356 μM to 0.809 μM, and inhibited Mps1-associated cellular functions such as centrosome duplication and the spindle checkpoint in triple negative breast cancer cells. The most promising analog, compound 13 , significantly decreased tumor growth in nude mice containing Cal-51 triple negative breast cancer cell xenografts. Using drug discovery technologies, computational modeling, medicinal chemistry, cell culture and in vivo assays, novel small molecule Mps1/TTK inhibitors have been identified as potential targeted therapies for breast cancers. [ABSTRACT FROM AUTHOR]

Monopolar spindle1 (Mps1, also known as TTK) is the core component of the spindle assembly checkpoint, which functions to ensure proper distribution of chromosomes to daughter cells. Mps1 is hardly detectable in normal organs except the testis and placenta. However, high levels of Mps1 are found in many types of human malignancies, including glioblastoma, thyroid carcinoma, breast cancer, and other cancers. Several Mps1 inhibitors can inhibit the proliferation of cancer cells and exhibit demonstrable survival benefits. Mps1 can be utilized as a new immunogenic epitope, which is able to induce potent cytotoxic T lymphocyte activity against cancer cells while sparing normal cells. Some clinical trials have validated its safety, immunogenicity and clinical response. Thus, Mps1 may be a novel target for cancer therapy. Mps1 is differentially expressed between normal and malignant tissues, indicating its potential as a molecular biomarker for diagnosis. Meanwhile, the discovery that it clearly correlates with recurrence and survival time suggests it may serve as an independent prognostic biomarker as well. [ABSTRACT FROM PUBLISHER]

Glioma is a malignant cancer with high mortality. A key prognostic factor of glioma is radiosensitivity. It has also been known that microRNAs (miR) significantly contribute to the development of glioma. miR-132 has been previously reported to inhibit tumor growth in some cancers, but not well studied in glioma. It is necessary to understand the association between miR-132 and glioma, including miR-132 expression in glioma, effects of miR-132 on cancer metastasis and radiosensitivity, and the involved molecular mechanism. We first explored the expression levels of miR-132 in human normal and glioma tissues, then correlated the expression levels with different stages of glioma. Utilizing human glioma U87 cells, lentiviral transduction technique, luciferase reporter assay, wound healing assay, transwell invasion assay and clonogenic assay, we investigated the effects of hepatic leukemia factor (HLF), miR-132 and TTK protein kinase (TTK) on cancer cell viability, proliferation, migration, invasion and radiosensitivity. The expression of miR-132 was low in human glioma tissues, and the downregulated expression was associated with advanced glioma grades. HLF directly bound to the BS1 site of miR-132 promoter to enhance the expression of miR-132. HLF-mediated miR-132 was able to directly target and inhibit a downstream factor TTK, which had an oncogenic role. Overexpression of TTK could reverse the inhibitory effects of either miR-132 or HLF on cancer cell proliferation, metastasis and radioresistance. TTK acts as an oncogene in glioma. HLF-mediated miR-132 directly suppresses TTK expression, thus exerting inhibitory effects on cancer cell proliferation, metastasis and radioresistance. [ABSTRACT FROM AUTHOR]