Photoactivation Inducing Multifunctional Coupling of Fluorophore for Efficient Tumor Therapy In Situ.

Photoactivatable molecules, with high-precision spatialtemporal control, have largely promoted bioimaging and phototherapy applications of fluorescent dyes. Here, the first photoactivatable sensor (BI) is described that can be triggered by broad excitation light (405-660 nm), which further undergoes intersystem crossing and H-atom transfer processes to forming superoxide anion radicals (O2 -• ) and carbon radicals. Particularly, the photoinduced gain of carbon-centered radicals (BI•) allows for radical-radical coupling to afford the combined crosslink product (BI─BI), which would be oxidized in the presence of O2 -• to produce an extended conjugate system with near infrared emission (820 nm). Besides, the photochemically generated product (Cy─BI) possesses ultra-high photothermal conversion efficiency up to 90.9%, which optimized phototherapy potential. What's more, Western Blot assay reveals that both BI and the photoproduct Cy─BI can efficiently inhibit the expression of CHK1, and the irradiation of BI and Cy─BI further induces apoptosis and ultimately enhances the phototherapeutic effects. Thus, the combination of cell cycle block inducing apoptosis, photodynamic therapy and photothermal therapy treatments significantly suppress solid tumor in vivo antitumor efficacy explorations. This is a novel finding in developing photoactivatable molecules, as well as the broad applicability of photoimaging and phototherapy in tumor-related areas.

Mitochondrial-related genes markers that predict survival in patients with head and neck squamous cell carcinoma affect immunomodulation through hypoxia, glycolysis, and angiogenesis pathways.

Mitochondria play a crucial role in the occurrence and development of tumors. We used mitochondria-related genes for consistent clustering to identify three stable molecular subtypes of head and neck squamous cell carcinoma (HNSCC) with different prognoses, mutations, and immune characteristics. Significant differences were observed in clinical characteristics, immune microenvironment, immune cell infiltration, and immune cell scores. TP53 was the most significantly mutated; cell cycle-related pathways and tumorigenesis-related pathways were activated in different subtypes. Risk modeling was conducted using a multifactor stepwise regression method, and nine genes were identified as mitochondria-related genes affecting prognosis (DKK1, EFNB2, ITGA5, AREG, EPHX3, CHGB, P4HA1, CCND1, and JCHAIN). Risk score calculations revealed significant differences in prognosis, immune cell scores, immune cell infiltration, and responses to conventional chemotherapy drugs. Glycolysis, angiogenesis, hypoxia, and tumor-related pathways were positively correlated with the RiskScore. Clinical samples were subjected to qPCR to validate the results. In this work, we constructed a prognostic model based on the mitochondrial correlation score, which well reflects the risk and positive factors for the prognosis of patients with HNSCC. This model can be used to guide individualized adjuvant and immunotherapy in patients with HNSCC.

Construction of an index system of core competence assessment for otolaryngology nurse specialists in China: A Delphi study.

BACKGROUND: Clinical nurse specialists play a vital role in the work quality, patient safety and team development of nurses. However, there is currently no prior study constructing the index of core competence assessment for otolaryngology Nurse Specialists. OBJECTIVES: To establish an index system for the evaluation of Chinese otolaryngology Nurse Specialists' core competence. DESIGN: A Delphi study. SETTINGS: The study was mainly conducted in a university-affiliated hospital in China. PARTICIPANTS: Twenty-two experts with otolaryngology knowledge and practical experience from different regions and organizations in China. METHODS: We used literature reviews and expert meetings to establish a draft index system . Subsequently, a two-round Delphi survey was utilized to consult opinions from 22 experts about the index for the evaluation of otolaryngology nurse specialists' core competence and provide qualitative comments on their ratings. Consensus was predefined as a mean important score of 4.0 or above and a coefficient of variation is not above 0.25 among the participants. RESULTS: The final evaluation indexes of the core competencies for otolaryngology Nurse Specialists included 5 first-level indexes (clinical competence, critical thinking competence, leadership, professional development competence, professionalism), 19 second-level indexes, and 85 third-level indexes. The effective response rates of the two expert consultation rounds were 100 %. The expert authority coefficients were 0.864 and 0.859 in the first and second rounds of consultation, respectively. In the second round of consultation, the first, second and third indexes of Kendall's coefficient of concordance were 0.357, 0.330, and 0.232, respectively (P < 0.001). CONCLUSIONS: The constructed evaluation indexes of the core competencies of otolaryngology Nurse Specialists are scientific, reasonable, comprehensive, and specific and may provide references for the training and evaluation of otolaryngology Nurse Specialists.

Prediction model of cervical lymph node metastasis based on clinicopathological characteristics of papillary thyroid carcinoma: a dual-center retrospective study.

Background: The overall prevalence of papillary thyroid carcinoma (PTC) patients is expanding along with an ongoing increase in thyroid cancer incidence. Patients with PTC who have lymph node metastases have a poor prognosis and a high death rate. There is an urgent need for indicators that can predict lymph node metastasis (LNM) before surgery as current imaging techniques, such as ultrasonography, do not have sufficient sensitivity to detect LNM. To predict independent risk factors for Central lymph node metastasis (CLNM) or Lateral lymph node metastasis (LLNM), we therefore developed two nomograms based on CLNM and LLNM, separately. Methods: In two centers, the Second Affiliated Hospital of Nanchang University and Yichun People's Hospital, we retrospectively analyzed clinicopathological characteristics of PTC patients. We utilized multivariate analysis to screen for variables that might be suspiciously related to CLNM or LLNM. Furthermore, we developed nomograms to graphically depict the independent risk valuables connected to lymph node metastasis in PTC patients. Result: Ultimately, 6068 PTC patients in all were included in the research. Six factors, including age<45, male, mETE, TSH>1.418, tumor size>4cm, and location (multicentric and lobe), were observed to be related to CLNM. Age<45, male, mETE (minimal extrathyroidal extension), multifocality, TSH≥2.910, CLNM positive, and tumor size>4cm were regarded as related risk factors for LLNM. The two nomograms developed subsequently proved to have good predictive power with 0.706 and 0.818 and demonstrated good clinical guidance functionality with clinical decision curves and impact curves. Conclusion: Based on the successful establishment of this dual-institution-based visual nomogram model, we found that some clinical features are highly correlated with cervical lymph node metastasis, including CLNM and LLNM, which will better help clinicians make individualized clinical decisions for more effectively rationalizing managing PTC patients.

Risk Factors for Lymph Node Metastasis in Papillary Thyroid Carcinoma: A Retrospective Study.

At present, the risk factors of cervical lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC) are still controversial. This study was aimed to investigate the risk factors of various types of LNM in PTC with tumor diameter>1 cm. The clinical data of 2216 PTC patients were retrospectively analyzed. Univariate and multivariate logistic regression models were used to analyze the risk factors of LNM. In addition, the receiver operator characteristic (ROC) curve was used to find the best cut-off value of CLNM for predicting LLNM. Finally, the independent risk factors of LLNM were used to construct the prediction of LLNM nomogram. Age≤55 years old, male, bilateral lobe tumors, ETE, 2-3 cm tumor diameters, and fasting plasma glucose (FPG) were independent risk factors for CLNM. The ROC curve showed that the best cut-off value was 2.5. Age, male, bilateral lobe tumors, tumor diameters≥2 cm and CLNM≥3 were significantly associated with LLNM , while CLNM=1 or 2 was a protective factor for LLNM. Only tumor diameters≥3 cm was significantly associated with skip LLNM. The nomogram model (C-index=0.745) can be used to predict LLNM in PTC patients and guide the clinical selection of appropriate treatment options. Patients with high risk factors should undergo prophylactic lymph node dissection. The nomogram we established has a good predictive ability for LLNM, and for high-risk groups, it is necessary to actively perform prophylactic lateral lymph node dissection.

Overexpressed ZC3H13 suppresses papillary thyroid carcinoma growth through m6A modification-mediated IQGAP1 degradation.

PURPOSE: The purpose of this study was to clarify the effect of ZC3H13 on the growth of papillary thyroid carcinoma (PTC). METHODS: Firstly, we used qRT-PCR and Western blot to compare the difference in the expression of ZC3H13 between normal thyroid epithelial cells and PTC cell lines. Then, ZC3H13 overexpression/knockout thyroid cancer cells were constructed by lentivirus transfection, and the effects of overexpression of ZC3H13 on the proliferation, migration and invasion of PTC cells were detected by CCK8 and transwell experiments. Lastly, MeRIP-qPCR, RIP and o Actinomycin D were used to verify that ZC3H13 regulated the expression of downstream target gene IQGAP1 through m6A modification. RESULTS: ZC3H13 expression was decreased in PTC cell lines BCPAP, KTC-1, k1, HTH83, and TPC-1. Proliferation, invasion, and migration of PTC cells were inhibited by overexpressed ZC3H13 but increased by knockdown of ZC3H13. IQGAP1 expression was suppressed by ZC3H13 overexpression but enhanced by ZC3H13 knockdown. In ZC3H13-overexpressed PTC cells, the m6A level of IQGAP1 mRNA was increased, and the IQGAP1 mRNA expression was decreased with the increasing time of Actinomycin D treatment. YTHDF2 enriched more IQGAP1 mRNA than IgG and knockdown of YTHDF2 reversed the effect of ZC3H13 overexpression on IQGAP1 mRNA stability. The xenograft tumor experiment in nude mice confirmed that the overexpression of ZC3H13 inhibited tumor growth, while overexpression of IQGAP1 could reverse the inhibitory effect of ZC3H13 overexpression on tumor growth. CONCLUSION: ZC3H13 mediates IQGAP1 mRNA degradation by promoting m6A modification of IQGAP1 mRNA, this provides a prospective therapeutic target for PTC.

Identification and validation of a prognostic model based on ferroptosis-associated genes in head and neck squamous cancer.

Ferroptosis is that under the action of ferrous iron or ester oxygenase, unsaturated fatty acids highly expressed on the cell membrane are catalyzed to undergo lipid peroxidation, thereby inducing cell death. In this study, we used ferroptosis marker genes to identify 3 stable molecular subtypes (C1, C2, C3) with distinct prognostic, mutational, and immune signatures by consensus clustering; TP53, CDKN2A, etc. Have higher mutation frequencies in the three subtypes. C3 has a better prognosis, while the C1 subtype has a worse prognosis. WGCNA is used to identify molecular subtype-related gene modules.After filting, we obtained a total of 540 genes related to the module feature vector (correlation>0.7).We performed univariate COX regression analysis on these genes, and identified a total of 97 genes (p < 0.05) that had a greater impact on prognosis, including 8 ''Risk" and 89 ''Protective" genes. After using lasso regression, we identified 8 genes (ZNF566, ZNF541, TMEM150C, PPAN, PGLYRP4, ENDOU, RPL23 and MALSU1) as ferroptosis-related genes affecting prognosis. The ferroptosis prognosis-related risk score (FPRS) was calculated for each sample in TCGA-HNSC dataset. The results showed that FPRS was negatively correlated with prognosis.The activated pathways in the PFRS-high group mainly include immune-related pathways and invasion-related pathways. We assessed the extent of immune cell infiltration in patients in our TCGA-HNSC cohort by using the expression levels of gene markers in immune cells. The FPRS-high group had a higher level of immune cell infiltration. We found that the expression of immune checkpoints was significantly up-regulated in the FPRS-low group and the FPRS-high group had a higher probability of immune escape and a lower probability of benefiting from immunotherapy. In this work, we constructed a scoring Ferroptosis-related prognostic model that can well reflect risk and positive factors for prognosis in patients with head and neck squamous cell carcinoma. It can be used to guide individualized adjuvant therapy and chemotherapy for patients with head and neck cancer. Therefore, it has a good survival prediction ability and provides an important reference for clinical treatment.

Viscosity-sensitive NIR probe for in vivo imaging of early-stage hepatic fibrosis.

Herein, a viscosity-sensitive and hepatic-targeted NIR fluorescent probe has been developed for early diagnosis of hepatic fibrosis. Importantly, we observed increased liver viscosity upon CCl4-induced hepatotoxicity and decreased liver viscosity after metformin treatment, which confirmed its high clinical application prospects.

Inflammation Markers Have Important Value in Predicting Relapse in Patients with papillary thyroid carcinoma: A Long-Term Follow-Up Retrospective Study.

PURPOSE: Many markers of inflammation are increasingly found to have prognostic significance in some cancers. This study investigated the prognostic value of albumin/globulin (AGR), lymphocyte/monocyte ratio (LMR), and other inflammatory markers, including neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR), in patients with papillary thyroid carcinoma (PTC). METHODS: We retrospectively analyzed the data of 764 patients newly diagnosed with PTC (608 women, 156 men) aged 10-83 years. Univariate and multivariate analyses were used to analyze recurrence rates and assess potential prognostic factors. Furthermore, we used random survival forests to construct a random survival forest score (RSFscore). The correlations between various inflammatory factors and traditional prognostic factors were analyzed. We also compared the areas under the curve (AUCs) of the RSFscore and 4 inflammation-based markers. RESULTS: AGR, NLR, PLR, and LMR were strongly associated with invasive clinicopathological features (tumor size, lesions, lymph node metastasis, and lymph node metastasis rate) and postoperative recurrence. In the multivariate analysis, AGR and LMR were independent prognostic markers for recurrent PTC. Higher NLR and PLR values indicated a higher risk of recurrence, while higher LMR and AGR values suggested a lower recurrence risk. The predictive power of the combined indicators was stronger than that of single indicators alone. CONCLUSION: Compared to the analysis of a single indicator, the combination of inflammatory markers was more helpful in determining the risk of PTC recurrence, which has an important impact on predicting patients' cancer-free survival and quality of life.

Biological roles of sulfur dioxide and sulfite in the regulation of mitochondrial viscosity.

Herein, a NIR fluorescent probe has been developed for visualization of the roles of SO2/SO32- in mitochondrial viscosity. The results showed that SO32- would increase mitochondrial viscosity and decrease mitochondrial membrane potential (MMP). However, increasing SO2 stimulation decreased mitochondrial viscosity and caused inconspicuous MMP changes.

Combined prognostic value of preoperative serum thyrotrophin and thyroid hormone concentration in papillary thyroid cancer.

BACKGROUND: A growing number of studies have found a close association between thyroid hormones and thyrotrophin (TSH), and they also have prognostic significance in some cancer types; this study aimed to investigate the prognostic value of free triiodothyronine (fT3), free thyroxine (fT4), fT3/fT4, TSH, and their combination in patients with papillary thyroid carcinoma (PTC). METHODS: This study retrospectively analyzed the relevant data of 726 newly diagnosed PTC patients. Both univariate and multivariate analyses were used to predict the recurrence rate, and a risk score was established. In addition, with the use of a random survival forest, a random forest (RF) score was constructed. After calculating the area under the curve (AUC), the diagnostic efficacy of risk score, RF score, and four indicators was compared. RESULTS: fT3, fT4, fT3/fT4, and TSH were strongly associated with some invasive clinicopathological features and postoperative recurrence. Patients with high expression of fT4 and TSH have a high risk of recurrence. By contrast, patients with high expression of fT3 and fT3/fT4 have a low risk of recurrence. At the same time, the combined use of various indicators is more helpful for establishing an accurate diagnosis. By comparison, we found that the RF score was better than the risk score in terms of predicting the recurrence of PTC. CONCLUSION: The diagnostic accuracy of a combination of fT3, fT4, fT3/fT4, and TSH can help improve our clinical estimate of the risk of recurrent PTC, thus allowing the development of a more effective treatment plan for patients.

Fasting serum glucose and lymph node metastasis in non-diabetic PTC patients: a 10-Year multicenter retrospective study.

Background: Mostly current studies are limited to the impact of lymph node metastasis(LNM) on the prognosis of papillary thyroid cancer(PTC) or the impact of glucose metabolism on the occurrence of PTC, but no one has paid attention to the connection between fasting serum glucose(FSG) and LNM. The purpose of our study was to explore the relationship between FSG and LNM in non-diabetic PTC patients. Methods: In this study, we performed a multicenter, retrospective study on 6034 non-diabetic patients with PTC. The associations of FSG with three types of LNM including central lymph node metastasis (CLNM), lateral cervical lymph node metastasis (LLNM) and both were estimated. Results: Compared with PTC patients without LNM, those with LNM had higher FSG. We also found that FSG was associated with tumor extension, maximum tumor diameter and TSH. In order to further explore the association between FSG and different types of LNM, we analyzed three groups of data separately. Our study reveals that by comparing FSG between patients without LNM and patients with three LNM types, it was statistically different in the PTC patients with CLNM and the PTC patients with CLNM combined with LLNM. Conclusion: Our study provides evidence for the association of FSG and LNM in non-diabetic PTC patients, with a gradual increase in FSG over the course of the PTC from no lymph node metastasis to CLNM combined with LLNM. Meanwhile, higher FSG is a risk factor for CLNM and CLNM combined with LLNM. In the future, FSG might be used as an indicator for lymph node dissection in PTC patients. However, larger relative studies are needed.

Dendrobium officinale polysaccharides attenuate uropathogenic Escherichia coli (UPEC)-induced pyroptosis in macrophage cells.

Urinary tract infections (UTI) are recognized as one of the most common infectious diseases worldwide, and uropathogenic Escherichia coli (UPEC) is the main causative agent of UTI. Dendrobium officinale polysaccharides (DOPs), the main effective ingredient in Dendrobium officinale, have been reported to possess an anti-inflammatory role. Whether DOPs can attenuate the inflammatory injury (pyroptosis) induced by UPEC remains unknown. The present study aimed to assess the protective effect and potential mechanism of DOPs in UPEC-induced pyroptosis. Cell viability of THP-1 differentiated macrophage cells with DOPs was determined using MTT assay. Pyroptosis by UPEC in macrophage cells with or not DOPs pre-treatment was evaluated with flow cytometry analysis, lactate dehydrogenase (LDH) assay, and proinflammatory cytokines secretion. Expression level of key proteins in the NLRP3/Caspase-1/GSDMD pyroptotic pathway was analyzed with western blot. Furthermore the effect of DOPs on ROS activation was investigated. Results indicated that DOPs attenuated UPEC-induced cell damage in macrophage cells, inhibited the activation of NLRP3 mediated inflammasome, subsequently decreased induction and activation of caspase-1/GSDMD, and reduced the secretion of pro-inflammatory cytokine (IL-1ß et al.). Moreover, pretreatment with DOPs significantly reduces ROS production, an important/putative pyroptosis stimulus signal. These results suggested that DOPs successfully mitigate UPEC-promoted pyroptosis in macrophage cells. The protective effects of DOPs are associated with the inhibition of the NLRP3/Caspase-1/GSDMD pathway and ROS signal activation.

CEBPB knockdown sensitizes nasopharyngeal carcinoma cells to cisplatin by promoting the expression of serine protease inhibitor Kazal-type 5.

Serine protease inhibitor Kazal-type 5 (SPINK5) has been indicated to act as a prognostic predictor for patients with head and neck squamous cell carcinoma. However, its specific role in nasopharyngeal carcinoma (NPC), a malignancy that has a high propensity for chemoresistance, remains largely obscure. We, thus, sought to investigate the importance of SPINK5 expression in regulating chemoresistance in NPC. Differentially expressed genes in NPC were screened using the cancer genome atlas-head and neck squamous cell carcinoma database and microarray analysis. SPINK5 was downregulated in NPC tissues and cells. After SPINK5 upregulation, the cells treated with cisplatin showed reduced cell survival and the ability to migrate, invade and metastasize. Mechanistically, the transcription factors regulating SPINK5 were queried through the JASPAR website, followed by dual-luciferase and Chromatin immunoprecipitation assay validation. CCAAT enhancer-binding protein (CEBP) beta (CEBPB) bound to the SPINK5 promoter region in NPC cells. The silencing of CEBPB enhanced the expression of SPINK5. CEBPB overexpression reversed the inhibitory effects of cisplatin on NPC cell malignant phenotype in the presence of SPINK5 overexpression. In conclusion, CEBPB silencing promoted chemoresistance of NPC cells via activating SPINK5, signifying that targeting CEBPB was a new approach to enhance the chemotherapy efficacy in NPC.

Construction of an immune-related signature with prognostic value for colon cancer.

BACKGROUND: Colon cancer is the third most common malignant tumor in the world. Although immunotherapy has been used in cancer treatment, there is still no first-line immunotherapy method for colon cancer. Therefore, it is essential to search for potential immunotherapy targets and molecular biomarkers for early diagnosis and prognosis. METHODS: In this study, we downloaded transcriptome data from The Cancer Genome Atlas (TCGA) and immune-related genes from the ImmPort database. Then we filtered genes with prognostic value and constructed an immune-related signature. Patients were classified into low- and high-risk groups, and we exerted a series of analysis between the signature and clinical phenotypes. Additionally, we used protein-protein interaction networks, gene set enrichment analysis (GSEA) and single-sample gene-set enrichment analysis (ssGSEA) to explore the underlying mechanism of this signature. Furthermore, the accuracy of this signature was verified, using two data sets from Gene Expression Omnibus (GEO). RESULTS: We selected 12 immune-related genes to construct the immune-related signature. Low-risk group had a higher level of immunity compared to high-risk group. The expression level of HLA genes and checkpoint-related genes were statistically different in low- and high-risk groups. This signature showed its prognostic value in TCGA cohort and 2 GEO data sets. The signature also had strong correlation with TNM classification, stage, survival state and lymphatic invasion. The mechanism of the signature may be related to several transcription factors and CD8+ T cell in the tumor microenvironment. CONCLUSION: In conclusion, this immune-related signature is of great prognosis value for colon cancer and its biofunction might be correlated with HLA genes, checkpoint-related genes and high-infiltrating T cells in tumor tissues.

The landscape of tumors-infiltrate immune cells in papillary thyroid carcinoma and its prognostic value.

INTRODUCTION: Thyroid cancer is a very common malignant tumor in the endocrine system, while the incidence of papillary thyroid carcinoma (PTC) throughout the world also shows a trend of increase year by year. In this study, we constructed two models: ICIscore and Riskscore. Combined with these two models, we can make more accurate and reasonable inferences about the prognosis of PTC patients. METHODS: We selected 481 PTC samples from TCGA and 147 PTC samples from GEO (49 samples in GSE33630, 65 samples in GSE35570 and 33 samples in GSE60542). We performed consistent clustering for them and divided them into three subgroups and screened differentially expressed genes from these three subgroups. Then we divided the differential genes into three subtypes. We also distinguished the up-regulated and down-regulated genes and calculated ICIscore for each PTC sample. ICIscore consists of two parts: (1) the PCAu was calculated from up-regulated genes. (2) the PCAd was calculated from down-regulated genes. The PCAu and PCAd of each sample were the first principal component of the relevant gene. What's more, we divided the patients into two groups and constructed mRNA prognostic signatures. Additionally we also verified the independent prognostic value of the signature. RESULTS: Though ICIscore, we were able to observe the relationship between immune infiltration and prognosis. The result suggests that the activation of the immune system may have both positive and negative consequences. Though Riskscore, we could make more accurate predictions about the prognosis of patients with PTC. Meanwhile, we also generated and validated the ICIscore group and Riskscore group respectively. CONCLUSION: All the research results show that by combining the two models constructed, ICIscore and Riskscore, we can make a more accurate and reasonable inference about the prognosis of patients with clinical PTC patients. This suggests that we can provide more effective and reasonable treatment plan for clinical PTC patients.

A multi-dimensional EBP educational program to improve evidence-based practice and critical thinking of hospital-based nurses: Development, implementation, and preliminary outcomes.

Improving outcomes and quality of care through evidence-based practice (EBP) is a priority globally. But most nurses have insufficient competence in EBP. How to conduct Educational interventions to enhance clinical nurses' EBP competencies and critical thinking disposition (CTD) requires more evidence. One hundred eleven clinical nurses from a Chinese four-campus hospital were enrolled in our EBP education program. The Johns Hopkins Nursing Evidence-Based Practice Model was used to develop and guide the educational and practical sessions. Multi-dimensional learning strategies -including online self-learning, on-site lectures, workshops, and social media-facilitated group discussions-were used to facilitate the implementation of the education sessions. After education, nurses embedded evidence into practice. The Chinese versions of the EBP Believe scale (EBPB), EBP Implementation scale (EBPI), and the Simplified Chinese Version of the Critical Thinking Disposition Inventory (CTDI-SCV) were applied to assess the relevant competencies among clinical nurses before and after the education program. Clinical nurses' EBPB, EBPI, and CTDI-SCV scores improved. But only EBPB and EBP skills and attitudes were enhanced with a statistical difference (t = -2.980, -4.141, and -2.695, with all p < 0.01). There was a small positive association between EBPB and CTDI-SCV (r = 0.396, p < 0.01). Fifteen EBP programs were successfully accomplished.

Harmine inhibits the proliferation and migration of glioblastoma cells via the FAK/AKT pathway.

AIMS: Glioblastoma is one of the most invasive tumors of the central nervous system, and has a high degree of malignancy and poor prognosis. Harmine, an active ingredient extracted from perennial herbs, has been reported to have obvious antitumor effects on various tumors. However, the effects of harmine on glioblastoma growth remain unknown. We here explored the effects of harmine on glioblastoma and its underlying molecular mechanisms related to tumorigenesis. MATERIALS AND METHODS: CCK-8 and immunofluorescent assay were performed to measure anti-proliferative effect of harmine on U251-MG and U373-MG cells. Wound healing assay was performed to measure the effects of harmine on cell migration. qRT-PCR and western blot were performed to detect the protein/gene expression. BALB/c nude mice bearing U251-MG xenografts was used to measure the effects of harmine on the growth of glioblastoma in vivo. KEY FINDINGS: Harmine treatment significantly suppressed the proliferation of U251-MG and U373-MG cells in a dose and time-dependent way. Mechanistically, harmine reduced the basal and EGF-enhanced the phosphorylation level of FAK and AKT. Moreover, harmine inhibited the cell viability of U251-MG and U373-MG cells by downregulating the phosphorylation of the FAK/AKT pathway. Besides, harmine significantly suppressed the migration of U251-MG cells by suppressing the expression of MMP2, MMP9 and VEGF. Subsequently, orthotopic xenograft models revealed that harmine treatment dramatically inhibited the growth of glioblastoma in vivo. SIGNIFICANCE: In conclusion, these results suggest that harmine suppresses the proliferation and migration of U251-MG and U373-MG cells by inhibiting the FAK/AKT signaling pathway. Our findings elucidate harmine could be a promising drug for glioblastoma therapy.

Kin17 facilitates thyroid cancer cell proliferation, migration, and invasion by activating p38 MAPK signaling pathway.

Kin17 DNA and RNA binding protein (Kin17) is an extremely conserved nuclear protein that is almost expressed in every type of mammal cells. Recently, Kin17 has been implicated into the regulation of tumorigenesis of diverse human cancers. However, its functions in thyroid cancer (TC) are still largely unexplored. Kin17 mRNA and protein level were tested by qRT-PCR and western blot, respectively. Effects of Kin17 on TC cell proliferation were estimated by colony formation assay and flow cytometry analysis in vitro as well as by in vivo tumor growth experiment. TC cell migratory and invasive capacities were assessed via wound-healing and transwell experiments. Epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin and N-cadherin) and p38 MAPAK signaling pathway-related proteins (p-p38, p38, Cyclin D1, and p27) were examined via western blot. Kin17 was remarkably increased in TC tissue samples and cell lines at both mRNA and protein levels compared to normal tissue and control cell line. Knockdown of Kin17 obviously repressed TC cell proliferation, arrested cell cycle, and inhibited TC cell migration and invasion in vitro, while overexpression of Kin17 produced opposite effects. Kin17 knockdown suppressed p38 MAPK signaling pathway, while Kin17 overexpression activated this pathway. Treatment of p38 agonist (p79350) abolished the repressive effects of sh-Kin17 on TC cell proliferation, migration, and invasion, as well as on p38 pathway. Kin17 knockdown was also found to enhance the sensitivity of Doxorubicin of TC cells. In addition, Kin17 knockdown in vivo also markedly repressed TC tumor growth and p38 pathway. Kin17 functioned as an oncogene of TC by activating p38 MAPK signaling pathway.