APLN promotes the proliferation, migration, and glycolysis of cervical cancer through the PI3K/AKT/mTOR pathway.

Apelin (APLN) is an endogenous ligand of the G protein-coupled receptor APJ (APLNR). APLN has been implicated in the development of multiple tumours. Herein, we determined the effect of APLN on the biological behaviour and underlying mechanisms of cervical cancer. The expression and survival curves of APLN were determined using Gene Expression Profiling Interactive Analysis. The cellular functions of APLN were detected using CCK-8, clone formation, EdU, Transwell assays, flow cytometry, and seahorse metabolic analysis. The underlying mechanisms were elucidated using gene set enrichment analysis and Western blotting. APLN was upregulated in the samples of patients with cervical cancer and is associated with poor prognosis. APLN knockdown decreased the proliferation, migration, and glycolysis of cervical cancer cells. The opposite results were observed when APLN was overexpressed. Mechanistically, we determined that APLN was critical for activating the PI3K/AKT/mTOR pathway via APLNR. APLN receptor inhibitor ML221 reversed the effect of APLN overexpression on cervical cancer cells. Treatment with LY294002, the PI3K inhibitor, drastically reversed the oncological behaviour of APLN-overexpressing C-33A cells. APLN promoted the proliferation, migration, and glycolysis of cervical cancer cells via the PI3K/AKT/mTOR pathway.

A novel oncolytic virus-based biomarker participates in prognosis and tumor immune infiltration of glioma.

Background: Glioma is the most common central nervous malignancy. Due to its poor survival outcomes, it is essential to identify novel individualized therapy. Oncolytic virus (OV) treatment is a key therapy regulating tumor microenvironment in malignant glioma. Herein, we aim to identify the key genes after OV infection and its role in glioma. Methods: Performing an RNA-seq analysis, the differentially expressed genes (DEGs) between EV-A71-infection and mock group were screened with GFold values. DAVID online analysis was performed to identify the functional classification. Overall survival (OS) or disease-free survival (DFS) was evaluated to analyze the relation between PTBP1 expression levels and prognosis of glioma patients. Additionally, the ssGSEA and TIMER algorithms were applied for evaluating immune cell infiltration in glioma. Results: Following EV-A71 infection in glioma cells, PTBP1, one of the downregulated DEGs, was found to be associated with multiple categories of GO and KEGG enrichment analysis. We observed elevated expression levels of PTBP1 across various tumor grades of glioma in comparison to normal brain samples. High PTBP1 expression had a notable impact on the OS of patients with low-grade glioma (LGG). Furthermore, we observed an obvious association between PTBP1 levels and immune cell infiltration in LGG. Notably, PTBP1 was regarded as an essential prognostic biomarker in immune cells of LGG. Conclusion: Our research uncovered a critical role of PTBP1 in outcomes and immune cell infiltration of glioma patients, particularly in those with LGG.

Identification of lymph node metastasis in pre-operation cervical cancer patients by weakly supervised deep learning from histopathological whole-slide biopsy images.

BACKGROUND: Lymph node metastasis (LNM) significantly impacts the prognosis of individuals diagnosed with cervical cancer, as it is closely linked to disease recurrence and mortality, thereby impacting therapeutic schedule choices for patients. However, accurately predicting LNM prior to treatment remains challenging. Consequently, this study seeks to utilize digital pathological features extracted from histopathological slides of primary cervical cancer patients to preoperatively predict the presence of LNM. METHODS: A deep learning (DL) model was trained using the Vision transformer (ViT) and recurrent neural network (RNN) frameworks to predict LNM. This prediction was based on the analysis of 554 histopathological whole-slide images (WSIs) obtained from Qilu Hospital of Shandong University. To validate the model's performance, an external test was conducted using 336 WSIs from four other hospitals. Additionally, the efficiency of the DL model was evaluated using 190 cervical biopsies WSIs in a prospective set. RESULTS: In the internal test set, our DL model achieved an area under the curve (AUC) of 0.919, with sensitivity and specificity values of 0.923 and 0.905, respectively, and an accuracy (ACC) of 0.909. The performance of the DL model remained strong in the external test set. In the prospective cohort, the AUC was 0.91, and the ACC was 0.895. Additionally, the DL model exhibited higher accuracy compared to imaging examination in the evaluation of LNM. By utilizing the transformer visualization method, we generated a heatmap that illustrates the local pathological features in primary lesions relevant to LNM. CONCLUSION: DL-based image analysis has demonstrated efficiency in predicting LNM in early operable cervical cancer through the utilization of biopsies WSI. This approach has the potential to enhance therapeutic decision-making for patients diagnosed with cervical cancer.

A Novel Prognostic Marker and Therapeutic Target Associated with Glioma Progression in a Tumor Immune Microenvironment.

Background: Immune microenvironment serves a vital role in glioma progression, and a large number of studies have found that tumor progression can be reduced to some extent by modulating the immune process in tumors. Materials and Methods: ImmuneScore of each sample in CGGA datasets were calculated with Estimate R package, and samples were grouped by median ImmuneScore values for differential analysis to obtain immune microenvironment differential genes. We further conducted survival analysis, ROC curve analysis, independent prognostic analysis, and clinical correlation analysis on glioma sample genes in CGGA to obtain glioma prognostic genes, and then identified their intersection with immune microenvironment DEGs by Venn tool. The GEPIA and UALCAN databases were used to verify the differential expression of intersecting genes in the glioma and normal brain and to identify our target gene. After validation of their prognostic value, we constructed a nomogram to calculate the risk score and to estimate the accuracy of prognostic model. We mined co-expression genes, enriched functions and pathways, and correlations to immune cell infiltration of unigene with an online database. Finally, we verified the differential expression of FCGBP in glioma by immunohistochemical staining. Results: We finally selected Fc fragment of IgG-binding protein (FCGBP) as our study gene. The prognostic values of FCGBP were validated by a series of analyses. Immunohistochemical staining showed that FCGBP expression increased in gliomas and was up-regulated with the progression of glioma grade. Conclusion: As a key unigene in glioma progression, FCGBP contributes to the regulation of immune microenvironment and has the potential to be a prognostic biomarker and immune targets.

S100A gene family: immune-related prognostic biomarkers and therapeutic targets for low-grade glioma.

BACKGROUND: Despite the better prognosis given by surgical resection and chemotherapy in low-grade glioma (LGG), progressive transformation is still a huge concern. In this case, the S100A gene family, being capable of regulating inflammatory responses, can promote tumor development. METHODS: The analysis was carried out via ONCOMINE, GEPIA, cBioPortal, String, GeneMANIA, WebGestalt, LinkedOmics, TIMER, CGGA, R 4.0.2 and immunohistochemistry. RESULTS: S100A2, S100A6, S100A10, S100A11, and S100A16 were up-regulated and S100A1 and S100A13 were down-regulated in LGG compared to normal tissues. S100A3, S100A4, S100A8, and S100A9 expression was up-regulated during the progression of glioma grade. In addition, genetic variation of the S100A family was high in LGG, and the S100A family genes mostly function through IL-17 signaling pathway, S100 binding protein, and inflammatory responses. The TIMER database also revealed a relationship between gene expression and immune cell infiltration. High expression of S100A2, S100A3, S100A4, S100A6, S100A8, S100A9, S100A10, S100A11, S100A13, and S100A16 was significantly associated with poor prognosis in LGG patients. S100A family genes S100A2, S100A3, S100A6, S100A10, and S100A11 may be prognosis-related genes in LGG, and were significantly associated with IDH mutation and 1p19q codeletion. The immunohistochemical staining results also confirmed that S100A2, S100A3, S100A6, S100A10, and S100A11 expression was upregulated in LGG. CONCLUSION: The S100A family plays a vital role in LGG pathogenesis, presumably facilitating LGG progression via modulating inflammatory state and immune cell infiltration.

ENO1 monoclonal antibody inhibits invasion, proliferation and clone formation of cervical cancer cells.

α-enolase (ENO1), highly expressing in cell membranes, cytoplasm and nuclei of cervical cancer and other tumors, acts as a plasminogen receptor and a glycolytic enzyme. ENO1 is found to be associated with tumorigenesis, invasion and migration, and proves to be an ideal target of tumor therapy. In this study, ENO1 monoclonal antibodies (ENO1mAb) was prepared to blockade ENO1 and the therapeutic role was observed in cervical cancer cells. First, ENO1mAb was prepared and screened by evaluating the inhibitory effect on migration and invasion of cervical cancer cells, which is supposed to block ENO1 expressed on cell membrane. Second, folic acid (FA) conjugated PLGA nanoparticles (FA-SS-PLGA) targeting tumor cells were prepared to mediate ENO1mAb entry into cells and its anti-tumor effects were investigated in vitro. We found that PLGA/FA-SS-PLGA nanoparticles-mediated ENO1mAb could antagonize the activity of ENO1 enzyme, significantly decreased the contents of lactic acid and pyruvate, and inhibited the proliferation, migration and clone formation of cervical cancer cells compared with the sham control (P < 0.05). In summary, ENO1mAb could specifically block ENO1 expressed on cell membrane and inhibit ENO1 glycolysis enzyme activity inside tumor cells, and plays a therapeutic role against cervical cancer cells. It suggests that ENO1mAb has promising anti-tumor effects.

A Novel Immune-Related Prognostic Biomarker and Target Associated With Malignant Progression of Glioma.

BACKGROUND: Glioma is one of the most common malignancies in the central nervous system and has limited effective therapeutic options. Therefore, we sought to identify a suitable target for immunotherapy. MATERIALS AND METHODS: We screened prognostic genes for glioma in the CGGA database and GSE43378 dataset using survival analysis, receiver operating characteristic (ROC) curves, independent prognostic analysis, and clinical correlation analysis. The results were intersected with immune genes from the ImmPort database through Venn diagrams to obtain likely target genes. The target genes were validated as prognostically relevant immune genes for glioma using survival, ROC curve, independent prognostic, and clinical correlation analyses in samples from the CGGA database and GSE43378 dataset, respectively. We also constructed a nomogram using statistically significant glioma prognostic factors in the CGGA samples and verified their sensitivity and specificity with ROC curves. The functions, pathways, and co-expression-related genes for the glioma target genes were assessed using PPI networks, enrichment analysis, and correlation analysis. The correlation between target gene expression and immune cell infiltration in glioma and the relationship with the survival of glioma patients were investigated using the TIMER database. Finally, target gene expression in normal brain, low-grade glioma, and high-grade glioma tissues was detected using immunohistochemical staining. RESULTS: We identified TNFRSF12A as the target gene. Satisfactory results from survival, ROC curve, independent prognosis, and clinical correlation analyses in the CGGA and GSE43378 samples verified that TNFRSF12A was significantly associated with the prognosis of glioma patients. A nomogram was constructed using glioma prognostic correlates, including TNFRSF12A expression, primary-recurrent-secondary (PRS) type, grade, age, chemotherapy, IDH mutation, and 1p19q co-deletion in CGGA samples with an AUC value of 0.860, which illustrated the accuracy of the prognosis prediction. The results of the TIMER analysis validated the significant correlation of TNFRSF12A with immune cell infiltration and glioma survival. The immunohistochemical staining results verified the progressive up-regulation of TNFRSF12A expression in normal brain, low-grade glioma, and high-grade glioma tissues. CONCLUSION: We concluded that TNFRSF12A was a viable prognostic biomarker and a potential immunotherapeutic target for glioma.

A Novel Four-Gene Signature Associated With Immune Checkpoint for Predicting Prognosis in Lower-Grade Glioma.

The overall survival of patients with lower grade glioma (LGG) varies greatly, but the current histopathological classification has limitations in predicting patients' prognosis. Therefore, this study aims to find potential therapeutic target genes and establish a gene signature for predicting the prognosis of LGG. CD44 is a marker of tumor stem cells and has prognostic value in various tumors, but its role in LGG is unclear. By analyzing three glioma datasets from Gene Expression Omnibus (GEO) database, CD44 was upregulated in LGG. We screened 10 CD44-related genes via protein-protein interaction (PPI) network; function enrichment analysis demonstrated that these genes were associated with biological processes and signaling pathways of the tumor; survival analysis showed that four genes (CD44, HYAL2, SPP1, MMP2) were associated with the overall survival (OS) and disease-free survival (DFS)of LGG; a novel four-gene signature was constructed. The prediction model showed good predictive value over 2-, 5-, 8-, and 10-year survival probability in both the development and validation sets. The risk score effectively divided patients into high- and low- risk groups with a distinct outcome. Multivariate analysis confirmed that the risk score and status of IDH were independent prognostic predictors of LGG. Among three LGG subgroups based on the presence of molecular parameters, IDH-mutant gliomas have a favorable OS, especially if combined with 1p/19q codeletion, which further confirmed the distinct biological pattern between three LGG subgroups, and the gene signature is able to divide LGG patients with the same IDH status into high- and low- risk groups. The high-risk group possessed a higher expression of immune checkpoints and was related to the activation of immunosuppressive pathways. Finally, this study provided a convenient tool for predicting patient survival. In summary, the four prognostic genes may be therapeutic targets and prognostic predictors for LGG; this four-gene signature has good prognostic prediction ability and can effectively distinguish high- and low-risk patients. High-risk patients are associated with higher immune checkpoint expression and activation of the immunosuppressive pathway, providing help for screening immunotherapy-sensitive patients.

Bioinformatics analysis of potential core genes for glioblastoma.

BACKGROUND: Glioblastoma (GBM) has a high degree of malignancy, aggressiveness and recurrence rate. However, there are limited options available for the treatment of GBM, and they often result in poor prognosis and unsatisfactory outcomes. MATERIALS AND METHODS: In order to identify potential core genes in GBM that may provide new therapeutic insights, we analyzed three gene chips (GSE2223, GSE4290 and GSE50161) screened from the GEO database. Differentially expressed genes (DEG) from the tissues of GBM and normal brain were screened using GEO2R. To determine the functional annotation and pathway of DEG, Gene Ontology (GO) and KEGG pathway enrichment analysis were conducted using DAVID database. Protein interactions of DEG were visualized using PPI network on Cytoscape software. Next, 10 Hub nodes were screened from the differentially expressed network using MCC algorithm on CytoHubba software and subsequently identified as Hub genes. Finally, the relationship between Hub genes and the prognosis of GBM patients was described using GEPIA2 survival analysis web tool. RESULTS: A total of 37 up-regulated and 187 down-regulated genes were identified through microarray analysis. Amongst the 10 Hub genes selected, SV2B appeared to be the only gene associated with poor prognosis in glioblastoma based on the survival analysis. CONCLUSION: Our study suggests that high expression of SV2B is associated with poor prognosis in GBM patients. Whether SV2B can be used as a new therapeutic target for GBM requires further validation.

Synthetic chloroinconazide compound exhibits highly efficient antiviral activity against tobacco mosaic virus.

BACKGROUND: Development of anti-plant-virus compounds and improvement of biosafety remain hot research topics in controlling plant viral disease. Tobacco mosaic virus (TMV) infects all tobacco species as well as many other plants worldwide and causes severe losses in tobacco production. To date, no efficient chemical treatments are known to protect plants from virus infection. Therefore, the search for a highly active antiviral compound with high efficacy in field application is required. RESULTS: We reported the synthesis of a novel antiviral halogenated acyl compound Chloroinconazide (CHI) using tryptophan as a substrate and examined its anti-TMV activity. We found that CHI displayed the ability to strongly inhibit the infection of TMV on Nicotiana benthamiana via multiple mechanisms. We observed that CHI was able to impair the virulence of TMV by directly altering the morphological structure of virions and increasing the activity of anti-oxidative enzymes, resulting in reduced TMV-induced ROS production during infection of the plant. In addition, the expression of salicylic acid-responsive genes was significantly increased after CHI application. However, after application of CHI on SA-deficient NahG plants no obvious anti-TMV activity was observed, suggesting that the SA signaling pathway was required for CHI-induced anti-TMV activity associated with reduced infection of TMV. CHI exhibited no effects on plant growth and development. CONCLUSION: The easily synthesized CHI can actively induce plant resistance against TMV as well as act on virus particles and exhibits high biosafety, which provides a potential for commercial application of CHI in controlling plant virus disease in the future. © 2020 Society of Chemical Industry.

Label-free diagnosis of lung cancer with tissue-slice surface-enhanced Raman spectroscopy and statistical analysis.

Despite the rapid development of medical science, the diagnosis of lung cancer is still quite challenging. Due to the ultrahigh detection sensitivity of surface-enhanced Raman spectroscopy (SERS), SERS has a broad application prospect in biomedicine, especially in the field of tumor blood detection. Although Raman spectroscopy can diagnose lung cancer through tissue slices, its weak cross sections are problematic. In this study, silver nanoparticles (AgNPs) were added to the surface of lung tissue slices to enhance the Raman scattering signals of biomolecules. The electromagnetic field distribution of AgNPs prepared was simulated using the COMSOL software. SERS obtained from the slices reflected the difference in biochemical molecules between normal (n = 23) and cancerous (n = 23) lung tissues. Principal component-linear discriminate analysis (PCA-LDA) was utilized to classify lung cancer and healthy lung tissues. The receiver operating characteristic curve gave the sensitivity (95.7%) and specificity (95.7%) of the PCA-LDA method. This study sheds new light on the general applicability of SERS analysis of tissue slices in clinical trials.

Genistein inhibits human papillary thyroid cancer cell detachment, invasion and metastasis.

Papillary thyroid carcinoma (PTC) is the most commonly diagnosed endocrine cancer, and those with BRAFV600E mutation have high recurrence rate and less favorable clinical behavior. Genistein having anti-carcinoma effects in various types of carcinomas as an estrogen analog, but the mechanism of Genistein in the progression of PTC remains unknown. Genistein significantly inhibits the proliferation and the invasion (P < 0.01), and the apoptosis (P < 0.001) of all tumor cell lines, which was probably due to the inducing of the arrest in G2/M phase of the cell cycle (P < 0.001). The anti-proliferation and apoptosis inducing effects are more obvious in BCPAP, IHH4 cell lines harboring BRAFV600E mutation. Genistein significantly decreased the invasion of PTC cell lines and partially reverses epithelial mesenchymal transition in PTC cell lines. Functional study indicated that small interfering RNA (siRNA) knockdown of ß-catenin significantly reverses the effect of genistein on EMT at protein levels. In conclusion, for the first time, our study suggested that genistein has anticarcinoma effect for PTC patients in the range of 2.5 and 80 µg/ml in thyroid carcinoma cells, which was probably through cytoplasmic translocation of ß-catenin. Further study will be needed to determine whether genistein could be used in clinical trial of high-risk PTC.

Sohlh2 inhibits breast cancer cell proliferation by suppressing Wnt/ß-catenin signaling pathway.

Sohlh2 belongs to the superfamily of basic helix-loop-helix (bhlh) transcription factors. Aberrant expression of bhlh transcription factors has been shown to be associated with multiple tumorigenesis. We previously identified that sohlh2 functioned as a tumor suppressor in ovarian cancer. Here, we examined the expression levels of sohlh2 in human breast cancer and its potential role in disease pathogenesis. The results of sohlh2 immunohistochemistry (IHC) and Western blot analysis demonstrated the decreased sohlh2 expression in breast cancer specimens as compared to adjacent noncancerous tissues. Through in vitro MTT, BrdU, colony formation and cell cycle assays and in vivo tumor xenograft studies, we showed that forced expression of sohlh2 led to a significant reduction in proliferation due to G1 arrest in vitro and tumorigenesis in nude mice. Conversely, silencing of sohlh2 enhanced breast cancer cell proliferation. Furthermore, we confirmed that sohlh2 inhibited breast cancer cell proliferation by suppressing the Wnt/ß-catenin signaling pathway. APC was the direct target of sohlh2, and mediated the inhibitory activities of sohlh2 on Wnt/ß-catenin signaling pathway. Thus, our data indicate that sohlh2 likely functions as a tumor suppressor in breast cancer that is mediated by repressing Wnt/ß-catenin signaling pathway via upregulation of APC expression.

Knockdown of MRPL42 suppresses glioma cell proliferation by inducing cell cycle arrest and apoptosis.

Mammalian mitochondrial ribosomal proteins are functionally involved in protein synthesis in mitochondrion. Recently numerous studies have illuminated the role of mitochondrion in cancer development. However, the precise function of mitochondrial ribosomal protein L42 (MRPL42) remains unclear. Here in the present study, we identified MRPL42 as a novel oncogene in glioma. By analyzing the Cancer Genome Atlas (TCGA) database, we first found that MRPL42 was significantly up-regulated in glioma tissues compared with normal tissues. Functionally, we silenced MRPL42 in glioma cells and revealed that MRPL42 knockdown largely blunted the proliferation of U251 and A172 cells. Mechanistically, our results suggested that MRPL42 silencing resulted in increased distribution of cell cycle in G1 and G2/M phases, while the S-phase decreased. In addition, the apoptosis and caspase3/7 activity were both activated after MRPL42 knockdown. Taken together, MRPL42 is a novel oncogene in glioma and might help us develop promising targetted therapies for glioma patients.

Experimental research on preventing mechanical phlebitis arising from indwelling needles in intravenous therapy by external application of mirabilite.

Various types of complications arising from intravenous indwelling needles have become a challenge in clinical care. It is urgent to seek a simple and cost-effective method for prevention and treatment of phlebitis. We investigated the roles of mirabilite in preventing and treating phlebitis caused by intravenous indwelling needles and provide guidance for prevention and treatment of mechanical phlebitis caused by intravenous indwelling needles. A total of 57 healthy congeneric big-eared New Zealand rabbits were randomly divided into 3 groups: blank control, indwelling needle, and group with external application of mirabilite. The ear vein of each rabbit was punctured with an intravenous indwelling needle. The ear vein specimens were taken at 3, 5, and 7 days after indwelling. The hematoxylin and eosin stained pathological tissue sections of the ear veins of the rabbits in each group were observed. The expression levels of IL-1 and IL-6, and tumour necrosis factor-α (TNF-α) in the vascular tissue of the ear veins of the rabbits in each group were detected with the immunofluorescence method. In the blank control group, there was no inflammatory cellular infiltration and no proliferation of fibrous tissue around the vascular wall. With the increase of the indwelling time, proliferation of fibrous tissue in vascular wall, increased inflammatory cellular infiltration and organized thrombus in the vascular tissue occurred in the ear veins of the rabbits in the indwelling needle group and group with external application of mirabilite. Compared with the indwelling needle group, the group with external application of mirabilite had significantly decreased fibrous tissue in the vascular wall and significantly decreased inflammatory cellular infiltration. At the same point in indwelling time, the expression levels of IL-1, IL-6, and TNF-α in the indwelling needle and group with external application of mirabilite were significantly higher than that in the blank control group (P<0.05). The expression levels of IL-1, IL-6, and TNF-α in the group with external application of mirabilite were lower than that in the indwelling needle group (P<0.05). The expression levels of IL-1, IL-6, and TNF-α are positively correlated with the indwelling time within the same group at different points in time. In conclusion, external application of mirabilite can significantly decrease infiltration of venous inflammatory cells of the rabbit ear margin, proliferation of fibrous tissue and thrombosis in the vascular wall, significant decrease the expression levels of IL-1, IL-6, and TNF-α in the mechanical phlebitis caused by intravenous indwelling needles, and decrease the inflammatory responses of the ear veins of rabbits.

Up-regulation of ANKDR49, a poor prognostic factor, regulates cell proliferation of gliomas.

The Ankyrin repeat domain 49 (ANKRD49) is an evolutionarily conserved protein, which is related to mediate protein-protein interaction. However, the function of ANKRD49 in human glioma remains elusive. Mining through The Cancer Genome Atlas (TCGA) database, we found that the expression of ANKRD49 was increased in glioma tissues and that high expression of ANKRD49 was strongly associated with high disease grade and poor overall survival. To investigate the role of ANKRD49 in malignant glioma, lentivirus expressing shRNA targetting ANKRD49 was constructed in U251 and U87 malignant glioma cells. We demonstrated that ANKRD49 knockdown reduced the proliferation rate of U251 and U87 cells. Further mechanism analysis indicated that depletion of ANKRD49 led to the cell-cycle arrest and induced apoptosis in U251 and U87 cells. ANKRD49 knockdown also changed the expression of key effectors that are involved in stress response, cell cycle, and apoptosis, including p-HSP27 (heat shock protein 27), p-Smad2 (SMAD family member 2), p-p53, p-p38, p-MAPK (mitogen-activated protein kinase), p-SAPK/JNK (stress-activated protein kinase/c-jun n-terminal kinase), cleveagated Caspase-7, p-Chk1 (checkpoint kinase 1), and p-eIF2a (eukaryotic translation initiation factor 2a). Taken together, our findings implicate that ANKRD49 promotes the proliferation of human malignant glioma cells. ANKRD49 maybe an attractive target for malignant glioma therapy.

Efficacy and safety of anti-PD-1 and anti-PD-1 combined with anti-CTLA-4 immunotherapy to advanced melanoma: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, and anti-CTLA-4 antibody ipilimumab are being in clinic trials to treat melanoma. Here, we performed a meta-analysis to evaluate the efficacy and toxicity of them against advanced melanoma. METHODS: Eleven reports from 6 randomized control trials on treating metastatic melanoma, which were divided into 3 subgroups, nivolumab/pembrolizumab versus chemotherapy, nivolumab versus ipilimumab, and nivolumab-plus-ipilimumab versus ipilimumab, were included and the meta-analysis was performed for each subgroup. The outcome measures were objective response rates (ORR), median progression free survival (PFS), 1-year overall survival rates (OS), and toxicity estimated by grade 3 to 4 adverse events. RESULTS: For nivolumab/pembrolizumab versus chemotherapy, nivolumab versus ipilimumab, and nivolumab-plus-ipilimumab versus ipilimumab, the pooled risk ratios (RR) of the ORR were 3.43 (95% CI: 2.57-4.58), 2.51 (95% CI: 2.03-3.09), and 3.28 (95% CI: 2.58-4.17), respectively. The pooled HR of PFS were 0.42 (95% CI: 0.36-0.49), 0.58 (95% CI: 0.50-0.66), and 0.41 (95% CI: 0.30-0.52), respectively. The pooled RR of 1-year OS was 1.37 (95% CI: 1.08-1.74) and 1.54 (95% CI: 0.90-2.63) for nivolumab versus ipilimumab and nivolumab-plus-ipilimumab versus ipilimumab. These results suggested that anti-PD-1 monotherapy and nivolumab-plus-ipilimumab therapy had ORR and PFS benefit compared with the control group. Anti-PD-1 treatment increased 1-year OS for patients compared with ipililumab treatment. But there is no significantly difference on 1-year OS between the nivolumab-plus-ipilimumab treatment and the ipilimumab treatment group. The toxicity analysis showed that there is less risk of adverse events in the anti-PD-1 treatment group compared with the chemotherapy and ipilimumab group. Combining nivolumab with ipilimumab increased the risk for high-grade adverse events compared with ipilimumab alone but the adverse events were generally manageable. CONCLUSIONS: Anti-PD-1 monotherapy and nivolumab-plus-ipilimumab therapy improved ORR and prolonged PFS of patients with advanced melanoma and the adverse events are generally manageable. The therapy is indeed a promising approach for treatment of advanced melanoma.

TIPE3 protein promotes breast cancer metastasis through activating AKT and NF-κB signaling pathways.

TIPE3 (TNFAIP8L3) is the transfer protein of phosphoinositide second messengers that promote cancer. Its role in breast cancer has not been evaluated. We report here that TIPE3 protein was significantly upregulated in human breast cancer tissues as compared with adjacent non-tumor tissues from the same patients. The level of TIPE3 protein in invasive ductal carcinoma was significant higher than that in ductal carcinoma in situ (DCIS), and the level of TIPE3 in lymphatic metastasized carcinoma was higher than that in invasive ductal carcinoma from the same patients. Additionally, the level of TIPE3 protein was positively correlated with the level of human epidermal growth factor receptor 2 (HER-2), and TIPE3 expression was significantly higher in high-invasive breast cancer cell lines than that in low-invasive cell lines. Importantly, TIPE3 knockdown in breast cancer cells inhibited cell proliferation, migration, and invasion in vitro, whereas TIPE3 overexpression had the opposite effect. In mice, TIPE3 expression significantly promoted the metastasis of breast cancer cells. TIPE3 expression also increased the level of MMP2 and uPA, and the activation of the AKT and NF-κB signaling pathways. These results demonstrate that TIPE3 may promote breast cancer growth and metastasis through AKT and NF-κB, and may serve as a potential biomarker for breast cancer metastasis.

Data Mining of Lung Microbiota in Cystic Fibrosis Patients.

The major therapeutic strategy used to treat exacerbated cystic fibrosis (CF) is antibiotic treatment. As this approach easily generates antibiotic-resistant strains of opportunistic bacteria, optimized antibiotic therapies are required to effectively control chronic and recurrent bacterial infections in CF patients. A promising future for the proper use of antibiotics is the management of lung microbiota. However, the impact of antibiotic treatments on CF microbiota and vice versa is not fully understood. This study analyzed 718 sputum samples from 18 previous studies to identify differences between CF and uninfected lung microbiota and to evaluate the effects of antibiotic treatments on exacerbated CF microbiota. A reference-based OTU (operational taxonomic unit) picking method was used to combine analyses of data generated using different protocols and platforms. Findings show that CF microbiota had greater richness and lower diversity in the community structure than uninfected control (NIC) microbiota. Specifically, CF microbiota showed higher levels of opportunistic bacteria and dramatically lower levels of commensal bacteria. Antibiotic treatment affected exacerbated CF microbiota notably but only transiently during the treatment period. Limited decrease of the dominant opportunistic bacteria and a dramatic decrease of commensal bacteria were observed during the antibiotic treatment for CF exacerbation. Simultaneously, low abundance opportunistic bacteria were thriving after the antibiotic treatment. The inefficiency of the current antibiotic treatment against major opportunistic bacteria and the detrimental effects on commensal bacteria indicate that the current empiric antibiotic treatment on CF exacerbation should be reevaluated and optimized.