Nuclear isoform of RAPH1 interacts with FOXQ1 to promote aggressiveness and radioresistance in breast cancer.

Radioresistance limits the efficacy of radiotherapy against breast cancer, especially the most lethal subtype of breast cancer, triple-negative breast cancer (TNBC). Epithelial-to-mesenchymal transition (EMT) is closely related to tumor radioresistance. In this work, we attempted to identify the key EMT-related transcription factor(s) that can induce radioresistance in breast cancer cells. A set of 44 EMT transcription factors were analyzed in parental and radioresistant TNBC cell lines. The function of FOXQ1, a differentially expressed transcription factor, was determined in TNBC radioresistance. FOXQ1-interacting proteins were identified by co-immunoprecipitation and mass spectrometry. Compared with parental cells, FOXQ1 was significantly upregulated in radioresistant TNBC cells. Silencing of FOXQ1 increased the radiosensitiviy of radioresistant TNBC cells both in vitro and in vivo. FOXQ1 associated with a nuclear isoform of RAPH1 (named RAPH1-i3) in radioresistant TNBC cells. Overexpression of RAPH1-i3 enhanced TNBC cell proliferation and migration, and most interestingly, induced radioresistance in parental TNBC cells when co-expressed with FOXQ1. Similar findings were observed in estrogen receptor-positive breast cancer cell lines that had co-expression of RAPH1-i3 and FOXQ1. Mechanistically, co-expression of RAPH1-i3 and FOXQ1 activated STAT3 signaling and increased the expression of CCND1, MCL1, Bcl-XL, and MMP2. Depletion of RAPH1-i3 impaired the radioresistance of radioresistant TNBC cells. Additionally, RAPH1-i3 upregulation was associated with advanced tumor stage and reduced disease-free survival in TNBC patients. These results collectively show that RAPH1-i3 interacts with FOXQ1 to promote breast cancer progression and radioresistance. RAPH1-i3 and FOXQ1 represent therapeutic targets for the treatment of breast cancer including TNBC.

Different Sources of Bone Marrow Mesenchymal Stem Cells: A Comparison of Subchondral, Mandibular, and Tibia Bone-derived Mesenchymal Stem Cells.

BACKGROUND: Stem cell properties vary considerably based on the source and tissue site of mesenchymal stem cells (MSCs). The mandibular condyle is a unique kind of craniofacial bone with a special structure and a relatively high remodeling rate. MSCs here may also be unique to address specific physical needs. OBJECTIVE: The aim of this study was to compare the proliferation and multidirectional differentiation potential among MSCs derived from the tibia (TMSCs), mandibular ramus marrow (MMSCs), and condylar subchondral bone (SMSCs) of rats in vitro. METHODS: Cell proliferation and migration were assessed by CCK-8, laser confocal, and cell scratch assays. Histochemical staining and real-time PCR were used to evaluate the multidirectional differentiation potential and DNA methylation and histone deacetylation levels. RESULTS: The proliferation rate and self-renewal capacity of SMSCs were significantly higher than those of MMSCs and TMSCs. Moreover, SMSCs possessed significantly higher mineralization and osteogenic differentiation potential. Dnmt2, Dnmt3b, Hdac6, Hdac7, Hdac9, and Hdac10 may be instrumental in the osteogenesis of SMSCs. In addition, SMSCs are distinct from MMSCs and TMSCs with lower adipogenic differentiation and chondrogenic differentiation potential. The multidirectional differentiation capacities of TMSCs were exactly the opposite of those of SMSCs, and the results of MMSCs were intermediate. CONCLUSION: This research offers a new paradigm in which SMSCs could be a useful source of stem cells for further application in stem cell-based medical therapies due to their strong cell renewal and osteogenic capacity.

Intercellular mitochondrial transfer in the brain, a new perspective for targeted treatment of central nervous system diseases.

AIM: Mitochondria is one of the important organelles involved in cell energy metabolism and regulation and also play a key regulatory role in abnormal cell processes such as cell stress, cell damage, and cell canceration. Recent studies have shown that mitochondria can be transferred between cells in different ways and participate in the occurrence and development of many central nervous system diseases. We aim to review the mechanism of mitochondrial transfer in the progress of central nervous system diseases and the possibility of targeted therapy. METHODS: The PubMed databank, the China National Knowledge Infrastructure databank, and Wanfang Data were searched to identify the experiments of intracellular mitochondrial transferrin central nervous system. The focus is on the donors, receptors, transfer pathways, and targeted drugs of mitochondrial transfer. RESULTS: In the central nervous system, neurons, glial cells, immune cells, and tumor cells can transfer mitochondria to each other. Meanwhile, there are many types of mitochondrial transfer, including tunneling nanotubes, extracellular vesicles, receptor cell endocytosis, gap junction channels, and intercellular contact. A variety of stress signals, such as the release of damaged mitochondria, mitochondrial DNA, or other mitochondrial products and the elevation of reactive oxygen species, can trigger the transfer of mitochondria from donor cells to recipient cells. Concurrently, a variety of molecular pathways and related inhibitors can affect mitochondrial intercellular transfer. CONCLUSION: This study reviews the phenomenon of intercellular mitochondrial transfer in the central nervous system and summarizes the corresponding transfer pathways. Finally, we propose targeted pathways and treatment methods that may be used to regulate mitochondrial transfer for the treatment of related diseases.

The driving mechanism and targeting value of mimicry between vascular endothelial cells and tumor cells in tumor progression.

The difficulty and poor prognosis of malignant tumor have always been a difficult problem to be solved. The internal components of solid tumor are complex, including tumor cells, stromal cells and immune cells, which play an important role in tumor proliferation, migration, metastasis and drug resistance. Hence, targeting of only the tumor cells will not likely improve survival. Various studies have reported that tumor cells and endothelial cells have high plasticity, which is reflected in the fact that they can simulate each other's characteristics by endothelial-mesenchymal transition (EndMT) and vasculogenic mimicry (VM). In this paper, this mutual mimicry concept was integrated and reviewed for the first time, and their similarities and implications for tumor development are discussed. At the same time, possible therapeutic methods are proposed to provide new directions and ideas for clinical targeted therapy and immunotherapy of tumor.

Serial Cardiac MRI for Quantification of the Dynamics of Anthracycline-Induced Subclinical Myocardial Injury.

BACKGROUND: Anthracyclines are known to be associated with chemotherapy-induced cardiotoxicity. Limited data focus on dynamic myocardial injury during the course of chemotherapy in patients with breast cancer. PURPOSE: To investigate the variation of tissue characterization and myocardial deformation derived by cardiac MRI during anthracycline chemotherapy. STUDY TYPE: Prospective. POPULATION: Fifty-eight female breast cancer patients (mean age: 52.82 ± 2.61 years) were enrolled. FIELD STRENGTH/SEQUENCE: A 3.0-T, cardiac MRI including cine balanced steady-state free precession, a modified Looker-Locker inversion recovery (MOLLI), and a fast spin echo (FSE) T2-weighted sequences were performed. ASSESSMENT: Cardiac MRI was performed baseline and after two, four, and six cycles of chemotherapy. Assessment of global longitudinal strain (GLS), global circumstance strain (GCS), global radial strain (GRS), and strain rate (GLS-s, GCS-s, GRS-s) and T1, T2 and T2* were accomplished by CVI42. The anthracycline dose and risk factors were also collected before each cardiac MRI. STATISTICAL TESTS: Analysis of variance (ANOVA) for repeated measures was used to compare the changes in LVEF cardiac function, strain and T1/T2/T2* parameters over time. Pearson correlation analyses were performed to estimate the potential associations between differences in myocardial characteristics (∆) and the chemotherapy cycle. A P value <0.05 was considered statistically significant. RESULTS: LVEF was not significantly different from pretreatment MRI regarding each cycle of chemotherapy (P = 0.54). Compared with baseline, patients had significantly lower GLS (-15.85% ± 0.83%, -14.50% ± 0.88%, -12.34% ± 1.01% vs. -18.82% ± 0.92%) and GLS-s (-0.71% ± 0.07%, -0.65% ± 0.05%, -0.64% ± 0.04% vs. -0.95 ± 0.06%) and increased T2 values (57.21 ± 4.27 msec, 58.60 ± 3.93 msec, 58.10 ± 3.17 msec vs. 43.88 ± 3.28 msec) at two, four and six cycles of chemotherapy treatment. ∆GLS and ∆GLS-s were significantly associated with the chemotherapy cycle (correlation coefficients for GLS = 0.75, GLS-s = 0.75). DATA CONCLUSION: Cardiac MRI can precisely detect the dynamic changes of anthracycline-induced subclinical myocardial injury that is represented as a gradually decrease in GLS and GLS-s. These parameters may provide new insight for monitoring risk and therapy in patients with breast cancer. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 1.

Regulation of secretory pathway kinase or kinase-like proteins in human cancers.

Secretory pathway kinase or kinase-like proteins (SPKKPs) are effective in the lumen of the endoplasmic reticulum (ER), Golgi apparatus (GA), and extracellular space. These proteins are involved in secretory signaling pathways and are distinctive from typical protein kinases. Various reports have shown that SPKKPs regulate the tumorigenesis and progression of human cancer via the phosphorylation of various substrates, which is essential in physiological and pathological processes. Emerging evidence has revealed that the expression of SPKKPs in human cancers is regulated by multiple factors. This review summarizes the current understanding of the contribution of SPKKPs in tumorigenesis and the progression of immunity. With the epidemic trend of immunotherapy, targeting SPKKPs may be a novel approach to anticancer therapy. This study briefly discusses the recent advances regarding SPKKPs.

[Corrigendum] MicroRNA-148a inhibits breast cancer migration and invasion by directly targeting WNT-1.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that the data panel for the MDA­MB­231/migration/NC experiment in Fig. 2B on p. 1428 was strikingly similar to the data shown for the MDA­MB­231/invasion/Blank experiment in Fig. 2C, such that these data appeared to have been derived from the same original source. The authors have referred back to their original data, and realize that the data panel was selected incorrectly for Fig. 2B. The corrected version of Fig. 2, showing the correct data for the MDA­MB­231/migration/NC experiment in Fig. 2B, is shown on the next page. The authors regret the error that was made during the preparation of this figure, and can confirm that the error in the assembly of this figure did not adversely affect the conclusions reported in the study. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish a Corrigendum, and all the authors agree to this Corrigendum. Furthermore, they apologize to the readership for any inconvenience caused. [the original article was published in Oncology Reports 35: 1425­1432, 2016; DOI: 10.3892/or.2015.4502].

Erratum: MiR-487a Promotes TGF-ß1-induced EMT, the Migration and Invasion of Breast Cancer Cells by Directly Targeting MAGI2.

[This corrects the article DOI: 10.7150/ijbs.13475.].

HES1 promotes breast cancer stem cells by elevating Slug in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. TNBC is enriched with breast cancer stem cells (BCSCs), which are responsible for cancer initiation, cancer progression and worse prognosis. Our previous study found that HES1 was overexpressed and promoted invasion in TNBC. However, the role of HES1 in modulating BCSC stemness of TNBC remains unclear. Here, we found that HES1 upregulates Slug both in transcriptional level and in protein level. HES1 also has a positive correlation with Slug expression in 150 TNBC patient samples. TNBC patients with high HES1 and Slug levels show worse prognosis in both progression-free survival and overall survival analyses. Survival analyses indicate that the effects of HES1 on survival prognosis may depend on Slug. Furthermore, we reveal that HES1 is a novel transcriptional activator for Slug through acting directly on its promoter. Meanwhile, HES1 knockdown reduces BCSC self-renewal, BCSC population, and cancer cell proliferation in TNBC, whereas overexpression of Slug restores the oncogenic function of HES1, both in vitro and in vivo, suggesting that HES1 performs its oncogenic role through upregulating Slug. Taken together, HES1 promotes BCSC stemness properties via targeting Slug, highlighting that HES1 might be a novel candidate for BCSC stemness regulation in TNBC and providing new clues for identifying promising prognostic biomarkers and therapeutic targets of TNBC.

Immune-related lncRNAs as predictors of survival in breast cancer: a prognostic signature.

BACKGROUND: Breast cancer is a highly heterogeneous disease, this poses challenges for classification and management. Long non-coding RNAs play acrucial role in the breast cancersdevelopment and progression, especially in tumor-related immune processes which have become the most rapidly investigated area. Therefore, we aimed at developing an immune-related lncRNA signature to improve the prognosis prediction of breast cancer. METHODS: We obtained breast cancer patient samples and corresponding clinical data from The Cancer Genome Atlas (TCGA) database. Immune-related lncRNAs were screened by co-expression analysis of immune-related genes which were downloaded from the Immunology Database and Analysis Portal (ImmPort). Clinical patient samples were randomly separated into training and testing sets. In the training set, univariate Cox regression analysis and LASSO regression were utilized to build a prognostic immune-related lncRNA signature. The signature was validated in the training set, testing set, and whole cohorts by the Kaplan-Meier log-rank test, time-dependent ROC curve analysis, principal component analysis, univariate andmultivariate Cox regression analyses. RESULTS: A total of 937 immune- related lncRNAs were identified, 15 candidate immune-related lncRNAs were significantly associated with overall survival (OS). Eight of these lncRNAs (OTUD6B-AS1, AL122010.1, AC136475.2, AL161646.1, AC245297.3, LINC00578, LINC01871, AP000442.2) were selected for establishment of the risk prediction model. The OS of patients in the low-risk group was higher than that of patients in the high-risk group (p = 1.215e - 06 in the training set; p = 0.0069 in the validation set; p = 1.233e - 07 in whole cohort). The time-dependent ROC curve analysis revealed that the AUCs for OS in the first, eighth, and tenth year were 0.812, 0.81, and 0.857, respectively, in the training set, 0.615, 0.68, 0.655 in the validation set, and 0.725, 0.742, 0.741 in the total cohort. Multivariate Cox regression analysis indicated the model was a reliable and independent indicator for the prognosis of breast cancer in the training set (HR = 1.432; 95% CI 1.204-1.702, p < 0.001), validation set (HR = 1.162; 95% CI 1.004-1.345, p = 0.044), and whole set (HR = 1.240; 95% CI 1.128-1.362, p < 0.001). GSEA analysis revealed a strong connection between the signature and immune-related biological processes and pathways. CONCLUSIONS: We constructed and verified a robust signature of 8 immune-related lncRNAs for the prediction of breast cancer patient survival.

Secretory Pathway Kinase FAM20C, a Marker for Glioma Invasion and Malignancy, Predicts Poor Prognosis of Glioma.

PURPOSE: Glioblastoma (GBM) is the most lethal primary cancer in adult central nervous system, and new strategies are desperately needed. The secretory pathway kinase or kinase-like proteins (SPKKPs) have been shown to mediate multiple physiological functions by phosphorylating extracellular proteins and proteoglycans. However, their roles in cancers, especially GBM, remain poorly defined. METHODS: The least absolute shrinkage and selection operator (LASSO) regression was employed for establishing the SPKKPs signature for IDH wild type (wt) GBM prognosis. Integrative analyses with multiple datasets were employed to identify the core member of this gene family in glioma. The receiver operator characteristic (ROC) curves and immunohistochemistry were further used for evaluating its association with progressive malignancy in glioma and GBM patients' survival, respectively. Gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to interpret its functions in GBM, which were further verified in vitro. RESULTS: A SPKKPs classifier was constructed with 3 genes of this family. This signature could effectively distinguish IDH wt GBM survival. Family with sequence similarity 20 C (FAM20C) was further identified as the core member of this family in glioma. Elevated FAM20C expression was not only closely correlated with glioma malignancy progression and the mesenchymal subtype of GBM but also indicated unfavorable survival of GBM patients. FAM20C was also found to be associated with the disrupted immune response in GBM microenvironment and was required for the migration of glioma and immune cells. CONCLUSION: These data indicate that the potential of FAM20C serving as a predictive molecule and a therapeutic target for GBM.

Analysis of indications for pulmonary peripheral lesions diagnosed using radial endobronchial ultrasound-guided transbronchial lung biopsy.

The aim of the present study was to determine the indications for radial endobronchial ultrasound-guided transbronchial lung biopsy (rEBUS-D-TBLB) for the diagnosis of peripheral pulmonary lesions (PPL) located at the bronchopulmonary segments and subsegments. Data collected from 774 patients who underwent rEBUS-D-TBLB for suspected PPL, including clinical information, distribution of lesions, diagnostic spectrum and diagnostic rate, were collected and retrospectively reviewed. Additionally, the Wilcoxon signed-rank test was performed to analyze the diagnostic yield of lesions in bronchopulmonary subsegments under the lesion diameter limit of 3 cm. In total, 802 lesions were found in 774 patients. The diagnostic yield of rEBUS-D-TBLB for all lesions was 67.18%. Overall, 362 cases of malignant disease and 158 cases of benign disease were diagnosed, with sensitivities of 70.98 and 79.00% respectively. Lesions were distributed throughout the 18 bronchopulmonary segments of the lungs. The bronchopulmonary segments with >5% of the majority of the discovered lesions were LB1+2, LB3, LB6, LB10, RB1-4 and RB9. The diagnostic yield of rEBUS-D-TBLB was found to be >65% for lesions located at LB3, RB1-3 and RB9. Further rEBUS-D-TBLB examinations of the LB1+2a, LB6a and RB4b segments produced diagnostic yields of 81.25, 66.67 and 71.43% respectively. Finally, at segment RB4a, rEBUS-D-TBLB examination was more effective for lesions with diameters >3 cm compared with lesions with diameters <3 cm. The diagnostic yields for PPL distributed at LB1+2a, LB3, LB6a, RB1-3, RB4a (diameter >3 cm), RB4b, and RB9 using rEBUS-D-TBLB were higher compared with for other segments, providing a theoretical basis for the clinical application of rEBUS-D-TBLB for the diagnosis of PPL in patients.

Dihydromyricetin Alleviates Diabetic Neuropathic Pain and Depression Comorbidity Symptoms by Inhibiting P2X7 Receptor.

Diabetic neuropathic pain (DNP) and major depressive disorder (MDD) are common complications of diabetes mellitus and mutually affect each other. As a member of the ATP-gated ion channel family, P2X7 receptor is associated with the transduction of pain signal and the onset of depression. The aim of this study was to investigate the effects of dihydromyricetin (DHM) on rats with comorbid DNP and MDD. After the comorbid model was established, rat behavior changes were monitored by measuring the mechanical withdrawal threshold, thermal withdrawal latency, sugar water preference, immobility time in the forced-swim test, and open-field test parameters. The expressions of P2X7 receptor in the dorsal root ganglia (DRGs), spinal cord, and hippocampus were assessed by quantitative real-time PCR, Western blotting, and double immunofluorescence. We found that hyperalgesia, allodynia, and depressive behaviors of rats with comorbid DNP and MDD were relieved by treatment with DHM or application of a short-hairpin RNA for P2X7 receptor. The expression levels of P2X7, phosphorylated extracellular signal-regulated kinase 1/2, tumor necrosis factor α, and interleukin 1ß were increased in the DRGs, spinal cord, and hippocampus of rats in the model group but restored after DHM or P2X7 short-hairpin RNA treatment. In conclusion, P2X7 receptor in the DRGs, spinal cord, and hippocampus participates in the transduction of DNP and MDD signals. DHM seems to relieve comorbid DNP and MDD by reducing the expression of P2X7 receptor in the DRGs, spinal cord, and hippocampus and may be an effective new drug for the treatment of patients with both DNP and MDD.

Breast Cancer Risk-Associated SNPs in the mTOR Promoter Form De Novo KLF5- and ZEB1-Binding Sites that Influence the Cellular Response to Paclitaxel.

ZEB1 (a positive enhancer) and KLF5 (a negative silencer) affect transcription factors and play inherently conserved roles in tumorigenesis and multidrug resistance. In humans, the rs2295080T-allele at the mTOR promoter locus has been associated with human cancer risk; however, the 63 bp spacing of another SNP rs2295079 has not been identified. Here, we discovered, for the first time, that rs2295079 (-78C/G) and rs2295080 (-141G/T) formed linkage haplotypes, with Ht1 (-78C/-141G) and Ht2 (-78G/-141T) being dominant, which were associated with distinct susceptibility to breast cancer, response to paclitaxel, and clinical outcomes in breast cancer. At the cellular level, compared with Ht1, Ht2 exhibits a much stronger effect on promoting mTOR expression, leading to enhanced tumor cell growth and strengthened resistance to PTX treatment. Mechanistically, the -141T allele of Ht2 creates a novel ZEB1-binding site; meanwhile, the -78C allele of Ht1 exists as an emerging KLF5-binding site, which synergistically induces promote/inhibit mTOR expression, cell proliferation, and excretion of cytotoxic drugs through the ZEB1/KLF5-mTOR-CCND1/ABCB1 cascade, thereby affecting the response to paclitaxel treatment in vivo and in vitro. Our results suggest the existence of a ZEB1/KLF5-mTOR-CCND1/ABCB1 axis in human cells that could be involved in paclitaxel response pathways and functionally regulate interindividualized breast cancer susceptibility and prognosis. IMPLICATIONS: This study highlights the function of haplotypes of mTOR -78C/-141G and -78G/-141T, in affecting breast cancer susceptibility and paclitaxel response regulated by ZEB1/KLF5-mTOR-CCND1/ABCB1 axis.

Associations of mRNA expression of DNA repair genes and genetic polymorphisms with cancer risk: a bioinformatics analysis and meta-analysis.

A systematical bioinformatics and meta-analysis were carried out to establish our understanding of possible relationships between DNA repair genes and the development of cancer. The bioinformatics analysis confirmed that lower XPA and XPC levels and higher XPD, XPF, and WRN levels were observed in 19 types of cancer, and subsequently results indicated that elevated XPA and XPC had a better impact on overall survival, however, higher XPD, XPF, and WRN showed worse influence on cancer prognosis. The meta-analysis included 58 eligible studies demonstrated that harboring XPA rs10817938, XPD rs238406 increased overall cancer risk, however, XPA rs2808668 SNP in overall cancer analysis and XPF rs3136038 in the digestive system remarkably reduced the cancer risk. Moreover, no correlation was investigated for XPC rs1870134, WRN rs1346044 and rs1801195. These suggest that the DNA repair gene was associated with carcinogenesis, and contribute to the prognosis, and the critical SNPs further involved in affecting cancer risk.

Polymorphisms in DNA repair pathway genes and ABCG2 gene in advanced colorectal cancer: correlation with tumor characteristics and clinical outcome in oxaliplatin-based chemotherapy.

OBJECTIVE: Multiple factors are involved in oxaliplatin-resistant process in colorectal cancer (CRC) patients including decreased drug accumulation and enhanced capacity to repair and tolerate DNA damage. In the present study, we aimed to assess the impact of six single-nucleotide polymorphisms (SNPs) in DNA repair genes and ABCG2 gene on prognosis in advanced CRC patients treated with oxaliplatin-based chemotherapy. METHODS: In this study, 580 advanced CRC patients were recruited. Six SNPs of DNA repair genes (XPA rs10817938, XPA rs2808668, XPC rs2607775, and WRN rs1346044) and ABCG2 gene (rs2231142 and rs2622621) were genotyped by using the TaqMan assay. RESULTS: Regarding interaction with environmental factors, ABCG2 rs2231142 and the first-degree family history of cancer and XPC rs2607775 or ABCG2 rs2622621 and lymph node metastases status demonstrated significant interactions. Of these six SNPs, XPA rs10817938 CT/ TT genotypes retained its significant association with longer overall survival (OS) (P=0.008) in CRC patients receiving oxaliplatin-based chemotherapy (n=580). Furthermore, a significantly better impact on the disease-free survival (DFS) (P=0.001) and OS (P<0.0001) was found in ABCG2 rs2231142CA/AA carriers. Furthermore, ABCG2 rs2622621 CG/GG genotype was verified to be an independent poor prognostic factor in DFS (P=0.010) and OS (P=0.030). In the stratification analysis, XPA rs10817938 CT/CC, rs2231142 CA/AA, and rs2622621 CC genotypes of ABCG2 were predictive of significantly better prognosis in the patients with tumor differentiation grade 3 (n=523), clinical stage IV (n=73), or lymph node-positive status (n=557). Additionally, multivariate logistic regression and multiple dimension reduction analysis consistently revealed that the combination of selected SNPs and five known risk factors showed a better prediction prognosis and represented the best model to predict CRC prognosis. CONCLUSION: The current data indicated that the XPA gene and ABCG2 gene had significant interaction with environmental factors and prognosis, which could provide a comprehensive understanding of the implications of those SNPs in the prediction of prognosis in advanced CRC patients receiving oxaliplatin-based chemotherapy.

Vitamin D aggravates breast cancer by inducing immunosuppression in the tumor bearing mouse.

The aim of this approach is to test the effects and related mechanism of vitamin D (VD) treatment on the outcomes of breast cancer. BALB/c mice were injected with 4T1 breast cancer cell suspension. The test group was treated with VD reagent. The survival and tumor size of mice were observed. The proliferation of 4T1 in vitro was detected by MTS analysis. The changes of immune parameters and microenvironment in mice were evaluated by flow cytometry and real-time RT-PCR. Our results demonstrate that VD administration caused a decline in survival time and raising the volume of tumor, the decreasing numbers of CD3+CD4+ T, CD3+CD8+ T and CD4+T-bet+IFN-γ+ Th1 cells and transcriptions of T-bet and IFN-γ, an increasing number of myeloid-derived suppressor cells and transcription of TGF-ß. Our data suggest that the routine clinical application of any strategies targeting VD status for breast cancer therapy is deserved serious consideration.

Three new alkaloids isolated from the stem tuber of Pinellia pedatisecta.

The present study was designed to determine the chemical constituents of the stem tuber of Pinellia pedatisecta. The chemical constituents were isolated and purified by various chromatographic techniques, and their structures were elucidated on the basis of physicochemical properties and spectral data. Three new alkaloids (compounds 1, 2, and 3) were obtained and identified as 9-((5-methoxypyridin-2-yl)methyl)-9H-purin-6-amine (1), 4-(2-(2, 5-dioxopyrrolidin-1-yl)ethyl)phenyl acetate (2), and N-(9-((5-methoxypyridin-2-yl)methyl)-9H-purin-6-yl)acetamide (3). These compounds were evaluated for their cytotoxicity against human cervical cancer HeLa cells. Compounds 1 and 3 significantly inhibited the proliferation of HeLa cells with IC50 values being 3.02 ± 0.54 and 7.16 ± 0.62 µmol·L-1, respectively.

Effects of palmatine on rats with comorbidity of diabetic neuropathic pain and depression.

Diabetic neuropathic pain (DNP) is one of the common complications of diabetes. Depression (DP) is also one of the common complications of diabetes. P2X7 receptors play an important role in the transmission of nociceptive signal and are associated with depressive illness. In the study, the hyperalgesia, allodynia and depressive behaviours of rats with comorbidity of DNP and DP were confirmed by the thermal withdrawal latency (TWL) test, mechanical withdrawal threshold (MWT) test, sucrose preference test (SPT), immobility time of forced swimming test (IMFST) and open-field test (OFT). The change in expression of the P2X7 receptor of the hippocampus was observed through RT-PCR, qPCR, Western blotting and immunohistochemical staining methods The results showed that palmatine treatment can alleviate the hyperalgesia, allodynia and depressive behaviours of rats with comorbidity of DNP and DP. Meanwhile, the expression of P2X7 receptors, GFAP, TNF-α and IL-1ß in the hippocampus of the rats with comorbidity of DNP and DP was significantly increased compared with the control rats, and palmatine treatment could decrease the expression. Furthermore, the enhanced phosphorylation of ERK1/2 in the hippocampus of rats with DNP and DP was decreased noticeably by palmatine treatment. The results of this study suggest that palmatine can alleviate the comorbidity of DNP and DP by inhibiting the expression of P2X7 receptors in the hippocampus, and its action may be related to suppression of the phosphorylation of ERK1/2 and the release of TNF-α and IL-1ß in the hippocampus.

Protective Effects of Oxymatrine on Vascular Endothelial Cells from High-Glucose-Induced Cytotoxicity by Inhibiting the Expression of A2B Receptor.

BACKGROUND/AIMS: Diabetes mellitus (DM) has become an increasingly epidemic metabolic disease. Vascular endothelial cells play a key role in developing the cardiovascular complications of DM. The A2B receptor is expressed in vascular endothelial cells, and may help regulate the function of endothelial cells. The aim of this study was to investigate the protective effects of oxymatrine (OMT) on human umbilical vein endothelial cells (HUVECs) from high glucose-induced cytotoxicity. METHODS: Homology modeling and molecular docking analysis were used to detect the binding sites between the adenosine A2B receptor and OMT. HUVECs were cultured with control (5.5 mM) or elevated glucose (22.2 mM) in the presence or absence of 3 µM OMT or A2B siRNA for 3 days. The MTS cell viability assay was used to measure the toxicity of high glucose on HUVECs and the protective effect of OMT or A2B siRNA. The expression of the adenosine A2B receptor and CCL5 in HUVECs was detected with real-time quantitative PCR (qPCR) and Western blotting methods in each group. Levels of IL-1ß and TNF-α were measured using an enzyme-linked immunosorbent assay (ELISA) kit, and the concentration of NO was detected with the nitrate reductase method. Monocyte chemotactic activity in each group was detected using Transwell chambers. Furthermore, the phosphorylation of p38 and ERK1/2 in each group was observed through the Western blotting method. RESULTS: Homology modeling and molecular docking analysis showed that OMT contains well-fitted binding sites to the A2B receptor. After chronic culture at high glucose, the rate of cell viability was significantly lower than that of the control group. After co-treatment with OMT or A2B siRNA, cell viability was significantly increased compared with the high-glucose group. The results from real-time quantitative RT-PCR (qRT-PCR) and Western blotting indicated that high glucose could increase the expression of A2B receptors in HUVECs, an effect that was inhibited by OMT. In addition, the results revealed that the expression of CCL5, IL-1ß and TNF-α was increased in the high-glucose group, and that the NO produced by HUVECs decreased due to hyperglycemia; however, co-culture with OMT or A2B siRNA abolished these effects. Meanwhile, the chemotaxis activity of monocytes to HUVECs cultured in high-glucose medium was enhanced 2.59-fold compared to the control cells. However, the inflammatory reactions in HUVECs were completely relieved by co-treatment with OMT or A2B siRNA. Moreover, the phosphorylation of p38 and ERK1/2 in HUVECs in the high-glucose group was significantly higher than that of the control group; these effects were reversed after co-treatment with OMT or A2B siRNA. CONCLUSION: OMT may protect the HUVECs from high glucose-induced cytotoxicity through inhibitting the expression of A2B receptor and inflammatory factors as well as decreasing the phosphorylation of p38 and ERK1/2.