Pretreatment fibrinogen levels are associated with survival outcome in patients with cancer using immunotherapy as a second­line treatment.

The present study aimed to investigate the predictive value of pretreatment fibrinogen (FIB) levels in patients with cancer who received immunotherapy as a second-line treatment. A total of 61 patients with stage III-IV cancer were included. The cut-off value of FIB for predicting overall survival (OS) was determined by receiver operating characteristic curve analysis. The prognostic value of pretreatment FIB on progression-free survival (PFS) and OS was determined by univariate and multivariate analyses. Based on a cut-off point of 3.47 g/l, patients were divided into low pretreatment FIB (<3.47 g/l) and high pretreatment FIB (≥3.47 g/l) groups. A high pretreatment FIB level was more common in older patients (P=0.03). Kaplan-Meier analysis showed that patients with high pretreatment FIB levels had shorter PFS and OS times than patients with low FIB levels (P<0.05). In multivariate analysis, pretreatment FIB was an independent prognostic factor for OS [hazard ratio (HR), 6.06; 95% CI, 2.01-18.28; P<0.01] and OS from the initiation of second-line treatment (HR, 3.69; 95% CI, 1.28-10.63; P=0.02). Overall, FIB is associated with survival outcome in patients with cancer who are administered immunotherapy as a second-line treatment.

Pretreatment levels of serum alkaline phosphatase are associated with the prognosis of patients with non­small cell lung cancer receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have been an encouraging treatment method in non-small cell lung cancer (NSCLC). However, bone and liver metastases are considered to restrain immunotherapy efficacy. Since serum alkaline phosphatase (ALP) is associated with bone and liver metastases, it was investigated whether serum ALP could be a novel biomarker to predict the efficacy of ICIs treatment. In the present study, 143 patients with NSCLC receiving ICIs treatment were retrospectively analyzed. The objective response rate (ORR) was compared between the ALP high and low groups, bone metastasis and non-bone metastasis groups, and liver metastasis or non-liver metastasis groups. The associations between clinical characteristics, including ALP level, bone or liver metastasis and median progression-free survival (mPFS) time were analyzed by univariate and multivariate Cox regression analysis. It was found that bone metastasis was associated with a lower ORR (24 vs. 43%; P<0.05) and shorter mPFS (10.2 vs. 17.3 months; P=0.010) in patients with NSCLC receiving ICIs. Liver metastasis was associated with lower ORR (22 vs. 38%; P<0.05), but not with mPFS (P=0.119). The ALP level was higher in patients with bone or liver metastasis than in those without (119.6 or 103.6 vs. 83.3 U/l, respectively; P<0.05). Higher ALP levels were also associated with bone or liver metastasis, lower ORR (20 vs. 39%; P<0.05) and shorter mPFS (8.5 vs. 15.4 months; P=0.009). Cox regression analysis demonstrated that ALP was an independent prognostic indicator of mPFS (hazard ratio, 1.856; 95% confidence interval, 1.030-3.343; P=0.040). In conclusion, pretreatment levels of serum ALP might be a predictive indicator of clinical outcome in patients with NSCLC after ICIs treatment.

Effects of ultraviolet radiation on microorganism and nitrogen metabolism in sewage under plateau background.

The experiments were conducted in the Tibetan plateau environment, and the sewage treatment conditions were designed with ultraviolet (UV) irradiation for 5 min, 10 min, 30 min, and 180 min. The Illumina MiSeq high-throughput sequencing technology was used to analyze the microbiological and metabolomic patterns of the plateau sewage treatment at the experimental scale, and then the response mechanisms of microbial and nitrogen metabolism in sewage treatment were explored. The abundance of metabolism at the first level and global and overview maps at the second level were higher in the plateau environment than in other regions. The KEGG pathway shows the effect of UV on nitrogen metabolism and its aptitude to improving or inhibit it. The two main nitrogen removal processes are nitrification and dissimilatory nitrate reduction. This study reveals the response of activated sludge to UV radiation in a plateau environment from microbiological and metabolomic perspectives, providing ideas and perspectives for the study of water treatment system methods, as well as laying a valuable theoretical foundation for the enhancement of plateau sewage treatment capacity.

Prognostic and clinical significance of HER-2 low expression in early-stage gastric cancer.

INTRODUCTION: Gastric cancer is the most fifth common tumor worldwide. Human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis and clinical characteristics in gastric cancer. Nevertheless, the biology of HER2-low expression has not reported in gastric cancer. MATERIALS AND METHODS: A total of 157 patients with early-stage gastric cancer were retrospectively analyzed. The associations between HER-2 low expression and clinical characteristics were analyzed by Chi-square test. And the prognostic value of HER-2 low expression and clinical characteristics in disease-free survival (DFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression analysis. RESULTS: Of 157 patients with early-stage gastric cancer, 31.8% had HER2-low tumors and 50.3% had HER2-negative tumors. HER2-low expression was associated with age, histological differentiation, tumor location and Ki-67 index. However, HER2-low expression was not associated with DFS or OS in early-stage gastric cancer. CONCLUSION: HER2-low expression might result in distinct biology, but it was not an independent prognostic factor of DFS or OS in early-stage gastric cancer.

Postoperative Fasting Blood Glucose Predicts Prognosis in Stage I-III Colorectal Cancer Patients Undergoing Resection.

PURPOSE: The relationship between high blood glucose and colorectal cancer (CRC) has been studied, but the role of postoperative fasting blood glucose (FBG) in patients with a prior normal FBG has never been addressed. METHODS: A total of 120 CRC patients staged I-III were enrolled, and the prognostic value of postoperative FBG for disease-free survival (DFS) was determined by Kaplan-Meier analysis. Univariate and multivariate analyses were conducted to test other clinicopathological parameters, including preoperative hemoglobin (HGB) and the neutrophil-lymphocyte ratio (NLR). RESULTS: By a cut-off point of 5.11 mmol/L, 51 and 69 patients were divided into low postoperative FBG (<5.11 mmol/L) and high postoperative FBG (≥5.11 mmol/L) groups, respectively. A high postoperative FBG was more common in older age (P = 0.01), left-located tumor (P = 0.02), smaller tumor diameter (P = 0.01), node negative involvement (P = 0.01), lesser positive lymph nodes (P = 0.02), and high preoperative HGB (P = 0.01). Further, high postoperative FBG patients displayed a significantly better DFS than low postoperative FBG patients (48.80 ± 22.12 months vs. 40.06 ± 24.36 months, P = 0.04), but it was less likely to be an independent prognostic factor. CONCLUSIONS: Postoperative FBG plays a temporal prognostic role for patients with stage I-III CRC with a prior normal FBG, but it is not an independent prognostic factor.

Value of Magnetic Resonance Imaging Texture Analysis in the Differential Diagnosis of Benign and Malignant Breast Tumors.

Objective To investigate the difference in texture features on diffusion weighted imaging (DWI) images between breast benign and malignant tumors.Methods Patients including 56 with mass-like breast cancer, 16 with breast fibroadenoma, and 4 with intraductal papilloma of breast treated in the Hainan Hospital of Chinese PLA General Hospital were retrospectively enrolled in this study, and allocated to the benign group (20 patients) and the malignant group (56 patients) according to the post-surgically pathological results. Texture analysis was performed on axial DWI images, and five characteristic parameters including Angular Second Moment (ASM), Contrast, Correlation, Inverse Difference Moment (IDM), and Entropy were calculated. Independent sample t-test and Mann-Whitney U test were performed for intergroup comparison. Regression model was established by using Binary Logistic regression analysis, and receiver operating characteristic curve (ROC) analysis was carried out to evaluate the diagnostic efficiency.Results The texture features ASM, Contrast, Correlation and Entropy showed significant differences between the benign and malignant breast tumor groups (PASM=0.014, Pcontrast=0.019, Pcorrelation=0.010, Pentropy=0.007). The area under the ROC curve was 0.685, 0.681, 0.754, and 0.683 respectively for the positive texture variables mentioned above, and that for the combined variables (ASM, Contrast, and Entropy) was 0.802 in the model of Logistic regression. Binary Logistic regression analysis demonstrated that ASM, Contrast and Entropy were considered as the specific imaging variables for the differential diagnosis of breast benign and malignant tumors.Conclusions The texture analysis of DWI may be a simple and effective tool in the differential diagnosis between breast benign and malignant tumors.

MG132 selectively upregulates MICB through the DNA damage response pathway in A549 cells.

Natural killer (NK) cells recognize stress­activated NK group 2, member D (NKG2D) ligands in tumors. In the present study, the expression levels of NKG2D ligands were examined in four lung cancer cell lines (A549, PLA801D, NCI­H157 and NCI­H520). In the A549 cells, the expression of MHC class I polypeptiderelated sequence (MIC)A/B and UL16 binding protein (ULBP)1 was weak, the expression of ULBP2 was typical, and neither ULBP3 nor ULBP4 were expressed. The mechanism underlying the regulatory effect of a cancer treatment agent on the expression of NKG2D ligands was investigated using the proteasome inhibitor MG132. Following treatment for 8 h with MG132, the transcription levels of MICB and ULBP1 were upregulated 10.62­ and 11.09­fold, respectively, and the expression levels of MICB and ULBP1 were increased by 68.18 and 23.65%, respectively. Notably, MICB exhibited significant time­dependent change. MG132 increased the transcription of MICB by acting at a site in the 480­bp MICB upstream promoter. The activity of the MICB promoter was upregulated 1.77­fold following treatment with MG132. MG132 treatment improved the cytotoxicity of NK cells, which was partially blocked by an antibody targeting NKG2D, and more specifically the MICB molecule. The expression of MICB induced by MG132 was inhibited by KU­55933 [ataxia telangiectasia mutated (ATM) kinase inhibitor], wortmannin (phosphoinositide 3 kinase inhibitor) and caffeine (ATM/ATM­Rad3­related inhibitor). The phosphorylation of checkpoint kinase 2 (Chk2), an event associated with DNA damage, was observed following treatment with MG132. These results indicated that MG132 selectively upregulates the expression of MICB in A549 cells, and increases the NKG2D­mediated cytotoxicity of NK cells. The regulatory effect of MG132 may be associated with the activation of Chk2, an event associated with DNA damage. The combination of MG132 with NK cell immunotherapy may have a synergistic effect that improves the therapeutic effect of lung cancer treatment.

Gastric adenocarcinoma is concurrent with metastatic neuroendocrine cancer treated with nivolumab and chemotherapy: A case report.

Gastric adenocarcinoma concurrent with metastatic neuroendocrine cancer (NEC) is rare. In the present case report, a 39-year-old male was first pathologically diagnosed by gastric endoscopy as having a highly differentiated adenocarcinoma. Next, positron emission tomography-computed tomography examination and bone marrow biopsy confirmed extensive metastasis. Subsequently, the patient underwent 6 cycles of immunotherapy (nivolumab, 160 mg) and 5 cycles of chemotherapy based on the XELOX regimen (oxaliplatin + capecitabine). Following this, the patient received the final cycles of nivolumab and XELOX; however, the patient then succumbed. Further biopsy of the metastatic collarbone lymph nodes indicated NEC. Overall, the progression-free survival was ~3.5 months, and overall survival (OS) was ~6 months. The case presented the possibility of concurrent gastric adenocarcinoma and NEC in the clinic. In addition, the efficacy of a combined regimen such as immunotherapy and chemotherapy for such disorders still requires further validation in the future.

A signal-on electrochemiluminescence sensor for clenbuterol detection based on zinc-based metal-organic framework-reduced graphene oxide-CdTe quantum dot hybrids.

Clenbuterol (CLB) is harmful to human health when used long term, and it has been listed by the World Anti-Doping Agency (WADA). In this work, a novel zinc-based metal-organic frameworks-reduced graphene oxide-CdTe quantum dots (ZnMOF-RGO-CdTe QDs) hybrid was used to construct an electrochemiluminescence (ECL) sensor for detecting CLB. CdTe QDs, loaded by RGO, exhibited an enhanced ECL signal. In addition, the ZnMOFs catalyzed OH• generation by coreactant H2O2, which further strengthened the ECL signal of the CdTe QDs. The integration of ZnMOFs and RGO-CdTe QDs endowed the sensor with high sensitivity for CLB detection. The intensity of the ECL signal increased as the concentration of CLB increased. The linear range of CLB detection was 3.0 × 10-13 M to 6.0 × 10-10 M, and the detection limit was estimated to be 1.0 × 10-13 M. Furthermore, the sensor displayed a good repeatability and stability. The ZnMOF-RGO-CdTe QD hybrids described in this study provide a foundation for the development of new methods of detecting CLB. Graphical abstract ᅟ.

S100B promotes chemoresistance in ovarian cancer stem cells by regulating p53.

Chemoresistance is one of the most important causes of ovarian cancer­related deaths. Recently, cancer stem cells (CSCs) have been recognized as the source of chemoresistance in ovarian cancer. However, the underlying mechanisms that regulate the chemoresistance of ovarian CSCs (OCSCs) remain unclear. The aim of the present study was to investigate the roles of S100B in the regulation of OCSC chemoresistance, which provides a novel therapeutic target. We observed high expression of S100B in CD133+ OCSCs derived from ovarian cancer cell lines and primary tumors and in cisplatin­resistant patient samples. Then, we determined that S100B knockdown promoted the apoptosis of OCSCs after treatment with different concentrations of cisplatin. The underlying mechanism of S100B­mediated chemoresistance in OCSCs may be through p53 inhibition. Furthermore, drug­resistance genes, including MDR1 and MRP1, were involved in the process of S100B­mediated OCSC chemoresistance. In conclusion, our results elucidated the importance of S100B in the maintenance of OCSC chemoresistance, which may provide a promising therapeutic target for ovarian cancer.

Docetaxel/S-1 Versus Docetaxel/Capecitabine as First-Line Treatment for Advanced Breast Cancer: A Retrospective Study.

The treatment efficacy of advanced breast cancer is still not promising. This study aimed to compare the efficacy and safety of docetaxel/S-1 (DS1) versus docetaxel/capecitabine (DX) as the first-line treatment for advanced breast cancer.From June 2008 to June 2013, 22 patients with advanced breast cancer were treated with the DS1 regimen. Another 26 age- and disease status-matched patients treated with the DX regimen served as controls. The 2 groups were compared in terms of time to progression (TTP), objective response rate, disease control rate, clinical benefit rate, and safety profiles.Median TTP did not differ significantly between the DS1 group and the DX group (9.04 vs 10.94 months, P = 0.473). There were no significant differences in objective response rate, disease control rate, and clinical benefit rate between the 2 groups. Both the DS1 and the DX regimens showed good tolerability. The 2 regimens showed no significant difference in adverse events except degree III hand-foot syndrome (DS1 0 vs DX 23.1%, P = 0.025).For the first-line treatment of advanced breast cancer, the DS1 and the DX regimens showed similar efficacy and safety. The DS1 regimen had less severe hand-foot syndrome than the DX regimen.

Association between interleukin-8 -251A/T polymorphism and risk of lung cancer: a meta-analysis.

This study is to evaluate the association between IL-8 -251A/T polymorphism and lung cancer risk in diverse populations. We performed a meta-analysis of six case-control studies that included 3,265 lung-cancer cases and 3,607 case-free controls. Overall, results showed that the IL-8 -251A/T polymorphism was not associated with a significantly increased risk of lung cancer in all genetic models. However, stratified by ethnicity, a significantly increased risk was found among Asians. In conclusion, IL-8 -251A/T polymorphism is associated with lung cancer susceptibility in Asians and the -251 A allele may increase risk of lung cancer in Asians.

Common polymorphism in the MMP-13 gene may contribute to the risk of human cancers: a meta-analysis.

Cancer was viewed to be driven by accumulating genetic abnormalities that generally include chromosomal abnormalities, mutations in tumor-suppressor genes, and oncogenes. The aim of this meta-analysis was to systematically summarize the possible associations between MMP-13 rs2252070 A>G variant and cancer risks. We systematically reviewed studies focusing on MMP-13 polymorphisms with human cancer susceptibility that were published before April 30, 2014. Relevant articles were identified through research of PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CBM, and CNKI databases. All analyses were calculated using the Version 12.0 STATA software. Odds ratios (OR) and 95 % confidence interval (95 % CI) were calculated. Eleven independent case-control studies were included in the meta-analysis, which involved 3,465 patients with cancers and 4,073 healthy controls. The results identified a positive association between rs2252070 A>G polymorphism and susceptibility to cancer under five genetic models (all P < 0.05). Ethnicity subgroup analysis implied that significant difference was detected for rs2252070 A>G polymorphism with increased risk of cancers among Asians and Caucasians in majority of the groups. Our findings suggest significant association for MMP-13 rs2252070 A>G to increased susceptibility to human cancer, especially in the progression of lung carcinoma.

Effects of ARHI on breast cancer cell biological behavior regulated by microRNA-221.

The aplysia ras homolog member I (ARHI) is a tumor suppressor gene and is downregulated in various cancers. The downregulation of ARHI was regulated by miR-221 in prostate cancer cell lines. However, it has not been reported whether ARHI is regulated by miR-221 in breast cancer. Here, we reported that the ARHI protein level was downregulated in breast cancer tissues and breast cancer cell lines. The overexpression of ARHI could inhibit cell proliferation and invasion and induce cell apoptosis. To address whether ARHI is regulated by miR-221 in breast cancer cell lines, the results in this study showed that a significant inverse correlation existed between ARHI and miR-221. MiR-221 displayed an upregulation in breast cancer tissues and breast cancer cell lines. The inhibition of miR-221 induced a significant upregulation of ARHI in MCF-7 cells. To prove a direct interaction between miR-221 and ARHI mRNA, ARHI 3'UTR, which includes the potential target site for miR-221, was cloned downstream of the luciferase reporter gene of the pMIR-REPORT vector to generate the pMIR-ARHI-3'UTR vector. The results confirmed a direct interaction of miR-221 with a target site on the 3'UTR of ARHI. In conclusion, ARHI is a tumor suppressor gene that is downregulated in breast cancer. The overexpression of ARHI could inhibit breast cancer cell proliferation and invasion and induce cell apoptosis. This study demonstrated for the first time that the downregulation of ARHI in breast cancer cells could be regulated by miR-221.

[Effects of single versus combined use of trastuzumab and cantide on breast cancer cells SKBR3 over-expressing HER2].

OBJECTIVE: To evaluate the in vitro cytotoxic effects of cantide or herceptin on human breast cancer SKBR3 cells over-expressing HER2. METHODS: The distribution of HER2 and hTERT protein in SKBR3 cells and the effects of cantide and/or herceptin on the subcellular localization of HER2 and hTERT were observed by indirect immunofluorescent assay. The inhibition rate of herceptin and/or cantide at different concentrations on SKBR3 cells was detected by MTT assay. And the apoptotic rate of cells was evaluated by flow cytometer. RESULTS: (1) The expressions of both HER2 and hTERT proteins in SKBR3 cells were found. HER2 protein was predominant in cell membranes while hTERT protein in nuclei. After the addition of herceptin, the cytoplasmic migration of HER2 was found while there was no distinct location change of cantide. (2) In MTT assay, the single use of cantide or herceptin and the combined use of both produced inhibitory effects on SKBR3 cells while the inhibition rate was higher for combined use. The inhibitory effects became additive in the combined use of 0.4 µmol/L cantide and 0.85 µg/ml herceptin. And there were synergistic effects in the combined use of 0.4 µmol/L cantide and 1.70, 3.40, 6.88 or 13.75 µg/ml herceptin. (3) The apoptotic rate was 25.75% for cantide alone, 11.26% for herceptin alone and 41.41% for their combined use (apoptotic cells predominant in advanced stage). CONCLUSION: Due to different localizations, cantide and herceptin have different action sites in their combined use. When in single use, the inhibition rate is linearly correlated with the concentration of herceptin or cantide. And their combined use produces additive or synergistic antitumor effects on SKBR3 breast cancer cells.

Four-and-a-half-LIM protein 1 down-regulates estrogen receptor α activity through repression of AKT phosphorylation in human breast cancer cell.

The Four-and-a-half LIM protein 1 (FHL-1) is a member of LIM-only protein family. It plays important roles in proliferation and apoptosis regulation of certain hepatocellular carcinoma and human breast cancer. Estrogen receptor α (ERα) is involved in the development and progression of human breast cancer. IGF/PI3K/AKT signaling pathway also plays certain roles in the program and regulation of human breast cancer and ovary cancer. However, the biological function of FHL-1 in regulation of human breast cancer and in the cross-talk of estrogen and IGF signaling pathway remains largely unknown. In this paper, we show that FHL-1 protein interacts with ERα and AKT. FHL-1 represses the translation and transcription of estrogen receptor-responsive genes through down-regulating AKT activation. In addition, FHL-1 is not only an ERα-interacting co-regulation protein, but also decreases the phosphorylation of AKT and ERα. Depression of endogenous FHL-1 by FHL-1 targeted small interfering RNA enhances the expression of these proteins and phosphorylation of AKT and ERα. These data suggest that FHL-1 may regulate ER signaling function through regulation of AKT activation besides the physical and functional interaction with ERα. By establishing a linkage role of the FHL-1 between the estrogen ERα signaling pathway and IGF/PI3K/AKT signaling pathway, this study identifies that FHL-1 proteins may be a useful molecular target for human breast cancer therapy.

Expression of Y-Box-binding protein 1 in Chinese patients with breast cancer.

The purpose of this study was to investigate the expression of Y-Box-binding protein 1 (YB-1) in breast cancer and its correlation with clinicopathological characteristics and prognosis. Paraffin sections were retrospectively collected from 239 cases of stage I-III breast cancer patients and 30 healthy females who received surgery between January 2000 and December 2004 in the Chinese People's Liberation Army General Hospital. The protein expression of YB-1 was detected by immunohistochemistry. The expression difference between the two groups and the correlation between YB-1 expression and clinicopathological characteristics and breast cancer prognosis were analyzed. Within the breast cancer group, YB-1 was expressed in the cytoplasm in 100.0% (239/239) of cases and in the nucleus in 36.8% (88/239) of cases. Within the control group of normal breast tissue, YB-1 was expressed in the cytoplasm in 100.0% (30/30) of cases and in the nucleus in 16.7% (5/30) of cases. The expression of YB-1 in the nucleus of breast cancer cells was significantly higher than that in normal breast tissue (P = 0.029). The expression of YB-1 in the nucleus of breast cancer cells positively correlated with the Scarff-Bloom-Richardson grade (P = 0.007) and HER-2 expression (P = 0.005), negatively correlated with ER expression (P = 0.004), and was independent of the age, menstrual status, pathological type, tumor size, lymph node status, presence of thrombosis, PR expression, and EGFR expression. The 5-year disease-free survival (DFS) and overall survival (OS) of patients with positive YB-1 expression in the nucleus were significantly lower than those of patients who were negative for nuclear YB-1 expression, and the difference was statistically significant (DFS 65.9% vs. 82.1%, P = 0.000; OS 79.5% vs. 92.1%, P = 0.000). Multivariate analysis suggested that the expression of YB-1 in the nucleus is an independent prognostic factor that affects DFS and OS in breast cancer patients (DFS P = 0.015; OS P = 0.035). In conclusion, the expression of YB-1 in the nucleus is related to carcinogenesis and the development of breast cancer. Therefore, YB-1 is an important molecular marker that can be used to predict breast cancer prognosis.