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BACKGROUND: Recent studies have shown that pyroptosis is related to cancer development. Our previous study also found that gasdermins (GSDMs) was associated with the tumor immune microenvironment. Therefore, we wanted to observe the relationship between pyroptosis and the immune microenvironment and prognosis of skin cutaneous melanoma (SKCM). METHODS: Pyroptosis-related genes were used for pan-cancer prognostic analysis using the GEPIA2 online analysis website. Prognosis-related genes were clustered using R software and related R packages, and the best clustering results were screened for prognosis analysis. The prognosis-related genes were also used to establish a prognosis-related model. Assess the predictive power of a model by comparing area under the curve (AUC). The t-test was used to analyze the differences of immune-related indicators between the two clusters and between high and low risk groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed on the differential genes. RESULTS: By clustering the prognosis-related genes, SKCM could be divided into 2 clusters with significant differences in prognosis P

Phthalate esters (PAEs) have been extensively used in industry as plasticizers and there remains concerns about their safety. The present study aimed to determine the inhibition of phthalate esters (PAEs) on the activity of the phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone was used to investigate the inhibition potentials of PAEs towards various s UGTs. PAEs exhibited no significant inhibition of UGT1A1, UGT1A3, UGT1A8, UGT1A10, UGT2B15, and UGT2B17, and limited inhibition of UGT1A6, UGT1A7 and UGT2B4. However, UGT1A9 was strongly inhibited by PAEs. In silico docking demonstrated a significant contribution of hydrogen bonds and hydrophobic interactions contributing to the inhibition of UGT by PAEs. The Ki values were 15.5, 52.3, 23.6, 12.2, 5.61, 2.79, 1.07, 22.8, 0.84, 73.7, 4.51, 1.74, 0.58, 6.79, 4.93, 6.73, and 7.23 μM for BBOP-UGT1A6, BBZP-UGT1A6, BBOP-UGT1A7, BBZP-UGT1A7, DiPP-UGT1A9, DiBP-UGT1A9, DCHP-UGT1A9, DBP-UGT1A9, BBZP-UGT1A9, BBOP-UGT1A9, DMEP-UGT1A9, DPP-UGT1A9, DHP-UGT1A9, DiBP-UGT2B4, DBP-UGT2B4, DAP-UGT2B4, and BBZP-UGT2B4, respectively. In conclusion, exposure to PAEs might influence the metabolic elimination of endogenous compounds and xenobiotics through inhibiting UGTs.

Background: The present study sought to explore the role of microRNA-330 (miR-330) in predicting the radiation response and prognosis of patients with brain metastasis (BM) from lung cancer (LC). Methods: Patients with BM from LC were identified and classified into radiation-sensitive and radiation-resistant groups according to the overall survival rate, local and distant recurrence rate after conventional whole-brain radiation therapy. Quantitative realtime polymerase chain reaction (qRT-PCR) was used to detect miR-330 expression in serum. Receiver operating characteristic (ROC) curves were used to evaluate the prognostic value of miR-330 for the radiation sensitivity of brain metastasis from LC. Related clinical factors for radiation sensitivity were assessed by logistic regression analysis, and a survival analysis was conducted using COX regression and the Kaplan-Meier method. Results: MiR-330 exhibited lower expression in the radiation-sensitive group than in the radiation-resistant group. The area under the ROC curve of miR-330 for predicting radiation sensitivity was 0.898 (optimal cut-off value, 0.815), with a sensitivity of 71.7% and a specificity of 90.1%. After radiation therapy, patients with low miR-330 expression, compared to patients with high miR-330 expression, displayed a lower survival rate and a median survival time. MiR-330 expression was correlated with extracranial metastasis, maximum BM diameter, tumor-node-metastasis (TNM) stage and node (N) stage. Logistic regression and COX regression analyses revealed that extracranial metastasis, TNM stage, N stage and miR-330 expression were factors that influenced both radiation sensitivity and individual prognostic factors in patients with BM from LC. Conclusions: These findings indicate that the downregulation of miR-330 correlates with radiation sensitivity and poor prognosis in patients with BM from LC.

// Li-Peng Jiang 1 , Chun-Yan He 2 , Zhi-Tu Zhu 3 1 Department of Radiation Oncology, First Affiliated Hospital of Liaoning Medical University, Jinzhou 121000, P.R. China 2 Department of Prosthodontics, Second Affiliated Hospital of Liaoning Medical University, Jinzhou 121000, P.R. China 3 Department of Oncology, First Affiliated Hospital of Liaoning Medical University, Jinzhou 121000, P.R. China Correspondence to: Zhi-Tu Zhu, email: ZHUzhitu_806@163.com Keywords: microRNA-21, PDCD4, non-small cell lung cancer, radiotherapy, PI3K Received: April 09, 2016 Accepted: December 26, 2016 Published: February 23, 2017 ABSTRACT This study aims to explore the effects of microRNA-21 (miR-21) on radiosensitivity in non-small cell lung cancer (NSCLC) by targeting programmed cell deanth 4 (PDCD4) and regulating PI3K/AKT/mTOR signaling pathway. Cancer tissues and adjacent normal tissues were collected from 97 NSCLC patients who received a standard radiotherapy regimen. TUNEL assay was applied to determine cell apoptosis in tissues. The qRT-PCR assay was used to detect the expressions of miR-21 expression and PDCD4 mRNA. The protein expressions of PDCD4 and PI3K/AKT/mTOR signaling pathway-related proteins were determined by Western blotting. Colony formation assay was used to observe the sensitivity to radiotherapy of NSCLC cells. Flow cytometry was adopted to testify cell apoptosis. Compared with adjacent normal tissues, miR-21 expression was significantly increased and the mRNA and protein expressions of PDCD4 were decreased in NSCLC tissues. Higher miR-21 expression was associated with attenuated radiation efficacy and shorter median survival time. PDCD4 was the target gene of miR-21. The miR-21 mimics and siRNA-PDCD4 decreased the sensitivity to radiotherapy and cell apoptosis of A549 and H1299 cells and activated PI3K/AKT/mTOR pathway. The sensitivity of A549 and H1299 cells was strengthened in the miR-21 inhibitors group and the PI3K/AKT/mTOR inhibitors group. The siRNA-PDCD4 could reverse the effects of miR-21 inhibitors on sensitivity to radiotherapy and cell apoptosis of NSCLC cells. Our findings provide strong evidence that miR-21 could inhibit PDCD4 expression and activate PI3K/AKT/mTOR signaling pathway, thereby affecting the radiation sensitivity of NSCLC cells.

Cerebral infarction (CI) and intracerebral hemorrhage are lethal cerebrovascular diseases, sometimes sharing similar clinical manifestations but with distinct therapeutic strategies. Delayed treatment usually resulted in poor prognosis. A timely diagnosis report is highly warranted especially in emergency. One hundred twenty-nine CI patients, 73 intracerebral hemorrhage (ICH) patients, and 98 controls were enrolled in this study. A direct injection mass spectrometry metabolomics approach was adopted using dried blood spot samples. This targeted metabolomics analysis focused on absolute quantitation of 23 amino acids, 26 carnitine/carnitine esters, and 22 calculated ratios parameters. Compared to the normal control group, CI and ICH showed distinct metabolite changes, respectively. For stroke differentiation, Tyr, C5-OH/C0, Cit, Asn, Pro, Val, Arg/Orn, Leu, and Val/Phe were elevated in the CI group. On the contrary, C5:1, Phe/Tyr, (C0 + C2 + C3 + C16 + C18:1)/Cit, and Met/Leu were of lower levels in the CI group. Using regression model based on some of the above-mentioned parameters, 79.07% of stroke patients from a new set could be definitely confirmed. This study proved the targeted metabolomics analysis was a promising tool for rapid and timely stroke differentiation.

Background. We performed a systematic review and meta-analysis to study the association between serum endostatin levels and gastric cancer (GC) progression.Method. We searched the MEDLINE, Science Citation Index, Cochrane Library, PubMed, Embase, Current Contents Index, and several Chinese databases for published studies relevant to our study topic. Carefully selected studies were pooled and SMD and its corresponding 95% CI were calculated. Version 12.0 STATA software was used for statistical analysis.Results. Serum endostatin levels were analyzed in 12 case-control studies (736 GC patients and 350 controls). Significant differences in serum endostatin levels were observed between GC patients and the healthy controls (SMD = 1.418, 95% CI = 1.079~1.757,P<0.001). Importantly, significantly lower levels of serum endostatin were found in I-II grade patients compared to those with III-IV grade tumors (P<0.001). Further, higher serum endostatin levels were observed in the LN invasion-positive GC subjects in comparison with LN invasion-negative subjects (P<0.001).Conclusion. Patients with GC exhibited elevated levels of serum endostatin than controls and its level showed a statistical correlation with the more aggressive type of GC, exhibiting invasion and LN metastasis. Thus, serum levels of endostatin being a useful prognostic biomarker for GC patients warrants further investigation.

The aim of the present study was to investigate the role of breast cancer stem cells (BCSCs) in the angiogenesis of breast cancer tumors. The expression levels of mutant p53, cluster of differentiation (CD)31, vascular endothelial factor (VEGF), in addition to human epidermal growth factor (HER)2, were detected in the blood vessels of human breast cancer (BC) tissue samples. CD44+/CD24−/low cells were selected from single-cell suspensions of BC tissues to assess the expression of CD31 and CD105, in addition to the ability of these cells to metabolize acetylated low-density lipoprotein (Ac-LDL). Furthermore, vascular-like structures were observed histologically. Mutant p53, CD31 and VEGF were all expressed in these tissues. CD44+ cells comprised 7.5±2.6 and 94.3±4.7% of the cell population prior to and following sorting, respectively. CD24+ cells comprised 48.2±9.4 and 4.3±4% of the cell population prior to and following sorting, respectively. A low proportion of CD24+ cells corresponded to a high proportion of CD24−/low cells. The percentages of CD105+ and CD31+ glomus cells in the mammary gland were 4.5±0.9 and 6.2±1.3%, respectively, and following passaging for three generations, these increased to 79.6±9.3 and 84.1±10.7%, respectively (P

1. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of everolimus on the activity of phase-II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs).2. The results showed that 100 μM of everolimus exerted more than 80% inhibition toward UGT1A1, UGT-1A3 and UGT-2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus toward the activity cavity of UGT1A3 and UGT2B7. Inhibition kinetic-type analysis using Lineweaver–Burk plot showed competitive inhibition toward all these UGT isoforms. The inhibition kinetic parameters (Ki) were calculated to be 2.3, 0.07 and 4.4 μM for the inhibition of everolimus toward UGT1A1, UGT-1A3 and UGT-2B7, respectively.3. In vitro–in vivo extrapolation (IVIVE) showed that [I]/K...

Gomisin C (GC) and gomisin G (GG) are two lignan analogs isolated from the Traditional Chinese Medicine Schisandra chinensis which possesses multiple pharmacological activities. However, the potential herb-drug interactions (HDI) between these lignans and other drugs through inhibiting human cytochrome P450 3A4 (CYP3A4) and CYP3A5 remains unclear. In the present study, the inhibitory action of GC and GG on CYP3A4 and CYP3A5 were investigated. The results demonstrated that both GC and GG strongly inhibited CYP3A-mediated midazolam 1′-hydroxylation, nifedipine oxidation and testosterone 6β-hydroxylation. Notably, the inhibitory intensity of GC towards CYP3A4 was stronger than CYP3A5 when using midazolam and nifedipine as substrates. While inhibition of GC towards CYP3A5 was weaker than CYP3A4 when using testosterone as substrate. In contrast, GG showed a stronger inhibitory activity on CYP3A5 than CYP3A4 without substrate-dependent behavior. In addition, docking simulations indicated that the π–π interaction between CYP3A4 and GC, and hydrogen-bond interaction between CYP3A5 and GG might result in their different inhibitory actions. Furthermore, the AUC of drugs metabolized by CYP3A was estimated to increase by 8%–321% and 2%–3190% in the presence of GC and GG, respectively. These findings strongly suggested that GC and GG showed high HDI potentials, and the position of methylenedioxy group determined their different inhibitory effect towards CYP3A4 and CYP3A5, which are of significance for the application of Schisandra chinensis-containing herbs.

Scutellarin is an important bioactive flavonoid extracted from Erigeron breviscapus (Vant.) Hand-Mazz, and scutellarein is the corresponding aglycone of scutellarin. The present study aims to compare the inhibition potential of scutellarin and scutellarein towards several important UDP-glucuronosyltransferase (UGT) isoforms, including UGT1A1, UGT1A6, UGT1A9 and UGT2B7. It was demonstrated that scutellarein exerted stronger inhibition towards the tested UGT isoforms than scutellarin. Furthermore, the inhibition kinetic type and parameters (K-i) were determined for the scutellarein's inhibition towards these UGT isoforms. Competitive inhibition of scutellarein towards all these UGT isoforms was demonstrated, and the K-i values were calculated to be 0.02, 5.0, 5.8 and 35.9 mu M for UGT1A1, 1A6, 1A9 and 2B7, respectively. Using in vivo maximum plasma concentration of scutellarein in rat, the in vitro-in vivo extrapolation was performed to predict in vivo situation, indicating the most possible in vivo adverse effects due to the inhibition of scutellarein towards UGT1A1. All these results remind us to monitor the utilization of scutellarin and scutellarein, and the herbs containing these two components. Copyright (c) 2013 John Wiley & Sons, Ltd.

In this paper, the microbial transformation of desacetylcinobufagin (1) by Fusarium avenaceum AS 3.4594 was investigated, and four metabolites were isolated and characterized as 3-keton-desacetylcinobufagin (2), 3-epi-desacetylcinobufagin (3), bufadienolide A (4), and 15β,16α-dihydroxyl-17βH-bufalin (5), respectively. Among them, 4 and 5 are new compounds. The cytotoxicities of transformed products (2-5) against Hela cells were also investigated.

Alpha-naphthyl isothiocyanate (ANIT)-induced liver damage is regarded as a useful model to study drug-induced cholestatic hepatitis. Ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry (UPLC-ESI-QTOF MS)-based metabolomics revealed clues to the mechanism of ANIT-induced liver injury, which facilitates the elucidation of drug-induced liver toxicity. 1-Stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC 18:0) and 1-oleoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC 18:1) were significantly increased in serum from ANIT-treated mice, and this increase resulted from altered expression of genes encoding the lipid metabolism enzymes Chka and Scd1. ANIT also increased NF-κB/IL-6/STAT3 signaling, and in vitro luciferase reporter gene assays revealed that LPC 18:0 and LPC 18:1 can activate NF-κB in a concentration-dependent manner. Activation of PPARα through feeding mice a Wy-14,643-containing diet (0.1%) reduced ANIT-induced liver injury, as indicated by lowered ALT and AST levels, and liver histology. In conclusion, the present study demonstrated a role for the lipid-regulated NF-κB/IL-6/STAT3 axis in ANIT-induced hepatotoxicity, and that PPARα may be a potential therapeutic target for the prevention of drug-induced cholestatic liver injury.

Objective: To investigate the correlation between miR-26b and non-small-cell lung cancer (NSCLC). Materials & methods: NSCLC tissues and normal lung tissues that were more than 7 cm adjacent from tumor were collected from 154 NSCLC patients. Additionally, 63 normal specimens from benign lung disease were selected as the control group. Real-time fluorescent quantitative PCR was used to detect miR-26b expression in tissues. Result: miR-26b expression in NSCLC tissues was significantly lower than in other two types of tissues. Receiver operating characteristic curve analysis showed that the area under the curve was 0.856 with sensitivity and specificity of 79.9 and 79.4%, respectively. miR-26b expression was a risk factor for poor prognosis of NSCLC. Conclusion: The expression of miR-26b is downregulated in NSCLC tissues, and it might be useful in the diagnosis and prognosis of NSCLC patients.

AIM: To investigate the targeted inhibition of proliferation and migration of SW620 human colon cancer cells by upregulating miRNA-145 (miR-145). METHODS: Forty-five samples of colon cancer tissues and 45 normal control samples were obtained from the biological database of the First Affiliated Hospital of Liaoning Medical University. We performed quantitative analysis of miR-145 and N-ras expression in tissues; reverse transcriptase polymerase chain reaction analysis of miR-145 expression in SW620 colon cancer cells and normal colonic epithelial cells; construction of miR-145 lentiviral vector and determination of miR-145 expression in SW620 cells transduced with miR-145 vector; analysis of the effect of miR-145 overexpression on SW620 cell proliferation; analysis of the effect of miR-145 overexpression on SW620 cell migration using a wound healing assay; and analysis of the effect of miR-145 on N-ras expression using Western blotting. RESULTS: miR-145 expression was significantly downregulated in colon cancer tissues, with its expression in normal colonic tissues being 4-5-fold higher (two sample t test, P < 0.05), whereas N-ras expression showed the opposite trend. miR-145 expression in SW620 cells was downregulated, which was significantly lower compared to that in colonic epithelial cells (two sample t test, P < 0.05). miR-145 vector and control were successfully packaged; expression of miR-145 in SW620 cells transduced with miR-145 was 8.2-fold of that in control cells (two sample t test, P < 0.05). The proliferation of miR-145-transduced SW620 cells was significantly decreased compared to control cells (two sample t test, P < 0.05). At 48 h in the wound healing experiment, the migration indexes and controls were (97.27% ± 9.25%) and (70.22% ± 6.53%), respectively (two sample t test, P < 0.05). N-ras expression in miR-145-tranduced SW620 cells was significantly lower than others (one-way analysis of variance, P < 0.05). CONCLUSION: miR-145 is important in inhibiting colon cancer cell proliferation and migration. This is a good foundation for development of colon cancer therapy by targeting tumor suppressor miR-145.

To investigate the effects of metformin (Met) on the proliferation and apoptosis of a renal carcinoma cell line and study the underlying mechanisms.Renal cell carcinoma (RCC) line 786-O was cultured with media containing different concentrations of Met. The proliferation and apoptosis of 786-O cells were detected by the MTT method and flow cytometry, respectively. The invasion of 786-O cells was detected by scratch test, and the expression of pro-apoptotic proteins was determined by Western blot assay.The proliferation rates of 786-O cells with Met concentrations of 10, 15, and 20 mM were decreased by 62.8, 61.7, and 65.1%, respectively, with no significant difference among these concentrations (p0.05). Twenty-four hrs after the scratch assay, the mean migration index in the control group and Met treatment group was 51.6% +/- 5.9 and 28.1% +/- 4.3, and that after 48 hrs was 92.2% +/- 6.4 and 68.0% +/- 4.9, respectively (p0.05). At low serum concentration, the percentage of apoptotic cells in the Met treatment group (17.6%) was significantly higher (p0.05) than that in the control group (5.2%). Met (10 mM) treatment significantly increased the expression of Caspase-3 and Bax proteins in 786-O cells (p0.05).Metformin may be a potential drug of choice in the treatment of metastatic RCC.

Inhibitor of growth protein 2 (ING2) has an important role in the regulation of chromatin remodeling, cell proliferation, cell‑cycle arrest, senescence and apoptosis. The present study performed an immunohistochemical analysis for expression profiling of ING2 protein in an array of tissues comprising normal mouse and human tissues, as well as human hepatocellular (n=62), renal clear cell (n=62), pancreatic (n=62), esophageal squamous cell (n=45), cervical squamous cell (n=31), breast (n=144), gastric (n=196), colorectal (n=96), ovarian (n=208), endometrial (n=96) and lung (n=192) carcinoma tissues. In mouse tissues, ING2 was detected in the nuclei and cytoplasm of the glandular epithelium of breast, hepatocytes, intestine, bronchium and alveoli, as well as the squamous epithelium of skin and glomeruli, and in myocardial cells, while it was located in the cytoplasm of renal tubules and striated muscle cells. ING2 protein was scattered in the brain and spleen. In human tissues, ING2 protein was principally distributed in the cytoplasm, while in it was present in the cytoplasm and nuclei in the stomach, intestine, cervix, endometrium trachea, breast and pancreas. The nuclear location of ING2 in the stomach was more prominent than that in the cytoplasm. High ING2 immunoreactivity was detected in the tongue, stomach, skin, pancreas, cervix and breast, whereas weakly in the brain stem, thymus, thyroid, lung, striated muscle, testis, bladder and ovary. In total, 617 out of 1,194 of the tested cancer tissues (51.7%) were ING2-positive. In most cases, ING2 expression was found to be restricted to the cytoplasm of all cancer tissues, while in certain cancer types, including renal clear cell, ovarian and colorectal carcinoma, it was occasionally present in the nuclei. Among the cancer tissues examined, ING2 was most frequently expressed in breast cancer (67.4%) and gynecological cancer types, including ovarian cancer (61.5%) and endometrial cancer (57.3%). Compared with that in the respective normal tissues, ING2 expression in breast cancer tissues was decreased, while that in cervical cancer was upregulated in the nuclei as well as the cytoplasm. In endometrial cancer, expression of ING2 was increased in the nuclei and declined in the cytoplasm compared with that in the normal endometrium. ING2‑positive cases were less frequent for renal clear cell carcinoma (17.7%). The results of the present study suggested that ING2 may be involved in the repair and regeneration of organs or tissues and is associated with breast and gynecological carcinogenesis.

Aim: To investigate the expression of protein kinase CK2α (CK2α) in human thyroid disease and its relationship with thyroid cancer metastasis. Materials and Methods: Using immunohistochemistry we measured the expression of CK2α in 76 benign and malignant human thyroid cancer tissues, including 10 pairs of papillary carcinoma tissues with or without lymph node cancerous metastasis and similarly 10 pairs of lymph nodes. Results: The expression of CK2α was found to be higher in thyroid carcinoma cases (papillary carcinoma, follicular carcinoma, anaplastic carcinoma and medullary carcinoma) than in ones such as chronic lymphocytic thyroiditis, nodular goiter and adenoma. These findings were also confirmed by RT-PCR and Western blotting. More strikingly, elevated expression of CK2α in thyroid papillary carcinoma tissues was not only significantly associated with lymph node cancerous metastasis and clinical stage of thyroid cancers; but also correlated with epithelial-mesenchymal transition (EMT) and high tenascin C (TNC) expression. In addition, EMT and high TNC expression in thyroid carcinoma tissues was significantly associated with lymph node cancerous metastasis. Conclusions: Elevated expression of nuclear CK2α is a poor prognosis indicator in lymph node cancerous metastasis of human thyroid cancers.

The mechanism of shengmai injection- (SMI-) related drug-drug interaction remains unclear. Evaluation of the inhibition potential of SMI’s ingredients towards UDP-glucuronosyltransferases (UGTs) activity will provide a new insight to understand SMI-related drug-drug interaction.In vitroincubation system to model UGT reaction was used. Recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation and UGT1A4-catalyzed trifluoperazine (TFP) glucuronidation reactions were employed to phenotype the inhibition profile of maidong’s components towards the activity of UGT isoforms. Different inhibition potential of maidong’s components towards various UGT isoforms was observed. Based on the inhibition kinetic investigation results, ophiopogonin D (OD) noncompetitively inhibited UGT1A6 and competitively inhibited UGT1A8, ophiopogonin D′ (OD′) noncompetitively inhibited UGT1A6 and UGT1A10, and ruscorectal (RU) exhibited competitive inhibition towards UGT1A4. The inhibition kinetic parameters were calculated to be 20.6, 40.1, 5.3, 9.0, and 0.02 μM, respectively. In combination with our previous results obtained for the inhibition of UGT isoforms by ginsenosides and wuweizi components, the important SMI ingredients exhibiting strong inhibition towards UGT isoforms were highlighted. All the results obtained in the present study provide a new insight to understand SMI-related drug-drug interaction.

Qingjun Wang,1,2,* Tao Sun,3,* Yunfeng Cao,1,2,4,5 Peng Gao,2,4,6 Jun Dong,2,4 Yanhua Fang,2 Zhongze Fang,2 Xiaoyu Sun,2 Zhitu Zhu1,2 1Oncology Department 2, The First Affiliated Hospital of Liaoning Medical University, 2Personalized Treatment and Diagnosis Research Center, The First Affiliated Hospital of Liaoning Medical University and Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Jinzhou, 3Department of Internal Medicine 1, Cancer Hospital of China Medical University, Liaoning Cancer Hospital& Insititute, Shenyang, 4CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 5Key Laboratory of Contraceptives and Devices Research (NPFPC), Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, 6Clinical Laboratory, Dalian Sixth People’s Hospital, Dalian, People’s Republic of China *These authors contributed equally tothis work Objective: Breast cancer (BC) is still a lethal threat to women worldwide. An accurate screening and diagnosis strategy performed in an easy-to-operate manner is highly warranted in clinical perspective. Besides the routinely focused protein markers, blood is full of small molecular metabolites with diverse structures and properties. This study aimed to screen metabolite markers with BC diagnosis potentials.Methods: A dried blood spot-based direct infusion mass spectrometry (MS) metabolomic analysis was conducted for BC and non-BC differentiation. The targeted analytes included 23 amino acids and 26 acylcarnitines.Results: Multivariate analysis screened out 21 BC-related metabolites in the blood. Regression analysis generated a diagnosis model consisting of parameters Pip, Asn, Pro, C14:1/C16, Phe/Tyr, and Gly/Ala. Tested with another set of BC and non-BC samples, this model showed a sensitivity of 92.2% and a specificity of 84.4%. Compared to the routinely used protein markers, this model exhibited distinct advantage with its higher sensitivity.Conclusion: Blood metabolites screening is a more plausible approach for BC detection. Furthermore, this direct MS analysis could be finished within few minutes, which means that its throughput is higher than the currently used imaging techniques. Keywords: breast cancer, metabolomics, dried blood spot testing

Li-Peng Jiang,1 Zhi-Tu Zhu,2 Chun-Yan He3 1Department of Radiation Oncology, 2Department of Oncology, First Affiliated Hospital of Liaoning Medical University, 3Department ofProsthodontics, Second Affiliated Hospital of Liaoning Medical University, Jinzhou, People’s Republic of China Objective: We aimed to explore the impacts of the rs776746 polymorphism in the CYP3A5 gene and smoking on the prognosis of non-small-cell lung cancer (NSCLC). Materials and methods: Our study enrolled 104 early NSCLC patients undergoing surgery and 107 advanced NSCLC patients undergoing chemotherapy, hospitalized between December 2009 and December 2012 at the First Affiliated Hospital of Liaoning Medical University. All subjects with complete follow-up data were pathologically diagnosed. The rs776746 polymorphism and different genotypes (*1/*1, *1/*3, and *3/*3) were identified by polymerase chain-reaction restriction fragment-length polymorphism. Results: Clinical response to chemotherapy in NSCLC patients with *1/*1 + *1/*3 genotypes were significantly worse than in those with the *3/*3 genotype (17.78% vs 56.45%, P

To observe the effect of thalidomide in preventing nausea and vomiting induced by emetogenic cisplatin (CDDP) chemotherapy in patients with advanced non-small cell lung cancer.This study was carried out as a prospective, randomized control clinical trial. 61 patients with advanced non-small cell lung cancer were scheduled to receive chemotherapy (gemcitabin 1000 mg/m(2) i.v. gtt d1, 8 and CDDP 75 mg/m(2) i.v. gtt d1, GP regimen). The patients were randomly divided into a treatment and control groups. All patients in both groups received ramosetron 0.3 mg intravenously (i.v.) and metoclopramide 20 mg intramuscularly (i.m.) 30 min prior to chemotherapy to prevent nausea and emesis on day 1. In the treatment group, addition of thalidomide (50 mg p.o. bid) were administered on days 1 to 5 after the start of chemotherapy.Acute nausea was effectively controlled in 74.2% of the patients in the control group and in 90.0% of treatment group. Acute vomiting was effectively controlled in 90.3% of the patients in the control group and in 93.3% of treatment group. No statistically significant differences showed in effective control of acute nausea and vomiting between the 2 groups (P = 0.108; P = 1.000). Delayed nausea was effectively controlled in 19.4% of the patients in control group and in 56.7% in the treatment group. Delayed vomiting was effectively controlled in 48.4% of the patients in control group and 76.7% in treatment group. Statistically there was a significant differences in effective control of delayed nausea and vomiting between the 2 groups (P = 0.003, P = 0.023). Both antiemetic regimens were well tolerated, and no significant difference was observed in adverse events between the 2 groups (P0.05).Our results demonstrate that thalidomide is highly effective in controlling delayed nausea and vomiting episodes in patients induced by moderately emetogenic chemotherapy. Moreover, no serious toxic effects are induced by this treatment.

The precise mechanism of glucocorticoid-induced apoptosis has not yet been elucidated. Survivin, a member of the inhibitors of apoptosis protein family, correlates with inhibition of apoptosis, proliferation, angiogenesis and multiple drugs resistance. This study aimed to investigate the variation of the survivin gene expression in apoptosis induced by dexamethasone (Dex) in the human T-lineage acute lymphoblastic leukemia (ALL) cell line, CEM-WT cells.The logarithmically growing CEM cells cultured in vitro (cell density 2 x10(5)/mL) were exposed to 0.1, 0.5, 1, 5, and 10 microM Dex, then were collected 24, 48 and 72 hrs later. Untreated CEM cells were used as Controls. The cell viability was determined by trypan blue dye exclusion. Apoptosis was evaluated by morphology and flow cytometry. Survivin protein and gene were analyzed by Western Blot and RT-PCR.CEM cells growth was obviously inhibited by 0.1, 0.5, 1, 5, and 10 microM Dex from 48 hrs. The inhibition effect was dose- and time-dependent. CEM cells treated with Dex (or = 5 microM) exhibited typical apoptotic features. The apoptosis increased after 5 microM Dex treatment in a time-dependent manner, with the apoptosis percentage increasing from 14.9% (12 hrs) to 46.2% (48 hrs). Compared with that of the Control group, the expression of survivin protein was down-regulated, with the expression rate of 54.6%, 45.5%, 15.8% and 9.7% respectively at 12, 24, 48 and 72 hrs after 5 microM Dex treatment. 5 microM Dex treatment also resulted in a decrease of survivin mRNA expression. The survivin mRNA expression was 76.4%, 67.3%, 55.0%, 49.9%, 38.3% and 18.3% of the Control respectively at 6, 12, 24, 48 and 72 hrs after Dex treatment.Apoptosis induced by Dex in CEM cells is associated with downregulation of the survivin expression.

To investigate the effect of bufalin combined with all-trans retinoic acid-induced (ATRA) differentiation of acute promyelocytic leukemia (APL) cells in primary culture.Fresh leukemia cells were obtained from heparinized bone marrow aspirations of 12 newly diagnosed APL patients. Cell viability was determined by trypan blue dye exclusion. Apoptosis of APL cell was assessed by morphological analysis. Differentiation of APL cell was also assessed by morphological analysis. Nitro blue tetrazolium (NBT) reduction test and expression of the granulocyte/macrophage-specific antigen CD(11)b was carried out with flow cytometric assay.Bufalin combined with ATRA can induce differentiation of APL cells towards mature stages, NBT reduction was increased 15% - 52% and CD(11)b expression was also increased 16% - 69% in combination of bufalin and ATRA as compared with that of ATRA alone, while the concentration of ATRA needed in the combination group was reduced to 30% and the time of differentiation was reduced from 7 days to 4 days.The combination of ATRA with bufalin can significantly enhance the differentiation of acute promyelocytic leukemia cells in primary culture by ATRA.